Alzheimer Disease: Honig LS

Steinerman JR, Honig LS. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Columbia University College of Physician & Surgeons, 630 West 168th Street, New York, NY 10032, USA. · Curr Neurol Neurosci Rep. · Pubmed #17764627 No free full text.

Abstract: Diagnosis and monitoring of Alzheimer's disease and the related dementias have long depended principally on clinical examination, especially cognitive testing. Establishment of biomarkers, which might assist in diagnosis or tracking of disease progression, would be a highly valuable addition to the care of patients. Such biomarkers are potentially available from body fluids and tissues as well as from brain imaging data. As specific disease-modifying therapies for Alzheimer's disease are developed, biomarkers may improve diagnostic accuracy and facilitate clinical trials, allowing a better gauge of treatment response. In this review, we focus on biomarkers in cerebrospinal fluid and plasma, including measurements of the proteins tau and beta-amyloid.

Honig LS, Mayeux R. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, and Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032-3795, USA. · Aging (Milano). · Pubmed #11442300 No free full text.

Abstract: Alzheimer's disease (AD) is the principal cause of dementia in the elderly, and affects about 15 million people worldwide. The earliest symptom is usually an insidious impairment of memory. As the disease progresses, there is increasing impairment of language and other cognitive functions. Problems occur with naming and word-finding, and later with verbal and written comprehension and expression. Visuospatial, analytic and abstract reasoning abilities, judgment, and insight become affected. Behavioral changes may include delusions, hallucinations, irritability, agitation, verbal or physical aggression, wandering, and disinhibition. Ultimately, there is loss of self-hygiene, eating, dressing, and ambulatory abilities, and incontinence and motor dysfunction. Before diagnosis of AD, individuals may have memory complaints, which represent a period of mild cognitive impairment (MCI). Before MCI, there is a prodromal, ill-defined presymptomatic period of disease ('pre-MCI"). In this review, we particularly focus on these earliest stages. We also discuss the more advanced stages of AD, and address factors that may influence disease course. Understanding the natural history of AD will allow better targeting of the disease-modifying treatments that are on the horizon.

Chandler MJ, Lacritz LH, Cicerello AR, Chapman SB, Honig LS, Weiner MF, Cullum CM. · The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8846, USA. · J Clin Exp Neuropsychol. · Pubmed #15590465 No free full text.

Abstract: Three-word recall tasks are widely used as brief measures of verbal memory function, although interpretation of performance is complicated by variations in test instructions and procedures. The purpose of this study was to examine 3-word recall performance in samples of healthy subjects aged 5275 (M age = 70) and age 7692 (M age = 82) compared to patients with Alzheimer's Disease (AD) when explicit prompts to remember the words were given. Those in the younger aging group remembered significantly more words than those in the older sample after a brief delay (M= 2.8 and 2.3, respectively). However, the majority of control subjects recalled 2 or 3 words after the delay, with only 3% of the 5075 year old group and 17% of the 76+ year old group recalling 0 or 1 word on delayed recall. This is in stark contrast to the 87% of individuals with AD who recalled 0 or 1 word. Even though 3-word recall performance decreases with age, good recall (2 or 3 words) can be expected in most cases of normal aging.

Clark LN, Kartsaklis LA, Wolf Gilbert R, Dorado B, Ross BM, Kisselev S, Verbitsky M, Mejia-Santana H, Cote LJ, Andrews H, Vonsattel JP, Fahn S, Mayeux R, Honig LS, Marder K. · Taub Institute for Research onAlzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA. · Arch Neurol. · Pubmed #19433657 No free full text.

Abstract: BACKGROUND: Mutations in the glucocerebrosidase (GBA) gene are associated with Lewy body (LB) disorders. OBJECTIVE: To determine the relationship of GBA mutations and APOE4 genotype to LB and Alzheimer disease (AD) pathological findings. DESIGN: Case-control study. SETTING: Academic research. PARTICIPANTS: The 187 subjects included patients with primary neuropathological diagnoses of LB disorders with or without AD changes (95 cases), randomly selected patients with AD (without significant LB pathological findings; 60 cases), and controls with neither LB nor AD pathological findings (32 cases). MAIN OUTCOME MEASURES: GBA mutation status, APOE4 genotype, LB pathological findings (assessed according to the third report of the Dementia With Lewy Body Consortium), and Alzheimer plaque and tangle pathological findings (rated by criteria of Braak and Braak, the Consortium to Establish a Registry for Alzheimer Disease, and the National Institute on Aging-Reagan Institute). RESULTS: GBA mutations were found in 18% (34 of 187) of all subjects, including 28% (27 of 95) of those with primary LB pathological findings compared with 10% (6 of 60) of those with AD pathological findings and 3% (1 of 32) of those without AD or LB pathological findings (P=.001). GBA mutation status was significantly associated with the presence of cortical LBs (odds ratio, 6.48; 95% confidence interval, 2.45-17.16; P<.001), after adjusting for sex, age at death, and presence of APOE4. GBA mutation carriers were significantly less likely to meet AD pathological diagnostic (National Institute on Aging-Reagan Institute intermediate or high likelihood) criteria (odds ratio, 0.35; 95% confidence interval, 0.15-0.79; P=.01) after adjustment for sex, age at death, and APOE4. CONCLUSION: GBA mutations may be associated with pathologically "purer" LB disorders, characterized by more extensive (cortical) LB, and less severe AD pathological findings and may be a useful marker for LB disorders.

Brickman AM, Honig LS, Scarmeas N, Tatarina O, Sanders L, Albert MS, Brandt J, Blacker D, Stern Y. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 W 168th St, Campus Box 16, New York, NY 10032, USA. · Arch Neurol. · Pubmed #18779424 No free full text.

Abstract: OBJECTIVE: To determine if baseline measurements of cerebral atrophy and severity of white matter hyperintensity (WMH) predict the rate of future cognitive decline in patients with Alzheimer disease (AD). DESIGN: Data were drawn from the Predictors Study, a longitudinal study that enrolls patients with mild AD and reassesses them every 6 months with use of the Columbia modified Mini-Mental State (mMMS) examination (score range, 0-57). Magnetic resonance images were analyzed to determine the severity of WMH, using the Scheltens scale, and the degree of atrophy, using the bicaudate ratio. Generalized estimating equations were used to determine whether severity of baseline magnetic resonance image measurements and their interaction predicted the rate of mMMS score decline at subsequent visits. SETTING: Three university-based AD centers in the United States. PARTICIPANTS: At baseline, 84 patients with AD from the Predictors Study received structural magnetic resonance imaging and were selected for analysis. They had a mean of 6 follow-up evaluations. Main Outcome Measure The mMMS score. RESULTS: Generalized estimating equation models demonstrated that the degree of baseline atrophy (beta = -0.316; P = .04), the severity of WMH (beta = -0.173; P = .03), and their interaction (beta = -6.061; P = .02) predicted the rate of decline in mMMS scores. CONCLUSIONS: Both degree of cerebral atrophy and severity of WMH are associated with the rapidity of cognitive decline in AD. Atrophy and WMH may have a synergistic effect on future decline in AD, such that patients with a high degree of both have a particularly precipitous cognitive course. These findings lend further support to the hypothesis that cerebrovascular pathological abnormalities contribute to the clinical syndrome of AD.

Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E, Herman M, Ho L, Kreber R, Honig LS, Ganetzky B, Duff K, Arancio O, Small SA. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. · Proc Natl Acad Sci U S A. · Pubmed #18480253 links to  free full text

Abstract: Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Abeta peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Abeta aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.

Siedlecki KL, Honig LS, Stern Y. · Cognitive Neuroscience Division, Taub Institute, Columbia University College of Physicians and Surgeons. · Neuropsychology. · Pubmed #18444718 No free full text.

Abstract: An exploratory factor analysis (EFA) and a series of confirmatory factor analyses were conducted on 17 variables designed to assess different cognitive abilities in a sample of healthy older adults. In the EFA, 4 factors emerged corresponding to language, memory, processing speed, and fluid ability constructs. The results of the confirmatory factor analyses suggested that a 5-factor model with an additional Attention factor improved the fit. The invariance of the 5-factor model was examined across 3 groups: a group of cognitively healthy older adults, a group of patients diagnosed with questionable dementia (QD), and a group of patients diagnosed with probable Alzheimer's disease (AD). Results of the invariance analysis suggest that the model may have configural invariance across the 3 groups but not metric invariance. Specifically, preliminary analyses suggest that the memory construct may represent something different in the QD and AD groups as compared to the healthy older adult group, consistent with the underlying pathology in early AD.

Luchsinger JA, Honig LS, Tang MX, Devanand DP. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA. · Int J Geriatr Psychiatry. · Pubmed #18327871 links to  free full text

Abstract: BACKGROUND: Depressive symptoms in the elderly are associated with an increased Alzheimer's disease (AD) risk. We sought to determine whether the association between depressive symptoms and AD is explained by a history of vascular risk factors and stroke. METHODS: Five hundred and twenty-six elderly persons from New York City without dementia at baseline were followed for a mean of 5 years. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAM). Incident AD was ascertained using standard criteria. Diabetes, hypertension, heart disease, current smoking and stroke were ascertained by self-report. Proportional hazards regression was used to relate HAM scores to incident AD. RESULTS: HAM scores were higher in persons with hypertension, heart disease, and stroke, which in turn were related to higher AD risk. AD risk increased with increasing HAM scores as a continuous logarithmically transformed variable (HR for one point increase=1.4; 95% CI=1.1,1.8) and as a categorical variable (HR for HAM >or= 10=3.4; 95% CI=1.5,8.1; p for trend=0.004 with HAM=0 as the reference). These results were virtually unchanged after adjustment for vascular risk factors and stroke, individually (HR for HAM >or= 10=3.4; 95% CI=1.5,8.1; p for trend = 0.004), and in a composite measure (HR for HAM >or= 10=3.0; 95% CI=1.2,7.8; p for trend=0.02). CONCLUSION: The prospective relation between depressive symptoms and AD is not explained by a history of vascular risk factors and stroke, suggesting that other mechanisms may account for this association.

Lee JH, Cheng R, Honig LS, Vonsattel JP, Clark L, Mayeux R. · Gertrude H. Sergievsky Center, Columbia University, 630 W. 168 St., New York, NY 10032, USA. · Neurology. · Pubmed #17978276 links to  free full text

This publication has no abstract.

Gerstner E, Lazar RM, Keller C, Honig LS, Lazar GS, Marshall RS. · Columbia University College of Physicians and Surgeons, New York, NY, USA. · Cogn Behav Neurol. · Pubmed #17356339 No free full text.

Abstract: OBJECTIVE: To present the case of a man with progressive speech loss and other clinical features and diagnostic tests consistent with fronto-temporal dementia but whose postmortem neuropathologic findings revealed Alzheimer disease (AD). BACKGROUND: Progressive apraxia of speech presents without true language abnormalities, usually seen with frontal lesions and not associated with AD pathology. METHOD: We describe the clinico-pathologic case of an 87-year-old man with progressive loss of speech function and present the prospective presentation of his syndrome using structural (magnetic resonance imaging) and metabolic (positron emission tomography) neuro-imaging studies, neuropsychologic testing, and pathology. RESULTS: His syndrome was characterized over the first 6 to 9 years by progressive deterioration of speech production, alteration of mood, and dysphagia but near normal language, memory, and visual-spatial function. At 8 years, fluorodeoxyglucose-positron emission tomography showed largely frontal metabolic abnormality. Over his final 1(1/2) years, he was mute and withdrawn. Neuropathologic findings showed neuritic plaques and neurofibrillary tangles, but no signs of frontotemporal dementias such as Pick bodies or ubiquitinated tau-negative inclusions. CONCLUSIONS: There can be overlap in the presentation of fronto-temporal dementia and AD despite the disparate pathologic bases of the underlying diseases. It has yet to be determined how to differentiate these diseases in such variant presentations and whether such atypical AD syndromes are equally amenable to standard therapies for AD.

Devanand DP, Pradhaban G, Liu X, Khandji A, De Santi S, Segal S, Rusinek H, Pelton GH, Honig LS, Mayeux R, Stern Y, Tabert MH, de Leon MJ. · Department of Biological Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Neurology. · Pubmed #17353470 No free full text.

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

Wright CB, Vonsattel JP, Bell K, Honig LS. · Columbia University College of Physicians and Surgeons, Department of Neurology, New York, NY 10032, USA. · Sci Aging Knowledge Environ. · Pubmed #16807476 No free full text.

Abstract: In this case study, we review the symptoms, cognitive testing, brain imaging, and brain pathology of a woman with dementia, for whom the neuropathological findings suggest a prominent contribution of cerebrovascular disease. Vascular dementia is the term commonly used for persons with dementia resulting from strokes, either clinically evident or subclinical "silent" events. "Mixed dementia" is the term used when there is an admixture of pathological findings related to Alzheimer's disease (AD) and cerebrovascular disease, as in this situation. In some cases of mixed dementia, the pathological involvement of AD may be the principal contributory cause of the cognitive symptoms, and in others, the vascular changes may give the greater contribution.

Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. · Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. · Neurology. · Pubmed #16116114 links to  free full text

Abstract: BACKGROUND: The prevalence of Alzheimer disease (AD) is increasing in the elderly, and vascular risk factors may increase its risk. OBJECTIVE: To explore the association of the aggregation of vascular risk factors with AD. METHODS: The authors followed 1,138 individuals without dementia at baseline (mean age 76.2) for a mean of 5.5 years. The presence of vascular risk factors was related to incident possible and probable AD. RESULTS: Four risk factors (diabetes, hypertension, heart disease, and current smoking) were associated with a higher risk of AD (p < 0.10) when analyzed individually. The risk of AD increased with the number of risk factors (diabetes + hypertension + heart disease + current smoking). The adjusted hazards ratio of probable AD for the presence of three or more risk factors was 3.4 (95% CI: 1.8, 6.3; p for trend < 0.0001) compared with no risk factors. Diabetes and current smoking were the strongest risk factors in isolation or in clusters, but hypertension and heart disease were also related to a higher risk of AD when clustered with diabetes, smoking, or each other. CONCLUSIONS: The risk of Alzheimer disease (AD) increased with the number of vascular risk factors. Diabetes and current smoking were the strongest risk factors, but clusters including hypertension and heart disease also increased the risk of AD. These associations are unlikely to be explained by misclassification of the outcome, given strong associations when only probable AD is considered.

Honig LS, Kukull W, Mayeux R. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, the Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA. · Neurology. · Pubmed #15699381 No free full text.

Abstract: BACKGROUND: Epidemiologic studies have implicated cerebrovascular disease and its antecedents as risk factors for Alzheimer disease (AD). Cerebral atherosclerosis or strokes may increase the deposition of neuritic plaques or the formation of neurofibrillary tangles. Alternatively, they may simply hasten the age at onset of disease, or increase the severity of disease symptoms. This investigation examined the association between cerebrovascular disease and the pathologic manifestations of AD in an autopsy series. METHODS: This was a cross-sectional study using data from the United States National Alzheimer's Coordinating Center database. The primary analysis included 1,054 individuals with clinical information and semiquantitative neuropathologic measurements: 921 had AD as the primary neuropathologic diagnosis and 133 were considered neuropathologically normal. RESULTS: Overall, 9% of the individuals had clinical history of stroke during life, but 33% had evidence of cerebral infarcts at postmortem. There was no association between neuritic plaques or neurofibrillary tangles, the primary neuropathologic manifestations of AD, with either clinical history of stroke or the presence of cerebral infarcts at postmortem. The authors did find a higher frequency of neuritic plaques and neurofibrillary tangles with increased amyloid angiopathy. Neither plaques nor tangles were associated with small vessel cerebrovascular disease, arteriosclerosis. However, the presence of large-vessel cerebrovascular disease, or atherosclerosis, was strongly associated with an increased frequency of neuritic plaques. CONCLUSIONS: Atherosclerotic cerebrovascular disease may have a role in the pathogenesis of Alzheimer disease, because of a strong association with frequent neuritic plaques.

Scarmeas N, Hadjigeorgiou GM, Papadimitriou A, Dubois B, Sarazin M, Brandt J, Albert M, Marder K, Bell K, Honig LS, Wegesin D, Stern Y. · Cognitive Neuroscience Division, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, and Department of Neurology, New York, NY 10032, USA. · Neurology. · Pubmed #15452286 No free full text.

Abstract: BACKGROUND: Motor signs (MOSIs) are common in Alzheimer disease (AD) and may be associated with rates of cognitive decline, mortality, and cost of care. OBJECTIVE: To describe the progression and identify predictors of individual MOSIs in AD. METHODS: A cohort of 474 patients with AD at early stages was followed semiannually for up to 13.1 years (mean 3.6 years) in five centers in Europe and the United States. MOSIs were rated using a standardized portion of the Unified Parkinson's Disease Rating Scale. Overall, 3,030 visits/assessments of MOSIs (average 6.4/patient) were performed. Prevalence and incidence rates were calculated, and cumulative risk graphs were plotted for individual non-drug-induced MOSI domains. Rates of change over time taking into account potential covariates were also estimated. With use of each MOSI domain as outcome in Cox models, predictors of MOSI incidence were identified. RESULTS: At least one MOSI was detected in 13% of patients at first examination and in 36% for the last evaluation. Total MOSI score increased at an annual rate of 3% of total possible score. Rates of annual change for speech/facial expression (4%), rigidity (2.45%), posture/gait (3.9%), and bradykinesia (3.75%) were of similar magnitude, and their occurrence increased from first (3 to 6%) to last (22 to 29%) evaluation. Tremor was less frequent throughout the course of the disease (4% at first and 7% at last evaluation) and worsened less (0.75% increase/year). CONCLUSIONS: Most motor signs occur frequently and progress rapidly in Alzheimer disease. Tremor is an exception in that it occurs less frequently and advances at slower rates.

Scarmeas N, Habeck CG, Zarahn E, Anderson KE, Park A, Hilton J, Pelton GH, Tabert MH, Honig LS, Moeller JR, Devanand DP, Stern Y. · Cognitive Neuroscience Division of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. · Neuroimage. · Pubmed #15325350 No free full text.

Abstract: Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.

Scarmeas N, Zarahn E, Anderson KE, Honig LS, Park A, Hilton J, Flynn J, Sackeim HA, Stern Y. · Cognitive Neuroscience Division, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons of Columbia University, New York, NY, USA. · Arch Neurol. · Pubmed #14732623 links to  free full text

Abstract: BACKGROUND: Cognitive reserve (CR) is the ability of an individual to cope with advancing brain pathological abnormalities so that he or she remains free of symptoms. Epidemiological data and evidence from positron emission tomography suggest that it may be mediated through education or IQ. OBJECTIVE: To investigate CR-mediated differential brain activation in Alzheimer disease (AD) subjects compared with healthy elderly persons. PARTICIPANTS: Using radioactive water positron emission tomography, we scanned 12 AD patients and 17 healthy elderly persons while performing a serial recognition memory task for nonverbalizable shapes under 2 conditions: low demand, in which one shape was presented in each study trial, and titrated demand, in which the study list length was adjusted so that each subject recognized shapes at approximately 75% accuracy. Positron emission tomographic scan acquisition included the encoding and recognition phases. A CR factor score that summarized years of education, National Adult Reading Test estimated IQ, and Wechsler Adult Intelligence Scale-Revised vocabulary subtest score (explaining 71% of the total variance) was used as an index of CR. Voxel-wise, multiple regression analyses were performed with the "activation" difference (titrated demand-low demand) as the dependent variables and the CR factor score as the independent one. Brain regions where regression slopes differed between the 2 groups were identified. RESULTS: The slopes were significantly more positive for the AD patients in the left precentral gyrus and in the left hippocampus and significantly more negative in the right fusiform, right middle occipital, left superior occipital, and left middle temporal gyri. CONCLUSION: Brain regions where systematic relationships (slopes) between subjects' education-IQ and brain activation differ as a function of disease status may mediate the differential ability to cope with (ie, delay or modify) clinical manifestations of AD.

Honig LS, Tang MX, Albert S, Costa R, Luchsinger J, Manly J, Stern Y, Mayeux R. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, the Gertrude H. Sergievsky Center, Columbia University, New York, · Arch Neurol. · Pubmed #14676044 links to  free full text

Abstract: BACKGROUND: Alzheimer disease (AD) and stroke are common in elderly individuals, but the relation between these 2 disorders remains uncertain. OBJECTIVE: To investigate the association between a clinical history of stroke and subsequent risk of AD. DESIGN: A cohort of 1766 Medicare recipients without dementia participated in a longitudinal follow-up study from 1992 through 1999 in upper Manhattan, New York, NY. History of stroke and presence of cardiovascular risk factors were ascertained at the onset of the study. Incidence rates for AD among those with and without stroke were calculated; proportional hazards ratios were computed using age at onset of the disease as the time-to-event variable. RESULTS: The annual incidence for AD was 5.2% among individuals with stroke vs 4% for those without stroke. The hazards ratio for AD among those with a history of stroke was 1.6 (95% confidence interval, 1.0-2.4) compared with those without stroke. Of the vascular risk factors, hypertension, diabetes, and heart disease, only diabetes related to risk of AD in the absence of stroke. Stroke remained weakly associated with AD in the absence of these factors, but risk significantly increased with the additional factors of hypertension (relative risk, 2.3; 95% confidence interval, 1.4-3.6), diabetes (relative risk, 4.6; 95% confidence interval, 2.2-9.5), or heart disease (relative risk, 2.0; 95% confidence interval, 1.2-3.2). CONCLUSIONS: Stroke is associated with AD among elderly individuals. The relation is strongest in the presence of known vascular risk factors. The observed association between stroke and AD might relate to an underlying systemic vascular disease process, or alternatively, to the additive effects of stroke and AD pathologic features, leading to an earlier age at onset of disease.

Mayeux R, Honig LS, Tang MX, Manly J, Stern Y, Schupf N, Mehta PD. · Taub Alzheimer's Disease Research Center, School of Public Health, Columbia University, New York, NY 10032, USA. · Neurology. · Pubmed #14610118 No free full text.

Abstract: BACKGROUND: Plasma amyloid [beta]-peptide (A[beta]) 40 and A[beta]42 levels are increased in persons with mutations causing early-onset familial Alzheimer's disease (AD). Plasma A[beta]42 levels were also used to link microsatellite genetic markers to a putative AD genetic locus on chromosome 10 and were observed in patients with incipient sporadic AD. METHODS: The authors measured plasma A[beta]40 and A[beta]42 levels using a sandwich ELISA after the initial examination of 530 individuals participating in an epidemiologic study of aging and dementia. Participants were examined at 18-month intervals, and plasma A[beta]40 and A[beta]42 levels were repeated in 307 subjects 3 years after baseline. RESULTS: Compared with individuals who never developed AD, patients with AD at baseline and those who developed AD during the follow-up had significantly higher A[beta]42, but not A[beta]40, plasma levels. The risk of AD in the highest quartile of plasma A[beta]42 was increased by more than twofold over that in the lowest quartile. The highest plasma A[beta]42 levels were observed in patients with AD who died during the follow-up. Plasma A[beta]42, but not A[beta]40, levels decreased over time in patients with newly acquired AD. CONCLUSIONS: Plasma A[beta]40 and A[beta]42 increase with age and are strongly correlated with each other. Plasma A[beta]40 and A[beta]42 levels are elevated in some patients before and during the early stages of AD but decline thereafter. High plasma A[beta]42 levels may also be associated with mortality in patients with AD.

Honig LS, Chin SS. · Columbia University College of Physicians and Surgeons, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, The Alzheimer's Disease Research Center, Department of Neurology, New York, NY 10032, USA. · Sci Aging Knowledge Environ. · Pubmed #14602942 No free full text.

Abstract: In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with Alzheimer's disease (AD). AD commonly presents with impairment of memory and language function. In this case, language difficulties were noted more prominently than was memory impairment. Throughout the limbic system and neocortex of the patient were large numbers of senile plaques and neurofibrillary tangles, the pathological hallmarks of AD.

Kaltreider LB, Cicerello AR, Lacritz LH, Honig LS, Rosenberg RN, Cullum MC. · The University of Texas Southwestern Medical Center at Dallas, TX 75390-8898, USA. · Clin Neuropsychol. · Pubmed #11262701 No free full text.

Abstract: This investigation examined the relationship of the word list from the CERAD neuropsychological battery to the California Verbal Learning Test (CVLT) in a sample of 138 subjects with Probable Alzheimer's disease (AD). Results revealed modest but statistically significant associations between the two measures on many key variables. Total words learned showed the strongest association, with lower correlations for delayed recall, intrusion errors, and recognition variables. As expected, the CERAD and CVLT assess similar aspects of verbal learning in patients with AD. However, the modest level of many of the correlations suggests that caution should be exercised in applying the same interpretive strategies derived on more comprehensive measures to shorter ones.

Weiner MF, Vega G, Risser RC, Honig LS, Cullum CM, Crumpacker D, Rosenberg RN. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, USA. · Biol Psychiatry. · Pubmed #10088051 No free full text.

Abstract: BACKGROUND: The epsilon 4 allele of apolipoprotein E (apoE epsilon 4) is associated with late-onset Alzheimer's disease (AD), but its relationship to various aspects of AD has become increasingly unclear. We studied the relationship of apoE genotype in AD to educational attainment, history of heart disease or head injury, age of onset, gender, severity of illness, depression, psychotic symptoms, rate of dementia progression, and time from initial evaluation to nursing home placement. METHODS: ApoE epsilon 4 genotype was determined for 97 clinically diagnosed AD patients and 61 neuropathologically confirmed cases of AD. RESULTS: Presence of one or more epsilon 4 alleles occurred in 66% of AD cases as compared with 27% in control subjects (allele frequency was .40 for AD, .15 for control subjects). Among AD subjects there was no significant relationship between epsilon 4 alleles and educational attainment, history of heart disease, head injury, age of onset, severity of illness, depression, history of depression, rate of dementia progression, or time to nursing home placement. Marginal correlations emerged between number of epsilon 4 alleles, and delusions (p = .05) and hallucinations (p = .05). There was a trend toward increased epsilon 4 homozygosity in patients with onset between ages 65 and 70 years. CONCLUSIONS: We did not find that individuals with one or two apoE epsilon 4 alleles differed significantly in clinical course of AD from those without epsilon 4 except for a trend toward increased psychotic symptoms in the group as a whole and an increase in epsilon 4 homozygosity in patients with reported symptom onset in the late 60s.

Honig LS, Scarmeas N. · No affiliation provided · Neurology. · Pubmed #15781851 No free full text.

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