Showing papers in "Alzheimers & Dementia in 2012"

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

Abstract: A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

2012 Alzheimer's disease facts and figures Alzheimer's Association ∗

Abstract: This report provides information to increase understanding of the public health impact of Alzheimer's disease (AD). Topics addressed include incidence, prevalence, mortality rates, health expenditures and costs of care, and effect on caregivers and society. The report also explores issues that arise when people with AD and other dementias live alone. The characteristics, risks, and unmet needs of this population are described.

The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception.

Abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.

Mild cognitive impairment: Disparity of incidence and prevalence estimates

Abstract: Background The purpose of conducting this study was to identify areas of concordance and sources of variation for the published rates of prevalence and incidence associated with various definitions for mild cognitive impairment (MCI). Methods The study used systematic review of studies published in English since 1984. Studies were identified by searching MEDLINE and EMBASE databases. Population-based observational studies of incidence or prevalence of MCI and related terms were eligible for inclusion. Results A total of 3,705 citations were identified, and 42 were accepted for inclusion; 35 included data on prevalence and 13 on incidence. The following four terms predominated: age-associated memory impairment (AAMI); cognitive impairment no dementia (CIND); MCI; and amnestic MCI (aMCI). Within each term, the operational definition varied. Substantial variation was observed for both incidence (MCI: 21.5–71.3; aMCI: 8.5–25.9 per 1,000 person-years) and prevalence of each definition of cognitive impairment (AAMI 3.6%–38.4%; CIND 5.1%–35.9%; MCI 3%–42%; aMCI 0.5%–31.9%). CIND and MCI showed increasing prevalence among older age groups, whereas age-specific rates of aMCI were lower and without any apparent age relationship. Conclusions Prevalence and incidence estimates associated with MCI vary greatly both between definitions and within a definition across the 42 publications. These wide differences pose a significant challenge to our understanding of the social burden of this disease. Enhancement and standardization of operational definitions of the subtypes of cognitive impairment could improve estimates of disease burden and provide a mechanism to assist in the identification of individuals at risk for future Alzheimer's disease and other dementias.

Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease

Abstract: Background Chronic inflammation in periodontal disease has been suggested as a potential risk factor in Alzheimer's disease (AD). The purpose of this study was to examine serum antibody levels to bacteria of periodontal disease in participants who eventually converted to AD compared with the antibody levels in control subjects. Methods Serum samples from 158 participants in the Biologically Resilient Adults in Neurological Studies research program at the University of Kentucky were analyzed for immunoglobulin G antibody levels to seven oral bacteria associated with periodontitis, including Aggregatibacter actinomycetemcomitans , Porphyromonas gingivalis, Campylobacter rectus, Treponema denticola, Fusobacterium nucleatum , Tannerella forsythia, and Prevotella intermedia . All 158 participants were cognitively intact at baseline venous blood draw. In all, 81 of the participants developed either mild cognitive impairment (MCI) or AD or both, and 77 controls remained cognitively intact in the years of follow-up. Antibody levels were compared between controls and subjects with AD at baseline draw and after conversion and controls and subjects with MCI at baseline draw and after conversion using the Wilcoxon rank-sum test. AD and MCI participants were not directly compared. Linear regression models were used to adjust for potential confounding. Results Antibody levels to F nucleatum and P intermedia were significantly increased (α = 0.05) at baseline serum draw in the patients with AD compared with controls. These results remained significant when controlling for baseline age, Mini-Mental State Examination score, and apolipoprotein epsilon 4 status. Conclusions This study provides initial data that demonstrate elevated antibodies to periodontal disease bacteria in subjects years before cognitive impairment and suggests that periodontal disease could potentially contribute to the risk of AD onset/progression. Additional cohort studies profiling oral clinical presentation with systemic response and AD and prospective studies to evaluate any cause-and-effect association are warranted.

Intensity of dementia through latent variable modelling (I-DeLV) in the AIBL cohort

Abstract: 69% of Mild Cognitively Impaired and 96% of AD. Conclusions: The described models provide accurate estimations of NAB based on demographic corrected cognitive test scores. If NAB is a predictor for progression to AD and given such models can accurately predict NAB, it follows that this work may lead to an effective and economical screen for early detection of individuals at risk of developing AD, in-turn providing justification for further confirmatory tests (e.g. PET) or to identify suitable participants for intervention or therapeutic trials.

Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: a consensus paper from the Alzheimer's Biomarkers Standardization Initiative.

Abstract: Background Numerous studies show that the cerebrospinal fluid biomarkers total tau (T-tau), tau phosphorylated at threonine 181 (P-tau 181P ), and amyloid-β (1-42) (Aβ 1–42 ) have high diagnostic accuracy for Alzheimer's disease. Variability in concentrations for Aβ 1–42 , T-tau, and P-tau 181P drives the need for standardization. Methods Key issues were identified and discussed before the first meeting of the members of the Alzheimer's Biomarkers Standardization Initiative (ABSI). Subsequent ABSI consensus meetings focused on preanalytical issues. Results Consensus was reached on preanalytical issues such as the effects of fasting, different tube types, centrifugation, time and temperature before storage, storage temperature, repeated freeze/thaw cycles, and length of storage on concentrations of Aβ 1–42 , T-tau, and P-tau 181P in cerebrospinal fluid. Conclusions The consensus reached on preanalytical issues and the recommendations put forward during the ABSI consensus meetings are presented in this paper.

Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease

Abstract: Objectives To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer's disease. Cognitive measures were also obtained. Methods In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer's disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer's Disease Assessment Scale–cognitive portion was administered. Results Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ 1–40 and Aβ 1–42 in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aβ 1–40 and Aβ 1–42 in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ 1–40 in CSF ( P 1–42 in CSF in a dose-dependent manner. The Alzheimer's Disease Assessment Scale–cognitive portion was unchanged after the 12-week antibody administration. Conclusions Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ 1–42 suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ 1–42 from amyloid plaques.

Fornix integrity and hippocampal volume predict memory decline and progression to Alzheimer’s disease

Abstract: Background The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer's disease (AD). The aims of the present study were to: (1) examine the cross-sectional relationship between fornix diffusion tensor imaging (DTI) measurements (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity, and radial diffusivity), hippocampal volume, and memory performance, and (2) compare fornix DTI measures with hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment to AD dementia. Methods Twenty-three mild cognitive impairment participants for whom hippocampal volumetry and DTI were conducted at baseline received detailed evaluations at baseline; 3, 6, and 12 months; and 2.5 years. Six participants converted to AD over the follow-up period. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the Mini-Mental State Examination, Clinical Dementia Rating-sum of boxes, and memory z scores; receiver operating characteristic analyses examined the predictive value for conversion to AD. Results There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, radial diffusivity, and axial diffusivity) were cross-sectionally correlated with memory z scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression, with likelihood ratios >83, and better than 90% accuracy. Conclusion Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually drawn region of interest within the fornix shows promise comparable with hippocampal volume as a predictive biomarker of progression, and this finding warrants replication in a larger study.

Direct comparison of fluorodeoxyglucose positron emission tomography and arterial spin labeling magnetic resonance imaging in Alzheimer's disease.

Abstract: Background The utility of fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in Alzheimer's disease (AD) diagnosis has been well established. Recently, measurement of cerebral blood flow using arterial spin labeling magnetic resonance imaging (ASL-MRI) has shown diagnostic potential in AD, although it has never been directly compared with FDG-PET. Methods We used a novel imaging protocol to obtain FDG-PET and ASL-MRI images concurrently in 17 AD patients and 19 age-matched control subjects. Paired FDG-PET and ASL-MRI images from 19 control subjects and 15 AD patients were included for qualitative analysis, and paired images from 18 control subjects and 13 AD patients were suitable for quantitative analyses. Results The combined imaging protocol was well tolerated. Both modalities revealed similar regional abnormalities in AD, as well as comparable sensitivity and specificity for the detection of AD after visual review by two expert readers. Interobserver agreement was better for FDG-PET (κ: 0.75, standard error: 0.12) than ASL-MRI (κ: 0.51, standard error: 0.15); intermodality agreement was moderate to strong (κ: 0.45–0.61); and readers were more confident of FDG-PET reads. Simple quantitative analysis of global cerebral fluorodeoxyglucose uptake (FDG-PET) or whole-brain cerebral blood flow (ASL-MRI) showed excellent diagnostic accuracy for both modalities, with area under receiver operating characteristic curves of 0.90 for FDG-PET (95% confidence interval: 0.79–0.99) and 0.91 for ASL-MRI (95% confidence interval: 0.80–1.00). Conclusions Our results demonstrate that FDG-PET and ASL-MRI identify similar regional abnormalities and have comparable diagnostic accuracy in a small population of AD patients, and support the further study of ASL-MRI in dementia diagnosis.

Nonstationarity in the ‘resting brain's’ modular architecture

Abstract: Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n=892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain’s modular organization and assign each region to a ‘‘meta-modular’’ group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer’s dementia and 56 cognitively normal elderly subjects matched 1:2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer’s disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer’s dementia.

An economic evaluation of early assessment for Alzheimer's disease in the United Kingdom

Abstract: Background Diagnosing and treating patients with Alzheimer's disease (AD) at an early stage should improve the quality of life of the patient and caregiver. In the United Kingdom, cost-effectiveness of early assessment of individuals presenting with subjective memory complaints and treating those with AD with donepezil was evaluated. Methods A discrete event simulation of AD progression and the effect of treatment interventions was developed. Patient-level data from donepezil trials and a 7-year follow-up registry were used to model correlated longitudinal rates of change in cognition, behavior, and function. Other epidemiological and health services data, including estimates of undiagnosed dementia and delays in diagnosis, were based on published sources. Simulated individuals were followed up for 10 years. Results In the base-case estimates, 17 patients need to be assessed to diagnose one patient with AD, resulting in an average assessment cost of £4100 ($6000; $1 US=£0.68 UK) per patient diagnosed (2007 cost year). In comparison with a scenario without early assessment or pharmacologic treatment, early assessment reduces health care costs by £3600 ($5300) per patient and societal costs by £7750 ($11,400). Savings are also substantial compared with treatment without early assessment, averaging £2100 ($3100) in health care costs, and £5700 ($8400) in societal costs. Results are most sensitive to estimates of patient care costs and the probability of patients reporting subjective memory complaints. In probabilistic sensitivity analysis, early assessment leads to savings or is highly cost-effective in the majority of cases. Conclusions Although early assessment has significant up-front costs, identifying AD patients at an early stage results in cost savings and health benefits compared with no treatment or treatment in the absence of early assessment.

Development of biomarkers to chart all Alzheimer's disease stages: the royal road to cutting the therapeutic Gordian Knot.

Abstract: The aim of this perspective article is to stimulate radical shifts in thinking and foster further discussion on the effective discovery, development, validation, and qualification process of biological markers derived from all available technical modalities that meet the complex conceptual and pathophysiological challenges across all stages of the complex, nonlinear, dynamic, and chronically progressive sporadic Alzheimer's disease (AD). This perspective evaluates the current state of the science regarding a broad spectrum of hypothesis-driven and exploratory technologies and "markers" as candidates for all required biomarker functions, in particular, surrogate indicators of adaptive to maladaptive and compensatory to decompensatory, reversible to irreversible brain "systems failure." We stress the future importance of the systems biology (SB) paradigm (next to the neural network paradigm) for substantial progress in AD research. SB represents an integrated and deeper investigation of interacting biomolecules within cells and organisms. This approach has only recently become feasible as high-throughput technologies and mass spectrometric analyses of proteins and lipids, together with rigorous bioinformatics, have evolved. Existing high-content data derived from clinically and experimentally derived neural tissues point to convergent pathophysiological pathways during the course of AD, transcending traditional descriptive studies to reach a more integrated and comprehensive understanding of AD pathophysiology, derived systems biomarkers, and "druggable" system nodes. The discussion is continued on the premise that the lack of integration of advanced biomarker technologies and transfertilization from more mature translational research fields (e.g., oncology, immunology, cardiovascular), which satisfy regulatory requirements for an accurate, sensitive, and well-validated surrogate marker of specific pathophysiological processes and/or clinical outcomes, is a major rate-limiting factor for the successful development and approval of effective treatments for AD prevention. We consider the conceptual, scientific, and technical challenges for the discovery-development-validation-qualification process of biomarker tools and analytical algorithms for detection of the earliest pathophysiological processes in asymptomatic individuals at elevated risk during preclinical stages of AD. The most critical need for rapid translation of putative markers into validated (performance) and standardized (harmonized standard operating procedures) biomarker tools that fulfill regulatory requirements (qualify for use in treatment trials: e.g., safety, target engagement, mechanism of action, enrichment, stratification, secondary and primary outcome, surrogate outcome) is the availability of a large-scale worldwide comprehensive longitudinal database that includes the following cohorts: (a) healthy aging, (b) people at elevated risks (genetic/epigenetic/lifestyle/comorbid conditions), and (c) asymptomatic–preclinical/prodromal–mild cognitive impairment/syndromal mild, moderate, or severe AD. Our proposal, as initial strategic steps for integrating markers into future development of diagnostic and therapy trial technologies, is to work toward: (a) creating the essential research and development infrastructure as an international shared resource, (b) building the organizational structure for managing such a multinational shared resource, and (c) establishing an integrated transsectoral multidisciplinary global network of collaborating investigators to help build and use the shared research resource.

Analysis of case management programs for patients with dementia: A systematic review

Abstract: Background People suffering from dementia are particularly vulnerable to the gaps between the health and social service systems. Case management is a professional field that seeks to fill in these gaps and remedy this fragmentation. Methods We report the results of a systematic literature review of the impact of case management programs on clinical outcomes and the utilization of resources by persons with dementia. We focused on randomized controlled trials (RCTs) and attempted to identify the factors that might contribute to greater program efficacy. Because the evaluation methods in these studies varied, we used the effect size method to estimate the magnitude of the statistically significant effects reported. Results Our search strategy identified 17 references relating to six RCTs. Four of these six RCTs reported moderately statistically significant effects (effect size, 0.2–0.8) on their primary end point: the clinical outcome in three and resource utilization in one. Two of the RCTs reported weak or no effects (effect size, Conclusions Integration and case management intensity seem to determine the magnitude of the clinical effects in this new professional field. Further studies are needed to clarify the economic impact.

Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B.

Abstract: Down syndrome (DS) is one of the most common causes of intellectual disability. Although DS accounts for only 15% of all individuals with intellectual disabilities, adults with DS account for approximately 60% of individuals with intellectual disabilities and Alzheimer's disease. This is thought to be because of overproduction of the β-amyloid (Aβ) protein due to trisomy for the Aβ precursor protein gene on chromosome 21. Pittsburgh compound B (PiB) is a noninvasive in vivo positron emission tomography tracer used to image amyloid deposition in living humans. Studies using PiB have shown an age-dependent asymptomatic amyloid deposition in more than 20% of the cognitively normal elderly population. Presymptomatic carriers of presenilin (PS-1) and Aβ precursor protein gene mutations who are destined to develop Alzheimer's disease also show preclinical amyloid deposition. This report describes a pilot study involving the use of PiB in seven adults with DS (age: 20–44 years). Compared with objective cutoffs for amyloid positivity in older non-DS cognitively normal control subjects, only two of the seven DS subjects (age: 38 and 44 years) showed increased PiB retention. The remaining five subjects aged between 20 and 35 years showed no detectable increase in PiB retention. Interestingly, the two subjects who showed elevated PiB retention showed a striatal-predominant pattern similar to that previously reported for PS-1 mutation carriers. These results demonstrate the feasibility of conducting PiB positron emission tomography scanning in this special population, and suggest a link between Aβ overproduction and early striatal deposition of fibrillar Aβ.

Predictive validity and diagnostic stability of mild cognitive impairment subtypes

Abstract: Background Mild cognitive impairment (MCI) is subclassified into four subtypes by the presence of impairment in the memory domain (amnestic vs nonamnestic) and the number of impaired cognitive domains (single vs multiple). However, predictive validity for outcomes of these criteria and the diagnostic stability of the subtypes are questionable. Methods We investigated the outcomes of 140 patients with MCI who participated in the baseline study of the Korean Longitudinal Study on Health and Aging and completed the 18-month follow-up evaluation (mean duration of follow-up = 1.57 ± 0.24 years). We evaluated the predictive validity of the criteria using multinomial logistic regression analyses, and the diagnostic stability of MCI subtypes using annual conversion rates between subtypes. Results Compared with the single-domain type (MCIs), the multiple-domain type (MCIm) had a lower chance of reversion to normal cognition (MCIm = 10.94%, MCIs=43.42%) and higher risk of conversion to dementia (MCIm = 23.44%, MCIs=5.26%). The difference in the reversion rate between the multiple- and single-domain type was statistically significant (odds ratio=0.233, 95% confidence interval=0.070–0.771, P = .017). However, neither the chance of reversion nor the risk of conversion was different between amnestic and nonamnestic subtypes. Among the 81 participants who neither converted to dementia nor reverted to normal cognition, 39 converted to different subtype (annual conversion rate=17.74%). Conclusions The number of impaired cognitive domains, but not the presence of memory impairment, predicted poor outcomes in people with MCI. However, MCI subtype was diagnostically unstable.

Cardiovascular risk factors, cortisol, and amyloid-β deposition in Alzheimer's Disease Neuroimaging Initiative.

Abstract: Background There is epidemiological evidence that cardiovascular risk factors (CVRF) also are risk factors for Alzheimer’s disease, but there is limited information on this from neuro-pathological studies, and even less from in vivo studies. Therefore, we examined the relationship between CVRF and amyloid-β (Aβ) brain burden measured by Pittsburgh Compound B-positron emission tomography (PiB-PET) studies in the Alzheimer’s Disease Neuroimaging Initiative.

Psychosocial stress at work is associated with increased dementia risk in late life

Abstract: Objective: To test the hypothesis that high job stress during working life might lead to an increased risk of dementia and Alzheimer's disease (AD) in late life. Methods: A dementia-free cohort of ...

Potentially avoidable hospitalizations among Medicare beneficiaries with Alzheimer's disease and related disorders

Abstract: Background Individuals with Alzheimer's disease and related disorders (ADRD) have more frequent hospitalizations than individuals without ADRD, and some of these admissions may be preventable with proactive outpatient care. Methods This study was a cross-sectional analysis of Medicare claims data from 195,024 fee-for-service ADRD beneficiaries aged ≥65 years and an equal number of matched non-ADRD controls drawn from the 5% random sample of Medicare beneficiaries in 2007–2008. We analyzed the proportion of patients with potentially avoidable hospitalizations (PAHs, as defined by the Medicare Ambulatory Care Indicators for the Elderly) and used logistic regression to examine patient characteristics associated with PAHs. We used paired t tests to compare Medicare expenditures by ADRD status, stratified by whether there were PAHs related to a particular condition. Results Compared with matched non-ADRD subjects, Medicare beneficiaries with ADRD were significantly more likely to have PAHs for diabetes short-term complications (OR = 1.43; 95% CI 1.31–1.57), diabetes long-term complications (OR = 1.08; 95% CI=1.02–1.14), and hypertension (OR = 1.22; 95% CI 1.08–1.38), but less likely to have PAHs for chronic obstructive pulmonary disease (COPD)/asthma (OR = 0.85; 95% CI 0.82–0.87) and heart failure (OR = 0.89; 95% CI 0.86–0.92). Risks of PAHs increased significantly with comorbidity burden. Among beneficiaries with a PAH, total Medicare expenditures were significantly higher for those subjects who also had ADRD. Conclusion Medicare beneficiaries with ADRD were at a higher risk of PAHs for certain uncontrolled comorbidities and incurred higher Medicare expenditures compared with matched controls without dementia. ADRD appears to make the management of some comorbidities more difficult and expensive. Ideally, ADRD programs should involve care management targeting high-risk patients with multiple chronic conditions.

Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer's disease.

Abstract: Background Some observational studies have established an association between exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and a decreased risk of subsequently developing Alzheimer's disease (AD). Mild cognitive impairment or cognitive impairment, not dementia (CIND) is more likely to convert to AD, and no specific preventive method is currently available. The objective of this study was to determine the association of NSAID use in 5276 cognitively normal subjects of the Canadian Study of Health and Aging, a 10-year population-based cohort study, with the incidence of CIND, AD, and all-cause dementia. Methods Hazard ratios were calculated from Cox proportional hazards models with age as the time scale according to three study samples including 824 cases of dementia (563 cases of AD), 630 cases of dementia (435 cases of AD), and 883 cases of CIND, respectively. Adjustments were made for gender, education, lifestyle factors, comorbid diseases, and vascular risk factors. Results Lower risks for AD and all-cause dementia were significantly associated with the use of any NSAIDs and the salicylates without barbiturates subgroup in the study sample including subjects with CIND at baseline. There was a weak association between any NSAIDs and the risk of CIND (hazard ratio, 0.87; 95% confidence interval, 0.76–1.00). Conclusion These results suggest that there is an association between NSAID use and a lower incidence of AD and, to a lesser extent, of CIND.

Glucose metabolism, gray matter structure and memory decline in subjective memory impairment

Abstract: OBJECTIVE To identify biological evidence for Alzheimer disease (AD) in individuals with subjective memory impairment (SMI) and unimpaired cognitive performance and to investigate the longitudinal cognitive course in these subjects. METHOD [¹⁸F]fluoro-2-deoxyglucose PET (FDG-PET) and structural MRI were acquired in 31 subjects with SMI and 56 controls. Cognitive follow-up testing was performed (average follow-up time: 35 months). Differences in baseline brain imaging data and in memory decline were assessed between both groups. Associations of memory decline with brain imaging data were tested. RESULTS The SMI group showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe. Gray matter volume was reduced in the right hippocampus in the SMI group. At follow-up, subjects with SMI showed a poorer performance than controls on measures of episodic memory. Longitudinal memory decline in the SMI group was associated with reduced glucose metabolism in the right precuneus at baseline. CONCLUSION The cross-sectional difference in 2 independent neuroimaging modalities indicates early AD pathology in SMI. The poorer memory performance at follow-up and the association of reduced longitudinal memory performance with hypometabolism in the precuneus at baseline support the concept of SMI as the earliest manifestation of AD.

Worldwide Alzheimer’s Disease Neuroimaging Initiative

Abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI) was launched in 2003 to speed drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public–private partnership, the first phase of ADNI (ADNI 1) set a new standard for data sharing without embargo. In addition, it has been extended to 2017 by additional funding (North American-ADNI Grand Opportunities and ADNI 2) as well as multiple projects around the world, collectively known as Worldwide ADNI (WW-ADNI). The goal of WW-ADNI is to harmonize projects and results across different geographical sites and to encourage and harmonize data management and availability to investigators around the world. WW-ADNI projects are currently underway in North America, Europe, Japan, Australia, Korea, Taiwan, and Argentina, with a nascent program in China and a possible future program in Brazil.

Alzheimer’s disease: Pathogenesis and prevention

Abstract: Tau lesions (pretangles, neuropil threads, neurofibrillary tangles) in select neuronal types are essential to the pathogenesis of Alzheimer's disease. Pretangle formation marks the beginning of the pathological process and is of particular interest because it is temporally closer to the prevailing conditions that induce the pathological process underlying Alzheimer's disease in contrast to late-stage disease. However, not all pretangles convert into neurofibrillary tangles. We propose that the development of tau lesions in Alzheimer's disease is traceable to differences between early- versus late-maturing oligodendrocytes and to the exceptionally protracted myelination of late-developing portions of the human brain. Conclusions drawn from these considerations should encourage development of new preventative and disease-modifying strategies.

Atherosclerotic calcification relates to cognitive function and to brain changes on magnetic resonance imaging.

Abstract: Background Increasing evidence suggests a role of atherosclerosis in the pathogenesis of cognitive impairment and dementia. Calcification volume measured with computed tomography (CT) is a valid marker of atherosclerosis. This study investigates associations of atherosclerosis (measured using CT) at four locations with cognition and brain changes on magnetic resonance imaging (MRI). Methods To quantify calcification volume, 2414 nondemented people from the Rotterdam Study underwent CT of the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. To assess global cognition and performance on memory, executive function, information processing speed, and motor speed, they also underwent neuropsychological tests. In a random subgroup of 844 participants, brain MRI was performed. Automated segmentation and quantification of brain MRI scans yielded brain tissue volumes in milliliters. Diffusion tensor imaging was used to measure the microstructural integrity of the white matter. Relationships of atherosclerotic calcification with cognition, brain tissue volumes, and diffusion tensor imaging measures were assessed with linear regression models and adjusted for relevant confounders. Results With larger calcification volumes, lower cognitive scores were observed. When calcification volumes were larger, total brain volumes were also smaller. Specifically, larger coronary artery calcification volumes related to smaller gray matter volumes, and extracranial and intracranial carotid calcification volumes related to smaller white matter volumes. Larger calcification volume in all vessel beds was accompanied by worse microstructural integrity of the white matter. Conclusions Larger calcification volume is associated with worse cognitive performance. It also relates to smaller brain tissue volumes and worse white matter microstructural integrity, revealing possible mechanisms through which atherosclerosis may lead to poorer cognition.

A new informant-based questionnaire for instrumental activities of daily living in dementia

Abstract: Background Interference in everyday functioning is part of the diagnostic criteria for dementia. Questionnaires measuring "instrumental activities of daily living" (IADL) are used to measure this interference, but the psychometric quality of these questionnaires is often questioned. In addition, these questionnaires are less suited for early-onset patients. This is problematic, given the high frequency of relatively young patients in memory clinics. In this article, we describe the development and psychometric properties of a new informant-based IADL questionnaire aimed at detecting incipient dementia and appropriate for a broad age range. Methods We defined IADL in consensus with experts and constructed items based on existing items and suggestions from experts and informants. Informants of subjects (n = 206) who visited the Alzheimer Center of the VU University Medical Center completed the questionnaire. Factor structure was investigated using classical exploratory factor analysis and item response theory. We assessed test–retest reliability in 73 informants using weighted κ values. Results The questionnaire consisted of 75 items and was computerized to enhance ease of administration. Exploratory factor analysis supported a single-factor model, with 48.3% of the variance being explained by the first factor. We removed five items, as they did not fit the model. High internal consistency was demonstrated. Test–retest reliability showed that the majority of items (87.9%) had substantial-to-almost perfect κ values. Conclusion The Amsterdam IADL Questionnaire (Amsterdam IADL questionnaire is a registered trademark of Alzheimer Center VU University Medical Center, Amsterdam, The Netherlands) is a 70-item informant-based computerized questionnaire aimed at detecting early dementia and early-onset dementia. Initial results show that this questionnaire is a promising new tool.

White matter atrophy in Alzheimer's disease variants

Abstract: Background In comparison with late-onset Alzheimer’s disease (LOAD, onset, >65 years), early-age-of-onset Alzheimer’s disease (EOAD, onset, Methods Using structural magnetic resonance imaging and voxel-based morphometry, we investigated WM damage in patients with EOAD (n = 16), PCA (n = 13), lv-PPA (n = 10), and LOAD (n = 14) at presentation and 72 age-matched control subjects. Results In patients with EOAD, PCA, and lv-PPA, WM atrophy was centered on the lateral temporal and parietal regions, including the cingulum and posterior corpus callosum. Compared with control subjects, patients with lv-PPA showed more severe left parietal damage, and patients with PCA showed more severe occipital atrophy. Moreover, patients with EOAD had greater cingulum atrophy compared with those with LOAD. LOAD showed WM damage in the medial temporal regions and less extensive hemispheric involvement. Conclusion Patterns of WM damage in EOAD, lv-PPA, and PCA are consistent with the clinical syndromes and GM atrophy patterns. WM injury in AD atypical variants may contribute to symptoms and disease pathogenesis.

White matter imaging changes in subjective and mild cognitive impairment.

Abstract: Background To determine whether white matter (WM) memory network changes accompany early cognitive impairment and whether these changes represent early, pathologically independent axonal affection, we combined WM diffusion tensor imaging and cortical morphometric measurements of normal control subjects, patients with only subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Methods We included 66 patients with SCI or MCI and 21 control subjects from a university-hospital-based memory clinic in a cross-sectional study. Morphometric analysis was performed in FreeSurfer, and Tract-Based Spatial Statistics was used for analysis of diffusion tensor imaging-derived WM fractional anisotropy, radial diffusivity (DR), and mean diffusivity (MD). Relationships between WM measures and stage were assessed with whole-brain voxelwise statistics and on a region-of-interest basis, with subsequent correction for cortical atrophy. Results In SCI patients, as compared with control subjects, there were widespread changes in DR and MD. No significant differences in thickness could be demonstrated. In MCI patients, as compared with control subjects, there were widespread changes in DR, MD, and fractional anisotropy; the precuneal and inferior parietal cortices were thinner; and the hippocampus was smaller. Multiple logistic regression analysis eliminated morphometry as an explanatory variable in favor of DR/MD for all regions of interest, except in the precuneus, where both thickness and DR/MD were significant explanatory variables. Conclusions WM tract degeneration is prominent in SCI and MCI patients, and is at least in part independent of overlying gray matter atrophy.

Medical and environmental risk factors associated with frontotemporal dementia: a case-control study in a veteran population

Abstract: Background Compared with other major dementias, very little is known about the medical and environmental risk factors associated with frontotemporal dementia (FTD). In this study, we evaluated medical and environmental disorders associated with FTD in a veteran population. Methods The medical records of 845 consecutive veterans who were evaluated for cognitive and/or behavioral complaints at a cognitive disorders clinic in an academic medical center between March 1, 2003, and June 30, 2008, were reviewed and 554 patients received a diagnosis of dementia. Medical disorders and environmental risk factors in 63 patients with behavioral variant of FTD were compared with 491 patients with non-FTD dementias. Results The prevalence of traumatic brain injury (TBI) was significantly greater in patients with FTD versus those with non-FTD dementias (12.7% vs 3.5%; P P P P > .05 for all). In multivariate analysis, the risk for FTD was increased in patients with TBI (OR, 4.4; 95% CI, 1.6–11.8). The risk for FTD was marginally decreased in patients with heart disease (OR, 0.4; 95% CI, 0.3–0.96). Conclusions In a clinical sample of veterans, risk of FTD was increased in patients with TBI and marginally decreased in patients with heart disease. Prospective studies are needed to confirm these associations temporally and to identify their underlying mechanisms.

Computer-related self-efficacy and anxiety in older adults with and without mild cognitive impairment.

Abstract: Background This study examines differences in computer-related self-efficacy and anxiety in subgroups of older adults, and changes in those measures after exposure to a systematic training program and subsequent computer use. Methods Participants were volunteers in the Intelligent Systems for Assessment of Aging Changes study (ISAAC) carried out by the Oregon Center for Aging and Technology. Participants were administered two questionnaires before training and again 1 year later, which were related to computer self-efficacy and anxiety. Continuous recording of computer use was also assessed for a subset of participants. Results Baseline comparisons by sex, age, education, living arrangement, and computer proficiency, but not cognitive status, yielded significant differences in confidence and anxiety related to specific aspects of computer use. At 1-year follow-up, participants reported less anxiety and greater confidence. However, the benefits of training and exposure varied by group and task. Comparisons based on cognitive status showed that the cognitively intact participants benefited more from training and/or experience with computers than did participants with mild cognitive impairment (MCI), who after 1 year continued to report less confidence and more anxiety regarding certain aspects of computer use. Conclusion After 1 year of consistent computer use, cognitively intact participants in this study reported reduced levels of anxiety and increased self-confidence in their ability to perform specific computer tasks. Participants with MCI at baseline were less likely to demonstrate increased efficacy or confidence than their cognitively intact counterparts.