The 21-point Brain Care Score (BCS) is a novel tool designed to motivate individuals and care providers to take action to reduce the risk of stroke and dementia by motivating lifestyle changes (Fig 1). In this study we aimed to assess if the BCS is also associated with brain changes on MRI in people who have not yet developed dementia or stroke. Methods: This study was conducted within the MRI substudy of the longitudinal cohort study UK Biobank. The assessed MRI neuroimaging markers included: brain volume, white matter hyperintensities (WMH) volume, fractional anisotropy (FA) and mean diffusivity (MD). FA/MD metrics were calculated as the average across 48 discrete brain regions. We used multivariable linear regression to test for association between the BCS computed using baseline data (2006-2010) and neuroimaging markers, measured both during first (2014+) and repeat (2019+) MRI assessments. Results: There were 34,772 study participants with MRIs and available BCS data (mean age 55, 53% female). Every five-point increase in the BCS was associated with an 11% increase in brain volume (Beta 0.11, SE 0.01), a 26% reduction in WMH volume (Beta -0.26, SE 0.01), a 13% increase in average FA (Beta 0.13, SE 0.02), and a 9% decrease in average MD (Beta -0.09, SE 0.01). There were 3,778 study participants with first and repeat MRI (mean age 53, 53% female). Comparing the first and repeat imaging assessments, every five-point increase in baseline BCS was associated with a slower growth in WMH volume (Beta -0.08, SE 0.03) and a slower reduction in average FA (Beta 0.11, SE 0.03). Discussion: Among middle-aged adults without dementia or stroke, a higher BCS is strongly associated with better neuroimaging brain health profiles and slower rates of brain health decline. Given that the neuroimaging markers evaluated in our study are recognized risk factors that precede stroke and dementia by many years, our results support the BCS is a promising tool for early intervention to prevent these conditions.
Current treatments for ischemic stroke are insufficient. The lack of effective pharmacological approaches can be mainly attributed to the difficulty in overcoming the blood–brain barrier. Here, we report a simple strategy to synthesize protease-responsive, brain-targeting nanoparticles for the improved treatment of stroke. The resulting nanoparticles respond to proteases enriched in the ischemic microenvironment, including thrombin or matrix metalloproteinase-9, by shrinking or expanding their size. Targeted delivery was achieved using surface conjugation of ligands that bind to proteins that were identified to enrich in the ischemic brain using protein arrays. By screening a variety of formulations, we found that AMD3100-conjugated, size-shrinkable nanoparticles (ASNPs) exhibited the greatest delivery efficiency. The brain targeting effect is mainly mediated by AMD3100, which interacts with CXCR4 that is enriched in the ischemic brain tissue. We showed that ASNPs significantly enhanced the efficacy of glyburide, a promising stroke therapeutic drug whose efficacy is limited by its toxicity. Due to their high efficiency in penetrating the ischemic brain and low toxicity, we anticipate that ASNPs have the potential to be translated into clinical applications for the improved treatment of stroke patients.
Abstract Background At least 60% of stroke, 40% of dementia, and 35% of late-life depression (LLD) are attributable to modifiable risk factors, with great overlap due to a shared underlying pathophysiology. This study aims to systematically identify overlapping risk factors for these diseases and calculate their relative impact on a composite outcome. Methods A systematic literature review was performed in Pubmed, Embase, and PsycInfo, between January 2000 and September 2023. We included meta-analyses reporting effect sizes of modifiable risk factors on the incidence of stroke, dementia, and/or LLD. The most relevant meta-analyses were selected, and Disability Adjusted Life Year (DALY) weighted beta-coefficients were calculated for a composite outcome. The beta-coefficients were then normalized to assess relative impact. Results Our search yielded 182 meta-analyses meeting the inclusion criteria, of which 59 were selected to calculate DALY-weighted risk factors for a composite outcome. Identified risk factors included alcohol use (normalized beta-coefficient highest category: -20), blood pressure (87), BMI (42), fasting plasma glucose (57), total cholesterol (14), leisure time cognitive activity (-54), depressive symptoms (34), diet (27), hearing loss (35), kidney function (60), pain (25), physical activity (-34), purpose in life (-30), sleep (44), smoking (58), social engagement (32), and stress (32). Discussion This study identified overlapping modifiable risk factors and calculated the relative impact of these factors on the risk of a composite outcome of stroke, dementia, and LLD. These findings could guide preventative strategies and serve as an empirical foundation for future development of tools that can empower people to reduce their risk of these diseases. Funding US National Institutes of Health and American Heart Association.
Type 2 diabetes mellitus (T2DM) is highly genetically determined, and polygenic susceptibility to T2DM (PSD) increases the risk of worse glycemic control and adverse vascular outcomes. Its role in stroke patients remains unknown. We aim to determine whether higher PSD is associated with worse glycemic control in stroke survivors. We conducted a 2-stage genetic association study. In a cross-sectional design, we selected stroke survivors from the UK Biobank (enrollment between 2006 and 2010) to evaluate the relationship between PSD and glycemic control. Second, we replicated the results using data from All of Us (enrollment between 2018 and 2022). Exposures were low, intermediate, and high PSD, modeled through percentiles (<20, 20-80, >80) of a polygenic risk score of 2,522 independent risk variants associated with T2DM at genome-wide levels (p < 5 × 10-8). Outcomes were hemoglobin A1c (HbA1c) levels, uncontrolled diabetes (HbA1c ≥7.0%), and resistant diabetes (uncontrolled despite antidiabetic treatment). Stage 1 included 6,908 stroke survivors (mean age 61 years, 42% female), including 977 (14%) with diabetes. Compared with low PSD, participants with high PSD had an increase of 0.49 in HbA1c (β = 0.49, standard error 0.03, p-trend <0.001), 6.9 times the odds of uncontrolled diabetes (odds ratio [OR] 6.92, 95% CI 4.71-10.52), and 7.8 times the odds of resistant diabetes (OR 7.76, 95% CI 4.92-12.89). Stage 2 (replication) confirmed the association with HbA1c in 4,451 stroke survivors, including 2,163 (49%) with diabetes (mean age 64 years, 53% female, p-trend <0.05 for all tests). Among stroke survivors, a higher PSD was associated with poorer glycemic control. Further research should determine precision medicine strategies using PSD to improve clinical management of stroke patients.
Objective: It remains unclear whether patients with unruptured intracranial aneurysms (UICAs) should be treated. Vessel wall enhancement (VWE) in vessel wall MRI is emerging as a useful biomarker of aneurysm instability. We sought to evaluate whether VWE correlates with clinical and radiological markers of aneurysm instability in patients with UICAs. Methods: We conducted a retrospective analysis of a prospective cohort of patients with UICAs imaged with vessel wall MRI. Two blinded reviewers evaluated the presence of VWE. Univariate and multivariate logistic regression modelling was utilized to assess for association between VWE and (1) presence of cranial nerve palsy (CNP) and thunderclap headache on presentation, two well-established clinical markers of aneurysm instability; and (2) aneurysm size, a well-established radiological marker of aneurysm instability. Results: 94 patients with UICAs were included in the analysis; of these, 34 (36%) had VWE, 60 (64%) did not, 10 (11%) had CNP, 14 (15%) presented with thunderclap headache, and 40 (43%) had aneurysms >7mm in size. Inter-rater reliability for VWE ascertainment was excellent (kappa 0.86, 95%CI 0.75-0.97). 9 out of 10 patients (90%) with CNP had VWE (association testing not possible due to sparse counts). In multivariable analysis, thunderclap headache (OR 8.55, 95%CI 1.89-45.64; p=0.007) and aneurysm size (1.26, 95%CI 1.10-1.50; p=0.003) were independently associated with VWE. Conclusions: VWE independently associates with clinical and radiological markers of aneurysm instability. Prospective studies are needed to evaluate the clinical utility of this imaging biomarker.
Introduction: Prior studies of critically ill patients found that non-whites are less likely to pursue comfort measures only status (CMOs). We sought to identify determinants of CMOs in a large multi-ethnic cohort study of intracerebral hemorrhage (ICH). Methods: We analyzed cases enrolled from 2010 to 2015 in the Ethnic/Racial Variations of ICH (ERICH) study, a multi-center study in the USA. Clinical, demographic and radiologic data on non-traumatic ICH patients were prospectively collected. Univariate and multivariate logistic regression was used to evaluate the association between ethnicity/race and CMOs after adjustment for potential confounders. Results: 2705 ICH cases were included in this study (mean age 62 (14), female sex 1119 [41%]). Of these, 912 were black (34%), 893 Hispanic (33%) and 900 white (33%). CMOs patients comprised 276 (10%), 64 (7%), 79 (9%) and 133 (15%) of the entire cohort and the black, Hispanic and white cohorts, respectively (p<0.001) (Table 1). In multivariate analysis, black patients were half as likely as white patients to be made CMO (OR 0.50, 95% CI 0.34-0.75; p=0.001) and there was a trend for Hispanic patients to have CMOs less often than white patients (OR 0.72, 95% CI 0.49-1.06, p=0.093) (Table 2). Other factors associated with CMOs included age, premorbid modified Rankin Scale, dementia, admission Glasgow Coma Scale, ICH volume, intraventricular hematoma volume, lobar and brainstem bleeds and intubation. Conclusion: Black patients were less likely than white patients to be made CMO after controlling for potential confounders. Further investigation is warranted to understand the causes and implications of racial disparities in CMO decisions.
Wiley is a founding member of the UN-backed HINARI, AGORA, and OARE initiatives.They are now collectively known as Research4Life, making online scientific content available free or at nominal cost to researchers in
Slow waves are a distinguishing feature of non-rapid-eye-movement (NREM) sleep, an evolutionarily conserved process critical for brain function. Non-human studies suggest that the claustrum, a small subcortical nucleus, coordinates slow waves. We show that, in contrast to neurons from other brain regions, claustrum neurons in the human brain increase their spiking activity and track slow waves during NREM sleep, suggesting that the claustrum plays a role in coordinating human sleep architecture.
Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment.
Background and Purpose— It is unknown whether admission systolic blood pressure (SBP) differs among causes of intracerebral hemorrhage (ICH). We sought to elucidate an association between admission BP and ICH cause. Methods— We compared admission SBP across ICH causes among patients in the Cornell Acute Stroke Academic Registry, which includes all adults with ICH at our center from 2011 through 2017. Trained analysts prospectively collected demographics, comorbidities, and admission SBP, defined as the first recorded value in the emergency department or on transfer from another hospital. ICH cause was adjudicated by a panel of neurologists using the SMASH-U criteria. We used ANOVA to compare mean admission SBP among ICH causes. We used multiple linear regression to adjust for age, sex, race, Glasgow Coma Scale score, and hematoma size. In secondary analyses, we compared hourly SBP measurements during the first 72 hours after admission, using mixed-effects linear models adjusted for the covariates above plus antihypertensive agents. Results— Among 484 patients with ICH, admission SBP varied significantly across ICH causes, ranging from 138 (±24) mm Hg in those with structural vascular lesions to 167 (±35) mm Hg in those with hypertensive ICH ( P <0.001). The mean admission SBP in hypertensive ICH was 17 (95% CI, 11–24) mm Hg higher than in ICH of all other causes combined. These differences remained significant after adjustment for age, sex, race, Glasgow Coma Scale score, and hematoma size ( P <0.001), and this persisted throughout the first 72 hours of hospitalization ( P <0.001). Conclusions— In a single-center ICH registry, SBP varied significantly among ICH causes, both on admission and during hospitalization. Our results suggest that BP in the acute post-ICH setting is at least partly associated with ICH cause rather than simply representing a physiological reaction to the ICH itself.
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