Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their ...brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-β species-monomers, dimers and higher molecular weight oligomers-in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-β plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-β and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer's pathology. Amyloid-β deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-β assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer's pathological changes.
The potential benefit of the anti‐amyloid drug aducanumab based on results of recent EMERGE and ENGAGE clinical trials has generated great controversy and has very important implications for the ...future of anti‐amyloid drug therapies. The two trials of 18‐month duration were done in patients with mild cognitive impairment (MCI) and early dementia. The ENGAGE trial showed no benefit while the high‐dose EMERGE trial initially also showed no benefit but with longer follow‐up there was a significant positive benefit. A recent review form the U.S. Food and Drug Administration (FDA) Advisory Committee was negative while the FDA Office of Neurological Drugs was positive and the statisticians negative. This has generated debate about whether the drug should be approved, disapproved, require a new clinical trial, or approved for a subsample only. The implications for treating both MCI and Alzheimer's disease (AD) patients with anti‐amyloid drugs is very substantial as well as the brain amyloid‐AD‐dementia hypothesis.
Summary Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and ...pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging–Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β −4·0, 95% CI −5·5 to −2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (–2·0, −3·2 to −0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. Funding US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).
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.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The study of the incidence and prevalence of dementia is important to understand the distribution of dementing illness among age and sex groups, and for the detection of possible causes of these ...disorders. A variation in the incidence or prevalence of dementia, especially Alzheimer's disease (AD) by region or specific populations can be because of greater or lesser exposure to the causal agents of dementia. For example, in the past the striking differences in the incidence of coronary heart disease (CHD) led to the understanding of the relationship between dietary factors, such as saturated fat and dietary cholesterol, and the incidence of CHD. However, there is a high prevalence of dementia in elderly individuals around the world, and multiple studies conducted in industrialized and nonindustrialized countries have shown an age-standardized prevalence of dementia ranging from 5% to 7% in most countries. Dementia is not a specific disease but rather a constellation of cognitive changes and disability due to several "causes," i.e., AD, Lewy bodies, vascular disease, drugs, and alcohol. Whether there is a trend for reduced incidence of dementia has to be further evaluated. It is possible that the improvement in the treatments of risk factors, especially vascular disease, has resulted in decreased incidence. However, this could result in an increase in prevalence, since the improved therapies for risk factors will lead to increased longevity in patients with dementia.
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.
Inflammatory processes may contribute to risk for Alzheimer's disease (AD) and age-related brain degeneration. Metabolic and genetic risk factors, and physical activity may, in turn, influence these ...inflammatory processes. Some of these risk factors are modifiable, and interact with each other. Understanding how these processes together relate to brain aging will help to inform future interventions to treat or prevent cognitive decline.
We used brain magnetic resonance imaging (MRI) to scan 335 older adult humans (mean age 77.3 ± 3.4 years) who remained non-demented for the duration of the 9-year longitudinal study. We used structural equation modeling (SEM) in a subset of 226 adults to evaluate whether measures of baseline peripheral inflammation (serum C-reactive protein levels; CRP), mediated the baseline contributions of genetic and metabolic risk, and physical activity, to regional cortical thickness in AD-relevant brain regions at study year 9.
We found that both baseline metabolic risk and AD risk variant apolipoprotein E ε4 (APOE4), modulated baseline serum CRP. Higher baseline CRP levels, in turn, predicted thinner regional cortex at year 9, and mediated an effect between higher metabolic risk and thinner cortex in those regions. A higher polygenic risk score composed of variants in immune-associated AD risk genes (other than APOE) was associated with thinner regional cortex. However, CRP levels did not mediate this effect, suggesting that other mechanisms may be responsible for the elevated AD risk.
We found interactions between genetic and environmental factors and structural brain health. Our findings support the role of metabolic risk and peripheral inflammation in age-related brain decline.
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•Higher baseline blood C-reactive protein levels were correlated with thinner posterior cingulate cortex, at study year 9.•Higher metabolic risk was strongly associated with higher blood CRP levels.•Higher blood CRP levels mediated an effect between higher metabolic risk and thinner cortex.•A polygenic score of AD risk variants in immune-related genes was associated with thinner cortex but not with CRP levels.
Background Brain health may be affected by modifiable lifestyle factors; consuming fish and antioxidative omega-3 fatty acids may reduce brain structural abnormality risk. Purpose To determine ...whether dietary fish consumption is related to brain structural integrity among cognitively normal elders. Methods Data were analyzed from 260 cognitively normal individuals from the Cardiovascular Health Study with information on fish consumption from the National Cancer Institute Food Frequency Questionnaire and brain magnetic resonance imaging (MRI). The relationship between fish consumption data collected in 1989–1990 and brain structural MRI obtained in 1998–1999 was assessed using voxel-based morphometry in multiple regression analyses in 2012. Covariates were age, gender, race, education, white matter lesions, MRI-identified infarcts, waist–hip ratio, and physical activity as assessed by the number of city blocks walked in 1 week. Volumetric changes were further modeled with omega-3 fatty acid estimates to better understand the mechanistic link between fish consumption, brain health, and Alzheimer disease. Results Weekly consumption of baked or broiled fish was positively associated with gray matter volumes in the hippocampus, precuneus, posterior cingulate, and orbital frontal cortex even after adjusting for covariates. These results did not change when including omega-3 fatty acid estimates in the analysis. Conclusions Dietary consumption of baked or broiled fish is related to larger gray matter volumes independent of omega-3 fatty acid content. These findings suggest that a confluence of lifestyle factors influence brain health, adding to the growing body of evidence that prevention strategies for late-life brain health need to begin decades earlier.
OBJECTIVE:To assess the association of the number and anatomic location of cerebral microbleeds (CMBs), visible indicators of microvascular damage on MRI, with incident cognitive disease in the ...general population of older people.
METHODS:In the longitudinal population-based Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study, 2,602 participants 66 to 93 years of age and free of prevalent dementia underwent brain MRI and cognitive testing of verbal memory, processing speed, and executive function at baseline and a mean of 5.2 years later. Adjudicated incident dementia cases were diagnosed according to international guidelines.
RESULTS:In the multiple linear regression models adjusted for demographic, genetic, cardiovascular risk, and other cerebrovascular MRI markers, the presence of CMBs located in deep or mixed (deep and lobar) areas was associated with a greater decline in all 3 cognitive domains. Mixed CMBs were the strongest correlate for decline in memory and speed. Compared to those with no CMBs, participants with ≥3 CMBs had a steeper decline in a composite measure of global cognitive function, memory, and speed. Among those with ≥3 deep or mixed CMBs, associations were strongest for memory; the association with speed was strongest in those having ≥3 strictly lobar CMBs. People with ≥3 CMBs, regardless of their locations, had a higher incidence of all-cause dementia and vascular dementia.
CONCLUSIONS:Mixed or a higher load of CMBs, with some specificity for location, is associated with accelerated cognitive decline in older people. These findings suggest a role for hypertensive vasculopathy and the combined effect of hypertensive and cerebral amyloid angiopathy in the pathogenesis of cognitive deterioration.
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