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There is increasing interest in the role of physical exercise as a therapeutic strategy for individuals with Alzheimer's disease (AD). We assessed the effect of 26 weeks (6 months) of a supervised aerobic exercise program on memory, executive function, functional ability and depression in early AD. This study was a 26-week randomized controlled trial comparing the effects of 150 minutes per week of aerobic exercise vs. non-aerobic stretching and toning control intervention in individuals with early AD. A total of 76 well-characterized older adults with probable AD (mean age 72.9 [7.7]) were enrolled and 68 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. Neuropsychological tests and surveys were conducted at baseline,13, and 26 weeks to assess memory and executive function composite scores, functional ability (Disability Assessment for Dementia), and depressive symptoms (Cornell Scale for Depression in Dementia). Cardiorespiratory fitness testing and brain MRI was performed at baseline and 26 weeks. Aerobic exercise was associated with a modest gain in functional ability (Disability Assessment for Dementia) compared to individuals in the ST group (X2 = 8.2, p = 0.02). There was no clear effect of intervention on other primary outcome measures of Memory, Executive Function, or depressive symptoms. However, secondary analyses revealed that change in cardiorespiratory fitness was positively correlated with change in memory performance and bilateral hippocampal volume. Aerobic exercise in early AD is associated with benefits in functional ability. Exercise-related gains in cardiorespiratory fitness were associated with improved memory performance and reduced hippocampal atrophy, suggesting cardiorespiratory fitness gains may be important in driving brain benefits. ClinicalTrials.gov NCT01128361.

Epidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes. However, no direct data from randomized trials exists to support these indirect observations. The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition. Underactive or sedentary participants without cognitive impairment were randomized to one of four groups: no-change control, 75, 150, and 225 minutes per week of moderate-intensity semi-supervised aerobic exercise for 26-weeks in a community setting. Cognitive outcomes were latent residual scores derived from a battery of 16 cognitive tests: Verbal Memory, Visuospatial Processing, Simple Attention, Set Maintenance and Shifting, and Reasoning. Other outcome measures were cardiorespiratory fitness (peak oxygen consumption) and measures of function functional health. In intent-to-treat (ITT) analyses (n = 101), cardiorespiratory fitness increased and perceived disability decreased in a dose-dependent manner across the 4 groups. No other exercise-related effects were observed in ITT analyses. Analyses restricted to individuals who exercised per-protocol (n = 77) demonstrated that Simple Attention improved equivalently across all exercise groups compared to controls and a dose-response relationship was present for Visuospatial Processing. A clear dose-response relationship exists between exercise and cardiorespiratory fitness. Cognitive benefits were apparent at low doses with possible increased benefits in visuospatial function at higher doses but only in those who adhered to the exercise protocol. An individual’s cardiorespiratory fitness response was a better predictor of cognitive gains than exercise dose (i.e., duration) and thus maximizing an individual’s cardiorespiratory fitness may be an important therapeutic target for achieving cognitive benefits. ClinicalTrials.gov NCT01129115.

Our goal was to investigate the role of physical exercise to protect brain health as we age, including the potential to mitigate Alzheimer's-related pathology. We assessed the effect of 52 weeks of a supervised aerobic exercise program on amyloid accumulation, cognitive performance, and brain volume in cognitively normal older adults with elevated and sub-threshold levels of cerebral amyloid as measured by amyloid PET imaging. This 52-week randomized controlled trial compared the effects of 150 minutes per week of aerobic exercise vs. education control intervention. A total of 117 underactive older adults (mean age 72.9 [7.7]) without evidence of cognitive impairment, with elevated (n = 79) or subthreshold (n = 38) levels of cerebral amyloid were randomized, and 110 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. We conducted 18F-AV45 PET imaging of cerebral amyloid and anatomical MRI for whole brain and hippocampal volume at baseline and Week 52 follow-up to index brain health. Neuropsychological tests were conducted at baseline, Week 26, and Week 52 to assess executive function, verbal memory, and visuospatial cognitive domains. Cardiorespiratory fitness testing was performed at baseline and Week 52 to assess response to exercise. The aerobic exercise group significantly improved cardiorespiratory fitness (11% vs. 1% in the control group) but there were no differences in change measures of amyloid, brain volume, or cognitive performance compared to control. Aerobic exercise was not associated with reduced amyloid accumulation in cognitively normal older adults with cerebral amyloid. In spite of strong systemic cardiorespiratory effects of the intervention, the observed lack of cognitive or brain structure benefits suggests brain benefits of exercise reported in other studies are likely to be related to non-amyloid effects. NCT02000583; ClinicalTrials.gov.

Physical activity shows promise for reduced risk of Alzheimer's disease (AD) and protection against cognitive decline among individuals with and without AD. Older adults face many barriers to adoption of physically active lifestyles and people with AD face even further challenges. Physical activity is a promising non-pharmacological approach to improve depressive symptoms, but little is known about the impact of depressive symptoms as a potential barrier to engagement in physical activity. The present study aimed to investigate depressive symptoms as a potential barrier for participation in physical activity across a range of dementia severity. We used longitudinal structural equation modelling to investigate the bi-directional relationship between depressive symptoms and physical activity in 594 older adults with and without AD over a 2 year longitudinal follow up. Participants ranged from no cognitive impairment to moderately severe AD. We found that depressive symptoms predicted reduced engagement in subsequent physical activity, but physical activity did not predict subsequent reductions in depressive symptoms. We conclude that depressive symptoms may be an important barrier to engagement in physical activity that may be addressed in clinical practice and intervention research.

Cognitive workload is increasingly recognized as an important determinant of performance in cognitive tests and daily life activities. Cognitive workload is a measure of physical and mental effort allocation to a task, which can be determined through self-report or physiological measures. However, the reliability and validity of these measures have not been established in older adults with a wide range of cognitive ability. The aim of this study was to establish the test–retest reliability of the National Aeronautics and Space Administration Task Load Index (NASA-TLX) and Index of Cognitive Activity (ICA), extracted from pupillary size. The convergent validity of these measures against event-related potentials (ERPs) was also investigated. A total of 38 individuals with scores on the Montreal Cognitive Assessment ranging between 17 and 30 completed a working memory test (n-back) with three levels of difficulty at baseline and at a two-week follow-up. The intraclass correlation coefficients (ICC) values of the NASA-TLX ranged between 0.71 and 0.81, demonstrating good to excellent reliability. The mean ICA scores showed fair to good reliability, with ICCs ranging between 0.56 and 0.73. The mean ICA and NASA-TLX scores showed significant and moderate correlations (Pearson’s r ranging between 0.30 and 0.33) with the third positive peak of the ERP at the midline channels. We conclude that ICA and NASA-TLX are reliable measures of cognitive workload in older adults. Further research is needed in dissecting the subjective and objective constructs of cognitive workload.

PurposeIt is plausible that statins could improve cerebral blood flow through pleiotropic mechanisms. The purpose of this investigation was to assess the contribution of statins to cerebrovascular variables in older adults with dyslipidemia and familial history of dementia. Furthermore, we explored the interaction between statin use and sex due to prevalent bias in statin trials.MethodsMiddle cerebral artery blood flow velocity (MCAv) was measured using transcranial Doppler ultrasound. Continuous supine rest recordings lasted 8 min. Participants included in analyses were statin (n = 100) or non-statin users (n = 112).ResultsMCAv and cerebrovascular conductance were significantly higher in statin users (p = 0.047; p = 0.04), and pulsatility index (PI) was significantly lower in statin users (p < 0.01). An interaction effect between statin use and sex was present for PI (p = 0.02); female statin users had significantly lower cerebrovascular resistance than the other three groups.ConclusionIn this cross-sectional analysis, statin use was positively associated with cerebrovascular variables in older adults at risk for dementia. Female statin users had significantly higher resting MCAv and cerebrovascular conductance than female non-statin users. The greatest contribution of statin use was the association with reduced cerebrovascular resistance. Given that cerebrovascular dysregulation is one of the earliest changes in Alzheimer’s disease and related dementia pathology, targeting the cerebrovasculature with statins may be a promising prevention strategy.

Alzheimer’s disease (AD) is a progressive neurodegenerative condition characterized by clinical decline in memory and other cognitive functions. A classic AD neuropathological hallmark includes the accumulation of amyloid-β (Aβ) plaques, which may precede onset of clinical symptoms by over a decade. Efforts to prevent or treat AD frequently emphasize decreasing Aβ through various mechanisms, but such approaches have yet to establish compelling interventions. It is still not understood exactly why Aβ accumulates in AD, but it is hypothesized that Aβ and other downstream pathological events are a result of impaired bioenergetics, which can also manifest prior to cognitive decline. Evidence suggests that individuals with AD and at high risk for AD have functional brain ketone metabolism and ketotherapies (KTs), dietary approaches that produce ketone bodies for energy metabolism, may affect AD pathology by targeting impaired brain bioenergetics. Cognitively normal individuals with elevated brain Aβ, deemed “preclinical AD”, and older adults with peripheral metabolic impairments are ideal candidates to test whether KTs modulate AD biology as they have impaired mitochondrial function, perturbed brain glucose metabolism, and elevated risk for rapid Aβ accumulation and symptomatic AD. Here, we discuss the link between brain bioenergetics and Aβ, as well as the potential for KTs to influence AD risk and progression.

Disruptions in estrogen exposure (i.e., surgically induced menopause) have been linked to poorer cognitive aging and dementia risk. Hormone therapy use (e.g., birth control, menopausal hormone therapy) has shown mixed associations with cognitive performance, possibly due to limited cognitive test batteries. To address previous inconsistencies, we investigated baseline data from Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE). We hypothesized that (1) oophorectomy prior to natural menopause would be associated with poorer cognitive performance, (2) timing and duration of birth control and menopausal hormone therapy would influence associations with cognitive performance, and (3) carrier status would interact with oophorectomy and hormone therapy to influence cognitive performance. In 461 post-menopausal females (M age = 69.6) we assessed oophorectomy and hormone therapy use to examine associations with the Montreal Cognitive Assessment (MoCA) and factor-analytically derived composite scores for episodic memory, processing speed, working memory, executive function/attentional control, and visuospatial processing. Hypothesis (1) We did not observe associations between oophorectomy prior to natural menopause and poorer cognitive performance. However, hormone therapy use, started on average within 2 years of oophorectomy, was associated with better episodic memory (β = 0.106, = 0.02), working memory (β = 0.120, = 0.005), and visuospatial processing (β = 0.095, = 0.03). Hypothesis (2) Birth control use was associated with better performance on the MoCA (β = 0.093, = 0.04), working memory (β = 0.102, = 0.02), and executive function/attentional control (β = 0.103, = 0.02). However, duration and timing of birth control and menopausal hormone therapy were not associated with cognitive performance. Hypothesis (3) We did not observe significant interactions between status and oophorectomy or hormone therapy in their associations with cognitive performance. Our results suggest exposure to estrogen during adulthood, specifically birth control and hormone therapy among women undergoing pre-menopausal oophorectomy, benefits cognitive function in older adulthood. Our comprehensive cognitive battery allowed us to examine cognitive function with a high degree of granularity. Future work should evaluate causal mechanisms of associations between lifetime estrogen exposure and later life cognitive function.

Background Although growing evidence links beta-amyloid (Aβ) and neuronal hyperexcitability in preclinical mouse models of Alzheimer’s disease (AD), a similar association in humans is yet to be established. The first aim of the study was to determine the association between elevated Aβ (Aβ+) and cognitive processes measured by the P3 event-related potential (ERP) in cognitively normal (CN) older adults. The second aim was to compare the event-related power between CNAβ+ and CNAβ−. Methods Seventeen CNAβ+ participants (age: 73 ± 5, 11 females, Montreal Cognitive Assessment [MoCA] score 26 ± 2) and 17 CNAβ- participants group-matched for age, sex, and MOCA completed a working memory task ( n -back with n  = 0, 1, 2) test while wearing a 256-channel electro-encephalography net. P3 peak amplitude and latency of the target, nontarget and task difference effect (nontarget−target), and event-related power in the delta, theta, alpha, and beta bands, extracted from Fz, Cz, and Pz, were compared between groups using linear mixed models. P3 amplitude of the task difference effect at Fz and event-related power in the delta band were considered main outcomes. Correlations of mean Aβ standard uptake value ratios (SUVR) using positron emission tomography with P3 amplitude and latency of the task difference effect were analyzed using Pearson Correlation Coefficient r . Results The P3 peak amplitude of the task difference effect at Fz was lower in the CNAβ+ group ( P  = 0.048). Similarly, power was lower in the delta band for nontargets at Fz in the CNAβ+ participants ( P  = 0.04). The CNAβ+ participants also demonstrated higher theta and alpha power in channels at Cz and Pz, but no changes in P3 ERP. Strong correlations were found between the mean Aβ SUVR and the latency of the 1-back ( r  =  − 0.69; P  = 0.003) and 2-back ( r  =  − 0.69; P  = 0.004) of the task difference effect at channel Fz in the CNAβ+ group. Conclusions Our data suggest that the elevated amyloid in cognitively normal older adults is associated with neuronal hyperexcitability. The decreased P3 task difference likely reflects early impairments in working memory processes. Further research is warranted to determine the validity of ERP in predicting clinical, neurobiological, and functional manifestations of AD.

Background There is a high prevalence of cognitive impairment in dialysis patients. The prevalence of cognitive impairment after kidney transplantation is unknown. Methods Study Design : Cross-sectional study . Setting and Participants : Single center study of prevalent kidney transplant recipients from a transplant clinic in a large academic center. Intervention : Assessment of cognition using the Montreal Cognitive Assessment (MoCA). Demographic and clinical variables associated with cognitive impairment were also examined. Outcomes and Measurements : a) Prevalence of cognitive impairment defined by a MoCA score of <26. b) Multivariable linear and logistic regression to examine the association of demographic and clinical factors with cognitive impairment. Results Data from 226 patients were analyzed. Mean (SD) age was 54 (13.4) years, 73% were white, 60% were male, 37% had diabetes, 58% had an education level of college or above, and the mean (SD) time since kidney transplant was 3.4 (4.1) years. The prevalence of cognitive impairment was 58.0%. Multivariable linear regression demonstrated that older age, male gender and absence of diabetes were associated with lower MoCA scores ( p  < 0.01 for all). Estimated glomerular filtration rate (eGFR) was not associated with level of cognition. The logistic regression analysis confirmed the association of older age with cognitive impairment. Conclusion Cognitive impairment is common in prevalent kidney transplant recipients, at a younger age compared to general population, and is associated with certain demographic variables, but not level of eGFR.