Susan M De Santi, Ph.D.

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,

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,

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,

Errors in ADAS-cog administration and scoring may undermine clinical trials results
Schafer, K; De Santi, S; Schneider, L S
2011 Jun;8(4):373-376, Current Alzheimer research
BACKGROUND: The Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) is the most widely used cognitive outcome measure in AD trials. Although errors in administration and scoring have been suggested as factors masking accurate estimates and potential effects of treatments, there have been few formal examinations of errors with the ADAS-cog. METHODS: We provided ADAS-cog administration training using standard methods to raters who were designated as experienced, potential raters by sponsors or contract research organizations for two clinical trials. Training included 1 hour sessions on test administration, scoring, question periods, and required that raters individually view and score a model ADAS-cog administration. Raters scores were compared to the criterion scores established for the model administration. RESULTS: A total of 108 errors were made by 80.6% of the 72 raters; 37.5% made 1 error, 25.0% made 2 errors and 18.0% made 3 or more. Errors were made in all ADAS-cog subsections. The most common were in word finding difficulty (67% of the raters), word recognition (22%), and orientation (22%). For the raters who made 1, 2, or >/= 3 errors the ADAS-cog score was 17.5 (95% CI, 17.3 - 17.8), 17.8 (17.0 - 18.5), and 18.8 (17.6 - 20.0), respectively, and compared to the criterion score, 18.3. ADAS-cog means differed significantly and the variances were more than twice as large between those who made errors on word finding and those who did not, 17.6 (SD=1.4) vs. 18.8 (SD=0.9), respectively (chi(2) = 37.2, P < .001). CONCLUSIONS: Most experienced raters made at least one error that may affect ADAS-cog scores and clinical trials outcomes. These errors may undermine detection of medication effects by contributing both to a biased point estimate and increased variance of the outcome
— id: 147909, year: 2011, vol: 8, page: 373, 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,

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,

Cognitive impairment in patients with mid- to late-stage Parkinson's disease (PD)
De Santi S.; Anand R.; Lucini V.; Rice P.
2010 ;17:475-475, European journal of neurology
Introduction: Many patients with PD experience cognitive dysfunction. Objective: To assess cognitive function in patients with mid- to late-stage PD (>3 years' duration). Methods: A customised, computerised cognitive testing system (Cogtest) was used to test cognitive function in 656 patients with PD (mean age: 60+/-9 years) receiving L-dopa and other PD medications and experiencing motor fluctuations. Eight cognitive variables were assessed at screening. Data were converted to z-scores based on healthy control data from the Cogtest database (n=240; mean age: 50+/-17 years). Z-scores of 0 and -1 represent average performance and performance that is one standard deviation (SD) below the normative group mean, respectively. Impairment within a test was defined as a performance >1.5 SD below the normal mean (i.e., z-score <-1.5). Results: At screening visit, impairment in <=1 cognitive variable was demonstrated in 96% of patients when compared with the normative group. The percentages of patients showing impairment in the individual cognitive variables compared with age-matched healthy volunteers were:Auditory Number Sequencing (ANS), 84%;Word List Memory, with and without delayed recall and recognition, both 39%; Symbol Digit Substitution, 36%; Tower Of London, 48%; Strategic Target Detection, 46%; Spatial WorkingMemory (SWM)-short, 48%; SWM-long, 64%. In contrast, in a non-PD population, only 7% of people would be expected to show cognitive impairment in any individual test. Conclusions: These data imply that cognitive deficits are widespread in patients with mid- to late-stage PD. The most common impairment was in verbal working memory (84%, assessed by ANS)
— id: 113822, year: 2010, vol: 17, page: 475, 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,

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,

Computerised cognitive testing in schizophrenia: patients' experiences
Pandey-Bhat, S.; Nath, G.; Arneja, A.; Sharma, A.; Kaviani, H.; De Santi, S.
2010 AUG ;20(1-2):S319-S320, European neuropsychopharmacology
— id: 113926, year: 2010, vol: 20, page: S319, 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,

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,

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,

Cognitive assessment using cog-test battery of abnormal brain activation
De Santi, S
2008 APR ;23(6):S70-S71, European psychiatry
— id: 78875, year: 2008, vol: 23, page: S70, 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,

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,

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,

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,

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,

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,

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,

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,

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,

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,

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,

Imaging is superior to cognitive testing for early diagnosis of Alzheimer's disease
Zamrini, Edward; De Santi, Susan; Tolar, Martin
2004 May-Jun;25(5):685-691, Neurobiology of aging
Alzheimer's disease (AD) starts at a molecular level possibly decades earlier than could be detected by neuropsychological tests (NPTs). Neuropathological and neuroimaging data suggest that amyloid accumulation precedes the clinical onset of AD. Disease-modifying agents would have to be used early to alter the course of AD. Therefore, preclinical diagnosis is necessary. Structural and functional neuroimaging are superior for detection of the earliest stages of AD. Magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques, including amyloid visualization, will have therapeutic importance for prevention as well as intervention as further refinements of current imaging techniques and biochemical markers occur. Neuropsychological tests measure the effect of pathology for an individual based upon norms obtained from an artificial population-often white and relatively highly educated. Unless serial NPTs are performed, the individual is compared to a population to which they may not conform. Neuroimaging can provide objective measures of preclinical disease state and, when measured serially, rate of change. Such information can be used in prevention trials
— id: 45484, year: 2004, vol: 25, page: 685, 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,

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,

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,

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,

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,

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,

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,

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,

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,

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,

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,

FAMILIAR LANGUAGE IN AGING AND ALZHEIMERS-DISEASE
DESANTI, S; OBLER, LK; GERSTMAN, L; ROSEN, W; REDMOND, C
1995 JUN ;28(1):83-84, Brain & cognition
— id: 87264, year: 1995, vol: 28, page: 83, stat: Journal Article,

COMPREHENSION OF IDIOMATIC AND NOVEL LANGUAGE IN AGING AND AD
DESANTI, S; OBLER, LK; ROSEN, W
1995 JUN ;28(1):123-123, Brain & cognition
— id: 87265, year: 1995, vol: 28, page: 123, stat: Journal Article,

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,