Exercise to Mitigate Cerebrovascular Aging: A Geroscience Perspective.

Aging is characterized by a progressive loss of cellular functions that increase the risk of developing chronic diseases, vascular dysfunction, and neurodegenerative conditions. The field of geroscience has identified cellular and molecular hallmarks of aging that may serve as targets for future interventions to reduce the risk of age-related disease and disability. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Several studies show that exercise may favorably affect these processes and thereby have antiaging properties. The primary mechanisms through which exercise confers protective benefits in the brain are still incompletely understood. To better understand these effects and leverage them to help promote brain health, we present current findings supporting the notion that adaptive responses to exercise play a pivotal role in mitigating the hallmarks of aging and their effects on the aging cerebrovasculature, and ultimately contribute to the maintenance of brain function across the healthspan.

Cerebral blood flow and neurocognition in patients undergoing transcatheter aortic valve replacement for severe aortic stenosis.

Aims: Aortic valve stenosis (AS) results in higher systolic pressure to overcome resistance from the stenotic valve, leading to heart failure and decline in cardiac output. There has been no assessment of cerebral blood flow (CBF) association with neurocognition in AS or the effects of valve replacement. The goal was to determine if AS is associated with altered cerebral haemodynamics and impaired neurocognition, and whether transcatheter aortic valve replacement (TAVR) improves haemodynamics and cognition. Methods and results: In 42 patients with planned TAVR, transcranial Doppler (TCD) assessed bilateral middle cerebral artery (MCA) mean flow velocities (MFVs); abnormality was <34.45 cm/s. The neurocognitive battery assessed memory, language, attention, visual-spatial skills, and executive function, yielding a composite Z-score. Impairment was <1.5 SDs below the normative mean. The mean age was 78 years, 59% Male, and the mean valve gradient was 46.87 mm/Hg. Mean follow-up was 36 days post-TAVR (range 27-55). Pre-TAVR, the mean MFV was 42.36 cm/s (SD = 10.17), and the mean cognitive Z-score was -0.22 SDs (range -1.99 to 1.08) below the normative mean. Among the 34 patients who returned after TAVR, the MFV was 41.59 cm/s (SD = 10.42), not different from baseline (P = 0.66, 2.28-3.67). Post-TAVR, average Z-scores were 0.17 SDs above the normative mean, not meeting the pre-specified threshold for a clinically significant 0.5 SD change. Conclusion: Among patients with severe AS, there was little impairment of MFV on TCD and no correlation with cognition. Transcatheter aortic valve replacement did not affect MFV or cognition. Assumptions about diminished CBF and improvement after TAVR were not supported.

Effects of a brief HIIT intervention on cognitive performance in older women.

Cardiorespiratory fitness (CRF) mitigates age-related decline in cognition and brain volume. Little is known, however, about the effects of high-intensity interval training (HIIT) on cognitive aging and the relationship between HIIT, cognition, hippocampal subfield volumes, and cerebral oxygen extraction fraction (OEF). Older sedentary women participated in an 8-week HIIT intervention. We conducted cognitive assessments, fitness assessments (VO2max), MRI scans: asymmetric spin echo oxygen extraction fraction (ASE-OEF), high-resolution multiple image co-registration and averaging (HR-MICRA) imaging, and transcranial Doppler ultrasonography before and after the intervention. VO2max increased from baseline (M = 19.36, SD = 2.84) to follow-up (M = 23.25, SD = 3.61), Z = - 2.93, p < .001, r = 0.63. Composite cognitive (Z = - 2.05, p = 0.041), language (Z = - 2.19, p = 0.028), and visuospatial memory (Z = - 2.22, p = 0.026), z-scores increased significantly. Hippocampal subfield volumes CA1 and CA3 dentate gyrus and subiculum decreased non-significantly (all p > 0.05); whereas a significant decrease in CA2 (Z = - 2.045, p = 0.041, r = 0.436) from baseline (M = 29.51; SD = 24.50) to follow-up (M = 24.50; SD = 13.38) was observed. Right hemisphere gray matter was correlated with language z-scores (p = 0.025; r = 0.679). The subiculum was correlated with attention (p = 0.047; r = 0.618) and verbal memory (p = 0.020; r = 0.700). The OEF and CBF were unchanged at follow-up (all p > .05). Although we observed cognitive improvements following 8 weeks of our HIIT intervention, they were not explained by hippocampal, OEF, or CBF changes.

Longitudinal associations of anticholinergic medications on cognition and possible mitigating role of physical activity.

BACKGROUND: Many older adults take at least one prescription medication with anticholinergic (ACH) activity, which can impact the central nervous system and can lead to cognitive decline and impairment especially in an aging population susceptible to cognitive changes. We examined this relationship between ACH burden and cognitive function in middle-aged and older adults. We further determined if increased activity levels mitigated the relationships between ACH burden and cognition. METHODS: Data from The Reasons for Geographic and Racial Differences in Stroke project were used. We included 20,575 adults aged ≥45 years with longitudinal cognitive testing. The anticholinergic cognitive burden (ACB) scale was used to assess for ACH use and overall burden. Cognitive data included an overall composite score, a memory, and verbal fluency composites. Mixed effects models were conducted to determine if cognitive function worsened over time for participants with higher ACB (>3) scores. The full model adjusted for age, sex, race, education, diabetes, hypertension, cardiovascular disease, congestive heart failure, and dyslipidemia, self-reported physical activity (PA) and depressive symptoms. RESULTS: A significant relationship between ACH burden and composite cognitive scores was found (p = <0.001), with those with higher ACB showing more rapid cognitive decline over time. There was an effect of age for participants with higher ACB (>3) scores and ACB as a continuous variable. Baseline PA level was associated with less cognitive decline over time and this effect was greater in older cohorts. CONCLUSIONS: We observed an effect of ACHs on cognition in adults ≥45 years old that worsened with age. ACH users showed more cognitive effects, whereas PA emerged as a possible mitigating factor.

Silent Brain Infarction, Delirium, and Cognition in Three Invasive Cardiovascular Procedures: a Systematic Review.

Silent brain infarctions (SBIs) are brain lesions noted on neuroimaging that are not associated with clinical symptoms. SBIs are associated with a number of vascular risk factors and are common following invasive cardiovascular procedures such as atrial fibrillation (AF) ablation, coronary artery bypass graft (CABG), and transcatheter aortic valve replacement (TAVR). Although not eliciting signs of clinical stroke, SBIs are associated with increased frailty, and motor and mood features. Less is known, however, about the relationship between SBI, cognition, and delirium following invasive cardiac procedures and most investigations into these relationships have been reported in large-scale epidemiological studies. In the current paper, we conducted a systematic review to evaluate evidence of a relationship between SBI, delirium, and cognitive decline following CABG, AF ablation, and TAVR. Twenty studies met inclusion criteria. In general, our review identified conflicting results for each cardiac procedure, with some studies suggesting a relationship between SBI, cognitive impairment, and delirium, whereas others showed no relationship between SBI, cognitive impairment, and delirium. Potential reasons for this discrepancy as well as suggestions for future research are discussed.

The role of exercise in the reversal of IGF-1 deficiencies in microvascular rarefaction and hypertension.

Hypertension has been linked with peripheral and central reductions in vascular density, and with devastating effects on brain function. However, the underlying mechanisms in the relationship between blood pressure and cognitive impairment have yet to be fully elucidated. Here, we review compelling evidence from two lines of inquiry: one that links microvascular rarefaction with insulin-like growth factor 1 (IGF-1) deficiencies, and another which posits that vascular dysfunction precedes hypertension. Based on the findings from experimental and clinical studies, we propose that these lines of evidence converge, and suggest that age-related declines in IGF-1 concentrations precede microvascular rarefaction, initiate an increase in vascular resistance, and therefore are causally linked to onset of hypertension. Physical exercise provides a relevant model for supporting our premise, given the well-established effects of exercise in attenuating vascular dysfunction, hypertension, IGF-1 deficiency, and cognitive decline. We highlight here the role of exercise-induced increases in blood flow in improving vascular integrity and enhancing angiogenesis via the actions of IGF-1, resulting in reversal of rarefaction and hypertension, and enhancement of cerebral blood flow and cognition.

Is Hemispheric Hypoperfusion a Treatable Cause of Cognitive Impairment?

PURPOSE OF REVIEW: To review the current literature that supports the notion that cerebral hemodynamic compromise from internal carotid artery stenosis may be a cause of vascular cognitive impairment that is amenable to treatment by revascularization. RECENT FINDINGS: Converging evidence suggests that successful carotid endarterectomy and carotid artery stenting are associated with reversal of cognitive decline in many patients with severe but asymptomatic carotid artery stenosis. Most of these findings have been derived from cohort studies and comparisons with either normal or surgical controls. Failure to find treatment benefit in a number of studies appears to have been the result of patient heterogeneity or confounding from concomitant conditions independently associated with cognitive decline, such as heart failure and other cardiovascular risk factors, or failure to establish pre-procedure hemodynamic failure. Patients with severe carotid artery stenosis causing cerebral hemodynamic impairment may have a reversible cause of cognitive decline. None of the prior studies, however, were done in the context of a randomized clinical trial with large numbers of participants. The ongoing CREST-2 trial comparing revascularization with medical therapy versus medical therapy alone, and its associated CREST-H study determining whether cognitive decline is reversible among those with hemodynamic compromise may address this question.