Faculty Bibliography

INTRODUCTION/BACKGROUND:Mechanisms underlying social determinants of stroke and dementia are unclear and brain-derived neurotrophic factor (BDNF) may contribute as a molecular link. METHODS:Using the Framingham Study, we examined social relationship measures as predictors of higher serum BDNF level and cumulative incidence of stroke and dementia. RESULTS:Among 3294 participants, controlling for age and sex, isolation trended with lower BDNF (odds ratio = 0.69 [0.47-1.00]). Participants with more companionship had reduced risk for stroke (hazard ratio [HR] = 0.59 [0.41-0.83]) and dementia (HR = 0.67 [0.49-0.92]). Greater emotional support was associated with higher BDNF (odds ratio = 1.27 [1.04-1.54]), reduced dementia risk (HR = 0.69 [0.51-0.94], and among smokers, reduced stroke risk (HR = 0.23 [0.10-0.57]). Associations persisted after additional adjustments. BDNF partly mediated the total effect between emotional support and dementia risk. CONCLUSIONS:Availability of social support appears to be associated with increased BDNF levels and, in certain subsets, reduce risk of subsequent dementia and stroke, thus warranting study of these pathways to understand their role in neuroprotection.

Emerging evidence suggests microRNAs (miRNAs) may play an important role in explaining variation in stroke risk and recovery in humans, yet there are still few longitudinal studies examining the association between whole blood miRNAs and stroke. Accounting for multiple testing and adjusting for potentially confounding technical and clinical variables, here we show that whole blood miR-574-3p expression was significantly lower in participants with chronic stroke compared to non-cases. To explore the functional relevance of our findings, we analyzed miRNA-mRNA whole blood co-expression, pathway enrichment, and brain tissue gene expression. Results suggest miR-574-3p is involved in neurometabolic and chronic neuronal injury response pathways, including brain gene expression of DBNDD2 and ELOVL1. These results suggest miR-574-3p plays a role in regulating chronic brain and systemic cellular response to stroke and thus may implicate miR-574-3p as a partial mediator of long-term stroke outcomes.

Importance/UNASSIGNED:Cognitive resilience refers to the general capacity of cognitive processes to be less susceptible to differences in brain structure from age- and disease-related changes. Studies suggest that supportive social networks reduce Alzheimer disease and related disorder (ADRD) risk by enhancing cognitive resilience, but data on specific social support mechanisms are sparse. Objective/UNASSIGNED:To examine the association of individual forms of social support with a global neuroanatomical measure of early ADRD vulnerability and cognition. Design, Setting, and Participants/UNASSIGNED:This retrospective cross-sectional analysis used prospectively collected data from Framingham Study participants without dementia, stroke, or other neurological conditions who underwent brain magnetic resonance imaging and neuropsychological testing at the same visit. Data from this large, population-based, longitudinal cohort were collected from June 6, 1997, to December 13, 1999 (original cohort), and from September 11, 1998, to October 26, 2001 (offspring cohort). Data were analyzed from May 22, 2017, to June 1, 2021. Exposures/UNASSIGNED:Total cerebral volume and, as a modifying exposure variable, self-reported availability of 5 types of social support measured by the Berkman-Syme Social Network Index. Main Outcomes and Measures/UNASSIGNED:The primary outcome was a global measure of cognitive function. Cognitive resilience was defined as the modification of total cerebral volume's association with cognition, such that smaller β estimates (presented in SD units) indicate greater cognitive resilience (ie, better cognitive performance than estimated by lower total cerebral volume). Results/UNASSIGNED:The study included 2171 adults (164 in the original cohort and 2007 in the offspring cohort; mean [SD] age, 63 [10] years; 1183 [54%] female). High listener availability was associated with greater cognitive resilience (β = 0.08, P < .001) compared with low listener availability (β = 0.20, P = .002). Overall findings persisted after adjustment for potential confounders. Other forms of social support were not significant modifiers (advice: β = -0.04; P = .40 for interaction; love-affection: β = -0.07, P = .28 for interaction; emotional support: β = -0.02, P = .73 for interaction; and sufficient contact: β = -0.08; P = .11 for interaction). Conclusions and Relevance/UNASSIGNED:The results of this cross-sectional cohort study suggest that social support in the form of supportive listening is associated with greater cognitive resilience, independently modifying the association between lower total cerebral volume and poorer cognitive function that would otherwise indicate increased ADRD vulnerability at the preclinical stage. A refined understanding of social support mechanisms has the potential to inform strategies to reduce ADRD risk and enhance cognitive resilience.

Social distancing has been a critical public health measure for the COVID-19 pandemic, yet a long history of research strongly suggests that loneliness and social isolation play a major role in several cognitive health issues. What is the true severity and extent of risks involved and what are potential approaches to balance these competing risks? This review aimed to summarize the neurological context of social isolation and loneliness in population health and the long-term effects of social distancing as it relates to neurocognitive aging, health, and Alzheimer's disease and related dementias. The full scope of the underlying causal mechanisms of social isolation and loneliness in humans remains unclear partly because its study is not amenable to randomized controlled trials; however, there are many detailed experimental and observational studies that may provide a hypothesis-generating theoretical framework to better understand the pathophysiology and underlying neurobiology. To address these challenges and inform future studies, we conducted a topical review of extant literature investigating associations of social isolation and loneliness with relevant biological, cognitive, and psychosocial outcomes, and provide recommendations on how to approach the need to fill key knowledge gaps in this important area of research.

BACKGROUND:Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. OBJECTIVE:The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator. METHODS:Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored. RESULTS:Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012). CONCLUSION:Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

BACKGROUND:An association between chronic infectious diseases and development of dementia has been suspected for decades, based on the finding of pathogens in postmortem brain tissue and on serological evidence. However, questions remain regarding confounders, reverse causality, and how accurate, reproducible and generalizable those findings are. OBJECTIVE:Investigate whether exposure to Herpes simplex (manifested as herpes labialis), Chlamydophila pneumoniae (C. pneumoniae), Helicobacter pylori (H. pylori), and cytomegalovirus (CMV) modifies the risk of dementia in a populational cohort. METHODS:Questionnaires regarding incidence of herpes infections were administered to Original Framingham Study participants (n = 2,632). Serologies for C. pneumoniae, H. pylori, and CMV were obtained in Original (n = 2,351) and Offspring cohort (n = 3,687) participants. Participants are under continuous dementia surveillance. Brain MRI and neuropsychological batteries were administered to Offspring participants from 1999-2005. The association between each infection and incident dementia was tested with Cox models. Linear models were used to investigate associations between MRI or neuropsychological parameters and serologies. RESULTS:There was no association between infection serologies and dementia incidence, total brain volume, and white matter hyperintensities. Herpes labialis was associated with reduced 10-year dementia risk (HR 0.66, CI 0.46-0.97), but not for the duration of follow-up. H. pylori antibodies were associated with worse global cognition (β -0.14, CI -0.22, -0.05). CONCLUSION:We found no association between measures of chronic infection and incident dementia, except for a reduction in 10-year dementia risk for patients with herpes labialis. This unexpected result requires confirmation and further characterization, concerning antiviral treatment effects and capture of episodes.

Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 μm (PM2.5) may increase the risk for Alzheimer's disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer's disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer's disease associated with exposure. Participants included older females (n = 998; aged 73-87) enrolled in both the Women's Health Initiative Study of Cognitive Aging and the Women's Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999-2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1-3; List B) and delayed free recall (short- and long-delay), and up to two brain scans (MRI-1: 2005-06; MRI-2: 2009-10). Subjects were assigned Alzheimer's disease pattern similarity scores (a brain-MRI measured neuroanatomical risk for Alzheimer's disease), developed by supervised machine learning and validated with data from the Alzheimer's Disease Neuroimaging Initiative. Based on residential histories and environmental data on air monitoring and simulated atmospheric chemistry, we used a spatiotemporal model to estimate 3-year average PM2.5 exposure preceding MRI-1. In multilevel structural equation models, PM2.5 was associated with greater declines in immediate recall and new learning, but no association was found with decline in delayed-recall or composite scores. For each interquartile increment (2.81 μg/m3) of PM2.5, the annual decline rate was significantly accelerated by 19.3% [95% confidence interval (CI) = 1.9% to 36.2%] for Trials 1-3 and 14.8% (4.4% to 24.9%) for List B performance, adjusting for multiple potential confounders. Long-term PM2.5 exposure was associated with increased Alzheimer's disease pattern similarity scores, which accounted for 22.6% (95% CI: 1% to 68.9%) and 10.7% (95% CI: 1.0% to 30.3%) of the total adverse PM2.5 effects on Trials 1-3 and List B, respectively. The observed associations remained after excluding incident cases of dementia and stroke during the follow-up, or further adjusting for small-vessel ischaemic disease volumes. Our findings illustrate the continuum of PM2.5 neurotoxicity that contributes to early decline of immediate free recall/new learning at the preclinical stage, which is mediated by progressive atrophy of grey matter indicative of increased Alzheimer's disease risk, independent of cerebrovascular damage.

Objective/UNASSIGNED:The amyotrophic lateral sclerosis (ALS) trial outcome measures are clinic based. Active and passive smartphone data can provide important longitudinal information about ALS progression outside the clinic. Methods/UNASSIGNED:We used Beiwe, a research platform for smartphone-based digital phenotyping, to collect active (self-report ALSFRS-R surveys and speech recordings) and passive (phone sensors and logs) data from patients with ALS for approximately 24 weeks. In clinics, at baseline and every 3 months, we collected vital capacity, ALSFRS-R, and ALS-CBS at enrollment, week 12, and week 24. We also collected ALSFRS-R by telephone at week 6. Results/UNASSIGNED: < 0.001). ALSFRS-R slopes were equivalent and within-subject standard deviation was smaller for smartphone-based self-report (0.26 vs. 0.56). Use of Beiwe afforded weekly collection of speech samples amenable to a variety of analyses, and we found mean pause time to increase by 0.02 sec per month across the sample. Interpretation/UNASSIGNED:Smartphone-based digital phenotyping in people with ALS is feasible and informative. Self-administered smartphone ALSFRS-R scores correlate highly with clinic-based ALSFRS-R scores, have low variability, and could be used in clinical trials. More research is required to fully analyze speech recordings and passive data, and to identify optimal digital markers for use in future ALS clinical trials.

BACKGROUND AND PURPOSE:Although depression is a risk factor for stroke in large prospective studies, it is unknown whether these conditions have a shared genetic basis. METHODS:We applied a polygenic risk score (PRS) for major depressive disorder derived from European ancestry analyses by the Psychiatric Genomics Consortium to a genome-wide association study of ischemic stroke in the Stroke Genetics Network of National Institute of Neurological Disorders and Stroke. Included in separate analyses were 12 577 stroke cases and 25 643 controls of European ancestry and 1353 cases and 2383 controls of African ancestry. We examined the association between depression PRS and ischemic stroke overall and with pathogenic subtypes using logistic regression analyses. RESULTS:=0.011) samples from the Stroke Genetics Network. Ischemic stroke risk increased by 3.0% (odds ratio, 1.03; 95% confidence interval, 1.00-1.05) for every 1 SD increase in PRS for those of European ancestry and by 8% (odds ratio, 1.08; 95% confidence interval, 1.04-1.13) for those of African ancestry. Among stroke subtypes, elevated risk of small artery occlusion was observed in both European and African ancestry samples. Depression PRS was also associated with higher risk of cardioembolic stroke in European ancestry and large artery atherosclerosis in African ancestry persons. CONCLUSIONS:Higher polygenic risk for major depressive disorder is associated with increased risk of ischemic stroke overall and with small artery occlusion. Additional associations with ischemic stroke subtypes differed by ancestry.