Hypertension is a highly prevalent condition which has been established as a risk factor for cardiovascular and cerebrovascular disease. Although the understanding of the relationship between ...cardiocirculatory dysfunction and brain health has improved significantly over the last several decades, it is still unclear whether hypertension constitutes a potentially treatable risk factor for cognitive decline and dementia. While it is clear that hypertension can affect brain structure and function, recent findings suggest that the associations between blood pressure and brain health are complex and, in many cases, dependent on factors such as age, hypertension chronicity, and antihypertensive medication use. Whereas large epidemiological studies have demonstrated a consistent association between high midlife BP and late-life cognitive decline and incident dementia, associations between late-life blood pressure and cognition have been less consistent. Recent evidence suggests that hypertension may promote alterations in brain structure and function through a process of cerebral vessel remodeling, which can lead to disruptions in cerebral autoregulation, reductions in cerebral perfusion, and limit the brain’s ability to clear potentially harmful proteins such as β-amyloid. The purpose of the current review is to synthesize recent findings from epidemiological, neuroimaging, physiological, genetic, and translational research to provide an overview of what is currently known about the association between blood pressure and cognitive function across the lifespan. In doing so, the current review also discusses the results of recent randomized controlled trials of antihypertensive therapy to reduce cognitive decline, highlights several methodological limitations, and provides recommendations for future clinical trial design.
Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has ...been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging - and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.
Human and animal studies suggest that inflammation occurring outside the central nervous system (systemic inflammation) may play a key role in promoting neurodegeneration, Alzheimer’s disease ...pathology, and cognitive decline in older adults. Systemic inflammation, which is marked by increased blood levels of circulating proinflammatory cytokines and chemokines, may occur as a result of events such as infection, chronic disease, and physical and psychological stress, but may also occur outside the context of these conditions as a result of subclinical processes such as cellular senescence. Proinflammatory cytokines within the body can promote a proinflammatory environment in the central nervous system by crossing the blood-brain barrier, signaling through endothelial cells or circumventricular organs, and by stimulating the vagus nerve, which signals the detection of inflammatory proteins via direct afferent connections to the brain stem. Through each of these routes, systemic inflammation is believed to induce reactive, proinflammatory microglia and astrocytic phenotypes which can promote tau hyperphosphorylation, β-amyloid oligomerization, complement activation, and the breakdown of neurotransmitters into potentially harmful bioactive metabolites. Together, these molecular changes are believed initiate or exacerbate neurodegenerative processes that can eventually lead to cognitive decline and dementia in vulnerable older adults.
SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands of proteins with a broad range of endogenous concentrations. In its most current ...version, the 7k SomaScan assay v4.1 is capable of measuring 7288 human proteins. In this work, we present an extensive technical assessment of this platform based on a study of 2050 samples across 22 plates. Included in the study design were inter-plate technical duplicates from 102 human subjects, which allowed us to characterize different normalization procedures, evaluate assay variability by multiple analytical approaches, present signal-over-background metrics, and discuss potential specificity issues. By providing detailed performance assessments on this wide range of technical aspects, we aim for this work to serve as a valuable resource for the growing community of SomaScan users.
Objective: While some reports suggest that HIV+ individuals continue to display executive function (EF) impairment in the era of cART, findings have been contradictory and appear to differ based on ...the aspect of EF being measured. To improve the understanding of how discrete executive abilities may be differentially affected or spared in the context of HIV infection, we conducted a systematic review and meta-analysis to (a) determine whether and to what extent HIV+ adults experience deficits in EFs, and (b) understand how demographic and clinical characteristics may modify the associations between HIV infection and executive abilities.
Method: Studies comparing HIV+ and HIV-uninfected groups on measures of working memory, set-shifting, inhibition, decision-making, and apathy between 2000 and 2017 were identified from three databases. Effect sizes (Cohen's d) were calculated using inverse variance weighted random effects models. Meta-regression was used to examine the moderating effect of demographic and clinical variables.
Results: Thirty-seven studies (n = 3935 HIV+; n = 2483 HIV-uninfected) were included in the meta-analysis. Pooled effect sizes for deficits associated with HIV infection were small for domains of set-shifting (d = −0.34, 95% CI −0.47, −0.20) and inhibition (d = −0.31, 95% CI −0.40, −0.21), somewhat larger for measures of decision-making (d = −0.41, 95% CI −0.53, −0.28) and working memory (d = −0.42, 95% CI −0.59, −0.29), and largest for apathy (d = −0.87, 95% CI −1.09, −0.66). Meta-regression demonstrated that age, sex, education, current CD4 count, and substance dependence differentially moderated the effects of HIV infection on specific EFs. However, lower nadir CD4 count was the only variable associated with greater deficits in nearly all EF domains.
Conclusions: Our results suggest that discrete domains of EF may be differentially affected by HIV infection and moderating demographic and clinical variables. These findings have implications for the development of targeted cognitive remediation strategies.
In their recent Nature paper, Oh et al. use 4979 plasma proteins collected across multiple cohorts, publicly available gene expression data, and machine learning models to identify 11 organ-specific ...aging scores that are linked to organ-specific disease and mortality risk, including heart failure, cognitive decline, and Alzheimer’s disease.
In their recent Nature paper, Oh et al. use 4979 plasma proteins collected across multiple cohorts, publicly available gene expression data, and machine learning models to identify 11 organ-specific aging scores that are linked to organ-specific disease and mortality risk, including heart failure, cognitive decline, and Alzheimer’s disease.
To examine the association between systemic inflammation measured during midlife and 20-year cognitive decline.
Within the Atherosclerosis Risk in Communities cohort study, inflammatory biomarkers ...were measured during middle adulthood. We created an inflammation composite score using 4 blood biomarkers measured at visit 1 (fibrinogen, white blood cell count, von Willebrand factor, and factor VIII); we measured C-reactive protein (CRP) at visit 2. Cognition was assessed over 3 visits spanning 20 years using measures of memory, executive function, and language.
A total of 12,336 participants (baseline age 56.8 5.7, 21% black, 56% women) were included. After adjusting for demographic variables, vascular risk factors, and comorbidities, each standard deviation (SD) increase in midlife inflammation composite score was associated with an additional 20-year decline of -0.035 SD (95% confidence interval: -0.062 to -0.007) on the cognitive composite score. We found a similar association between each SD increase in midlife CRP level and additional 20-year cognitive decline (-0.038 SD, 95% confidence interval: -0.057 to -0.019). Participants with a midlife inflammation composite score in the top quartile had a 7.8% steeper cognitive decline, compared to participants in the lowest quartile; CRP in the top quartile was associated with an 11.6% steeper cognitive decline. In cognitive domain-specific analyses, elevated midlife inflammatory markers were most consistently associated with declines in memory. Results were similar after adjusting for attrition using inverse probability weighting.
Our findings highlight what may be an early pathogenic role for systemic inflammation as a driver of cognitive decline in the decades leading up to older adulthood.
Based on recent studies from our group and others, we hypothesize that mitochondrial dysfunction during aging may be the root cause of mobility decline through deficits in the musculoskeletal and ...central nervous systems. Mitochondrial dysfunction could be a therapeutic target to prevent mobility decline in aging.
Abstract
Background
Evidence suggests that systemic inflammation may have a mechanistic role in age-related frailty, yet prospective data is limited. We examined whether systemic inflammation during ...midlife was associated with late-life frailty within the community-based Atherosclerosis Risk in Communities Study.
Methods
Plasma levels of four inflammatory markers (fibrinogen, von Willebrand factor, and Factor VIII, and white blood cell count) were measured during Visit 1 (1987–1989; mean age: 52 5), standardized into z-scores, and combined to create an inflammation composite score. High-sensitivity C-reactive protein (CRP) was measured 3 (Visit 2, 1990–1992) and 9 (Visit 4, 1996–1999) years later. Frailty was evaluated in 5,760 participants during late life (Visit 5, 2011–2013; mean age: 75 5). Analyses were adjusted for demographic and physiological variables, and midlife medical comorbidity using logistic regression.
Results
A 1 SD increase in midlife inflammation composite score was associated with higher odds of frailty 24 years later (odds ratio OR = 1.39, 95% confidence interval CI: 1.18–1.65). Similarly, each standard deviation increase in Visit 2 CRP (OR = 1.24, 95% CI: 1.09–1.40) and Visit 4 CRP (OR = 1.35, 95% CI: 1.19–1.53) was associated with a higher odds of frailty 21 and 15 years later. Participants who maintained elevated CRP (≥3 mg/L) at Visits 2 and 4 or transitioned to a state of elevated CRP during this period were more likely to subsequently meet frailty criteria compared to those who maintained low CRP. These associations were stronger among white, compared to African American, participants (p-interactions < .038).
Conclusions
Systemic inflammation during midlife may independently promote pathophysiological changes underlying frailty in a subset of the population.
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