Genetic variation supports a causal role for valproate in prevention of ischemic stroke.

BACKGROUND: Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. AIMS: We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. METHODS: We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank. RESULTS: Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%, p trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)). CONCLUSION: These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention. DATA ACCESS STATEMENT: UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables.

Life-Course Brain Health as a Determinant of Late-Life Mental Health: American Association for Geriatric Psychiatry Expert Panel Recommendations.

This position statement of the Expert Panel on Brain Health of the American Association for Geriatric Psychiatry (AAGP) emphasizes the critical role of life course brain health in shaping mental well-being during the later stages of life. Evidence posits that maintaining optimal brain health earlier in life is crucial for preventing and managing brain aging-related disorders such as dementia/cognitive decline, depression, stroke, and anxiety. We advocate for a holistic approach that integrates medical, psychological, and social frameworks with culturally tailored interventions across the lifespan to promote brain health and overall mental well-being in aging adults across all communities. Furthermore, our statement underscores the significance of prevention, early detection, and intervention in identifying cognitive decline, mood changes, and related mental illness. Action should also be taken to understand and address the needs of communities that traditionally have unequal access to preventive health information and services. By implementing culturally relevant and tailored evidence-based practices and advancing research in geriatric psychiatry, behavioral neurology, and geroscience, we can enhance the quality of life for older adults facing the unique challenges of aging. This position statement emphasizes the intrinsic link between brain health and mental health in aging, urging healthcare professionals, policymakers, and a broader society to prioritize comprehensive strategies that safeguard and promote brain health from birth through later years across all communities. The AAGP Expert Panel has the goal of launching further activities in the coming months and years.

Outcome after acute ischemic stroke is linked to sex-specific lesion patterns.

Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n = 503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.

Feasibility and Efficacy of a Resiliency Intervention for the Prevention of Chronic Emotional Distress Among Survivor-Caregiver Dyads Admitted to the Neuroscience Intensive Care Unit: A Randomized Clinical Trial.

Importance: To our knowledge, there are no evidence-based interventions to prevent chronic emotional distress (ie, depression, anxiety, and posttraumatic stress [PTS]) in critical care survivors and their informal caregivers. Objective: To determine the feasibility and preliminary effect of the novel dyadic resiliency intervention Recovering Together (RT) on reducing symptoms of depression, anxiety, and PTS among hospitalized patients and their informal caregivers. Design, Setting, and Participants: This single-blind, pilot randomized clinical trial of RT vs an educational control was conducted among 58 dyads in which either the survivor or caregiver endorsed clinically significant symptoms of depression, anxiety, or PTS. The study was conducted in the neuroscience intensive care unit at Massachusetts General Hospital. Data were collected from September 2019 to March 2020. Interventions: Both RT and control programs had 6 sessions (2 at bedside and 4 via live video after discharge), and both survivor and caregiver participated together. Main Outcomes and Measures: The primary outcomes were feasibility of recruitment and intervention delivery, credibility, and satisfaction. The secondary outcomes included depression and anxiety (measured by the Hospital Depression and Anxiety Scale), PTS (measured by the PTSD Checklist-Civilian Version), and intervention targets (ie, mindfulness, measured by the Cognitive and Affective Mindfulness Scale-Revised; coping, measured by the Measure of Current Status-Part A; and dyadic interpersonal interactions, measured by the Dyadic Relationship Scale). Main outcomes and targets were assessed at baseline, 6 weeks, and 12 weeks. Results: The 58 dyads were randomized to RT (29 dyads [50.0%]; survivors: mean [SD] age, 49.3 [16.7] years; 9 [31.0%] women; caregivers: mean [SD] age, 52.4 [14.3] years; 22 [75.9%] women) or control (29 dyads [50.0%]; survivors: mean [SD] age, 50.3 [16.4] years; 12 [41.3%] women; caregivers, mean [SD] age, 52.1 [14.9], 17 [58.6%] women). Feasibility (recruitment [76%], randomization [100%], and data collection [83%-100%]), adherence (86%), fidelity (100%; κ = 0.98), satisfaction (RT: 57 of 58 [98%] with scores >6; control: 58 of 58 [100%] with scores >6), credibility (RT: 47 of 58 [81%] with scores >6; control: 46 of 58 [80%] with scores >6), and expectancy (RT: 49 of 58 [85%] with scores >13.5; 51 of 58 [87%] with scores >13.5) exceeded benchmarks set a priori. Participation in RT was associated with statistically and clinically significant improvement between baseline and postintervention in symptoms of depression (among survivors: -4.0 vs -0.6; difference, -3.4; 95% CI, -5.6 to -1.3; P = .002; among caregivers: -3.8 vs 0.6; difference, -4.5; 95% CI, -6.7 to -2.3; P < .001), anxiety (among survivors: -6.0 vs 0.3; difference, -6.3; 95% CI, -8.8 to -3.8; P < .001; among caregivers: -5.0 vs -0.9; difference, -4.1; 95% CI, -6.7 to -1.5, P = .002), and PTS (among survivors: -11.3 vs 1.0; difference, -12.3; 95% CI, -18.1 to -6.5, P < .001; among caregivers, -11.4 vs 5.0; difference, -16.4, 95% CI, -21.8 to -10.9; P < .001). Improvements sustained through the 12-week follow-up visit. We also observed RT-dependent improvement in dyadic interpersonal interactions for survivors (0.2 vs -0.2; difference, 0.4; 95% CI, 0.0 to 0.8; P = .04). Conclusions and Relevance: In this pilot randomized clinical trial, RT was feasible and potentially efficacious in preventing chronic emotional distress in dyads of survivors of the neuroscience intensive care unit and their informal caregivers. Trial Registration: ClinicalTrials.gov Identifier: NCT03694678.

Baseline Resilience and Posttraumatic Symptoms in Dyads of Neurocritical Patients and Their Informal Caregivers: A Prospective Dyadic Analysis.

BACKGROUND: Admission to a neuroscience intensive care unit (Neuro-ICU) is sudden and often traumatic for both patients and their informal caregivers. No prior studies have assessed prospectively risk and resiliency factors for chronic posttraumatic symptoms, as well as the potential interdependence between patients' and caregivers' symptoms over time. OBJECTIVE: To analyze the impact of baseline resiliency factors on symptoms of posttraumatic stress (PTS) longitudinally in dyads of patients admitted to the Neuro-ICU and their primary family caregivers. METHODS: We recruited dyads (M = 108) of patients admitted to the Neuro-ICU (total N = 102) and their family caregivers (total N = 103). Dyads completed self-report assessments of PTS and resiliency factors (mindfulness and coping) at baseline in the Neuro-ICU. PTS was measured again at 3- and 6-month follow-up. RESULTS: Clinically significant PTS symptoms were high at baseline in both patients (20%) and caregivers (16%) and remained high through 6 months (25% in patients; 14% in caregivers). Actor-partner interdependence modeling demonstrated that severity of PTS symptoms was predictive of PTS symptoms at subsequent time points (P < 0.001). High baseline mindfulness and coping predicted less severe PTS symptoms in patients and caregivers (P < 0.001) at all time points. Own degree of PTS symptoms at 3 months predicted worse PTS symptoms in one's partner at 6 months, for both patients and caregivers (P = 0.02). CONCLUSIONS: Findings highlight the need to prioritize assessment and treatment of PTS in Neuro-ICU patients and their informal caregivers through a dyadic approach.

Baseline resilience and depression symptoms predict trajectory of depression in dyads of patients and their informal caregivers following discharge from the Neuro-ICU.

OBJECTIVE: To explore the impact of resiliency factors on the longitudinal trajectory of depressive symptoms in patients admitted to the Neuroscience Intensive Care Unit (Neuro-ICU) and their family caregivers. MATERIALS AND METHODS: Patients (N = 102) and family caregivers (N = 103) completed self-report assessments of depressive symptoms (depression subscale of the Hospital Anxiety and Depression Scale; HADS-D) and resiliency factors (i.e., mindfulness and coping) during Neuro-ICU hospitalization. The HADS-D was administered again at 3 and 6 months after discharge. The Actor-Partner Interdependence Model (APIM) was used to assess patient-caregiver interdependence. RESULTS: Baseline rates of clinically significant depressive symptoms were high among patients (23%) and caregivers (19%), and remained elevated through 6-months. Higher depressive symptoms predicted higher levels of symptoms at the subsequent timepoint (ps < 0.05). Higher baseline mindfulness and coping were associated with lower levels of depressive symptoms at all timepoints (ps < 0.001). APIM analysis showed that one's own higher baseline mindfulness was associated with concurrent levels of depressive symptoms in a partner (p < 0.05). CONCLUSIONS: Depressive symptoms in Neuro-ICU patient-caregiver dyads are high through 6 months. Mindfulness is protective against depressive symptoms and interdependent between patients and caregivers. Early, dyadic, mindfulness-based interventions may prevent the development of chronic depression in both patients and caregivers.

Gender Differences in Longitudinal Associations Between Intimate Care, Resiliency, and Depression Among Informal Caregivers of Patients Surviving the Neuroscience Intensive Care Unit.

BACKGROUND/OBJECTIVE: Informal caregivers (e.g., family and friends) are at risk for developing depression, which can be detrimental to both caregiver and patient functioning. Initial evidence suggests that resiliency may reduce the risk of depression. However, gender differences in associations between multiple psychosocial resiliency factors and depression have not been examined among neuroscience intensive care unit (neuro-ICU) caregivers. We explored interactions between caregiver gender and baseline resiliency factors on depression symptom severity at baseline through 3 and 6 months post-discharge. METHODS: Caregivers (N = 96) of neuro-ICU patients able to provide informed consent to participate in research were enrolled as part of a prospective, longitudinal study in the neuro-ICU of a major academic medical center. Caregiver sociodemographics and resiliency factors (coping, mindfulness, self-efficacy, intimate care, and preparedness for caregiving) were assessed during the patient's hospitalization (i.e., baseline). Levels of depressive symptoms were measured using the Hospital Anxiety and Depression Scale at baseline, 3 months, and 6 months post-discharge. RESULTS: Baseline depressive symptoms predicted depressive symptoms at both 3- and 6-month follow-ups, with no difference at any time point in rates of depression by gender. At baseline, greater levels of coping, mindfulness, and preparedness for caregiving were individually associated with lower levels of concurrent depression regardless of gender (ps < 0.006). The main effect of baseline coping remained significant at 3-month follow-up (p = 0.045). We observed a trend-level interaction between gender and baseline intimate care, such that among male caregivers only, high baseline intimate care was associated with lower depression at 3-month follow-up (p = 0.055). At 6-month follow-up, we observed a significant interaction between caregiver gender and baseline intimate care, such that male caregivers reporting high intimate care reported lower symptoms of depression than females reporting high intimate care (p = 0.037). CONCLUSIONS: Results support implementation of psychosocial resiliency interventions for caregivers of patients admitted to the neuro-ICU early in the recovery process. Male caregivers may particularly benefit from strategies focused on increasing intimate care (e.g., physical and emotional affection with their loved one) and quality of the patient-caregiver dyadic relationship.

Resiliency is independently associated with greater quality of life among informal caregivers to neuroscience intensive care unit patients.

OBJECTIVE: Every year, millions of Americans become informal caregivers to loved ones admitted to Neuroscience Intensive Care Units (Neuro-ICU), and face challenges to Quality of Life (QoL). This study sought to identify associations between resiliency, distress, and caregiver QoL at time of Neuro-ICU admission. METHODS: Informal caregivers (N = 79, Mage = 53, 64% female) of Neuro-ICU patients were recruited and completed self-report questionnaires during the hospitalization. We used hierarchical regression to test relative contributions of caregiver mindfulness, perceived coping abilities, and preparedness for caregiving to caregiver QoL, above-and-beyond non-modifiable patient and caregiver factors (e.g., gender) and caregiver psychological distress (i.e., anxiety, depression, history of mental health conditions). RESULTS: Preparedness for caregiving was uniquely and positively associated with Physical Health QoL (sr2 = 0.07, p = 0.001), Social QoL (sr2 = 0.05, p = 0.021), and Environmental QoL (sr2 = 0.14, p < 0.001), even after accounting for psychological distress. Mindfulness was uniquely and positively associated with Physical Health QoL (sr2 = 0.12, p < 0.001) and Psychological QoL (sr2 = 0.07, p = 0.004), above-and-beyond variance accounted for by psychological distress. CONCLUSIONS: Mindfulness and preparedness for caregiving emerged as consistent, unique resiliency factors associated with greater caregiver QoL across QoL dimensions. Results highlight the importance of resiliency factors in QoL among Neuro-ICU caregivers and the need for early interventions to support resiliency.

Mindfulness and Coping Are Inversely Related to Psychiatric Symptoms in Patients and Informal Caregivers in the Neuroscience ICU: Implications for Clinical Care.

OBJECTIVE: To assess the correlation of psychosocial resiliency factors (mindfulness and coping) with symptoms of posttraumatic stress, anxiety, and depression in patients recently admitted to the neuroscience ICU and their primary informal caregivers. DESIGN: A descriptive, cross-sectional correlational study. SETTING: Neuroscience ICU in a major medical center. PARTICIPANTS: A total of 78 dyads of patients (total n = 81) and their primary caregivers (total n = 92) from June to December 2015. Study enrollment occurred within the first 2 weeks of patient admission to the neuroscience ICU. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Dyads completed self-report measures of mindfulness (Cognitive and Affective Mindfulness Scale-Revised), coping (Measure of Coping Status-A), posttraumatic stress (Posttraumatic Checklist-Specific Stressor), anxiety (Hospital Anxiety and Depression Scale-A), and depression (Hospital Anxiety and Depression Scale-D). Rates of clinically significant posttraumatic stress, anxiety, and depressive symptoms were high and comparable between patient and caregiver samples. Own psychological resilience factors and psychiatric symptoms were strongly correlated for both patients and caregivers. Depressive symptoms were interdependent between patients and their caregivers, and one's own mindfulness was independently related to one's partner's depressive symptoms. CONCLUSIONS: Rates of clinically significant psychiatric symptoms were high, equally prevalent in patients and caregivers, and interdependent between patients and their caregivers. For both patients and caregivers, psychological resiliency factors were associated with both self and partner psychiatric symptoms. Findings suggest that attending to the psychiatric health of both patients and caregivers in the neuroscience ICU is a priority and that patients and their caregivers must be considered together in a system to fully address either individual's psychiatric symptoms.

Psychosocial resiliency is associated with lower emotional distress among dyads of patients and their informal caregivers in the neuroscience intensive care unit.

PURPOSE: The purpose of the study is to examine the associations of patients' and their informal caregivers' psychosocial resiliency factors with their own and their partners' emotion domains (distress, anxiety, depression, and anger) after admission to the neuroscience intensive care unit (Neuro-ICU). MATERIALS AND METHODS: Eighty-three dyads of patients (total n = 87) and their informal caregivers (total n = 99) participated in this observational, cross-sectional study by self-reporting demographics and measures of resiliency factors (mindfulness [Cognitive and Affective Mindfulness Scale Revised], coping [Measure of Coping Status-A], intimate bond [Intimate Bond Measure], self-efficacy [patients: General Self-Efficacy Scale; caregivers: Revised Caregiver Self-Efficacy Scale]) and emotion domains (Emotion Thermometers) within 2 weeks of Neuro-ICU admission. RESULTS: There were no differences between patients' and caregivers' levels of psychosocial resiliency, distress, or anxiety. Patients reported greater depression and anger relative to their caregivers. Overall, roughly half of patients (50.6%) and caregivers (42.4%) reported clinically significant emotional distress. Patients' and caregivers' own psychosocial resiliency factors were associated with their own, but not their partner's, emotion domains. CONCLUSIONS: Findings of high distress among both patients and caregivers at admission emphasize the importance of attending to the mental health of both patients and caregivers in the Neuro-ICU. As modifiable psychosocial resiliency factors were associated with emotion domains for both patients and caregivers, interventions to enhance these factors may ameliorate emotional distress among these vulnerable populations.

Predictors of hematoma volume in deep and lobar supratentorial intracerebral hemorrhage.

IMPORTANCE: Hematoma volume is the strongest predictor of outcome in intracerebral hemorrhage (ICH). Despite known differences in the underlying biology between deep and lobar ICHs, limited data are available on location specificity of factors reported to affect hematoma volume. OBJECTIVE: To evaluate whether determinants of ICH volume differ by topography, we sought to estimate location-specific effects for potential predictors of this radiological outcome. DESIGN: Prospective cohort study. SETTING: Academic medical center. PARTICIPANTS: A total of 744 supratentorial primary ICH patients (388 deep and 356 lobar) aged older than 18 years admitted between January 1, 2000, and December 31, 2010. MAIN OUTCOMES AND MEASURES: Intracerebral hemorrhage volume measured from the computed tomography scan obtained on presentation to the emergency department. Linear regression analysis, stratified by ICH location, was implemented to identify determinants of log-transformed ICH volume. RESULTS: Median ICH volume was larger in lobar hemorrhages (39 mL; interquartile range, 16-75 mL) than in deep hemorrhages (13 mL; interquartile range, 5-40 mL; P < .001). In multivariable linear regression, independent predictors of deep ICH volume were intensity of anticoagulation (ß = 0.32; standard error [SE] = 0.08; P < .001; test for trend across 4 categories of the international normalized ratio), history of coronary artery disease (ß = 0.33; SE = 0.17; P = .05), male sex (ß = 0.28; SE = 0.14; P = .05), and age (ß = -0.02; SE = 0.01; P = .001). Independent predictors of lobar ICH volume were intensity of anticoagulation (ß = 0.14; SE = 0.06; P = .02) and antiplatelet treatment (ß = 0.27; SE = 0.13; P = .03). CONCLUSIONS AND RELEVANCE: Predictors of hematoma volume only partially overlap between deep and lobar ICHs. These findings suggest that the mechanisms that determine the extent of bleeding differ for deep and lobar ICHs. Further studies are needed to characterize the specific biological pathways that underlie the observed associations.

Effect of statins on intracerebral hemorrhage outcome and recurrence.

BACKGROUND AND PURPOSE: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved outcome after ischemic stroke and subarachnoid hemorrhage but an increased risk of incident intracerebral hemorrhage (ICH). We investigated (1) whether statin use before ICH was associated with functional independence at 90 days, and (2) whether survivors exposed to statins after ICH had an increased risk of recurrence. METHODS: We analyzed 629 consecutive ICH patients with 90-day outcome data enrolled in a prospective cohort study between 1998 to 2005. Statin use was determined by patient interview at the time of ICH and supplemented by medical record review. Independent status was defined as Glasgow Outcome Scale 4 or 5. ICH survivors were followed by telephone interview every 6 months. RESULTS: Statins were used by 149/629 (24%) before ICH. There was no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%, P=0.84) or mortality (46% versus 45%, P=0.93). Medical comorbidities and warfarin use were more common in statin users. Hematoma volumes were similar (median 28 cm(3) in pre-ICH statin users compared to 22 cm(3) in nonusers, P=0.18). The multivariable-adjusted odds ratio for independent status in pre-ICH statin users was 1.16 (95% CI 0.65 to 2.10, P=0.62). ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34 to 1.99, P=0.66). CONCLUSIONS: Pre-ICH statin use is not associated with improved ICH functional outcome or mortality. Post-ICH statin use is not associated with an increased risk of ICH recurrence.