Lisa Mosconi, 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,

PET/CT in diagnosis of dementia
Berti, Valentina; Pupi, Alberto; Mosconi, Lisa
2011 Jun;1228(1):81-92, Annals of the New York Academy of Sciences
Clinical use of positron emission tomography (PET) is now well established in neurodegenerative disorders, especially in the diagnosis of dementia. Measurement of cerebral glucose metabolism is of significant value, and it facilitates early diagnosis, appropriate differential diagnosis, and the evaluation of drug treatment in patients with dementia. In addition, tracers offer new perspectives for studying the neuropathology of underlying dementia, such as the accumulation of amyloid proteins, tau-proteins, or the presence of neuroinflammation. Finally, PET tracer studies of different neurotransmitter systems in dementia may not only increase the understanding of pathophysiologic mechanisms of the different disorders, but also improve diagnostic accuracy. In conclusion, PET imaging with different tracers offers reliable biomarkers in dementia, which can assist clinicians in the diagnosis of different dementing disorders, especially in the situation of overlapping phenotypes
— id: 134917, year: 2011, vol: 1228, page: 81, stat: Journal Article,

PET/CT in diagnosis of movement disorders
Berti, Valentina; Pupi, Alberto; Mosconi, Lisa
2011 Jun;1228(1):93-108, Annals of the New York Academy of Sciences
Molecular imaging with PET offers a broad variety of tools supporting the diagnosis of movement disorders. The more widely applied PET imaging techniques have focused on the assessment of neurotransmitter systems, predominantly the pre- and postsynaptic dopaminergic system. Additionally, PET imaging with [(18) F]fluorodeoxyglucose has been extensively used to assess local synaptic activity in the resting state and to highlight local changes in brain metabolism accompanying changes in neural activity in movement disorders. PET imaging has provided us with diagnostic agents as well as tools for evaluation of novel therapeutics, and has served as a powerful means for revealing in vivo changes at different stages of movement disorders and within the course of an individual patient's illness
— id: 134918, year: 2011, vol: 1228, page: 93, stat: Journal Article,

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

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

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

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

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

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

FDG- and amyloid-PET in Alzheimer's disease: is the whole greater than the sum of the parts?
Mosconi, L; McHugh, P F
2011 Jun;55(3):250-264, Quarterly Journal of Nuclear Medicine & Molecular Imaging
The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to subtle brain changes occurring prior to the onset of clinical symptoms, when the potential for preservation of function is at the greatest. In vivo brain imaging is a promising tool for the early detection of AD through visualization of abnormalities in brain structure, function and histopathology. Currently, positron emission tomography (PET) imaging with amyloid-beta (Abeta) tracers and 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) is largely utilized in the diagnosis of AD. This paper reviews brain Abeta- and FDG-PET studies in AD patients as well as in non-demented individuals at risk for AD. We then discuss the potential of combining symptoms-sensitive FDG-PET measures with pathology-specific Abeta-PET to improve the early detection of AD
— id: 131969, year: 2011, vol: 55, page: 250, 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,

Brain amyloid imaging: the challenge of the third millennium
Pupi, A; Mosconi, L
2011 Jun;55(3):223-224, Quarterly Journal of Nuclear Medicine & Molecular Imaging
— id: 146238, year: 2011, vol: 55, page: 223, stat: Journal Article,

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

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

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

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

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

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

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

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

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,

Differences in hippocampal metabolism between amnestic and non-amnestic MCI subjects: automated FDG-PET image analysis
Clerici, F; Del Sole, A; Chiti, A; Maggiore, L; Lecchi, M; Pomati, S; Mosconi, L; Lucignani, G; Mariani, C
2009 Dec;53(6):646-657, Quarterly Journal of Nuclear Medicine & Molecular Imaging
AIM: The aim of this study was to assess whether 18F-fluorodeoxyglucose positron emission tomography differentiates amnestic (aMCI) from single-non-amnestic mild cognitive impairment (snaMCI) with executive dysfunction. METHODS: Sixteen aMCI subjects (62% females, age 75+/-8 years) and 14 snaMCI subjects (71% females, age 74+/-6 years) underwent [18F]FDG-PET and clinical follow-up. Comparisons between MCI subgroups and with seven cognitively normal elderly subjects were performed using SPM2. RESULTS: At baseline aMCI and snaMCI exhibited a similar pattern of hypometabolism, mostly in the posterior cingulate gyrus, as compared with controls. In the comparison between the MCI subtypes, the aMCI subjects showed reduced metabolism in the medial temporal lobes (MTL) (hippocampus, fusiform gyrus and amygdala). At follow-up 12 aMCI developed Alzheimer's disease (AD), while snaMCI had a heterogeneous course, including five subjects who developed Lewy body dementia. CONCLUSIONS: The patterns of altered brain metabolism in aMCI and snaMCI subjects compared to controls are similar and do not provide evidence for making clinical distinctions between them. Comparison between the two MCI subtypes showed MTL hypometabolism in aMCI subjects, possibly reflecting the fact that most had prodromal AD
— id: 133753, year: 2009, vol: 53, page: 646, 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,

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

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

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

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

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

Individual cerebral metabolic deficits in Alzheimer's disease and amnestic mild cognitive impairment: an FDG PET study
Del Sole, Angelo; Clerici, Francesca; Chiti, Arturo; Lecchi, Michela; Mariani, Claudio; Maggiore, Laura; Mosconi, Lisa; Lucignani, Giovanni
2008 Jul;35(7):1357-1366, European journal of nuclear medicine & molecular imaging
PURPOSE: The purpose of the study was the identification of group and individual subject patterns of cerebral glucose metabolism (CMRGlu) in patients with Alzheimer's disease (AD) and with amnestic mild cognitive impairment (aMCI). METHODS: [(18)F]fluorodeoxyglucose positron emission tomography (PET) studies and neuropsychological tests were performed in 16 aMCI patients (ten women, age 75+/-8 years) and in 14 AD patients (ten women, age 75+/-9 years). Comparisons between patient subgroups and with a control population were performed using Statistical Parametric Mapping. RESULTS: Clusters of low CMRGlu were observed bilaterally in the posterior cingulate cortex (PCC), in the precuneus, in the inferior parietal lobule and middle temporal gyrus of AD patients. In aMCI patients, reduced CMRGlu was found only in PCC. Areas of low CMRGlu in PCC were wider in AD compared to aMCI and extended to the precuneus, while low CMRGlu was found in the lateral parietal cortex in AD but not in aMCI patients. Individual subject pattern analysis revealed that 86% of AD patients had low CMRGlu in the PCC (including the precuneus in 71%), 71% in the temporal cortex, 64% in the parietal cortex and 35% in the frontal cortex. Among the aMCI patients, 56% had low CMRGlu in the PCC, 44% in the temporal cortex, 18% in the frontal cortex and none in the parietal cortex. CONCLUSION: This study demonstrates that both AD and aMCI patients have highly heterogeneous metabolic impairment. This potential of individual metabolic PET imaging in patients with AD and aMCI may allow timely identification of brain damage on individual basis and possibly help planning tailored early interventions
— id: 140576, year: 2008, vol: 35, page: 1357, stat: Journal Article,

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

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

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

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

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

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

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

Positron emission tomography scans obtained for the evaluation of cognitive dysfunction
Silverman, Daniel H S; Mosconi, Lisa; Ercoli, Linda; Chen, Wei; Small, Gary W
2008 Jul;38(4):251-261, Seminars in nuclear medicine
The degree of intactness of human cognitive functioning for a given individual spans a wide spectrum, ranging from normal to severely demented. The differential diagnosis for the causes of impairment along that spectrum is also wide, and often difficult to distinguish clinically, which has led to an increasing role for neuroimaging tools in that evaluation. The most frequent causes of dementia are neurodegenerative disorders, Alzheimer's disease being the most prevalent among them, and they produce significant alterations in brain metabolism, with devastating neuropathologic, clinical, social, and economic consequences. These alterations are detectable through positron emission tomography (PET), even in their earliest stages. The most commonly performed PET studies of the brain are performed with (18)F-fluorodeoxyglucose as the imaged radiopharmaceutical. Such scans have demonstrated diagnostic and prognostic utility for clinicians evaluating patients with cognitive impairment and in distinguishing among primary neurodegenerative disorders and other etiologies contributing to cognitive decline. In addition to focusing on the effects on cerebral metabolism examined with (18)F-fluorodeoxyglucose PET, some other changes occurring in the brains of cognitively impaired patients assessable with other radiotracers will be considered. As preventive and disease-modifying treatments are developed, early detection of accurately diagnosed disease processes facilitated by the use of PET has the potential to substantially impact on the enormous human toll exacted by these diseases
— id: 140577, year: 2008, vol: 38, page: 251, stat: Journal Article,

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

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

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

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

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

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,

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

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

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,

Metabolic interaction between ApoE genotype and onset age in Alzheimer's disease: implications for brain reserve
Mosconi, L; Herholz, K; Prohovnik, I; Nacmias, B; De Cristofaro, M T R; Fayyaz, M; Bracco, L; Sorbi, S; Pupi, A
2005 Jan;76(1):15-23, Journal of neurology neurosurgery & psychiatry
BACKGROUND: Clinically apparent Alzheimer's disease (AD) is thought to result when brain tissue damage exceeds a critical threshold of 'brain reserve', a process possibly accelerated by the apolipoprotein E (ApoE) E4 allele. The interaction between onset age and ApoE genotype was investigated to assess whether early disease onset (<65 years) in patients carrying the E4 allele is associated with greater cerebral metabolic (regional cerebral metabolic rate of glucose utilisation, rCMRgl) reduction. METHODS: AD patients, divided into early (EOAD; 27 patients) and late onset (LOAD; 65 patients) groups, both groups balanced as to the number of E4 carriers (E4+) and non-carriers (E4-), and matched controls (NC; 35 cases) underwent (18)F-FDG PET ([(18)F]fluorodeoxyglucose positron emission tomography) scanning. SPM'99 software was used to compare AD patients to NC and to perform a two way ANOVA with onset age and ApoE genotype as grouping factors. Results were considered significant at p<0.001, uncorrected. RESULTS: AD patients demonstrated rCMRgl reductions compared to NC, with rCMRgl lower in association cortex and relatively higher in limbic areas in EOAD compared to LOAD subjects. rCMRgl was lower in the anterior cingulate and frontal cortex for E4+ compared to E4- subjects. A significant onset age by ApoE interaction was detected in the hippocampi and basal frontal cortex, with EOAD E4+ subjects having the greatest rCMRgl reduction. CONCLUSIONS: The interactive effects of early onset age, possibly reflecting lower brain reserve, and ApoE E4 allele, possibly leading to greater tissue damage, lead to reduced tolerance to the pathophysiological effects of AD in key brain regions
— id: 70162, year: 2005, vol: 76, page: 15, 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,

Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD
Mosconi, Lisa
2005 Apr;32(4):486-510, European journal of nuclear medicine & molecular imaging
The demographics of aging suggest a great need for the early diagnosis of dementia and the development of preventive strategies. Neuropathology and structural MRI studies have pointed to the medial temporal lobe (MTL) as the brain region earliest affected in Alzheimer's disease (AD). MRI findings provide strong evidence that in mild cognitive impairments (MCI), AD-related volume losses can be reproducibly detected in the hippocampus, the entorhinal cortex (EC) and, to a lesser extent, the parahippocampal gyrus; they also indicate that lateral temporal lobe changes are becoming increasingly useful in predicting the transition to dementia. Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging has revealed glucose metabolic reductions in the parieto-temporal, frontal and posterior cingulate cortices to be the hallmark of AD. Overall, the pattern of cortical metabolic changes has been useful for the prediction of future AD as well as in distinguishing AD from other neurodegenerative diseases. FDG-PET on average achieves 90% sensitivity in identifying AD, although specificity in differentiating AD from other dementias is lower. Moreover, recent MRI-guided FDG-PET studies have shown that MTL hypometabolism is the most specific and sensitive measure for the identification of MCI, while the utility of cortical deficits is controversial. This review highlights cross-sectional, prediction and longitudinal FDG-PET studies and attempts to put into perspective the value of FDG-PET in diagnosing AD-like changes, particularly at an early stage, and in providing diagnostic specificity. The examination of MTL structures, which has so far been exclusive to MRI protocols, is then examined as a possible strategy to improve diagnostic specificity. All told, there is considerable promise that early and specific diagnosis is feasible through a combination of imaging modalities
— id: 70033, year: 2005, vol: 32, page: 486, stat: Journal Article,

Toward the validation of functional neuroimaging as a potential biomarker for Alzheimer's disease: implications for drug development
Pupi, Alberto; Mosconi, Lisa; Nobili, Flavio M; Sorbi, Sandro
2005 Jan-Feb;7(1):59-68, Molecular Imaging & Biology
Despite investments carried out in the research since Alzheimer's disease (AD) was firstly defined as an isolated clinical entity, there is still a lack of appropriate cure and effective therapies to halt or slow the disease progression. While fundamental research has provided a better characterization of AD, much remains to be done for the development of new biological treatment strategies. It is now being debated whether functional neuroimaging (FNI) could help improve diagnostic accuracy and become a possible biomarker of AD. The primary purpose of this review was to determine whether data already published in the literature meet formal technology assessment standards for using regional cerebral blood flow (rCBF) or glucose metabolism (rCMRGlu) as a biomarker for AD. The secondary purpose was to identify any remaining gaps that might need to be systematically addressed before drug developers and regulators accept FNI as a biomarker for AD. The present paper reviews the literature regarding metabolic positron emission tomography (PET) and perfusion single photon emission computed tomography (SPECT) studies in AD. There is evidence that treatment with acetylcholinesterase inhibitors (AChEI) leads to changes in brain physiology within the brain regions critical to AD pathology, i.e. the temporal, parietal and frontal association cortex. However, a thorough analysis combining functional and neuropsychological data has not yet been attempted, and much research is needed to validate the role of FNI as a surrogate endpoint for AD clinical trials
— id: 70032, year: 2005, vol: 7, page: 59, stat: Journal Article,

Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer's disease
Mosconi, L; Nacmias, B; Sorbi, S; De Cristofaro, M T R; Fayazz, M; Tedde, A; Bracco, L; Herholz, K; Pupi, A
2004 Mar;75(3):370-376, Journal of neurology neurosurgery & psychiatry
OBJECTIVES: Declines in brain glucose metabolism have been described early in Alzheimer's disease (AD), and there is evidence that a genetic predisposition to AD contributes to accelerate this process. The epsilon 4 (e4) allele of the apolipoprotein E (ApoE) gene has been implicated as a major risk factor in this process. The aim of this FDG-PET study was to assess the ApoE e4 dose related effect on regional cerebral glucose metabolism (METglc) in clinical AD patients, with statistical voxel based methods. METHODS: Eighty six consecutive mild to moderate AD patients included in the Network for Efficiency and Standardisation of Dementia Diagnosis database underwent FDG-PET scans at rest. PCR was used to determine the ApoE genotype. Patients were grouped as e4 non-carriers (n = 46), e3/e4 (n = 27) and e4/e4 (n = 13) carriers. A voxel-based mapping program was used to compare each AD subgroup with a database of 35 sex and age matched controls (p<0.001, corrected for cluster extent) and also to compare between the subgroups (p<0.001, uncorrected). RESULTS: No difference was found as to age at examination, age at onset, sex, disease duration, educational level, or severity of dementia between AD subgroups. Compared with controls, all AD subgroups had equivalent METglc reductions in the precuneus, posterior cingulate, parietotemporal, and frontal regions. Direct comparisons between AD subgroups indicated that patients with at least one e4 allele had METglc reductions within additional associative and limbic areas compared with e4 non-carriers. CONCLUSIONS: The present FDG-PET study showed different metabolic phenotypes related to the ApoE genotype in clinical AD patients, as revealed with voxel based statistical methods. The results suggest a generalised disorder in e4 carriers impairing metabolism globally, in addition to the more localised changes typical of AD patients
— id: 70163, year: 2004, vol: 75, page: 370, stat: Journal Article,

MCI conversion to dementia and the APOE genotype: a prediction study with FDG-PET
Mosconi, L; Perani, D; Sorbi, S; Herholz, K; Nacmias, B; Holthoff, V; Salmon, E; Baron, J-C; De Cristofaro, M T R; Padovani, A; Borroni, B; Franceschi, M; Bracco, L; Pupi, A
2004 Dec 28;63(12):2332-2340, Neurology
OBJECTIVES: To investigate whether the combination of fluoro-2-deoxy-d-glucose (FDG) PET measures with the APOE genotype would improve prediction of the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). METHOD: After 1 year, 8 of 37 patients with MCI converted to AD (22%). Differences in baseline regional glucose metabolic rate (rCMRglc) across groups were assessed on a voxel-based basis using a two-factor analysis of variance with outcome (converters [n = 8] vs nonconverters [n = 29]) and APOE genotype (E4 carriers [E4+] [n = 16] vs noncarriers [E4-] [n = 21]) as grouping factors. Results were considered significant at p < 0.05, corrected for multiple comparisons. RESULTS: All converters showed reduced rCMRglc in the inferior parietal cortex (IPC) as compared with the nonconverters. Hypometabolism in AD-typical regions, that is, temporoparietal and posterior cingulate cortex, was found for the E4+ as compared with the E4- patients, with the E4+/converters (n = 5) having additional rCMRglc reductions within frontal areas, such as the anterior cingulate (ACC) and inferior frontal (IFC) cortex. For the whole MCI sample, IPC rCMRglc predicted conversion to AD with 84% overall diagnostic accuracy (p = 0.003). Moreover, ACC and IFC rCMRglc improved prediction for the E4+ group, yielding 100% sensitivity, 90% specificity, and 94% accuracy (p < 0.0005), thus leading to an excellent discrimination. CONCLUSION: Fluoro-2-deoxy-d-glucose-PET measures may improve prediction of the conversion to Alzheimer disease, especially in combination with the APOE genotype
— id: 70161, year: 2004, vol: 63, page: 2332, stat: Journal Article,

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

Functional interactions of the entorhinal cortex: an 18F-FDG PET study on normal aging and Alzheimer's disease
Mosconi, Lisa; Pupi, Alberto; De Cristofaro, M Teresa R; Fayyaz, Mozghan; Sorbi, Sandro; Herholz, Karl
2004 Mar;45(3):382-392, Journal of nuclear medicine
Alzheimer's disease (AD) is a brain disorder characterized by reduced cerebral glucose metabolism (CMRgl) in several cortical regions. Evidence from neuropathology studies, animal models of AD, and (18)F-FDG PET studies on cognitive impairment suggest that disrupted connections with the entorhinal cortex (EC) could be implicated in the emergence of the cortical hypometabolism. This (18)F-FDG PET study assessed the functional interactions-that is, the intercorrelations between the EC and the whole brain in vivo-in normal aging and AD. METHODS: Eighty-seven consecutive clinical AD patients underwent (18)F-FDG PET scanning at rest. Thirty-five sex- and age-matched healthy elderly subjects were studied as controls (NC). A voxel-based correlation analysis was performed with statistical parametric mapping to assess significant correlations between relative CMRgl (rCMRgl) in the EC and the rest of the brain, for NC and AD patients. Results were considered significant at P < 0.001. RESULTS: The pattern of EC functional interactions varies between normal aging and AD patients. In NC, the left and right EC were bilaterally correlated with several cortical and limbic regions, in accord with the major anatomic pathways identified in nonhuman primates. Alternatively, in AD patients, the EC correlations with the contralateral hemisphere were entirely lost, whereas those within the ipsilateral hemisphere were preserved only with the inferior temporooccipital (T-O) areas. CONCLUSION: This (18)F-FDG PET correlation study indicates that AD-related processes lead to an altered functional relationship between the EC and several cortical and limbic regions, with respect to normal aging. Our results suggest that the assessment of coupled rCMRgl reductions between the EC and the ipsilateral T-O cortex, besides the typical pattern of cortical reduction, could increase (18)F-FDG PET diagnostic sensitivity and further motivate its inclusion in the clinical assessment of AD
— id: 70035, year: 2004, vol: 45, page: 382, stat: Journal Article,

Age and ApoE genotype interaction in Alzheimer's disease: an FDG-PET study
Mosconi, Lisa; Sorbi, Sandro; Nacmias, Benedetta; De Cristofaro, Maria Teresa R; Fayyaz, Mozhgan; Bracco, Laura; Herholz, Karl; Pupi, Alberto
2004 Feb 15;130(2):141-151, Psychiatry research
Previous positron emission tomography (PET) studies with fluorodeoxglucose (FDG) as tracer in healthy elders showed that the epsilon4 allele of the apolipoprotein E (ApoE) gene is disruptive to cerebral glucose metabolism (rCMRglu), possibly through the interaction with the aging process. The present study was aimed at assessing whether this interaction occurs in patients with Alzheimer's disease (AD). Eight-six AD patients, including 40 ApoE4 carriers and 46 non-carriers, underwent (18)F-FDG PET scanning at rest. ApoE groups were comparable for age, gender, age at onset and disease duration. SPM'99 was used to assess rCMRGlu correlations with age, differences between ApoE groups and ApoE by age interaction, correcting for disease severity. Results were reported at P<0.001, uncorrected. Correlations between age and rCMRGlu confirmed the well-known negative relationship for both groups. Lower rCMRGlu was found within the frontal and cingulate areas for ApoE4 carriers as compared with the non-carriers. Additionally, a significant ApoE by age interaction was detected in the frontal and anterior cingulate cortex, with the ApoE4 carriers having a steeper regression slope with respect to the non-carriers. These results indicate that age-related regional rCMRglu decreases within the frontal and anterior cingulate areas may be more severe in AD patients carrying the ApoE4 allele
— id: 70034, year: 2004, vol: 130, page: 141, stat: Journal Article,

Brain metabolic differences between sporadic and familial Alzheimer's disease
Mosconi, L; Sorbi, S; Nacmias, B; De Cristofaro, M T R; Fayyaz, M; Cellini, E; Bagnoli, S; Bracco, L; Herholz, K; Pupi, A
2003 Oct 28;61(8):1138-1140, Neurology
This FDG-PET study with SPM99 compared 46 patients with sporadic Alzheimer disease (SAD) to 40 patients with familial AD (FAD) and to 35 matched controls. AD groups had equivalent metabolic (METglu) reductions in several cortical and limbic areas with respect to the controls. Patients with FAD showed decreased METglu in the posterior cingulate, parahippocampal, and occipital cortex as compared to the patients with SAD (p < 0.001). Genetic factors lead to phenotypic differences in AD
— id: 70164, year: 2003, vol: 61, page: 1138, stat: Journal Article,