Mony John de Leon

Structural brain changes in normal individuals with a maternal history of Alzheimer's
Berti, Valentina; Mosconi, Lisa; Glodzik, Lidia; Li, Yi; Murray, John; De Santi, Susan; Pupi, Alberto; Tsui, Wai; De Leon, Mony J
2011 Dec;32(12):2325.e17-2325.e26, Neurobiology of aging
Having a parent affected with late-onset Alzheimer's disease (LOAD) is a major risk factor for developing the disease among cognitively normal (NL) individuals. This magnetic resonance imaging (MRI) study examines whether NL with a LOAD-affected parent show preclinical brain atrophy, and whether there are parent-of-origin effects. Voxel-based morphometry (VBM) on Statistical parametric mapping (SPM8) was used to examine volumetric T1-MRI scans of 60 late-middle-aged NL subjects, divided into 3 size-matched, demographically balanced groups of 20 subjects each, including NL with a maternal (FHm), paternal (FHp), or negative family history (FH-) of LOAD. There were no group differences for clinical and neuropsychological measures, and ApoE status. On VBM, FHm showed reduced gray matter volumes (GMV) in frontal, parietal, and temporal cortices and precuneus as compared with FH-, and in precuneus compared with FHp (p < 0.05, family-wise error [FWE]-corrected). Results remained significant controlling for age, gender, education, ApoE, and total intracranial volume. No differences were observed between FHp and FH- in any regions. NL FHm showed reduced GMV in LOAD-affected brain regions compared with FH- and FHp, indicating higher risk for Alzheimer's disease. Our findings support the use of regional brain atrophy as a preclinical biomarker for LOAD among at-risk individuals
— id: 138706, year: 2011, vol: 32, page: 2325.e17, stat: Journal Article,

Estimating the impact of differences among protocols for manual hippocampal segmentation on alzheimer's disease-related atrophy: Preparatory phase for a harmonized protocol
Boccardi M.; Bocchetta M.; Ganzola R.; Robitaille N.; Redolfi A.; Bartzokis G.; Camicioli R.; Csernansky J.; De Leon M.; DeToledo-Morrell L.; Killiany R.; Lehericy S.; Pantel J.; Pruessner J.; Soininen H.; Watson C.; Duchesne S.; Jack C.; Frisoni G.
2011 ;7(4 SUPPL 1):S7-S8, Alzheimer's & Dementia
Background: To quantify the impact of the differences among Magnetic Resonance Imaging (MRI)-based hippocampal segmentation protocols on volume estimates of Alzheimer's disease (AD)-related atrophy, in order to support evidence-based decisions for an internationally harmonized protocol. A harmonized procedure is required, since quantitative MRI should help diagnosis and tracking of AD. A survey of segmentation protocols allowed to operationalize the landmarks variability into segmentation units (SUs) (Figure), and their impact on volume estimates has been preliminarily quantified. Methods: A power analysis was carried out on a preliminary sample, to define the sample size allowing reliable computation. Then, we manually traced each SU within the right and left hippocampi of a larger sample of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, which included Mild Cognitive Impairment (MCI) patients who subsequently converted to AD and AD patients, all with abnormal Cerebrospinal Fluid (CSF) As levels, and controls (CTRL), with normal CSF As levels. Results: The power analysis indicated a required sample size for the quantification of SUs impact on AD-related volume differences of n=77 (31 CTRL, 23 MCI, 23 AD). So far, 40 subjects (16 CTRL, 12 MCI, 12 AD) have been traced and analyzed. The minimum hippocampal body (red SU in Figure) accounted for over 62% of AD-related volume difference across groups (left: 68.5%, right: 62%, p<0.001); the left alveus/fimbria (yellow SU in Figure) for 7.5% (p=0.01) and the right alveus/fimbria for 3% (p=0.7); the subiculum (green SUs in Figure) for 5% bilaterally (left: p=0.08; right: p=0.03); the left tail (blue SUs in Figure) for 19% (p=0.003), and the right tail for the 30% (p=0.001) of the global difference across groups. Conclusions: The informative value for identifying AD-related atrophy differs across SUs. Its quantification may help a panel of experts to define which SU should be included in a harmonized protocol. (Figure presented)
— id: 136975, year: 2011, vol: 7, page: S7, stat: Journal Article,

Estimating the impact of differences among protocols for manual hippocampal segmentation on Alzheimer's disease-related atrophy: Preparatory phase for a harmonized protocol
Boccardi M.; Bocchetta M.; Ganzola R.; Robitaille N.; Redolfi A.; Bartzokis G.; Camicioli R.; Csernansky J.; De Leon M.; DeToledo-Morrell L.; Killiany R.; Lehericy S.; Pantel J.; Pruessner J.; Soininen H.; Watson C.; Duchesne S.; Jack C.; Frisoni G.
2011 ;7(4 SUPPL 1):S205-S206, Alzheimer's & Dementia
Background: To quantify the impact of the differences among Magnetic Resonance Imaging (MRI)-based hippocampal segmentation protocols on volume estimates of Alzheimer's disease (AD)-related atrophy, in order to support evidence-based decisions for an internationally harmonized protocol. A harmonized procedure is required, since quantitative MRI should help diagnosis and tracking of AD. A survey of segmentation protocols allowed to operationalize the landmarks variability into segmentation units (SUs) (Figure), and their impact on volume estimates has been preliminarily quantified. Methods: A power analysis was carried out on a preliminary sample, to define the sample size allowing reliable computation. Then, we manually traced each SU within the right and left hippocampi of a larger sample of Alzheimer's disease Neuroimaging Initiative (ADNI) participants, which included Mild Cognitive Impairment (MCI) patients who subsequently converted to AD and AD patients, all with abnormal Cerebrospinal Fluid (CSF) As levels, and controls (CTRL), with normal CSF As levels. Results: The power analysis indicated a required sample size for the quantification of SUs impact on AD-related volume differences of n = 77 (31 CTRL, 23 MCI, 23 AD). So far, 40 subjects (16 CTRL, 12 MCI, 12 AD) have been traced and analyzed. The minimum hippocampal body (red SU in Figure) accounted for over 62% of AD-related volume difference across groups (left: 68.5%, right: 62%, p<0.001); the left alveus/ fimbria (yellow SU in Figure) for 7.5% (p = 0.01) and the right alveus/fimbria for 3% (p=0.7); the subiculum (green SUs in Figure) for 5% bilaterally (left: p = 0.08; right: p = 0.03); the left tail (blue SUs in Figure) for 19% (p = 0.003), and the right tail for the 30% (p = 0.001) of the global difference across groups. Conclusions: The informative value for identifying AD-related atrophy differs across SUs. Its quantification may help a panel of experts to define which SU should be included in a harmonized protocol
— id: 136971, year: 2011, vol: 7, page: S205, stat: Journal Article,

Survey of protocols for manual hippocampal volumetry: Preparatory steps for an EADC-ADNI harmonized protocol
Boccardi M.; Bocchetta M.; Ganzola R.; Robitaille N.; Redolfi A.; Bartzokis G.; Camicioli R.; Csernansky J.G.; De Leon M.J.; Detoledo-Morrell L.; Killiany R.J.; Lehericy S.; Pantel J.; Pruessner J.C.; Soininen H.; Watson C.; Duchesne S.; Jack C.R.; Frisoni G.B.
2011 ;8:?-?, Neuro-degenerative diseases
Introduction: A harmonized protocol for hippocampal MR-based segmentation is required for diagnosis and tracking of Alzheimer's disease (AD) and other disorders. A survey of segmentation protocols identified anatomical sources of heterogeneity in volume estimates. Aim: To identify differences among segmentation protocols and provide quantitative information supporting decisions for an international harmonized protocol. Methods: We selected 12 most used hippocampal tracing protocols in the AD literature for evaluation. The same rater carried out complete tracings on two MR scans (one control, one matched AD ADNI subjects) on 1.2 mm slices, using each of the 12 protocols. We arranged individual interactive web conferences with the primary author of each protocol, to check the appropriate execution of the tracing, and correct it when necessary. Landmark differences were extracted from the semantically harmonized landmarks obtained from the certified protocols (available at www.hippocampal-protocol.net). Results: The main differences between the protocols consisted in (a) inclusion/exclusion of hippocampal white matter (alveus/fimbria) (b) definition of the posterior most slice, and (c) definition of the separation between the subiculum and the parahippocampal gyrus. Heterogeneities in the definition of the boundary with the amygdala are no longer an issue due to the currently available software allowing 3D navigation. Conclusions: These results are preparatory to an international consensus for a harmonized protocol for the manual tracing of the hippocampus
— id: 136533, year: 2011, vol: 8, page: ?, stat: Journal Article,

Survey of protocols for the manual segmentation of the hippocampus: preparatory steps towards a joint EADC-ADNI harmonized protocol
Boccardi, Marina; Ganzola, Rossana; Bocchetta, Martina; Pievani, Michela; Redolfi, Alberto; Bartzokis, George; Camicioli, Richard; Csernansky, John G; de Leon, Mony J; deToledo-Morrell, Leyla; Killiany, Ronald J; Lehericy, Stephane; Pantel, Johannes; Pruessner, Jens C; Soininen, H; Watson, Craig; Duchesne, Simon; Jack, Clifford R Jr; Frisoni, Giovanni B
2011 ;26 Suppl 3:61-75, Journal of Alzheimer's Disease
Manual segmentation from magnetic resonance imaging (MR) is the gold standard for evaluating hippocampal atrophy in Alzheimer's disease (AD). Nonetheless, different segmentation protocols provide up to 2.5-fold volume differences. Here we surveyed the most frequently used segmentation protocols in the AD literature as a preliminary step for international harmonization. The anatomical landmarks (anteriormost and posteriormost slices, superior, inferior, medial, and lateral borders) were identified from 12 published protocols for hippocampal manual segmentation ([Abbreviation] first author, publication year: [B] Bartzokis, 1998; [C] Convit, 1997; [dTM] deToledo-Morrell, 2004; [H] Haller, 1997; [J] Jack, 1994; [K] Killiany, 1993; [L] Lehericy, 1994; [M] Malykhin, 2007; [Pa] Pantel, 2000; [Pr] Pruessner, 2000; [S] Soininen, 1994; [W] Watson, 1992). The hippocampi of one healthy control and one AD patient taken from the 1.5T MR ADNI database were segmented by a single rater according to each protocol. The accuracy of the protocols' interpretation and translation into practice was checked with lead authors of protocols through individual interactive web conferences. Semantically harmonized landmarks and differences were then extracted, regarding: (a) the posteriormost slice, protocol [B] being the most restrictive, and [H, M, Pa, Pr, S] the most inclusive; (b) inclusion [C, dTM, J, L, M, Pr, W] or exclusion [B, H, K, Pa, S] of alveus/fimbria; (c) separation from the parahippocampal gyrus, [C] being the most restrictive, [B, dTM, H, J, Pa, S] the most inclusive. There were no substantial differences in the definition of the anteriormost slice. This survey will allow us to operationalize differences among protocols into tracing units, measure their impact on the repeatability and diagnostic accuracy of manual hippocampal segmentation, and finally develop a harmonized protocol
— id: 148713, year: 2011, vol: 26 Suppl 3, page: 61, stat: Journal Article,

Midbrain atrophy in vascular parkinsonism
Choi, Seong-Min; Kim, Byeong C; Nam, Tai-Seung; Kim, Joon-Tae; Lee, Seung-Han; Park, Man-Seok; Kim, Myeong-Kyu; de Leon, Mony J; Cho, Ki-Hyun
2011 ;65(5):296-301, European neurology
Background: Midbrain atrophy is a well-known feature of progressive supranuclear palsy (PSP). Some clinical features of vascular parkinsonism (VP) such as pseudobulbar phenomena, lower body predominance and early postural instability suggest that the brainstem could be associated with VP. The aim of this study was to determine whether midbrain atrophy was present in patients with VP. Methods: We measured the midbrain (Amd) and pons area (Apn) of 20 patients with VP, 15 patients with probable PSP and 30 patients with idiopathic Parkinson's disease (IPD). The Amd and Apn were measured on mid-sagittal T(1)-weighted MRI scans using a computerized image analysis system. Results: For the Amd, the patients with VP (99.86 mm(2)) and PSP (87.30 mm(2)) had significantly smaller areas than the patients with IPD (130.52 mm(2)). For the Apn, there was a significant difference only between the VP (407.23 mm(2)) and the IPD (445.05 mm(2)) patients. The Amd/Apn ratios of the patients with VP (0.245) and PSP (0.208) were significantly smaller than in the patients with IPD (0.292). Conclusions: Our study shows that brainstem atrophy often occurs in patients with VP and the midbrain is more vulnerable than the pons to atrophic changes
— id: 134283, year: 2011, vol: 65, page: 296, stat: Journal Article,

Correlations between amyloid and metabolic PET imaging in cognitively normal adults with a family history of late-onset Alzheimer's disease
Cummings M.; Rinne J.; Mosconi L.; Tsui W.; Murray J.; Li Y.; Glodzik L.; McHugh P.; Williams S.; Goldsmith S.; Vallabhajosula S.; Scheinin N.; Viljanen T.; Nagren K.; De Leon M.
2011 ;7(4 SUPPL 1):S209-S210, Alzheimer's & Dementia
Background: Having a parent affected with late-onset Alzheimer's disease (LOAD) is a major risk factor among cognitively normal (NL) individuals. This study examines whether NL with LOAD-parents show preclinical evidence of brain AD, as reflected in increased fibrillar amyloid- beta (As) deposition on C-Pittsburgh Compound B (PiB)-PET, a major hallmark of AD pathology, and reduced glucose metabolism on 18F-fluorodeoxyglucose (FDG)-PET, a proxy for neuronal dysfunction. Methods: Forty-five 40-80 year-old NL with 8F-FDG and 11C-PIB PETexaminations were examined, including 15 NL with a maternal history (MH), 15 NL with a paternal history (PH), and 15 NL with negative family history of LOAD (NH). For all cases, the parents' AD diagnosis was clinician certified. Automated regions-of-interest, statistical parametric mapping, voxelwise inter-modality correlations and logistic regression were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. Results: Groups were comparable for clinical and demographical measures. The MH group showed higher PiB retention and lower metabolism in AD-regions compared to NH and PH, while the PH group showed milder PiB increases and no metabolic reductions compared to NH. Results remained significant controlling for age, gender, education and ApoE. Metabolism and PiB retention were negatively correlated locally in PCC, frontal and parieto-temporal regions in MHPY, whereas no correlations were observed in NH and PH. The combination of As deposition and metabolism improved group separation over either measure alone, yielding 65% accuracy for MH vs NH and PH (P < 0.05). Conclusions: Among NL with LOAD-parents, only MH show co-occurring As increases and hypometabolism in AD-vulnerable regions, suggesting that these subjects may be at a MHPYincreased risk for AD than PH. Present findings may motivate further research on familial transmission and parent-of-origin effects in LOAD, and indicate a great need for early intervention trials targeting adult children of LOAD-parents. (Figure presented)
— id: 136970, year: 2011, vol: 7, page: S209, stat: Journal Article,

The concept of FDG-PET endophenotype in Alzheimer's disease
During, Emmanuel H; Osorio, R S; Elahi, F M; Mosconi, L; de Leon, M J
2011 Aug;32(4):559-569, Neurological sciences
Often viewed as a potential tool for preclinical diagnosis in early asymptomatic stages of Alzheimer's disease (AD), the term 'endophenotype' has acquired a recent popularity in the field. In this review, we analyze the construct of endophenotype-originally designed to discover genes, and examine the literature on potential endophenotypes for the late-onset form of AD (LOAD). We focus on the [18F]-fluoro-2-deoxyglucose (FDG) PET technique, which shows a characteristic pattern of hypometabolism in AD-related regions in asymptomatic carriers of the ApoE E4 allele and in children of AD mothers. We discuss the pathophysiological significance and the positive predictive accuracy of an FDG-endophenotype for LOAD in asymptomatic subjects, and discuss several applications of this endophenotype in the identification of both promoting and protective factors. Finally, we suggest that the term 'endophenotype' should be reserved to the study of risk factors, and not to the preclinical diagnosis of LOAD
— id: 135258, year: 2011, vol: 32, page: 559, stat: Journal Article,

Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly
Glodzik L; Mosconi L; Tsui W; de Santi S; Zinkowski R; Pirraglia E; Rich KE; McHugh P; Li Y; Williams S; Ali F; Zetterberg H; Blennow K; Mehta P; de Leon MJ
2011 Apr 27;:?-? #, Neurobiology of aging
It is not well known whether Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers are associated with brain damage in cognitively normal elderly. The combined influence of CSF biomarkers and hypertension (HTN) on the gray matter (GM) is also not well described. One hundred fifteen cognitively healthy subjects (mean age 62.6 +/- 9.5%, 62% women) received clinical assessment, a high resolution magnetic resonance imaging (MRI), and a lumbar puncture. The CSF levels of total tau (t-tau), hyperphosphorylated tau (p-tau(231)), amyloid beta (Abeta42/Abeta40), p-tau(231)/Abeta42, and t-tau/Abeta42 were dichotomized as 'high' and 'low' based on accepted cut off values. Statistical parametric mapping was used to examine MRI scans for regional GM density, studied as a function of the CSF markers, HTN, and combination of both. Global and medial temporal lobe (MTL) GM was also assessed. Voxel based morphometry revealed that higher t-tau was associated with lower GM density in the precunei. Subjects with higher p-tau(231) and p-tau(231)/Abeta42 had less GM in temporal lobes. Low Abeta42/Abeta40 was related to less GM in the thalami, caudate, and midbrain. Subjects with hypertension showed more GM atrophy in the cerebellum, occipital, and frontal regions. Simultaneous presence of elevated CSF AD biomarkers and HTN was associated with more GM atrophy than either marker individually, but no interaction effects were identified. In conclusion, in normal elderly CSF tau markers were associated predominantly with lower GM estimates in structures typically affected early in the AD process. In this presymptomatic stage when no cognitive impairment is present, AD biomarkers and HTN have additive effects on gray matter damage
— id: 140516, year: 2011, vol: , page: ?, stat: Journal Article,

Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia
Glodzik, Lidia; Rusinek, Henry; Brys, Miroslaw; Tsui, Wai H; Switalski, Remigiusz; Mosconi, Lisa; Mistur, Rachel; Pirraglia, Elizabeth; de Santi, Susan; Li, Yi; Goldowsky, Alexander; de Leon, Mony J
2011 Feb;31(2):671-679, Journal of cerebral blood flow & metabolism
Vascular risk factors affect cerebral blood flow (CBF) and cerebral vascular reactivity, contributing to cognitive decline. Hippocampus is vulnerable to both Alzheimer's disease (AD) pathology and ischemia; nonetheless, the information about the impact of vascular risk on hippocampal perfusion is minimal. Cognitively, healthy elderly (NL=18, 69.9+/-6.7 years) and subjects with mild cognitive impairment (MCI=15, 74.9+/-8.1 years) were evaluated for the Framingham cardiovascular risk profile (FCRP). All underwent structural imaging and resting CBF assessment with arterial spin labeling (ASL) at 3T magnetic resonance imaging (MRI). In 24 subjects (NL=17, MCI=7), CBF was measured after a carbon dioxide rebreathing challenge. Across all subjects, FCRP negatively correlated with hippocampal (rho=-0.41, P=0.049) and global cortical (rho=-0.46, P=0.02) vasoreactivity to hypercapnia (VR(h)). The FCRP-VR(h) relationships were most pronounced in the MCI group: hippocampus (rho=-0.77, P=0.04); global cortex (rho=-0.83, P=0.02). The FCRP did not correlate with either volume or resting CBF. The hippocampal VR(h) was lower in MCI than in NL subjects (Z=-2.0, P=0.047). This difference persisted after age and FCRP correction (F([3,20])=4.6, P=0.05). An elevated risk for vascular pathology is associated with a reduced response to hypercapnia in both hippocampal and cortical tissue. The VR(h) is more sensitive to vascular burden than either resting CBF or brain volume
— id: 138222, year: 2011, vol: 31, page: 671, stat: Journal Article,

Developing a global strategy to prevent Alzheimer's disease: Leon Thal Symposium 2010
Khachaturian, Zaven S; Petersen, Ronald C; Snyder, Peter J; Khachaturian, Ara S; Aisen, Paul; de Leon, Mony; Greenberg, Barry D; Kukull, Walter; Maruff, Paul; Sperling, Reisa A; Stern, Yaakov; Touchon, Jacques; Vellas, Bruno; Andrieu, Sandrine; Weiner, Michael W; Carrillo, Maria C; Bain, Lisa J
2011 Mar;7(2):127-132, Alzheimer's & Dementia
The fourth Leon Thal Symposium (LTS2010) was convened in Toulouse, France, on November 3, 2010. This symposium reviewed design parameters that are necessary to develop comprehensive national databases on healthy aging. Such datasets offer the potential to serve as the foundation for a systems-approach to solve the dual public health problems of: (1) early detection of people who are at elevated risk for Alzheimer's disease, and (2) the development of interventions to delay onset of, or prevent, late-life dementia. The symposium considered three interrelated components of a National Database for Longitudinal Studies on Healthy Aging as follows: (a) a registry of healthy aging adults; (b) refined computer-based assessments for data gathering, including assessments of behavioral/memory changes associated with aging that are appropriate for broad use in nonexpert settings; and (c) high performance computing/supercomputer-based approaches for health data modeling and mining
— id: 134236, year: 2011, vol: 7, page: 127, stat: Journal Article,

Effects of surgery on cortical atrophy
Kline R.; Pirraglia E.; Cheng H.; Li Y.; Haile M.; De Leon M.; Bekker A.
2011 ;7(4 SUPPL 1):S3-S3, Alzheimer's & Dementia
Background: There have been numerous reports of acute and delayed impairment of neurocognitive performance following surgery. Structural MRI has been used to successfully diagnose and monitor Alzheimer's disease, and is here applied to examine the impact of surgery on baseline atrophy in elderly patients. We compared changes in cortical anatomy for defined inter-visit intervals between a surgical cohort and a frequency matched non-surgical control. Methods: Data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (www.loni.ucla.edu/ADNI), and included subjects either cognitively normal (NL) or diagnosed with mild cognitive impairment (MCI), and who did not progress. Ages are from 55 through 90, with minimum 6 grades of education. Putative surgical patients were selected by searching the comment fields for positive key words (e.g. surgery, thoracotomy, operative etc.) and then screening manually for confirmation. The final cohort contained 32 subjects and 79 non-surgical subjects, frequency matched by follow up time. Repeated Measures ANCOVA was used to evaluate the change in bilateral grey (GM) and white matter (WM) volume, before and after surgery, or between the last two evaluations for non-surgery group. Covariants included intracranial volume, age, and months to follow-up evaluation with diagnostic group (NL or MCI) a cofactor. Statistical significance was p < 0.05 (SPSS version 18.0; Chicago, IL). Results: Examining GM volume (left hemisphere), the 3-way interaction of evaluation, diagnosis, and surgery was significant (F1,104 =6.4, p<.05) indicating that slopes were different depending on diagnostic group; where MCI with surgery showed a significantly greater decrease inGMvolume compared toMCIwithout surgery (F1,47=7.9, p<.01); no significant difference for NL. Examining GM (right hemisphere), the 3-way interaction was not significant, but there was a significant decrease in GM volume (F1,105 =4.1, p<.05) for surgery compared to non-surgery subjects. No significant differences found for WM volume. Conclusions: In our cohort of elderly subjects, surgery resulted in amore pronounced GMvolume atrophy than seen in non-surgical subjects, with MCI subjects at higher risk. An examination of neurocognitive effects of surgery, in progress, suggests a correlation between atrophy and function
— id: 136976, year: 2011, vol: 7, page: S3, stat: Journal Article,

Reduced Mitochondria Cytochrome Oxidase Activity in Adult Children of Mothers with Alzheimer's Disease
Mosconi L; de Leon M; Murray J; E L; Lu J; Javier E; McHugh P; Swerdlow RH
2011 Jan 1;27(3):483-490, Journal of Alzheimer's Disease
Biomarker studies demonstrate inheritance of glucose hypometabolism and increased amyloid-beta deposition in adult offspring of mothers, but not fathers, affected by late-onset Alzheimer's disease (LOAD). The underlying genetic mechanisms are unknown. We investigated whether cognitively normal (NL) individuals with a maternal history of LOAD (MH) have reduced platelet mitochondrial cytochrome oxidase activity (COX, electron transport chain complex IV) compared to those with paternal (PH) or negative family history (NH). Thirty-six consecutive NL individuals (age 55 +/- 15 y, range 27-71 y, 56% female, CDR = 0, MMSE >/=28, 28% APOE-4 carriers), including 12 NH, 12 PH, and 12 MH, received a blood draw to measure platelet mitochondrial COX activity. Citrate synthase activity (CS) was measured as a reference. Groups were comparable for clinical and neuropsychological measures. We found that after correcting for CS, COX activity was reduced by 29% in MH compared to NH, and by 30% in MH compared to PH (p </= 0.006). Results remained significant controlling for age, gender, education, and APOE. No differences were found between PH and NH. COX measures discriminated MH from the other groups with accuracy >/=75%, and relative risk >/=3 (p </= 0.005). Among NL with LOAD-parents, only those with MH showed reduced COX activity in platelet mitochondria compared to PH and NH. The association between maternal history of LOAD and systemic COX reductions suggests transmission via mitochondrial DNA, which is exclusively maternally inherited in humans
— id: 140515, year: 2011, vol: 27, page: 483, stat: Journal Article,

Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer's disease
Mosconi L; Tsui W; Murray J; McHugh P; Li Y; Williams S; Pirraglia E; Glodzik L; De Santi S; Vallabhajosula S; de Leon MJ
2011 Mar;33(3):624.e1-624.e9, Neurobiology of aging
Cognitively normal (NL) individuals with a maternal history of late-onset Alzheimer's disease (MH) show reduced brain glucose metabolism on FDG-PET as compared to those with a paternal history (PH) and those with negative family history (NH) of Alzheimer's disease (AD). This FDG-PET study investigates whether metabolic deficits in NL MH are associated with advancing maternal age at birth. Ninety-six NL individuals with FDG-PET were examined, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with parental age across groups using automated regions-of-interest and statistical parametric mapping. Groups were comparable for clinical and neuropsychological measures. Brain metabolism in AD-vulnerable regions was lower in MH compared to NH and PH, and negatively correlated with maternal age at birth only in MH. There were no associations between paternal age and metabolism in any group. Evidence for a maternally inherited, maternal age-related mechanism provides further insight on risk factors and genetic transmission in late-onset AD
— id: 140517, year: 2011, vol: 33, page: 624.e1, stat: Journal Article,

Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer's disease
Murray J.; Mosconi L.; Tsui W.; McHugh P.; Williams S.; Pirraglia E.; Cummings M.; Glodzik L.; De Santi S.; Vallabhajosula S.; De Leon M.
2011 ;7(4 SUPPL 1):S217-S217, Alzheimer's & Dementia
Background: Having a parent affected with late-onset Alzheimer's disease (AD) is a major risk factor for cognitively normal (NL) individuals. Among individuals with affected parents, those with a maternal history of AD (MH) show reductions of brain glucose metabolism on FDG-PET compared to those with a paternal history (PH) and those with negative family history (NH). This FDG-PET study investigates whether these metabolic deficits are associated with advancing maternal age at birth. Methods: Ninety-six NL individuals (age 60+10 yrs, 64% female) were examined with FDGPET, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with maternal or paternal age across groups using automated regions-of-interest and statistical parametric mapping. Results: Groups were comparable for clinical and neuropsychological measures, maternal and paternal age at birth. After controlling for subjects' age, significant negative correlations between maternal age at birth and metabolism were found in AD-vulnerable regions only for NL MH. Results remained significant after including paternal age, gender, education, and ApoE genotype in the model. There were no associations between paternal age and metabolism in any group. Conclusions: Advanced maternal age at birth negatively affects brain metabolism in the offspring of mothers, but not of fathers affected by late-onset AD. These data indicate a maternally inherited, maternal age-related mechanism that may increase risk for AD and provides further insight on risk factors and genetic transmission in late-onset AD
— id: 136969, year: 2011, vol: 7, page: S217, stat: Journal Article,

Greater risk of Alzheimer's disease in older adults with insomnia
Osorio, Ricardo S; Pirraglia, Elizabeth; Aguera-Ortiz, Luis F; During, Emmanuel H; Sacks, Hayley; Ayappa, Indu; Walsleben, Joyce; Mooney, Anne; Hussain, Asad; Glodzik, Lidia; Frangione, Blas; Martinez-Martin, Pablo; de Leon, Mony J
2011 Mar;59(3):559-562, Journal of the American Geriatrics Society
— id: 134223, year: 2011, vol: 59, page: 559, stat: Journal Article,

Hippocampal blood flow in normal aging measured with arterial spin labeling at 3T
Rusinek, Henry; Brys, Miroslaw; Glodzik, Lidia; Switalski, Remigiusz; Tsui, Wai-Hon; Haas, Francois; McGorty, Kellyanne; Chen, Qun; de Leon, Mony J
2011 Jan;65(1):128-137, Magnetic resonance in medicine
Due to methodological difficulties related to the small size, variable distribution of hippocampal arteries, and the location of the hippocampus in the proximity of middle cranial fossa, little is known about hippocampal blood flow (HBF). We have tested the utility of a pulsed arterial spin labeling sequence based on multi-shot true fast imaging in steady precession to measure HBF in 34 normal volunteers (17 women, 17 men, 26-92 years old). Flow sensitivity to a mild hypercapnic challenge was also examined. Coregistered 3D MPRAGE sequence was used to eliminate from hippocampal and cortical regions of interest all voxel with <75% of gray matter. Large blood vessels were also excluded. HBF in normal volunteers averaged 61.2 +/- 9.0 mL/(100 g min). There was no statistically significant age or gender effect. Under a mild hypercapnia challenge (end tidal CO(2) pressure increase of 6.8 +/- 1.9 mmHg over the baseline), HBF response was 14.1 +/- 10.8 mL/(100 g min), whereas cortical gray matter flow increased by 18.0 +/- 12.2 mL/(100 g min). Flow response among women was significantly larger than in the men. The average absolute difference between two successive HBF measures was 3.6 mL/(100 g min) or 5.4%. The 3T true fast imaging in steady precession arterial spin labeling method offers a HBF measurement strategy that combines good spatial resolution, sensitivity, and minimal image distortions. Magn Reson Med, 2010. (c) 2010 Wiley-Liss, Inc
— id: 116206, year: 2011, vol: 65, page: 128, stat: Journal Article,

Resting-state glucose metabolism level is associated with the regional pattern of amyloid pathology in Alzheimer's disease
Shin, Jonghan; Tsui, Wai; Li, Yi; Lee, Sang-Yoon; Kim, Seog Ju; Cho, Seong-Jin; Kim, Young-Bo; de Leon, Mony J
2011 ;2011:759780-759780, International journal of Alzheimer's disease
It has been suggested that glucose metabolism within the brain's default network is directly associated with-and may even cause-the amyloid pathology of Alzheimer's disease (AD). Here we performed 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) and [(11)C]-labeled Pittsburgh Compound B (PIB) positron emission tomography (PET) on cognitively normal elderly subjects and on AD patients and conducted quantitative regional analysis of FDG- and PIB-PET images using an automated region of interest technique. We confirmed that resting glucose metabolism within the posterior components of the brain's default network is high in normal elderly subjects and low in AD patients, which is partially in agreement with the regional pattern of PIB uptake within the default network of AD patients. However, in several regions outside the default network, glucose metabolism was high in normal elderly subjects but was not depressed in AD patients, who exhibited significantly increased PIB uptakes in these regions. In contrast, the level of resting glucose metabolism in the default network and in regions outside the default network in normal elderly subjects was significantly correlated with the level of regional PIB uptake in AD patients. These results are discussed with experimental evidence suggesting that beta amyloid production and amyloid precursor protein regulation are dependent on neuronal activity
— id: 132323, year: 2011, vol: 2011, page: 759780, stat: Journal Article,

Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome
Wegiel, Jerzy; Kaczmarski, Wojciech; Barua, Madhabi; Kuchna, Izabela; Nowicki, Krzysztof; Wang, Kuo-Chiang; Wegiel, Jarek; Yang, Shuang Ma; Frackowiak, Janusz; Mazur-Kolecka, Bozena; Silverman, Wayne P; Reisberg, Barry; Monteiro, Isabel; de Leon, Mony; Wisniewski, Thomas; Dalton, Arthur; Lai, Florence; Hwang, Yu-Wen; Adayev, Tatyana; Liu, Fei; Iqbal, Khalid; Iqbal, Inge-Grundke; Gong, Cheng-Xin
2011 Jan;70(1):36-50, Journal of neuropathology & experimental neurology
Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage-proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus, and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68 x of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R tau-positive NFTs in DS/AD subjects compared with that in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS
— id: 134289, year: 2011, vol: 70, page: 36, stat: Journal Article,

Detection of amyloid plaques targeted by USPIO-Abeta1-42 in Alzheimer's disease transgenic mice using magnetic resonance microimaging
Yang, Jing; Zaim Wadghiri, Youssef; Minh Hoang, Dung; Tsui, Wai; Sun, Yanjie; Chung, Erika; Li, Yongsheng; Wang, Andrew; de Leon, Mony; Wisniewski, Thomas
2011 Apr 15;55(4):1600-1609, Neuroimage
Amyloid plaques are one of the pathological hallmarks of Alzheimer's disease (AD). The visualization of amyloid plaques in the brain is important to monitor AD progression and to evaluate the efficacy of therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques in vivo using magnetic resonance microimaging (muMRI) in AD transgenic mice, where we used intra-carotid mannitol to enhance blood-brain barrier (BBB) permeability. In the present study, we used ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Abeta1-42 peptide to detect amyloid deposition along with mannitol for in vivo muMRI by femoral intravenous injection. A 3D gradient multi-echo sequence was used for imaging with a 100mum isotropic resolution. The amyloid plaques detected by T2*-weighted muMRI were confirmed with matched histological sections. Furthermore, two different quantitative analyses were used. The region of interest-based quantitative measurement of T2* values showed contrast-injected APP/PS1 mice had significantly reduced T2* values compared to wild-type mice. In addition, the scans were examined with voxel-based morphometry (VBM) using statistical parametric mapping (SPM) for comparison of contrast-injected AD transgenic and wild-type mice. The regional differences seen in VBM comparing USPIO-Abeta1-42 injected APP/PS1 and wild-type mice correlated with the amyloid plaque distribution histologically, contrasting with no differences between the two groups of mice without contrast agent injection in regions of the brain with amyloid deposition. Our results demonstrated that both approaches were able to identify the differences between AD transgenic mice and wild-type mice, after injected with USPIO-Abeta1-42. The feasibility of using less invasive intravenous femoral injections for amyloid plaque detection in AD transgenic mice facilitates using this method for longitudinal studies in the pathogenesis of AD
— id: 128789, year: 2011, vol: 55, page: 1600, stat: Journal Article,

Subregional hippocampal atrophy predicts Alzheimer's dementia in the cognitively normal
Apostolova, Liana G; Mosconi, Lisa; Thompson, Paul M; Green, Amity E; Hwang, Kristy S; Ramirez, Anthony; Mistur, Rachel; Tsui, Wai H; de Leon, Mony J
2010 Jul;31(7):1077-1088, Neurobiology of aging
Atrophic changes of the hippocampus are typically regarded as an early sign of Alzheimer's dementia (AD). Using the radial distance atrophy mapping approach, we compared the longitudinal MRI data of 10 cognitively normal elderly subjects who remained normal at 3-year and 6-year follow-up (NL-NL) and 7 cognitively normal elderly subjects who were diagnosed with mild cognitive impairment (MCI) 2.8 (range 2.0-3.9) and with AD 6.8 years (range 6.1-8.2) after baseline (NL-MCI(AD)). 3D statistical maps revealed greater hippocampal atrophy in the NL-MCI(AD) relative to the NL-NL group at baseline (left p=0.05; right p=0.06) corresponding to 10-15% CA1, and 10-25% subicular atrophy, and bilateral differences at 3-year follow-up (left p=0.001, right p<0.02) corresponding to 10-30% subicular, 10-20% CA1, and 10-20% newly developed CA2-3 atrophy. This preliminary study suggests that excess CA1 and subicular atrophy is present in cognitively normal individuals predestined to decline to amnestic MCI, while progressive involvement of the CA1 and subiculum, and atrophy spreading to the CA2-3 subfield in amnestic MCI, suggests future diagnosis of AD
— id: 96313, year: 2010, vol: 31, page: 1077, stat: Journal Article,

Does mild cognitive impairment increase the risk of developing postoperative cognitive dysfunction?
Bekker, Alex; Lee, Cynthia; de Santi, Susan; Pirraglia, Elizabeth; Zaslavsky, Alexander; Farber, Sonya; Haile, Michael; de Leon, Mony J
2010 Jun;199(6):782-788, American journal of surgery
BACKGROUND: Increasingly, postoperative cognitive dysfunction (POCD) is recognized as a complication after surgery in the elderly. We sought to determine whether patients with mild cognitive impairment (MCI) would have an accelerated progression of dementia postoperatively when compared with the patients without MCI. METHODS: The Center for Brain Health at the New York University (NYU) Medical Center maintains records of volunteers who undergo a series of neurological assessments. We reviewed records of 670 patients who received at least 2 evaluations and whose surgery occurred before the second assessment. Longitudinal differences of several cognitive domains were examined. RESULTS: Individuals with MCI and surgery had a greater decline in performance on the Digit Span Forward test compared with those with MCI without surgery on their postoperative evaluation (F(3,158) = 3.12, P = .03). No performance changes were detected in the normal subjects. CONCLUSION: These preliminary findings suggest that surgery negatively impacts attention/concentration in patients with MCI but not in normal individuals. This is the first study that identified a specific subgroup of patients who are predisposed to POCD
— id: 110877, year: 2010, vol: 199, page: 782, stat: Journal Article,

Cortical hypometabolism in untreated de novo Parkinson's disease: comparison of different normalization procedures
Berti, V.; Polito, C.; Borghammer, P.; Ramat, S.; Mosconi, L.; de Leon, M.; Pupi, A.
2010 OCT ;37(1):S218-S218, European journal of nuclear medicine & molecular imaging
— id: 122276, year: 2010, vol: 37, page: S218, stat: Journal Article,

Early detection of Alzheimer's disease with PET imaging
Berti, V; Osorio, R S; Mosconi, L; Li, Y; De Santi, S; de Leon, M J
2010 ;7(1-3):131-135, Neuro-degenerative diseases
Preclinical diagnosis of Alzheimer's disease (AD) is one of the major challenges for the prevention of AD. AD biomarkers are needed not only to reveal preclinical pathologic changes, but also to monitor progression and therapeutics. PET neuroimaging can reliably assess aspects of the molecular biology and neuropathology of AD. The aim of this article is to review the use of FDG-PET and amyloid PET imaging in the early detection of AD
— id: 132605, year: 2010, vol: 7, page: 131, stat: Journal Article,

Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: findings from the Alzheimer's Disease Neuroimaging Initiative
Chen, Kewei; Langbaum, Jessica B S; Fleisher, Adam S; Ayutyanont, Napatkamon; Reschke, Cole; Lee, Wendy; Liu, Xiaofen; Bandy, Dan; Alexander, Gene E; Thompson, Paul M; Foster, Norman L; Harvey, Danielle J; de Leon, Mony J; Koeppe, Robert A; Jagust, William J; Weiner, Michael W; Reiman, Eric M
2010 Jun;51(2):654-664, Neuroimage
Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically pre-defined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66 AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two-tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments
— id: 148714, year: 2010, vol: 51, page: 654, stat: Journal Article,

Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders
Glodzik L; de Santi S; Tsui WH; Mosconi L; Zinkowski R; Pirraglia E; Wang HY; Li Y; Rich KE; Zetterberg H; Blennow K; Mehta P; de Leon MJ
2010 Dec;32(12):2131-2141, Neurobiology of aging
Little is known whether cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) can predict both memory decline and associated longitudinal medial temporal lobe (MTL) gray matter (GM) reductions in cognitively healthy individuals. Fifty-seven normal elderly subjects received comprehensive evaluation at baseline and 2 years later. The baseline phosphorylated tau(231) (p-tau(231)), total tau, the amyloid beta (Abeta) Abeta42/Abeta40, t-tau/Abeta42 and p-tau(231)/Abeta42 ratios were examined as predictors of memory change and reductions in the global and MTL GM, determined from T1-weighted MRI. Twenty out of 57 participants experienced reduced memory performance at follow-up. The group with decreased memory performance showed higher baseline p-tau(231) (Z=-2.2, p=0.03), lower Abeta42/Abeta40 (t=-2.2 [55], p=0.04) and greater longitudinal MTL GM reductions (t([52])=-2.70, p=0.01). Higher baseline p-tau(231) was also associated with the absolute decrease in memory scores (rho=-0.30, p=0.02) and with longitudinal MTL GM reduction (F([2,52])=4.4, p=0.04, age corrected). Our results indicate that in normal individuals, elevated p-tau(231), a marker of neurofibrillary pathology is related to both a decrease in declarative memory and progressive atrophy of the MTL, suggesting its diagnostic potential in preclinical stage
— id: 138221, year: 2010, vol: 32, page: 2131, stat: Journal Article,

Pre-clinical detection of Alzheimer's disease using FDG-PET, with or without amyloid imaging
Mosconi, Lisa; Berti, Valentina; Glodzik, Lidia; Pupi, Alberto; De Santi, Susan; de Leon, Mony J
2010 ;20(3):843-854, Journal of Alzheimer's Disease
The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to subtle brain changes occurring in the preclinical stage of the disease. Early diagnostics is necessary to identify and treat at risk individuals before irreversible neuronal loss occurs. In vivo imaging has long been used to evaluate brain structural and functional abnormalities as predictors of future AD in non-demented persons. Prior to development of amyloid-beta (Abeta) tracers for positron emission tomography (PET), the most widely utilized PET tracer in AD was 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) PET. For over 20 years, FDG-PET has been used to measure cerebral metabolic rates of glucose (CMRglc), a proxy for neuronal activity, in AD. Many studies have shown that CMRglc reductions occur early in AD, correlate with disease progression, and predict histopathological diagnosis. This paper reviews reports of clinical and preclinical CMRglc reductions observed in association with genetic and non-genetic risk factors for AD. We then briefly review brain Abeta PET imaging studies in AD and discuss the potential of combining symptoms-sensitive FDG-PET measures with pathology-specific Abeta-PET to improve the early detection of AD
— id: 110093, year: 2010, vol: 20, page: 843, stat: Journal Article,

Maternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes
Mosconi, Lisa; Berti, Valentina; Swerdlow, Russell H; Pupi, Alberto; Duara, Ranjan; de Leon, Mony
2010 Feb;4(3):170-193, Human Genomics
After advanced age, having a parent affected with Alzheimer's disease (AD) is the most significant risk factor for developing AD among cognitively normal (NL) individuals. Although rare genetic mutations have been identified among the early-onset forms of familial AD (EOFAD), the genetics of the more common forms of late-onset AD (LOAD) remain elusive. While some LOAD cases appear to be sporadic in nature, genetically mediated risk is evident from the familial aggregation of many LOAD cases. The patterns of transmission and biological mechanisms through which a family history of LOAD confers risk to the offspring are not known. Brain imaging studies using 2-[ (18) F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG PET) have shown that NL individuals with a maternal history of LOAD, but not with a paternal family history, express a phenotype characterised by a pattern of progressive reductions of brain glucose metabolism, similar to that in AD patients. As maternally inherited AD may be associated with as many as 20 per cent of the total LOAD population, understanding the causes and mechanisms of expression of this form of AD is of great relevance. This paper reviews known genetic mutations implicated in EOFAD and their effects on brain chemistry, structure and function; epidemiology and clinical research findings in LOAD, including in vivo imaging findings showing selective patterns of hypometabolism in maternally inherited AD; possible genetic mechanisms involved in maternal transmission of AD, including chromosome X mutations, mitochondrial DNA and imprinting; and genetic mechanisms involved in other neurological disorders with known or suspected maternal inheritance. The review concludes with a discussion of the potential role of brain imaging for identifying endophenotypes in NL individuals at risk for AD, and for directing investigation of potential susceptibility genes for AD
— id: 109061, year: 2010, vol: 4, page: 170, stat: Journal Article,

Oxidative stress and amyloid-beta pathology in normal individuals with a maternal history of Alzheimer's
Mosconi, Lisa; Glodzik, Lidia; Mistur, Rachel; McHugh, Pauline; Rich, Kenneth E; Javier, Elizabeth; Williams, Schantel; Pirraglia, Elizabeth; De Santi, Susan; Mehta, Pankaj D; Zinkowski, Raymond; Blennow, Kaj; Pratico, Domenico; de Leon, Mony J
2010 Nov 15;68(10):913-921, Biological psychiatry
BACKGROUND: Epidemiology and imaging studies showed that cognitively normal (NL) individuals with a maternal history (MH) of late-onset Alzheimer's disease (LOAD) might be at increased risk for Alzheimer's disease (AD) compared with NL with a paternal history (PH) and NL with a negative family history of LOAD (NH). With a panel of cerebrospinal fluid (CSF) markers, this study examined whether NL MH showed evidence for AD pathology compared with PH and NH. METHODS: Fifty-nine 40-80-year-old NL subjects were examined, including 23 MH and 14 PH whose parents had a clinician-certified diagnosis of LOAD and 22 NH. All subjects completed clinical neuropsychological examinations and a lumbar puncture to measure CSF levels of amyloid-beta (Abeta(40), Abeta(42), Abeta(42/40)), total and hyperphosphorylated tau (T-Tau and P-Tau(231); markers of axonal degeneration and neurofibrillary tangles, respectively), and F-isoprostanes (IsoP) (a marker of oxidative stress). RESULTS: Groups were comparable for demographic and neuropsychological measures. The MH subjects showed higher IsoP and reduced Abeta(42/40) CSF levels compared with NH and with PH (p values </= .05), whereas no differences were found between NH and PH. No group differences were found for P-Tau(231) and T-Tau. The IsoP and Abeta(42/40) levels were correlated only within the MH group (R(2) = .32, p = .005) and discriminated MH from the other subjects with 70% accuracy (relative risk = 3.7%, 95% confidence interval = 1.6-9.7, p < .001). Results remained significant controlling for age, gender, education, and apolipoprotein E genotype. CONCLUSIONS: Adult children of LOAD-affected mothers express a pathobiological phenotype characterized by Abeta-associated oxidative stress consistent with AD, which might reflect increased risk for developing the disease
— id: 138223, year: 2010, vol: 68, page: 913, stat: Journal Article,

Increased fibrillar amyloid-{beta} burden in normal individuals with a family history of late-onset Alzheimer's
Mosconi, Lisa; Rinne, Juha O; Tsui, Wai H; Berti, Valentina; Li, Yi; Wang, Huiyu; Murray, John; Scheinin, Noora; Nagren, Kjell; Williams, Schantel; Glodzik, Lidia; De Santi, Susan; Vallabhajosula, Shankar; de Leon, Mony J
2010 Mar 30;107(13):5949-5954, Proceedings of the National Academy of Sciences of the United States of America
Having a parent affected with late-onset Alzheimer's disease (LOAD) is a major risk factor among cognitively normal (NL) individuals. This (11)C-Pittsburgh Compound B (PiB)-PET study examines whether NL individuals with LOAD parents show increased fibrillar amyloid-beta (Abeta) deposition, a hallmark of Alzheimer's disease (AD) pathology and whether there are parent-of-origin effects. Forty-two 50- to 80-year-old NL persons were examined with PiB-PET. These individuals included 14 NL subjects with a maternal family history (FH) of LOAD (FHm), 14 NL subjects with a paternal FH (FHp), and 14 NL subjects with a negative family history of any dementia (FH-). Statistical parametric mapping and automated regions-of-interest were used to compare cerebral-to-cerebellar PiB standardized uptake value ratios, reflecting fibrillar Abeta burden, across groups. FH groups did not differ in age, gender, education, and apolipoprotein E (ApoE) status. NL FHm subjects showed higher PiB retention in AD-affected anterior and posterior cingulate cortex (PCC), precuneus, parietal, temporal, occipital, and frontal cortices, right basal ganglia, and thalamus, compared with FH- and FHp subjects. FHp subjects showed increased PiB retention in the PCC and frontal cortex, intermediate between FHm and FH- subjects. Results remained significant after controlling for age, gender, education, and ApoE status. Children of parents with LOAD, particularly those with affected mothers, have increased fibrillar Abeta load in AD-vulnerable regions compared with controls, perhaps accounting for the known increased risk for AD. Present findings may motivate further research on familial transmission and parent-of-origin effects in LOAD
— id: 108923, year: 2010, vol: 107, page: 5949, stat: Journal Article,

The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes
Wegiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof; Imaki, Humi; Wegiel, Jarek; Marchi, Elaine; Ma, Shuang Yong; Chauhan, Abha; Chauhan, Ved; Bobrowicz, Teresa Wierzba; de Leon, Mony; Louis, Leslie A Saint; Cohen, Ira L; London, Eric; Brown, W Ted; Wisniewski, Thomas
2010 Jun;119(6):755-770, Acta neuropathologica
Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4-60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-mum-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype
— id: 119248, year: 2010, vol: 119, page: 755, stat: Journal Article,

Magnetic resonance imaging improves cerebrospinal fluid biomarkers in the early detection of Alzheimer's disease
Brys, Miroslaw; Glodzik, Lidia; Mosconi, Lisa; Switalski, Remigiusz; De Santi, Susan; Pirraglia, Elizabeth; Rich, Kenneth; Kim, Byeong C; Mehta, Pankaj; Zinkowski, Ray; Pratico, Domenico; Wallin, Anders; Zetterberg, Henrik; Tsui, Wai H; Rusinek, Henry; Blennow, Kaj; de Leon, Mony J
2009 Feb;16(2):351-362, Journal of Alzheimer's Disease
Little is known of combined utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers for prediction of Alzheimer's disease (AD) and longitudinal data is scarce. We examined these biomarkers at baseline and longitudinally in incipient AD. Forty-five subjects [21 controls (NL-NL), 16 stable MCI (MCI-MCI), 8 MCI who declined to AD (MCI-AD)] received MRI and lumbar puncture at baseline and after 2 years. CSF measures included total and phosphorylated tau (T-tau, P-tau<formula>_{231}</formula>), amyloid-beta (Abeta<formula>_{42}</formula>/Abeta<formula>_{40}</formula>) and isoprostane. Voxel-based morphometry identified gray matter concentration (GMC) differences best distinguishing study groups and individual GMC values were calculated. Rate of medial temporal lobe (MTL) atrophy was examined using regional boundary shift (rBS) method. At baseline, for MRI, MCI-AD showed reduced GMC-MTL, and for CSF higher CSF T-tau, P-tau<formula>_{231}</formula>, IP and lower Abeta<formula>_{42}</formula>/Abeta<formula>_{40}</formula> as compared with MCI-MCI or NL-NL. Longitudinally, rBS-MTL atrophy was higher in MCI-AD than in either MCI-MCI or NL-NL, particularly in the left hemisphere. CSF data showed longitudinally greater increases of isoprostane in MCI-AD as compared with NL-NL. Combining baseline CSF-P-tau<formula>_{231}</formula> and GMC-MTL significantly increased overall prediction of AD from 74% to 84% (p<formula>_{step}</formula> < 0.05). These results provide support for including multiple modalities of biomarkers in the identification of memory clinic patients at increased risk for dementia
— id: 93784, year: 2009, vol: 16, page: 351, stat: Journal Article,

Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment
Brys, Miroslaw; Pirraglia, Elizabeth; Rich, Kenneth; Rolstad, Sindre; Mosconi, Lisa; Switalski, Remigiusz; Glodzik-Sobanska, Lidia; De Santi, Susan; Zinkowski, Ray; Mehta, Pankaj; Pratico, Domenico; Saint Louis, Leslie A; Wallin, Anders; Blennow, Kaj; de Leon, Mony J
2009 May;30(5):682-690, Neurobiology of aging
OBJECTIVES: To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: A baseline and 2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau(231)), amyloid beta (Abeta) Abeta(42)/Abeta(40) ratio, isoprostane (IP) as well as P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios. RESULTS: At baseline and at follow-up MCI-AD showed higher levels P-tau(231), T-tau, IP, P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios and lower Abeta(42)/Abeta(40) than MCI-MCI or NL-NL. Baseline P-tau(231) best predicted MCI-AD (80%, p<0.001) followed in accuracy by P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios (both 75%, p's<0.001), T-tau (74%, p<0.001), Abeta(42)/Abeta(40) (69%, p<0.01), and IP (68%, p<0.01). Only IP showed longitudinal effects (p<0.05). CONCLUSIONS: P-tau(231) is the strongest predictor of the decline from MCI to AD. IP levels uniquely show longitudinal progression effects. These results suggest the use of CSF biomarkers in secondary prevention trials
— id: 86777, year: 2009, vol: 30, page: 682, stat: Journal Article,

Effects of memantine on cerebrospinal fluid biomarkers of neurofibrillary pathology
Glodzik, Lidia; De Santi, Susan; Rich, Kenneth E; Brys, Miroslaw; Pirraglia, Elizabeth; Mistur, Rachel; Switalski, Remigiusz; Mosconi, Lisa; Sadowski, Martin; Zetterberg, Henrik; Blennow, Kaj; de Leon, Mony J
2009 Nov;18(3):509-513, Journal of Alzheimer's Disease
Previous studies showed that memantine inhibits tau hyperphosphorylation in vitro. In this study, phosphorylated tau (P-tau) and total tau (T-tau) were measured before and after 6 month treatment with memantine in 12 subjects ranging from normal cognition with subjective memory complaints, through mild cognitive impairment to mild Alzheimer's disease. Thirteen non-treated individuals served as controls. Treatment was associated with a reduction of P-tau in subjects with normal cognition. No treatment effects were seen among impaired individuals, suggesting that longer treatment time may be necessary to achieve biomarker effect in this group
— id: 108783, year: 2009, vol: 18, page: 509, stat: Journal Article,

The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer's disease
Glodzik-Sobanska, Lidia; Pirraglia, Elizabeth; Brys, Miroslaw; de Santi, Susan; Mosconi, Lisa; Rich, Kenneth E; Switalski, Remigiusz; Saint Louis, Leslie; Sadowski, Martin J; Martiniuk, Frank; Mehta, Pankaj; Pratico, Domenico; Zinkowski, Raymond P; Blennow, Kaj; de Leon, Mony J
2009 May;30(5):672-681, Neurobiology of aging
While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimer's disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60+/-10 years, range 36-86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Abeta42/Abeta40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by varepsilon4 genotype interactions were found for P-tau231 (beta=1.82; p<0.05) and IP (beta=1.6; p<0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in varepsilon4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Abeta changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study
— id: 86778, year: 2009, vol: 30, page: 672, stat: Journal Article,

TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer's disease patients and normal subjects
Kamer, Angela R; Craig, Ronald G; Pirraglia, Elizabeth; Dasanayake, Ananda P; Norman, Robert G; Boylan, Robert J; Nehorayoff, Andrea; Glodzik, Lidia; Brys, Miroslaw; de Leon, Mony J
2009 Nov 30;216(1-2):92-97, Journal of neuroimmunology
The associations of inflammation/immune responses with clinical presentations of Alzheimer's disease (AD) remain unclear. We hypothesized that TNF-alpha and elevated antibodies to periodontal bacteria would be greater in AD compared to normal controls (NL) and their combination would aid clinical diagnosis of AD. Plasma TNF-alpha and antibodies against periodontal bacteria were elevated in AD patients compared with NL and independently associated with AD. The number of positive IgG to periodontal bacteria incremented the TNF-alpha classification of clinical AD and NL. This study shows that TNF-alpha and elevated numbers of antibodies against periodontal bacteria associate with AD and contribute to the AD diagnosis
— id: 112410, year: 2009, vol: 216, page: 92, stat: Journal Article,

Justification des marqueurs biologiques dans la maladie d'Alzheimer = [Rationale for biomarkers in Alzheimer's disease]
Leon, M. J. de; Blennow, K
2009 ;20(1):18-24, Age & nutrition
— id: 148712, year: 2009, vol: 20, page: 18, stat: Journal Article,

CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment
Mattsson, Niklas; Zetterberg, Henrik; Hansson, Oskar; Andreasen, Niels; Parnetti, Lucilla; Jonsson, Michael; Herukka, Sanna-Kaisa; van der Flier, Wiesje M; Blankenstein, Marinus A; Ewers, Michael; Rich, Kenneth; Kaiser, Elmar; Verbeek, Marcel; Tsolaki, Magda; Mulugeta, Ezra; Rosen, Erik; Aarsland, Dag; Visser, Pieter Jelle; Schroder, Johannes; Marcusson, Jan; de Leon, Mony; Hampel, Harald; Scheltens, Philip; Pirttila, Tuula; Wallin, Anders; Jonhagen, Maria Eriksdotter; Minthon, Lennart; Winblad, Bengt; Blennow, Kaj
2009 Jul 22;302(4):385-393, JAMA
CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures
— id: 119197, year: 2009, vol: 302, page: 385, stat: Journal Article,

Positron emission tomography in Alzheimer's disease: Early prediction and differentiation
Mistur R.; Mosconi L.; De Santi S.; Li Y.; Tsui W.; de Leon M.
2009 ;4(1):23-38, Future Neurology
The development of biomarkers for the preclinical detection of neurodegenerative diseases such as Alzheimer's disease (AD) is a vital step in developing prevention therapies. One consistent feature of AD is a reduction in the cerebral metabolic rate of glucose (CMRglc), a measure of neuronal function. In vivo brain 2-(18F) fluoro-2-deoxy-D-glucose-PET imaging demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. There is increasing evidence that CMRglc reductions occur at the preclinical stages of AD and predict decline years in advance of clinical symptoms. This review will give an overview of FDG-PET results in individuals at risk for developing dementia, including: presymptomatic individuals carrying mutations responsible for early-onset familial AD; patients with mild cognitive impairment, often a prodrome to late-onset sporadic AD; nondemented carriers of the ApoE 4[dot]allele, a strong genetic risk factor for late-onset AD; cognitively normal subjects with a family history of AD; subjects with subjective memory complaints; and normal elderly who were followed longitudinally until they expressed the clinical symptoms and later received postmortem confirmation of AD. We will then review the most recent studies using FDG-PET as an early differential diagnostic tool in AD. copyright 2009 Future Medicine
— id: 100470, year: 2009, vol: 4, page: 23, stat: Journal Article,

Current Challenges for the Early Detection of Alzheimer's Disease: Brain Imaging and CSF Studies
Mistur, Rachel; Mosconi, Lisa; Santi, Susan De; Guzman, Marla; Li, Yi; Tsui, Wai; de Leon, Mony J
2009 Dec;5(4):153-166, Journal of clinical neurology (Seoul, Korea)
The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to the subtle brain changes that occur in the preclinical stage of the disease. Reductions in the cerebral metabolic rate of glucose (CMRglc), a measure of neuronal function, have proven to be a promising tool in the early diagnosis of AD. In vivo brain 2-[(18)F]fluoro-2-Deoxy-D-glucose-positron emission tomography (FDG-PET) imaging demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. There is increasing evidence that hypometabolism appears during the preclinical stages of AD and can predict decline years before the onset of symptoms. This review will give an overview of FDG-PET results in individuals at risk for developing dementia, including: presymptomatic individuals carrying mutations responsible for early-onset familial AD; patients with Mild Cognitive Impairment (MCI), often a prodrome to late-onset sporadic AD; non-demented carriers of the Apolipoprotein E (ApoE) epsilon4 allele, a strong genetic risk factor for late-onset AD; cognitively normal subjects with a family history of AD; subjects with subjective memory complaints; and normal elderly followed longitudinally until they expressed the clinical symptoms and received post-mortem confirmation of AD. Finally, we will discuss the potential to combine different PET tracers and CSF markers of pathology to improve the early detection of AD
— id: 106279, year: 2009, vol: 5, page: 153, stat: Journal Article,

Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease
Mosconi, L; Mistur, R; Switalski, R; Brys, M; Glodzik, L; Rich, K; Pirraglia, E; Tsui, W; De Santi, S; de Leon, M J
2009 Feb 10;72(6):513-520, Neurology
BACKGROUND: At cross-section, cognitively normal individuals (NL) with a maternal history of late-onset Alzheimer disease (AD) have reduced glucose metabolism (CMRglc) on FDG-PET in the same brain regions as patients with clinical AD as compared to those with a paternal and a negative family history (FH) of AD. This longitudinal FDG-PET study examines whether CMRglc reductions in NL subjects with a maternal history of AD are progressive. METHODS: Seventy-five 50- to 82-year-old NL received 2-year follow-up clinical, neuropsychological, and FDG-PET examinations. These included 37 subjects with negative family history of AD (FH-), 9 with paternal (FHp), and 20 with maternal AD (FHm). Two subjects had parents with postmortem confirmed AD. Statistical parametric mapping was used to compare CMRglc across FH groups at baseline, follow-up, and longitudinally. RESULTS: At both time points, the FH groups were comparable for demographic and neuropsychological characteristics. At baseline and at follow-up, FHm subjects showed CMRglc reductions in the parieto-temporal, posterior cingulate, and medial temporal cortices as compared to FH- and FHp (p < 0.001). Longitudinally, FHm had significant CMRglc declines in these regions, which were significantly greater than those in FH- and FHp (p < 0.05). CONCLUSIONS: A maternal history of Alzheimer disease (AD) predisposes normal individuals to progressive CMRglc reductions in AD-vulnerable brain regions, which may be related to a higher risk for developing AD
— id: 93785, year: 2009, vol: 72, page: 513, stat: Journal Article,

FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease
Mosconi, Lisa; Mistur, Rachel; Switalski, Remigiusz; Tsui, Wai Hon; Glodzik, Lidia; Li, Yi; Pirraglia, Elizabeth; De Santi, Susan; Reisberg, Barry; Wisniewski, Thomas; de Leon, Mony J
2009 May;36(5):811-822, European journal of nuclear medicine & molecular imaging
PURPOSE: We report the first clinicopathological series of longitudinal FDG-PET scans in post-mortem (PM) verified cognitively normal elderly (NL) followed to the onset of Alzheimer's-type dementia (DAT), and in patients with mild DAT with progressive cognitive deterioration. METHODS: Four NL subjects and three patients with mild DAT received longitudinal clinical, neuropsychological and dynamic FDG-PET examinations with arterial input functions. NL subjects were followed for 13 +/- 5 years, received FDG-PET examinations over 7 +/- 2 years, and autopsy 6 +/- 3 years after the last FDG-PET. Two NL declined to mild cognitive impairment (MCI), and two developed probable DAT before death. DAT patients were followed for 9 +/- 3 years, received FDG-PET examinations over 3 +/- 2 years, and autopsy 7 +/- 1 years after the last FDG-PET. Two DAT patients progressed to moderate-to-severe dementia and one developed vascular dementia. RESULTS: The two NL subjects who declined to DAT received a PM diagnosis of definite AD. Their FDG-PET scans indicated a progression of deficits in the cerebral metabolic rate for glucose (CMRglc) from the hippocampus to the parietotemporal and posterior cingulate cortices. One DAT patient showed AD with diffuse Lewy body disease (LBD) at PM, and her last in vivo PET was indicative of possible LBD for the presence of occipital as well as parietotemporal hypometabolism. CONCLUSION: Progressive CMRglc reductions on FDG-PET occur years in advance of clinical DAT symptoms in patients with pathologically verified disease. The FDG-PET profiles in life were consistent with the PM diagnosis
— id: 91500, year: 2009, vol: 36, page: 811, stat: Journal Article,

An entorhinal cortex sulcal pattern is associated with Alzheimer's disease
Zhan, Jiong; Brys, Miroslaw; Glodzik, Lidia; Tsui, Wai; Javier, Elizabeth; Wegiel, Jerzy; Kuchna, Izabela; Pirraglia, Elizabeth; Li, Yi; Mosconi, Lisa; Saint Louis, Leslie A; Switalski, Remigiusz; De Santi, Susan; Kim, Byeong C; Wisniewski, Thomas; Reisberg, Barry; Bobinski, Matthew; de Leon, Mony J
2009 Mar;30(3):874-882, Human brain mapping
OBJECTIVES:: Magnetic resonance (MRI) studies rely on sulcal boundaries to delineate the human entorhinal cortex (EC) and typically show that EC size is reduced in Alzheimer's disease (AD) and a predictor of future dementia. However, it is unknown if variations in the EC sulcal patterns are associated with AD. We classified the lateral EC sulcal boundary as either a rhinal or collateral pattern and tested the hypotheses that the rhinal pattern was (1) more common in AD and (2) associated with a smaller EC size. EXPERIMENTAL DESIGN:: MRI was used to determine the prevalence of the rhinal and collateral EC patterns in 421 subjects (212 AD, 107 old normal (ONL), and 102 young NL (YNL). Anatomical validation studies of normal subjects were conducted at postmortem in 34 brain hemispheres and in vivo with 21 MRI volume studies. EC pattern reliability was studied with MRI in both cross-sectional and longitudinal designs. PRINCIPAL OBSERVATIONS:: The rhinal pattern was more frequent in the right hemisphere in AD (47%) compared with ONL (28%, odds ratio = 2.25, P = 0.001). EC pattern was not related to ApoE genotype. The validations showed that the EC sulcal pattern was not associated with the neuronal number, surface area, or volume of the EC. In patients with antemortem MRI studied at postmortem it was equivalently determined, that EC patterns are reliably determined on MRI and do not change with the progressive atrophy of AD. CONCLUSIONS:: The data indicate that the right hemisphere rhinal pattern is over represented in AD as compared with control. However, in normal subjects the EC rhinal pattern is not associated with a diminished EC tissue size. It remains to be demonstrated if the right EC rhinal sulcus pattern association with AD reflects genetic or developmental influences. Hum Brain Mapp, 2008. (c) 2008 Wiley-Liss, Inc
— id: 76758, year: 2009, vol: 30, page: 874, stat: Journal Article,

Robust and conventional neuropsychological norms: diagnosis and prediction of age-related cognitive decline
De Santi, Susan; Pirraglia, Elizabeth; Barr, William; Babb, James; Williams, Schantel; Rogers, Kimberley; Glodzik, Lidia; Brys, Miroslaw; Mosconi, Lisa; Reisberg, Barry; Ferris, Steven; de Leon, Mony J
2008 Jul;22(4):469-484, Neuropsychology
The aim of the study was to compare the performance of Robust and Conventional neuropsychological norms in predicting clinical decline among healthy adults and in mild cognitive impairment (MCI). The authors developed Robust baseline cross sectional and longitudinal change norms from 113 healthy participants retaining a normal diagnosis for at least 4 years. Baseline Conventional norms were separately created for 256 similar healthy participants without follow-up. Conventional and Robust norms were tested in an independent cohort of longitudinally studied healthy (n=223), MCI (n=136), and Alzheimer's disease (AD, n=162) participants; 84 healthy participants declined to MCI or AD (NL-->DEC), and 44 MCI declined to AD (MCI-->AD). Compared to Conventional norms, baseline Robust norms correctly identified a higher proportion of NL-->DEC with impairment in delayed memory and attention-language domains. Both norms predicted decline from MCI-->AD. Change norms for delayed memory and attention-language significantly incremented baseline classification accuracies. These findings indicate that Robust norms improve identification of healthy individuals who will decline and may be useful for selecting at-risk participants for research studies and early interventions
— id: 86549, year: 2008, vol: 22, page: 469, stat: Journal Article,

Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer's disease
Devanand, Davangere P; Liu, Xinhua; Tabert, Matthias H; Pradhaban, Gnanavalli; Cuasay, Katrina; Bell, Karen; de Leon, Mony J; Doty, Richard L; Stern, Yaakov; Pelton, Gregory H
2008 Nov 15;64(10):871-879, Biological psychiatry
BACKGROUND: The utility of combining early markers to predict conversion from mild cognitive impairment (MCI) to Alzheimer's Disease (AD) remains uncertain. METHODS: Included in the study were 148 outpatients with MCI, broadly defined, followed at 6-month intervals. Hypothesized baseline predictors for follow-up conversion to AD (entire sample: 39/148 converters) were cognitive test performance, informant report of functional impairment, apolipoprotein E genotype, olfactory identification deficit, and magnetic resonance imaging (MRI) hippocampal and entorhinal cortex volumes. RESULTS: In the 3-year follow-up patient sample (33/126 converters), five of eight hypothesized predictors were selected by backward and stepwise logistic regression: Pfeffer Functional Activities Questionnaire (FAQ; informant report of functioning), University of Pennsylvania Smell Identification Test (UPSIT; olfactory identification), Selective Reminding Test (SRT) immediate recall (verbal memory), MRI hippocampal volume, and MRI entorhinal cortex volume. For 10% false positives (90% specificity), this five-predictor combination showed 85.2% sensitivity, combining age and Mini-Mental State Examination (MMSE) showed 39.4% sensitivity; combining age, MMSE, and the three clinical predictors (SRT immediate recall, FAQ, and UPSIT) showed 81.3% sensitivity. Area under ROC curve was greater for the five-predictor combination (.948) than age plus MMSE (.821; p = .0009) and remained high in subsamples with MMSE > or = 27/30 and amnestic MCI. CONCLUSIONS: The five-predictor combination strongly predicted conversion to AD and was markedly superior to combining age and MMSE. Combining the clinically administered measures also led to strong predictive accuracy. If independently replicated, the findings have potential utility for early detection of AD
— id: 96314, year: 2008, vol: 64, page: 871, stat: Journal Article,

Memantine decreases hippocampal glutamate levels: a magnetic resonance spectroscopy study
Glodzik, Lidia; King, Kevin G; Gonen, Oded; Liu, Songtao; De Santi, Susan; de Leon, Mony J
2008 May 15;32(4):1005-1012, Progress in neuro-psychopharmacology & biological psychiatry
Glutamate (Glu) is associated with excitotoxic cell damage. Memantine modulates the glutamate induced excitotoxicity in Alzheimer's disease (AD). No information is available as to the influence of memantine on in vivo brain glutamate levels. Hippocampal Glu levels were measured in cognitively impaired and normal individuals (n=10) before and after 6 months of memantine treatment, using three dimensional high spatial resolution (0.5 cm(3) voxels) proton magnetic resonance spectroscopy at 3 T. These measurements were also repeated in a non-treated cognitively normal group (n=6). Treatment with memantine decreased Glu/Cr (creatine) ratio in the left hippocampal region. Memantine reduced hippocampal glutamate levels, which may be consistent with its anti-excitotoxic property
— id: 86779, year: 2008, vol: 32, page: 1005, stat: Journal Article,

Inflammation and Alzheimer's disease: possible role of periodontal diseases
Kamer, Angela R; Craig, Ronald G; Dasanayake, Ananda P; Brys, Miroslaw; Glodzik-Sobanska, Lidia; de Leon, Mony J
2008 Jul;4(4):242-250, Alzheimer's & Dementia
The molecular and cellular mechanisms responsible for the etiology and pathogenesis of Alzheimer's disease (AD) have not been defined; however, inflammation within the brain is thought to play a pivotal role. Studies suggest that peripheral infection/inflammation might affect the inflammatory state of the central nervous system. Chronic periodontitis is a prevalent peripheral infection that is associated with gram-negative anaerobic bacteria and the elevation of serum inflammatory markers including C-reactive protein. Recently, chronic periodontitis has been associated with several systemic diseases including AD. In this article we review the pathogenesis of chronic periodontitis and the role of inflammation in AD. In addition, we propose several potential mechanisms through which chronic periodontitis can possibly contribute to the clinical onset and progression of AD. Because chronic periodontitis is a treatable infection, it might be a readily modifiable risk factor for AD
— id: 86780, year: 2008, vol: 4, page: 242, stat: Journal Article,

Alzheimer's disease and peripheral infections: the possible contribution from periodontal infections, model and hypothesis
Kamer, Angela R; Dasanayake, Ananda P; Craig, Ronald G; Glodzik-Sobanska, Lidia; Bry, Miroslow; de Leon, Mony J
2008 May;13(4):437-449, Journal of Alzheimer's Disease
Alzheimer's disease (AD) affects approximately 4.5 million people in the U.S. and this number will increase as the population ages and the life-span increases. Therefore, of paramount importance is identifying mechanisms and factors that affect the risk of developing AD. The etiology and pathogenic mechanisms for AD have not been defined, although inflammation within the brain is thought to play a role. Consistent with this hypothesis, studies suggest that peripheral infections contribute to the inflammatory state of the central nervous system. Periodontitis is a prevalent, persistent peripheral infection associated with gram negative, anaerobic bacteria that are capable of exhibiting localized and systemic infections in the host. This review offers a hypothetical link between periodontitis and AD and will present possible mechanistic links between periodontitis related inflammation and AD. It will review the pathogenesis of periodontitis and the mechanisms by which periodontal infections may affect the onset and progression of AD. Since periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD
— id: 79420, year: 2008, vol: 13, page: 437, stat: Journal Article,

Anteroposterior hippocampal metabolic heterogeneity: three-dimensional multivoxel proton 1H MR spectroscopic imaging--initial findings
King, Kevin G; Glodzik, Lidia; Liu, Songtao; Babb, James S; de Leon, Mony J; Gonen, Oded
2008 Oct;249(1):242-250, Radiology
PURPOSE: To quantify proton magnetic resonance (MR) spectroscopy-detectable metabolite concentrations along anteroposterior axis of hippocampus in healthy young and elderly subjects. MATERIALS AND METHODS: Young (three women, three men; age range, 25-35 years) and elderly (four women, two men; age range, 68-72 years) groups underwent MR imaging and proton MR spectroscopic imaging at 3 T in this HIPAA-compliant prospective study and gave institutional review board-approved written consent. Volume of interest was centered on and tilted parallel to hippocampal anteroposterior plane. Absolute N-acetylaspartate (NAA), choline, and creatine levels were obtained in each voxel, with phantom replacement. RESULTS: Mean NAA, creatine, and choline concentrations in the young group were higher in posterior hippocampus (12.9 mmol/L +/- 2.0 [standard deviation], 7.8 mmol/L +/- 1.2, 2.3 mmol/L +/- 0.4, respectively) than anterior hippocampus (8.0 mmol/L +/- 1.1, 6.0 mmol/L +/- 1.4, 1.5 mmol/L +/- 0.2; P = .005, .02, and .0002, respectively). In the elderly group, mean concentrations were higher in posterior hippocampus (8.6 mmol/L +/- 0.9, 5.6 mmol/L +/- 0.6, 1.5 mmol/L +/- 0.2, respectively) than anterior hippocampus (7.2 mmol/L +/- 1.0, 2.4 mmol/L +/- 0.3, 1.0 mmol/L +/- 0.2; P = .006, .0001, .04, respectively). Mean concentrations were significantly higher in the young group (13.2 mmol/L +/- 1.0, 7.4 mmol/L +/- 0.8, 2.1 mmol/L +/- 0.3, respectively) than in the elderly group (9.0 mmol/L +/- 1.0, 5.8 mmol/L +/- 0.8, 1.8 mmol/L +/- 0.3; P = .0001, .01, .05, respectively). Posteroanterior metabolic gradients differed: NAA decreased faster in the young group (-1.0 mmol/L x cm(-1)) than the elderly group (-0.7 mmol/L x cm(-1)); creatine and choline concentrations decreased faster in the elderly group (-0.8 and -0.058 mmol/L x cm(-1), respectively) than the young group (-0.16 and -0.008 mmol/L x cm(-1), respectively). No left-right metabolic differences were found. CONCLUSION: Significant metabolic heterogeneity was observed between groups and along anteroposterior axis of healthy hippocampus in both groups. Age matching and consistent voxel placement are important for correct comparisons of both absolute metabolic levels and metabolite ratios in longitudinal intra- and intersubject cross-sectional studies
— id: 86781, year: 2008, vol: 249, page: 242, stat: Journal Article,

Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer's disease
Li, Yi; Rinne, Juha O; Mosconi, Lisa; Pirraglia, Elizabeth; Rusinek, Henry; DeSanti, Susan; Kemppainen, Nina; Nagren, Kjell; Kim, Byeong-Chae; Tsui, Wai; de Leon, Mony J
2008 Dec;35(12):2169-2181, European journal of nuclear medicine & molecular imaging
OBJECTIVE: The objective of the study is to compare the diagnostic value of regional sampling of the cerebral metabolic rate of glucose metabolism (MRglc) using [18F]-fluoro-2-deoxyglucose ([18F]FDG)-positron emission tomography (PET) and amyloid-beta pathology using Pittsburgh Compound-B ([11C]PIB)-PET in the evaluation of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) compared to normal elderly (NL). MATERIALS AND METHODS: AD patients, 7 NL, 13 MCI, and 17, received clinical, neuropsychological, magnetic resonance imaging (MRI), FDG, and PIB-PET exams. Parametric images of PIB uptake and MRglc were sampled using automated regions-of-interest (ROI). RESULTS: AD showed global MRglc reductions, and MCI showed reduced hippocampus (HIP) and inferior parietal lobe (IP) MRglc compared to NL. On PIB, AD patients showed significantly increased uptake in the middle frontal gyrus (MFG), posterior cingulate cortex (PCC), and IP (ps < 0.05). PIB uptake in MCI subjects was either AD or NL-like. HIP MRglc and MFG PIB uptake were the best discriminators of NL from MCI and NL from AD. These two best measures showed high diagnostic agreement for AD (94%) and poor agreement for MCI (54%). For the NL vs. MCI discrimination, combining the two best measures increased the accuracy for PIB (75%) and for FDG (85%) to 90%. CONCLUSION: For AD, the pattern of regional involvement for FDG and PIB differ, but both techniques show high diagnostic accuracy and 94% case by case agreement. In the classification of NL and MCI, FDG is superior to PIB, but there is only 54% agreement at a case level. Combining the two modalities improves the diagnostic accuracy for MCI
— id: 96315, year: 2008, vol: 35, page: 2169, stat: Journal Article,

Hypometabolism and altered cerebrospinal fluid markers in normal apolipoprotein E E4 carriers with subjective memory complaints
Mosconi, Lisa; De Santi, Susan; Brys, Miroslaw; Tsui, Wai H; Pirraglia, Elizabeth; Glodzik-Sobanska, Lidia; Rich, Kenneth E; Switalski, Remigius; Mehta, Pankaj D; Pratico, Domenico; Zinkowski, Ray; Blennow, Kay; de Leon, Mony J
2008 Mar 15;63(6):609-618, Biological psychiatry
BACKGROUND: We examined whether cerebral metabolic rates for glucose (CMRglc) on 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) and cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) are altered in cognitively normal apolipoprotein E (ApoE) E4 carriers with subjective memory complaints (SMC). METHODS: Twenty-eight middle-aged normal subjects (NL) were examined, including 13 E4 carriers (E4+; 6 with SMC [SMC+] and 7 without SMC [SMC-]) and 15 noncarriers (E4-; 7 SMC+ and 8 SMC-). Subjects received an FDG-PET scan and a lumbar puncture to measure CSF total (T-Tau) and hyperphosphorylated tau(231) (P-Tau), 40 and 42 amino acid forms of beta-amyloid (Abeta40 and Abeta42), and F(2)-isoprostane (IP). RESULTS: As compared with E4-, E4+ subjects showed decreased CMRglc in AD-related brain regions and associated higher CSF IP, P-Tau, T-Tau, and P-Tau/Abeta42 levels (p's < .05). As compared with SMC-, SMC+ subjects showed reduced parietotemporal and parahippocampal gyrus (PHG) CMRglc. A significant ApoE by SMC status interaction was found, with the E4+/SMC+ showing the lowest PHG CMRglc and the highest CSF IP, P-Tau, and P-Tau/Abeta42 levels as compared with all other subgroups (p's < or = .05). The combination of CSF and CMRglc measures significantly improved the accuracy of either measures alone in discriminating ApoE groups (86% accuracy, odds ratio [OR] = 4.1, p < .001) and E4+/SMC+ from all other subgroups (86% accuracy, OR = 3.7, p = .005). Parahippocampal gyrus CMRglc was the most accurate discriminator of SMC groups (75% accuracy, OR = 2.4, p < .001). CONCLUSIONS: Normal E4 carriers with SMC show altered AD-related CSF and FDG-PET measures. Longitudinal studies are needed to assess whether these brain abnormalities foreshadow clinical decline
— id: 78013, year: 2008, vol: 63, page: 609, stat: Journal Article,

Hippocampal hypometabolism predicts cognitive decline from normal aging
Mosconi, Lisa; De Santi, Susan; Li, Juan; Tsui, Wai Hon; Li, Yi; Boppana, Madhu; Laska, Eugene; Rusinek, Henry; de Leon, Mony J
2008 May;29(5):676-692, Neurobiology of aging
OBJECTIVE: This longitudinal study used FDG-PET imaging to predict and monitor cognitive decline from normal aging. METHODS: Seventy-seven 50-80-year-old normal (NL) elderly received longitudinal clinical examinations over 6-14 years (561 person-years, mean per person 7.2 years). All subjects had a baseline FDG-PET scan and 55 subjects received follow-up PET exams. Glucose metabolic rates (MRglc) in the hippocampus and cortical regions were examined as predictors and correlates of clinical decline. RESULTS: Eleven NL subjects developed dementia, including six with Alzheimer's disease (AD), and 19 declined to mild cognitive impairment (MCI), on average 8 years after the baseline exam. The baseline hippocampal MRglc predicted decline from NL to AD (81% accuracy), including two post-mortem confirmed cases, from NL to other dementias (77% accuracy), and from NL to MCI (71% accuracy). Greater rates of hippocampal and cortical MRglc reductions were found in the declining as compared to the non-declining NL. CONCLUSIONS: Hippocampal MRglc reductions using FDG-PET during normal aging predict cognitive decline years in advance of the clinical diagnosis. Future studies are needed to increase preclinical specificity in differentiating dementing disorders
— id: 70030, year: 2008, vol: 29, page: 676, stat: Journal Article,

Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer's disease
Mosconi, Lisa; Pupi, Alberto; De Leon, Mony J
2008 Dec;1147:180-195, Annals of the New York Academy of Sciences
One of the main features of Alzheimer's disease (AD) is the severe reduction of the cerebral metabolic rate for glucose (CMRglc). In vivo imaging using positron emission tomography with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG-PET) demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. Increasing evidence suggests that CMRglc reductions occur at the preclinical stages of AD. CMRglc reductions were observed on FDG-PET before the onset of disease in several groups of at-risk individuals, including patients with mild cognitive impairment (MCI), often a prodrome to AD; presymptomatic individuals carrying mutations responsible for early-onset familial AD; cognitively normal elderly individuals followed for several years until they declined to MCI and eventually to AD; normal, middle-aged individuals who expressed subjective memory complaints and were carriers of the apolipoprotein E epsilon-4 allele, a strong genetic risk factor for late-onset AD. However, the causes of the early metabolic dysfunction forerunning the onset of AD are not known. An increasing body of evidence indicates a deficient or altered energy metabolism that could change the overall oxidative microenvironment for neurons during the pathogenesis and progression of AD, leading to alterations in mitochondrial enzymes and in glucose metabolism in AD brain tissue. The present paper reviews findings that implicate hypometabolism and oxidative stress as crucial players in the initiation and progression of synaptic pathology in AD
— id: 91465, year: 2008, vol: 1147, page: 180, stat: Journal Article,

Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias
Mosconi, Lisa; Tsui, Wai H; Herholz, Karl; Pupi, Alberto; Drzezga, Alexander; Lucignani, Giovanni; Reiman, Eric M; Holthoff, Vjera; Kalbe, Elke; Sorbi, Sandro; Diehl-Schmid, Janine; Perneczky, Robert; Clerici, Francesca; Caselli, Richard; Beuthien-Baumann, Bettina; Kurz, Alexander; Minoshima, Satoshi; de Leon, Mony J
2008 Mar;49(3):390-398, Journal of nuclear medicine
This multicenter study examined (18)F-FDG PET measures in the differential diagnosis of Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) from normal aging and from each other and the relation of disease-specific patterns to mild cognitive impairment (MCI). METHODS: We examined the (18)F-FDG PET scans of 548 subjects, including 110 healthy elderly individuals ('normals' or NLs), 114 MCI, 199 AD, 98 FTD, and 27 DLB patients, collected at 7 participating centers. Individual PET scans were Z scored using automated voxel-based comparison with generation of disease-specific patterns of cortical and hippocampal (18)F-FDG uptake that were then applied to characterize MCI. RESULTS: Standardized disease-specific PET patterns were developed that correctly classified 95% AD, 92% DLB, 94% FTD, and 94% NL. MCI patients showed primarily posterior cingulate cortex and hippocampal hypometabolism (81%), whereas neocortical abnormalities varied according to neuropsychological profiles. An AD PET pattern was observed in 79% MCI with deficits in multiple cognitive domains and 31% amnesic MCI. (18)F-FDG PET heterogeneity in MCI with nonmemory deficits ranged from absent hypometabolism to FTD and DLB PET patterns. CONCLUSION: Standardized automated analysis of (18)F-FDG PET scans may provide an objective and sensitive support to the clinical diagnosis in early dementia
— id: 79093, year: 2008, vol: 49, page: 390, stat: Journal Article,

Mild cognitive impairment (MCI): a historical perspective
Reisberg, Barry; Ferris, Steven H; Kluger, Alan; Franssen, Emile; Wegiel, Jerzy; de Leon, Mony J
2008 Feb;20(1):18-31, International psychogeriatrics
Descriptions of dementia can be traced to antiquity. Prichard (1837) described four dementia stages and Kral (1962) described a 'benign senescent forgetfulness' condition. The American Psychiatric Association's DSM-III (1980) identified an early dementia stage.In 1982, the Clinical Dementia Rating (CDR) and the Global Deterioration Scale (GDS) were published, which identified dementia antecedents. The CDR 0.5 'questionable dementia' stage encompasses both mild dementia and earlier antecedents. GDS stage 3 described a predementia condition termed 'mild cognitive decline' or, alternatively, beginning in 1988, 'mild cognitive impairment' (MCI). This GDS stage 3 MCI condition is differentiated from both a preceding GDS stage 2, 'subjective cognitive impairment' (SCI) stage and a subsequent GDS 4 stage of mild dementia.GDS stage 3 MCI has been well characterized. For example, specific clinical concomitants, mental status and psychological assessment score ranges, behavioral and emotional changes, neuroimaging concomitants, neurological reflex changes, electrophysiological changes, motor and coordination changes, and changes in activities, accompanying GDS stage 3 MCI have been described.Petersen and associates proposed a definition of MCI in 2001 which has been widely used (hereafter referred to as 'Petersen's MCI'). Important differences between GDS stage 3 MCI and Petersen's MCI are that, because of denial, GDS stage 3 MCI does not require memory complaints. Also, GDS stage 3 MCI recognizes the occurrence of executive level functional deficits, which Petersen's MCI did not. Nevertheless, longitudinal and other studies indicate essential compatibility between GDS stage 3 MCI and Petersen's MCI duration and outcomes
— id: 78351, year: 2008, vol: 20, page: 18, stat: Journal Article,

The pre-mild cognitive impairment, subjective cognitive impairment stage of Alzheimer's disease
Reisberg, Barry; Prichep, Leslie; Mosconi, Lisa; John, E Roy; Glodzik-Sobanska, Lidia; Boksay, Istvan; Monteiro, Isabel; Torossian, Carol; Vedvyas, Alok; Ashraf, Nauman; Jamil, Imran A; de Leon, Mony J
2008 Jan;4(1 Suppl 1):S98-S108, Alzheimer's & Dementia
BACKGROUND: Subjective cognitive impairment (SCI) has been a common, but poorly understood condition, frequently occurring in older persons. METHODS: The past and the emerging literature on SCI and synonymously named conditions is reviewed. RESULTS: Findings include: (1) There is support from at least one longitudinal study for a long-standing concept of SCI as a pre-mild cognitive impairment (MCI) condition lasting approximately 15years. (2) There are complex relationships between SCI and depression and anxiety. (3) Differences in SCI subjects from age-matched non-SCI persons are being published in terms of cognitive tests, hippocampal gray matter density, hippocampal volumes, cerebral metabolism, and urinary cortisol levels. Psychometric and dementia test score differences between SCI and MCI subjects have long been evident. (4) Predictive electrophysiologic features of subsequent decline in SCI subjects are being published. CONCLUSIONS: Studies of therapeutic agents in SCI treatment and resultant Alzheimer's disease prevention appear to be feasible. These trials are also necessary from a public health perspective
— id: 81577, year: 2008, vol: 4, page: S98, stat: Journal Article,

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice
Sigurdsson, Einar M; Wadghiri, Youssef Z; Mosconi, Lisa; Blind, Jeffrey A; Knudsen, Elin; Asuni, Ayodeji; Scholtzova, Henrieta; Tsui, Wai H; Li, Yongsheng; Sadowski, Martin; Turnbull, Daniel H; de Leon, Mony J; Wisniewski, Thomas
2008 Jun;29(6):836-847, Neurobiology of aging
Amyloid plaques are a characteristic feature in Alzheimer's disease (AD). A novel non-toxic contrast agent is presented, Gd-DTPA-K6Abeta1-30, which is homologous to Abeta, and allows plaque detection in vivo. muMRI was performed on AD model mice and controls prior to and following intracarotid injection with Gd-DTPA-K6Abeta1-30 in mannitol solution, to transiently open the blood-brain barrier. A gradient echo T2(*)-weighted sequence was used to provide 100mum isotropic resolution with imaging times of 115min. The scans were examined with voxel-based analysis (VBA) using statistical parametric mapping, for un-biased quantitative comparison of ligand-injected mice and controls. The results indicate that: (1) Gd-DTPA-K6Abeta1-30 is an effective, non-toxic, ligand for plaque detection when combined with VBA (p</=0.01-0.001), comparing pre and post-ligand injection scans. (2) Large plaques can be detected without the use of a contrast agent and this detection co-localizes with iron deposition. (3) Smaller, earlier plaques require contrast ligand for MRI visualization. Our ligand when combined with VBA may be useful for following therapeutic approaches targeting amyloid in transgenic mouse models
— id: 71031, year: 2008, vol: 29, page: 836, stat: Journal Article,

The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome
Wegiel, Jerzy; Dowjat, Karol; Kaczmarski, Wojciech; Kuchna, Izabela; Nowicki, Krzysztof; Frackowiak, Janusz; Mazur Kolecka, Bozena; Wegiel, Jarek; Silverman, Wayne P; Reisberg, Barry; Deleon, Mony; Wisniewski, Thomas; Gong, Cheng-Xin; Liu, Fei; Adayev, Tatyana; Chen-Hwang, Mo-Chou; Hwang, Yu-Wen
2008 Oct;116(4):391-407, Acta neuropathologica
The gene encoding the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A (DYRK1A) is located in the Down syndrome (DS) critical region of chromosome 21. The third copy of DYRK1A is believed to contribute to abnormal brain development in patients with DS. In vitro studies showing that DYRK1A phosphorylates tau protein suggest that this kinase is also involved in tau protein phosphorylation in the human brain and contributes to neurofibrillary degeneration, and that this contribution might be enhanced in patients with DS. To explore this hypothesis, the brain tissue from 57 subjects including 16 control subjects, 21 patients with DS, and 20 patients with sporadic Alzheimer's disease (AD) was examined with two antibodies to the amino-terminus of DYRK1A (7F3 and G-19), as well as two polyclonal antibodies to its carboxy-terminus (X1079 and 324446). Western blots demonstrated higher levels of full-length DYRK1A in the brains of patients with DS when compared to control brains. Immunocytochemistry revealed that DYRK1A accumulates in neurofibrillary tangles (NFTs) in subjects with sporadic AD and in subjects with DS/AD. Overexpression of DYRK1A in patients with DS was associated with an increase in DYRK1A-positive NFTs in a gene dosage-dependent manner. Results support the hypothesis that overexpressed DYRK1A contributes to neurofibrillary degeneration in DS more significantly than in subjects with two copies of the DYRK1A gene and sporadic AD. Immunoreactivity with antibodies against DYRK1A not only in NFTs but also in granules in granulovacuolar degeneration and in corpora amylacea suggests that DYRK1A is involved in all three forms of degeneration and that overexpression of this kinase may contribute to the early onset of these pathologies in DS
— id: 80400, year: 2008, vol: 116, page: 391, stat: Journal Article,

Annals of the New York Academy of Sciences: Foreword
De Leon MJ; de Leon MJ (Ed); Snider DA (Ed); Federoff H (Ed)
2007 ;1097:xi-xii=, Annals of the New York Academy of Sciences
— id: 73351, year: 2007, vol: 1097, page: xi, stat: Journal Article,

Imaging and CSF studies in the preclinical diagnosis of Alzheimer's disease
de Leon, M J; Mosconi, L; Blennow, K; DeSanti, S; Zinkowski, R; Mehta, P D; Pratico, D; Tsui, W; Saint Louis, L A; Sobanska, L; Brys, M; Li, Y; Rich, K; Rinne, J; Rusinek, H
2007 Feb;1097:114-145, Annals of the New York Academy of Sciences
It is widely believed that the path to early and effective treatment for Alzheimer's disease (AD) requires the development of early diagnostic markers that are both sensitive and specific. To this aim, using longitudinal study designs, we and others have examined magnetic resonance imaging (MRI), 2-fluoro-2-deoxy-d-glucose-positron emission tomography (FDG/PET), and cerebrospinal fluid (CSF) biomarkers in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI). Such investigations have led to the often replicated findings that structural evidence of hippocampal atrophy as determined by MRI, as well as metabolic evidence from FDG-PET scan of hippocampal damage, predicts the conversion from MCI to AD. In this article we present a growing body of evidence of even earlier diagnosis. Brain pathology can be detected in NL subjects and used to predict future transition to MCI. This prediction is enabled by examinations revealing reduced glucose metabolism in the hippocampal formation (hippocampus and entorhinal cortex [EC]) as well as by the rate of medial temporal lobe atrophy as determined by MRI. However, neither regional atrophy nor glucose metabolism reductions are specific for AD. These measures provide secondary not primary evidence for AD. Consequently, we will also summarize recent efforts to improve the diagnostic specificity by combining imaging with CSF biomarkers and most recently by evaluating amyloid imaging using PET. We conclude that the combined use of conventional imaging, that is MRI or FDG-PET, with selected CSF biomarkers incrementally contributes to the early and specific diagnosis of AD. Moreover, selected combinations of imaging and CSF biomarkers measures are of importance in monitoring the course of AD and thus relevant to evaluating clinical trials
— id: 71870, year: 2007, vol: 1097, page: 114, stat: Journal Article,

Longitudinal CSF isoprostane and MRI atrophy in the progression to AD
de Leon, M J; Mosconi, L; Li, J; De Santi, S; Yao, Y; Tsui, W H; Pirraglia, E; Rich, K; Javier, E; Brys, M; Glodzik, L; Switalski, R; Saint Louis, L A; Pratico, D
2007 Dec;254(12):1666-1675, Journal of neurology
Very little data exist to evaluate the value of longitudinal CSF biological markers for Alzheimer's disease (AD).Most studies indicate that tau and amyloid beta markers do not reflect disease progression. We now report on a longitudinal, three-time point, CSF Isoprostane (IsoP) and quantitative MRI study that examined 11 normal elderly (NL) volunteers and 6 Mild Cognitive Impairment (MCI) patients. After 4 years, all 6 MCI patients declined to AD and 2 of the NL subjects declined to MCI. At baseline and longitudinally, the MCI patients showed reduced delayed memory, increased IsoP levels, and reduced medial temporal lobe gray matter concentrations as compared to NL. A group comprised of all decliners to AD or to MCI (n = 8) was distinguished at baseline from the stable NL controls (n = 9) by IsoP with 100% accuracy.Moreover, both at baseline and longitudinally, the IsoP measures significantly improved the diagnostic and predictive outcomes of conventional memory testing and quantitative MRI measurements. These data indicate that IsoP is potentially useful for both the early detection of AD-related pathology and for monitoring the course of AD
— id: 78349, year: 2007, vol: 254, page: 1666, stat: Journal Article,

Imaging and CSF studies in the preclinical diagnosis of Alzheimer's disease
de Leon, M. J; Mosconi, L; Blennow, K; DeSanti, S; Zinkowski, R; Mehta, P. D; Pratico, D; Tsui, W; Saint Louis, L. A; Sobanska, L; Brys, M; Li, Y; Rich, K; Rinne, J; Rusinek, H
Imaging and the aging brain Malden, MA, US: Blackwell Publishing, 2007,
(from the chapter) It is widely believed that the path to early and effective treatment for Alzheimer's disease (AD) requires the development of early diagnostic markers that are both sensitive and specific. To this aim, using longitudinal study designs, we and others have examined magnetic resonance imaging (MRI), 2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG/PET), and cerebrospinal fluid (CSF) biomarkers in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI). Such investigations have led to the often replicated findings that structural evidence of hippocampal atrophy as determined by MRI, as well as metabolic evidence from FDG-PET scan of hippocampal damage, predicts the conversion from MCI to AD. In this article we present a growing body of evidence of even earlier diagnosis. Brain pathology can be detected in NL subjects and used to predict future transition to MCI. This prediction is enabled by examinations revealing reduced glucose metabolism in the hippocampal formation (hippocampus and entorhinal cortex [EC]) as well as by the rate of medial temporal lobe atrophy as determined by MRI. However, neither regional atrophy nor glucose metabolism reductions are specific for AD. These measures provide secondary not primary evidence for AD. Consequently, we will also summarize recent efforts to improve the diagnostic specificity by combining imaging with CSF biomarkers and most recently by evaluating amyloid imaging using PET. We conclude that the combined use of conventional imaging, that is MRI or FDG-PET, with selected CSF biomarkers incrementally contributes to the early and specific diagnosis of AD. Moreover, selected combinations of imaging and CSF biomarkers measures are of importance in monitoring the course of AD and thus relevant to evaluating clinical trials.
— id: 4482, year: 2007, vol: , page: 114, stat: Chapter,

Seeing what Alzheimer saw
de Leon, Mony J; Mosconi, Lisa; Logan, Jean
2007 Feb;13(2):129-131, Nature medicine
— id: 71230, year: 2007, vol: 13, page: 129, stat: Journal Article,

Imaging and the aging brain
de Leon, Mony J; Snider, Donald A; Federoff, Howard
Malden, MA, US: Blackwell Publishing, 2007,
(from the foreword) We have produced a summary that captures the current breadth of in vivo imaging technologies as applied to the neurobiology of brain aging and Alzheimer's disease. In addition, Judy Illes was invited to contribute a chapter on the ethical challenges associated with brain imaging. This Annals issue is divided into three sections: basic cellular and animal systems studies; normal human aging and transitions to cognitive impairment; and diagnostic applications of imaging to Alzheimer's disease. We envision that the knowledge acquired by imaging at cellular and mechanistic levels will translate to further improvements in the use of imaging for the early sensitive and specific clinical diagnoses of age-related cognitive disorders. While we trust that the scholarly contributions herein are continuously being updated, our still unrealized goal is to apply early diagnosis in the service of preventing symptomatic expression of those brain diseases that affect the quality of life of so many older individuals.
— id: 1339, year: 2007, vol: , page: , stat: ,

Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease
Devanand, D P; Pradhaban, G; Liu, X; Khandji, A; De Santi, S; Segal, S; Rusinek, H; Pelton, G H; Honig, L S; Mayeux, R; Stern, Y; Tabert, M H; de Leon, M J
2007 Mar 13;68(11):828-836, Neurology
OBJECTIVE: To evaluate the utility of MRI hippocampal and entorhinal cortex atrophy in predicting conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). METHODS: Baseline brain MRI was performed in 139 patients with MCI, broadly defined, and 63 healthy controls followed for an average of 5 years (range 1 to 9 years). RESULTS: Hippocampal and entorhinal cortex volumes were each largest in controls, intermediate in MCI nonconverters, and smallest in MCI converters to AD (37 of 139 patients converted to AD). In separate Cox proportional hazards models, covarying for intracranial volume, smaller hippocampal volume (risk ratio [RR] 3.62, 95% CI 1.93 to 6.80, p < 0.0001), and entorhinal cortex volume (RR 2.43, 95% CI 1.56 to 3.79, p < 0.0001) each predicted time to conversion to AD. Similar results were obtained for hippocampal and entorhinal cortex volume in patients with MCI with Mini-Mental State Examination (MMSE) scores > or = 27 out of 30 (21% converted to AD) and in the subset of patients with amnestic MCI (35% converted to AD). In the total patient sample, when both hippocampal and entorhinal volume were entered into an age-stratified Cox model with sex, MMSE, education, and intracranial volume, smaller hippocampal volume (RR 2.21, 95% CI 1.14 to 4.29, p < 0.02) and entorhinal cortex volume (RR 2.48, 95% CI 1.54 to 3.97, p < 0.0002) predicted time to conversion to AD. Similar results were obtained in a Cox model that also included Selective Reminding Test (SRT) delayed recall and Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol as predictors. Based on logistic regression models in the 3-year follow-up sample, for a fixed specificity of 80%, the sensitivities for MCI conversion to AD were as follows: age 43.3%, MMSE 43.3%, age + MMSE 63.7%, age + MMSE + SRT delayed recall + WAIS-R Digit Symbol 80.6% (79.6% correctly classified), hippocampus + entorhinal cortex 66.7%, age + MMSE + hippocampus + entorhinal cortex 76.7% (85% correctly classified), age + MMSE + SRT delayed recall + WAIS-R Digit Symbol + hippocampus + entorhinal cortex 83.3% (86.8% correctly classified). CONCLUSIONS: Smaller hippocampal and entorhinal cortex volumes each contribute to the prediction of conversion to Alzheimer disease. Age and cognitive variables also contribute to prediction, and the added value of hippocampal and entorhinal cortex volumes is small. Nonetheless, combining these MRI volumes with age and cognitive measures leads to high levels of predictive accuracy that may have potential clinical application
— id: 71973, year: 2007, vol: 68, page: 828, stat: Journal Article,

Prefrontal N-acetylaspartate and poststroke recovery: a longitudinal proton spectroscopy study
Glodzik-Sobanska, L; Li, J; Mosconi, L; Slowik, A; Walecki, J; Szczudlik, A; Sobiecka, B; de Leon, M J
2007 Mar;28(3):470-474, AJNR. American journal of neuroradiology
BACKGROUND AND PURPOSE: Functional imaging studies suggest that poststroke recovery is related to the reorganization in both contralesional and ipsilesional prefrontal cortex. Little is known, however, about how longitudinal metabolic changes in prefrontal regions relate to the improvement after stroke. We sought to determine whether poststroke recovery is associated with changes in N-acetylaspartate/creatine (NAA/Cr) ratio within contralesional prefrontal regions. MATERIALS AND METHODS: Twenty-seven patients with a first ischemic stroke located outside the frontal lobes were included. Proton MR spectroscopy ((1)H-MRS) was performed on a 1.5T scanner. Point-resolved spectroscopy sequence (PRESS) was used. NAA/Cr was measured both in ipsilesional and contralesional prefrontal regions in early (14 +/- 6 days after stroke) and chronic phases of the disease (110 +/- 30 days after). Patients' neurologic status was assessed using Scandinavian Stroke Scale (SSS) at discharge from the stroke unit and during second (1)H-MRS examination. RESULTS: Subjects showing increased contralesional NAA/Cr from first to follow-up examination improved significantly more on the SSS than patients not showing this increase. Analysis was performed while correcting for change in NAA/Cr levels in the ipsilesional hemisphere. For the whole group, the change in contralesional NAA/Cr was significantly correlated to the change in SSS scores (r = 0.40, P = .03). Change in the ipsilesional NAA/Cr measures did not correlate with the change in SSS scores. CONCLUSION: Poststroke recovery was related to the increase in contralesional prefrontal NAA/Cr. This association may reflect recovery mechanisms involving the nonaffected hemisphere. Further assessment of these regions may provide information about mechanisms contributing to neurologic improvement
— id: 71587, year: 2007, vol: 28, page: 470, stat: Journal Article,

Subjective memory complaints: presence, severity and future outcome in normal older subjects
Glodzik-Sobanska, Lidia; Reisberg, Barry; De Santi, Susan; Babb, James S; Pirraglia, Elizabeth; Rich, Kenneth E; Brys, Miroslaw; de Leon, Mony J
2007 ;24(3):177-184, Dementia geriatric & cognitive disorders
Background/Aims: Subjective memory complaint (SMC) in normal individuals may predict future cognitive decline. The goal of this study was to examine whether the probability of decline increases with growing intensity of complaint. Methods: Normal subjects over the age of 50 years were included in a longitudinal retrospective study (mean follow-up time = 8 years). All subjects (n = 230) underwent cognitive and medical examination at baseline. The presence of SMC was determined based on Global Deterioration Scale staging. A subgroup of 83 participants also received baseline assessment for the intensity of SMC. Logistic regression was used to predict outcome from baseline variables. Three outcome groups were established at the final visit: nondeclining, declining and diagnostically unstable (i.e. the diagnosis changed over time: from normal to mild cognitive impairment, then back to normal). Results: The presence of SMC was a predictor of future decline but also increased the likelihood of the unstable diagnosis. Increasing intensity of SMC did not further raise the risk for decline. High intensity of complaints and more pronounced affective symptoms predicted the unstable clinical diagnosis. Conclusions: The presence of SMC contributes to the risk of future decline, however, the increasing intensity of the perceived impairment does not further enhance the risk.
— id: 73937, year: 2007, vol: 24, page: 177, stat: Journal Article,

Early detection of Alzheimer's disease using neuroimaging
Mosconi, Lisa; Brys, Miroslaw; Glodzik-Sobanska, Lidia; De Santi, Susan; Rusinek, Henry; de Leon, Mony J
2007 Jan-Feb;42(1-2):129-138, Experimental gerontology
Neuroimaging is being increasingly used to complement clinical assessments in the early detection of Alzheimer's disease (AD). Structural magnetic resonance imaging (MRI) and metabolic positron emission tomography (FDG-PET) are the most clinically used and promising modalities to detect brain abnormalities in individuals who might be at risk for AD but who have not yet developed symptoms. The knowledge of established risk factors for AD enabled investigators to develop enrichment strategies for longitudinal imaging studies to reduce the sample sizes and study duration. The present review focuses on the results obtained by MRI and FDG-PET studies that examined the preclinical AD stages in several at risk populations: (1) individuals from families with autosomal dominant early-onset AD (FAD), (2) patients with mild cognitive impairment (MCI), particularly in memory, who are at very high risk for declining to AD with an estimated decline rate of 10-30% per year, (3) normal young and middle-age subjects carriers of known susceptibility genes for late-onset AD such as the Apolipoprotein E (ApoE) E4 allele, and (4) as age is the main risk factor for AD, normal elderly individuals followed to the onset of MCI and AD. Overall, these studies show that the use of imaging for the early detection of AD is successful even in the earlier stages of disease when clinical symptoms are not fully expressed and the regional brain damage may be limited
— id: 70031, year: 2007, vol: 42, page: 129, stat: Journal Article,

Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism
Mosconi, Lisa; Brys, Miroslaw; Switalski, Remigiusz; Mistur, Rachel; Glodzik, Lidia; Pirraglia, Elizabeth; Tsui, Wai; De Santi, Susan; de Leon, Mony J
2007 Nov 27;104(48):19067-19072, Proceedings of the National Academy of Sciences of the United States of America
Having a parent affected with late-onset Alzheimer's disease (AD) is a risk factor for developing AD among cognitively normal subjects. We examined whether cognitively normal subjects with a parental family history of AD show cerebral metabolic rate of glucose (CMRglc) reductions consistent with AD as compared with those without a family history and whether there are parent gender effects. Forty-nine 50- to 80-year-old normal subjects were examined who received clinical, neuropsychological, and 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography examinations, including 16 subjects with a maternal (FHm) and eight with a paternal (FHp) family history of AD and 25 with no family history (FH(-)). FH groups were comparable for demographic and neuropsychological measures. As compared with both FH(-) and FHp groups, FHm subjects showed CMRglc reductions in the same regions as clinically affected AD patients, involving the posterior cingulate cortex/precuneus, parietotemporal and frontal cortices, and medial temporal lobes (P < 0.05, corrected for multiple comparisons). These effects remained significant after accounting for possible risk factors for AD, including age, gender, education, apolipoprotein E genotype, and subjective memory complaints. No CMRglc differences were found between FHp and FH(-) subjects. This study shows a relationship between reduced CMRglc in AD-vulnerable brain regions and a maternal family history of AD in cognitively normal individuals
— id: 75484, year: 2007, vol: 104, page: 19067, stat: Journal Article,

Quantitation, regional vulnerability, and kinetic modeling of brain glucose metabolism in mild Alzheimer's disease
Mosconi, Lisa; Tsui, Wai H; Rusinek, Henry; De Santi, Susan; Li, Yi; Wang, Gene-Jack; Pupi, Alberto; Fowler, Joanna; de Leon, Mony J
2007 Sep;34(9):1467-1479, European journal of nuclear medicine & molecular imaging
PURPOSE: To examine CMRglc measures and corresponding glucose transport (K (1) and k (2)) and phosphorylation (k (3)) rates in the medial temporal lobe (MTL, comprising the hippocampus and amygdala) and posterior cingulate cortex (PCC) in mild Alzheimer's disease (AD). METHODS: Dynamic FDG PET with arterial blood sampling was performed in seven mild AD patients (age 68 +/- 8 years, four females, median MMSE 23) and six normal (NL) elderly (age 69 +/- 9 years, three females, median MMSE 30). Absolute CMRglc (mumol/100 g/min) was calculated from MRI-defined regions of interest using multiparametric analysis with individually fitted kinetic rate constants, Gjedde-Patlak plot, and Sokoloff's autoradiographic method with population-based rate constants. Relative ROI/pons CMRglc (unitless) was also examined. RESULTS: With all methods, AD patients showed significant CMRglc reductions in the hippocampus and PCC, and a trend towards reduced parietotemporal CMRglc, as compared with NL. Significant k (3) reductions were found in the hippocampus, PCC and amygdala. K (1) reductions were restricted to the hippocampus. Relative CMRglc had the largest effect sizes in separating AD from NL. However, the magnitude of CMRglc reductions was 1.2- to 1.9-fold greater with absolute than with relative measures. CONCLUSION: CMRglc reductions are most prominent in the MTL and PCC in mild AD, as detected with both absolute and relative CMRglc measures. Results are discussed in terms of clinical and pharmaceutical applicability
— id: 71229, year: 2007, vol: 34, page: 1467, stat: Journal Article,

(18)F-FDG PET database of longitudinally confirmed healthy elderly individuals improves detection of mild cognitive impairment and Alzheimer's disease
Mosconi, Lisa; Tsui, Wai Hon; Pupi, Alberto; De Santi, Susan; Drzezga, Alexander; Minoshima, Satoshi; de Leon, Mony J
2007 Jul;48(7):1129-1134, Journal of nuclear medicine
The normative reference sample is crucial for the diagnosis of Alzheimer's disease (AD) with automated (18)F-FDG PET analysis. We tested whether an (18)F-FDG PET database of longitudinally confirmed healthy elderly individuals ('normals,' or NLs) would improve diagnosis of AD and mild cognitive impairment (MCI). METHODS: Two (18)F-FDG PET databases of 55 NLs with 4-y clinical follow-up examinations were created: one of NLs who remained NL, and the other including a fraction of NLs who declined to MCI at follow-up. Each (18)F-FDG PET scan of 19 NLs, 37 MCI patients, and 33 AD patients was z scored using automated voxel-based comparison to both databases and examined for AD-related abnormalities. RESULTS: Our database of longitudinally confirmed NLs yielded 1.4- to 2-fold higher z scores than did the mixed database in detecting (18)F-FDG PET abnormalities in both the MCI and the AD groups. (18)F-FDG PET diagnosis using the longitudinal NL database identified 100% NLs, 100% MCI patients, and 100% AD patients, which was significantly more accurate for MCI patients than with the mixed database (100% NLs, 68% MCI patients, and 94% AD patients identified). CONCLUSION: Our longitudinally confirmed NL database constitutes reliable (18)F-FDG PET normative values for MCI and AD
— id: 73701, year: 2007, vol: 48, page: 1129, stat: Journal Article,

Intraneuronal Abeta immunoreactivity is not a predictor of brain amyloidosis-beta or neurofibrillary degeneration
Wegiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof; Frackowiak, Janusz; Mazur-Kolecka, Bozena; Imaki, Humi; Wegiel, Jarek; Mehta, Pankaj D; Silverman, Wayne P; Reisberg, Barry; Deleon, Mony; Wisniewski, Thomas; Pirttilla, Tuula; Frey, Harry; Lehtimaki, Terho; Kivimaki, Tarmo; Visser, Frank E; Kamphorst, Wouter; Potempska, Anna; Bolton, David; Currie, Julia R; Miller, David L
2007 Apr;113(4):389-402, Acta neuropathologica
Amyloid beta (Abeta) immunoreactivity in neurons was examined in brains of 32 control subjects, 31 people with Down syndrome, and 36 patients with sporadic Alzheimer's disease to determine if intraneuronal Abeta immunoreactivity is an early manifestation of Alzheimer-type pathology leading to fibrillar plaque formation and/or neurofibrillary degeneration. The appearance of Abeta immunoreactivity in neurons in infants and stable neuron-type specific Abeta immunoreactivity in a majority of brain structures during late childhood, adulthood, and normal aging does not support this hypothesis. The absence or detection of only traces of reaction with antibodies against 4-13 aa and 8-17 aa of Abeta in neurons indicated that intraneuronal Abeta was mainly a product of alpha- and gamma-secretases (Abeta(17-40/42)). The presence of N-terminally truncated Abeta(17-40) and Abeta(17-42) in the control brains was confirmed by Western blotting and the identity of Abeta(17-40) was confirmed by mass spectrometry. The prevalence of products of alpha- and gamma -secretases in neurons and beta- and gamma-secretases in plaques argues against major contribution of Abeta-immunopositive material detected in neuronal soma to amyloid deposit in plaques. The strongest intraneuronal Abeta(17-42) immunoreactivity was observed in structures with low susceptibility to fibrillar Abeta deposition, neurofibrillary degeneration, and neuronal loss compared to areas more vulnerable to Alzheimer-type pathology. These observations indicate that the intraneuronal Abeta immunoreactivity detected in this study is not a predictor of brain amyloidosis or neurofibrillary degeneration. The constant level of Abeta immunoreactivity in structures free from neuronal pathology during essentially the entire life span suggests that intraneuronal amino-terminally truncated Abeta represents a product of normal neuronal metabolism
— id: 71032, year: 2007, vol: 113, page: 389, stat: Journal Article,

Alzheimer's disease
Blennow, Kaj; de Leon, Mony J; Zetterberg, Henrik
2006 Jul 29;368(9533):387-403, Lancet
Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies
— id: 71966, year: 2006, vol: 368, page: 387, stat: Journal Article,

Cerebrospinal fluid biomarkers for mild cognitive impairment
Brys M; Mosconi L; De Santi S; Rich K; de Leon MJ
2006 ;2(1):111-121, Aging Health
This article discusses the current knowledge on the most promising cerebrospinal fluid diagnostic biomarkers for mild cognitive impairment and early Alzheimer's disease. The considered biomarkers include total and phosphorylated Tau proteins, 40- and 42-residue forms of amyloid beta and isoprostanes. Both the biological rationales and validation histories for each of the cerebrospinal fluid biomarkers are briefly presented and clinical results from relevant studies in the field are discussed. Comments on issues related to the cerebrospinal fluid clearance kinetics and how this may affect detection of the biomarkers in the cerebrospinal fluid are also presented. The concept of mild cognitive impairment and current views on this potential stage of the transition from normal aging to Alzheimer's disease and to other dementias are also discussed. Future perspectives, including limitations in identifying reliable, sensitive and specific mild cognitive impairment/Alzheimer's disease biomarkers, are presented. copyright 2006 Future Medicine Ltd
— id: 64335, year: 2006, vol: 2, page: 111, stat: Journal Article,

Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment
de Leon, M J; DeSanti, S; Zinkowski, R; Mehta, P D; Pratico, D; Segal, S; Rusinek, H; Li, J; Tsui, W; Saint Louis, L A; Clark, C M; Tarshish, C; Li, Y; Lair, L; Javier, E; Rich, K; Lesbre, P; Mosconi, L; Reisberg, B; Sadowski, M; DeBernadis, J F; Kerkman, D J; Hampel, H; Wahlund, L-O; Davies, P
2006 Mar;27(3):394-401, Neurobiology of aging
The diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) is limited because it is based on non-specific behavioral and neuroimaging findings. The lesions of Alzheimer's disease: amyloid beta (Abeta) deposits, tau pathology and cellular oxidative damage, affect the hippocampus in the earlier stages causing memory impairment. In a 2-year longitudinal study of MCI patients and normal controls, we examined the hypothesis that cerebrospinal fluid (CSF) markers for these pathological features improve the diagnostic accuracy over memory and magnetic resonance imaging (MRI)-hippocampal volume evaluations. Relative to control, MCI patients showed decreased memory and hippocampal volumes and elevated CSF levels of hyperphosphorylated tau and isoprostane. These two CSF measures consistently improved the diagnostic accuracy over the memory measures and the isoprostane measure incremented the accuracy of the hippocampal volume achieving overall diagnostic accuracies of about 90%. Among MCI patients, over 2 years, longitudinal hippocampal volume losses were closely associated with increasing hyperphosphorylated tau and decreasing amyloid beta-42 levels. These results demonstrate that CSF biomarkers for AD contribute to the characterization of MCI
— id: 62680, year: 2006, vol: 27, page: 394, stat: Journal Article,

Biomarkers for the early diagnosis of Alzheimer's disease
de Leon, Mony J; Klunk, William
2006 Mar;5(3):198-199, Lancet neurology
— id: 71968, year: 2006, vol: 5, page: 198, stat: Journal Article,

Mild cognitive impairment
Gauthier, Serge; Reisberg, Barry; Zaudig, Michael; Petersen, Ronald C; Ritchie, Karen; Broich, Karl; Belleville, Sylvie; Brodaty, Henry; Bennett, David; Chertkow, Howard; Cummings, Jeffrey L; de Leon, Mony; Feldman, Howard; Ganguli, Mary; Hampel, Harald; Scheltens, Philip; Tierney, Mary C; Whitehouse, Peter; Winblad, Bengt
2006 Apr 15;367(9518):1262-1270, Lancet
Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level but that does not interfere notably with activities of daily life. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years. Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension. The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder. Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia
— id: 71967, year: 2006, vol: 367, page: 1262, stat: Journal Article,

Hippocampal cerebrospinal fluid spaces on MR imaging: Relationship to aging and Alzheimer disease
Li, Y; Li, J; Segal, S; Wegiel, J; De Santi, S; Zhan, J; de Leon, M J
2006 Apr;27(4):912-918, AJNR. American journal of neuroradiology
BACKGROUND AND PURPOSE: Perihippocampal fissures (PHFs) and hippocampal sulcus residual cavities (HSCs) are common findings in the MR imaging examination of the hippocampus in aging and Alzheimer disease (AD); however, little is known about how to distinguish them or their relative clinical relevance. We hypothesized that prominence of the HSC, unlike PHF, is not significantly influenced by the hippocampal atrophy related to aging or AD. METHODS: We studied and evaluated these hippocampal CSF spaces on MR imaging scans from 130 normal control (NC) subjects (20-90 years of age) and 27 AD patients. RESULTS: HSC is poorly correlated with age and is not related to the magnitude of hippocampal atrophy. There is no significant difference of HSCs between AD and age-matched NCs, but in the extremely high HSCs group (top 20%), 91% of cases are NC. PHFs, on the other hand, are strongly correlated with age and are valuable in the diagnosis of AD. Location and communication with ambient cistern is the key to distinguish HSC from PHF. CONCLUSION: Identifying hippocampal atrophy (enlarged PHF) may be particularly challenging in the presence of HSC. Distinguishing among the CSF spaces in hippocampus may help in the radiologic evaluation of hippocampal atrophy. Patients with extremely high HSCs (>8.4) can be excluded from AD risk with 93% specificity
— id: 67848, year: 2006, vol: 27, page: 912, stat: Journal Article,

Visual rating of medial temporal lobe metabolism in mild cognitive impairment and Alzheimer's disease using FDG-PET
Mosconi, Lisa; De Santi, Susan; Li, Yi; Li, Juan; Zhan, Jiong; Tsui, Wai Hon; Boppana, Madhu; Pupi, Alberto; de Leon, Mony J
2006 Feb;33(2):210-221, European journal of nuclear medicine & molecular imaging
PURPOSE: This study was designed to examine the utility of visual inspection of medial temporal lobe (MTL) metabolism in the diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) using FDG-PET scans. METHODS: Seventy-five subjects [27 normal controls (NL), 26 MCI, and 22 AD] with FDG-PET and MRI scans were included in this study. We developed a four-point visual rating scale to evaluate the presence and severity of MTL hypometabolism on FDG-PET scans. The visual MTL ratings were compared with quantitative glucose metabolic rate (MR(glc)) data extracted using regions of interest (ROIs) from the MRI-coregistered PET scans of all subjects. A standard rating evaluation of neocortical hypometabolism was also completed. Logistic regressions were used to determine and compare the diagnostic accuracy of the MTL and cortical ratings. RESULTS: For both MTL and cortical ratings, high intra- and inter-rater reliabilities were found (p values <0.001). The MTL rating was highly correlated with and yielded a diagnostic accuracy equivalent to the ROI MR(glc) measures (p values <0.001). The combination of MTL and cortical ratings significantly improved the diagnostic accuracy over the cortical rating alone, with 100% of AD, 77% of MCI, and 85% of NL cases being correctly identified. CONCLUSION: This study shows that the visual rating of MTL hypometabolism on PET is reliable, yields a diagnostic accuracy equal to the quantitative ROI measures, and is clinically useful and more sensitive than cortical ratings for patients with MCI. We suggest this method be further evaluated for its potential in the early diagnosis of AD
— id: 64579, year: 2006, vol: 33, page: 210, stat: Journal Article,

Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease
Mosconi, Lisa; Sorbi, Sandro; de Leon, Mony J; Li, Yi; Nacmias, Benedetta; Myoung, Paul S; Tsui, Wai; Ginestroni, Andrea; Bessi, Valentina; Fayyazz, Mozghan; Caffarra, Paolo; Pupi, Alberto
2006 Nov;47(11):1778-1786, Journal of nuclear medicine
The aim of the present study is to compare brain atrophy with hypometabolism as preclinical markers of Alzheimer's disease (AD) by studying presymptomatic individuals from families with known early-onset autosomal dominant AD (FAD) carrying mutations in the Presenilin 1 gene. METHODS: Seven asymptomatic at-risk FAD individuals (age, 35-49 y; 4 women; education >/= 12 y) and 7 matched healthy control subjects received complete clinical, neuropsychologic, MRI, and (18)F-FDG PET examinations. Regions of interest (ROIs: whole brain [WB], hippocampus [Hip], entorhinal cortex [EC], posterior cingulate cortex [PCC], inferior parietal lobule [IPL], and superior temporal gyrus (STG]) were drawn on the MRI scans of all subjects and used to measure volumes on MRI and glucose metabolism (MRglc) from the MRI-coregistered, atrophy-corrected PET scans. RESULTS: Compared with controls and after correcting for head size, MRI volume reductions in FAD subjects were restricted to the IPL (18%, P < 0.02). After atrophy correction and adjusting for pons MRglc, PET MRglc reductions were found in all FAD subjects compared with controls in the WB (13%), bilaterally in the IPL (17%) and in the STG (12%), and in the left EC (21%), PCC (20%), and Hip (12%) (P values < 0.05). PET MRglc measurements were consistently less variable than MRI measures, yielding significantly larger effect sizes in separating FAD from controls. CONCLUSION: Presymptomatic FAD individuals show widespread MRglc reductions consistent with the typical AD PET pattern in the relative absence of structural brain atrophy. These data further suggest that PET MRglc measures may serve as biomarkers for the preclinical diagnosis of AD
— id: 69600, year: 2006, vol: 47, page: 1778, stat: Journal Article,

CSF biomarkers add to delayed recall and hippocampal volume in diagnosing MCI
De Leon, MJ; DeSanti, S; Zinkowski, R; Mehta, PD; Pratico, D; Rusinek, H; Li, J; Tsui, W; Reisberg, B; Zhan, J; Rich, K; Davies, P
2005 DEC ;30(53):S17-S17, Neuropsychopharmacology
— id: 59555, year: 2005, vol: 30, page: S17, stat: Journal Article,

The role of quantitative structural imaging in the early diagnosis of Alzheimer's disease
Glodzik-Sobanska, Lidia; Rusinek, Henry; Mosconi, Lisa; Li, Yi; Zhan, Jiong; de Santi, Susan; Convit, Antonio; Rich, Kenneth; Brys, Miroslaw; de Leon, Mony J
2005 Nov;15(4):803-26, x, Neuroimaging clinics of North America
The goal of this article is to review the role of structural neuroimaging in the diagnosis of Alzheimer's disease (AD). We present relevant neuroanatomy, highlight progress in the domain of AD imaging, and review the clinical characteristics of the prodromal phase of AD. We describe the history of the diagnostic issue by examining at cross-section and longitudinally the differences between patients who have AD and normal controls. We also present how subsequent works applied these characteristic traits to the early detection of the prodromal disease and to prediction of future decline. The article delineates the differences between subjects who have mild cognitive impairment and AD, which illustrate the spreading of the pathology with disease progression. The last section describes problems encountered in the differential diagnosis
— id: 64158, year: 2005, vol: 15, page: 803, stat: Journal Article,

Absence of hippocampal volume differences in survivors of the Nazi Holocaust with and without posttraumatic stress disorder
Golier, Julia A; Yehuda, Rachel; De Santi, Susan; Segal, Salomoa; Dolan, Susan; de Leon, Mony J
2005 May 30;139(1):53-64, Psychiatry research
It remains unclear whether smaller hippocampal volume is a consistent feature of chronic posttraumatic stress disorder (PTSD) and whether it accounts for the associated memory deficits observed in this illness. Hippocampal volume, comparison regions and memory performance were examined in Holocaust survivors with PTSD (PTSD+: n=14; 5 men, 9 women) and without PTSD (PTSD-: n=13; 6 men, 7 women) and a non-exposed control group of healthy Jewish adults (n=20; 13 men, 7 women). The subjects had medical examinations, high-resolution magnetic resonance imaging, and memory testing. PTSD+ subjects had poorer memory performance than non-exposed subjects and PTSD- subjects, but they did not differ from either group in right or left hippocampal volume when gender and head size were taken into account. Older age and smaller left hippocampal volume were more strongly associated in the PTSD+ group than in the PTSD- groups. Holocaust survivors had larger superior temporal gyral and lateral temporal lobe volumes bilaterally than non-exposed subjects. Smaller hippocampal volume is not invariably associated with chronic PTSD and does not explain the substantial explicit memory impairment observed in Holocaust survivors with this disorder. Larger temporal lobe volumes may be associated with early traumatization and survival or may reflect some other characteristic of Holocaust survivors
— id: 71970, year: 2005, vol: 139, page: 53, stat: Journal Article,

Bayesian applications to longitudinal analysis on medical data with discrete outcomes
Li, Juan; Zhu, Wei; Wang, Xuena; Desanti, Susan; De Leon, Mony
2005 ;2:1204-1207, Conference Proceedings (IEEE Engineering in Medicine & Biology Society)
Many prediction studies of medical research lead to discrete longitudinal data with repeated measurement and categorical outcomes. Therefore the traditional likelihood-based methods for continuous outcome measures are no longer suitable. With the development of modern computing technologies and improved scope for estimation via iterative sampling methods, Bayesian analysis is becoming increasingly popular among biostatisticians. Markov Chain Monte Carlo (MCMC), for the implementation of Bayesian methods has rendered the implementation of complex Bayesian models a reality. In addition, the availability of software like WinBUGS has made the utilization of MCMC straightforward. In this study, we developed a full Bayesian version of generalized linear models for binary longitudinal data and applied it to a longitudinal prediction study of Alzheimer's disease conducted at New York University School of Medicine
— id: 71965, year: 2005, vol: 2, page: 1204, stat: Journal Article,

Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis
Mosconi, L; Tsui, W-H; De Santi, S; Li, J; Rusinek, H; Convit, A; Li, Y; Boppana, Madhu; de Leon, M J
2005 Jun 14;64(11):1860-1867, Neurology
BACKGROUND: To facilitate image analysis, most recent 2-[18F]fluoro-2-deoxy-d-glucose PET (FDG-PET) studies of glucose metabolism (MRglc) have used automated voxel-based analysis (VBA) procedures but paradoxically none reports hippocampus MRglc reductions in mild cognitive impairment (MCI) or Alzheimer disease (AD). Only a few studies, those using regions of interest (ROIs), report hippocampal reductions. The authors created an automated and anatomically valid mask technique to sample the hippocampus on PET (HipMask). METHODS: Hippocampal ROIs drawn on the MRI of 48 subjects (20 healthy elderly [NL], 16 MCI, and 12 AD) were used to develop the HipMask. The HipMask technique was applied in an FDG-PET study of NL (n = 11), MCI (n = 13), and AD (n = 12), and compared to both MRI-guided ROIs and VBA methods. RESULTS: HipMask and ROI hippocampal sampling produced significant and equivalent MRglc reductions for contrasts between MCI and AD relative to NL. The VBA showed typical cortical effects but failed to show hippocampal MRglc reductions in either clinical group. Hippocampal MRglc was the only discriminator of NL vs MCI (78% accuracy) and added to the cortical MRglc in classifying NL vs AD and MCI vs AD. CONCLUSIONS: The new HipMask technique provides accurate and rapid assessment of the hippocampus on PET without the use of regions of interest. Hippocampal glucose metabolism reductions are found in both mild cognitive impairment and Alzheimer disease and contribute to their diagnostic classification. These results suggest re-examination of prior voxel-based analysis 2-[18F]fluoro-2-deoxy-d-glucose PET studies that failed to report hippocampal effects
— id: 61248, year: 2005, vol: 64, page: 1860, stat: Journal Article,

Subjective memory complaints in aging are associated with elevated cortisol levels
Wolf, Oliver T; Dziobek, Isabel; McHugh, Pauline; Sweat, Victoria; de Leon, Mony J; Javier, Elizabeth; Convit, Antonio
2005 Nov-Dec;26(10):1357-1363, Neurobiology of aging
The origin and clinical significance of subjective memory complaints among middle aged and older individuals is not well understood. Associations with objective memory impairments, personality traits or mood disturbances have been reported. Elevated cortisol levels occur in aging and depression and causal links to cognitive or emotional problems have been suggested. The goal of this study was to investigate the associations between basal and feedback indices of cortisol regulation and subjective memory impairment in a sample of healthy middle aged and older subjects (mean age 61.8 years) with (n=27) and without (n=19) subjective memory complaints. Participants with memory complaints had both higher basal cortisol levels and higher cortisol levels after dexamethasone. There was a significant group by gender interaction for basal cortisol levels, where women without memory complaints showed significantly lower cortisol levels, whereas no such difference was found for the men. All effects were not due to slight differences in depression scores. Differences in personality traits or in stress susceptibility might underlie the present findings. Future studies of memory complaints should take a comprehensive approach including relevant endocrine parameters
— id: 71969, year: 2005, vol: 26, page: 1357, stat: Journal Article,

MRI and CSF studies in the early diagnosis of Alzheimer's disease
de Leon, M J; DeSanti, S; Zinkowski, R; Mehta, P D; Pratico, D; Segal, S; Clark, C; Kerkman, D; DeBernardis, J; Li, J; Lair, L; Reisberg, B; Tsui, W; Rusinek, H
2004 Sep;256(3):205-223, Journal of internal medicine
Abstract. de Leon MJ, DeSanti S, Zinkowski R, Mehta PD, Pratico D, Segal S, Clark C, Kerkman D, DeBernardis J, Li J, Lair L, Reisberg B, Tsui W, Rusinek H. (New York University School of Medicine, NY; Nathan Kline Institute, NY; Molecular Geriatrics, Vernon Hills, IL; Institute for Basic Research, NY; and University of Pennsylvania, PA; USA). MRI and CSF studies in the early diagnosis of Alzheimer's disease (Key Symposium). J Intern Med 2004; 256: 205-223.The main goal of our studies has been to use MRI, FDG-PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimer's disease (AD). A second goal has been to describe the cross-sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI-determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi-automated regional boundary shift analysis (BSA-R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1-42 (Abeta42). Many CSF studies of MCI and AD report elevated T-tau levels (a marker of neuronal damage) and reduced Abeta42 levels (possibly due to increased plaque sequestration). However, CSF T-tau and Abeta42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P-tau, tau hyperphosphorylated at threonine 231 (P-tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the hypothesis that elevations in P-tau231 are accurate and specific indicators of AD-related changes in brain and cognition. In cross-section and longitudinally, our results show that evaluations of the P-tau231 level are highly correlated with reductions in the MRI hippocampal volume and by using CSF and MRI measures together one improves the separation of NL and MCI. The data suggests that by combining MRI and CSF measures, an early (sensitive) and more specific diagnosis of AD is at hand. Numerous studies show that neither T-tau nor P-tauX (X refers to all hyper-phosphorylation site assays) levels are sensitive to the longitudinal progression of AD. The explanation for the failure to observe longitudinal changes is not known. One possibility is that brain-derived proteins are diluted in the CSF compartment. We recently used MRI to estimate ventricular CSF volume and demonstrated that an MRI-based adjustment for CSF volume dilution enables detection of a diagnostically useful longitudinal P-tau231 elevation. Curiously, our most recent data show that the CSF isoprostane level does show significant longitudinal elevations in MCI in the absence of dilution correction. In summary, we conclude that the combined use of MRI and CSF incrementally contributes to the early diagnosis of AD and to monitor the course of AD. The interim results also suggest that a panel of CSF biomarkers can provide measures both sensitive to longitudinal change as well as measures that lend specificity to the AD diagnosis
— id: 44525, year: 2004, vol: 256, page: 205, stat: Journal Article,

Biomarkers for Alzheimer's disease improve early diagnosis
de Leon, MJ; De Santi, S; Zinkowski, R; Mehta, P; Pratico, D; Segal, S; Rusinek, H; Li, J; Tsui, W; Saint Louis, L; Clark, C; Tarshish, C; Lair, L; Javier, E; Lesbre, P; Bobinski, M; Reisberg, B; DeBernardis, J; Kerkman, D; Davies, P
2004 JUL ;25(10):S33-S34, Neurobiology of aging
— id: 47712, year: 2004, vol: 25, page: S33, stat: Journal Article,

Longitudinal neuroimaging measures of hippocampal formation atrophy and biomarkers for early Alzheimer disease
de Leon, MJ; DeSanti, S; Segal, S; Convit, A; Rusinek, H; Saint Louis, LA; Li, Y; Li, J; Mehta, PD; Zinkowski, R; Pratico, D; DeBernardis, J; Kerkman, D; Hampel, H; Clark, C
2004 APR ;25(12):S7-S7, Neurobiology of aging
— id: 42444, year: 2004, vol: 25, page: S7, stat: Journal Article,

A 4-year, 3 timepoint MRI hippocampal study of MCI transition to AD
De Santi, S; Bobinski, M; Li, J; Monteiro, I; Boksay, I; Ferris, S; Reisberg, B; de Leon, MJ
2004 JUL ;25(10):S12-S12, Neurobiology of aging
— id: 47708, year: 2004, vol: 25, page: S12, stat: Journal Article,

Atrophy rate in medial temporal lobe: A correlate of AD progression
Endo, Y; Rusinek, H; De Santi, S; Frid, D; Tsui, WH; Segal, S; Convit, AJ; de Leon, MJ
2004 JUL ;25(10):S377-S377, Neurobiology of aging
— id: 47735, year: 2004, vol: 25, page: S377, stat: Journal Article,

MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease
Helpern, Joseph A; Lee, Sang-Pil; Falangola, Maria F; Dyakin, Victor V; Bogart, Adam; Ardekani, Babak; Duff, Karen; Branch, Craig; Wisniewski, Thomas; de Leon, Mony J; Wolf, Oliver; O'Shea, Jacqueline; Nixon, Ralph A
2004 Apr;51(4):794-798, Magnetic resonance in medicine
The cerebral deposition of amyloid beta-peptide, a central event in Alzheimer's disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Noninvasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. In this study, high-field MRI was used to detect changes in regional brain MR relaxation times in three types of mice: 1). transgenic mice (PS/APP) carrying both mutant genes for amyloid precursor protein (APP) and presenilin (PS), which have high levels and clear accumulation of beta-amyloid in several brain regions, starting from 10 weeks of age; 2). transgenic mice (PS) carrying only a mutant gene for presenilin (PS), which show subtly elevated levels of Abeta-peptide without beta-amyloid deposition; and 3). nontransgenic (NTg) littermates as controls. The transverse relaxation time T(2), an intrinsic MR parameter thought to reflect impaired cell physiology, was significantly reduced in the hippocampus, cingulate, and retrosplenial cortex, but not the corpus callosum, of PS-APP mice compared to NTg. No differences in T(1) values or proton density were detected between any groups of mice. These results indicate that T(2) may be a sensitive marker of abnormalities in this transgenic mouse model of AD
— id: 42285, year: 2004, vol: 51, page: 794, stat: Journal Article,

Magnetic resonance and PET studies in the early diagnosis of Alzheimer's disease
Mosconi, Lisa; De Santi, Susan; Rusinek, Henry; Convit, Antonio; de Leon, Mony J
2004 Sep;4(5):831-849, Expert review of neurotherapeutics
The demographics of aging identify an immediate need for the early diagnosis and development of dementia prevention strategies. Recent neuropathological studies have pointed to the early involvement of the hippocampus and entorhinal cortex in the progression of Alzheimer's disease in the brain. In particular, these studies have implicated tau-related pathology as an important cause of neuronal death. In addition, there is a large body of evidence showing that beta-amyloid, which has a predilection for the neocortex, is also involved early in the course of the disease and may also have toxic effects on cells. In vivo cerebrospinal fluid studies have shown that markers for these brain changes have a diagnostic value for Alzheimer's disease and that some measures also provide diagnostic specificity for Alzheimer's disease. Structural and metabolic imaging studies demonstrate brain changes in impaired and at-risk individuals. While currently available magnetic resonance and positron emission tomography techniques are not by themselves specific for the pathologic features of Alzheimer's disease, there are patterns of change that have been useful for the early diagnosis. As such, both prediction and longitudinal imaging studies demonstrate a capacity to recognize abnormalities that relate to future Alzheimer's disease and most recently to future mild cognitive impairment. This review highlights cross-sectional, prediction, and longitudinal magnetic resonance and positron emission tomography imaging studies and attempts to put into perspective their utility for the early diagnosis of Alzheimer's disease, and for their utility to provide diagnostic specificity. It is concluded that there is considerable promise for an early and specific diagnosis for Alzheimer's disease by combining information from imaging and biomarker modalities
— id: 56016, year: 2004, vol: 4, page: 831, stat: Journal Article,

Cholesterol in neurologic disorders of the elderly: stroke and Alzheimer's disease
Reiss, Allison B; Siller, Keith A; Rahman, Mohammad M; Chan, Edwin S L; Ghiso, Jorge; de Leon, Mony J
2004 Oct;25(8):977-989, Neurobiology of aging
Mechanisms for the regulation of intracellular cholesterol levels in various types of brain and vascular cells are of considerable importance in our understanding of the pathogenesis of a variety of diseases, particularly atherosclerosis and Alzheimer's disease (AD). It is increasingly clear that conversion of brain cholesterol into 24-hydroxycholesterol and its subsequent release into the periphery is important for the maintenance of brain cholesterol homeostasis. Recent studies have shown elevated plasma concentrations of 24-hydroxycholesterol in patients with AD and vascular dementia, suggesting increased brain cholesterol turnover during neurodegeneration. The oxygenases involved in the degradation and excretion of cholesterol, including the cholesterol 24-hydroxylase and the 27-hydroxylase, are enzymes of the cytochrome P-450 family. This review focuses on the newly recognized importance of cholesterol and its oxygenated metabolites in the pathogenesis of ischemic stroke and AD. The reduction in stroke and AD risk in patients treated with cholesterol-lowering statins is also discussed
— id: 45967, year: 2004, vol: 25, page: 977, stat: Journal Article,

Atrophy rate in medial temporal lobe during progression of Alzheimer disease
Rusinek, H; Endo, Y; De Santi, S; Frid, D; Tsui, W-H; Segal, S; Convit, A; de Leon, M J
2004 Dec 28;63(12):2354-2359, Neurology
OBJECTIVE: To establish the progression of brain atrophy rates in patients with a known date of onset of Alzheimer disease (AD). METHODS: Each of 18 subjects had two high-resolution T1-weighted three-dimensional MRI examinations. The two MRIs were coregistered and the annual rate of brain tissue atrophy was derived both for the entire brain and regionally for the left and right medial temporal lobe (MTL). Time since onset (TSO) of AD, defined as the interval between the date of onset and the midpoint of MRI dates, ranged from -2.9 to 4.2 years. RESULTS: In patients with AD, TSO was a correlate of the atrophy rate for both the left MTL (R2 = 0.58, p = 0.001) and right MTL (R2 = 0.30, p = 0.03). When serial measurements were applied to a control group of 21 cognitively normal elderly subjects, MTL atrophy rate classified the group membership (AD vs normal cognition) with an accuracy of 92.3%. CONCLUSION: Increased annual atrophy rate in the medial temporal lobe is a potential diagnostic marker of the progression of Alzheimer disease
— id: 57659, year: 2004, vol: 63, page: 2354, stat: Journal Article,

Brain structural changes in MCI
Segal, S; Li, Y; Li, J; Ehlers, BC; Lesbre, P; De Santi, S; de Leon, MJ
2004 JUL ;25(10):S382-S382, Neurobiology of aging
— id: 47736, year: 2004, vol: 25, page: S382, stat: Journal Article,

Cell type- and brain structure-specific patterns of distribution of minibrain kinase in human brain
Wegiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof; Frackowiak, Janusz; Dowjat, Karol; Silverman, Wayne P; Reisberg, Barry; DeLeon, Mony; Wisniewski, Thomas; Adayev, Tatyana; Chen-Hwang, Mo-Chou; Hwang, Yu-Wen
2004 Jun 4;1010(1-2):69-80, Brain research
The minibrain kinase (Mnb/Dyrk1A) gene is localized in the Down syndrome (DS) critical region of chromosome 21. This gene encodes a proline-directed serine/threonine protein kinase (minibrain kinase-Mnb/Dyrk1A), which is required for the proliferation of distinct neuronal cell types during postembryonic neurogenesis. To study the distribution of Mnb/Dyrk1A during human brain development and aging, we raised Mnb/Dyrk1A-specific antibody (mAb 7F3) and examined 22 brains of normal subjects from 8 months to 90 years of age. We found that neurons were the only cells showing the presence of 7F3-positive product in both cell nucleus and cytoplasm. Nuclear localization supports the concept that Mnb/Dyrk1A may be involved in control of gene expression. Synaptic localization of Mnb/Dyrk1A also supports our previous studies suggesting that Mnb/Dyrk1A is a regulator of assembly of endocytic apparatus and appears to be involved in synaptic vesicle recycling and synaptic signal transmission. Accumulation of numerous 7F3-positive corpora amylacea in the memory and motor system subdivisions in subjects older than 33 years of age indicates that Mnb/Dyrk1A is colocalized with markers of astrocyte and neuron degeneration. Differences in the topography and the amount of Mnb/Dyrk1A in neurons, astrocytes, and ependymal and endothelial cells appear to reflect cell type- and brain structure-specific patterns in trafficking and utilization of Mnb/Dyrk1A
— id: 44515, year: 2004, vol: 1010, page: 69, stat: Journal Article,

Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderly
Convit, Antonio; Wolf, Oliver T; Tarshish, Chaim; de Leon, Mony J
2003 Feb 18;100(4):2019-2022, Proceedings of the National Academy of Sciences of the United States of America
Poor glucose tolerance and memory deficits, short of dementia, often accompanies aging. The purpose of this study was to ascertain whether, among nondiabetic, nondemented middle-aged and elderly individuals, poorer glucose tolerance is associated with reductions in memory performance and smaller hippocampal volumes. We studied 30 subjects who were evaluated consecutively in an outpatient research setting. The composition of the participant group was 57% female and 68.6 +/- 7.5 years of age; the participants had an average education of 16.2 +/- 2.3 years, a score on the Mini Mental State Examination of 28.6 +/- 1.5, a glycosylated hemoglobin (HbA1C) of 5.88 +/- 0.74%, and a body mass index of 24.9 +/- 4.1 kg/m(2). Glucose tolerance was measured by an i.v. glucose tolerance test. Memory was tested by using the Wechsler Paragraphs recall tests at the time of administering the i.v. glucose tolerance test. The hippocampus and other brain volumes were measured by using validated methods on standardized MRIs. Decreased peripheral glucose regulation was associated with decreased general cognitive performance, memory impairments, and atrophy of the hippocampus, a brain area that is key for learning and memory. These associations were independent of age and Mini Mental State Examination scores. Therefore, these data suggest that metabolic substrate delivery may influence hippocampal structure and function. This observation may bring to light a mechanism for aging brain injury that may have substantial medical impact, given the large number of elderly individuals with impaired glucose metabolism
— id: 39314, year: 2003, vol: 100, page: 2019, stat: Journal Article,

Biological markers for therapeutic trials in Alzheimer's disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease
Frank, Richard A; Galasko, Douglas; Hampel, Harald; Hardy, John; de Leon, Mony J; Mehta, Pankaj D; Rogers, Joseph; Siemers, Eric; Trojanowski, John Q
2003 Jul-Aug;24(4):521-536, Neurobiology of aging
— id: 71971, year: 2003, vol: 24, page: 521, stat: Journal Article,

Regional brain atrophy rate predicts future cognitive decline: 6-year longitudinal MR imaging study of normal aging
Rusinek, Henry; De Santi, Susan; Frid, Dina; Tsui, Wai-Hon; Tarshish, Chaim Y; Convit, Antonio; de Leon, Mony J
2003 Dec;229(3):691-696, Radiology
PURPOSE: To determine if medial temporal lobe (MTL) atrophy rate, assessed by using an automated procedure over the initial time interval of a 6-year, three-time-point longitudinal study, is predictive of future memory decline. MATERIALS AND METHODS: Healthy elderly subjects (age, >60 years) were administered a comprehensive battery of neuropsychometric tests and underwent magnetic resonance (MR) imaging at baseline and two or more follow-up examinations. The rate of brain atrophy between the baseline and first follow-up examinations was assessed by using an automated procedure that included spatial coregistration of the two images and regional brain boundary shift analysis. At final observation, the 45 subjects were separated into a group of those who did and a group of those who did not show objective evidence of cognitive decline. A forward stepwise logistic regression model was used to identify variables that predicted decline. RESULTS: Thirty-two subjects remained healthy, and 13 showed cognitive decline. Among subjects who showed cognitive decline, six declined after the second observation. MTL atrophy rate, through its interactions with sex and age, was the most significant predictor of decline. The overall accuracy of prediction was 89% (in 40 of 45 subjects), with 91% specificity (in 29 of 32 subjects) and 85% sensitivity (in 11 of 13 subjects). CONCLUSION: Among healthy elderly individuals, increased MTL atrophy rate appears to be predictive of future memory decline
— id: 43857, year: 2003, vol: 229, page: 691, stat: Journal Article,

Redistribution of minibrain kinase in aging and neurodegeneration
Wegiel, J; Kuchna, I; Nowicki, K; Dowiat, K; Reisberg, B; deLeon, M; Wisniewski, T; Chen-Hwang, M; Hwang, Y
2003 MAY ;62(5):546-546, Journal of neuropathology & experimental neurology
— id: 38568, year: 2003, vol: 62, page: 546, stat: Journal Article,

Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderly
Wolf, OT; Convit, A; de Leon, MJ
2003 NOV ;17(3):186-187, Journal of psychophysiology
— id: 55460, year: 2003, vol: 17, page: 186, stat: Journal Article,

Glucose metabolism and memory in aging: Links to hippocampus
Convit, A; de Leon, M; McHugh, P; Thorn, E; Wolf, O; Craft, S
2002 Jul-Aug;23(1):425-, Neurobiology of aging
— id: 32411, year: 2002, vol: 23, page: 425, stat: Journal Article,

Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment
de Leon, M J; Segal, S; Tarshish, C Y; DeSanti, S; Zinkowski, R; Mehta, P D; Convit, A; Caraos, C; Rusinek, H; Tsui, W; Saint Louis, L A; DeBernardis, J; Kerkman, D; Qadri, F; Gary, A; Lesbre, P; Wisniewski, T; Poirier, J; Davies, P
2002 Nov 29;333(3):183-186, Neuroscience letters
Cross-sectional cerebrospinal fluid (CSF) levels of tau and amyloid (A) beta (beta) are of diagnostic importance for Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, most longitudinal studies of tau fail to demonstrate progression. Because predominantly brain-derived proteins such as tau, have higher ventricle to lumbar ratios, we hypothesized that adjusting for the ventricular enlargement of AD would correct for the dilution of tau, and improve detection of longitudinal change. Abeta which is not exclusively brain derived, shows a ratio <1, and no benefit was expected from adjustment. In a 1 year longitudinal study of eight MCI and ten controls, we examined CSF levels of hyperphosphorylated (P) tau231, Abeta40, and Abeta42. In cross-section, MCI patients showed elevated Ptau231 and Abeta40 levels, and greater ventricular volumes. Longitudinally, only after adjusting for the ventricular volume and only for Ptau231, were increases seen in MCI. Further studies are warranted on mechanisms of tau clearance and on using imaging to interpret CSF studies
— id: 39372, year: 2002, vol: 333, page: 183, stat: Journal Article,

Can cognition predict future mild cognitive impairment in highly educated normal elderly?
De Santi, S; de Leon, M; Tarshish, C; Convit, A; Imossi, A; Ferris, S
2002 Jul-Aug;23(1):122-, Neurobiology of aging
— id: 32409, year: 2002, vol: 23, page: 122, stat: Journal Article,

Hippocampal atrophy disrupts transfer generalization in nondemented elderly
Myers, Catherine E; Kluger, Alan; Golomb, James; Ferris, Steven; de Leon, Mony J; Schnirman, Geoffrey; Gluck, Mark A
2002 Summer;15(2):82-90, Journal of geriatric psychiatry & neurology
Specific reductions in hippocampal volume in nondemented elderly individuals with mild cognitive impairment have been shown to correlate with future development of Alzheimer's disease (AD). Hippocampal atrophy (HA) is also correlated with cognitive impairments, leading to the promise of behavioral markers for early AD. Prior theoretical work has suggested that hippocampal dysfunction may selectively impair generalization involving novel recombinations of familiar stimuli. In this study, nondemented elderly individuals were trained on a series of concurrent visual discriminations and were then tested for transfer when stimulus features were recombined in new ways. Presence or absence of HA, revealed by neuroimaging, was not correlated with concurrent discrimination performance; however, individuals with mild HA showed significant decreases in transfer performance relative to nonatrophied participants. These preliminary results suggest that even very mild degrees of hippocampal atrophy may be associated with subtle behavioral impairments
— id: 32396, year: 2002, vol: 15, page: 82, stat: Journal Article,

Changes in brain functional homogeneity in subjects with Alzheimer's disease
Volkow, Nora D; Zhu, Wei; Felder, Christoph A; Mueller, Klaus; Welsh, Tomihisa F; Wang, Gene Jack; de Leon, Mony J
2002 Feb 15;114(1):39-50, Psychiatry research
Imaging studies have reported marked reductions in brain glucose metabolism in Alzheimer's Disease (AD). However, less is known about disruptions in the patterns of brain metabolic activity. Here we questioned whether AD affects the patterns of homogeneity/heterogeneity in brain metabolism. PET images of 35 AD subjects were compared with those of 35 controls. A template was applied to extract a cortical rim, which was partitioned into 990 contiguous regions. Estimates of metabolic homogeneity were obtained using the coefficient of variation (CV). The CV of the entire cortex was found to be significantly larger in AD, suggesting increased heterogeneity at the whole brain level. In contrast, regional CV was significantly lower in AD in temporal and parietal cortices, which were the regions that along with the precuneus had the largest metabolic decrements, though the precuneus had increased CV. The enhanced heterogeneity for the global cortical pattern most likely reflects variability in the degree of pathology among brain regions as well as neuroanatomical disconnection. The enhanced homogeneity in parietal and temporal cortices is likely to reflect loss of regional differentiation (i.e. macrocolumnar disorganization). The enhanced CV in precuneus, despite its marked reductions in metabolism, suggests that increases in regional homogeneity in parietal and temporal cortices are not a mere reflection of the decrement in metabolism
— id: 71972, year: 2002, vol: 114, page: 39, stat: Journal Article,

Vascular fibrosis and calcification in the hippocampus in aging, Alzheimer disease, and Down syndrome
Wegiel, J; Kuchna, I; Wisniewski, T; de Leon, M J; Reisberg, B; Pirttila, T; Kivimaki, T; Lehtimaki, T
2002 Apr;103(4):333-343, Acta neuropathologica
Study of the hippocampal formation of 82 subjects, including 25 control subjects from 33 to 83 years of age, 34 subjects with Alzheimer disease (AD) from 65 to 89 years of age, and 23 subjects with Down syndrome (DS) from 33 to 72 years of age, revealed hippocampal vasculopathy with fibrosis and calcification (VFC) in 40% of control, 59% of AD, and 4% of DS subjects. VFC starts in the precapillaries/capillaries in the molecular layer of the dentate gyrus (DG) and expands to the granule cell and polymorphic cell layer of the DG, and to the stratum lacunosum/molecular in the CA1 sector. Vasculopathy spreads from the tail to the body and, in a few cases, to the head of the hippocampal formation. Light and electron microscopy reveal thickening of the vascular wall with fibrosis, calcification, and enforcement of the astrocyte interface with vessels with anchorage densities associated with hemidesmosome-like structures. In moderately and severely affected cases, fragmentation and removal of calcified and occluded vessels result in local reduction of vascular network. In two AD subjects, severe vascular calcification extending from the tail to the head of the hippocampal formation was associated with loss of almost all neurons in the CA1 sector and in the subiculum proper, corresponding to hippocampal sclerosis. The topography of affected vessels and the patterns of neuronal loss reflect the middle hippocampal artery distribution with its precapillary/capillary network. The similar prevalence of vasculopathy in the AD group and in the age-matched control group, and the presence of hippocampal VFC in only one subject in the DS cohort, 96% of which is affected by Alzheimer-type pathology, oppose the link between AD and this form of vasculopathy. However, severe VFC affects the pattern of AD pathology locally by deletion of neurofibrillary degeneration and beta-amyloidosis in the CA1 sector, subiculum proper, and the molecular layer of the dentate gyrus. Hippocampal VFC appears to be a form of vascular pathology with a unique predilection for the middle hippocampal artery and corresponding capillary network, which results in patchy neuronal loss in moderately affected subjects and in almost total neuronal loss in the area of impaired blood supply in severely affected subjects. These observations suggest an etiologic link between hippocampal VFC and hippocampal sclerosis
— id: 34298, year: 2002, vol: 103, page: 333, stat: Journal Article,

Volumetric structural magnetic resonance imaging (MRI) of the rat hippocampus following kainic acid (KA) treatment
Wolf, O T; Dyakin, V; Patel, A; Vadasz, C; de Leon, M J; McEwen, B S; Bulloch, K
2002 May 3;934(2):87-96, Brain research
An in vivo MRI study employing a high field (7T) magnet and a T1- and T2-weighted imaging sequence with subsequent histopathological evaluations was undertaken to develop and evaluate MRI-based volumetric measurements in the rat. The brain structures considered were the hippocampus, the cingulate cortex, the retrosplenial granular cortex and the ventricles. Control (n=3) and kainic acid (KA; n=4) treated rats were scanned 10 days following the manifestation of stage four seizures. The MRI images exhibited anatomical details (125 microm in-plane resolution) that enabled volumetric analysis with high intra-rater reliability. Volumetric analysis revealed that KA-treated rats had significantly smaller hippocampi, and a significant increase in ventricular size. The cingulate cortex and the retrosplenial granular cortex did not differ in volume between the two groups. The histological observations supported the MRI data showing neuronal loss and neuronal degeneration in CA1 and CA3 of the hippocampus, which was accompanied by strong microglia activation. These data demonstrate a reliable and valid method for the measurement of the rat hippocampus in vivo using MRI with a high field magnet, thereby providing a useful tool for future studies of rodent models of neuro-degenerative diseases
— id: 32478, year: 2002, vol: 934, page: 87, stat: Journal Article,

Volumetric measurement of the hippocampus, the anterior cingulate cortex, and the retrosplenial granular cortex of the rat using structural MRI
Wolf, O T; Dyakin, V; Vadasz, C; de Leon, M J; McEwen, B S; Bulloch, K
2002 Aug;10(1):41-46, Brain research protocols
MRI imaging of the rodent brain is a rapidly growing field in the neurosciences. Relatively limited information is available for regional volume determination. The present paper describes a reliable method for the assessment of the hippocampus, the anterior cingulate cortex, the retrosplenial granular cortex and the ventricles in rats. MRI scans were acquired using a 7 T magnet. The anatomical sampling method was found to be highly reliable with an intra-rater reliability of greater than 0.93. The current protocol should facilitate future in vivo neuroimaging research using animal models of neurodegenerative diseases
— id: 71974, year: 2002, vol: 10, page: 41, stat: Journal Article,

Basal hypothalamo-pituitary-adrenal axis activity and corticotropin feedback in young and older men: relationships to magnetic resonance imaging-derived hippocampus and cingulate gyrus volumes
Wolf, Oliver T; Convit, Antonio; de Leon, Mony J; Caraos, Conrado; Qadri, Syed F
2002 Apr;75(4):241-249, Neuroendocrinology
Alterations in basal cortisol secretion and feedback sensitivity are reported in aging. However, it is not known whether these hypothalamus-pituitary-adrenal (HPA) axis alterations are related to structural brain changes. This study was designed to investigate these relationships in the human. Nine young (24.0 +/- 1.2 years; mean +/- SE; range: 19-30) and 11 older (69.0 +/- 1.8 years; range: 59-76) men, in addition to having standardized magnetic resonance imaging of their brains, were given 0.5 mg/kg cortisol or placebo intravenously in a double-blind, crossover study. As expected, older men had significantly smaller volumes for all brain regions. Although the groups did not differ in baseline HPA axis activity, there were significant and specific relationships between the brain volumes and the baseline measures of HPA activity. Namely, for young and older subjects combined and after controlling for age and cerebral vault size, hippocampal volumes were inversely associated with 24-hour urinary cortisol and basal corticotropin (ACTH) levels, and the anterior cingulate gyrus volume was negatively correlated with baseline ACTH. Elderly subjects had a slower decrease in ACTH levels (percent of baseline level) during the first 30 min after cortisol administration. However, no associations were observed between the ACTH feedback indices and any brain measure. This report, although based on a small number of subjects, supports previous studies showing a blunted ACTH fast feedback during normal aging. Hippocampal atrophy appears to be related to increased basal measures of HPA axis activity, but not to fast ACTH feedback. It remains possible that age-associated changes in fast feedback may be related to changes to other brain sites, such as hypothalamus or pituitary
— id: 39663, year: 2002, vol: 75, page: 241, stat: Journal Article,

Salivary cortisol day profiles in elderly with mild cognitive impairment
Wolf, Oliver T; Convit, Antonio; Thorn, Elissa; de Leon, Mony J
2002 Oct;27(7):777-789, Psychoneuroendocrinology
It is unknown whether hypothalamus-pituitary-adrenal (HPA) axis dysfunction is associated with the memory impairments observed among elderly participants with mild cognitive impairment (MCI), a group considered at increased risk for Alzheimer's disease (AD). Therefore, salivary cortisol levels were measured at six points over the course of the day while at-home in MCI participants (n=16), normal elderly (n=28), and young controls (n=14). Results revealed that MCI participants did not show elevated salivary cortisol levels. The 9 a.m. cortisol level of the MCI group was significantly lower than the 9 a.m. level of the young controls, but did not differ from those of the normal elderly group. In contrast to the other two groups, within the MCI group mean cortisol levels were inversely related to immediate recall of paragraphs. No association was observed between mean cortisol levels and performance in paired associates and digit span. Whether cortisol levels, in conjunction with other factors, such as hippocampal volume, will lead to improved prediction of future decline to AD in participants with MCI remains to be established in longitudinal studies
— id: 39606, year: 2002, vol: 27, page: 777, stat: Journal Article,

HPA axis activity and fast ACTH feedback in young and older subjects: Relationships to MRI-derived hippocampus and cingulate gyrus volumes
Wolf, OT; Convit, A; de Leon, MJ; Caraos, C; Qadri, SF
2002 OCT ;16(4):235-235, Journal of psychophysiology
— id: 55527, year: 2002, vol: 16, page: 235, stat: Journal Article,

Volumetric analysis of the pre-frontal regions: findings in aging and schizophrenia
Convit A; Wolf OT; de Leon MJ; Patalinjug M; Kandil E; Caraos C; Scherer A; Saint Louis LA; Cancro R
2001 Aug 25;107(2):61-73, Psychiatry research
Frontal lobe dysfunction is thought to be involved in schizophrenia and age-associated cognitive decline. Frontal lobe volume changes have been investigated in these conditions using MRI, but results have been inconsistent. Few volumetric MRI protocols exist that divide the pre-frontal cortex into its sub-regions. In the present article, we describe a new method, which allows assessment of the superior, middle and inferior frontal gyrus, as well as the orbitofrontal and cingulate regions. The method uses multiple planes to help guide the anatomical decisions and combines this with a geometric approach utilizing readily apparent anatomical landmarks. Using this protocol, the frontal lobe volumes in young healthy subjects were contrasted with those of young schizophrenic patients and elderly healthy subjects (nine male subjects per group). The results showed that the method could be reproduced with high reliability (r(icc)> or =0.88-0.99). Schizophrenic as well as old subjects had specific significant reductions in the superior frontal gyrus and orbitofrontal regions compared with the young group. However, old and schizophrenic subjects did not differ from each another. No volume differences were observed in the other three regions assessed. Whether or not these volume reductions reflect a common pathological process remains to be investigated in future studies
— id: 26623, year: 2001, vol: 107, page: 61, stat: Journal Article,

Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET)
de Leon MJ; Convit A; Wolf OT; Tarshish CY; DeSanti S; Rusinek H; Tsui W; Kandil E; Scherer AJ; Roche A; Imossi A; Thorn E; Bobinski M; Caraos C; Lesbre P; Schlyer D; Poirier J; Reisberg B; Fowler J
2001 Sep 11;98(19):10966-10971, Proceedings of the National Academy of Sciences of the United States of America
Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimer's disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex. Related observations with in vivo imaging have enabled the prediction of dementia from MCI. Although individuals with normal cognition may have focal EC lesions, this anatomy has not been studied as a predictor of cognitive decline and brain change. The objective of this MRI-guided 2-[(18)F]fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET) study was to examine the hypothesis that among normal elderly subjects, EC METglu reductions predict decline and the involvement of the Hip and neocortex. In a 3-year longitudinal study of 48 healthy normal elderly, 12 individuals (mean age 72) demonstrated cognitive decline (11 to MCI and 1 to Alzheimer's disease). Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender. At baseline, metabolic reductions in the EC accurately predicted the conversion from normal to MCI. Among those who declined, the baseline EC predicted longitudinal memory and temporal neocortex metabolic reductions. At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip. Among those subjects who declined, apolipoprotein E E4 carriers showed marked longitudinal temporal neocortex reductions. In summary, these data suggest that an EC stage of brain involvement can be detected in normal elderly that predicts future cognitive and brain metabolism reductions. Progressive E4-related hypometabolism may underlie the known increased susceptibility for dementia. Further study is required to estimate individual risks and to determine the physiologic basis for METglu changes detected while cognition is normal
— id: 26662, year: 2001, vol: 98, page: 10966, stat: Journal Article,

Hippocampal formation glucose metabolism and volume losses in MCI and AD
De Santi S; de Leon MJ; Rusinek H; Convit A; Tarshish CY; Roche A; Tsui WH; Kandil E; Boppana M; Daisley K; Wang GJ; Schlyer D; Fowler J
2001 Jul-Aug;22(4):529-539, Neurobiology of aging
We used MRI volume sampling with coregistered and atrophy corrected FDG-PET scans to test three hypotheses: 1) hippocampal formation measures are superior to temporal neocortical measures in the discrimination of normal (NL) and mild cognitive impairment (MCI); 2) neocortical measures are most useful in the separation of Alzheimer disease (AD) from NL or MCI; 3) measures of PET glucose metabolism (MRglu) have greater diagnostic sensitivity than MRI volume. Three groups of age, education, and gender matched NL, MCI, and AD subjects were studied. The results supported the hypotheses: 1) entorhinal cortex MRglu and hippocampal volume were most accurate in classifying NL and MCI; 2) both imaging modalities identified the temporal neocortex as best separating MCI and AD, whereas widespread changes accurately classified NL and AD; 3) In most between group comparisons regional MRglu measures were diagnostically superior to volume measures. These cross-sectional data show that in MCI hippocampal formation changes exist without significant neocortical changes. Neocortical changes best characterize AD. In both MCI and AD, metabolism reductions exceed volume losses
— id: 21136, year: 2001, vol: 22, page: 529, stat: Journal Article,

In vivo detection of neuropathology in an animal model of Alzheimer's disease by magnetic resonance imaging
Helpern, J. A.; Wisniewski, T.; Duff, K.; Dyakin, V.; de Leon, M.; Ardekani, B.; Wolf, O.; Branch, C.; O'Shea, J.; Wegiel, J.; Nixon, R. A.
2001 ;27(1):1217-343, Abstracts (Society for Neuroscience)
The cerebral deposition of amyloid beta-peptide, a central event in Alzheimer's disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Non-invasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. Here, we demonstrate the ability of high field strength MRI to detect regional brain volume reductions and ventricular enlargement in the PS-APP transgenic mouse model of AD more sensitively than histopathologic analysis by unbiased stereology. Moreover, the transverse relaxation time T2, an intrinsic MR parameter thought to reflect impaired cell physiology, was altered substantially in cortical regions containing beta-amyloid but only slightly in cerebellum, which contains little beta-amyloid. MR measures were also minimally altered in mice expressing mutant presenilin-1, which do not deposit beta-amyloid, supporting the view that the MR abnormalities in PS-APP mice are partly related to amyloid beta-peptide deposition. These results set the stage for MRI to aid in the early diagnosis of AD and the evaluation of potential therapies in transgenic animal models and in patients
— id: 97624, year: 2001, vol: 27, page: 1217, stat: Journal Article,

Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome
Silverman, D H; Small, G W; Chang, C Y; Lu, C S; Kung De Aburto, M A; Chen, W; Czernin, J; Rapoport, S I; Pietrini, P; Alexander, G E; Schapiro, M B; Jagust, W J; Hoffman, J M; Welsh-Bohmer, K A; Alavi, A; Clark, C M; Salmon, E; de Leon, M J; Mielke, R; Cummings, J L; Kowell, A P; Gambhir, S S; Hoh, C K; Phelps, M E
2001 Nov 7;286(17):2120-2127, JAMA
CONTEXT: Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be defined. OBJECTIVE: To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia. DESIGN, SETTING, AND PATIENTS: Positron emission tomography (PET) studies of [(18)F]fluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000. MAIN OUTCOME MEASURES: Regional distribution of [(18)F]fluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses. RESULTS: Progressive dementia was detected by PET with a sensitivity of 93% (191/206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P<.001). CONCLUSION: In patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of AD and of neurodegenerative disease in general. A negative PET scan indicated that pathologic progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur
— id: 71975, year: 2001, vol: 286, page: 2120, stat: Journal Article,

Changes in brain functional homogeneity in subjects with Alzheimer's Disease
Volkow, N; Zhu, W; Felder, C; Mueller, K; Welsh, T; Wang, GJ; de Leon, M
2001 JUN ;13(6):S276-S276, Neuroimage
— id: 98276, year: 2001, vol: 13, page: S276, stat: Journal Article,

Shift from fibrillar to nonfibrillar Abeta deposits in the neocortex of subjects with Alzheimer disease
Wegiel J; Bobinski M; Tarnawski M; Dziewiatkowski J; Popovitch E; Bobinski M; Lach B; Reisberg B; Miller DC; De Santi S; De Leon MJ
2001 Feb;3(1):49-57, Journal of Alzheimer's Disease
A morphometric study of amyloid-beta-positive plaques in the neocortex of eight non-demented people from 68 to 82 years of age and 17 subjects with late-stage Alzheimer disease (GDS stage 7/FAST stages 7a-f) from 73 to 93 years of age shows a shift from prevalence of fibrillar plaques to prevalence of nonfibrillar plaques. In the aged, non-demented subjects, about 4/mm^2 plaques are detectable in the neocortex, and the majority are fibrillar plaques. Specifically, 64% found to be classical fibrillar and Thioflavin-S-positive bright primitive plaques. A lower percentage of pale primitive plaques (35%) relatively small proportion of plaques that are poor in thioflavin S-positive fibrils. The numerical density of plaques in the severe stage of AD increases to about 41/mm^2. Severely demented subjects appear to maintain an active process of fibrillar plaque formation. This is reflected in the presence of 3% bright primitive plaques. Severely demented subjects also manifest plaque degradation, reflected in the presence of 22% and 48% percentages of classical fibrillar plaques in non-demented subjects and in the end stage of disease suggest that once activated, the process of fibrillar plaque formation persists at a somewhat stable rate during the whole course of brain amyloidosis
— id: 34297, year: 2001, vol: 3, page: 49, stat: Journal Article,

Fibrillar amyloid-beta affects neurofibrillary changes but only in neurons already involved in neurofibrillary degeneration
Wegiel J; Bobinski M; Tarnawski M; Dziewiatkowski J; Popovitch E; Miller DC; Wisniewski T; Golomb J; de Leon MJ; Reisberg B
2001 Jun;101(6):585-590, Acta neuropathologica
The aim of this study of the cerebral cortex of 8 non-demented elderly subjects and of 17 subjects in the severe stage of Alzheimer's disease (AD) (Global Deterioration Scale stage 7/Functional Assessment Staging procedure stage 7a-f) was to examine the relationships between amyloid-beta (Abeta) deposits and neurofibrillary degeneration. The study shows that neuronal processes with neurofibrillary changes are detectable in only a minority of fibrillar plaques: from 31% to 49% of fibrillar plaques within frontal, temporal, parietal, limbic, occipital, and insular cortices. The correlations observed between the numerical densities of neurons with neurofibrillary tangles (NFTs) and the densities of Thioflavin-S-positive fibrillar plaques with neurofibrillary changes (r=0.61; P<0.01) indicate that neurofibrillary pathology in neocortical plaques reflects the topography and rate of neurofibrillary changes in neocortical neurons. The accumulation of abnormally phosphorylated tau in only some plaques indicates that fibrillar Abeta enhances paired helical filament accumulation locally only in dystrophic neurites already involved in neurofibrillary degeneration. The lack of correlation between the number of neurons with neurofibrillary changes and the number of all Thioflavin-S-positive fibrillar plaques (with and without neurofibrillary changes) suggests that beta-amyloidosis does not contribute to initiation of neurofibrillary degeneration in neurons
— id: 34299, year: 2001, vol: 101, page: 585, stat: Journal Article,

Cortisol differentially affects memory in young and elderly men
Wolf OT; Convit A; McHugh PF; Kandil E; Thorn EL; De Santi S; McEwen BS; de Leon MJ
2001 Oct;115(5):1002-1011, Behavioral neuroscience
Nine young and 11 elderly men participated in this placebo-controlled, double-blind, crossover study (0.5 mg/kg cortisol or intravenous placebo). Participants learned a word list before cortisol administration, and delayed recall was then tested. A 2nd word list was learned and recalled after drug administration. In addition, the Paragraph Recall Test and tests measuring working memory (Digit Span), attention (timed cancellation), and response inhibition (Stroop Color and Word Test) were administered at 2 time points after drug administration. Cortisol reduced recall from the word list learned before treatment in both groups but did not influence recall of the list learned after treatment. In contrast, Digit Span performance was decreased by cortisol in young but not elderly participants. The possibility that differential age-associated brain changes might underlie the present results is discussed
— id: 39480, year: 2001, vol: 115, page: 1002, stat: Journal Article,

The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer's disease
Bobinski M; de Leon MJ; Wegiel J; Desanti S; Convit A; Saint Louis LA; Rusinek H; Wisniewski HM
2000 ;95(3):721-725, Neuroscience
For 11 AD cases and four normal elderly controls, post mortem volumes of the hippocampal subdivisions were calculated by using magnetic resonance imaging and histological sections. After at least six weeks of fixation in formalin, brains were examined on a 1.5-T Philips Gyroscan imager producing T1-weighted coronal images with a 3-mm slice thickness. Brains were then processed and embedded in paraffin. Serial coronal sections, 3 mm apart and stained with Cresyl Violet, were used for the planimetry and unbiased estimation of the total numbers of neurons in the hippocampal subdivisions. For all 15 cases, magnetic resonance imaging- and histology-based measurements were performed along the whole rostrocaudal extent of the hippocampal formation and included three subvolumes: (i) the hippocampus (CA1-CA4 and the dentate gyrus); (ii) hippocampus/subiculum; and (iii) hippocampus/parahippocampal gyrus. After controlling for shrinkage, strong correlations were found between magnetic resonance imaging and histological measurements for the hippocampus (r = 0.97, P < 0.001), hippocampus/subiculum (r = 0.95, P < 0.001) and hippocampus/parahippocampal gyrus (r = 0.89, P < 0.001). We also calculated the total number of neurons in the hippocampus and hippocampus/subiculum subvolumes. Strong correlations between the magnetic resonance imaging subvolumes and neuronal counts were found for the hippocampus (r = 0.90, P < 0.001) and the hippocampus/subiculum subvolume (r = 0.84, P < 0.001). We conclude that very accurate volumetric measurements of the whole hippocampal formation can be obtained by using a magnetic resonance imaging protocol. Moreover, the strong correlations between magnetic resonance imaging-based hippocampal volumes and neuronal numbers suggest the anatomical validity of magnetic resonance imaging volume measurements
— id: 8584, year: 2000, vol: 95, page: 721, stat: Journal Article,

Atrophy of the medial occipitotemporal, inferior, and middle temporal gyri in non-demented elderly predict decline to Alzheimer's disease
Convit A; de Asis J; de Leon MJ; Tarshish CY; De Santi S; Rusinek H
2000 Jan-Feb;21(1):19-26, Neurobiology of aging
Our goal was to ascertain, among normal elderly and individuals with mild cognitive impairment, which temporal lobe neocortical regions predicted decline to dementia of the Alzheimer's type (DAT). Individuals received an MRI at baseline and a clinical and cognitive evaluation at baseline and follow-up. By using the baseline MRI we assessed the anatomical subdivisions of the temporal lobe: anteromedial temporal lobe (hippocampus and parahippocampal gyrus), medial occipitotemporal (fusiform) gyrus, middle and inferior temporal gyri, and superior temporal gyrus. We studied two groups of carefully screened age- and education-matched elderly individuals: 26 normal elderly (NL) and 20 individuals with mild cognitive impairment (MCI). Fourteen individuals (12 from the MCI group and two from the NL group) declined to DAT within the 3.2-year follow-up interval. We used logistic regression analyses to ascertain whether the baseline brain volumes were useful predictors of decline to DAT at follow-up after accounting for age, gender, individual differences in brain size, and other variables known to predict DAT. After accounting for age, gender, and head size, adding the volume of the anteromedial temporal lobe (the aggregate of hippocampus and parahippocampal gyrus) and an index of global atrophy raised the accuracy of overall classification to 80.4%. However, the ability to detect those individuals who declined (sensitivity) was low at 57%. When baseline medial occipitotemporal and the combined middle and inferior temporal gyri were added to the logistic model, the overall classification accuracy reached 95.6% and, most importantly, the sensitivity rose to 92.8%. These data indicate that the medial occipitotemporal and the combined middle and inferior temporal gyri may be the first temporal lobe neocortical sites affected in AD; atrophy in these areas may herald the presence of future AD among nondemented individuals. No other clinical baseline variables examined predicted decline with sensitivities above 71%. The apolipoprotein APOE epsilon4 genotype was not associated with decline
— id: 9442, year: 2000, vol: 21, page: 19, stat: Journal Article,

Shift from fibrillar to nonfibrillar A beta deposits in the neocortex of subjects with Alzheimer disease
Wegiel, J; Bobinski, M; Tarnawski, M; Popovitch, E; Lach, B; Reisberg, B; Miller, DC; Wisniewski, T; de Leon, MJ
2000 MAY ;59(5):421-421, Journal of neuropathology & experimental neurology
— id: 54608, year: 2000, vol: 59, page: 421, stat: Journal Article,

MRI of entorhinal cortex in mild Alzheimer's disease
Bobinski M; de Leon MJ; Convit A; De Santi S; Wegiel J; Tarshish CY; Saint Louis LA; Wisniewski HM
1999 Jan 2;353(9146):38-40, Lancet
— id: 9443, year: 1999, vol: 353, page: 38, stat: Journal Article,

MRI volume of the amygdala: a reliable method allowing separation from the hippocampal formation
Convit A; McHugh P; Wolf OT; de Leon MJ; Bobinski M; De Santi S; Roche A; Tsui W
1999 Apr 26;90(2):113-123, Psychiatry research
Studies of MRI-derived volume of the amygdala have been mostly performed on coronal sections where its boundaries with the hippocampus and the entorhinal cortex are indistinct. To date, all reports of in vivo amygdala volume have consistently overestimated the size of the structure. We have developed a method for the MRI-based in vivo measurement of the amygdala volume which allows a better separation of the amygdala from the adjoining hippocampal formation. In nine normal volunteers we obtained three-dimensional spoiled gradient recalled acquisition, 1.3-mm thick, T1 weighted sagittal MR images and created electronically linked reformatted images in the coronal and axial planes. On the original sagittal and the reformatted axial planes, where it is more readily apparent, we delineated the boundaries between the amygdala and the hippocampus and the amygdala and the hippocampo-amygdala transition area, respectively. We then projected those markings onto the coronal plane, where the other boundaries of the amygdala are more easily seen. Using these markings as a guide and utilizing extra-amygdalar coronal landmarks for the anterior end, we outlined the whole amygdala on the coronal plane and determined its volume. We observed that 45% of the coronal slices that contained amygdala also contained some hippocampus. The amygdala measurement had high test-retest reliability, with an intra-class correlation coefficient (rICC) of 0.99 for the total volume and an rICC of 0.93 for the measurement at the level of the individual slice. The average amygdala volume was 1.05 +/- 0.17 cm3 on the right and 1.14 +/- 0.15 cm3 on the left. Our amygdala volumes are in agreement with those reported in postmortem studies, which provides the reported method with face validity
— id: 6200, year: 1999, vol: 90, page: 113, stat: Journal Article,

Hippocampal formation atrophy: An early marker for Alzheimer's disease (AD)
de Leon, MJ
1999 MAR 12 ;13(4):A379-A379, FASEB journal
— id: 53911, year: 1999, vol: 13, page: A379, stat: Journal Article,

An atlas of Alzheimer's disease
De Leon, Mony J; Braak, Heiko
New York : Parthenon Publishing, 1999,
— id: 1795, year: 1999, vol: , page: , stat: ,

Corticosteroids, the Aging Brain and Cognition
McEwen BS; de Leon MJ; Lupien SJ; Meaney MJ
1999 Apr;10(3):92-96, Trends in endocrinology & metabolism
The hippocampal region of the brain is a useful model system for understanding the plasticity and resilience of brain cells to stress hormone action and aging. Hippocampal neurons show both structural and functional plasticity, and individual differences in hippocampal function are shaped by early life experiences. For human brain aging, there are new non-invasive imaging tools to relate to the animal models, and these can help to assess the vulnerability of the aging hippocampus in relation to stress and Alzheimer's disease
— id: 9786, year: 1999, vol: 10, page: 92, stat: Journal Article,

Cerebellar atrophy in Alzheimer's disease-clinicopathological correlations
Wegiel J; Wisniewski HM; Dziewiatkowski J; Badmajew E; Tarnawski M; Reisberg B; Mlodzik B; De Leon MJ; Miller DC
1999 Feb 6;818(1):41-50, Brain research
Morphometry of the cerebellum of 11 subjects who died in the severe, final stage of Alzheimer's disease (AD) and of five age-matched subjects without dementia revealed significant atrophy in the AD group, with a decrease in the volume of the molecular layer by 24% and of the granular layer by 22% in comparison with controls. The 32% decrease in the total number of Purkinje cells that was observed correlates with the atrophy of the molecular layer, whereas the 30% reduction in the total number of granule cells correlates with the atrophy of the molecular and granular layers. A unique pattern of Alzheimer-type pathology was observed in the cerebellum: (1) there were no neurofibrillary changes in the cerebellum of either the control or the AD subjects, (2) there was almost the same extent of leptomeningeal and cortical amyloid angiopathy in the normal aged subjects and in the AD patients, and (3) the presence of plaques was noted in the AD group, but not in the control group. This pattern of pathology suggests that two factors might be considered in the etiopathogenesis of cerebellar atrophy: (1) transneuronal degeneration and neuronal loss resulting from primary pathologic changes in cerebral structures and (2) parenchymal cerebellar ss-amyloidosis. The correlation between the temporal duration of AD and both the decrease of the total number of granule cells (r=0.86, p<0.01) and the volumetric loss of the molecular (r=0.73, p<0.05) and granular (r=0.93, p<0.001) layers of the cerebellar cortex indicates that these cerebellar atrophic changes are likely to be related to the basic pathologic process of AD. Similarly, the correlation between the most complex parameter the atrophy of the cerebellar cortex and the Functional Assessment Staging (FAST) measure of the clinical severity of AD at the time of demise (r=0.63, p<0.05) as well as with the duration of AD (r=0.78, p<0.01) indicates that cerebellar pathology, when viewed holistically, evolves continuously in association with clinical changes throughout the clinically manifest course of AD.
— id: 7465, year: 1999, vol: 818, page: 41, stat: Journal Article,

Effects of cortisol on memory and attention in healthy young and old men
Wolf, OT; Convit, A; Singh, A; Kandil, E; de, Santi S; Tarshish, CY; Gruen, RJ; McEwen, BS; de Leon, MJ
1999 Oct 23-28;25(1-2):896-896, Abstracts (Society for Neuroscience)
— id: 15852, year: 1999, vol: 25, page: 896, stat: Journal Article,

Neuronal and volume loss in CA1 of the hippocampal formation uniquely predicts duration and severity of Alzheimer disease
Bobinski M; de Leon MJ; Tarnawski M; Wegiel J; Reisberg B; Miller DC; Wisniewski HM
1998 Sep 14;805(1-2):267-269, Brain research
In a series of multiple regression models predicting either duration or severity of Alzheimer disease (AD) patients, significant linear correlations were found consistently for the volume of CA1, the subiculum, and the entorhinal cortex. Similarly, the total number of neurons in CA1, CA4, and the subiculum was correlated significantly with both the duration and the severity of AD. A hierarchical multiple regression model was used to examine whether any of these intercorrelated measures had any unique relationship to disease duration or severity. The results showed that only CA1 demonstrated a unique contribution to the explained variance in predicting duration or severity of AD for volume and for neuronal numbers. These results indicate that in the hippocampal formation, volume and neuronal numbers of CA1 appear to show a unique relationship with clinical measures of AD.
— id: 7509, year: 1998, vol: 805, page: 267, stat: Journal Article,

Duration of neurofibrillary changes in the hippocampal pyramidal neurons
Bobinski M; Wegiel J; Tarnawski M; de Leon MJ; Reisberg B; Miller DC; Wisniewski HM
1998 Jul 13;799(1):156-158, Brain research
The total number of neurons with and without neurofibrillary changes in sectors CA1 to CA4, subiculum, and dentate gyrus of 16 subjects with Alzheimer disease (AD) was estimated. The duration of neurofibrillary changes was calculated on the basis of regressions between the duration of AD and neuronal numbers. In the CA1 and subiculum, it takes 3.4 and 5.4 years, respectively, for an intact neuron affected by neurofibrillary pathology to become a ghost tangle.
— id: 7508, year: 1998, vol: 799, page: 156, stat: Journal Article,

What have we learned in 20 years about Alzheimer's disease using (18)FDG-PET?
deLeon, MJ; Alavi, A; Ferris, SH; Christman, DR; Fowler, JS; Wolf, AP
1998 APR 2 ;215(3):U964-U964, Abstracts of papers (American Chemical Society)
— id: 53545, year: 1998, vol: 215, page: U964, stat: Journal Article,

Your shrinking brain [viderecording]
Ferris, Steven; Green, Cynthia R; Leon, Mony J. de
1998,
— id: 724, year: 1998, vol: , page: , stat: ,

Focal dilation and paradoxical collapse of cortical fissures and sulci in patients with normal-pressure hydrocephalus
Holodny AI; George AE; de Leon MJ; Golomb J; Kalnin AJ; Cooper PR
1998 Nov;89(5):742-747, Journal of neurosurgery
OBJECT: The authors describe a subgroup of patients with shunt-proven normal-pressure hydrocephalus (NPH) who presented with focal fissural and sulcal dilation on imaging studies. The specific radiological features and methods of differentiating this condition from cortical atrophy are delineated. METHODS: Normal-pressure hydrocephalus has been described as dilation of the ventricles that is out of proportion to the sulci. Sulcal dilation has been taken as evidence of cortical atrophy and has even been used as a criterion to exclude patients from undergoing a shunting procedure. The authors describe five cases of patients with shunt-proven NPH who presented with focal dilation of cortical fissures and sulci. In three of the cases, there was a paradoxical decrease in the size of the dilated fissures and sulci that paralleled the decrease in the size of the lateral ventricles following successful shunting. CONCLUSIONS: This study demonstrates that focal fissural and sulcal dilation may represent reservoirs of cerebrospinal fluid analogous to the ventricular system. Patients should not be denied a shunting procedure solely on the basis of focally dilated fissures of sulci
— id: 7348, year: 1998, vol: 89, page: 742, stat: Journal Article,

The perihippocampal fissures: normal anatomy and disease states
Holodny AI; George AE; Golomb J; de Leon MJ; Kalnin AJ
1998 May-Jun;18(3):653-665, Radiographics
Understanding the three-dimensional anatomy of the perihippocampal fissures (PHFs) can be helpful in making the correct diagnosis of diseases of the mesial temporal lobe. Disorders of the parenchyma and cerebrospinal fluid spaces are reflected by specific changes in the PHFs. A marker for Alzheimer disease and mesial temporal sclerosis is atrophy of the hippocampus and associated dilatation of the PHFs. This finding is best visualized on coronal magnetic resonance images but can and should be appreciated on routine computed tomographic scans. Hydrocephalus is characterized by dilatation of the temporal horn of the lateral ventricle without dilatation of the transverse fissure and its extensions. Normal-pressure hydrocephalus can usually be distinguished from Alzheimer disease on the basis of the pattern of dilatation of the PHFs. Understanding the anatomy of the PHFs often makes it possible to better characterize the extents of intra- and extraaxial tumors of the mesial temporal lobe
— id: 7606, year: 1998, vol: 18, page: 653, stat: Journal Article,

MR differential diagnosis of normal-pressure hydrocephalus and Alzheimer disease: significance of perihippocampal fissures
Holodny AI; Waxman R; George AE; Rusinek H; Kalnin AJ; de Leon M
1998 May;19(5):813-819, AJNR. American journal of neuroradiology
PURPOSE: In the older patient with dilated ventricles, it is often difficult to differentiate normal pressure hydrocephalus (NPH) from cerebral atrophy caused by Alzheimer disease (AD). This study was undertaken to see if dilatation of the perihippocampal fissures (PHFs) could be used as a distinguishing characteristic of these two disorders. METHODS: MR images of 17 patients with AD were compared with those from an equal number of patients with NPH who improved after ventriculoperitoneal shunting. The PHFs, lateral ventricles, third ventricle, and temporal horns were graded subjectively. Objective, computer-aided volumetric measurements of the PHFs and lateral ventricles were obtained. The preshunt images of the NPH patients were evaluated. RESULTS: Significant differences between the two groups were found for the PHFs and lateral ventricles by both the subjective and objective methods, with a high degree of correlation between the two methods. CONCLUSION: The degree of dilatation of PHFs appears to be a sensitive and specific marker for differentiating AD from NPH by both subjective and objective means, with a very small overlap between the two groups. This observation may have relevance in day-to-day practice
— id: 12119, year: 1998, vol: 19, page: 813, stat: Journal Article,

Cortisol levels during human aging predict hippocampal atrophy and memory deficits [see comments] [published erratum appears in Nat Neurosci 1998 Aug;1(4):329]
Lupien SJ; de Leon M; de Santi S; Convit A; Tarshish C; Nair NP; Thakur M; McEwen BS; Hauger RL; Meaney MJ
1998 May;1(1):69-73, Nature neuroscience
Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Previously we related persistent cortisol increases to memory impairments in elderly humans studied over five years. Here we demonstrate that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans
— id: 7666, year: 1998, vol: 1, page: 69, stat: Journal Article,

Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease
Reiman EM; Uecker A; Caselli RJ; Lewis S; Bandy D; de Leon MJ; De Santi S; Convit A; Osborne D; Weaver A; Thibodeau SN
1998 Aug;44(2):288-291, Annals of neurology
Brain imaging techniques have the potential to characterize neurobiological changes that precede the onset of cognitive impairment in persons at risk for Alzheimer's disease. As previously described, positron emission tomography (PET) was used to compare 11 cognitively normal persons 50 to 62 years of age who were homozygous for the epsilon4 allele of apolipoprotein E and 22 persons without the epsilon4 allele with a reported family history of Alzheimer's dementia who were matched for sex, age, and level of education. The epsilon4 homozygotes had significantly reduced glucose metabolism in the same brain regions as patients with Alzheimer's dementia; the largest reduction was in the posterior cingulate cortex. As described here, magnetic resonance imaging (MRI) was used to compare hippocampal volumes in the same subject groups. The epsilon4 homozygotes showed nonsignificant trends for smaller left and right hippocampal volumes; overall, smaller hippocampal volumes were associated with reduced performance on a long-term memory test. Whereas PET measurements of cerebral glucose metabolism begin to decrease before the onset of memory decline, MRI measurements of hippocampal volume begin to decrease in conjunction with memory decline in cognitively normal persons at risk for Alzheimer's disease
— id: 7752, year: 1998, vol: 44, page: 288, stat: Journal Article,

Relationships between regional neuronal loss and neurofibrillary changes in the hippocampal formation and duration and severity of Alzheimer disease
Bobinski M; Wegiel J; Tarnawski M; Bobinski M; Reisberg B; de Leon MJ; Miller DC; Wisniewski HM
1997 Apr;56(4):414-420, Journal of neuropathology & experimental neurology
The total numbers of neurons with and without neurofibrillary changes in the hippocampal subdivisions were estimated in 16 subjects with Alzheimer disease (AD) and in 5 normal elderly controls. On the basis of clinical symptoms, AD patients were subdivided into relatively less (AD-1. Functional Assessment Staging [FAST] stages 7a to 7c) and more severely affected (AD-2, FAST stages 7e to 7f) patient groups. In the AD-1 group relative to controls, the total number of neurons was reduced only in CA1 and in the subiculum. In the AD-2 group, neuronal losses were found in all sectors of the cornu Ammonis and in the subiculum and ranged from 53% in CA3 to 86% in CA1. The dentate gyrus was the only hippocampal subdivision without significant neuronal loss. Within the combined AD patient groups, significant correlations were noted between both clinical stage and duration of AD and both the total number of neurons and the percentage of neurons with neurofibrillary changes in CA1, CA4, and the subiculum. Regression analyses predicted neuronal losses over the maximal observed duration of 22 years of 87% in CA1, 63% in CA4, and 77% in the subiculum. Our data suggest that over the course of AD, continuous neurofibrillary tangle formation and continuous neuronal loss occur in the hippocampal subdivisions. The rate of neuronal loss appears to be similar for CA1, CA4, and the subiculum
— id: 9448, year: 1997, vol: 56, page: 414, stat: Journal Article,

Specific hippocampal volume reductions in individuals at risk for Alzheimer's disease
Convit A; De Leon MJ; Tarshish C; De Santi S; Tsui W; Rusinek H; George A
1997 Mar-Apr;18(2):131-138, Neurobiology of aging
Our goal was to ascertain the involvement of the temporal lobe in the preclinical (not yet diagnosable) stages of dementia of the Alzheimer's type (DAT) by using MRI-derived volumes. We assessed anatomical subdivisions of the temporal lobe on three groups of carefully screened age- and education-matched elderly individuals: 27 normal elderly (NL), 22 individuals with minimal cognitive impairment (MCI), who did not fulfill DAT criteria but were regarded at high risk for future DAT, and 27 DAT individuals. We found hippocampal volume reductions of 14% for the MCI and 22% for the DAT group compared to the NL group. Utilizing regression analyses and after accounting for gender head size-age, generalized atrophy (CSF), and other temporal lobe subvolumes, the hippocampal volume separated NL from MCI individuals, correctly classifying 74%. For NL and MCI groups combined the hippocampal volume was the only temporal lobe subvolume related to delayed recall memory performance. When contrasting MCI and DAT individuals, the fusiform gyrus volume uniquely improved the ability of the hippocampal volume to separate MCI from DAT individuals from 74 to 80%. Our cross-sectional data suggest that, within the temporal lobe, specific hippocampal volume reductions separated the group at risk for DAT from the normal group. By the time impairments are sufficient to allow a diagnosis of DAT to be made, in addition to the medial temporal lobe volume reductions, the lateral temporal lobe is also showing volume reductions, most saliently involving the fusiform gyrus
— id: 7134, year: 1997, vol: 18, page: 131, stat: Journal Article,

Hippocampal atrophy as detected by width of the temporal horn is greater in Alzheimer dementia than in nondementing cognitive impairment - Comment
Convit, A; deLeon, MJ; Tarshish, C; DeSanti, S; Wells, C; George, A; SaintLouis, LA; Rusinek, H
1997 JUN-JUL ;18(6):1193-1195, AJNR. American journal of neuroradiology
— id: 73272, year: 1997, vol: 18, page: 1193, stat: Journal Article,

Contribution of structural neuroimaging to the early diagnosis of Alzheimer's disease
de Leon MJ; Convit A; DeSanti S; Bobinski M; George AE; Wisniewski HM; Rusinek H; Carroll R; Saint Louis LA
1997 ;9 Suppl 1:183-190, International psychogeriatrics
There is compelling evidence for the early involvement of the hippocampal formation in the natural history of Alzheimer's disease (AD). The evidence comes from recent neuropathology, neuropsychology, and neuroimaging studies. AD-type histopathologic changes limited to the hippocampus have been described and may be seen in normal aging subjects. The sites of maximal neuronal loss in the hippocampal formation are in the CA1, subiculum, and entorhinal cortex. Minimally cognitively impaired (MCI) individuals (defined by ratings of functional capacity and psychiatric symptomatology) exhibit a neuropsychological profile that is distinct from that of the unimpaired elderly. Pathologic evidence suggests that most of these cases already have AD brain changes accentuated in the hippocampal region, and our own longitudinal studies reveal that 70% of this group develop dementia within a 4-year period. We have developed a negative-angle axial view designed to cut parallel to the anterior-posterior plane of the hippocampus. Using this modified axial plane of section in conjunction with computed tomography (CT) and magnetic resonance imaging (MRI), we estimated the prevalence of hippocampal atrophy in normal aging and across severity levels of cognitively impaired elderly patients. Longitudinal study shows that hippocampal atrophy is a sensitive and specific predictor of future AD for patients with MCI. MRI volume study of AD patients, controls, and MCI patients shows specific hippocampal volume loss in MCI. We conclude that the atrophic changes associated with early AD can be visualized using qualitative techniques and are readily quantifiable with volumetry. This article is not intended to be comprehensive, but to provide an overview of some of the structural neuroimaging data from our laboratory
— id: 9444, year: 1997, vol: 9 Suppl 1, page: 183, stat: Journal Article,

Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease
De Leon MJ; George AE; Golomb J; Tarshish C; Convit A; Kluger A; De Santi S; McRae T; Ferris SH; Reisberg B; Ince C; Rusinek H; Bobinski M; Quinn B; Miller DC; Wisniewski HM
1997 Jan-Feb;18(1):1-11, Neurobiology of aging
We used CT and MR to examine the frequency of occurrence of hippocampal formation atrophy (HA) in a research clinic population of 130 normal elderly, 72 nondemented patients with very mild memory and cognitive impairments (MCI), 73 mild Alzheimer's disease (AD) patients, and 130 patients with moderate to severe AD. HA was found in 29% of the normal elderly group and its frequency of occurrence was strongly related to increasing age. For normal elderly 60-75 years of age, 15% had HA: the proportion rose to 48% in subjects 76-90 years of age. Among the three groups of impaired patients, the frequencies of HA ranged from 78% in the MCI patients to 96% in the advanced AD group. Unlike the normal elderly group, the percentages were not related to age. In both the normal elderly group and MCI group disproportionately more males than females had HA. After controlling for learning and the effects of generalized brain changes as reflected in ventricular size, only in the normal group was HA associated with reduced delayed verbal recall performance. Follow-up examinations for 15 individuals with baseline HA. 4 who at entry were MCI and 11 probable AD, yielded clinical and neuropathologic diagnoses of AD in all cases. The results of the present study indicate that hippocampal formation atrophy is associated with memory and cognitive impairments. Further longitudinal and neuropathologic work is required to validate the relationship between hippocampal formation atrophy and AD
— id: 9449, year: 1997, vol: 18, page: 1, stat: Journal Article,

Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimer's disease
de Leon MJ; McRae T; Rusinek H; Convit A; De Santi S; Tarshish C; Golomb J; Volkow N; Daisley K; Orentreich N; McEwen B
1997 Oct;82(10):3251-3259, Journal of clinical endocrinology & metabolism
Glucocorticoids are known to play a role in the regulation of peripheral glucose mobilization and metabolism. Although several animal studies have shown that hippocampal glucose metabolism is reduced acutely and chronically by the action of corticosterone and that excess glucocorticoids are harmful to hippocampal neurons, little is known about the central effects of glucocorticoids in the human. In this study we examined the brain glucose utilization (CMRglu) response to hydrocortisone (cortisol) in seven normal elderly and eight Alzheimer's disease (AD) patients. On 2 separate days, immediately after the administration of a bolus of either 35 mg hydrocortisone or placebo, we administered 2-deoxy-2-[18F]fluoro-D-glucose. After a 35-min radiotracer uptake period, positron emission tomography (PET) images were collected. PET CMRglu images were analyzed using two methods: an image transformation that allowed analyses across cases on a voxel by voxel basis, and an anatomically based region of interest method that used coregistered magnetic resonance imaging scans. Both image analysis methods yielded similar results, identifying relative to placebo, a specific hippocampal CMRglu reduction in response to the hydrocortisone challenge that was restricted to the normal group. The region of interest technique showed CMRglu reductions of 16% and 12% in the right and left hippocampi, respectively. Blood collected during the PET scans showed, for the normal group, a rise in plasma glucose levels, starting approximately 25 min after hydrocortisone administration. The AD group did not show this effect. Baseline cortisol was elevated in the AD group, but the clearance of hydrocortisone was not different between the groups. In conclusion, these data show that among normal individuals in the presence of a pharmacological dose of cortisol, the glucose utilization of the hippocampus is specifically reduced, and serum glucose levels increase. Based in part on other studies, we offer the interpretation that glucocorticoid-mediated regulation of glucose transport is altered in AD, and this may underlie both the hippocampal insensitivity to cortisol and the failure in these patients to mount a peripheral glucose response. As our findings could reflect an altered state of the AD patients, we interpret our results as preliminary with respect to evidence for metabolic abnormalities in AD. The results suggest the continued study of the hydrocortisone challenge as a test of hippocampal responsivity
— id: 9447, year: 1997, vol: 82, page: 3251, stat: Journal Article,

Imaging the brain in dementia: expensive and futile?
George AE; de Leon MJ; Golomb J; Kluger A; Convit A
1997 Nov-Dec;18(10):1847-1850, AJNR. American journal of neuroradiology
— id: 9445, year: 1997, vol: 18, page: 1847, stat: Journal Article,

Neurofibrillary pathology--correlation with hippocampal formation atrophy in Alzheimer disease
Bobinski M; Wegiel J; Wisniewski HM; Tarnawski M; Bobinski M; Reisberg B; De Leon MJ; Miller DC
1996 Nov-Dec;17(6):909-919, Neurobiology of aging
The three-dimensionally reconstructed hippocampal formations in three patients with very severe, immobile Alzheimer disease (AD) and three age-matched nondemented individuals were examined for a correlation between atrophy of hippocampal formation subdivisions and neurofibrillary changes, neuronal loss, and extent of amyloid deposition in plaques and vessels. In AD, a similar severe volume loss was observed in both cellular layers and layers composed of fibers. A strong correlation between the decrease in the volume of hippocampal formation subdivisions and the decrease in the total number of neurons suggests a causative role for neuronal loss in hippocampal formation volumetric loss. Strong regional correlations between the relative decreases in the total number of neurons and the relative increases in the total number of neurofibrillary tangles implicates neurofibrillary pathology as a possible etiologic proximate factor in neuronal and volumetric loss in the hippocampal formation of AD patients
— id: 9446, year: 1996, vol: 17, page: 909, stat: Journal Article,

In vivo structural studies of the hippocampus in normal aging and in incipient Alzheimer's disease
de Leon MJ; Convit A; George AE; Golomb J; de Santi S; Tarshish C; Rusinek H; Bobinski M; Ince C; Miller D; Wisniewski H
1996 Jan 17;777:1-13, Annals of the New York Academy of Sciences
Population trends indicate that in the near future the size of the elderly population will increase. This will result in a large increment in the numbers of persons suffering mild to severe levels of cognitive impairment. While considerable efforts continue to be made to explain brain changes associated with Alzheimer disease (AD), little is known of the brain changes in aging without dementia or so-called normal aging. Pathologic studies suggest that the medial temporal lobe is informative in the examination of the early brain changes related to AD. However, pathologic studies only offer a single observation and considerable uncertainty exists regarding the likelihood of progression of disease and the development of dementia. Several structural neuroimaging studies have recently investigated this anatomy and recent reports are encouraging for a medial temporal lobe based diagnosis for age-related cognitive impairments. We will present our findings on the MRI anatomy of the hippocampal formation as well as data bearing on the use of hippocampal formation imaging in the diagnosis of AD and as a predictive marker for future dementia. Our findings suggest an anatomically specific relationship between hippocampal volume and secondary memory performance. Because these observations apply to nondemented and normal elderly subjects, we are encouraged that the anatomy of age-related cognitive impairments can be reliably recognized and possibly put to use in therapeutic studies
— id: 6989, year: 1996, vol: 777, page: 1, stat: Journal Article,

Hippocampal formation size predicts declining memory performance in normal aging
Golomb J; Kluger A; de Leon MJ; Ferris SH; Mittelman M; Cohen J; George AE
1996 Sep;47(3):810-813, Neurology
Hippocampal formation (HF) atrophy, although common in normal aging, has unknown clinical consequences. We used MRI to derive HF size measurements at baseline on 44 cognitively normal older adults entering a longitudinal study of memory function (mean age = 68.4 years, mean follow-up = 3.8 years). Only one subject became demented at follow-up. Multiple regression analyses controlling for age, gender, education, and diffuse cerebral atrophy revealed that HF size significantly predicted longitudinal change on memory tests previously found sensitive to decline in normal aging. These results indicate HF atrophy may be a risk factor for accelerated memory dysfunction in normal aging
— id: 7157, year: 1996, vol: 47, page: 810, stat: Journal Article,

Mortality and temporal course of probable Alzheimer's disease: a 5-year prospective study
Reisberg B; Ferris SH; Franssen EH; Shulman E; Monteiro I; Sclan SG; Steinberg G; Kluger A; Torossian C; de Leon MJ; Laska E
1996 Summer;8(2):291-311, International psychogeriatrics
Alzheimer's disease (AD) is associated with an increased mortality in comparison with aged control populations. The relationship between the clinical and the temporal course of AD has not been well studied over significant intervals. Community-residing patients with probable AD (N = 103, 42 men, mean age = 70.2 +/- 8.0 years) were studied at baseline on demographic and clinical variables, including measures of global deterioration (Global Deterioration Scale; GDS), mental status and cognition (e.g., Mini-Mental State Examination; MMSE), and functional impairment (Functional Assessment Staging; FAST). Baseline characteristics included a GDS range of Stage 4, 5, or 6 (38.8%, 39.8%, and 21.4%, respectively) and a mean MMSE score of 15.4 +/- 5.6. The mean follow-up interval was 4.6 +/- 1.4 years. Follow-ups were done blind to baseline measures and when necessary were conducted in residential and nursing home settings. Of locatable subjects (n = 95, 92%), 30 (31.6%) were decreased. Survivors (n = 65) had a mean GDS stage of 6.2 +/- 0.9 and a mean MMSE score of 5.1 +/- 6.9; 51% had MMSE scores of 0. Increased age and male gender, but not baseline clinical dementia variables, increased the risk of death (ps < .01). Change in clinical variables correlated significantly with time elapsed (r = .32, p < .05, for MMSE change, to r = .48, p < .001, for GDS change). Significant variance in temporal change (i.e., time elapsed) was accounted for by change in two of the five clinical measures studied (i.e., GDS and FAST; multiple r = .53). The results support previous estimates of mean duration of the GDS and FAST stages. For subjects with probable AD followed over approximately 5 years, clinical variables changed significantly over time in survivors. However, the majority of temporal variance in the course of AD remains unexplained
— id: 9450, year: 1996, vol: 8, page: 291, stat: Journal Article,

Atrophy of hippocampal formation subdivisions correlates with stage and duration of Alzheimer disease
Bobinski M; Wegiel J; Wisniewski HM; Tarnawski M; Reisberg B; Mlodzik B; de Leon MJ; Miller DC
1995 Jul-Aug;6(4):205-210, Dementia
The hippocampal formations of 13 subjects with severe Alzheimer disease [AD; Global Deterioration Scale (GDS) stage 7] and of 5 age-matched subjects without symptoms of dementia were reconstructed from serial sections. Functional assessment staging (FAST) was used at the time of demise to assess 9 patients at stages 7a-c (incipient averbal and nonambulatory) and 4 patients at stages 7e-f (immobile). The duration of the disease from FAST stage 5 until demise ranged from 2 to 8 years in the first of these subgroups, and from 10 to 13 years in the second. The volumes of the entire hippocampal formation and of the cornu ammonis, its sectors and layers, the dentate gyrus, the subicular complex, and the entorhinal cortex were calculated. Hippocampal formation volume decreased by 36% in the incipient averbal and nonambulatory patients and by 60% in the severely functionally impaired immobile patients, in comparison with controls. In the final substages of AD, immobile patients exhibited significant atrophy, in comparison with controls, in the cornu ammonis and all of its sectors and layers except CA4, the subicular complex and all of its parts, and the entorhinal cortex (p < 0.05). Within the AD patient group, significant correlations were noted between both the magnitude of functional severity and the duration of AD and the volumes of most hippocampal formation subdivisions studied. For the cornu ammonis, subicular complex, and entorhinal cortex, volumetric loss correlations with FAST stage 7 ordinally enumerated substages were r = -0.71, -0.79, and -0.62, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 9451, year: 1995, vol: 6, page: 205, stat: Journal Article,

NEURONAL LOSS IN HIPPOCAMPAL-FORMATION SUBDIVISIONS CORRELATES WITH DURATION AND STAGE OF ALZHEIMER-DISEASE
BOBINSKI, M; WEGIEL, J; WISNIEWSKI, HM; TAMAWSKI, M; BOBINSKA, M; REISBERG, B; MLODZIK, B; DELEON, M; MILLER, DC
1995 MAY ;54(3):428-428, Journal of neuropathology & experimental neurology
— id: 87306, year: 1995, vol: 54, page: 428, stat: Journal Article,

Age-related changes in brain: I. Magnetic resonance imaging measures of temporal lobe volumes in normal subjects
Convit A; de Leon MJ; Hoptman MJ; Tarshish C; De Santi S; Rusinek H
1995 Winter;66(4):343-355, Psychiatric quarterly
The volume of temporal lobe structures was examined in twenty-seven older (mean age of 69.2 +/- 8.3 years) and ten younger subjects (mean age of 26.1 +/- 4.1 years) using quantitative magnetic resonance imaging (MRI) methods. Multiple regression analysis, using gender, overall atrophy, and head size as covariates, showed unique contributions of age to variance in both medial and lateral temporal lobe volumes. Temporal lobe subregions that showed the strongest unique age-related reductions were the hippocampus, fusiform gyrus, and parahippocampus. These results suggest age-related reductions in temporal lobe subvolumes
— id: 9455, year: 1995, vol: 66, page: 343, stat: Journal Article,

Hippocampal volume losses in minimally impaired elderly
Convit A; de Leon MJ; Tarshish C; De Santi S; Kluger A; Rusinek H; George AE
1995 Jan 28;345(8944):266-266, Lancet
— id: 9453, year: 1995, vol: 345, page: 266, stat: Journal Article,

HIPPOCAMPAL ATROPHY AND COGNITIVE IMPAIRMENT - REPLY
CONVIT, A; DELEON, MJ; TARSHISH, C; DESANTI, S; RUSINEK, H; GEORGE, AE
1995 APR 15 ;345(8955):992-992, Lancet
— id: 73276, year: 1995, vol: 345, page: 992, stat: Journal Article,

The hippocampus in aging and Alzheimer's disease
de Leon MJ; Convit A; DeSanti S; Golomb J; Tarshish C; Rusinek H; Bobinski M; Ince C; Miller DC; Wisniewski HM
1995 Feb;5(1):1-17, Neuroimaging clinics of North America
The role of imaging in the evaluation of neurodegenerative disorders is summarized. The primary role of imaging is to exclude potentially treatable disorders such as meningioma, extracerebral hematoma, Wernicke's disease, and hypothyroidism. Atrophic changes dominate in the hippocampal region on Alzheimer's disease versus the anterior, frontal, and temporal lobes in Pick's disease. Signal hypointensity in the putamen on T2-weighted spin-echo images favors poorly drug-responsive Parkinson's disease whereas putaminal hyperintensity is observed with Creutzfeldt-Jacob, Wilson's, and Leigh's diseases. As our population ages, a thorough understanding of imaging findings in a geriatric population assumes an increasing importance
— id: 6602, year: 1995, vol: 5, page: 1, stat: Journal Article,

Age-related changes in brain: II. Positron emission tomography of frontal and temporal lobe glucose metabolism in normal subjects
De Santi S; de Leon MJ; Convit A; Tarshish C; Rusinek H; Tsui WH; Sinaiko E; Wang GJ; Bartlet E; Volkow N
1995 Winter;66(4):357-370, Psychiatric quarterly
While many neuropsychological studies have demonstrated age-related performance alterations in tests thought to reflect frontal and temporal lobe function, there is little direct observation and comparison of these hypothesized brain changes in vivo. The cerebral glucose metabolism of frontal, temporal, and cerebellar regions was examined in 40 young (mean = 27.5 +/- 4.9) and 31 elderly (mean = 67.6 +/- 8.8) normal males using PET-FDG. Univariate analysis showed age-related metabolic reductions in all frontal and temporal lobe regions. The reductions ranged from 13%-24% with the greatest changes in the frontal lobes. Multiple regression analyses showed a stronger age relationship with frontal lobe than with temporal lobe metabolism. The dorsal lateral frontal lobe was the region that appears to change most within the frontal lobes. Examination of the temporal lobe showed that age contributed equally to the metabolic variance of both the lateral temporal lobe and hippocampus. These results suggest that age-related metabolic changes exist in both frontal and temporal lobes and that the frontal lobe change is greater
— id: 9454, year: 1995, vol: 66, page: 357, stat: Journal Article,

The differential diagnosis of Alzheimer's disease. Cerebral atrophy versus normal pressure hydrocephalus
George AE; Holodny A; Golomb J; de Leon MJ
1995 Feb;5(1):19-31, Neuroimaging clinics of North America
This article summarizes the neuroradiology of Alzheimer's disease (AD) and details the radiologic features that permit the identification of patients with normal pressure hydrocephalus (NPH). Patients with presumed AD show a characteristic atrophy pattern with specific involvement of the temporal lobes and hippocampus. These findings have prognostic implications. Patients with NPH typically show severe motoric and gait deficits and initially mild cognitive impairment. Marked improvement is shown in select patients after ventricular shunting
— id: 9452, year: 1995, vol: 5, page: 19, stat: Journal Article,

Nonspecific leukoencephalopathy associated with aging
Golomb J; Kluger A; Gianutsos J; Ferris SH; de Leon MJ; George AE
1995 Feb;5(1):33-44, Neuroimaging clinics of North America
With advancing age, the periventricular and subcortical white matter becomes susceptible to a heterogeneous assortment of tissue alterations that cannot be easily categorized in terms of traditionally defined neuropathologic disease. These alterations, which appear radiolucent on CT and hyperintense on T2-weighted MR imaging, are more common in patients with chronic hypertension and perhaps other microvascular arteriosclerotic risk factors. Examination of the affected tissue reveals a spectrum of histologic change that is graded with respect to pathologic severity. The majority of the alterations are of low histopathologic grade and exert minimal clinical effects. Frequently observed microscopic changes include dilated perivascular (Virchow-Robin) spaces, mild demyelination, gliosis, and diffuse regions neuropil vacuolation. Associated clinical abnormalities, when present, are usually confined to deficits of attention, mental processing speed, and psychomotor control. These deficits may often be demonstrable only through neuropsychologic testing. There is some evidence that the cognitive symptoms of AD may be exacerbated by the concomitant presence of these white matter alterations, but an etiologic link between AD and radiographically detectible white matter changes remains speculative. Occasionally, histologically severe white matter lesions may occur that result in dementia and focal neurologic impairment. These lesions are characterized by extensive arteriosclerosis, diffuse white matter necrosis, and lacunar infarction; affected patients may receive a diagnosis of Binswanger's disease or subcortical arteriosclerotic encephalopathy. Nevertheless, severe ischemic white matter pathology of this type is uncommon as an explanation for serious neurologic dysfunction, and clinicians must carefully weigh other categories of neuropathology before making a diagnosis of Binswanger's disease. Alternative diagnostic considerations include neurodegenerative illnesses such as AD, cerebral infarction, neoplasm, and other forms of white matter pathology such as those due to infection, inflammation, a primary demyelinative condition, or metabolic leukodystrophy
— id: 6631, year: 1995, vol: 5, page: 33, stat: Journal Article,

CEREBELLAR ATROPHY AND BETA-AMYLOIDOSIS IN AD
WEGIEL, J; WISNIEWSKI, HM; DZIEWIATKOWSKI, J; BADMAJEW, E; TAMAWSKI, M; REISBERG, B; MLODZIK, B; DELEON, M; MILLER, DC
1995 MAY ;54(3):428-428, Journal of neuropathology & experimental neurology
— id: 87305, year: 1995, vol: 54, page: 428, stat: Journal Article,

Hydrocephalus, cerebral atrophy and related disorders
George AE; de Leon MJ
Computed tomography and magnetic resonance imaging of the whole body St. Louis MO : Mosby, 1994,
— id: 4992, year: 1994, vol: , page: ?, stat: Chapter,

Hippocampal atrophy correlates with severe cognitive impairment in elderly patients with suspected normal pressure hydrocephalus
Golomb J; de Leon MJ; George AE; Kluger A; Convit A; Rusinek H; de Santi S; Litt A; Foo SH; Ferris SH
1994 May;57(5):590-593, Journal of neurology neurosurgery & psychiatry
Measurements of hippocampal formation atrophy using MRI have been useful in distinguishing demented patients with a diagnosis of probable Alzheimer's disease from cognitively normal controls. To determine whether there is a similar relationship between hippocampal size and dementia in elderly patients suspected of normal pressure hydrocephalus (NPH), the authors obtained mini-mental status examination (MMSE) scores and MRI measurements of hippocampal size and CSF volume on 16 elderly patients whose severe ventriculomegaly and unexplained gait impairment made NPH a probable diagnosis. Hippocampal size correlated strongly with MMSE score (r = 0.75, p < 0.001); no significant MMSE correlation was found for ventricular CSF volume or extra-ventricular/ventricular CSF ratio. It was concluded that hippocampal atrophy is associated with severe cognitive dysfunction in many elderly patients with a diagnosis of NPH. As a hypothesis for further investigation, the detection of such atrophy may help identify cases where the presence of a pathology of Alzheimer's disease complicates the diagnosis of NPH
— id: 6390, year: 1994, vol: 57, page: 590, stat: Journal Article,

Hippocampal formation size in normal human aging: a correlate of delayed secondary memory performance
Golomb J; Kluger A; de Leon MJ; Ferris SH; Convit A; Mittelman MS; Cohen J; Rusinek H; De Santi S; George AE
1994 May-Jun;1(1):45-54, Learning & memory
Although mild progressive memory impairment is commonly associated with normal human aging, it is unclear whether this phenomenon can be explained by specific structural brain changes. In a research sample of 54 medically healthy and cognitively normal elderly persons (ages 55-87, x = 69.0 +/- 7.9), magnetic resonance imaging (MRI) was used to derive head-size-adjusted measurements of the hippocampal formation (HF) (dentate gyrus, hippocampus proper, alveus, fimbria, subiculum), the superior temporal gyrus (STG), and the subarachnoid cerebrospinal fluid (CSF) (to estimate generalized cerebral atrophy). Subjects were administered tests of primary memory (digit span) and tests of secondary memory with immediate and delayed recall components (paragraph, paired associate, list recall; facial recognition). Separate composite scores for the immediate and delayed components were created by combining, with equal weighting, the subtests of each category. The WAIS vocabulary subtest was used as a control measure for language and intelligence. A highly significant correlation (P < 0.001), independent of age, gender, and generalized cerebral atrophy was found between HF size and delayed memory performance. No significant correlations were found between HF size and primary or immediate memory performance. STG size was not significantly correlated with any of the composite memory variables. These results suggest that HF atrophy may play an important independent role in contributing to the memory loss experienced by many aging adults
— id: 6632, year: 1994, vol: 1, page: 45, stat: Journal Article,

Hippocampal atrophy in early Alzheimer's disease: anatomic specificity and validation
Convit A; de Leon MJ; Golomb J; George AE; Tarshish CY; Bobinski M; Tsui W; De Santi S; Wegiel J; Wisniewski H
1993 Winter;64(4):371-387, Psychiatric quarterly
We evaluated three groups of elderly individuals who were carefully screened to rule out clinically significant diseases that could affect cognition. They were matched for age and education. The groups included normals (N = 18), Alzheimer's Disease (AD) patients (N = 15), and minimally impaired individuals with memory complaints and impairments but who did not fulfill criteria for AD (N = 17). Volumetric measurements of different regions of the temporal lobe on the coronal scan as well as ratings of the perihippocampal cerebrospinal fluid (CSF) accumulation (HCSF) on the negative angle axial MR were carried out. Volume reductions were found in AD relative to the normals for both medial and lateral temporal lobe volumes. Only hippocampal volume reductions were found in the minimal group. The minimally impaired individuals had equivalent hippocampal volume reductions and significantly larger parahippocampal and lateral temporal lobe gyri than the AD group. The axial HCSF was validated using the coronal volumes. The combination of coronal hippocampal and perihippocampal CSF was the best predictor of the axial HCSF rating. The parahippocampal volume did not add to the predictive ability of the hippocampal-perihippocampal CSF combination. Future work should validate these findings with longitudinal designs as well as assess the issue of normal aging of these structures and their relationship to cognitive function
— id: 6340, year: 1993, vol: 64, page: 371, stat: Journal Article,

Measurement of medial temporal lobe atrophy in diagnosis of Alzheimer's disease
de Leon MJ; Golomb J; Convit A; DeSanti S; McRae TD; George AE
1993 Jan 9;341(8837):125-126, Lancet
— id: 9457, year: 1993, vol: 341, page: 125, stat: Journal Article,

The radiologic prediction of Alzheimer disease: the atrophic hippocampal formation
de Leon MJ; Golomb J; George AE; Convit A; Tarshish CY; McRae T; De Santi S; Smith G; Ferris SH; Noz M; et al
1993 Jul-Aug;14(4):897-906, AJNR. American journal of neuroradiology
PURPOSE: To test the hypothesis that atrophy of the hippocampal formation in nondemented elderly individuals would predict subsequent Alzheimer disease. METHOD: We studied 86 subjects at two time points, 4 years apart. At baseline all study subjects were nondemented and included 54 control subjects and 32 persons who had memory complaints and minimal cognitive impairments. All subjects received a CT scan using a protocol designed to image the perihippocampal cerebrospinal fluid (HCSF) accumulating in the fissures along the axis of the hippocampal formation. Blind to the clinical evaluations, we subjectively assessed the presence of HCSF at the baseline. Retrospectively, we examined the predicted association between baseline HCSF and clinical decline as determined across the two evaluations. RESULTS: At follow-up 25 of the 86 subjects had deteriorated and received the diagnosis of Alzheimer disease. Of the declining subjects, 23 came from the minimally impaired group, and 2 came from the control group. In the minimally impaired group the baseline HCSF measure had a sensitivity of 91% and a specificity of 89% as a predictor of decline. Both control subjects who deteriorated were also correctly identified at baseline. One of these two subjects died, and an autopsy confirmed the presence of Alzheimer disease. M(r) validation studies demonstrated that HCSF is quantitatively related to dilatation of the transverse fissure of Bichat and the choroidal and hippocampal fissures. CONCLUSION: Our findings strongly suggest that among persons with mild memory impairments, dilatation of the perihippocampal fissures is a useful radiologic marker for identifying the early features of Alzheimer disease
— id: 9456, year: 1993, vol: 14, page: 897, stat: Journal Article,

Hippocampal atrophy in normal aging. An association with recent memory impairment
Golomb J; de Leon MJ; Kluger A; George AE; Tarshish C; Ferris SH
1993 Sep;50(9):967-973, Archives of neurology
OBJECTIVE--To estimate the prevalence of radiographically detectable hippocampal atrophy (HA) in a normal aging sample and to test whether such atrophy is associated with memory dysfunction. DESIGN--One hundred fifty-four medically healthy and cognitively normal elderly persons (aged 55 to 88 years) received magnetic resonance imaging and/or computed tomographic scans designed to identify HA. One hundred forty-five of these subjects also underwent psychometric tests of memory function. Multivariate analyses of variance were used to evaluate differences in memory performance between subjects with and without HA. SETTING--This study was conducted at a research clinic for the investigation of age-associated neuropsychological and neuroradiologic changes. PARTICIPANTS--Based on the following criteria, 154 subjects were consecutively selected from a larger group of elderly research volunteers participating in a study of normal aging: age of 55 years or greater; Global Deterioration Scale score of 2 or less; and Mini-Mental State examination score of 28 or greater. Subjects with evidence for significant medical, psychiatric, or neurologic disease were excluded. MAIN OUTCOME MEASURES--Outcome measurements included individual psychometric test scores and computed tomographic-magnetic resonance imaging hippocampal atrophy ratings. RESULTS--Nearly 33% of the subjects had radiographic evidence for HA. The prevalence of HA increased significantly with age and was more common in male than female subjects. After controlling for age, level of education, and vocabulary, subjects with HA were found to perform more poorly on tests of recent (secondary) verbal memory when compared with subjects without HA (P < .01). No significant differences were found for tests of immediate (primary) memory. CONCLUSION--We conclude that HA is a common accompaniment of normal aging and is associated with mild memory impairment. Additional research is needed to determine whether HA constitutes a significant risk for future dementia
— id: 6389, year: 1993, vol: 50, page: 967, stat: Journal Article,

Dilatation of the lateral part of the transverse fissure of the brain in Alzheimer's disease
Narkiewicz O; de Leon MJ; Convit A; George AE; Wegiel J; Morys J; Bobinski M; Golomb J; Miller DC; Wisniewski HM
1993 ;53(3):457-465, Acta neurobiologiae experimentalis
Post-mortem MRI (magnetic resonance images) studies followed by histopathological examination were used to study the size and the shape of the lateral part of the transverse fissure of the brain in seven individuals with Alzheimer disease (AD) and five controls. In control brains, the lateral part of the transverse fissure is a narrow cleft protruding laterally as choroid and hippocampal recesses. In AD-affected brains, the lateral part of the transverse fissure becomes a large subarachnoid space as a result of different degrees of atrophy of various hippocampal and parahippocampal structures. Our findings directly indicate the relationship between changes in the hippocampal and parahippocampal structures and the size of the lateral part of the transverse fissure. Sector CA1, the subiculum, the entorhinal cortex, and the parahippocampal isocortex are the most affected, whereas the dentate gyrus is much less affected. Adjacent thalamic structures, which are less vulnerable to the AD pathology, do not appear to contribute to transverse fissure changes. The size and the shape of the lateral part of the transverse fissure of the brain in AD reflect the atrophy of the hippocampus and parahippocampal structures
— id: 9458, year: 1993, vol: 53, page: 457, stat: Journal Article,

Principal axes and surface fitting methods for three-dimensional image registration
Rusinek H; Tsui WH; Levy AV; Noz ME; de Leon MJ
1993 Nov;34(11):2019-2024, Journal of nuclear medicine
We evaluated the effect of the image acquisition parameters on the accuracy of the principal axes and surface-fitting techniques for three-dimensional image registration. Using two types of phantom objects, MR brain image and a mathematically defined ellipsoid, we simulated pairs of scans with known acquisition parameters, including longitudinal coverage, magnitude of mis-registration, number of sections and section thickness. Both methods are sensitive to the systematic deformation of contours. The principal axes method is also sensitive to incomplete scan coverage and to the x-axis and y-axis misangulation. Both methods are insensitive to the number of sections, section thickness and the number of points per section. Surface fitting performed well without user supervision. There is no need for routine inclusion of the scaling factors as search parameters. The results confirm the feasibility of three-dimensional multimodality registration of brain scans with accuracy 1-2 mm, with surface fitting being the method of choice
— id: 6504, year: 1993, vol: 34, page: 2019, stat: Journal Article,

CT, MRI, and PET studies of hippocampal pathology in Alzheimer's disease
de Leon, M. J; Smith, G; George, A. E; McRae, T; Golomb, J; Convit, A; Kluger, Alan; Tsui, W; Ferris, Steven H; et al
Neurodevelopment, aging and cognition Cambridge, MA, US: Birkhauser, 1992,
(from the chapter) the observations of hippocampal pathology in the absence of neocortical pathology in normal elderly and in nondemented Down's syndrome cases suggests that an early focus of pathology in AD [Alzheimer's disease] is in the hippocampus / however, at present there is no direct neuropathological evidence to support this contention / longitudinal imaging of hippocampal changes is now providing the first opportunities to directly confirm the primacy of hippocampal change in early AD patients and individuals at risk for AD /// CT [computerized tomography] and MRI [magnetic resonance imaging] hippocampal studies / PET [positron emission tomography] / postmortem studies
— id: 4798, year: 1992, vol: , page: 323, stat: Chapter,

Topography of cross-sectional and longitudinal glucose metabolic deficits in Alzheimer's disease. Pathophysiologic implications
Smith GS; de Leon MJ; George AE; Kluger A; Volkow ND; McRae T; Golomb J; Ferris SH; Reisberg B; Ciaravino J; et al
1992 Nov;49(11):1142-1150, Archives of neurology
Positron emission tomographic studies of cerebral glucose metabolism have shown high diagnostic specificity in distinguishing among the degenerative dementias and differentiating between Alzheimer's disease (AD) and normal aging. The current investigation was undertaken to characterize the regional glucose metabolic deficits in AD, using cross-sectional and longitudinal study designs. All subjects met the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD (n = 45) or were normal (n = 20), and the AD subjects were subdivided into incipient and mild AD and moderate plus moderately severe subgroups based on the Global Deterioration Scale. The subjects underwent a non-contrast computed tomographic scan and a positron emission tomographic (PETT VI) scan. The AD subjects (n = 14) and normal control subjects (n = 15) received evaluations 2 to 3 years after baseline study. The brain regions that show glucose metabolic deficits cross-sectionally (temporal and parietal association areas, with lesser degrees of deficit in subcortical gray matter structures), over the stages of AD, also show further deficits longitudinally within the same AD subjects. The reduction in glucose metabolism is greater than would be expected from the degree of brain atrophy. The glucose metabolic deficits are discussed in the context of neuropathologic findings and neurotransmitter deficits in AD
— id: 9459, year: 1992, vol: 49, page: 1142, stat: Journal Article,

Alzheimer disease: measuring loss of cerebral gray matter with MR imaging [see comments]
Rusinek H; de Leon MJ; George AE; Stylopoulos LA; Chandra R; Smith G; Rand T; Mourino M; Kowalski H
1991 Jan;178(1):109-114, Radiology
The distributions of the cerebral gray matter, the white matter, and the intracranial cerebrospinal fluid (CSF) were measured in 14 patients with Alzheimer disease (AD) and in 14 healthy control subjects. The measurements, derived from two specifically designed magnetic resonance inversion-recovery sequences, compensate for partial signal averaging. The percentage of the gray matter in the brains of AD patients (44.9% +/- 4.4) was significantly lower than in control subjects (50.2% +/- 3.2). The most significant reduction (P less than .001) occurred in the temporal lobes (13.8%) and a central region (12.8); the reduction in frontal lobe (11.2%) and occipital lobe (9.2%) was also statistically significant (P less than .01). There was an increase in the CSF volume in the temporal, occipital, and frontal regions; no region showed a significant difference in the white matter content. The findings of diffuse changes and temporal lobe involvement in AD are consistent with pathologic observations of cortical cell loss
— id: 8260, year: 1991, vol: 178, page: 109, stat: Journal Article,

CLINICAL MARKERS OF EARLY ALZHEIMERS-DISEASE
Ferris, SH; Flicker, C; Reisberg, B; Deleon, MJ
1990 May-Jun;11(3):256-256, Neurobiology of aging
— id: 31938, year: 1990, vol: 11, page: 256, stat: Journal Article,

CT diagnostic features of Alzheimer disease: importance of the choroidal/hippocampal fissure complex [see comments]
George AE; de Leon MJ; Stylopoulos LA; Miller J; Kluger A; Smith G; Miller DC
1990 Jan-Feb;11(1):101-107, AJNR. American journal of neuroradiology
Neuropathologic changes in the temporal lobe, including focal atrophy of the subiculum and entorhinal cortex, have been described in association with Alzheimer disease. We studied the usefulness of detecting temporal-lobe structural changes on CT in making the diagnosis of Alzheimer disease. The dementia imaging protocol we use includes thin-section (5 mm) cuts of the temporal lobe oriented 20 degrees negative (caudal) to the plane of the canthomeatal line. Thirty-four patients with suspected Alzheimer disease and 20 normal elderly control subjects, all between 65 and 80 years old, were studied with a standard protocol that also included neurologic and medical examinations and detailed psychometric testing. All the temporal-lobe evaluations of the five variables measured were significantly associated with the presence or absence of Alzheimer disease. Almost all Alzheimer patients showed evidence of mild or greater severity of overall temporal-lobe atrophy. The absence of temporal-lobe atrophy, seen in approximately one half the normal cases, identified normal individuals with a high degree of specificity (95%). The presence of characteristic hippocampal lucency, apparently due to enlargement of the choroid and hippocampal fissures, showed the highest sensitivity and classification accuracy of all the variables tested (82 and 80% respectively; p less than .001), correctly identifying 82% of Alzheimer patients and 80% of Alzheimer patients and control subjects. These results indicate that CT detection of structural changes in the temporal lobe and hippocampus strongly support the diagnosis of Alzheimer disease. A temporal-lobe imaging protocol for CT, and by extension for MR, is suggested for the evaluation of patients with the clinical diagnosis of a dementing disorder
— id: 9460, year: 1990, vol: 11, page: 101, stat: Journal Article,

ALTERED GLUCOSE-METABOLISM IN ALZHEIMERS-DISEASE - REPLY
Marcus, DL; Deleon, MJ; Pearson, J; Freedman, ML
1990 Jun;27(6):692-693, Annals of neurology
— id: 31933, year: 1990, vol: 27, page: 692, stat: Journal Article,

THE CLINICAL COURSE OF ALZHEIMERS-DISEASE
Reisberg, B; Franssen, E; Kluger, A; Sclan, S; Shulman, E; Steinberg, G; Deleon, MJ; Ferris, SH
1990 May-Jun;11(3):253-253, Neurobiology of aging
— id: 31937, year: 1990, vol: 11, page: 253, stat: Journal Article,

Computed tomography scans and negative symptoms in schizophrenia: chronic schizophrenics with negative symptoms and nonenlarged lateral ventricles
Serban G; George A; Siegel S; DeLeon M; Gaffney M
1990 May;81(5):441-447, Acta psychiatrica Scandinavica
Computed tomography scans of 31 chronic schizophrenics with negative symptoms and 31 age-matched normal volunteers were assessed for ventricular size, cortical atrophies, third ventricle diameter, and cerebellar atrophies. No significant differences were found in the size of the lateral ventricles or third ventricles between the chronic schizophrenics and the controls. The frontal horns in patients did show a tendency toward increased size compared with controls. Sulci width showed significant differences between patients and controls. The clinical variables, except for the memory test, did not correlate with any brain morphology. A meta-analysis was performed on 17 studies that used the planimetric method in order to evaluate the relationships between the size of the lateral ventricles in patients and their respective controls. We found significant differences between the group of studies using normal controls and the group using medical controls
— id: 65746, year: 1990, vol: 81, page: 441, stat: Journal Article,

PET-deoxyglucose, CT, and neuropathology of age-related white matter pathology in normals and Alzheimer's patients
de Leon MJ; George AE; Kluger A; Franssen E; Ferris SH; Wolf AP
1989 Sep;29(3):359-360, Psychiatry research
— id: 9462, year: 1989, vol: 29, page: 359, stat: Journal Article,

Alzheimer's disease: longitudinal CT studies of ventricular change
de Leon MJ; George AE; Reisberg B; Ferris SH; Kluger A; Stylopoulos LA; Miller JD; La Regina ME; Chen C; Cohen J
1989 Jun;152(6):1257-1262, American journal of roentgenology
A 3-year longitudinal study was conducted with 50 Alzheimer's disease patients and 45 elderly control subjects. All study participants received an extensive evaluation that included brain CT at baseline and follow-up. Quantitation of ventricular size, using both linear and volume methods, revealed highly significant cross-sectional and longitudinal differences between the Alzheimer patients and control subjects. Specifically, the annual rate of change in ventricular volume was approximately 9% in the Alzheimer patients and approximately 2% in the controls. The presence of age-related white matter lesions had no effect on the clinical course of the patients or on the changes in ventricular size. Among the Alzheimer patients, the rate of clinical decline was strongly related to the rate of change in ventricular size. Baseline ventricular measurements were of no value in predicting the subsequent rate of clinical deterioration or ventricular enlargement. The results suggest that changes in ventricular size closely reflect the clinical changes in Alzheimer patients
— id: 9464, year: 1989, vol: 152, page: 1257, stat: Journal Article,

Early marker for Alzheimer's disease: the atrophic hippocampus
de Leon MJ; George AE; Stylopoulos LA; Smith G; Miller DC
1989 Sep 16;2(8664):672-673, Lancet
— id: 9461, year: 1989, vol: 2, page: 672, stat: Journal Article,

ALZHEIMERS-DISEASE - LONGITUDINAL CT STUDIES OF VENTRICULAR CHANGE
Deleon, MJ; George, AE; Reisberg, B; Ferris, SH; Kluger, A; Stylopoulos, LA; Miller, JD; Laregina, ME; Chen, C; Cohen, J
1989 Mar-Apr;10(2):371-376, AJNR. American journal of neuroradiology
— id: 31644, year: 1989, vol: 10, page: 371, stat: Journal Article,

Altered glucose metabolism in microvessels from patients with Alzheimer's disease [see comments]
Marcus DL; de Leon MJ; Goldman J; Logan J; Christman DR; Wolf AP; Fowler JS; Hunter K; Tsai J; Pearson J; et al
1989 Jul;26(1):91-94, Annals of neurology
Microvessels isolated from temporal cortex of patients with Alzheimer's disease showed decreased uptake of glucose when compared with vessels from age-matched or young control subjects. This was due to decreased hexokinase activity in the Alzheimer samples, as determined by ion exchange chromatography. This finding was confirmed independently by determination of the phosphorylation constant for hexokinase, K3, using positron emission tomography. The results suggest that Alzheimer's disease may result from a global defect in brain energy metabolism
— id: 9463, year: 1989, vol: 26, page: 91, stat: Journal Article,

The stage specific temporal course of Alzheimer's disease: functional and behavioral concomitants based upon cross-sectional and longitudinal observation
Reisberg B; Ferris SH; de Leon MJ; Kluger A; Franssen E; Borenstein J; Alba RC
1989 ;317:23-41, Progress in clinical & biological research
A series of studies published over the past 6 years now permit a relatively precise description of the temporal course of Alzheimer's disease (AD). Initially, 7 global stages of CNS aging and AD were described. Subsequently, data on the stage specific relationship between these stages and widely employed mental status, psychometric, and other assessment measures were collected. Longitudinal studies helped to clarify the borders between normal CNS aging and AD using these measures. Other studies described functioning and self-care correlates of the 7 global stages. These were ultimately divisible into 16 clearly defined, ordinal functional stages. Empirical longitudinal observations permitted the description of the mean temporal course of each of the 16 functional stages of aging and AD. The cross-sectional stage specific data on mental status and other measures can now be applied to the mean temporal course observations and the validity of the temporal estimates forwarded can be investigated in detail. Etiologic hypotheses based upon the observed phenomenologic and temporal course of AD are discussed
— id: 9465, year: 1989, vol: 317, page: 23, stat: Journal Article,

CT AND MR FEATURES OF HYDROCEPHALUS - PARADOXICAL SYLVIAN FISSURE ENLARGEMENT AND SIGNIFICANCE OF THE HIPPOCAMPAL LUCENCY
Shier, CK; George, AE; Deleon, MJ; Sheerwilliams, M; Stylopoulos, LA; Pinto, R
1989 Jul-Aug;10(4):904-904, AJNR. American journal of neuroradiology
— id: 31685, year: 1989, vol: 10, page: 904, stat: Journal Article,

Positron emission tomography with the deoxyglucose technique and the diagnosis of Alzheimer's disease
de Leon MJ; George AE; Marcus DL; Miller JD
1988 Jan-Feb;9(1):88-90, Neurobiology of aging
Riege and Metter provide a useful review of the application of PET in the evaluation of Alzheimer's disease (AD). We share their enthusiasm for continued support and development of tools to image metabolic processes. Our commentary focuses on neuroimaging and the diagnosis of AD and introduces some new data that directly impacts on the interpretation of PET-2-deoxyglucose (2DG) data
— id: 9471, year: 1988, vol: 9, page: 88, stat: Journal Article,

Altered patterns of positron-emission tomography glucose metabolism in Alzheimer patients with microvascular white matter disease
De Leon MJ; George AE; Miller JD; Ferris SH; Klinger AJ; Franssen E; Kluger A; Sachs H; Gianutsos JG; La Regina ME; et al
1988 ;3(1):52-53, American journal of physiologic imaging
— id: 9470, year: 1988, vol: 3, page: 52, stat: Journal Article,

Abnormal cortisol response in Alzheimer's disease linked to hippocampal atrophy
de Leon MJ; McRae T; Tsai JR; George AE; Marcus DL; Freedman M; Wolf AP; McEwen B
1988 Aug 13;2(8607):391-392, Lancet
— id: 9466, year: 1988, vol: 2, page: 391, stat: Journal Article,

Elevated cerebellar glucose metabolism in microvascular white matter disease: normal aging and Alzheimer's disease
Klinger A; de Leon MJ; George AE; Miller JD; Wolf AP
1988 Jun;8(3):433-435, Journal of cerebral blood flow & metabolism
Young normal, elderly, and clinically diagnosed Alzheimer disease subjects who had undergone positron emission tomography (PET) and computed tomography (CT) examinations were studied to determine the effect of periventricular white matter lesions on cerebellar glucose metabolic rates. PET-determined cerebellar metabolic rates were elevated in subjects with periventricular white matter lesions. These results suggest the cautious use of cortical-to-cerebellar ratios in future PET or single-photon-emission CT (SPECT) studies
— id: 9468, year: 1988, vol: 8, page: 433, stat: Journal Article,

Significance of age-related white matter lesions
Kluger A; Gianutsos J; de Leon MJ; George AE
1988 Aug;19(8):1054-1055, Stroke
— id: 9467, year: 1988, vol: 19, page: 1054, stat: Journal Article,

DECREASED BRAIN GLUCOSE-METABOLISM INVIVO AND IN MICROVESSELS IN PATIENTS WITH ALZHEIMERS-DISEASE
Marcus, DL; Deleon, M; Swerdlow, R; Kaplan, H; Tsai, J; Freedman, ML
1988 Apr;36(3):A486-A486, Clinical research
— id: 31501, year: 1988, vol: 36, page: A486, stat: Journal Article,

Global Deterioration Scale (GDS)
Reisberg B; Ferris SH; de Leon MJ; Crook T
1988 ;24(4):661-663, Psychopharmacology bulletin
— id: 9472, year: 1988, vol: 24, page: 661, stat: Journal Article,

STAGE-SPECIFIC BEHAVIORAL, COGNITIVE, AND INVIVO CHANGES IN COMMUNITY RESIDING SUBJECTS WITH AGE-ASSOCIATED MEMORY IMPAIRMENT AND PRIMARY DEGENERATIVE DEMENTIA OF THE ALZHEIMER TYPE
Reisberg, B; Ferris, SH; Deleon, MJ; Sinaiko, E; Franssen, E; Kluger, A; Mir, P; Borenstein, J; George, AE; Shulman, E; Steinberg, G; Cohen, J
1988 Nov 30;15(2-3):101-114, Drug development research
— id: 31654, year: 1988, vol: 15, page: 101, stat: Journal Article,

Longitudinal CT study of parenchymal brain changes in glioma survivors
Stylopoulos LA; George AE; de Leon MJ; Miller JD; Foo SH; Hiesiger E; Wise A
1988 May-Jun;9(3):517-522, AJNR. American journal of neuroradiology
We reviewed the serial CT studies obtained between 1974 and 1986 of 31 patients with malignant glioma who survived for 2 to 11 years after surgical removal of their tumors. In all cases surgery was followed by radiation therapy to the head (6000 rad) and chemotherapy. Patients were divided into two age groups: those under age 40 (n = 13) and those over age 40 (n = 18). By 2 years all patients in the older group developed evidence of leukoencephalopathy characterized by periventricular zones of decreased attenuation. Only 58% of the younger group showed evidence of white matter changes at this point. All patients from both age groups who survived for 4 years developed leukoencephalopathy. The severity of leukoencephalopathy from 6 months after surgery and beyond was always greater in the older group. All patients developed cerebral atrophy as evidenced by sulcal dilatation and ventricular enlargement. Atrophy was progressive beginning with the first postirradiation scan, and was always more severe in the older patients. A significant difference was found in the clinical status of the two age groups as determined by the mental status score and the Karnofsky scale. Despite progressive brain changes, survivors under age 40 maintained a nearly normal mental status and Karnofsky scores until their death, whereas survivors over age 40 showed progressive clinical decline
— id: 9469, year: 1988, vol: 9, page: 517, stat: Journal Article,

Positron emission tomography studies of normal aging: a replication of PET III and 18-FDG using PET VI and 11-CDG
de Leon MJ; George AE; Tomanelli J; Christman D; Kluger A; Miller J; Ferris SH; Fowler J; Brodie JD; van Gelder P; et al
1987 Jul-Aug;8(4):319-323, Neurobiology of aging
Using PET VI and 11-CDG we replicated our earlier PET III and 18-FDG normal aging findings. Examination of young and old normal volunteers revealed the absence of any absolute regional age-related changes in glucose utilization. For the combined sample (N = 81) we did find evidence to suggest a relative hypofrontal change with increasing age. A strong relationship between age and ventricular size (CT) was also found. These findings suggest the preserved glucose metabolism of the resting aging brain in the presence of structural atrophic changes.
— id: 9473, year: 1987, vol: 8, page: 319, stat: Journal Article,

LEUKOENCEPHALOPATHY IN NORMAL AND PATHOLOGICAL AGING - REPLY
George, AE; Deleon, MJ
1987 Jul-Aug;8(4):734-734, AJNR. American journal of neuroradiology
— id: 31161, year: 1987, vol: 8, page: 734, stat: Journal Article,

TEMPORAL-LOBE CT DIAGNOSTIC FEATURES OF ALZHEIMER-DISEASE
George, AE; Stylopoulos, LA; Deleon, MJ; Klinger, A; Kluger, A; Miller, JD
1987 Sep-Oct;8(5):931-931, AJNR. American journal of neuroradiology
— id: 31129, year: 1987, vol: 8, page: 931, stat: Journal Article,

Abnormal temporal lobe response in Alzheimer's disease during cognitive processing as measured by 11C-2-deoxy-D-glucose and PET
Miller JD; de Leon MJ; Ferris SH; Kluger A; George AE; Reisberg B; Sachs HJ; Wolf AP
1987 Apr;7(2):248-251, Journal of cerebral blood flow & metabolism
Elderly controls and probable Alzheimer's disease patients underwent serial positron emission tomography (PET) studies during a baseline condition and while performing a verbal memory task. For the temporal lobes, all 7 Alzheimer patients demonstrated a relative shift in glucose metabolic rates to the right hemisphere during the memory condition relative to baseline, and 5 of 7 controls showed a shift to the left hemisphere. Baseline absolute regional metabolic rates replicate previous findings and were somewhat less useful than the memory challenge in differentiating patients from controls. These results indicate that a temporal lobe abnormality in Alzheimer's disease is related to memory performance.
— id: 9474, year: 1987, vol: 7, page: 248, stat: Journal Article,

LONGITUDINAL CT STUDY OF PARENCHYMAL BRAIN CHANGES IN GLIOMA SURVIVORS
Stylopoulos, LA; George, AE; Deleon, MJ; Miller, J; Foo, SH; Hiesiger, E
1987 Sep-Oct;8(5):948-949, AJNR. American journal of neuroradiology
— id: 31132, year: 1987, vol: 8, page: 948, stat: Journal Article,

Reduced incidence of left-handedness in clinically diagnosed dementia of the Alzheimer type
de Leon MJ; la Regina ME; Ferris SH; Gentes CI; Miller JD
1986 May-Jun;7(3):161-164, Neurobiology of aging
Although it is generally held that about 10% of the population is left-handed, reported figures vary widely due to differences in handedness classification criteria and subject characteristics. Among those population studies that have used the same handedness classification criteria, a consistent relationship between increasing right-hand preference and increasing age has been reported. One recent study of Alzheimer's disease (AD) reported a higher incidence of left-handedness in early onset relative to late onset cases. In the present study we examined handedness patterns in three elderly groups; normal (N = 217), depression (N = 73), and AD (N = 114). Our results indicated a reduced frequency of left handedness in AD (2.6%) relative to control (11.1%) and depression (13.7%) groups. Within the limited age range we studied (60-80 years), no relationships were found between age and handedness preference either within or across the groups. Furthermore, for the AD group there was no relationship between severity of global impairment and strength of handedness. Our results suggest that compared to right handers, left handers are less vulnerable to the cognitive changes associated with AD. Nevertheless it is also possible that left handers are overrepresented among early onset dementia patients and die before entering the pool of senile dementia patients. Further work is required to determine if early and late onset AD are associated with different incidences of left handedness.
— id: 9478, year: 1986, vol: 7, page: 161, stat: Journal Article,

STRUCTURAL AND FUNCTIONAL NEUROIMAGING IN ALZHEIMERS-DISEASE
DELEON, MJ; GEORGE, AE
1986 SEP-OCT ;7(5):396-398, Neurobiology of aging
— id: 41338, year: 1986, vol: 7, page: 396, stat: Journal Article,

CT AND PET STUDY OF LEUKOENCEPHALOPATHY IN ALZHEIMERS-DISEASE
Deleon, MJ; George, AE; Ferris, SH; Christman, DR; Fowler, J; Budzilovich, G; Miller, JD; Reisberg, B; Wolf, AP
1986 Dec;31(1-4):219-220, International journal of neuroscience
— id: 31292, year: 1986, vol: 31, page: 219, stat: Journal Article,

Leukoencephalopathy in normal and pathologic aging: 1. CT of brain lucencies
George AE; de Leon MJ; Gentes CI; Miller J; London E; Budzilovich GN; Ferris S; Chase N
1986 Jul-Aug;7(4):561-566, AJNR. American journal of neuroradiology
Central white matter lucencies are commonly seen in CT scans of elderly patients. Reports in the literature have implicated demyelination due to subcortical vascular disease (Binswanger disease) as the cause of these lucencies. Binswanger disease, however, is thought to be rare. Because of this apparent discrepancy we decided to determine the incidence and to attempt to define the clinical significance of the CT white-matter changes in a study population at New York University Medical Center. The studies of 275 normal and demented subjects, ages 23 to 85 years, were reviewed. All subjects received neurologic, psychiatric, and medical evaluation, formal psychometric evaluation of their cognitive status, and a CT scan. CT scans were evaluated for the presence and severity of white-matter changes (leukoencephalopathy). The incidence and severity of white-matter changes increased significantly with age (p less than 0.01). Leukoencephalopathy was consistently more common in demented patients than in normal subjects, but the difference was not statistically significant, and the severity of the leukoencephalopathy was not related to the severity of dementia (p less than 0.05). Five patients (ages 74 to 95 years) with a clinical diagnosis of Alzheimer disease who had CT evidence of lucencies were examined at autopsy. Neuropathology demonstrated extensive changes of Alzheimer disease in one brain and mild-to-moderate changes in the other four brains; areas of white-matter rarefaction were present in all brains, with microscopic evidence of arteriolar hyalinization. This study demonstrates that leukoencephalopathy is strongly related to the aging process and is seen in both 'normal' and cognitively impaired individuals who have no other evidence of vascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 9477, year: 1986, vol: 7, page: 561, stat: Journal Article,

Leukoencephalopathy in normal and pathologic aging: 2. MRI of brain lucencies
George AE; de Leon MJ; Kalnin A; Rosner L; Goodgold A; Chase N
1986 Jul-Aug;7(4):567-570, AJNR. American journal of neuroradiology
A pilot study was performed to test the ability of MR to evaluate the brain lucencies shown by CT in Alzheimer disease patients and in normal control subjects. Eight patients with presumed Alzheimer disease and 47 normal controls, 12 over the age of 45 years and 35 under age 45, were studied. Each group included subjects with and without CT evidence of leukoencephalopathy. Inversion recovery, saturation recovery, and spin-echo scans were obtained using a 0.3-T permanent magnet prototype unit. Results indicated that MR was more sensitive than CT to parenchymal disease. Seven of the eight patients with Alzheimer disease showed patches of increased signal intensity on SE scans; only three had lucencies on their CT studies. None of the normal subjects under the age of 45 showed periventricular patches of increased SE signal intensity. T2-weighted SE imaging was performed in nine of the 12 normal subjects over 45 years old. Eight of the nine demonstrated periventricular patches of increased SE signal intensity. Faint CT lucencies were present in only one of these. The configuration of the patches of increased signal intensity was similar for both the normal and Alzheimer groups, but the extent of white-matter involvement was greater in the Alzheimer group.
— id: 9476, year: 1986, vol: 7, page: 567, stat: Journal Article,

Positron emission tomography of hydrocephalus. Metabolic effects of shunt procedures
George AE; de Leon MJ; Miller J; Klinger A; Foo SH; Christman DL; Wolf A
1986 ;369:435-439, Acta radiologica. Supplementum
Five patients with hydrocephalus were studied with carbon-11-2-deoxyglucose or 2-deoxy-2-(18F) fluoro-D-glucose and positron emission tomography both prior to and following ventricular shunting. Four subjects had communicating hydrocephalus; the fifth had aqueductal stenosis, two patients had hydrocephalus for three months or less. The three chronic patients were felt to have hydrocephalus for three years or more. After shunting ventricular size decreased in all patients, and all patients showed clinical improvement. The glucose cerebral metabolic rates increased after shunt in the two subjects with recent onset hydrocephalus but paradoxially decreased in the three chronic patients despite clinical improvement. These findings suggest that the cerebrum was metabolically hyperactive prior to shunt due to an unknown mechanism and presumably in response to the presence of hydrocephalus. A dissociation may also exist in the post-shunt period between cerebral metabolism and cerebral blood flow
— id: 9480, year: 1986, vol: 369, page: 435, stat: Journal Article,

Periventricular lucencies in the CT scans of aged and demented patients
London E; de Leon MJ; George AE; Englund E; Ferris S; Gentes C; Reisberg B
1986 Aug;21(10):960-962, Biological psychiatry
— id: 9475, year: 1986, vol: 21, page: 960, stat: Journal Article,

Longitudinal course of normal aging and progressive dementia of the Alzheimer's type: a prospective study of 106 subjects over a 3.6 year mean interval
Reisberg B; Ferris SH; Shulman E; Steinberg G; Buttinger C; Sinaiko E; Borenstein J; de Leon MJ; Cohen J
1986 ;10(3-5):571-578, Progress in neuro-psychopharmacology & biological psychiatry
Elderly, community residing subjects (N = 106; mean age = 70.6 +/- 6.02 years) with cognitive functioning consistent with normal aging or dementia of the Alzheimer's type (DAT), were followed over a 3.6 year mean interval (range = 2.78 to 5.12 years). All subjects were assessed at baseline on the Global Deterioration Scale (GDS), a global clinical instrument reflecting the continuum of cognitive dysfunction from normal aging to severe DAT. At follow-up subjects were reassessed with respect to mortality, institutionalization and clinical change, defined as at least a two-point change on the 7-point GDS. Our results suggest that patients at deterioration levels GDS greater than or equal to 4, are more likely to show negative outcomes, specifically, institutionalization (Ps less than .001), death (Ps less than .01), or, for the community residing remainder, clinical deterioration (Ps less than .05), than subjects from less impaired (GDS = 2 or GDS = 3) subject groups. Seventy-six per cent of subjects at deterioration levels four or greater (N = 34) had negative outcomes at follow-up, whereas ninety percent of subjects with deterioration levels less than four (N = 72) did not.
— id: 9479, year: 1986, vol: 10, page: 571, stat: Journal Article,

Periventricular high signal lesions and signal void on magnetic resonance imaging in hydrocephalus. Diagnostic and prognostic significance
Stollman AL; George AE; Pinto RS; de Leon MJ
1986 ;369:388-391, Acta radiologica. Supplementum
The presence of periventricular high signal lesions and ventricular signal void was tabulated and compared in three groups: patients with unshunted hydrocephalus (n = 24), cerebral atrophy (n = 14), and a subgroup of treated hydrocephalus subjects studied both pre- and post-shunting (n = 6). We found that T2 high signal lesions and ventricular signal void are common in both hydrocephalus and atrophy and are of no value in distinguishing between the two. The pre-treatment presence or absence of periventricular high signal lesions and signal void were of no use in predicting the clinical outcome of shunting in hydrocephalus
— id: 9481, year: 1986, vol: 369, page: 388, stat: Journal Article,

CT AND PET STUDY OF LEUKOENCEPHALOPATHY IN ALZHEIMERS-DISEASE
Deleon, MJ; George, AE; Ferris, SH; Gentes, CI; Christman, DR; Fowler, J; Budzilovich, G; London, E; Miller, JD; Reisberg, B; Wolf, AP
1985 ;6(3):468-468, AJNR. American journal of neuroradiology
— id: 30911, year: 1985, vol: 6, page: 468, stat: Journal Article,

THE DIFFERENTIATION OF COMMUNICATING HYDROCEPHALUS FROM ATROPHY USING POSITRON EMISSION TOMOGRAPHY (PET)
George, AE; Deleon, MJ; Foo, SH; Miller, J; Ferris, SH; Christman, DR; Wolf, A
1985 ;6(3):468-469, AJNR. American journal of neuroradiology
— id: 30912, year: 1985, vol: 6, page: 468, stat: Journal Article,

Positron emission tomography and computed tomography assessments of the aging human brain
de Leon MJ; George AE; Ferris SH; Christman DR; Fowler JS; Gentes CI; Brodie J; Reisberg B; Wolf AP
1984 Feb;8(1):88-94, Journal of computer assisted tomography
The relationship between alterations in brain structure and brain function was studied in vivo in both young and elderly human subjects. Computed tomography revealed significant age-related ventricular and cortical sulcal dilatation. The cortical changes were most closely related to age. Positron emission tomography failed to show regional changes in brain glucose metabolic rate. The results suggest that the normal aging brain undergoes structural atrophic changes without incurring regional metabolic changes. Examination of the correlations between the structural and the metabolic measures revealed no significant relationships. These data are discussed with respect to the significant structure-function relationships that have been reported in Alzheimer disease.
— id: 9482, year: 1984, vol: 8, page: 88, stat: Journal Article,

Wandering and parietal signs in senile dementia of Alzheimer's type
de Leon MJ; Potegal M; Gurland B
1984 ;11(3):155-157, Neuropsychobiology
Among a population of nursing home patients with a diagnosis of senile dementia of Alzheimer's type (SDAT), a subgroup was identified who often became lost and wandered even in familiar surroundings. This subgroup differed from the rest of the SDAT patients on tests of parietal function but not on a generalized test of mental status. Thus, wandering in SDAT patients may be an indication of a specific parietal lobe involvement.
— id: 9483, year: 1984, vol: 11, page: 155, stat: Journal Article,

REGIONAL BRAIN GLUCOSE-METABOLISM IN CHRONIC-SCHIZOPHRENIA - A POSITRON EMISSION TRANSAXIAL TOMOGRAPHIC STUDY
FARKAS, T; WOLF, AP; JAEGER, J; BRODIE, JD; CHRISTMAN, DR; FOWLER, JS; MACGREGOR, RR; DELEON, MJ; DEFINA, P; GOLDMAN, A; YONEKURA, Y; BRILL, AB; SCHWARTZ, M; LOGAN, J; CANCRO, R
1984 ;41(3):293-300, Archives of general psychiatry
— id: 41102, year: 1984, vol: 41, page: 293, stat: Journal Article,

LEUKOENCEPHALOPATHY OF AGING .1. CT CLINICAL-NEURO-PATHOLOGIC STUDY OF BRAIN LUCENCIES
GEORGE, AE; DELEON, M; GENTES, CI; MILLER, J; LONDON, E; ENGLUND, E; BUDZILOVICH, G; FERRIS, S; CHASE, N
1984 ;5(5):678-678, AJNR. American journal of neuroradiology
— id: 40914, year: 1984, vol: 5, page: 678, stat: Journal Article,

LEUKOENCEPHALOPATHY OF AGING .2. CT CLINICAL MRI STUDY OF BRAIN LUCENCIES
GEORGE, AE; DELEON, M; KALNIN, A; ROSNER, L; GOODGOLD, A; CHASE, N
1984 ;5(5):678-678, AJNR. American journal of neuroradiology
— id: 40915, year: 1984, vol: 5, page: 678, stat: Journal Article,

MAGNETIC-RESONANCE AND POSITRON EMISSION TOMOGRAPHY EVALUATIONS OF HYDROCEPHALUS
GEORGE, AE; DELEON, M; KALNIN, A; ROSNER, L; MILLER, J; COOPER, P; FOO, S; CHRISTMAN, D; GOODGOLD, A; WOLF, A; CHASE, N
1984 ;5(5):671-672, AJNR. American journal of neuroradiology
— id: 40913, year: 1984, vol: 5, page: 671, stat: Journal Article,

Familial nature of Alzheimer's disease?
Reisberg B; deLeon MJ; Ferris SH
1984 Nov 15;311(20):1318-1319, New England journal of medicine
— id: 18815, year: 1984, vol: 311, page: 1318, stat: Journal Article,

FUNCTIONAL STAGING OF DEMENTIA OF THE ALZHEIMER TYPE
REISBERG, B; FERRIS, SH; ANAND, R; DELEON, MJ; SCHNECK, MK; BUTTINGER, C; BORENSTEIN, J
1984 ;435(DEC):481-483, Annals of the New York Academy of Sciences
— id: 41241, year: 1984, vol: 435, page: 481, stat: Journal Article,

LONGITUDINAL COURSE OF COMMUNITY RESIDING SUBGROUPS WITH NORMAL AGING AND DEMENTIA OF THE ALZHEIMER TYPE
REISBERG, B; FERRIS, SH; SINAIKO, E; BUTTINGER, C; DELEON, MJ
1984 ;24(3):97-97, Gerontologist
— id: 40873, year: 1984, vol: 24, page: 97, stat: Journal Article,

CT prognostic criteria of survival after malignant glioma surgery
Andreou, J; George, A E; Wise, A; de Leon, M; Kricheff, I I; Ransohoff, J; Foo, S H
1983 May-Jun;4(3):488-490, AJNR. American journal of neuroradiology
The serial pre- and postoperative computed tomographic (CT) scans of 115 patients entered in the Cooperative Brain Tumor Study between 1975 and 1982 were analyzed in order to define CT prognostic criteria and to test the hypothesis that radical glioma surgery prolongs patient survival. The CT parameters of mass size, associated edema, and intensity of enhancement were quantitated on all scans. Clinical parameters evaluated included gender, age, length of survival, and useful (Karnofsky greater than 30) survival. Data analyses indicated postoperative residual tumor burden was inversely related to length of survival (p less than 0.01). Postoperative associated edema and intensity of image enhancement were also of prognostic value and showed an inverse relation to survival. Younger patients proved more likely than older patients to attain long-term survival. Residual tumor burden of less than 45 mm diameter on postoperative CT scans was associated with 70% chance of long-term survival. These findings support the radical surgical management of glioma
— id: 67643, year: 1983, vol: 4, page: 488, stat: Journal Article,

Positron emission tomographic studies of aging and Alzheimer disease
de Leon MJ; Ferris SH; George AE; Christman DR; Fowler JS; Gentes C; Reisberg B; Gee B; Emmerich M; Yonekura Y; Brodie J; Kricheff II; Wolf AP
1983 May-Jun;4(3):568-571, AJNR. American journal of neuroradiology
In this study the positron emission tomographic (PET)-18F-2-deoxy-2-fluoro-D-glucose (FDG) technique was used to study both normal aging and senile dementia. The results derived from 15 young normal subjects (mean age, 26 +/- 5 years) and 22 elderly normal subjects (mean age, 66 +/- 7 years) failed to indicate significant metabolic changes associated with age. A group of 24 patients with senile dementia (mean age, 73 +/- 7 years) showed consistent diminutions in regional glucose use relative to the elderly normals. Across all brain regions the diminutions were 17%-24%. There were also significant correlations between the measures of glucose use and the measures of cognitive functioning. Discriminant function classification analysis results indicate that better than 80% classification accuracy can be achieved for individual PET measures. These data suggest a possible future diagnostic use of PET in senile dementia.
— id: 9486, year: 1983, vol: 4, page: 568, stat: Journal Article,

Computed tomography and positron emission transaxial tomography evaluations of normal aging and Alzheimer's disease
de Leon MJ; Ferris SH; George AE; Reisberg B; Christman DR; Kricheff II; Wolf AP
1983 Sep;3(3):391-394, Journal of cerebral blood flow & metabolism
Young normal subjects, old normal subjects, and patients with senile dementia of the Alzheimer's type (SDAT) were studied with both computed tomography (CT) and positron emission transaxial tomography (PETT). Increases in ventricular size with both aging and disease were measured. Regional glucose metabolic rate was not affected by age, but was markedly reduced in SDAT patients. These data indicate that in normal aging, structural brain changes may be more salient than biochemical changes. Although both structural and biochemical changes occur in SDAT, the biochemical changes are more marked. The results suggest that PETT is potentially more useful than CT in the in vivo diagnosis of SDAT.
— id: 9485, year: 1983, vol: 3, page: 391, stat: Journal Article,

Computed tomography in aging and senile dementia of the Alzheimer type
de Leon MJ; George AE
1983 ;38:103-122, Advances in neurology
— id: 9490, year: 1983, vol: 38, page: 103, stat: Journal Article,

Regional correlation of PET and CT in senile dementia of the Alzheimer type
de Leon MJ; George AE; Ferris SH; Rosenbloom S; Christman DR; Gentes CI; Reisberg B; Kricheff II; Wolf AP
1983 May-Jun;4(3):553-556, AJNR. American journal of neuroradiology
Alzheimer disease is manifested by both widespread and regionally restricted brain changes, some of which have recently been identified in vivo with computed tomography (CT) and positron emission tomography (PET). This is a report of the regional correlation of CT and PET measurements in 19 carefully diagnosed subjects comprising 11 controls and eight patients with senile dementia of the Alzheimer type. Regional CT attenuation values did not discriminate between the two groups, but PET using 18F-2-deoxy-2-fluoro-D-glucose demonstrated significant regional reductions (range, 21%-28%) in glucose utilization in the Alzheimer group. PET measures were also more consistently related to cognitive decline. The correlation between CT structural measures and PET metabolic measures demonstrated consistent relations between widespread PET regions and CT changes in the thalamus, posterior limb of the internal capsule, and temporal lobes. However, CT changes in the frontal white matter, caudate nucleus, and anterior limb of the internal capsule were not related to any regional PET changes. These data support previous findings of temporal lobe involvement in Alzheimer disease and suggest the involvement of structures in the region of the third ventricle.
— id: 9487, year: 1983, vol: 4, page: 553, stat: Journal Article,

POSITRON EMISSION TOMOGRAPHY (PET) AND COMPUTED-TOMOGRAPHY (CT) EVALUATIONS COMBINED IN THE STUDY OF SENILE DEMENTIA OF THE ALZHEIMERS TYPE
DELEON, MJ; GEORGE, AE; FERRIS, SH; ROSENBLOOM, S; CHRISTMAN, DR; FOWLER, J; GENTES, C; GEE, B; REISBERG, B; KRICHEFF, II; WOLF, A
1983 ;7(1):186-186, Journal of computer assisted tomography
— id: 40743, year: 1983, vol: 7, page: 186, stat: Journal Article,

Positron emission tomography in dementia
Ferris SH; de Leon MJ; Wolf AP; George AE; Reisberg B; Christman DR; Yonekura Y; Fowler JS
1983 ;38:123-129, Advances in neurology
— id: 9489, year: 1983, vol: 38, page: 123, stat: Journal Article,

Ventricular volume and cognitive deficit: a computed tomographic study
George AE; de Leon MJ; Rosenbloom S; Ferris SH; Gentes C; Emmerich M; Kricheff II
1983 Nov;149(2):493-498, Radiology
A group of 35 patients with presumptive diagnosis of Alzheimer disease and 29 normal volunteer spouse controls, all over the age of 60, underwent medical and neurologic evaluation, an extensive psychometric battery, and CT scanning. CT ventricular volume was derived for each CT section by algorithm summation of the number of pixels within a user-defined cerebrospinal fluid range. Composite ventricular volume for each patient, obtained by summation of the individual section ventricular volumes, was corrected for brain size by dividing by the sum of the five largest brain section volumes. For the normal group, composite ventricular volume thus derived was 5.2% and for the impaired group 7.5%; the 44% difference was significant (p less than .009). Increasing ventricular volume was significantly associated with increasing severity of cognitive impairment (p less than .05).
— id: 9484, year: 1983, vol: 149, page: 493, stat: Journal Article,

Effects of naloxone in senile dementia: a double-blind trial
Reisberg B; Ferris SH; Anand R; Mir P; Geibel V; De Leon MJ; Roberts E
1983 Mar 24;308(12):721-722, New England journal of medicine
— id: 9488, year: 1983, vol: 308, page: 721, stat: Journal Article,

Novel pharmacologic approaches to the treatment of senile dementia of the Alzheimer's type (SDAT)
Reisberg B; London E; Ferris SH; Anand R; de Leon MJ
1983 Spring;19(2):220-225, Psychopharmacology bulletin
— id: 9491, year: 1983, vol: 19, page: 220, stat: Journal Article,

NALOXONE EFFECTS ON PRIMARY DEGENERATIVE DEMENTIA (PDD)
Reisberg, B; Ferris, SH; Anand, R; Mir, P; Deleon, MJ; Roberts, E
1983 ;19(1):45-47, Psychopharmacology bulletin
— id: 30675, year: 1983, vol: 19, page: 45, stat: Journal Article,

THE BRIEF COGNITIVE RATING-SCALE - LANGUAGE, MOTORIC, AND MOOD CONCOMITANTS IN PRIMARY DEGENERATIVE DEMENTIA
Reisberg, B; London, E; Ferris, SH; Borenstein, J; Scheier, L; Deleon, MJ
1983 ;19(4):702-708, Psychopharmacology bulletin
— id: 30604, year: 1983, vol: 19, page: 702, stat: Journal Article,

THE BRIEF COGNITIVE RATING-SCALE (BCRS) - FINDINGS IN PRIMARY DEGENERATIVE DEMENTIA (PDD)
Reisberg, B; Schneck, MK; Ferris, SH; Schwartz, GE; Deleon, MJ
1983 ;19(1):47-50, Psychopharmacology bulletin
— id: 30676, year: 1983, vol: 19, page: 47, stat: Journal Article,

CLINICAL ASSESSMENTS OF AGE-ASSOCIATED COGNITIVE DECLINE AND PRIMARY DEGENERATIVE DEMENTIA - PROGNOSTIC CONCOMITANTS
Reisberg, B; Shulman, E; Ferris, SH; Deleon, MJ; Geibel, V
1983 ;19(4):734-739, Psychopharmacology bulletin
— id: 30605, year: 1983, vol: 19, page: 734, stat: Journal Article,

POSITRON EMISSION TOMOGRAPHY (PET) STUDIES OF NORMAL AGING AND SENILE DEMENTIA OF THE ALZHEIMERS TYPE (SDAT)
Deleon, MJ; Ferris, SH; George, AE; Christman, DR; Fowler, J; Gentes, C; Gee, B; Reisberg, B; Kricheff, II; Wolf, A
1982 ;22(4):53-54, Gerontologist
— id: 30369, year: 1982, vol: 22, page: 53, stat: Journal Article,

POSITRON EMISSION TOMOGRAPHY AND COMPUTED-TOMOGRAPHY CORRELATES IN SENILE DEMENTIA
Deleon, MJ; Ferris, SH; George, AE; Kricheff, II; Christman, D; Reisberg, B; Fowler, J; Rosenbloom, S; Gentes, C; Wolf, AP
1982 ;3(1):96-96, AJNR. American journal of neuroradiology
— id: 30470, year: 1982, vol: 3, page: 96, stat: Journal Article,

18F-2-deoxy-2-fluoro-D-glucose as a tracer in the positron emission tomographic study of senile dementia
Farkas T; Ferris SH; Wolf AP; De Leon MJ; Christman DR; Reisberg B; Alavi A; Fowler JS; George AE; Reivich M
1982 Mar;139(3):352-353, American journal of psychiatry
— id: 9494, year: 1982, vol: 139, page: 352, stat: Journal Article,

PARENCHYMAL AND STRUCTURAL CT CHANGES IN SENILE DEMENTIA - A- GREY AND WHITE MATTER ATTENUATION VALUES - B-VENTRICULAR VOLUME
George, AE; Deleon, MJ; Rosenbloom, S; Ferris, S; Gentes, C; Emmerich, M; Kricheff, I
1982 ;3(1):96-96, AJNR. American journal of neuroradiology
— id: 30471, year: 1982, vol: 3, page: 96, stat: Journal Article,

The Global Deterioration Scale for assessment of primary degenerative dementia
Reisberg B; Ferris SH; de Leon MJ; Crook T
1982 Sep;139(9):1136-1139, American journal of psychiatry
Cognitive decline associated with old age and consistent with the diagnosis of primary degenerative dementia is a unique clinical syndrome with characteristic phenomena and progression. The authors describe a Global Deterioration Scale for the assessment of primary degenerative dementia and delineation of its stages. The authors have used the Global Deterioration Scale successfully for more than 5 years and have validated it against behavioral, neuroanatomic, and neurophysiologic measures in patients with primary degenerative dementia.
— id: 9493, year: 1982, vol: 139, page: 1136, stat: Journal Article,

Relationship between cognition and mood in geriatric depression
Reisberg B; Ferris SH; Georgotas A; de Leon MJ; Schneck MJ
1982 Oct;18(4):191-193, Psychopharmacology bulletin
— id: 9492, year: 1982, vol: 18, page: 191, stat: Journal Article,

POSITRON EMISSION TOMOGRAPHY AND COMPUTED-TOMOGRAPHY EVALUATIONS OF REGIONAL BRAIN METABOLISM IN SENILE DEMENTIA
Deleon, MJ; Ferris, SH; George, AE; Rosenbloom, S; Reisberg, B; Christman, DR; Fowler, J; Gentes, C; Emmerich, M; Wolf, A
1981 ;4(4):146-146, Age
— id: 30505, year: 1981, vol: 4, page: 146, stat: Journal Article,

Parenchymal CT correlates of senile dementia (Alzheimer disease): loss of gray-white matter discriminability
George AE; de Leon MJ; Ferris SH; Kricheff II
1981 May-Jun;2(3):205-213, AJNR. American journal of neuroradiology
Neuropathologic studies have defined gross anatomic (structural) as well as histologic (parenchymal) changes of senile dementia (Alzheimer disease). This investigation suggests that loss of gray-white matter discriminability by computed tomography (CT) is related to cognitive impairment in this disease. Discriminability is defined as the relative ease of visual differentiation between gray and white tissues. Twenty-six elderly patients with dementia were subjected to extensive psychometric evaluation, a medical and neurologic examination, and CT scanning. Gray and white matter changes were assessed by subjectively evaluating three brain levels, the basal ganglia, the centrum semiovale, and the high convexity, on a five point scale. Quantitated gray and white matter scores were also obtained by sampling CT attenuation values. In addition, CT structural changes were evaluated by previously reported methods. there were significant correlations (P less than 0.05) between the subjectively assessed loss of gray-white matter discriminability at all brain levels and the measures of cognitive decline. At the high convexity level 91% of cognitive measures correlated with loss of gray-white discriminability. In the same patient group no gray-white discriminability correlation with age was demonstrated suggesting that gray-white discriminability does not simply change with age.
— id: 9495, year: 1981, vol: 2, page: 205, stat: Journal Article,

CT-VENTRICULAR VOLUME AND ITS RELATIONSHIP TO COGNITIVE IMPAIRMENT IN DEMENTIA
George, AE; Deleon, MJ; Rosenbloom, S; Ferris, SH; Gentes, C; Emmerich, M; Kricheff, II
1981 ;4(4):146-146, Age
— id: 30504, year: 1981, vol: 4, page: 146, stat: Journal Article,

Central amine metabolism in Alzheimer's disease: in vivo relationship to cognitive deficit
Mann JJ; Stanley M; Neophytides A; de Leon MJ; Ferris SH; Gershon S
1981 Spring;2(1):57-60, Neurobiology of aging
Levels of the amine metabolites homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) were measured in the cerebrospinal (CSF) fluid of drug-free patients with Alzheimer's disease and compared to levels in a group of controls. No significant differences were found in CSF HVA and MHPG, although the Alzheimer's group was severely demented. Platelet monoamine oxidase (MAO) enzyme kinetics were measured and did not differ between controls and Alzheimer patients. The degree of dementia did not show any significant correlation with the levels of HVA or MHPG. It was concluded that, unlike previous reports in the literature, the dementia of Alzheimer's disease was not related to changes in central catecholamine metabolism nor was it associated with increased platelet MAO activity.
— id: 9496, year: 1981, vol: 2, page: 57, stat: Journal Article,

The relationship between psychiatric assessments and cognitive test measures in mild to moderately cognitively impaired elderly [proceedings]
Reisberg B; Ferris SH; Schneck MK; de Leon MJ; Crook TH; Gershon S
1981 Jan;17(1):99-101, Psychopharmacology bulletin
— id: 9497, year: 1981, vol: 17, page: 99, stat: Journal Article,

Computed tomography evaluations of brain-behavior relationships in senile dementia of the Alzheimer's type
De Leon MJ; Ferris SH; George AE; Reisberg B; Kricheff II; Gershon S
1980 Summer;1(1):69-79, Neurobiology of aging
Neuropathological investigations have demonstrated brain-behavior relationships in senile dementia of the Alzheimer's type (SDAT), but CT studies have not produced consistent findings. We hypothesized that these discouraging results were in part due to limitations in the methods of CT scan evaluations, and to non-homogeneity of patient populations. The present study examined 43 out-patients with the presumptive diagnosis of SDAT using 37 cognitive test measures and 3 independent CT evaluation strategies. The CT methods included a new rank ordering procedure and two previously used techniques, physical measurement and 4-point rating. Highly significant (p less than or equal to 0.01) brain-behavior correlations were attained using the ranking and rating procedures for evaluation of ventricular and cortical pathology. It was found that rank ordering has high interrater reliability and is superior to the other methods for the evaluation of the ventricular system. The physical measurement of the third ventricle is the single most powerful linear correlate of cognitive impairment. Measurement of cortical sulci are of no correlational significance. Multiple regression analyses indicated that global assessments are the best cognitive predictors of both ventricular and cortical pathology. Thus the present study has demonstrated brain-behavior relationships in vivo in SDAT.
— id: 9498, year: 1980, vol: 1, page: 69, stat: Journal Article,

CORRELATES OF PARENCHYMAL-CT CHANGES IN SENILE DEMENTIA OF THE ALZHEIMERS TYPE
Deleon, MJ; George, AE; Ferris, SH; Kricheff, II
1980 ;20(5):91-91, Gerontologist
— id: 27953, year: 1980, vol: 20, page: 91, stat: Journal Article,

POSITRON EMISSION TOMOGRAPHY IN THE STUDY OF AGING AND SENILE DEMENTIA
FERRIS, SH; DELEON, MJ; WOLF, AP; FARKAS, T; CHRISTMAN, DR; REISBERG, B; FOWLER, JS; MACGREGOR, R; GOLDMAN, A; GEORGE, AE; RAMPAL, S
1980 ;1(2):127-131, Neurobiology of aging
— id: 40343, year: 1980, vol: 1, page: 127, stat: Journal Article,

PARENCHYMAL CT CORRELATES OF SENILE DEMENTIA - LOSS OF GREY-WHITE MATTER DISCRIMINABILITY .2
GEORGE, AE; DELEON, MJ; FERRIS, S; KRICHEFF, II
1980 ;1(4):373-373, AJNR. American journal of neuroradiology
— id: 40284, year: 1980, vol: 1, page: 373, stat: Journal Article,

STRUCTURAL CT CORRELATES OF SENILE DEMENTIA - INFLUENCE OF METHODOLOGY .1
GEORGE, AE; DELEON, MJ; FERRIS, S; KRICHEFF, II
1980 ;1(4):372-373, AJNR. American journal of neuroradiology
— id: 40283, year: 1980, vol: 1, page: 372, stat: Journal Article,

Correlations between computerised tomographic changes and behavioural deficits in senile dementia
de Leon MJ; Ferris SH; Blau I; George AE; Reisberg B; Kricheff II; Gershon S
1979 Oct 20;2(8147):859-860, Lancet
— id: 9499, year: 1979, vol: 2, page: 859, stat: Journal Article,