Purpose of Review: The term mild cognitive impairment (MCI) is used to describe older subjects with demonstrable cognitive impairment who have not crossed the threshold for dementia. Because patients with MCI have an increased risk of developing dementia, especially Alzheimer disease (AD), there is significant interest in the clinical characterization of these subjects and in understanding the pathophysiology of the transition from MCI to AD.
Recent Findings: The MCI syndrome, as an expression of an incipient disorder that may lead to dementia, is extremely heterogeneous and may coexist with systemic, neurologic, or psychiatric disorders that can cause cognitive deficits. Recent clinical criteria were designed to take into account the different forms of clinical presentation of the syndrome, and introduced the possible contribution of biomarkers to the clinical diagnosis. Bedside diagnosis of MCI can be difficult, since patients who report having cognitive problems may have normal scores in global cognitive scales or in brief neuropsychological instruments.
Summary: This article presents the evolution of the clinical concept of MCI, the operationalization of its current definitions, the development of biomarkers that can help to identify an underlying neurodegenerative process as the etiology of the syndrome, and its proposed treatments.
Alzheimer’s disease (AD) is the most frequent form of dementia in elderly individuals and its incidence and prevalence increases with age. This risk of AD is increased in the presence of genetic and demographic factors including apolipoprotein E 4 allele, lower education, and family history of AD. There are medical risk modifiers including systemic hypertension, diabetes mellitus, cardiovascular disease, and cerebrovascular disease that increase the vulnerability for AD. By contrast, there are lifestyle risk modifiers that reduce the effects of AD risk factors include diet and physical and cognitive activity. Our research has consistently shown that it is the interactions among these risk factors with the pathobiological cascade of AD that determine the likelihood of a clinical expression of AD—either as dementia or mild cognitive impairment. However, the association between “vulnerability” and “protective” factors varies with age, since the effects of these factors on the risk for AD may differ in younger (age < 80) versus older (age > 80) individuals. The understanding of the dynamic of these factors at different age periods will be essential for the implementation of primary prevention treatments for AD.
Alzheimer’s disease; cardiovascular disease; cerebrovascular disease; mild cognitive impairment
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
This study examined amyloid-β (Aβ) deposition in 190 non-demented subjects aged 82 and older to determine the proportion of Aβ-positive scans and associations with cognition, APOE status, brain volume, and Ginko biloba (Gb) treatment.
Subjects who agreed to participate had a brain MRI and positron emission tomography scan with 11C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82, and the mean age of the subjects was 85.5 at the time of the scans;152 (80%) were cognitively normal and 38 (20%) were diagnosed with mild cognitive impairment (MCI)at the time of the PiB study.
A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aβ deposition as determined by PiB.
The data revealed a 55% prevalence of PiB-positivity in non-demented subjects age >80 and 85% PiB-positivity in the APOE*4 non-demented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aβ deposition.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aβ) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aβ deposition from those in which Aβ deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(−)] subjects.
We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(−) subjects was not so distinct.
The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence.
The visual read and SKM methods, applied together, may optimize the identification of early Aβ deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.
Amyloid; Positron Emission Tomography; Pittsburgh Compound B; Visual Read; Cluster analysis
The authors sought to determine the effects of conventional and atypical antipsychotic use on time to nursing home admission and time to death in a group of outpatients with mild to moderate probable Alzheimer’s disease.
The authors examined time to nursing home admission and time to death in 957 patients with the diagnosis of probable Alzheimer’s disease who had at least one follow-up evaluation (mean follow-up time, 4.3 years [SD=2.7]; range, 0.78–18.0 years) using Cox proportional hazard models adjusted for age, gender, education level, dementia severity, hypertension, diabetes mellitus, heart disease, extrapyramidal signs, depression, psychosis, aggression, agitation, and dementia medication use.
A total of 241 patients (25%) were exposed to antipsychotics at some time during follow-up (conventional, N=138; atypical, N=95; both, N=8). Nursing home admission (63% compared with 23%) and death (69% compared with 34%) were more frequent in individuals taking conventional than atypical antipsychotics. In amodel that included demographic and cognitive variables, hypertension, diabetes mellitus, heart disease, incident strokes, and extrapyramidal signs, only conventional antipsychotic use was associated with time to nursing home admission. However, the association was no longer significant after adjustment for psychiatric symptoms. Psychosis was strongly associated with nursing home admission and time to death, but neither conventional nor atypical antipsychotics were associated with time to death.
The use of antipsychotic medications, both conventional and atypical, was not associated with either time to nursing home admission or time to death after adjustment for relevant covariates. Rather, it was the presence of psychiatric symptoms, including psychosis and agitation, that was linked to increased risk of institutionalization and death after adjustment for exposure to antipsychotics.
To determine whether a high prevalence (55%) of Aβ deposition in a cohort of individuals remaining dementia-free into their 9th and 10th decades is associated with cognitive decline prior to imaging.
A total of 194 participants (mean age 85.5 years, range 82–95) who completed the Ginkgo Evaluation of Memory Study (GEMS) and remained dementia-free subsequently completed Pittsburgh compound B–PET imaging. We examined cross-sectional associations between Aβ status and performance on a broad neuropsychological test battery completed at GEMS entry 7–9 years prior to neuroimaging. We also longitudinally examined cognition over annual evaluations using linear mixed models.
At GEMS screening (2000–2002), participants who were Aβ-positive in 2009 had lower performance on the Stroop test (p < 0.01) and Raven's Progressive Matrices (p = 0.05), with trend level difference for Block Design (p = 0.07). Longitudinal analyses showed significant slope differences for immediate and delayed recall of the Rey-Osterrieth figure, semantic fluency, and Trail-Making Test parts A and B, indicating greater performance decline prior to neuroimaging for Aβ-positive relative to Aβ-negative participants (ps < 0.05).
Highly prevalent Aβ deposition in oldest-older adults is associated with cognitive decline in visual memory, semantic fluency, and psychomotor speed beginning 7–9 years prior to neuroimaging. Mean differences in nonmemory domains, primarily executive functions, between Aβ-status groups may be detectable 7–9 years before neuroimaging.
Purpose of review
This review describes the evolution of the clinical criteria for Alzheimer’s disease over the past 25 years, with special emphasis on those recently published that have incorporated the use of biomarkers.
One of the most important advances in the knowledge of Alzheimer’s disease was the development of cerebrospinal fluid, PET and MRI biomarkers. These have shown that the Alzheimer’s disease is present in cognitively normal individuals, suggesting that there is a long incubation process that precedes the onset of the symptoms. Although there are diagnostic criteria for Alzheimer’s disease, the National Institute on Aging and the Alzheimer’s Association has proposed a set of diagnostic criteria oriented to provide a unified vision of the pathological process from preclinical, to mild cognitive impairment, and to full-blown dementia. These new criteria take advantage of different biomarkers to support the clinical diagnosis of the different stages of the disease.
The new guidelines provide a definition of the dementia syndrome and core diagnostic features to be used in research and clinical practice, although they caution about the use of biomarkers, since they still require validation, and the longitudinal interaction and dynamics of these biomarkers in relationship to the manifestation of the symptoms are not fully understood.
Alzheimer’s disease; dementia; diagnostic criteria; mild cognitive impairment; preclinical Alzheimer’s disease
Background. Dementia and cardiovascular disease (CVD) are frequently comorbid. The presence of dementia may have an effect on how CVD is treated. Objective. To examine the effect of dementia on the use of four medications recommended for secondary prevention of ischemic heart disease (IHD): angiotensin-converting enzyme inhibitors, beta-blockers, lipid-lowering medications, and antiplatelet medications. Design. Retrospective analysis of data from the Cardiovascular Health Study: Cognition Study. Setting and Subjects. 1,087 older adults in four US states who had or developed IHD between 1989 and 1998. Methods. Generalized estimating equations to explore the association between dementia and the use of guideline-recommended medications for the secondary prevention of IHD. Results. The length of follow-up for the cohort was 8.7 years and 265 (24%) had or developed dementia during the study. Use of medications for the secondary prevention of IHD for patients with and without dementia increased during the study period. In models, subjects with dementia were not less likely to use any one particular class of medication but were less likely to use two or more classes of medications as a group (OR, 0.60; 95% CI, 0.36–0.99). Conclusions. Subjects with dementia used fewer guideline-recommended medications for the secondary prevention of IHD than those without dementia.
To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy.
Genetic case-control association study.
Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269).
Main Outcome Measure
The APOE allele frequencies.
The APOE ε4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ42=185.25; P=5.56×10−39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, ε4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4–15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1–19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5–10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7–5.6).
The APOE ε4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ε4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ε4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
Background and Aims
The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts.
This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index.
For the ANU-ADRI using available data, the MAP study c-statistic was 0·637 (95% CI 0·596–0·678), for the KP study it was 0·740 (0·712–0·768) and for the CVHS it was 0·733 (0·691–0·776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650–0.727), 0.666 (0.628–0.704) and 0.734 (0.707–0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427–0.554) to 0.595 (0.565–0.625).
A composite risk score derived from the ANU-ADRI weights including 8–10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.
Low pulmonary function (PF) is associated with poor cognitive function and dementia. There are few studies of change in PF in mid-life and late-life cognitive status.
Design and Participants
We studied this is 3,665 subjects from AGES-Reykjavik Study who had at least one measure of forced expiratory volume/ 1 sec (FEV1) and were cognitively tested on average 23 years later. A subset of 1,281 subjects had two or three measures of FEV1 acquired over a 7.8 year period. PF was estimated as FEV1/Height2. Rate of PF decline was estimated as the slope of decline over time. Cognitive status was measured with continuous scores of memory, speed of processing, and executive function, and as the dichotomous outcomes of mild cognitive impairment (MCI) and dementia.
Lower PF measured in mid-life predicted lower memory, speed of processing, executive function, and higher likelihood of MCI and dementia 23 years later. Decrease of PF over a 7.8-year period in mid-life was not associated with lower cognitive function or dementia.
Reduced PF measured in mid-life may be an early marker of later cognitive problems. Additional studies characterizing early and late PF changes are needed.
Cognition; Dementia; Forced Expiratory Volume; Longitudinal Cohort Studies
Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in AD phenotype. Soluble β-amyloid induces loss of dendritic spine synapses through impairment of long term potentiation. In contrast, the Rho GEF kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble β-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from fifty-two AD subjects with and without psychosis. In subjects with psychosis, the β-amyloid1-42/β-amyloid1-40 ratio was increased, due primarily to reduced soluble β-amyloid1-40, and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical β-amyloid1-42/β-amyloid1-40 ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD.
β-amyloid; kalirin; psychosis; Alzheimer disease
Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both.
We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD).
Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8–31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2–17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2–6.6; p = 0.92). There was a highly significant trend test across groups (χ2(1) = 19.3; p = 1.1 × 10−5), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB.
GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.
In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer’s disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer’s disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health.
Objectives and Methods:
The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 years) in the Cardiovascular Health Study–Cognition Study from 1998–1999 to 2010–2011.
Two hundred (70%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95% confidence interval, 88.13–142.95) per 1,000 person-years. A total of 107 (53.5%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 ± 1.8 years. Forty (20%) of the incident MCI cases had an “unstable” course: 19 (9.5%) converted to MCI and later returned to normal; 10 (5%) converted to MCI, to normal, and later back to MCI; 7 (3.5%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years).
The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts.
NeuroAIDS persists in the era of cART. We describe here recovery of brain structure and function following after 6 months of therapy in a treatment-naïve patient presenting with HIV-Associated Dementia. The patient's neuropsychological test performance improved, and his total brain volume increased by more than 5%. Neuronal functional connectivity measured by magnetoencephalography changed from a pattern identical to that observed in other HIV-infected individuals, to one that was indistinguishable from that of uninfected control subjects. These data suggest that at least some of the effects of HIV on the brain can be fully reversed with treatment.
HIV Disease; NeuroAIDS; Magnetoencephalography; Functional Connectivity
Background and Purpose
This scientific statement provides an overview of the evidence on
vascular contributions to cognitive impairment and dementia. Vascular
contributions to cognitive impairment and dementia of later life are common.
Definitions of vascular cognitive impairment (VCI), neuropathology, basic
science and pathophysiological aspects, role of neuroimaging and vascular
and other associated risk factors, and potential opportunities for
prevention and treatment are reviewed. This statement serves as an overall
guide for practitioners to gain a better understanding of VCI and dementia,
prevention, and treatment.
Writing group members were nominated by the writing group co-chairs
on the basis of their previous work in relevant topic areas and were
approved by the American Heart Association Stroke Council Scientific
Statement Oversight Committee, the Council on Epidemiology and Prevention,
and the Manuscript Oversight Committee. The writing group used systematic
literature reviews (primarily covering publications from 1990 to May 1,
2010), previously published guidelines, personal files, and expert opinion
to summarize existing evidence, indicate gaps in current knowledge, and,
when appropriate, formulate recommendations using standard American Heart
Association criteria. All members of the writing group had the opportunity
to comment on the recommendations and approved the final version of this
document. After peer review by the American Heart Association, as well as
review by the Stroke Council leadership, Council on Epidemiology and
Prevention Council, and Scientific Statements Oversight Committee, the
statement was approved by the American Heart Association Science Advisory
and Coordinating Committee.
The construct of VCI has been introduced to capture the entire
spectrum of cognitive disorders associated with all forms of cerebral
vascular brain injury—not solely stroke—ranging from mild
cognitive impairment through fully developed dementia. Dysfunction of the
neurovascular unit and mechanisms regulating cerebral blood flow are likely
to be important components of the pathophysiological processes underlying
VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk
for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage
of the brain, and VCI. The neuropathology of cognitive impairment in later
life is often a mixture of Alzheimer disease and microvascular brain damage,
which may overlap and synergize to heighten the risk of cognitive
impairment. In this regard, magnetic resonance imaging and other
neuroimaging techniques play an important role in the definition and
detection of VCI and provide evidence that subcortical forms of VCI with
white matter hyperintensities and small deep infarcts are common. In many
cases, risk markers for VCI are the same as traditional risk factors for
stroke. These risks may include but are not limited to atrial fibrillation,
hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore,
these same vascular risk factors may be risk markers for Alzheimer disease.
Carotid intimal-medial thickness and arterial stiffness are emerging as
markers of arterial aging and may serve as risk markers for VCI. Currently,
no specific treatments for VCI have been approved by the US Food and Drug
Administration. However, detection and control of the traditional risk
factors for stroke and cardiovascular disease may be effective in the
prevention of VCI, even in older people.
Vascular contributions to cognitive impairment and dementia are
important. Understanding of VCI has evolved substantially in recent years,
based on preclinical, neuropathologic, neuroimaging, physiological, and
epidemiological studies. Transdisciplinary, translational, and transactional
approaches are recommended to further our understanding of this entity and
to better characterize its neuropsychological profile. There is a need for
prospective, quantitative, clinical-pathological-neuroimaging studies to
improve knowledge of the pathological basis of neuroimaging change and the
complex interplay between vascular and Alzheimer disease pathologies in the
evolution of clinical VCI and Alzheimer disease. Long-term vascular risk
marker interventional studies beginning as early as midlife may be required
to prevent or postpone the onset of VCI and Alzheimer disease. Studies of
intensive reduction of vascular risk factors in high-risk groups are another
important avenue of research.
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
Patients with late onset Alzheimer disease (AD) vary widely in their trajectory of cognitive decline. Genetic variations in CLU, PICALM, and CR1 are associated with AD, but it is unknown if they exert their effects via altering cognitive trajectory in elderly subjects at risk for AD.
We developed a Bayesian model to fit cognitive trajectories in a cohort of elderly subjects and test for genetic effects. We first validated the model’s ability to detect the previously established effects of APOE epsilon 4 alleles on age at cognitive decline and of psychosis on the rate of cognitive decline in 802 subjects from the Cardiovascular Health Study Cognition Study who were without dementia at study entry and developed incident dementia during follow-up. We then evaluated the effects of CLU, PICALM, and CR1 on age and rate of decline in 1831 subjects without dementia at study entry, including those who did, or did not develop incident dementia at study’s end.
Our model generated robust fits to the observed cognitive trajectory data. Validation analysis supported the utility of the model. CLU and CR1 were associated with more rapid cognitive decline. PICALM was associated with an earlier age at midpoint of cognitive decline. Associations remained after accounting for the effects of APOE and demographic factors.
Evaluation of cognitive trajectories provides a powerful approach to dissecting genetic effects on the processes leading to cognitive deterioration and AD.
Alzheime's disease; MCI (mild cognitive impairment); genetic; cognitive decline; endophenotype
There is need for a valid and reliable biomarker for HIV Associated Neurocognitive Disorder (HAND). The purpose of the present study was to provide preliminary evidence of the potential utility of neuronal functional connectivity measures obtained using magnetoencephalography (MEG) to identify HIV-associated changes in brain function. Resting state, eyes closed, MEG data from 10 HIV-infected individuals and 8 seronegative controls were analyzed using mutual information (MI) between all pairs of MEG sensors to determine whether there were functional brain networks that distinguished between subject groups based on cognition (global and learning) or on serostatus.
Three networks were identified across all subjects, but after permutation testing (at α < .005) only the one related to HIV serostatus was significant. The network included MEG sensors (planar gradiometers) above the right anterior region connecting to sensors above the left posterior region. A mean MI value was calculated across all connections from the anterior to the posterior groupings; that score distinguished between the serostatus groups with only one error (sensitivity = 1.00, specificity = .88 (X2 = 15.4, df = 1, p < .01, Relative Risk = .11). There were no significant associations between the MI value and the neuropsychological Global Impairment rating, substance abuse, mood disorder, age, education, CD4+ cell counts or HIV viral load.
We conclude that using a measure of functional connectivity, it may be possible to distinguish between HIV-infected and uninfected individuals, suggesting that MEG may have the potential to serve as a sensitive, non-invasive biomarker for HAND.
HIV Disease; Cognition; Magnetoencephalography; Functional Connectivity
We explored the potential value of amyloid imaging in patients with atypical presentations of dementia. Twenty-eight patients with atypical dementia underwent PET imaging with the amyloid imaging tracer Pittsburgh Compound-B (PiB). Twenty-six had [18F]fluoro-2-deoxy-D-glucose (FDG) PET scans. After extensive clinical evaluation, this group of patients generated considerable diagnostic uncertainty and received working diagnoses that included possible AD (pAD), focal dementias [e.g. posterior cortical atrophy (PCA)], or cases in which no clear diagnostic category could be determined (dementia of uncertain etiology; DUE). Patients were classified as PiB-positive, -negative, or -intermediate based on objective criteria. Anterior-posterior (A-P) and left-right (L-R) indices of PiB and FDG uptake were calculated to examine differences in distribution of amyloid pathology and metabolic changes associated with clinical phenotype. Eleven patients (39%) were PiB-positive, 16 were PiB-negative (57%) and one (4%) was intermediate. By diagnostic category, 3/10 patients (30%) with DUE, 1/5 (20%) with primary progressive aphasia (PPA), 3/5 (60%) with posterior cortical atrophy (PCA), and 4/7 (57%) with pAD were PiB-positive. Brain metabolism of both PiB-positive and -negative patients were generally similar by phenotype, but differed from typical AD. PCA patients also appeared to differ in their relative distribution of PiB compared to typical AD, consistent with their atypical phenotype. AD pathology is frequently present in atypical presentations of dementia and can be identified by amyloid imaging. Clinical phenotype is more related to the pattern of cerebral hypometabolism than the presence/absence of amyloid pathology. These findings have diagnostic, prognostic, and therapeutic implications.
Amyloid imaging; PiB; PET; Alzheimer’s Disease; Posterior Cortical Atrophy; dementia; focal dementia
Background and Purpose
The purpose of this study was to examine regional cerebral blood flow (rCBF) in normal cognitive-performing subjects with hypertension (HTN) using continuous arterial spin-labeled MRI. The most common explanation for the effect of blood pressure on cognition is that HTN increases the risk of cerebrovascular disease, and it may increase the risk for Alzheimer disease possibly through small vessel disease, ischemia, oxidative stress, and inflammation. However, few studies to date have examined the rCBF of cognitively normal subjects with HTN in population-based cohorts, and none have used continuous arterial spin-labeled MRI. This is a noninvasive technique that does not require either injections or ionizing radiation and can measure absolute rCBF rates over the entire brain.
rCBF was measured at 1.5 T using continuous arterial spin-labeled MRI in 41 cognitively normal subjects who were participating in the Cardiovascular Health Study Cognition Study. A deformable atrophy-corrected registration method was used to warp the rCBF maps to the standard colin27 brain space. Image and cluster-based statistical analyses were performed between subject groups.
Cognitively normal subjects with HTN (n=19) had decreased rCBF in the putamen, globus pallidus, bilaterally, and in the left hippocampus compared with normotensives (n=22). In addition, decreased rCBF was observed in the right and left anterior cingulate gyrus with extension to the subcallosal region, left posterior cingulate gyrus and medial precuneus, left lateral inferior and superior frontal, and inferior parietal, left orbitofrontal, and left superior temporal cortices
rCBF is affected in normal subjects with HTN, not only in the subcortical regions, but also in limbic and paralimbic structures. We hypothesize that the HTN creates a vulnerability state for the development of neurodegenerative disorders, especially Alzheimer disease.
CASL; cerebral blood flow; cognition; hypertension; MRI
Hispanics represent 10% of the U.S. population and are the fastest growing group. Studies show a higher prevalence and incidence of Alzheimer’s disease (AD) in Hispanics than in the non-Hispanic white population, with an earlier age of onset. Among the currently estimated 200,000 Hispanics with AD, a significant number remain undiagnosed and untreated, and Hispanic participation in AD clinical trials has been historically low. This study evaluated the efficacy and safety of donepezil hydrochloride (donepezil) in Hispanics with mild-to-moderate AD.
In this multicenter, open-label, 12-week study conducted in the United States, subjects were Hispanic men or women aged ≥50 years with a diagnosis of mild-to-moderate AD (DSMV-IV and NINCDS/ADRDA criteria), with Mini-Mental State Examination (MMSE) scores of 10–26 (inclusive) at screening. Subjects were treated with donepezil 5 mg/day for 6 weeks followed by 10 mg/day for 6 weeks. Clinical evaluation was performed at baseline, week 6 and week 12. Cognitive improvement was measured using the MMSE, Fuld Object Memory Evaluation (FOME) and Symbol Digit Modality Test (SDMT). Behavioral symptoms and associated caregiver distress were assessed with the Neuropsychiatric Inventory (NPI).
One-hundred-six patients with mild-to-moderate AD (mean age 68.6 years) were enrolled (intent to treat, n=97); most chose to have assessments conducted in Spanish. With 12 weeks of treatment, subjects showed statistically significant improvement from baseline on MMSE (P<0.0001), FOME retrieval (P=0.0042), FOME repeated retrieval (P=0.0020) and SDMT correct scores (P<0.0001). The NPI subdomain “apathy/indifference” showed statistically significant improvement (P=0.0010). The NPI Caregiver Distress scale (NPI-D) total score was statistically significantly improved (P=0.0500), suggesting a positive impact on relieving caregivers’ burden associated with patient behavior. Most patients tolerated the treatment well, with only 2 discontinuing because of adverse events. The most common (>5%) adverse events were insomnia (9.5%), dizziness (7.6%), diarrhea (5.7%) and nausea (5.7%).
The cognitive improvement and safety results from this study were consistent with those reported for donepezil in the general population. Increased awareness of AD in the Hispanic population will help more Hispanics with AD to benefit from early diagnosis and effective treatment.
Alzheimer’s disease; drugs; Latinos