Alzheimer Disease: de Leon MJ

Reisberg B, Prichep L, Mosconi L, John ER, Glodzik-Sobanska L, Boksay I, Monteiro I, Torossian C, Vedvyas A, Ashraf N, Jamil IA, de Leon MJ. · Silberstein Aging and Dementia Research Center, New York University School of Medicine, New York, NY, USA. · Alzheimers Dement. · Pubmed #18632010 No free full text.

Abstract: 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.

Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, de Leon MJ. · Department of Periodontology and Implant Dentistry, College of Dentistry, New York University, New York, NY, USA. · Alzheimers Dement. · Pubmed #18631974 No free full text.

Abstract: The molecular and cellular mechanisms responsible for the etiology and pathogenesis of Alzheimer's disease (AD) have not been defined; however, inflammation within the brain is thought to play a pivotal role. Studies suggest that peripheral infection/inflammation might affect the inflammatory state of the central nervous system. Chronic periodontitis is a prevalent peripheral infection that is associated with gram-negative anaerobic bacteria and the elevation of serum inflammatory markers including C-reactive protein. Recently, chronic periodontitis has been associated with several systemic diseases including AD. In this article we review the pathogenesis of chronic periodontitis and the role of inflammation in AD. In addition, we propose several potential mechanisms through which chronic periodontitis can possibly contribute to the clinical onset and progression of AD. Because chronic periodontitis is a treatable infection, it might be a readily modifiable risk factor for AD.

Kamer AR, Dasanayake AP, Craig RG, Glodzik-Sobanska L, Bry M, de Leon MJ. · Department of Periodontics and Implant Dentistry and Basic Sciences, NYU College of Dentistry, New York, NY 10010, USA. · J Alzheimers Dis. · Pubmed #18487851 No free full text.

Abstract: Alzheimer's disease (AD) affects approximately 4.5 million people in the U.S. and this number will increase as the population ages and the life-span increases. Therefore, of paramount importance is identifying mechanisms and factors that affect the risk of developing AD. The etiology and pathogenic mechanisms for AD have not been defined, although inflammation within the brain is thought to play a role. Consistent with this hypothesis, studies suggest that peripheral infections contribute to the inflammatory state of the central nervous system. Periodontitis is a prevalent, persistent peripheral infection associated with gram negative, anaerobic bacteria that are capable of exhibiting localized and systemic infections in the host. This review offers a hypothetical link between periodontitis and AD and will present possible mechanistic links between periodontitis related inflammation and AD. It will review the pathogenesis of periodontitis and the mechanisms by which periodontal infections may affect the onset and progression of AD. Since periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

de Leon MJ, Mosconi L, Blennow K, DeSanti S, Zinkowski R, Mehta PD, Pratico D, Tsui W, Saint Louis LA, Sobanska L, Brys M, Li Y, Rich K, Rinne J, Rusinek H. · Center for Brain Health, NYU School of Medicine, Department of Psychiatry, 560 First Ave., New York 10016, USA. · Ann N Y Acad Sci. · Pubmed #17413016 No free full text.

Abstract: 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.

Blennow K, de Leon MJ, Zetterberg H. · Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgren's University Hospital, Mölndal, Sweden. · Lancet. · Pubmed #16876668 No free full text.

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

Mosconi L, Brys M, Glodzik-Sobanska L, De Santi S, Rusinek H, de Leon MJ. · Center for Brain Health MHL-400, New York University School of Medicine, 560 1st Avenue, New York, NY 10016, USA. · Exp Gerontol. · Pubmed #16839732 No free full text.

Abstract: 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.

Glodzik-Sobanska L, Rusinek H, Mosconi L, Li Y, Zhan J, de Santi S, Convit A, Rich K, Brys M, de Leon MJ. · Center for Brain Health, New York University School of Medicine, New York, NY 10016, USA. · Neuroimaging Clin N Am. · Pubmed #16443492 No free full text.

Abstract: 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.

Mosconi L, De Santi S, Rusinek H, Convit A, de Leon MJ. · Department of Psychiatry, New York University School of Medicine, Center for Brain Health, 560 First Avenue, NY 10016, USA. · Expert Rev Neurother. · Pubmed #15853510 No free full text.

Abstract: 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.

Reiss AB, Siller KA, Rahman MM, Chan ES, Ghiso J, de Leon MJ. · Department of Medicine, New York University School of Medicine, New Bellevue 16N1, 550 First Avenue, New York, NY 10016, USA. · Neurobiol Aging. · Pubmed #15212822 No free full text.

Abstract: Mechanisms for the regulation of intracellular cholesterol levels in various types of brain and vascular cells are of considerable importance in our understanding of the pathogenesis of a variety of diseases, particularly atherosclerosis and Alzheimer's disease (AD). It is increasingly clear that conversion of brain cholesterol into 24-hydroxycholesterol and its subsequent release into the periphery is important for the maintenance of brain cholesterol homeostasis. Recent studies have shown elevated plasma concentrations of 24-hydroxycholesterol in patients with AD and vascular dementia, suggesting increased brain cholesterol turnover during neurodegeneration. The oxygenases involved in the degradation and excretion of cholesterol, including the cholesterol 24-hydroxylase and the 27-hydroxylase, are enzymes of the cytochrome P-450 family. This review focuses on the newly recognized importance of cholesterol and its oxygenated metabolites in the pathogenesis of ischemic stroke and AD. The reduction in stroke and AD risk in patients treated with cholesterol-lowering statins is also discussed.

Frank RA, Galasko D, Hampel H, Hardy J, de Leon MJ, Mehta PD, Rogers J, Siemers E, Trojanowski JQ, Anonymous00193. · Pharmacia Corporation, Mailstop 134, Peapack, NJ 07977, USA. · Neurobiol Aging. · Pubmed #12714109 No free full text.

This publication has no abstract.

Wolf OT, Convit A, Thorn E, de Leon MJ. · Center for Brain Health, Neuroimaging Laboratory, New York University School of Medicine, 560 First Avenue, NY, New York 10016, USA. · Psychoneuroendocrinology. · Pubmed #12183214 No free full text.

Abstract: It is unknown whether hypothalamus-pituitary-adrenal (HPA) axis dysfunction is associated with the memory impairments observed among elderly participants with mild cognitive impairment (MCI), a group considered at increased risk for Alzheimer's disease (AD). Therefore, salivary cortisol levels were measured at six points over the course of the day while at-home in MCI participants (n=16), normal elderly (n=28), and young controls (n=14). Results revealed that MCI participants did not show elevated salivary cortisol levels. The 9 a.m. cortisol level of the MCI group was significantly lower than the 9 a.m. level of the young controls, but did not differ from those of the normal elderly group. In contrast to the other two groups, within the MCI group mean cortisol levels were inversely related to immediate recall of paragraphs. No association was observed between mean cortisol levels and performance in paired associates and digit span. Whether cortisol levels, in conjunction with other factors, such as hippocampal volume, will lead to improved prediction of future decline to AD in participants with MCI remains to be established in longitudinal studies.

De Santi S, de Leon MJ, Rusinek H, Convit A, Tarshish CY, Roche A, Tsui WH, Kandil E, Boppana M, Daisley K, Wang GJ, Schlyer D, Fowler J. · Department of Psychiatry, New York University School of Medicine, New York, NY, USA. · Neurobiol Aging. · Pubmed #11445252 No free full text.

Abstract: We used MRI volume sampling with coregistered and atrophy corrected FDG-PET scans to test three hypotheses: 1) hippocampal formation measures are superior to temporal neocortical measures in the discrimination of normal (NL) and mild cognitive impairment (MCI); 2) neocortical measures are most useful in the separation of Alzheimer disease (AD) from NL or MCI; 3) measures of PET glucose metabolism (MRglu) have greater diagnostic sensitivity than MRI volume. Three groups of age, education, and gender matched NL, MCI, and AD subjects were studied. The results supported the hypotheses: 1) entorhinal cortex MRglu and hippocampal volume were most accurate in classifying NL and MCI; 2) both imaging modalities identified the temporal neocortex as best separating MCI and AD, whereas widespread changes accurately classified NL and AD; 3) In most between group comparisons regional MRglu measures were diagnostically superior to volume measures. These cross-sectional data show that in MCI hippocampal formation changes exist without significant neocortical changes. Neocortical changes best characterize AD. In both MCI and AD, metabolism reductions exceed volume losses.

Convit A, de Asis J, de Leon MJ, Tarshish CY, De Santi S, Rusinek H. · Department of Psychiatry, New York University Medical Center, 550 First Avenue, New York, NY, USA. · Neurobiol Aging. · Pubmed #10794844 No free full text.

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

Brys M, Glodzik L, Mosconi L, Switalski R, De Santi S, Pirraglia E, Rich K, Kim BC, Mehta P, Zinkowski R, Pratico D, Wallin A, Zetterberg H, Tsui WH, Rusinek H, Blennow K, de Leon MJ. · New York University School of Medicine, Center for Brain Health, NY 10016, USA. · J Alzheimers Dis. · Pubmed #19221425 No free full text.

Abstract: 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(231)), amyloid-beta (Abeta(42)/Abeta(40)) 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(231), IP and lower Abeta(42)/Abeta(40) 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(231) and GMC-MTL significantly increased overall prediction of AD from 74% to 84% (p(step)<0.05). These results provide support for including multiple modalities of biomarkers in the identification of memory clinic patients at increased risk for dementia.

Mosconi L, Mistur R, Switalski R, Brys M, Glodzik L, Rich K, Pirraglia E, Tsui W, De Santi S, de Leon MJ. · Department of Psychiatry, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA. · Neurology. · Pubmed #19005175 No free full text.

Abstract: 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.

Devanand DP, Liu X, Tabert MH, Pradhaban G, Cuasay K, Bell K, de Leon MJ, Doty RL, Stern Y, Pelton GH. · Division of Geriatric Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. · Biol Psychiatry. · Pubmed #18723162 No free full text.

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

Li Y, Rinne JO, Mosconi L, Pirraglia E, Rusinek H, DeSanti S, Kemppainen N, Någren K, Kim BC, Tsui W, de Leon MJ. · New York University School of Medicine, New York, NY 10016, USA. · Eur J Nucl Med Mol Imaging. · Pubmed #18566819 links to  free full text

Abstract: 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.

Zhan J, Brys M, Glodzik L, Tsui W, Javier E, Wegiel J, Kuchna I, Pirraglia E, Li Y, Mosconi L, Saint Louis LA, Switalski R, De Santi S, Kim BC, Wisniewski T, Reisberg B, Bobinski M, de Leon MJ. · Department of Psychiatry, New York University School of Medicine, New York 10016, USA. · Hum Brain Mapp. · Pubmed #18381771 links to  free full text

Abstract: 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.

Glodzik L, King KG, Gonen O, Liu S, De Santi S, de Leon MJ. · Center for Brain Health, Department of Psychiatry, New York University New York, NY 10016, USA. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #18343551 No free full text.

Abstract: Glutamate (Glu) is associated with excitotoxic cell damage. Memantine modulates the glutamate induced excitotoxicity in Alzheimer's disease (AD). No information is available as to the influence of memantine on in vivo brain glutamate levels. Hippocampal Glu levels were measured in cognitively impaired and normal individuals (n=10) before and after 6 months of memantine treatment, using three dimensional high spatial resolution (0.5 cm(3) voxels) proton magnetic resonance spectroscopy at 3 T. These measurements were also repeated in a non-treated cognitively normal group (n=6). Treatment with memantine decreased Glu/Cr (creatine) ratio in the left hippocampal region. Memantine reduced hippocampal glutamate levels, which may be consistent with its anti-excitotoxic property.

Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, Lucignani G, Reiman EM, Holthoff V, Kalbe E, Sorbi S, Diehl-Schmid J, Perneczky R, Clerici F, Caselli R, Beuthien-Baumann B, Kurz A, Minoshima S, de Leon MJ. · Center for Brain Health, New York University School of Medicine, New York, New York 10016, USA. · J Nucl Med. · Pubmed #18287270 links to  free full text

Abstract: 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.

Reisberg B, Ferris SH, Kluger A, Franssen E, Wegiel J, de Leon MJ. · Aging and Dementia Research Center, New York University School of Medicine, New York 10016, USA. · Int Psychogeriatr. · Pubmed #18031593 No free full text.

Abstract: Descriptions of dementia can be traced to antiquity. Prichard (1837) described four dementia stages and Kral (1962) described a "benign senescent forgetfulness" condition. The American Psychiatric Association's DSM-III (1980) identified an early dementia stage.In 1982, the Clinical Dementia Rating (CDR) and the Global Deterioration Scale (GDS) were published, which identified dementia antecedents. The CDR 0.5 "questionable dementia" stage encompasses both mild dementia and earlier antecedents. GDS stage 3 described a predementia condition termed "mild cognitive decline" or, alternatively, beginning in 1988, "mild cognitive impairment" (MCI). This GDS stage 3 MCI condition is differentiated from both a preceding GDS stage 2, "subjective cognitive impairment" (SCI) stage and a subsequent GDS 4 stage of mild dementia.GDS stage 3 MCI has been well characterized. For example, specific clinical concomitants, mental status and psychological assessment score ranges, behavioral and emotional changes, neuroimaging concomitants, neurological reflex changes, electrophysiological changes, motor and coordination changes, and changes in activities, accompanying GDS stage 3 MCI have been described.Petersen and associates proposed a definition of MCI in 2001 which has been widely used (hereafter referred to as "Petersen's MCI"). Important differences between GDS stage 3 MCI and Petersen's MCI are that, because of denial, GDS stage 3 MCI does not require memory complaints. Also, GDS stage 3 MCI recognizes the occurrence of executive level functional deficits, which Petersen's MCI did not. Nevertheless, longitudinal and other studies indicate essential compatibility between GDS stage 3 MCI and Petersen's MCI duration and outcomes.

Mosconi L, Brys M, Switalski R, Mistur R, Glodzik L, Pirraglia E, Tsui W, De Santi S, de Leon MJ. · Department of Psychiatry, New York University School of Medicine, 560 First Avenue, New York, NY 10016, USA. · Proc Natl Acad Sci U S A. · Pubmed #18003925 links to  free full text

Abstract: 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.

de Leon MJ, Mosconi L, Li J, De Santi S, Yao Y, Tsui WH, Pirraglia E, Rich K, Javier E, Brys M, Glodzik L, Switalski R, Saint Louis LA, Pratico D. · New York University, School of Medicine, Center for Brain Health MHL 400, New York, NY 10016, USA. · J Neurol. · Pubmed #17994313 No free full text.

Abstract: 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.

Glodzik-Sobanska L, Pirraglia E, Brys M, de Santi S, Mosconi L, Rich KE, Switalski R, Saint Louis L, Sadowski MJ, Martiniuk F, Mehta P, Pratico D, Zinkowski RP, Blennow K, de Leon MJ. · New York University School of Medicine, New York, NY 10016, United States. · Neurobiol Aging. · Pubmed #17920160 No free full text.

Abstract: 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 epsilon4 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 epsilon4 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.

Brys M, Pirraglia E, Rich K, Rolstad S, Mosconi L, Switalski R, Glodzik-Sobanska L, De Santi S, Zinkowski R, Mehta P, Pratico D, Saint Louis LA, Wallin A, Blennow K, de Leon MJ. · New York University School of Medicine, NY, USA. · Neurobiol Aging. · Pubmed #17889968 No free full text.

Abstract: 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.