Brain artery diameters and risk of dementia and stroke.

INTRODUCTION: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images. METHODS: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke. RESULT: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13-2.68) and 1.48 (95% CI, 1.12-1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04-2.42) for overall arteries and 2.11 (95% CI, 1.45-3.08) for basilar artery diameters > 95th percentile. DISCUSSION: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke.

Intensive Blood Pressure Treatment and Subclinical Brain Infarcts: A Secondary Analysis of SPRINT (Systolic Pressure Intervention Trial).

OBJECTIVE: Subclinical brain infarcts (SBI) increase the risk for stroke and dementia, but whether they should be considered equivalent to symptomatic stroke when determining blood pressure targets remains unclear. We tested whether intensive systolic blood pressure (SBP) treatment reduced the risk of new SBI or stroke and determined the association between SBI and cognitive impairment. METHODS: In this secondary analysis of SPRINT (Systolic Pressure Intervention Trial), participants ≥50 years old, with SBP 130-180mmHg and elevated cardiovascular risk but without known clinical stroke, dementia, or diabetes, were randomized to intensive (<120mmHg) or standard (<140mmHg) SBP treatment. Brain magnetic resonance images collected at baseline and follow-up were read for SBI. The occurrence of mild cognitive impairment (MCI) or probable dementia (PD) was evaluated. RESULTS: For 667 participants at baseline, SBI were identified in 75 (11%). At median 3.9 years follow-up, 12 of 457 had new SBI on magnetic resonance imaging (5 intensive, 7 standard), whereas 8 had clinical stroke (4 per group). Baseline SBI (subhazard ratio [sHR] = 3.90; 95% CI 1.49 to 10.24; p = 0.006), but not treatment group, was associated with new SBI or stroke. For participants with baseline SBI, intensive treatment reduced their risk for recurrent SBI or stroke (sHR = 0.050; 95% CI 0.0031 to 0.79; p = 0.033). Baseline SBI also increased risk for MCI or PD during follow-up (sHR = 2.38; 95% CI 1.23 to 4.61; p = 0.010). INTERPRETATION: New cerebral ischemic events were infrequent, but intensive treatment mitigated the increased risk for participants with baseline SBI, indicating primary prevention SBP goals are still appropriate when SBI are present. ANN NEUROL 2024;95:866-875.

Relationships of Hematocrit With Chronic Covert and Acute Symptomatic Lacunar Ischemic Lesions.

BACKGROUND AND OBJECTIVES: Red blood cell (RBC) concentrations are known to associate with ischemic stroke. It is unclear whether RBC concentrations associate specifically with small vessel disease lacunar infarcts. We investigated the hypothesis that RBC concentrations associate with both chronic covert and acute symptomatic brain MRI lacunar infarcts. METHODS: A cross-sectional observational analysis was performed across 2 cohorts with available hematocrit (as the assessment of RBC concentration exposure) and MRI outcome data. The primary setting was a population-based cohort of stroke-free, older adult (>50 years) participants from the Northern Manhattan Study (NOMAS) enrolled between 2003 and 2009. A second replication sample consisted of patients admitted with acute stroke and enrolled into the Columbia Stroke Registry (CSR) between 2005 and 2020. Associations of hematocrit with (1) chronic, covert lacunar infarcts and (2) symptomatic (i.e., acute) lacunar strokes were separately assessed from the NOMAS and CSR cohorts, respectively, using general additive models after adjusting for relevant covariates. RESULTS: Of 1,218 NOMAS participants analyzed, 6% had chronic, covert lacunar infarcts. The association between hematocrit and these covert lacunar infarcts was U-shaped (χ2 = 9.21 for nonlinear associations; p = 0.03), with people with hematocrit extremes being more likely to have covert lacunar infarcts. Of the 1,489 CSR patients analyzed, 23% had acute lacunar strokes. In this sample, only the relationships of increased hematocrit concentrations and lacunar strokes were replicated (adjusted coefficient ß = 0.020; SE = 0.009; p = 0.03). DISCUSSION: We identified relationships of hematocrit with MRI lacunar infarcts in both stroke-free and ischemic stroke cohorts, respectively. The relationship between increased hematocrit concentrations with lacunar infarcts was replicated in both cohorts. Further studies are required to clarify the mechanisms behind the relationships of hematocrit with ischemic cerebral small vessel disease.

Stroke Prevention in Atrial Fibrillation: Our Current Failures and Required Research.

Nonvalvular atrial fibrillation is a common rhythm disorder of middle-aged to older adults that can cause ischemic strokes and systemic embolism. Lifelong use of oral anticoagulants reduces the risk of these ischemic events but increases the risk of major and clinically relevant hemorrhages. These medications also require strict compliance for efficacy, and they have nontrivial failure rates in higher-risk patients. Left atrial appendage closure is a nonpharmacological method to prevent ischemic strokes in atrial fibrillation without the need for lifelong anticoagulant use, but this procedure has the potential for complications and residual embolic events. This workshop of the Roundtable of Academia and Industry for Stroke Prevention discussed future research needed to further decrease the ischemic and hemorrhagic risks among patients with atrial fibrillation. A direct thrombin inhibitor, factor Xa inhibitors, and left atrial appendage closure are FDA-approved approaches whereas factor XIa inhibitors are currently being studied in phase 3 randomized controlled trials for stroke prevention. The benefits, risks, and shortcomings of these treatments and future research required in different high-risk patient populations are reviewed in this consensus statement.

Herpes simplex virus 2 serology is associated with thinner whole-brain cortex in community-dwelling older adults.

Prior work in the Northern Manhattan Study (NOMAS) identified impaired cognition in cross-sectional analyses and more rapid memory decline in individuals with evidence of prior common infectious disease exposures. In this study, we sought to determine the cross-sectional relationship between prior exposure to cytomegalovirus, herpes simplex viruses 1 and 2, Chlamydia pneumoniae, and Helicobacter pylori and three magnetic resonance imaging (MRI) signatures (whole-brain cortical thickness, a previously validated AD signature, and hippocampal volume) in 455 NOMAS participants. We performed confounder-adjusted linear regression analyses between neuroimaging scores and both continuous serologies and categorical seropositivity of each pathogen, as well as a combined infectious burden index (IBI). We identified that increased serologic titers of herpes simplex virus 2 were associated with reduced whole-brain cortical thickness, and a combined score of HSV-2 and C. pneumoniae displayed an additive effect on reduced cortical thickness. Our findings suggest herpes simplex virus 2 seropositivity may contribute to accelerated brain aging, possibly resulting in an increased vulnerability to cognitive impairment and neurodegenerative disease in aging populations.

Diffusion tensor free water MRI predicts progression of FLAIR white matter hyperintensities after ischemic stroke.

Background: The progression of FLAIR white matter hyperintensities (WMHs) on MRI heralds vascular-mediated cognitive decline. Even before FLAIR WMH progression, adjacent normal appearing white matter (NAWM) already demonstrates microstructural deterioration on diffusion tensor imaging (DTI). We hypothesized that elevated DTI free water (FW) would precede FLAIR WMH progression, implicating interstitial fluid accumulation as a key pathological step in the progression of cerebral small vessel disease. Methods: Participants at least 3 months after an ischemic stroke or TIA with WMH on MRI underwent serial brain MRIs every 3 months over the subsequent year. For each participant, the WMHs were automatically segmented, serial MRIs were aligned, and a region of WMH penumbra tissue at risk was defined by dilating lesions at any time point and subtracting baseline lesions. Penumbra voxels were classified as either stable or progressing to WMH if they were segmented as new lesions and demonstrated increasing FLAIR intensity over time. Aligned DTI images included FW and FW-corrected fractional anisotropy (FATissue) and mean diffusivity (MDTissue). Logistic regression and area under the receiver-operator characteristic curve (AUC) were used to test whether baseline DTI predicted voxel-wise classification of stable penumbra or progression to WMH while covarying for clinical risk factors. Results: In the included participants (n = 26, mean age 71 ± 9 years, 31% female), we detected a median annual voxel-wise WMH growth of 2.9 ± 2.6 ml. Each baseline DTI metric was associated with lesion progression in the penumbra, but FW had the greatest AUC of 0.732 (0.730 - 0.733) for predicting voxel-wise WMH progression pooled across participants. Discussion: Baseline increased interstitial fluid, estimated as FW on DTI, predicted the progression of NAWM to WMH over the following year. These results implicate the presence of FW in the pathogenesis of cerebral small vessel disease progression.

Intensive systolic blood pressure treatment remodels brain perivascular spaces: A secondary analysis of the Systolic Pressure Intervention Trial (SPRINT).

BACKGROUND: Brain perivascular spaces (PVS) are part of the glymphatic system and facilitate clearance of metabolic byproducts. Since enlarged PVS are associated with vascular health, we tested whether intensive systolic blood pressure (SBP) treatment affects PVS structure. METHODS: This is a secondary analysis of the Systolic PRessure INtervention Trial (SPRINT) MRI Substudy: a randomized trial of intensive SBP treatment to goal < 120 mm Hg vs < 140 mm Hg. Participants had increased cardiovascular risk, pre-treatment SBP 130-180, and no clinical stroke, dementia, or diabetes. Brain MRIs acquired at baseline and follow-up were used to automatically segment PVS in the supratentorial white matter and basal ganglia using a Frangi filtering method. PVS volumes were quantified as a fraction of the total tissue volume. The effects of SBP treatment group and major antihypertensive classes on PVS volume fraction were separately tested using linear mixed-effects models while covarying for MRI site, age, sex, Black race, baseline SBP, history of cardiovascular disease (CVD), chronic kidney disease, and white matter hyperintensities (WMH). RESULTS: For 610 participants with sufficient quality MRI at baseline (mean age 67 ± 8, 40 % female, 32 % Black), greater PVS volume fraction was associated with older age, male sex, non-Black race, concurrent CVD, WMH, and brain atrophy. For 381 participants with MRI at baseline and at follow-up (median ± IQR = 3.9 ± 0.4 years), intensive treatment was associated with decreased PVS volume fraction relative to standard treatment (interaction coefficient: -0.029 [-0.055 to -0.0029] p = 0.029). Reduced PVS volume fraction was also associated with exposure to calcium channel blockers (CCB). CONCLUSIONS: PVS enlargement was partially reversed in the intensive SBP treatment group. The association with CCB use suggests that improved vascular compliance may be partly responsible. Improved vascular health may facilitate glymphatic clearance. Clincaltrials.gov: NCT01206062.

Osteopontin is associated with dementia in the presence of cerebral small vessel disease.

BACKGROUND: Osteopontin (OPN) is a proinflammatory cytokine that has been recently implicated in neuroinflammation and neurodegeneration. We hypothesized that an increase in plasma osteopontin is a deleterious neuroinflammatory marker in people with dementia and cerebral small vessel disease (CSVD). METHODS: A pilot study was conducted on participants in the Northern Manhattan Study (NOMAS). Three groups were selected based on their dementia status and evidence of subclinical CSVD and chosen to be similar in age, sex, and education attainment: No dementia/No CSVD (n=19), Dementia/No CSVD (n=22), and Dementia+CSVD (n=21). Dementia (any type) was diagnosed by consensus adjudication following a series of comprehensive neuropsychological assessments and a review of the medical history. CSVD was indicated by silent brain infarcts, enlarged perivascular spaces, cerebral microbleeds, and white matter hyperintensity volumes (WMHV) on MRI. Multinomial logistic regression was used to examine the difference in OPN levels across groups, adjusting for key determinants of CSVD and neurodegeneration. RESULTS: Plasma osteopontin levels were elevated in the Dementia+CSVD group (mean=70.69±39.00 ng/ml) but not in the Dementia/No CSVD group (mean=45.46±19.11 ng/ml) compared to the No dementia/No CSVD group (mean=36.43±15.72 ng/ml). Osteopontin was associated with Dementia+CSVD (Odds Ratio (OR) per ng/ml=1.06, 95%CI 1.02-1.11) after adjusting for covariates, including brain volume. OPN was strongly correlated with WMHV (Spearman's rank correlation =0.46, p=0.0001), but not with other components of CSVD. CONCLUSION: In this pilot, greater levels of plasma osteopontin were associated with dementia with evidence of CSVD. This link was predominately driven by the contribution of OPN to dementia through the burden of white matter lesions.

Mediterranean-style diet and intracranial large artery stenosis in the Northern Manhattan Study.

OBJECTIVES: Given Mediterranean-style diet (MeDi) reduces risk of cardiovascular events, we hypothesized MeDi may also be protective against intracranial large artery stenosis (ICAS), a common cause of stroke worldwide. METHODS: This cross-sectional study included stroke-free participants of the Northern Manhattan Study, a diverse population-based study of stroke risk factors. We represented MeDi continuously (range 0-8) based on enrollment food frequency questionnaires, excluding alcohol consumption. We evaluated ICAS both dichotomously at clinically relevant stenosis severities and continuously as a score (possible range 0-44), summated from stenosis severity scores of major intracranial arteries from time-of-flight magnetic resonance angiography. We used logistic or zero-inflated Poisson regression, adjusting for key confounders. RESULTS: Among 912 included participants (mean age 64±8 years, 59% female, 65% Hispanic, mean MeDi score 4±1.5), 5% and 8% of participants had ≥50% or ≥70% ICAS, respectively (score median [interquartile range]: 0 [0-2]). Increased MeDi score was inversely associated with ICAS, but did not reach statistical significance (≥50% stenosis odds ratio (OR) [95% confidence interval (CI)]: 0.89 [0.79-1.06]; ≥70% stenosis OR [95% CI]: 0.91 [0.74-1.13]; stenosis score ß-estimate [95% CI]: -0.02 [-0.06-0.01]). CONCLUSION: In this stroke-free subsample, we did not find a significant association between MeDi and ICAS. We may have been limited by statistical power.

Intensive Systolic Blood Pressure Treatment Remodels Brain Perivascular Spaces: A Secondary Analysis of SPRINT.

Background: Brain perivascular spaces (PVS) are part of the glymphatic system and facilitate clearance of metabolic byproducts. Since enlarged PVS are associated with vascular health, we tested whether intensive systolic blood pressure (SBP) treatment affects PVS structure. Methods: This is a secondary analysis of the Systolic PRessure INTervention (SPRINT) Trial MRI Substudy: a randomized trial of intensive SBP treatment to goal < 120 mm Hg vs. < 140 mm Hg. Participants had increased cardiovascular risk, pre-treatment SBP 130-180, and no clinical stroke, dementia, or diabetes. Brain MRIs acquired at baseline and follow-up were used to automatically segment PVS in the supratentorial white matter and basal ganglia using a Frangi filtering method. PVS volumes were quantified as a fraction of the total tissue volume. The effects of SBP treatment group and major antihypertensive classes on PVS volume fraction were separately tested using linear mixed-effects models while covarying for MRI site, age, sex, black race, baseline SBP, history of cardiovascular disease (CVD), chronic kidney disease, and white matter hyperintensities (WMH). Results: For 610 participants with sufficient quality MRI at baseline (mean age 67±8, 40% female, 32% black), greater PVS volume fraction was associated with older age, male sex, non-Black race, concurrent CVD, WMH, and brain atrophy. For 381 participants with MRI at baseline and at follow-up (median = 3.9 years), intensive treatment was associated with decreased PVS volume fraction relative to standard treatment (interaction coefficient: -0.029 [-0.055 to -0.0029] p=0.029). Reduced PVS volume fraction was also associated with exposure to calcium channel blockers (CCB) and diuretics. Conclusions: Intensive SBP lowering partially reverses PVS enlargement. The effects of CCB use suggests that improved vascular compliance may be partly responsible. Improved vascular health may facilitate glymphatic clearance. Clincaltrials.gov : NCT01206062.

Association of Brain Arterial Elongation With Risk of Stroke and Death in Stroke-Free Individuals: Results From NOMAS.

BACKGROUND: Brain arterial dilation and elongation characterize dolichoectasia, an arteriopathy associated with risk of stroke and death. We aim to determine whether brain arterial elongation increases the risk of stroke and death independent of brain arterial diameters. METHODS: We analyzed 1210 stroke-free participants (mean age 71±9 years, 41% men, 65% Hispanic) with available time-of-flight magnetic resonance angiogram from the Northern Manhattan Study, a population-based cohort study across a multiethnic urban community. We obtained baseline middle cerebral artery M1-segment (MCA-M1) and basilar artery (BA) mean lengths and diameters using a semi-automated software. Cox proportional hazards models adjusted for brain arterial diameters and potential confounders yielded adjusted hazards ratios with 95% CIs for the primary outcomes of incident stroke and all-cause mortality, as well as secondary outcomes including noncardioembolic stroke, vascular death, and any vascular event. RESULTS: Neither MCA-M1 nor BA lengths correlated with incident stroke or all-cause mortality. Both MCA-M1 and BA larger diameters correlated with all-cause mortality (MCA-M1 aHR, 1.52 [95% CI, 1.03-2.23], BA aHR, 1.28 [95% CI, 1.02-1.61]), as well as larger MCA-M1 diameters with vascular death (aHR, 1.84 [95% CI, 1.02-3.31]). Larger MCA-M1 and BA diameters did not correlate with incident stroke. However, larger BA diameters were associated with posterior circulation noncardioembolic stroke (aHR, 2.93 [95% CI, 1.07-8.04]). There were no statistical interactions between brain arterial lengths and diameters in relation to study outcomes. CONCLUSIONS: In a multiethnic cohort of stroke-free adults, brain arterial elongation did not correlate with risk of stroke or death, nor influenced the significant association between brain arterial dilation and vascular risk.

Association of Left Atrial Strain With Ischemic Stroke Risk in Older Adults.

Importance: The risk of ischemic stroke is higher among patients with left atrial (LA) enlargement. Left atrial strain (LAε) and LA strain rate (LASR) may indicate LA dysfunction when LA volumes are still normal. The association of LAε with incident ischemic stroke in the general population is not well established. Objective: To investigate whether LAε and LASR are associated with new-onset ischemic stroke among older adults. Design: The Cardiovascular Abnormalities and Brain Lesions study was conducted from September 29, 2005, to July 6, 2010, to investigate cardiovascular factors associated with subclinical cerebrovascular disease. A total of 806 participants in the Northern Manhattan Study who were aged 55 years or older without history of prior stroke or atrial fibrillation (AF) were included, and annual follow-up telephone interviews were completed May 22, 2022. Statistical analysis was performed from June through November 2022. Exposures: Left atrial strain and LASR were assessed by speckle-tracking echocardiography. Global peak positive longitudinal LAε and positive longitudinal LASR during ventricular systole, global peak negative longitudinal LASR during early ventricular diastole, and global peak negative longitudinal LASR during LA contraction were measured. Brain magnetic resonance imaging was used to detect silent brain infarcts and white matter hyperintensities at baseline. Main Outcomes and Measures: Risk analysis with cause-specific Cox proportional hazards regression modeling was used to assess the association of positive longitudinal LAε and positive longitudinal LASR with incident ischemic stroke, adjusting for other stroke risk factors, including incident AF. Results: The study included 806 participants (501 women [62.2%]) with a mean (SD) age of 71.0 (9.2) years; 119 participants (14.8%) were Black, 567 (70.3%) were Hispanic, and 105 (13.0%) were White. During a mean (SD) follow-up of 10.9 (3.7) years, new-onset ischemic stroke occurred in 53 participants (6.6%); incident AF was observed in 103 participants (12.8%). Compared with individuals who did not develop ischemic stroke, participants with ischemic stroke had lower positive longitudinal LAε and negative longitudinal LASR at baseline. In multivariable analysis, the lowest (ie, closest to zero) vs all other quintiles of positive longitudinal LAε (adjusted hazard ratio [HR], 3.12; 95% CI, 1.56-6.24) and negative longitudinal LASR during LA contraction (HR, 2.89; 95% CI, 1.44-5.80) were associated with incident ischemic stroke, independent of left ventricular global longitudinal strain and incident AF. Among participants with a normal LA size, the lowest vs all other quintiles of positive longitudinal LAε (HR, 4.64; 95% CI, 1.55-13.89) and negative longitudinal LASR during LA contraction (HR, 11.02; 95% CI 3.51-34.62) remained independently associated with incident ischemic stroke. Conclusions and Relevance: This cohort study suggests that reduced positive longitudinal LAε and negative longitudinal LASR are independently associated with ischemic stroke in older adults. Assessment of LAε and LASR by speckle-tracking echocardiography may improve stroke risk stratification in elderly individuals.

Genome-wide association study of executive function in a multi-ethnic cohort implicates LINC01362: Results from the northern Manhattan study.

Executive function is a cognitive domain with sizable heritability representing higher-order cognitive abilities. Genome-wide association studies (GWAS) of executive function are sparse, particularly in populations underrepresented in medical research. We performed a GWAS on a composite measure of executive function that included measures of mental flexibility and reasoning using data from the Northern Manhattan Study, a racially and ethnically diverse cohort (N = 1077, 69% Hispanic, 17% non-Hispanic Black and 14% non-Hispanic White). Four SNPs located in the long intergenic non-protein coding RNA 1362 gene, LINC01362, on chromosome 1p31.1, were significantly associated with the composite measure of executive function in this cohort (top SNP rs2788328, ß = 0.22, p = 3.1 × 10-10). The associated SNPs have been shown to influence expression of the tubulin tyrosine ligase like 7 gene, TTLL7 and the protein kinase CAMP-activated catalytic subunit beta gene, PRKACB, in several regions of the brain involved in executive function. Together, these findings present new insight into the genetic underpinnings of executive function in an understudied population.

Physical Activity Is Inversely Associated With Severe Intracranial Stenosis in Stroke-Free Participants of NOMAS.

BACKGROUND: Although protective in secondary stroke prevention of intracranial arterial stenosis (ICAS), it is uncertain if the benefits of leisure time physical activity (LTPA) extend to asymptomatic ICAS or extracranial carotid stenosis (ECAS). Therefore, we sought to determine LTPA's relationship with ECAS and ICAS in a stroke-free, race-ethnically diverse cohort. METHODS: This cross-sectional study included participants from the magnetic resonance imaging substudy of the Northern Manhattan Study, of whom 1274 had LTPA assessments at enrollment. LTPA was represented continuously as metabolic equivalent score (MET-score) and ordinally as model-based cluster analysis (LTPA-cluster), both based on the same LTPA assessments. We evaluated ECAS sonographically using carotid intima-media thickening and number of carotid plaques. ICAS was assessed with time-of-flight magnetic resonance angiograph and defined as ≥50% or ≥70% stenosis. We applied regression analyses to evaluate the association between LTPA with ECAS and ICAS, adjusting for confounders. RESULTS: Of 1274 included participants (mean age 71±9 years; 60% women; 65% Hispanic), the mean MET-score was 10±16 and 60% were in a LTPA-cluster with any activity. Among those with carotid ultrasound (n=1234), the mean carotid intima-media thickening was 0.97±0.09 mm, and 56% of participants had at least one carotid plaque identified. Among those with magnetic resonance angiograph (n=1211), 8% had ≥50% ICAS and 5% had ≥70% ICAS. For ICAS, MET-score was associated with ≥70% ICAS (adjusted odds ratio per unit increase in MET-score [95% CI, 0.97 [0.94-0.99]) but not with ECAS measures (carotid intima-media thickening, adjusted ß-estimate per unit increase in MET-score [95% CI], 0.002 [-0.003 to 0.006] or number of plaques, adjusted ß-estimate [95% CI], 0.0001 [-0.0001 to 0.0003]). Substituting MET-score with LTPA-clusters replicated the association between ≥70% ICAS and LTPA (adjusted odds ratio per each increased LTPA-cluster [95% CI], 0.83 [0.70-0.99]). CONCLUSIONS: In this diverse stroke-free population, we found LTPA most strongly associated with asymptomatic ≥70% ICAS. Given the high-risk nature of ≥70% ICAS, these findings may emphasize the role of LTPA in people at risk for ICAS.

Intracranial artery stenosis is associated with cortical thinning in stroke-free individuals of two longitudinal cohorts.

BACKGROUND: We examined the association between asymptomatic intracranial artery stenosis (aICAS) and cortical thickness using brain magnetic resonance morphometry in two cohorts. METHODS: This cross-sectional study included stroke-free participants from the Northern Manhattan Study (NOMAS) and the National Alzheimer's Coordinating Center (NACC). We represented the predictor aICAS in NOMAS as a continuous global stenosis score reflecting an overall burden of stenosis (possible range 0-44) assessed by magnetic resonance angiography and in NACC as a dichotomous autopsy-determined Circle of Willis (CoW) atherosclerosis (none-mild vs moderate-severe). The primary outcome of interest was total cortical thickness. We analyzed each dataset separately using multivariable linear regression. RESULTS: The analysis included 1209 NOMAS (46% had any stenosis, 5% had ≥70% stenosis of at least one vessel; stenosis score range 0-11) and 392 NACC (36% moderate-severe CoW atherosclerosis) participants. We found an inverse relationship between stenosis score and total cortical thickness (ß-estimate [95% confidence interval (CI)]: -2.98 [-5.85, -0.11]) in adjusted models. We replicated these results in NACC (ß-estimate [95% CI]: -0.06 [-0.11, -0.003]). Post-hoc, we segregated stenosis scores by location and only posterior circulation stenosis score was associated with total cortical thickness (anterior ß-estimate [95% CI]: -0.90 [-5.16, 3.36], posterior ß-estimate [95% CI]: -7.25 [-14.30, -0.20]). CONCLUSION: We found both radiographically and neuropathologically determined aICAS to be associated with global cortical thinning. Interestingly, posterior circulation stenoses appeared to drive this association with global cortical thinning, raising the possibility of pathophysiologic mechanisms for cortical thinning other than impaired hemodynamics.

Subclinical left ventricular systolic dysfunction and incident stroke in the elderly: long-term findings from Cardiovascular Abnormalities and Brain Lesions.

AIMS: Heart disease is associated with an increased risk for ischaemic stroke. However, the predictive value of reduced left ventricular ejection fraction (LVEF) for stroke is controversial and only observed in patients with severe reduction. LV global longitudinal strain (LV GLS) can detect subclinical LV systolic impairment when LVEF is normal. We investigated the prognostic role of LV GLS for incident stroke in a predominantly elderly cohort. METHODS AND RESULTS: Two-dimensional echocardiography with speckle tracking was performed in the Cardiac Abnormalities and Brain Lesions (CABL) study. Among 708 stroke-free participants (mean age 71.4 ± 9.4 years, 60.9% women), abnormal LV GLS (>-14.7%: 95% percentile of the subgroup without risk factors) was detected in 133 (18.8%). During a mean follow-up of 10.8 ± 3.9 years, 47 participants (6.6%) experienced an ischaemic stroke (26 cardioembolic or cryptogenic, 21 other subtypes). The cumulative incidence of ischaemic stroke was significantly higher in participants with abnormal LV GLS than with normal LV GLS (P < 0.001). In multivariate stepwise logistic regression analysis, abnormal LV GLS was associated with ischaemic stroke independently of cardiovascular risk factors including LVEF, LV mass, left atrial volume, subclinical cerebrovascular disease at baseline, and incident atrial fibrillation [hazard ratio (HR): 2.69, 95% confidence interval (CI): 1.47-4.92; P = 0.001]. Abnormal LV GLS independently predicted cardioembolic or cryptogenic stroke (adjusted HR: 3.57, 95% CI: 1.51-8.43; P = 0.004) but not other subtypes. CONCLUSION: LV GLS was a strong independent predictor of ischaemic stroke in a predominantly elderly stroke-free cohort. Our findings provide insights into the brain-heart interaction and may help improve stroke primary prevention strategies.

Global changes in diffusion tensor imaging during acute ischemic stroke and post-stroke cognitive performance.

Post-stroke cognitive impairment is related to the effects of the acute stroke and pre-stroke brain health. We tested whether diffusion tensor imaging (DTI) can detect acute, global effects of stroke and predict post-stroke cognitive performance. Patients with stroke or TIA enrolled in a prospective cohort study were included if they had 1) at least one DTI acquisition at acute presentation, 24 hours, 5 days, or 30 days, and 2) follow-up testing with the telephone Montreal Cognitive Assessment (T-MoCA) at 30 and/or 90 days. A whole brain, white-matter skeleton excluding the infarct was used to derive mean global DTI measures for mean diffusivity (MD), fractional anisotropy (FA), free water (FW), FW-corrected MD (MDtissue), and FW-corrected FA (FAtissue). In 74 patients with ischemic stroke or TIA, there was a transient 4.2% increase in mean global FW between acute presentation and 24 hours (p = 0.024) that returned to initial values by 30 days (p = 0.03). Each acute global DTI measure was associated with 30-day T-MoCA score (n = 61, p = 0.0011-0.0076). Acute global FW, MD, FA and FAtissue were also associated with 90-day T-MoCA (n = 56, p = 0.0034-0.049). Transient global FW elevation likely reflects stroke-related interstitial edema, whereas other global DTI measures are more representative of pre-stroke brain health.

Efficacy of mechanisms of neuroplasticity after a stroke.

BACKGROUND: The sequelae of stoke, including the loss and recovery of function, are strongly linked to the mechanisms of neuroplasticity. Rehabilitation and non-invasive brain stimulation (NIBS) paradigms have shown promise in modulating corticomotor neuroplasticity to promote functional recovery in individuals post-stroke. However, an important limitation to these approaches is that while stroke recovery depends on the mechanisms of neuroplasticity, those mechanisms may themselves be altered by a stroke. OBJECTIVE: Compare Transcranial Magnetic Stimulation (TMS)-based assessments of efficacy of mechanism of neuroplasticity between individuals post-stroke and age-matched controls. METHODS: Thirty-two participants (16 post-stroke, 16 control) underwent an assessment of mechanisms of neuroplasticity, measured by the change in amplitude of motor evoked potentials elicited by single-pulse TMS 10-20 minutes following intermittent theta-burst stimulation (iTBS), and dual-task effect (DTE) reflecting cognitive-motor interference (CMI). In stroke participants, we further collected: time since stroke, stroke type, location, and Stroke Impact Scale 16 (SIS-16). RESULTS: Although there was no between-group difference in the efficacy of TMS-iTBS neuroplasticity mechanism (p = 0.61, η2 = 0.01), the stroke group did not exhibit the expected facilitation to TMS-iTBS (p = 0.60, η2 = 0.04) that was shown in the control group (p = 0.016, η2 = 0.18). Sub-cohort analysis showed a trend toward a difference between those in the late-stage post-stroke and the control group (p = 0.07, η2 = 0.12). Within the post-stroke group, we found significant relationships between TMS-iTBS neuroplasticity and time since stroke onset, physical function (SIS-16), and CMI (all rs > |0.53| and p-values < 0.05). CONCLUSIONS: In this proof-of-principle study, our findings suggested altered mechanisms of neuroplasticity in post-stroke patients which were dependent on time since stroke and related to motor function. TMS-iTBS neuroplasticity assessment and its relationship with clinical functional measures suggest that TMS may be a useful tool to study post-stroke recovery. Due to insufficient statistical power and high variability of the data, generalization of the findings will require replication of the results in a larger, better-characterized cohort.