Alzheimer Disease: Blacker D

Anonymous00207, Rabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS, Tariot PN, Blass DM, Anonymous00208, McIntyre JS, Charles SC, Anzia DJ, Cook IA, Finnerty MT, Johnson BR, Nininger JE, Schneidman B, Summergrad P, Woods SM, Berger J, Cross CD, Brandt HA, Margolis PM, Shemo JP, Blinder BJ, Duncan DL, Barnovitz MA, Carino AJ, Freyberg ZZ, Gray SH, Tonnu T, Kunkle R, Albert AB, Craig TJ, Regier DA, Fochtmann LJ. · No affiliation provided · Am J Psychiatry. · Pubmed #18340692 No free full text.

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Blacker D. · No affiliation provided · N Engl J Med. · Pubmed #15829528 No free full text.

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Jarvik L, LaRue A, Blacker D, Gatz M, Kawas C, McArdle JJ, Morris JC, Mortimer JA, Ringman JM, Ercoli L, Freimer N, Gokhman I, Manly JJ, Plassman BL, Rasgon N, Roberts JS, Sunderland T, Swan GE, Wolf PA, Zonderman AB. · Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18317242 No free full text.

Abstract: Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent's fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring.

Albert MS, Blacker D. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21212, USA. · Annu Rev Clin Psychol. · Pubmed #17716075 No free full text.

Abstract: Mild cognitive impairment (MCI) is a clinical syndrome thought to represent the transition between normal function and dementia. This review describes data that support the existence of such a transitional phase, outlines the heterogeneity of MCI and how that has influenced the evolving concept of MCI, and discusses the impact of heterogeneity on recent MCI clinical trials.

Blacker D, Lovestone S. · Department of Psychiatry, Mass General Hospital/Harvard Medical School, Boston, MA, USA. · J Geriatr Psychiatry Neurol. · Pubmed #16880361 No free full text.

Abstract: In preparation for the development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed), the American Psychiatric Association convened workshops reviewing scientific evidence relevant to diagnosis of dementia. One of the domains covered was genetics, which is reviewed here. The following areas are reviewed: genetic data on Alzheimer's disease and other dementias; the impact of nosology on genetic research in terms of its potential to improve diagnostic sensitivity and specificity and to decrease heterogeneity; the impact of genetic research findings on nosology, specific diagnostic criteria, and subtypes; and recommendations and future directions. The focus is on Alzheimer's disease, where more genetic data are available, and other dementias are reviewed more briefly. In addition, a separate section reviews the relationship of genetic findings and mild cognitive impairment, a boundary zone between normal aging and dementia, particularly Alzheimer's disease.

Bertram L, Hsiao M, McQueen MB, Parkinson M, Mullin K, Blacker D, Tanzi RE. · Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. · Neurobiol Aging. · Pubmed #16378661 No free full text.

Abstract: Genetic linkage studies suggest the presence of an Alzheimer's disease (AD) risk gene on chromosome 19, acting independently of apolipoprotein E (apoE), a known AD risk factor on 19q13. The low density lipoprotein receptor (LDLR) is an interesting candidate because it maps within the linked interval, and is intimately involved in cholesterol homeostasis and the function of apoE. We tested three previously reported single nucleotide polymorphisms (SNPs) within LDLR in a large sample of discordant sibships from multiplex AD families, and failed to find evidence for genetic association with disease risk. In addition, we performed meta-analyses for SNP rs5925 on published data from five independent case control samples, but did not detect any significant summary odds ratios. Based on our data, it seems unlikely that these genetic variants in LDLR make a significant contribution to AD risk in the general population.

Blacker D. · Harvard Medical School, Gerontology Research Unit, Massachusetts General Hospital East, Boston, USA. · Postgrad Med. · Pubmed #11043085 No free full text.

Abstract: Genetic testing sometimes offers definitive information for patients who have a family history of early-onset Alzheimer's disease that occurs before age 50 in a Mendelian pattern. However, for patients who are already symptomatic, especially those with sufficient symptoms to warrant a clinical diagnosis of Alzheimer's disease, genetic testing may not contribute a great deal of information beyond that already available from the clinical and family history. For prediction of disease onset, genetic testing can sometimes give a clear picture of disease risk, but each patient must carefully weigh the risks and benefits of having that information. For early-onset Alzheimer's disease occurring beyond age 50 or without a clear Mendelian pattern, genetic testing is unlikely to be informative. In patients who have a family history of late-onset Alzheimer's disease, while APOE's contribution to increased risk is indisputable, its potential use as a genetic test is very limited. Testing may be helpful as an adjunct to clinical diagnosis but does not obviate the need for a full workup for treatable causes. Thus, the benefit of testing may be marginal. No consensus has been reached as to the value of genetic testing for early detection of late-onset disease, but APOE testing might become important in the future if it helps to define the need for intervention or to select an optimal intervention. There is a broad consensus that APOE testing lacks sufficient predictive value to be suitable for predictive testing in asymptomatic persons.

Bertram L, Hsiao M, Mullin K, Parkinson M, Menon R, Moscarillo TJ, Blacker D, Tanzi RE. · No affiliation provided · Mol Psychiatry. · Pubmed #15768051 No free full text.

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Schjeide BM, Hooli B, Parkinson M, Hogan MF, DiVito J, Mullin K, Blacker D, Tanzi RE, Bertram L. · Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th St, Charlestown, MA 02129, USA. · Arch Neurol. · Pubmed #19204163 No free full text.

Abstract: BACKGROUND: Genomewide association (GWA) studies have recently implicated 4 novel Alzheimer disease (AD) susceptibility loci (GAB2, GOLM1, and 2 uncharacterized loci to date on chromosomes 9p and 15q). To our knowledge, these findings have not been independently replicated. OBJECTIVE: To assess these GWA findings in 4 large data sets of families affected by AD. DESIGN: Follow-up of genetic association findings in previous studies. SETTING: Academic research. PARTICIPANTS: More than 4000 DNA samples from almost 1300 families affected with AD. MAIN OUTCOME MEASURES: Genetic association analysis testing of 4 GWA signals (rs7101429 [GAB2], rs7019241 [GOLM1], rs10519262 [chromosome 15q], and rs9886784 [chromosome 9p]) using family-based methods. RESULTS: In the combined analyses, only rs7101429 in GAB2 yielded significant evidence of association with the same allele as in the original GWA study (P =.002). The results are in agreement with recent meta-analyses of this and other GAB2 polymorphisms suggesting approximately a 30% decrease in risk for AD among carriers of the minor alleles. None of the other 3 tested loci showed consistent evidence for association with AD across the investigated data sets. CONCLUSIONS: GAB2 contains genetic variants that may lead to a modest change in the risk for AD. Despite these promising results, more data from independent samples are needed to better evaluate the potential contribution of GAB2 to AD risk in the general population.

Desikan RS, Cabral HJ, Fischl B, Guttmann CR, Blacker D, Hyman BT, Albert MS, Killiany RJ. · Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA. · AJNR Am J Neuroradiol. · Pubmed #19112067 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) represents a transitional state between normal aging and Alzheimer disease (AD). Our goal was to determine if specific temporoparietal regions can predict the time to progress from MCI to AD. MATERIALS AND METHODS: MR images from 129 individuals with MCI were analyzed to identify the volume of 14 neocortical and 2 non-neocortical brain regions, comprising the temporal and parietal lobes. In addition, 3 neuropsychological test scores were included to determine whether they would provide independent information. After a mean follow-up time of 5 years, 44 of these individuals had progressed to a diagnosis of AD. RESULTS: Cox proportional hazards models demonstrated significant effects for 6 MR imaging regions with the greatest differences being the following: the entorhinal cortex (hazard ratio [HR] = 0.54, P < .001), inferior parietal lobule (hazard ratio [HR] = 0.64, P < .005), and middle temporal gyrus (HR = 0.64, P < .004), indicating decreased risk with larger volumes. A multivariable model showed that a combination of the entorhinal cortex (HR = 0.60, P < .001) and the inferior parietal lobule (HR = 0.62, P < .01) was the best predictor of time to progress to AD. A multivariable model reiterated the importance of including both MR imaging and neuropsychological variables in the final model. CONCLUSIONS: These findings reaffirm the importance of the entorhinal cortex and present evidence for the importance of the inferior parietal lobule as a predictor of time to progress from MCI to AD. The inclusion of neuropsychological performance in the final model continues to highlight the importance of using these measures in a complementary fashion.

Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, Divito J, Ionita I, Jiang H, Laird N, Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE. · Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease (MIND), Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA. · Am J Hum Genet. · Pubmed #18976728 links to  free full text

Abstract: Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.

Zhu CW, Leibman C, McLaughlin T, Zbrozek AS, Scarmeas N, Albert M, Brandt J, Blacker D, Sano M, Stern Y. · Geriatric Research, Education, and Clinical Center (GRECC), James J. Peters VA Medical Center, Bronx, NY, NY 10468, USA. · Dement Geriatr Cogn Disord. · Pubmed #18946219 links to  free full text

Abstract: BACKGROUND/AIMS: To examine the incremental effect of patients' dependence on others, on cost of medical and nonmedical care, and on informal caregiving hours over time. METHODS: Data are obtained from 172 patients from the Predictors Study, a large, multicenter cohort of patients with probable Alzheimer disease (AD) followed annually for 4 years in 3 University-based AD centers in the USA. Enrollment required a modified Mini-Mental State Examination score >or=30. We examined the effects of patient dependence (measured by the Dependence Scale, DS) and function (measured by the Blessed Dementia Rating Scale, BDRS) on medical care cost, nonmedical care cost, and informal caregiving time using random effects regression models. RESULTS: A one-point increase in DS score was associated with a 5.7% increase in medical cost, a 10.5% increase in nonmedical cost, and a 4.1% increase in caregiving time. A one-point increase in BDRS score was associated with a 7.6% increase in medical cost, a 3.9% increase in nonmedical cost and an 8.7% increase in caregiving time. CONCLUSIONS: Both functional impairment and patient dependence were associated with higher costs of care and caregiving time. Measures of functional impairment and patient dependence provide unique and incremental information on the overall impact of AD on patients and their caregivers.

Scherer RK, Scarmeas N, Brandt J, Blacker D, Albert MS, Stern Y. · Cognitive Neuroscience Division, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, 630 West 168th St., P&S Box 16, New York, NY 10032, USA. · J Gerontol A Biol Sci Med Sci. · Pubmed #18840808 No free full text.

Abstract: BACKGROUND: Although there has been much research devoted to understanding the predictors of nursing home placement (NHP) in Alzheimer's disease (AD) patients, there is currently a lack of research concerning the predictors of home health care. The objective of this study was to examine whether the Dependence Scale can predict home health aide (HHA) use. METHODS: The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed annually for up to 7 years in three university-based AD centers in the United States. Markov analyses (n=75) were used to calculate annual transition probabilities for the "new onset" of HHA use (instances where an HHA was absent at the previous visit, but present at the next visit) as a function of HHA presence at the preceding year's visit and dependence level at that preceding year's visit. RESULTS: The dependence level at the previous year's visit was a significant predictor of HHA use at the next year's visit. Three specific items of the Dependence Scale (needing household chores done for oneself, needing to be watched or kept company when awake, and needing to be escorted when outside) were significant predictors of the presence of an HHA. CONCLUSION: The Dependence Scale is a valuable tool for predicting HHA use in AD patients. Obtaining a better understanding of home health care in AD patients may help delay NHP and have a positive impact on the health and well-being of both the caregiver and the patient.

Schjeide BM, McQueen MB, Mullin K, DiVito J, Hogan MF, Parkinson M, Hooli B, Lange C, Blacker D, Tanzi RE, Bertram L. · MassGeneral Institute for Neurodegenerative Disease (MIND), Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA. · Neurogenetics. · Pubmed #18830724 No free full text.

Abstract: The genetics of Alzheimer's disease (AD) is heterogeneous and remains only ill-defined. We have recently created a freely available and continuously updated online database (AlzGene; http://www.alzgene.org ) for which we collect all published genetic association studies in AD and perform systematic meta-analyses on all polymorphisms with sufficient genotype data. In this study, we tested 27 genes (ACE, BDNF, CH25H, CHRNB2, CST3, CTSD, DAPK1, GALP, hCG2039140, IL1B, LMNA, LOC439999, LOC651924, MAPT, MTHFR, MYH13, PCK1, PGBD1, PRNP, PSEN1, SORCS1, SORL1, TF, TFAM, TNK1, GWA_14q32.13, and GWA_7p15.2), all showing significant association with AD risk in the AlzGene meta-analyses, in a large collection of family-based samples comprised of 4,180 subjects from over 1,300 pedigrees. Overall, we observe significant association with risk for AD and polymorphisms in ACE, CHRNB2, TF, and an as yet uncharacterized locus on chromosome 7p15.2 [rs1859849]. For all four loci, the association was observed with the same alleles as in the AlzGene meta-analyses. The convergence of case-control and family-based findings suggests that these loci currently represent the most promising AD gene candidates. Further fine-mapping and functional analyses are warranted to elucidate the potential biochemical mechanisms and epidemiological relevance of these genes.

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.

Desikan RS, Fischl B, Cabral HJ, Kemper TL, Guttmann CR, Blacker D, Hyman BT, Albert MS, Killiany RJ. · Dept. of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA. · Neurology. · Pubmed #18672473 links to  free full text

Abstract: BACKGROUND: MRI studies have demonstrated differential rates of atrophy in the entorhinal cortex and hippocampus during the prodromal phase of Alzheimer disease (AD). The current study was designed to determine whether a broader set of temporoparietal regions show differential rates of atrophy during the evolution of AD. METHODS: Sixteen regions of interest (ROIs) were analyzed on MRI scans obtained at baseline and follow-up in 66 subjects comprising three groups: controls = individuals who were cognitively normal at both baseline and follow-up; nonconverters = subjects with mild cognitive impairment (MCI) at both baseline and follow-up; converters had MCI at baseline but had progressed to AD at follow-up. RESULTS: Annualized percent change was analyzed with multivariate analysis of variance (MANOVA), covaried for age. The MANOVA demonstrated an effect of group (p = 0.004). Post hoc comparisons demonstrated greater rates of atrophy for converters vs nonconverters for six ROIs: hippocampus, entorhinal cortex, temporal pole, middle temporal gyrus, fusiform gyrus, and inferior temporal gyrus. Converters showed differentially greater rates of atrophy than controls in five of the same ROIs (and inferior parietal lobule). Rates of change in clinical status were correlated with the atrophy rates in these regions. Comparisons between controls and nonconverters demonstrated no differences. CONCLUSION: These results demonstrate that temporoparietal regions show differential rates of atrophy on MRI during prodromal Alzheimer disease (AD). MRI data correlate with measures of clinical severity and cognitive decline, suggesting the potential of these regions of interest as antemortem markers of prodromal AD.

Zhu CW, Leibman C, McLaughlin T, Scarmeas N, Albert M, Brandt J, Blacker D, Sano M, Stern Y. · Geriatric Research, Education, and Clinical Center, Program of Research on Serious Physical and Mental Illness, James J Peters Veterans Affairs Medical Center, Bronx, New York 10468, USA. · J Am Geriatr Soc. · Pubmed #18662215 links to  free full text

Abstract: OBJECTIVES: To estimate incremental effects of patients' dependence and function on costs of care during the early stages of Alzheimer's disease (AD) and to compare strengths of their relationships with different cost components. DESIGN: Multicenter, cross-sectional, observational study. SETTING: Three university hospitals in the United States. PARTICIPANTS: One hundred seventy-nine community-living patients with probable AD, with modified Mini-Mental State Examination scores of 30 or higher. MEASUREMENTS: Patients' dependence was measured using the Dependence Scale (DS). Functional capacity was measured using the Blessed Dementia Rating Scale (BDRS). Total cost was measured by summing direct medical costs and informal costs. Direct medical costs included costs of hospitalization, outpatient treatment and procedures, assistive devices, and medications. Informal costs were estimated from time spent helping with basic and instrumental activities of daily living for up to three caregivers per patient using national average hourly earnings as wage rate. RESULTS: DS and BDRS were associated with higher total cost; a 1-point increase in DS was associated with a $1,832 increase in total cost, and a 1-point increase in BDRS was associated with a $3,333 increase. Examining component costs separately identified potential differences between DS and BDRS. A 1-point increase in BDRS was associated with a $1,406 increase in direct medical cost. A 1-point increase in DS was associated with a $1,690 increase in informal cost. CONCLUSION: Patients' dependence and function related differently to direct medical and informal cost, suggesting that measures of function and dependence provided unique information for explaining variations in cost of care for patients with AD, highlighting the value in measuring both constructs.

Zhu CW, Scarmeas N, Stavitsky K, Albert M, Brandt J, Blacker D, Sano M, Stern Y. · Geriatric Research, Education, and Clinical Center and Program of Research on Serious Physical and Mental Illness, Targeted Research Enhancement Program, James J. Peters VA Medical Center, Bronx, NY, USA. · Alzheimers Dement. · Pubmed #18631979 links to  free full text

Abstract: BACKGROUND: The objective of this study was to compare total costs of care and its major components for community-living patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB). This cross-sectional analysis of baseline data from the Predictors II Study took place in three university-based AD centers in the U.S. METHODS: Community-living patients clinically diagnosed with probable AD (n = 170) or DLB (n = 25) with a modified Mini-Mental State examination (mMMS) score > or =30, equivalent to a score of approximately > or =16 on the Folstein Mini-Mental State Examination (MMSE), participated in this study. Patient and informant reported on patients' use of direct medical care, direct nonmedical care, and informal care. Patients' clinical and demographic characteristics included global cognitive status (measured by MMSE), functional capacity (measured by Blessed Dementia Rating Scale), psychotic symptoms, behavioral problems, depressive symptoms, extrapyramidal signs, comorbidities, age, and sex. Costs were compared by using covariate matching methods. RESULTS: Unadjusted total costs and direct medical costs were not significantly different between AD and DLB patients. Compared with AD patients, unadjusted indirect costs were significantly higher and unadjusted direct nonmedical costs were significantly lower among DLB patients. After adjusting for age, sex, cognitive and functional status, differences in all cost components between DLB and AD patients were no longer statistically significant. CONCLUSIONS: Apparent cost differences were largely attributed to differences in patients' cognitive and functional status. However, the small sample size for DLB patients might have limited power to detect statistically significant differences in costs of care between these groups.

Steinerman JR, Irizarry M, Scarmeas N, Raju S, Brandt J, Albert M, Blacker D, Hyman B, Stern Y. · Departments of Neurology, Columbia University Medical Center, 630 W 168th St, P&S Box 16, New York, NY 10032, USA. · Arch Neurol. · Pubmed #18625856 links to  free full text

Abstract: OBJECTIVE: To determine whether beta-amyloid (Abeta) peptides segregated into distinct biochemical compartments would differentially correlate with clinical severity of Alzheimer disease (AD). DESIGN: Clinicopathologic correlation study. PARTICIPANTS: Twenty-seven patients from a longitudinal study of AD and 13 age- and sex-matched controls without a known history of cognitive impairment or dementia were included in this study. INTERVENTIONS: Temporal and cingulate neocortex were processed using a 4-step extraction, yielding biochemical fractions that are hypothesized to be enriched with proteins from distinct anatomical compartments: TRIS (extracellular soluble), Triton (intracellular soluble), sodium dodecyl sulfate (SDS) (membrane associated), and formic acid (extracellular insoluble). Levels of Abeta(40) and Abeta(42) were quantified in each biochemical compartment by enzyme-linked immunosorbent assay. RESULTS: The Abeta(42) level in all biochemical compartments was significantly elevated in patients with AD vs controls (P < .01). The Abeta(40) levels in the TRIS and formic acid fractions were elevated in patients with AD (temporal, P < .01; cingulate, P = .03); however, Triton and SDS Abeta(40) levels were similar in patients with AD and in controls. Functional impairment proximal to death correlated with Triton Abeta(42) (r = 0.48, P = .02) and SDS Abeta(42) (r = 0.41, P = .04) in the temporal cortex. Faster cognitive decline was associated with elevated temporal SDS Abeta(42) levels (P < .001), whereas slower decline was associated with elevated cingulate formic acid Abeta(42) and SDS Abeta(42) levels (P = .02 and P = .01, respectively). CONCLUSION: Intracellular and membrane-associated Abeta, especially Abeta(42) in the temporal neocortex, may be more closely related to AD symptoms than other measured Abeta species.

Zhu CW, Torgan R, Scarmeas N, Albert M, Brandt J, Blacker D, Sano M, Stern Y. · Geriatric Research, Education, and Clinical Center (GRECC), James J. Peters VA Medical Center, Bronx, NY 10468, USA. · Home Health Care Serv Q. · Pubmed #18510196 links to  free full text

Abstract: OBJECTIVES: To (1) compare home health and informal (unpaid) services utilization among patients with Alzheimer's disease (AD), (2) examine longitudinal changes in services use, and (3) estimate possible interdependence of home health and informal care utilization. METHODS: The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed annually for up to 7 years in three university-based AD centers. Bivariate probit models estimated the effects of patient characteristics on home health and informal care utilization. RESULTS: A large majority of the patients (80.6%) received informal care with a smaller proportion (18.6%) receiving home health services. Home health services utilization increased from 9.9% at baseline to 34.5% in year 4. Among users, number of days that services were provided in three-month recall increased from 21.9 to 56 days over time. Home health services utilization was significantly associated with function, depressive symptoms, being female, and not living with a spouse. Informal care utilization was significantly associated with cognition, function, comorbidities, and living with a spouse or child. CONCLUSIONS: Home health and informal care utilization relate differently to patient characteristics. Utilization of home health care or informal care was not influenced by utilization of the other.

Cosentino S, Scarmeas N, Helzner E, Glymour MM, Brandt J, Albert M, Blacker D, Stern Y. · Cognitive Neuroscience Division of the Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY 10032, USA. · Neurology. · Pubmed #18401023 links to  free full text

Abstract: OBJECTIVE: To determine whether APOE epsilon 4 predicts rate of cognitive change in incident and prevalent Alzheimer disease (AD). METHODS: Individuals were recruited from two longitudinal cohort studies-the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based)--and were followed for an average of 4 years. Three samples of participants diagnosed with AD, with diverse demographic characteristics and baseline cognitive functioning, were studied: 1) 199 (48%) of the incident WHICAP cases; 2) 215 (54%) of the prevalent WHICAP cases; and 3) 156 (71%) of the individuals diagnosed with AD in the Predictors Study. Generalized estimating equations were used to test whether rate of cognitive change, measured using a composite cognitive score in WHICAP and the Mini-Mental State Examination in Predictors, varied as a function of epsilon 4 status in each sample. RESULTS: The presence of at least one epsilon 4 allele was associated with faster cognitive decline in the incident population-based AD group (p = 0.01). Parallel results were produced for the two prevalent dementia samples only when adjusting for disease severity or excluding the most impaired participants from the analyses. CONCLUSION: APOE epsilon 4 may influence rate of cognitive decline most significantly in the earliest stages of Alzheimer disease.

Pihlajamäki M, DePeau KM, Blacker D, Sperling RA. · Memory Disorders Unit, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Am J Geriatr Psychiatry. · Pubmed #18378553 links to  free full text

Abstract: OBJECTIVES: Neural networks supporting encoding of new information are affected early in the course of Alzheimer disease (AD). Functional magnetic resonance imaging (fMRI) studies in AD have reported decreased medial temporal lobe (MTL) activation when comparing novel versus repeated stimuli. It is, however, unclear whether this finding is related to a failure of normal suppression of MTL activity to repeated stimuli in AD. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Twenty-nine healthy older subjects comprising a comparison group (OC) and 15 mild AD patients underwent fMRI during an associative memory paradigm in an academic medical center. The task consisted of blocks of Novel and Repeated face-name pairs and visual Fixation. To reveal neural correlates of processing repeatedly presented stimuli, Repeated blocks were contrasted to Fixation. RESULTS: AD patients demonstrated greater activation during Repeated stimuli in the MTL and in prefrontal and superior parietal cortices, compared with OC. In contrast, OC showed greater parietal task-induced deactivation than AD. Increased MTL activity during Repeated was correlated with more impaired parietal deactivation and poorer performance of the postscan recognition memory test of encoding the face-name pairs. CONCLUSION: Reduction of MTL activity to repeated stimuli, which become highly familiarized to healthy OC, was impaired in AD. This abnormal increased MTL activation was related to disrupted parietal deactivation and to poor recognition memory performance. These preliminary results suggest that the typical episodic memory impairment seen in mild AD may manifest as a failure of normal repetition suppression and loss of "beneficial" deactivation in the MTL-parietal memory networks.

Holland CM, Smith EE, Csapo I, Gurol ME, Brylka DA, Killiany RJ, Blacker D, Albert MS, Guttmann CR, Greenberg SM. · Center for Neurological Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Stroke. · Pubmed #18292383 links to  free full text

Abstract: BACKGROUND AND PURPOSE: White-matter hyperintensities (WMHs) detected by magnetic resonance imaging are thought to represent the effects of cerebral small-vessel disease and neurodegenerative changes. We sought to determine whether the spatial distribution of WMHs discriminates between different disease groups and healthy aging individuals and whether these distributions are related to local cerebral perfusion patterns. METHODS: We examined the pattern of WMHs by T2/fluid-attenuated inversion recovery-weighted magnetic resonance imaging in 3 groups of subjects: cerebral amyloid angiopathy (n=32), Alzheimer disease or mild cognitive impairment (n=41), and healthy aging (n=29). WMH frequency maps were calculated for each group, and spatial distributions were compared by voxel-wise logistic regression. WMHs were also analyzed as a function of normal cerebral perfusion patterns by overlaying a single photon emission computed tomography atlas. RESULTS: Although WMH volume was greater in cerebral amyloid angiopathy and Alzheimer disease/mild cognitive impairment than in healthy aging, there was no consistent difference in the spatial distributions when controlling for total WMH volume. Hyperintensities were most frequent in the deep periventricular WM in all 3 groups. A strong inverse correlation between hyperintensity frequency and normal perfusion was demonstrated in all groups, demonstrating that WMHs were most common in regions of relatively lower normal cerebral perfusion. CONCLUSIONS: WMHs show a common distribution pattern and predilection for cerebral WM regions with lower atlas-derived perfusion, regardless of the underlying diagnosis. These data suggest that across diverse disease processes, WM injury may occur in a pattern that reflects underlying tissue properties, such as relative perfusion.

Smith EE, Egorova S, Blacker D, Killiany RJ, Muzikansky A, Dickerson BC, Tanzi RE, Albert MS, Greenberg SM, Guttmann CR. · Neurology Clinical Trials Unit, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Arch Neurol. · Pubmed #18195145 links to  free full text

Abstract: OBJECTIVE: To determine whether magnetic resonance imaging (MRI) white matter hyperintensities (WMH), whole-brain atrophy, and cardiovascular risk factors predict the development of cognitive decline and dementia. DESIGN: Subjects were recruited into this prospective cohort study and followed for incident cognitive decline for mean (SD) 6.0 (4.1) years. Magnetic resonance imaging dual-echo sequences, obtained at baseline, were used to determine the volume of WMH and the brain parenchymal fraction (BPF), the proportion of the intracranial cavity occupied by brain. White matter hyperintensity volume was analyzed as the percentage of intracranial volume (WMHr); "high WMH" was defined as a WMHr more than 1 SD above the mean. SETTING: General community. PATIENTS: Volunteer sample consisting of 67 subjects with normal cognition and 156 subjects with mild cognitive impairment (MCI). MAIN OUTCOME MEASURES: Time to diagnosis of MCI (among those with normal cognition at baseline) or time to diagnosis of dementia, either all-cause or probable Alzheimer disease (AD) (among those with MCI at baseline). Cox proportional hazards models were used for multivariable analysis. RESULTS: High WMH was a predictor of progression from normal to MCI (adjusted hazard ratio [HR], 3.30; 95% confidence interval [CI], 1.33-8.17; P= .01) but not conversion from MCI to all-cause dementia. Conversely, BPF did not predict progression from normal to MCI but did predict conversion to dementia (adjusted HR, 1.10 for each 1% decrease in BPF; 95% CI, 1.02-1.19; P= .02). When conversion to AD dementia was considered as the outcome, BPF was likewise a predictor (adjusted HR, 1.16 for each 1% decrease in BPF; 95% CI, 1.08-1.24; P< .001), but high WMH was not. Past tobacco smoking was associated with both progression from normal to MCI (adjusted HR, 2.71; 95% CI, 1.12-6.55; P= .03) and conversion to all-cause dementia (adjusted HR, 2.08; 95% CI, 1.13-3.82; P= .02), but not AD dementia. CONCLUSIONS: These findings suggest that WMH are associated with the risk of progressing from normal to MCI. In persons whose cognitive abilities are already impaired, BPF predicts the conversion to dementia.

Dickson MR, Li J, Wiener HW, Perry RT, Blacker D, Bassett SS, Go RC. · Department of Epidemiology and International Health, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0001, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #18189239 links to  free full text

Abstract: We performed linkage analysis for age at onset (AAO) in the total Alzheimer's disease (AD) NIMH sample (N = 437 families). Families were subset as late-onset (320 families, AAO > or = 65) and early/mixed (117 families, at least 1 member with 50 < AAO < 65). Treating AAO as a censored trait, we obtained the gender and APOE adjusted residuals in a parametric survival model and analyzed the residuals as the quantitative trait (QT) in variance-component linkage analysis. For comparison, AAO-age at exam (AAE) was analyzed as the QT adjusting for affection status, gender, and APOE. Heritabilities for residual and AAO-AAE outcomes were 66.3% and 74.0%, respectively for the total sample, 56.0% and 57.0% in the late-onset sample, and 33.0% for both models in the early/mixed sample. The residual model yielded the largest peaks on chromosome 1 with LOD = 2.0 at 190 cM in the total set, LOD = 1.7 at 116 cM on chromosome 3 in the early/mixed subset, and LOD = 1.4 at 71 and 86 cM, respectively, on chromosome 6 in the late-onset subset. For the AAO-AAE outcome model the largest peaks were identified on chromosome 1 at 137 cM (LOD = 2.8) and chromosome 6 at 69 cM (LOD = 2.3) and 86 cM (LOD = 2.2) all in the late-onset subset. Additional peaks with LOD > or = 1 were identified on chromosomes 1, 2, 3, 6, 8, 9, 10, and 12 for the total sample and each subset. Results replicate previous findings, but identify additional suggestive peaks indicating the genetics of AAO in AD is complex with many chromosomal regions potentially containing modifying genes.