Associations between Vascular Function and Tau PET Are Associated with Global Cognition and Amyloid.

Tau pathology and vascular dysfunction are important contributors to Alzheimer's disease (AD), but vascular-tau associations and their effects on cognition are poorly understood. We investigated these associations in male and female humans by conducting voxelwise comparisons between cerebral blood flow (CBF) and tau positron emission tomography (PET) images in independent discovery [cognitively normal (CN), 19; mild cognitive impairment (MCI) risk, 43; MCI, 6] and replication (CN,73; MCI, 45; AD, 20) cohorts. In a subgroup, we assessed relationships between tau and soluble platelet-derived growth factor ß (sPDGFRß), a CSF marker of pericyte injury. We tested whether CBF/sPDGFRß-tau relationships differed based on Montreal Cognitive Assessment (MoCA) global cognition performance, or based on amyloid burden. Mediation analyses assessed relationships among CBF/sPDGFRß, tau, and cognition. Negative CBF-tau correlations were observed predominantly in temporal-parietal regions. In the replication cohort, early negative CBF-tau correlations increased in spatial extent and in strength of correlation with increased disease severity. Stronger CBF-tau and sPDGFRß-tau correlations were observed in participants with greater amyloid burden and lower MoCA scores. Importantly, when stratifying by amyloid status, stronger CBF-tau relationships in individuals with lower MoCA scores were driven by amyloid+ participants. Tau PET was a significant mediator CBF/sPDGFRß-MoCA relationships in numerous regions. Our results demonstrate vascular-tau associations across the AD spectrum and suggest that early vascular-tau associations are exacerbated in the presence of amyloid, consistent with a two-hit model of AD on cognition. Combination treatments targeting vascular health, as well as amyloid-ß and tau levels, may preserve cognitive function more effectively than single-target therapies.SIGNIFICANCE STATEMENT Emerging evidence demonstrates a role for vascular dysfunction as a significant contributor to Alzheimer's pathophysiology. However, associations between vascular dysfunction and tau pathology, and their effects on cognition remain poorly understood. Multimodal neuroimaging data from two independent cohorts were analyzed to provide novel in vivo evidence of associations between cerebral blood flow (CBF), an MRI measure of vascular health, and tau pathology using PET. CBF-tau associations were related to cognition and driven in part by amyloid burden. Soluble platelet-derived growth factor ß, an independent CSF vascular biomarker, confirmed vascular-tau associations in a subgroup analysis. These results suggest that combination treatments targeting vascular health, amyloid-ß, and tau levels may more effectively preserve cognitive function than single-target therapies.

Variability in objective sleep is associated with Alzheimer's pathology and cognition.

Both sleep duration and sleep efficiency have been associated with risk of Alzheimer's disease, suggesting that interventions to promote optimal sleep may be a way to reduce Alzheimer's disease risk. However, studies often focus on average sleep measures, usually from self-report questionnaires, ignoring the role of intra-individual variability in sleep across nights quantified from objective sleep measures. The current cross-sectional study sought to investigate the role of intra-individual variability in accelerometer-based objective sleep duration and sleep efficiency in relation to in vivo Alzheimer's disease pathology (ß-amyloid and tau) using positron emission tomography imaging and cognition (working memory, inhibitory control, verbal memory, visual memory and global cognition). To examine these relationships, we evaluated 52 older adults (age = 66.4 ± 6.89, 67% female, 27% apolipoprotein E4 carriers) with objective early mild cognitive impairment. Modifying effects of apolipoprotein E4 status were also explored. Less intra-individual variability in sleep duration was associated with lower ß-amyloid burden, higher global cognition and better inhibitory control, with a trend for lower tau burden. Less intra-individual variability in sleep efficiency was associated with lower ß-amyloid burden, higher global cognition and better inhibitory control, but not with tau burden. Longer sleep duration was associated with better visual memory and inhibitory control. Apolipoprotein E4 status significantly modified the association between intra-individual variability in sleep efficiency and ß-amyloid burden, such that less sleep efficiency variability was associated with lower ß-amyloid burden in apolipoprotein E4 carriers only. There was a significant interaction between sleep duration and apolipoprotein E4 status, suggesting that longer sleep duration is more strongly associated with lower ß-amyloid burden in apolipoprotein E4 carriers relative to non-carriers. These results provide evidence that lower intra-individual variability in both sleep duration and sleep efficiency and longer mean sleep duration are associated with lower levels of ß-amyloid pathology and better cognition. The relationships between sleep duration and intra-individual variability in sleep efficiency with ß-amyloid burden differ by apolipoprotein E4 status, indicating that longer sleep duration and more consistent sleep efficiency may be protective against ß-amyloid burden in apolipoprotein E4 carriers. Longitudinal and causal studies are needed to better understand these relationships. Future work should investigate factors contributing to intra-individual variability in sleep duration and sleep efficiency in order to inform intervention studies.

Erratum: Simultaneous Exercise and Cognitive Training in Virtual Reality Phase 2 Pilot Study: Impact on Brain Health and Cognition in Older Adults.

[This corrects the article DOI: 10.3233/BPL210126.].

Conducting a VR Clinical Trial in the Era of COVID-19.

The outbreak of severe acute respiratory syndrome coronavirus 2, also known as Coronavirus Disease 2019 (COVID-19) sparked a global public health pandemic that has impacted every aspect of daily life. Medical research was affected, and many clinical trials were halted to minimize COVID-19 transmission risk and spread while the world navigated this novel virus. Here we describe the relaunch of our virtual reality (VR) pilot clinical trial that uses an in-lab brain and body training program to promote brain health in mid-to-late life older adults, in the era of COVID-19. This case series includes five healthy female participants between 51 and 76 years of age, a subset of a larger VR pilot clinical trial that started pre-pandemic. We developed a revised study protocol based on the Center for Disease Control and World Health Organization guidelines to help manage the spread of COVID-19. Since the limited resumption of clinical trials at our institution in August 2020, we successfully completed over 200 in-lab virtual reality training sessions using our revised protocol. During this time, none of the five participants or three study staff reported any COVID-19 symptoms or reported a positive COVID-19 test. More than 40 voluntary COVID-19 tests were completed by our study staff over the last 6 months. All participants rated our safety protocol as very satisfied or extremely satisfied and that they would be very likely or extremely likely to participate in a VR clinical trial during the pandemic. Based on these findings, we suggest that continued VR clinical trial research during the COVID-19 pandemic is achievable and can be safely resumed if specific safety protocols are in place to mitigate the risk of exposure and spread of COVID-19.

Simultaneous Exercise and Cognitive Training in Virtual Reality Phase 2 Pilot Study: Impact on Brain Health and Cognition in Older Adults.

BACKGROUND: Aerobic exercise and environmental enrichment have been shown to enhance brain function. Virtual reality (VR) is a promising method for combining these activities in a meaningful and ecologically valid way. OBJECTIVE: The purpose of this Phase 2 pilot study was to calculate relative change and effect sizes to assess the impact of simultaneous exercise and cognitive training in VR on brain health and cognition in older adults. METHODS: Twelve cognitively normal older adults (64.7±8.8 years old, 8 female) participated in a 12-week intervention, 3 sessions/week for 25-50 minutes/session at 50-80% HRmax. Participants cycled on a custom-built stationary exercise bike while wearing a VR head-mounted display and navigating novel virtual environments to train spatial memory. Brain and cognitive changes were assessed using MRI imaging and a cognitive battery. RESULTS: Medium effect size (ES) improvements in cerebral flow and brain structure were observed. Pulsatility, a measure of peripheral vascular resistance, decreased 10.5% (ES(d) = 0.47). Total grey matter volume increased 0.73% (ES(r) = 0.38), while thickness of the superior parietal lobule, a region associated with spatial orientation, increased 0.44% (ES(r) = 0.30). Visual memory discrimination related to pattern separation showed a large improvement of 68% (ES(η p 2) = 0.43). Cognitive flexibility (Trail Making Test B) (ES(r) = 0.42) and response inhibition (ES(W) = 0.54) showed medium improvements of 14% and 34%, respectively. CONCLUSIONS: Twelve weeks of simultaneous exercise and cognitive training in VR elicits positive changes in brain volume, vascular resistance, memory, and executive function with moderate-to-large effect sizes in our pilot study.

Cycling and Spatial Navigation in an Enriched, Immersive 3D Virtual Park Environment: A Feasibility Study in Younger and Older Adults.

BACKGROUND: Cognitive decline is a significant public health concern in older adults. Identifying new ways to maintain cognitive and brain health throughout the lifespan is of utmost importance. Simultaneous exercise and cognitive engagement has been shown to enhance brain function in animal and human studies. Virtual reality (VR) may be a promising approach for conducting simultaneous exercise and cognitive studies. In this study, we evaluated the feasibility of cycling in a cognitively enriched and immersive spatial navigation VR environment in younger and older adults. METHODS: A total of 20 younger (25.9 ± 3.7 years) and 20 older (63.6 ± 5.6 years) adults participated in this study. Participants completed four trials (2 learning and 2 recall) of cycling while wearing a head-mounted device (HMD) and navigating a VR park environment. Questionnaires were administered to assess adverse effects, mood, presence, and physical exertion levels associated with cycling in the VR environment. RESULTS: A total of 4 subjects withdrew from the study due to adverse effects, yielding a 90% completion rate. Simulator sickness levels were enhanced in both age groups with exposure to the VR environment but were within an acceptable range. Exposure to the virtual environment was associated with high arousal and low stress levels, suggesting a state of excitement, and most participants reported enjoyment of the spatial navigation task and VR environment. No association was found between physical exertion levels and simulator sickness levels. CONCLUSION: This study demonstrates that spatial navigation while cycling is feasible and that older adults report similar experiences to younger adults. VR may be a powerful tool for engaging physical and cognitive activity in older adults with acceptable adverse effects and with reports of enjoyment. Future studies are needed to assess the efficacy of a combined exercise and cognitive VR program as an intervention for promoting healthy brain aging, especially in older adults with increased risk of age-related cognitive decline.