Alzheimer Disease: Albert M

Scarmeas N, Brandt J, Albert M, Devanand DP, Marder K, Bell K, Ciappa A, Tycko B, Stern Y. · Cognitive Neuroscience Division, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, New York, NY, USA. · Neurology. · Pubmed #11971084 No free full text.

Abstract: BACKGROUND: Psychiatric symptoms occur frequently in the course of AD, are a frequent contributor to institutionalization, predict cognitive decline and death, and often require treatment with psychotropic medications. Previous studies investigating the association between APOE genotype and psychiatric symptomatology in AD have reported contradictory results. OBJECTIVE: To determine whether APOE genotype predicts incident psychiatric symptomatology in patients with AD. METHODS: Eighty-seven patients with AD at early stages and no psychiatric history were followed semiannually for up to 9.3 years (mean 5.5 years) for development of delusions, illusions, hallucinations, behavioral symptoms, and depression. Cox proportional hazards models were used to examine the relative risk for incident psychiatric symptomatology (outcome) in relation to APOE genotype (predictor). RESULTS: The presence of one epsilon4 allele carried a 2.5-fold risk, whereas the presence of two epsilon4 alleles carried a 5.6-fold risk for development of delusions. The associations remained significant even when age, ethnicity, sex, education, duration of disease, and cognitive and functional performance were controlled for. The presence of two epsilon4 alleles was associated with reduced risk for developing hallucinations in the adjusted analysis only. No significant associations were detected between APOE genotype and the incidence of illusions, behavioral symptoms, or depression. CONCLUSION: The presence of one or more epsilon4 alleles is a significant predictor for the incidence of delusions in the course of AD.

Oishi K, Faria A, Jiang H, Li X, Akhter K, Zhang J, Hsu JT, Miller MI, van Zijl PC, Albert M, Lyketsos CG, Woods R, Toga AW, Pike GB, Rosa-Neto P, Evans A, Mazziotta J, Mori S. · The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuroimage. · Pubmed #19385016 No free full text.

Abstract: The purpose of this paper is to establish single-participant white matter atlases based on diffusion tensor imaging. As one of the applications of the atlas, automated brain segmentation was performed and the accuracy was measured using Large Deformation Diffeomorphic Metric Mapping (LDDMM). High-quality diffusion tensor imaging (DTI) data from a single-participant were B0-distortion-corrected and transformed to the ICBM-152 atlas or to Talairach coordinates. The deep white matter structures, which have been previously well documented and clearly identified by DTI, were manually segmented. The superficial white matter areas beneath the cortex were defined, based on a population-averaged white matter probability map. The white matter was parcellated into 176 regions based on the anatomical labeling in the ICBM-DTI-81 atlas. The automated parcellation was achieved by warping this parcellation map to normal controls and to Alzheimer's disease patients with severe anatomical atrophy. The parcellation accuracy was measured by a kappa analysis between the automated and manual parcellation at 11 anatomical regions. The kappa values were 0.70 for both normal controls and patients while the inter-rater reproducibility was 0.81 (controls) and 0.82 (patients), suggesting "almost perfect" agreement. A power analysis suggested that the proposed method is suitable for detecting FA and size abnormalities of the white matter in clinical studies.

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.

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.

Jack CR, Bernstein MA, Fox NC, Thompson P, Alexander G, Harvey D, Borowski B, Britson PJ, L Whitwell J, Ward C, Dale AM, Felmlee JP, Gunter JL, Hill DL, Killiany R, Schuff N, Fox-Bosetti S, Lin C, Studholme C, DeCarli CS, Krueger G, Ward HA, Metzger GJ, Scott KT, Mallozzi R, Blezek D, Levy J, Debbins JP, Fleisher AS, Albert M, Green R, Bartzokis G, Glover G, Mugler J, Weiner MW. · Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. · J Magn Reson Imaging. · Pubmed #18302232 links to  free full text

Abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal multisite observational study of healthy elders, mild cognitive impairment (MCI), and Alzheimer's disease. Magnetic resonance imaging (MRI), (18F)-fluorodeoxyglucose positron emission tomography (FDG PET), urine serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical/psychometric assessments are acquired at multiple time points. All data will be cross-linked and made available to the general scientific community. The purpose of this report is to describe the MRI methods employed in ADNI. The ADNI MRI core established specifications that guided protocol development. A major effort was devoted to evaluating 3D T(1)-weighted sequences for morphometric analyses. Several options for this sequence were optimized for the relevant manufacturer platforms and then compared in a reduced-scale clinical trial. The protocol selected for the ADNI study includes: back-to-back 3D magnetization prepared rapid gradient echo (MP-RAGE) scans; B(1)-calibration scans when applicable; and an axial proton density-T(2) dual contrast (i.e., echo) fast spin echo/turbo spin echo (FSE/TSE) for pathology detection. ADNI MRI methods seek to maximize scientific utility while minimizing the burden placed on participants. The approach taken in ADNI to standardization across sites and platforms of the MRI protocol, postacquisition corrections, and phantom-based monitoring of all scanners could be used as a model for other multisite trials.

Scarmeas N, Brandt J, Blacker D, Albert M, Hadjigeorgiou G, Dubois B, Devanand D, Honig L, Stern Y. · Gertrude H Sergievsky Center, Columbia University Medical Center, New York, NY 10032, USA. · Arch Neurol. · Pubmed #18071039 links to  free full text

Abstract: BACKGROUND: Disruptive behavior is common in Alzheimer disease (AD). There are conflicting reports regarding its ability to predict cognitive decline, functional decline, institutionalization, and mortality. OBJECTIVE: To examine whether the presence of disruptive behavior has predictive value for important outcomes in AD. DESIGN: Using the Columbia University Scale for Psychopathology in Alzheimer Disease (administered every 6 months, for a total of 3438 visit-assessments and an average of 6.9 per patient), the presence of disruptive behavior (wandering, verbal outbursts, physical threats/violence, agitation/restlessness, and sundowning) was extracted and examined as a time-dependent predictor in Cox models. The models controlled for the recruitment cohort, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and functional performance, and neuroleptic use. SETTING: Five university-based AD centers in the United States and Europe (Predictors Study). PARTICIPANTS: Four hundred ninety-seven patients with early-stage AD (mean Folstein Mini-Mental State Examination score, 20 of 30 at entry) who were recruited and who underwent semiannual follow-up for as long as 14 (mean, 4.4) years. MAIN OUTCOME MEASURES: Cognitive (Columbia Mini-Mental State Examination score, < or = 20 of 57 [approximate Folstein Mini-Mental State Examination score, < or = 10 of 30]) and functional (Blessed Dementia Rating Scale score, parts I and II, > or = 10) ratings, institutionalization equivalent index, and death. RESULTS: At least 1 disruptive behavioral symptom was noted in 48% of patients at baseline and in 83% at any evaluation. Their presence was associated with increased risks of cognitive decline (hazard ratio 1.45 [95% confidence interval (CI), 1.03-2.03]), functional decline (1.66 [95% CI, 1.17-2.36]), and institutionalization (1.47 [95% CI, 1.10-1.97]). Sundowning was associated with faster cognitive decline, wandering with faster functional decline and institutionalization, and agitation/restlessness with faster cognitive and functional decline. There was no association between disruptive behavior and mortality (hazard ratio, 0.94 [95% CI, 0.71-1.25]). CONCLUSION: Disruptive behavior is very common in AD and predicts cognitive decline, functional decline, and institutionalization but not mortality.

Blacker D, Lee H, Muzikansky A, Martin EC, Tanzi R, McArdle JJ, Moss M, Albert M. · Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Arch Neurol. · Pubmed #17562935 links to  free full text

Abstract: OBJECTIVE: To examine neuropsychological measures among normal individuals that predict time to subsequent cognitive decline. DESIGN: Cognitive performance, as measured by 6 neuropsychological tests, was examined at baseline. Participants were followed up for approximately 5 years. Cox proportional hazards models were used to evaluate the neuropsychological measures at baseline that predicted time to progression from normal cognition to mild impairment. Comparable data also examined time to progression from mild impairment to a diagnosis of Alzheimer disease. SETTING: Community volunteer-based sample examined at a medical institution. PARTICIPANTS: One hundred and seven individuals who were cognitively normal and 235 individuals with mild cognitive impairment at baseline. MAIN OUTCOME MEASURES: Time to progression from normal cognition to mild impairment and time to progression from mild impairment to a diagnosis of Alzheimer disease. RESULTS: The risk of progressing from normal to mild impairment was considerably greater among those with lower scores on tests of episodic memory (eg, hazard ratio for a 1-SD decrease in the California Verbal Learning Test, 0.55; P<.001). Normal individuals who carried at least 1 copy of the apolipoprotein E epsilon2 allele were less likely to develop cognitive impairments over time than individuals with no epsilon2 allele (hazard ratio for presence of allele, 0.13; P = .006). Measures of both episodic memory and executive function were significant predictors of time to progression from mild impairment to a clinical diagnosis of Alzheimer disease (eg, hazard ratio for a 1-SD decrease in California Verbal Learning Test score, 0.67; P = .005; hazard ratio for a 1-SD increase in the time to complete part B of the Trail Making test, 1.40; P = .007). Among individuals with mild impairments, the apolipoprotein E epsilon4 allele increased risk for Alzheimer disease in a dose-dependent manner; however, this effect was not significant within the context of multivariable models. CONCLUSIONS: Episodic memory performance among normal individuals predicts time to progression to mild impairment while apolipoprotein E epsilon2 status is associated with lower risk of cognitive decline among normal individuals. Tests of both episodic memory and executive function are predictors of time to progression from mild impairment to a clinical diagnosis of Alzheimer disease.

Zhu CW, Scarmeas N, Torgan R, 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, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York 10468, USA. · J Am Geriatr Soc. · Pubmed #17038080 No free full text.

Abstract: Most estimates of the cost of informal caregiving in patients with Alzheimer's disease (AD) remain cross-sectional. Longitudinal estimates of informal caregiving hours and costs are less frequent and are from assessments covering only short periods of time. The objectives of this study were to estimate long-term trajectories of the use and cost of informal caregiving for patients with AD and the effects of patient characteristics on the use and cost of informal caregiving. 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 (n=170). Generalized linear mixed models were used to estimate the effects of patient characteristics on use and cost of informal caregiving. Patients' clinical characteristics included cognitive status (Mini-Mental State Examination), functional capacity (Blessed Dementia Rating Scale (BDRS)), comorbidities, psychotic symptoms, behavioral problems, depressive symptoms, and extrapyramidal signs. Results show that rates of informal care use and caregiving hours (and costs) increased substantially over time but were related differently to patients' characteristics. Use of informal care was significantly associated with worse cognition, worse function, and higher comorbidities. Conditional on receiving informal care, informal caregiving hours (and costs) were mainly associated with worse function. Each additional point on the BDRS increased informal caregiving costs 5.4%. Average annual informal cost was estimated at $25,381 per patient, increasing from $20,589 at baseline to $43,030 in Year 4.

Stavitsky K, Brickman AM, Scarmeas N, Torgan RL, Tang MX, Albert M, Brandt J, Blacker D, Stern Y. · Gertrude H. Sergievsky Center and Department of Neurology, Columbia University Medical Center, New York, NY, USA. · Arch Neurol. · Pubmed #17030662 links to  free full text

Abstract: BACKGROUND: Although dementia with Lewy bodies (DLB) may be one of most common forms of dementia, relatively little is known about its cognitive and functional course. OBJECTIVE: To compare change over time in general cognitive status, memory test performance, psychiatric symptoms, neurological signs, and functional abilities in patients with probable DLB and probable Alzheimer disease (AD). DESIGN: Twenty-eight patients who met diagnostic criteria for DLB were recruited into the study from 3 sites. Patients with AD (n = 55) were selected from a larger cohort and matched 2 to 1 to the patients with DLB on age and baseline global cognitive status. Patients were followed up at 6-month intervals for an average of 6.2 visits and assessed at each visit with tests of global cognitive functioning and verbal learning and memory and measures of psychiatric, neurological, and functional status. RESULTS: At the baseline evaluation, patients with DLB performed more poorly on a measure of constructional praxis and all measures of functional status. They also had more severe psychiatric symptoms and neurological signs than the AD group. Despite these initial differences, generalized estimating equations applied to regression analyses with repeated measures determined that the only difference between the 2 groups in change in cognitive test performance was on a measure of recognition memory; patients with AD declined, while patients with DLB remained relatively stable. Patients with DLB had relatively stable behavioral symptoms and visual illusions, whereas patients with AD had a significant increase in these symptoms over time. Neurological and functional changes over time were similar in the 2 groups. CONCLUSIONS: Both baseline and longitudinal differences between patients with DLB and patients with AD were noted; these have implications for clinical diagnosis and treatment.

Zhu CW, Scarmeas N, Torgan R, Albert M, Brandt J, Blacker D, Sano M, Stern Y. · Geriatric Research, Education, and Clinical Center, Bronx VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA. · Neurology. · Pubmed #16914696 No free full text.

Abstract: OBJECTIVES: To estimate long-term trajectories of direct cost of caring for patients with Alzheimer disease (AD) and examine the effects of patients' characteristics on cost longitudinally. METHODS: The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed up annually for up to 7 years in three university-based AD centers in the United States. Random effects models estimated the effects of patients' clinical and sociodemographic characteristics on direct cost of care. Direct cost included cost associated with medical and nonmedical care. Clinical characteristics included cognitive status (measured by Mini-Mental State Examination), functional capacity (measured by Blessed Dementia Rating Scale [BDRS]), psychotic symptoms, behavioral problems, depressive symptoms, extrapyramidal signs, and comorbidities. The model also controlled for patients' sex, age, and living arrangements. RESULTS: Total direct cost increased from approximately 9,239 dollars per patient per year at baseline, when all patients were at the early stages of the disease, to 19,925 dollars by year 4. After controlling for other variables, a one-point increase in the BDRS score increased total direct cost by 7.7%. One more comorbid condition increased total direct cost by 14.3%. Total direct cost was 20.8% lower for patients living at home compared with those living in an institutional setting. CONCLUSIONS: Total direct cost of caring for patients with Alzheimer disease increased substantially over time. Much of the cost increases were explained by patients' clinical and demographic variables. Comorbidities and functional capacity were associated with higher direct cost over time.

Amatniek JC, Hauser WA, DelCastillo-Castaneda C, Jacobs DM, Marder K, Bell K, Albert M, Brandt J, Stern Y. · Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, USA. · Epilepsia. · Pubmed #16686651 No free full text.

Abstract: PURPOSE: To determine cumulative incidence and predictors of new-onset seizures in mild Alzheimer's disease (AD) with a cohort followed prospectively. Limited information is available on the incidence of seizures, and no reports exist of seizure predictors in AD patients. METHODS: Mild AD patients were prospectively followed at 6-month intervals to estimate incidence of unprovoked seizures, compare age-specific risk of unprovoked seizures with population norms, and identify characteristics at baseline (demographics, duration and severity of AD, physical and diagnostic test findings, and comorbid medical and psychiatric conditions) influencing unprovoked seizure risk. Review of study charts and medical records supplemented coded end-point data. RESULTS: The cumulative incidence of unprovoked seizures at 7 years was nearly 8%. In all age groups, risk was increased compared with a standard population, with an 87-fold increase in the youngest group (age 50-59 years) and more than a threefold increase in the oldest group (age 85+ years). In multivariate modeling, independent predictors of unprovoked seizures were younger age [relative risk (RR), 0.89 per year increase in age; 95% confidence interval (CI), 0.82-0.97], African-American ethnic background (RR, 7.35; 95% CI, 1.42-37.98), more-severe dementia (RR, 4.15; 95% CI, 1.06-16.27), and focal epileptiform findings on electroencephalogram (EEG) (RR, 73.36; 95% CI, 1.75-3075.25). CONCLUSIONS: Seizure incidence is increased in people starting with mild-to-moderate AD. Younger individuals, African Americans, and those with more-severe disease or focal epileptiform findings on EEG were more likely to have unprovoked seizures.

Zhu CW, Scarmeas N, Torgan R, Albert M, Brandt J, Blacker D, Sano M, Stern Y. · Geriatric Research, Education, and Clinical Center, Bronx VA Medical Center, Bronx, NY 10468, USA. · Neurology. · Pubmed #16606913 No free full text.

Abstract: BACKGROUND: Few studies on cost of caring for patients with Alzheimer disease (AD) have simultaneously considered multiple dimensions of disease costs and detailed clinical characteristics. OBJECTIVE: To estimate empirically the incremental effects of patients' clinical characteristics on disease costs. METHODS: Data are derived from the baseline visit of 180 patients in the Predictors Study, a large, multicenter cohort of patients with probable AD followed from early stages of the disease. All patients initially lived at home, in retirement homes, or in assisted living facilities. Costs of direct medical care included hospitalizations, outpatient treatment and procedures, assistive devices, and medications. Costs of direct nonmedical care included home health aides, respite care, and adult day care. Indirect costs were measured by caregiving time. Patients' clinical characteristics included cognitive status, functional capacity, psychotic symptoms, behavioral problems, depressive symptoms, extrapyramidal signs, comorbidities, and duration of illness. RESULTS: A 1-point increase in the Blessed Dementia Rating Scale score was associated with a $1,411 increase in direct medical costs and a $2,718 increase in unpaid caregiving costs. Direct medical costs also were $3,777 higher among subjects with depressive symptoms than among those who were not depressed. CONCLUSIONS: Medical care costs and unpaid caregiving costs relate differently to patients' clinical characteristics. Poorer functional status is associated with higher medical care costs and unpaid caregiving costs. Interventions may be particularly useful if targeted in the areas of basic and instrumental activities of daily living.

Holtzer R, Irizarry MC, Sanders J, Hyman BT, Wegesin DJ, Riba A, Brandt J, Albert M, Stern Y. · Sergievsky Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. · Arch Neurol. · Pubmed #16476811 links to  free full text

Abstract: BACKGROUND: Lewy bodies (LBs) and Lewy neurites are frequent concomitant neuropathologic observations in clinical and neuropathologically defined Alzheimer disease (AD), but their relation to clinical features in AD is uncertain. Most studies used semiquantitative measures to determine the presence or absence of LB abnormalities. OBJECTIVE: To determine the clinical consequences of LB abnormalities in the setting of AD. DESIGN: Prospective study. SETTING: Three outpatient research and treatment centers. PARTICIPANTS: Fourteen autopsy cases with a pathologic diagnosis of AD abnormalities and concomitant LBs followed semiannually for up to 8 years (mean age at intake, 72 years; mean age at death, 77 years; mean education, 15 years; 12 women). MAIN OUTCOME MEASURES: The modified Mini-Mental State Examination was used to assess cognitive function. The Unified Parkinson Disease Rating Scale was used to rate extrapyramidal motor signs. Hallucinations were evaluated using the Columbia University Scale for Psychopathology in Alzheimer's Disease. Time from the first evaluation in which diagnostic criteria for probable AD were met to death was used to determine illness duration. Quantitative measures of LB abnormalities were obtained for the frontal cortex, entorhinal cortex, substantia nigra, and hippocampus. RESULTS: Independent-samples t tests were used to assess whether the degree of LB abnormality varied as a function of the presence or absence of hallucinations and extrapyramidal signs. Pearson r correlations were run to examine whether there was a relation among LB abnormalities, cognitive function, and illness duration. There was no relation between quantitative neuropathologic indexes of LB abnormalities and clinical outcome. CONCLUSION: The variability of clinical features in AD was not related to the presence or degree of LB abnormalities.

Zaitchik D, Koff E, Brownell H, Winner E, Albert M. · Massachusetts General Hospital, Charlestown, MA 02129-2000, USA. · Neuropsychology. · Pubmed #16460218 No free full text.

Abstract: The present study compared 20 patients with mild to moderate Alzheimer's disease with 20 older controls (ages 69-94 years) on their ability to make inferences about emotions and beliefs in others. Six tasks tested their ability to make 1st-order and 2nd-order inferences as well as to offer explanations and moral evaluations of human action by appeal to emotions and beliefs. Results showed that the ability to infer emotions and beliefs in 1st-order tasks remains largely intact in patients with mild to moderate Alzheimer's. Patients were able to use mental states in the prediction, explanation, and moral evaluation of behavior. Impairment on 2nd-order tasks involving inference of mental states was equivalent to impairment on control tasks, suggesting that patients' difficulty is secondary to their cognitive impairments. ((c) 2006 APA, all rights reserved).

Holtzer R, Scarmeas N, Wegesin DJ, Albert M, Brandt J, Dubois B, Hadjigeorgiou GM, Stern Y. · Cognitive Neuroscience Division, Taub Institute, G.H. Gertrude Sergievsky Center and Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York 10032, USA. · J Am Geriatr Soc. · Pubmed #16398891 No free full text.

Abstract: OBJECTIVES: To examine the natural course of depressive symptoms in patients with probable Alzheimer's disease (AD), specifically, the temporal relationship between depressive symptoms, function, and cognitive status. DESIGN: Multicenter cohort study with follow-up of up to 14 years. SETTING: Patients from the two Multicenter Study of Predictors of Disease Course in Alzheimer's Disease (Predictors Study) cohorts were recruited at five sites in the United States and Europe. PARTICIPANTS: Patients diagnosed with probable AD (n=536) enrolled in a longitudinal study (Predictors Study). MEASUREMENTS: Depressive symptoms were evaluated at 6-month intervals using the Columbia Scale for Psychopathology in Alzheimer's Disease. The Modified Mini-Mental State (3MS) and Blessed Dementia Rating Scale (BDRS) were used to assess cognitive status and functional activity, respectively. RESULTS: The prevalence of depressive symptoms was stable over the first 3 years of follow-up, at approximately 40%. There was a significant drop to 28% and 24% in the fourth and fifth years of follow-up, respectively. Time-dependent Cox analysis revealed that functional activity (BDRS) but not cognitive status (3MS) was a significant predictor of the first episode of depressive symptoms during follow-up. Generalized estimating equation analyses showed that AD duration and functional activity but not cognitive status were significantly related to depressive symptoms over the entire follow-up period. CONCLUSION: Depressive symptoms are common in AD, but their prevalence decreases over time. Examination of the temporal relationship between depressive symptoms and risk factors suggests that decline in function but not in cognition precedes the first episode of depressive symptoms in patients with probable AD.

Scarmeas N, Brandt J, Albert M, Hadjigeorgiou G, Papadimitriou A, Dubois B, Sarazin M, Devanand D, Honig L, Marder K, Bell K, Wegesin D, Blacker D, Stern Y. · Cognitive Neuroscience Division of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, the Gertrude H. Sergievsky Center, New York, NY 10032, USA. · Arch Neurol. · Pubmed #16216946 links to  free full text

Abstract: BACKGROUND: Delusions and hallucinations are common in Alzheimer disease (AD) and there are conflicting reports regarding their ability to predict cognitive decline, functional decline, and institutionalization. According to all previous literature, they are not associated with mortality. OBJECTIVE: To examine whether the presence of delusions or hallucinations has predictive value for important outcomes in AD. DESIGN, SETTING, AND PARTICIPANTS: A total of 456 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] score of 21 of 30 at entry) were recruited and followed up semiannually for up to 14 years (mean, 4.5 years) in 5 university-based AD centers in the United States and Europe. Using the Columbia University Scale for Psychopathology in AD (administered every 6 months, for a total of 3266 visit-assessments, average of 7.2 per patient), the presence of delusions and hallucinations was extracted and examined as time-dependent predictors in Cox models. The models controlled for cohort effect, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and baseline functional performance, behavioral symptoms, and use of neuroleptics and cholinesterase inhibitors. MAIN OUTCOME MEASURES: Cognitive (Columbia MMSE score of < or =20/57 [approximate Folstein MMSE score of < or =10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of > or =10), institutionalization equivalent index, and death. RESULTS: During the full course of follow-up, 38% of patients reached the cognitive, 41% the functional, 54% the institutionalization, and 49% the mortality end point. Delusions were noted for 34% of patients at baseline and 70% at any evaluation. Their presence was associated with increased risk for cognitive (risk ratio [RR], 1.50; 95% confidence interval [CI], 1.07-2.08) and functional decline (RR, 1.41; 95% CI, 1.02-1.94). Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline (RR, 1.62; 95% CI, 1.06-2.47), functional decline (RR, 2.25; 95% CI, 1.54-2.27), institutionalization (RR, 1.60; 95% CI, 1.13-2.28), and death (RR, 1.49; 95% CI, 1.03-2.14). CONCLUSIONS: Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.

Scarmeas N, Albert M, Brandt J, Blacker D, Hadjigeorgiou G, Papadimitriou A, Dubois B, Sarazin M, Wegesin D, Marder K, Bell K, Honig L, Stern Y. · Cognitive Neuroscience Division of the Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA. · Neurology. · Pubmed #15911793 No free full text.

Abstract: OBJECTIVE: To examine whether the presence of motor signs has predictive value for important outcomes in Alzheimer disease (AD). METHODS: A total of 533 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] 21/30 at entry) were recruited and followed semiannually for up to 13.1 years (mean 3) in five University-based AD centers in the United States and European Union. Four outcomes, assessed every 6 months, were used in Cox models: cognitive endpoint (Columbia Mini-Mental State Examination < or = 20/57 [ approximately MMSE < or = 10/30]), functional endpoint (Blessed Dementia Rating Scale > or = 10), institutionalization equivalent index, and death. Using a standardized portion of the Unified PD Rating Scale (administered every 6 months for a total of 3,149 visit-assessments, average 5.9 per patient), the presence of motor signs, as well as of individual motor sign domains, was examined as time-dependent predictor. The models controlled for cohort, recruitment center, sex, age, education, a comorbidity index, and baseline cognitive and functional performance. RESULTS: A total of 39% of the patients reached the cognitive, 41% the functional, 54% the institutionalization, and 47% the mortality endpoint. Motor signs were noted for 14% of patients at baseline and for 45% at any evaluation. Their presence was associated with increased risk for cognitive decline (RR, 1.72; 95% CI, 1.24 to 2.38), functional decline (1.80 [1.33 to 2.45]), institutionalization (1.68 [1.26 to 2.25]), and death (1.38 [1.05 to 1.82]). Tremor was associated with increased risk for reaching the cognitive and bradykinesia for reaching the functional endpoints. Postural-gait abnormalities carried increased risk for institutionalization and mortality. Faster rates of motor sign accumulation were associated with increased risk for all outcomes. CONCLUSIONS: Motor signs predict cognitive and functional decline, institutionalization, and mortality in Alzheimer disease. Different motor sign domains predict different outcomes.

Sarazin M, Stern Y, Berr C, Riba A, Albert M, Brandt J, Dubois B. · INSERM U 610 and Fédération de Neurologie, Centre de Neuropsychologie, Hôpital de la Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France. · Neurology. · Pubmed #15781821 No free full text.

Abstract: OBJECTIVE: To determine whether specific cognitive deficits can predict the progression of Alzheimer disease (AD). METHODS: Two hundred fifty-two patients with AD enrolled in the Predictors Study were followed at 6-month intervals for up to 4.5 years with neurologic, cognitive, and psychiatric examinations. Neuropsychological functions were assessed by the Modified Mini-Mental State Examination (mMMSE). Items of mMMSE were divided into five cognitive domains: temporospatial orientation, short-term memory, long-term memory, language, and visuoconstructive functions. Loss of autonomy was assessed by both the Dependency Scale (DS) and the Equivalent Institutional Care (EIC) rating. Cox proportional hazards models, adjusted for age, sex, estimated duration of illness at entry into the study, and presence of extrapyramidal signs and behavioral disturbances, were used to determine the predictive value of each neuropsychological domain on dependency outcomes. RESULTS: Global mMMSE, temporospatial orientation, and short-term memory scores were associated with a greater relative risk of moderate or severe dependency. The visuoconstructive score predicted the development of severe dependency. Long-term memory and language scores were not predictive of the EIC or DS endpoints. CONCLUSIONS: The presence of certain neuropsychological deficits at a patient's initial visit, such as short-term memory, temporospatial orientation, and constructive apraxia, predict more rapid dependency in patients with Alzheimer disease. Neuropsychological items have different weights in term of predictive power, and these effects are independent of the influence of age and disease duration at baseline.

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.

Lange N, Lake S, Sperling R, Brown J, Routledge C, Albert M, Heckers S. · Department of Psychiatry, Harvard Medical School, Boston, MA, USA. · Stat Med. · Pubmed #14716733 No free full text.

Abstract: Among the many diseases that affect the hippocampus, a small yet highly important brain region responsible for memory and identity, Alzheimer's disease and schizophrenia are among the most devastating. We describe a two-stage, region-of-interest based linear mixed model approach to the analysis of a longitudinal functional magnetic resonance (FMRI) study of human memory function under several drug challenges. We then describe a Monte Carlo approach to testing members of nested hierarchies of linear models in a stereological study of different types and locations of human hippocampal neurons. Last, we attempt to draw the attention of the biostatistical community interested in imaging neuroscience to the intriguing complexities of human hippocampal research in early Alzheimer's disease, schizophrenia and other brain diseases via brain imaging methods.

Holtzer R, Wegesin DJ, Albert SM, Marder K, Bell K, Albert M, Brandt J, Stern Y. · Sergievsky Center, Columbia University College of Physicians and Surgeons, 630 W. 168th Street, New York, NY 10032, USA. · Arch Neurol. · Pubmed #12925372 links to  free full text

Abstract: BACKGROUND: Previous studies revealed that cognitive test scores were related to functional outcome in Alzheimer disease (AD). However, the relationship between the rate of cognitive decline at the initial disease phase and the risk of reaching clinical milestones in subsequent years has not yet been examined. OBJECTIVE: To examine whether the rate of cognitive decline predicts the risk of reaching functional milestones in patients with probable AD. DESIGN: A 5-year prospective study was conducted at 3 sites. SETTING: Outpatient research and treatment centers. PARTICIPANTS: Patients diagnosed with probable AD (N = 236; mean age, 73 years; 59% women; mean years of education, 13). MAIN OUTCOME MEASURES: Modified Mini-Mental State Examination (mMMSE) scores were used to assess the rate of cognitive decline over time. Total dependence score and 2 clinical milestones: (1) the need to be dressed, groomed, and washed and (2) receiving a level of care equivalent to a placement in a health-related facility, were derived from the Dependence Scale. RESULTS: General estimating equation analyses revealed that the rate of cognitive decline during the entire follow-up period was positively related to an increase in total dependence scores. Cox analyses showed that a fast rate of decline during the first year was related to an increase in the risk of reaching clinical milestones in subsequent years. Analyses controlled for age, sex, education, and baseline mMMSE scores. CONCLUSION: A fast rate of cognitive decline was associated with increasing risk of reaching clinical milestones in AD.