Showing papers on "Cognitive decline published in 2015"
TL;DR: In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a proof-of-concept randomised controlled trial, the authors aimed to assess a multidomain approach to prevent cognitive decline in at-risk elderly people from the general population.
2,006 citations
TL;DR: There is sufficiently strong evidence, from a population‐based perspective, to conclude that regular physical activity and management of cardiovascular risk factors reduce the risk of cognitive decline and may reduce therisk of dementia.
Abstract: An estimated 47 million people worldwide are living with dementia in 2015, and this number is projected to triple by 2050. In the absence of a disease-modifying treatment or cure, reducing the risk of developing dementia takes on added importance. In 2014, the World Dementia Council (WDC) requested the Alzheimer's Association evaluate and report on the state of the evidence on modifiable risk factors for cognitive decline and dementia. This report is a summary of the Association's evaluation, which was presented at the October 2014 WDC meeting. The Association believes there is sufficient evidence to support the link between several modifiable risk factors and a reduced risk for cognitive decline, and sufficient evidence to suggest that some modifiable risk factors may be associated with reduced risk of dementia. Specifically, the Association believes there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia. The Association also believes there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.
1,146 citations
TL;DR: The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms.
Abstract: The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.
987 citations
TL;DR: A timely Review on WMHs, including their relationship with cognitive decline and dementia, is provided, although evidence for effective interventions is still lacking.
Abstract: White matter hyperintensities (WMHs) in the brain are the consequence of cerebral small vessel disease, and can easily be detected on MRI. Over the past three decades, research has shown that the presence and extent of white matter hyperintense signals on MRI are important for clinical outcome, in terms of cognitive and functional impairment. Large, longitudinal population-based and hospital-based studies have confirmed a dose-dependent relationship between WMHs and clinical outcome, and have demonstrated a causal link between large confluent WMHs and dementia and disability. Adequate differential diagnostic assessment and management is of the utmost importance in any patient, but most notably those with incipient cognitive impairment. Novel imaging techniques such as diffusion tensor imaging might reveal subtle damage before it is visible on standard MRI. Even in Alzheimer disease, which is thought to be primarily caused by amyloid, vascular pathology, such as small vessel disease, may be of greater importance than amyloid itself in terms of influencing the disease course, especially in older individuals. Modification of risk factors for small vessel disease could be an important therapeutic goal, although evidence for effective interventions is still lacking. Here, we provide a timely Review on WMHs, including their relationship with cognitive decline and dementia.
763 citations
TL;DR: The most important changes in cognition with normal aging are declines in performance on cognitive tasks that require one to quickly process or transform information to make a decision, including measures of speed of processing, working memory and executive cognitive function.
Abstract: This article reviews the cognitive changes that occur with normal aging, the structural and functional correlates of these cognitive changes, and the prevalence and cognitive effects of age-associated diseases. Understanding these age-related changes in cognition is important given our growing elderly population and the importance of cognition in maintaining functional independence and effective communication with others. The most important changes in cognition with normal aging are declines in performance on cognitive tasks that require one to quickly process or transform information to make a decision, including measures of speed of processing, working memory, and executive cognitive function. Cumulative knowledge and experiential skills are well maintained into advanced age. Structural and function changes in the brain correlate with these age-related cognitive changes, including alterations in neuronal structure without neuronal death, loss of synapses, and dysfunction of neuronal networks. Age-related diseases accelerate the rate of neuronal dysfunction, neuronal loss, and cognitive decline, with many persons developing cognitive impairments severe enough to impair their everyday functional abilities. There is emerging evidence that healthy lifestyles may decrease the rate of cognitive decline seen with aging and help delay the onset of cognitive symptoms in the setting of age-associated diseases.
681 citations
TL;DR: These three dietary patterns to incident Alzheimer's disease are related and higher concordance to the MIND diet, a hybrid Mediterranean‐Dietary Approaches to Stop Hypertension diet, was associated with slower cognitive decline.
Abstract: Introduction In a previous study, higher concordance to the MIND diet, a hybrid Mediterranean-Dietary Approaches to Stop Hypertension diet, was associated with slower cognitive decline. In this study we related these three dietary patterns to incident Alzheimer's disease (AD). Methods We investigated the diet-AD relations in a prospective study of 923 participants, ages 58 to 98 years, followed on average 4.5 years. Diet was assessed by a semiquantitative food frequency questionnaire. Results In adjusted proportional hazards models, the second (hazards ratio or HR = 0.65, 95% confidence interval or CI 0.44, 0.98) and highest tertiles (HR = 0.47, 95% CI 0.26, 0.76) of MIND diet scores had lower rates of AD versus tertile 1, whereas only the third tertiles of the DASH (HR = 0.61, 95% CI 0.38, 0.97) and Mediterranean (HR = 0.46, 95% CI 0.26, 0.79) diets were associated with lower AD rates. Discussion High adherence to all three diets may reduce AD risk. Moderate adherence to the MIND diet may also decrease AD risk.
614 citations
TL;DR: It is indicated that aging processes can be quantified in people still young enough for prevention of age-related disease, opening a new door for antiaging therapies.
Abstract: Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their “biological aging” (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.
612 citations
TL;DR: In an older population, a Mediterranean diet supplemented with olive oil or nuts is associated with improved cognitive function, and this work is likely to be a first step towards addressing the underlying cause of dementia in patients at high cardiovascular risk.
Abstract: Importance Oxidative stress and vascular impairment are believed to partly mediate age-related cognitive decline, a strong risk factor for development of dementia. Epidemiologic studies suggest that a Mediterranean diet, an antioxidant-rich cardioprotective dietary pattern, delays cognitive decline, but clinical trial evidence is lacking. Objective To investigate whether a Mediterranean diet supplemented with antioxidant-rich foods influences cognitive function compared with a control diet. Design, Setting, and Participants Parallel-group randomized clinical trial of 447 cognitively healthy volunteers from Barcelona, Spain (233 women [52.1%]; mean age, 66.9 years), at high cardiovascular risk were enrolled into the Prevencion con Dieta Mediterranea nutrition intervention trial from October 1, 2003, through December 31, 2009. All patients underwent neuropsychological assessment at inclusion and were offered retesting at the end of the study. Interventions Participants were randomly assigned to a Mediterranean diet supplemented with extravirgin olive oil (1 L/wk), a Mediterranean diet supplemented with mixed nuts (30 g/d), or a control diet (advice to reduce dietary fat). Main Outcomes and Measures Rates of cognitive change over time based on a neuropsychological test battery: Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT), Animals Semantic Fluency, Digit Span subtest from the Wechsler Adult Intelligence Scale, Verbal Paired Associates from the Wechsler Memory Scale, and the Color Trail Test. We used mean z scores of change in each test to construct 3 cognitive composites: memory, frontal (attention and executive function), and global. Results Follow-up cognitive tests were available in 334 participants after intervention (median, 4.1 years). In multivariate analyses adjusted for confounders, participants allocated to a Mediterranean diet plus olive oil scored better on the RAVLT ( P = .049) and Color Trail Test part 2 ( P = .04) compared with controls; no between-group differences were observed for the other cognitive tests. Similarly adjusted cognitive composites (mean z scores with 95% CIs) for changes above baseline of the memory composite were 0.04 (−0.09 to 0.18) for the Mediterranean diet plus olive oil, 0.09 (−0.05 to 0.23; P = .04 vs controls) for the Mediterranean diet plus nuts, and −0.17 (−0.32 to −0.01) for the control diet. Respective changes from baseline of the frontal cognition composite were 0.23 (0.03 to 0.43; P = .003 vs controls), 0.03 (−0.25 to 0.31), and −0.33 (−0.57 to −0.09). Changes from baseline of the global cognition composite were 0.05 (−0.11 to 0.21; P = .005 vs controls) for the Mediterranean diet plus olive oil, −0.05 (−0.27 to 0.18) for the Mediterranean diet plus nuts, and −0.38 (−0.57 to −0.18) for the control diet. All cognitive composites significantly ( P Conclusions and Relevance In an older population, a Mediterranean diet supplemented with olive oil or nuts is associated with improved cognitive function. Trial Registration isrctn.org Identifier:ISRCTN35739639
610 citations
TL;DR: The Mediterranean and dash diets have been shown to slow cognitive decline; however, neither diet is specific to the nutrition literature on dementia prevention.
Abstract: Introduction The Mediterranean and dash diets have been shown to slow cognitive decline; however, neither diet is specific to the nutrition literature on dementia prevention. Methods We devised the Mediterranean-Dietary Approach to Systolic Hypertension (DASH) diet intervention for neurodegenerative delay (MIND) diet score that specifically captures dietary components shown to be neuroprotective and related it to change in cognition over an average 4.7 years among 960 participants of the Memory and Aging Project. Results In adjusted mixed models, the MIND score was positively associated with slower decline in global cognitive score (β = 0.0092; P Discussion The study findings suggest that the MIND diet substantially slows cognitive decline with age. Replication of these findings in a dietary intervention trial would be required to verify its relevance to brain health.
551 citations
TL;DR: The results presented in this study demonstrate the potential of the suggested approach for early AD diagnosis and an important role of MRI in the MCI-to-AD conversion prediction.
549 citations
TL;DR: It is demonstrated that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggested that the inhibition of neutrophil trafficking may be beneficial in Alzheimer’s disease and the results demonstrate that neutrophic adhesion to CNS and intraparenchymal motility is regulated.
Abstract: Inflammation is a pathological hallmark of Alzheimer's disease, and innate immune cells have been shown to contribute to disease pathogenesis. In two transgenic models of Alzheimer's disease (5xFAD and 3xTg-AD mice), neutrophils extravasated and were present in areas with amyloid-β (Aβ) deposits, where they released neutrophil extracellular traps (NETs) and IL-17. Aβ42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion to integrin ligands. In vivo, LFA-1 integrin controlled neutrophil extravasation into the CNS and intraparenchymal motility. In transgenic Alzheimer's disease models, neutrophil depletion or inhibition of neutrophil trafficking via LFA-1 blockade reduced Alzheimer's disease-like neuropathology and improved memory in mice already showing cognitive dysfunction. Temporary depletion of neutrophils for 1 month at early stages of disease led to sustained improvements in memory. Transgenic Alzheimer's disease model mice lacking LFA-1 were protected from cognitive decline and had reduced gliosis. In humans with Alzheimer's disease, neutrophils adhered to and spread inside brain venules and were present in the parenchyma, along with NETs. Our results demonstrate that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggest that the inhibition of neutrophil trafficking may be beneficial in Alzheimer's disease.
TL;DR: These data can be incorporated into ongoing efforts to identify individuals at the earliest stages of the disease for inclusion in future trials and to help understand progression in the earliest phase of Parkinson's disease.
Abstract: Summary Background Parkinson's disease has an insidious onset and is diagnosed when typical motor features occur. Several motor and non-motor features can occur before diagnosis, early in the disease process. We aimed to assess the association between first presentation of several prediagnostic features in primary care and a subsequent diagnosis of Parkinson's disease, and to chart the timeline of these first presentations before diagnosis. Methods We identified individuals with a first diagnosis of Parkinson's disease and those without Parkinson's disease from Jan 1, 1996, to Dec 31, 2012, from The Health Improvement Network UK primary care database. Codes were extracted for a range of possible prediagnostic or early symptoms, comprising motor features (tremor, rigidity, balance impairments, neck pain or stiffness, and shoulder pain or stiffness), autonomic features (constipation, hypotension, erectile dysfunction, urinary dysfunction, and dizziness), neuropsychiatric disturbances (memory problems, late-onset anxiety or depression, cognitive decline, and apathy), and additional features (fatigue, insomnia, anosmia, hypersalivation and rapid-eye-movement sleep behaviour disorder) in the years before diagnosis. We report the incidence of symptoms recorded in more than 1% of cases per 1000 person-years and incidence risk ratios (RRs) for individuals with and without Parkinson's disease at 2, 5, and 10 years before diagnosis. Findings 8166 individuals with and 46 755 individuals without Parkinson's disease were included in the study. Apathy, REM sleep behaviour disorder, anosmia, hypersalivation, and cognitive decline were all reported in less than 1% of people per 1000 person-years and were excluded from further analyses. At 2 years before Parkinson's disease diagnosis, the incidence of all studied prediagnostic features except neck pain or stiffness was higher in patients who went on to develop Parkinson's disease (n=7232) than in controls (n=40 541). At 5 years before diagnosis, compared with controls (n=25 544), patients who went on to develop Parkinson's disease (n=4769) had a higher incidence of tremor (RR 13·70, 95% CI 7·82–24·31), balance impairments (2·19, 1·09–4·16), constipation (2·24, 2·04–2·46), hypotension (3·23, 1·85–5·52), erectile dysfunction (1·30, 1·11–1·51), urinary dysfunction (1·96, 1·34–2·80), dizziness (1·99, 1·67–2·37), fatigue (1·56, 1·27–1·91), depression (1·76, 1·41–2·17), and anxiety (1·41, 1·09–1·79). At 10 years before diagnosis of Parkinson's disease, the incidence of tremor (RR 7·59, 95% CI 1·11–44·83) and constipation (2·01, 1·62–2·49) was higher in those who went on to develop Parkinson's disease (n=1680) than in controls (n=8305). Interpretation A range of prediagnostic features can be detected several years before diagnosis of Parkinson's disease in primary care. These data can be incorporated into ongoing efforts to identify individuals at the earliest stages of the disease for inclusion in future trials and to help understand progression in the earliest phase of Parkinson's disease. Funding Parkinson's UK.
TL;DR: It is found, in two separate human studies, that 1/f electrophysiological noise increases with aging, and it is observed that this age-related 1/ f noise statistically mediates age- related working memory decline.
Abstract: Aging is associated with performance decrements across multiple cognitive domains. The neural noise hypothesis, a dominant view of the basis of this decline, posits that aging is accompanied by an increase in spontaneous, noisy baseline neural activity. Here we analyze data from two different groups of human subjects: intracranial electrocorticography from 15 participants over a 38 year age range (15-53 years) and scalp EEG data from healthy younger (20-30 years) and older (60-70 years) adults to test the neural noise hypothesis from a 1/f noise perspective. Many natural phenomena, including electrophysiology, are characterized by 1/f noise. The defining characteristic of 1/f is that the power of the signal frequency content decreases rapidly as a function of the frequency (f) itself. The slope of this decay, the noise exponent (χ), is often <-1 for electrophysiological data and has been shown to approach white noise (defined as χ = 0) with increasing task difficulty. We observed, in both electrophysiological datasets, that aging is associated with a flatter (more noisy) 1/f power spectral density, even at rest, and that visual cortical 1/f noise statistically mediates age-related impairments in visual working memory. These results provide electrophysiological support for the neural noise hypothesis of aging. Significance statement: Understanding the neurobiological origins of age-related cognitive decline is of critical scientific, medical, and public health importance, especially considering the rapid aging of the world's population. We find, in two separate human studies, that 1/f electrophysiological noise increases with aging. In addition, we observe that this age-related 1/f noise statistically mediates age-related working memory decline. These results significantly add to this understanding and contextualize a long-standing problem in cognition by encapsulating age-related cognitive decline within a neurocomputational model of 1/f noise-induced deficits in neural communication.
TL;DR: Data from both animal and human studies support mechanistic links between IH and its adverse impact at the tissue level and data from observational studies in large population groups support the role for hypoxia in the pathogenesis of OSA comorbidity.
TL;DR: Standardised neuropsychological tests that are easy to administer and sensitive to disease-related abnormalities are needed to gain a better understanding of the factors affecting cognitive performance in patients with MS than exists at present.
Abstract: In patients with multiple sclerosis (MS), grey matter damage is widespread and might underlie many of the clinical symptoms, especially cognitive impairment. This relation between grey matter damage and cognitive impairment has been lent support by findings from clinical and MRI studies. However, many aspects of cognitive impairment in patients with MS still need to be characterised. Standardised neuropsychological tests that are easy to administer and sensitive to disease-related abnormalities are needed to gain a better understanding of the factors affecting cognitive performance in patients with MS than exists at present. Imaging measures of the grey matter are necessary, but not sufficient to fully characterise cognitive decline in MS. Imaging measures of both lesioned and normal-appearing white matter lend support to the hypothesis of the existence of an underlying disconnection syndrome that causes clinical symptoms to trigger. Findings on cortical reorganisation support the contribution of brain plasticity and cognitive reserve in limiting cognitive deficits. The development of clinical and imaging biomarkers that can monitor disease development and treatment response is crucial to allow early identification of patients with MS who are at risk of cognitive impairment.
TL;DR: Emerging evidence from epidemiological, clinicopathological, neuroimaging, biomarker, and experimental studies lends support to a strong relation between delirium and dementia, and to both shared and distinct pathological mechanisms.
Abstract: Summary Delirium and dementia are two of the most common causes of cognitive impairment in older populations, yet their interrelation remains poorly understood. Previous studies have shown that dementia is the leading risk factor for delirium and that delirium is an independent risk factor for subsequent development of dementia. However, a major area of controversy is whether delirium is simply a marker of vulnerability to dementia, whether the effect of delirium is solely related to its precipitating factors, or whether delirium itself can cause permanent neuronal damage and lead to dementia. Ultimately, all of these hypotheses are likely to be true. Emerging evidence from epidemiological, clinicopathological, neuroimaging, biomarker, and experimental studies lends support to a strong relation between delirium and dementia, and to both shared and distinct pathological mechanisms. New preventive and therapeutic approaches that target delirium might offer a sought-after opportunity for early intervention, preservation of cognitive reserve, and prevention of irreversible cognitive decline in ageing.
TL;DR: A state-of-the-art description of the usefulness and the interpretations of functional brain connectivity in the context of HA is provided and it is proposed that the use of complex modeling approaches studying effective connectivity may help to understand context-dependent functional reorganizations in the aging process.
Abstract: Healthy aging (HA) is associated with certain declines in cognitive functions, even in individuals that are free of any process of degenerative illness. Functional magnetic resonance imaging (fMRI) has been widely used in order to link this age-related cognitive decline with patterns of altered brain function. A consistent finding in the fMRI literature is that healthy old adults present higher activity levels in some brain regions during the performance of cognitive tasks. This finding is usually interpreted as a compensatory mechanism. More recent approaches have focused on the study of functional connectivity, mainly derived from resting state fMRI, and have concluded that the higher levels of activity coexist with disrupted connectivity. In this review, we aim to provide a state-of-the-art description of the usefulness and the interpretations of functional brain connectivity in the context of HA. We first give a background that includes some basic aspects and methodological issues regarding functional connectivity. We summarize the main findings and the cognitive models that have been derived from task-activity studies, and we then review the findings provided by resting-state functional connectivity in HA. Finally, we suggest some future directions in this field of research. A common finding of the studies included is that older subjects present reduced functional connectivity compared to young adults. This reduced connectivity affects the main brain networks and explains age-related cognitive alterations. Remarkably, the default mode network appears as a highly compromised system in HA. Overall, the scenario given by both activity and connectivity studies also suggests that the trajectory of changes during task may differ from those observed during resting-state. We propose that the use of complex modeling approaches studying effective connectivity may help to understand context-dependent functional reorganizations in the aging process.
TL;DR: Intervention studies which suggest that the restoration of insulin activity in the hippocampus may be an effective strategy to alleviate the cognitive decline associated with T2DM and AD are discussed.
Abstract: Clinical studies suggest a link between type 2 diabetes mellitus (T2DM) and insulin resistance (IR) and cognitive dysfunction, but there are significant gaps in our knowledge of the mechanisms underlying this relationship. Animal models of IR help to bridge these gaps and point to hippocampal IR as a potential mediator of cognitive dysfunction in T2DM, as well as in Alzheimer disease (AD). This Review highlights these observations and discusses intervention studies which suggest that the restoration of insulin activity in the hippocampus may be an effective strategy to alleviate the cognitive decline associated with T2DM and AD.
TL;DR: A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD and found the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2 DM and AD.
Abstract: Type 2 diabetes (T2DM), Alzheimer's disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer's disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.
18 Dec 2015
TL;DR: Results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age as well as the neuropathological markers may mediate the association between epigenetic age and cognitive decline.
Abstract: There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer's disease (AD) related cognitive decline, and AD related neuropathological markers. Epigenetic age acceleration of DLPFC is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). Further, it is associated with a decline in global cognitive functioning (β=-0.500, p=0.009), episodic memory (β=-0.411, p=0.009) and working memory (β=-0.405, p=0.011) among individuals with AD. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration is heritable (h2=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=-0.35, p=0.065). Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age.
TL;DR: In this paper, the authors identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus.
Abstract: Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.
TL;DR: Hearing aid use was associated with better cognition, independently of social isolation and depression, consistent with the hypothesis that hearing aids may improve cognitive performance, although if hearing aids do have a positive effect on cognition it is not likely to be via reduction of the adverse effects of hearing loss on social isolation or depression.
Abstract: Hearing loss is associated with poor cognitive performance and incident dementia and may contribute to cognitive decline. Treating hearing loss with hearing aids may ameliorate cognitive decline. The purpose of this study was to test whether use of hearing aids was associated with better cognitive performance, and if this relationship was mediated via social isolation and/or depression. Structural equation modelling of associations between hearing loss, cognitive performance, social isolation, depression and hearing aid use was carried out with a subsample of the UK Biobank data set (n = 164,770) of UK adults aged 40 to 69 years who completed a hearing test. Age, sex, general health and socioeconomic status were controlled for as potential confounders. Hearing aid use was associated with better cognition, independently of social isolation and depression. This finding was consistent with the hypothesis that hearing aids may improve cognitive performance, although if hearing aids do have a positive effect on cognition it is not likely to be via reduction of the adverse effects of hearing loss on social isolation or depression. We suggest that any positive effects of hearing aid use on cognition may be via improvement in audibility or associated increases in self-efficacy. Alternatively, positive associations between hearing aid use and cognition may be accounted for by more cognitively able people seeking and using hearing aids. Further research is required to determine the direction of association, if there is any direct causal relationship between hearing aid use and better cognition, and whether hearing aid use results in reduction in rates of cognitive decline measured longitudinally.
TL;DR: Investigation of cognitive function among survivors of incident stroke found incident stroke was associated with an acute decline in cognitive function and also accelerated and persistent cognitive decline over 6 years.
Abstract: Importance Cognitive decline is a major cause of disability in stroke survivors. The magnitude of survivors’ cognitive changes after stroke is uncertain. Objective To measure changes in cognitive function among survivors of incident stroke, controlling for their prestroke cognitive trajectories. Design, Setting, and Participants Prospective study of 23 572 participants 45 years or older without baseline cognitive impairment from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, residing in the continental United States, enrolled 2003-2007 and followed up through March 31, 2013. Over a median follow-up of 6.1 years (interquartile range, 5.0-7.1 years), 515 participants survived expert-adjudicated incident stroke and 23 057 remained stroke free. Exposure Time-dependent incident stroke. Main Outcomes and Measures The primary outcome was change in global cognition (Six-Item Screener [SIS], range, 0-6). Secondary outcomes were change in new learning (Consortium to Establish a Registry for Alzheimer Disease Word-List Learning; range, 0-30), verbal memory (Word-List Delayed Recall; range, 0-10), and executive function (Animal Fluency Test; range, ≥0), and cognitive impairment (SIS score Results Stroke was associated with acute decline in global cognition (0.10 points [95% CI, 0.04 to 0.17]), new learning (1.80 points [95% CI, 0.73 to 2.86]), and verbal memory (0.60 points [95% CI, 0.13 to 1.07]). Participants with stroke, compared with those without stroke, demonstrated faster declines in global cognition (0.06 points per year faster [95% CI, 0.03 to 0.08]) and executive function (0.63 points per year faster [95% CI, 0.12 to 1.15]), but not in new learning and verbal memory, compared with prestroke slopes. Among survivors, the difference in risk of cognitive impairment acutely after stroke, compared with immediately before stroke, was not statistically significant (odds ratio, 1.32 [95% CI, 0.95 to 1.83]; P = .10); however, there was a significantly faster poststroke rate of incident cognitive impairment compared with the prestroke rate (odds ratio, 1.23 per year [95% CI, 1.10 to 1.38]; P Conclusions and Relevance Incident stroke was associated with an acute decline in cognitive function and also accelerated and persistent cognitive decline over 6 years.
TL;DR: It is shown that transient depletion of Foxp3+ regulatory T cells (Tregs), or pharmacological inhibition of their activity, is followed by amyloid-β plaque clearance, mitigation of the neuroinflammatory response and reversal of cognitive decline in AD.
Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder in which chronic neuroinflammation contributes to disease escalation. Nevertheless, while immunosuppressive drugs have repeatedly failed in treating this disease, recruitment of myeloid cells to the CNS was shown to play a reparative role in animal models. Here we show, using the 5XFAD AD mouse model, that transient depletion of Foxp3(+) regulatory T cells (Tregs), or pharmacological inhibition of their activity, is followed by amyloid-β plaque clearance, mitigation of the neuroinflammatory response and reversal of cognitive decline. We further show that transient Treg depletion affects the brain's choroid plexus, a selective gateway for immune cell trafficking to the CNS, and is associated with subsequent recruitment of immunoregulatory cells, including monocyte-derived macrophages and Tregs, to cerebral sites of plaque pathology. Our findings suggest targeting Treg-mediated systemic immunosuppression for treating AD.
TL;DR: It is shown that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency and normalizes epilepsy-associated cognitive deficits, and suggests that targeting aberrant hippocampal neuroGenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.
Abstract: Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.
University of Wisconsin-Madison1, Emory University2, Brigham and Women's Hospital3, Mayo Clinic4, Foundation for Biomedical Research5, University of California, San Francisco6, Columbia University7, University of Washington8, Albert Einstein College of Medicine9, University of Colorado Denver10, Yale University11, Los Angeles Biomedical Research Institute12, University of Southern California13, New York University14, Veterans Health Administration15
TL;DR: The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized, and women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo period, compared to women on placebo.
Abstract: Background Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women. Methods and Findings KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was −5.36 × 10−2 (95% CI, −8.27 × 10−2 to −2.44 × 10−2; ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10−2 (95% CI, −5.09 × 10−2 to −9.34 × 10−3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y. Conclusions The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles. Trial Registration ClinicalTrials.gov NCT00154180 and NCT00623311
TL;DR: Examination of sleep quality for 78 community dwelling adults 55+ indicates for older adults the PSQI should not be used as a substitute for actigraphy, or vice versa and best practice is to include both subjective and objective measures when examining sleep quality in older adults.
Abstract: Sleep quality decreases with aging and thus sleep complaints are prevalent in older adults, particularly for those with cognitive impairment and dementia. For older adults, emerging evidence suggests poor sleep quality increases risk of developing cognitive impairment and dementia. Given the aging population-and the impending economic burden associated with increasing numbers of dementia patients-there is pressing need to improve sleep quality among older adults. As such, research efforts have increased focus on investigating the association between age-related sleep changes and cognitive decline in older adults. Sleep quality is a complex construct to evaluate empirically, and yet the Pittsburg Sleep Quality Index (PSQI) is commonly used in studies as their only measure of sleep quality. Furthermore, the PSQI may not be the best sleep quality measure for older adults, due to its reliance on the cognitive capacity to reflect on the past month. Further study is needed to determine the PSQI's validity among older adults. Thus, the current study examined sleep quality for 78 community dwelling adults 55+ to determine the PSQI's predictive validity for objective sleep quality (as measured by actigraphy). We compared two subjective measures of sleep quality-the PSQI and Consensus Sleep Diary (CSD)-with actigraphy (MotionWatch 8©; camntech). Our results suggest perceived sleep quality is quite different from objective reality, at least for adults 55+. Importantly, we show this difference is unrelated to age, gender, education, or cognitive status (assessed using standard screens). Previous studies have shown the PSQI to be a valuable tool for assessing subjective sleep quality; however, our findings indicate for older adults the PSQI should not be used as a substitute for actigraphy, or vice versa. Hence, we conclude best practice is to include both subjective and objective measures when examining sleep quality in older adults (i.e., the PSQI, CSD, and actigraphy).
TL;DR: Considering that aging and AD are related to cognitive impairment, here it is discussed the involving of neurotrophic factors in the aging process and AD.
Abstract: Aging is a normal physiological process accompanied by cognitive decline. This aging process has been the primary risk factor for development of aging-related diseases such as Alzheimer’s disease (AD). Cognitive deficit is related to alterations of neurotrophic factors level such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF). These strong relationship between aging and AD is important to investigate the time which they overlap, as well as, the pathophysiological mechanism in each event. Considering that aging and AD are related to cognitive impairment, here we discuss the involving these neurotrophic factors in the aging process and AD.
TL;DR: The findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment.
Abstract: Objective: To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimer9s Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline. Methods: From the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB− and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan–Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders. Results: SDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.63 vs 83.67; MC2: 72.15 vs 83.45; MC3: 77.40 vs 89.89; p p p Conclusions: Consistent with our hypothesis, the presence of SDB was associated with an earlier age at cognitive decline. Our findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment.
TL;DR: The findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-Amyloid deposits.
Abstract: Importance Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging. Objective To compare age, sex, and APOE e4 effects on memory, brain structure (adjusted hippocampal volume [HVa]), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old. Design, Setting, and Participants Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old. Main Outcomes and Measures Memory, HVa, and amyloid PET. Results Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall ( P P APOE e4 status at any age. From age 70 years onward, APOE e4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE e4 carriers and 64 years for noncarriers. Conclusions and Relevance Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE e4 is not. In contrast, APOE e4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.