Faculty Bibliography

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.

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.

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.

BACKGROUND:Psychosocial characteristics have a strong effect on risk of depression, and their direct treatment with behavioral interventions reduces rates of depression. Because new-onset poststroke depression (NPSD) is frequent, devastating, and often treatment-resistant, novel preventive efforts are needed. As a first step toward developing behavioral interventions for NPSD, we investigated whether prestroke psychosocial factors influenced rates of NPSD in a manner similar to the general population. METHODS AND RESULTS:Using the Women's Health Initiative, we analyzed 1424 respondents who were stroke-free at enrollment and had no self-reported history of depression from enrollment to their nonfatal ischemic stroke based on initiation of treatment for depression or the Burnam screening instrument for detecting depressive disorders. NPSD was assessed using the same method during the 5-year poststroke period. Logistic regression provided odds ratios of NPSD controlling for multiple covariates. NPSD occurred in 21.4% (305/1424) of the analytic cohort and varied by stroke severity as measured by the Glasgow scale, ranging from 16.7% of those with good recovery to 31.6% of those severely disabled. Women with total anterior circulation infarction had the highest level (31.4%) of NPSD while those with lacunar infarction had the lowest (16.1%). Prestroke psychosocial measures had different associations with NPSD depending on functional recovery of the individual. CONCLUSIONS:There is a difference in the relationship of prestroke psychosocial status and risk of NPSD depending on stroke severity; thus it may be that the same preventive interventions might not work for all stroke patients. One size does not fit all.

OBJECTIVE:To compare postoperative seizure-free survival between older and younger adults. METHODS:A retrospective cohort of 107 temporal lobe epilepsy patients with a diagnosis of mesial temporal sclerosis (MTS) received anterior temporal lobectomy (ATL) between 1993 and 2014. We divided the lower three quartiles (younger) and top quartile (older, all 47+ years) of patients, then reviewed patient registry and electronic medical records to determine time to first self-reported seizure after ATL, the primary outcome (mean=3.5years of follow-up, SD=3.6). We also assessed Engel classifications, intraoperative and postoperative treatment complications, and social disability. We used Cox proportional hazard models to assess the association between individual traits and time of seizure recurrence. RESULTS:During follow-up, 35/107 (32.7%) patients had post-operative seizure(s). After adjustment for potential confounders there were no significant differences in the probability of post-operative seizures between the older and younger groups, though we had limited precision (hazard ratio of 0.67 [0.28-1.59]), (p=0.36). There were more treatment complications and disability in older patients (18% vs. 1.3% for any complications, 84.62% vs. 58.23% for driving disability, and 84.6% vs. 60.7% for work disability, p<0.05). CONCLUSION:Older patients appear to have more complications after ATL, compared with younger patients. Age, however, does not appear to have a large independent association with seizure recurrence.

BACKGROUND AND PURPOSE/OBJECTIVE:Value-based health care aims to bring together patients and health systems to maximize the ratio of quality over cost. To enable assessment of healthcare value in stroke management, an international standard set of patient-centered stroke outcome measures was defined for use in a variety of healthcare settings. METHODS:A modified Delphi process was implemented with an international expert panel representing patients, advocates, and clinical specialists in stroke outcomes, stroke registers, global health, epidemiology, and rehabilitation to reach consensus on the preferred outcome measures, included populations, and baseline risk adjustment variables. RESULTS:Patients presenting to a hospital with ischemic stroke or intracerebral hemorrhage were selected as the target population for these recommendations, with the inclusion of transient ischemic attacks optional. Outcome categories recommended for assessment were survival and disease control, acute complications, and patient-reported outcomes. Patient-reported outcomes proposed for assessment at 90 days were pain, mood, feeding, selfcare, mobility, communication, cognitive functioning, social participation, ability to return to usual activities, and health-related quality of life, with mobility, feeding, selfcare, and communication also collected at discharge. One instrument was able to collect most patient-reported subdomains (9/16, 56%). Minimum data collection for risk adjustment included patient demographics, premorbid functioning, stroke type and severity, vascular and systemic risk factors, and specific treatment/care-related factors. CONCLUSIONS:A consensus stroke measure Standard Set was developed as a simple, pragmatic method to increase the value of stroke care. The set should be validated in practice when used for monitoring and comparisons across different care settings.

To better identify stroke survivors at risk for depression who may benefit from early prevention through targeted strategies in the acute-subacute poststroke period, we examined 118 Framingham Heart Study stroke survivors with longitudinal prestroke depression assessments. Among those who developed poststroke depression, most lacked a history of depressive symptoms 5 years prior to their stroke. Sex (female), advanced age, and prestroke factors (smoking and functional dependence) were associated with new-onset depression poststroke. These findings suggest fully characterizing and accounting for prestroke factors, including psychosocial and behavioral determinants, may inform the predictive modeling needed to determine whether targeted preventive trials early in stroke recovery will improve stroke outcomes.