Small Vessel Disease Markers Research Articles

Clinical Relevance of Enlarged Perivascular Spaces in Neurodegenerative Disease

Background: Enlarged perivascular space (ePVS) is recently reported to be associated with cerebral small vessel disease (SVD) and Alzheimer’s disease (AD). The topographical location of ePVS may relate to the underlying pathology; basal ganglia (BG)-ePVS has been associated with cerebral vascular diseases and centrum semi-ovale (CSO)-ePVS associated with cerebral amyloid angiopathy (CAA). However, the effects of ePVS on various neurological conditions remain still controversial. To investigate the clinical relevance of ePVS in neurodegenerative diseases, we tested relationships between ePVS and cognition, markers of SVD, vascular risk factors, or amyloid pathology.Methods: We retrospectively reviewed 292 patients (133 AD dementia, 106 mild cognitive impairment, 39 other neurodegenerative diseases, 14 subjective cognitive decline) who underwent both amyloid positron emission tomography and brain magnetic resonance imaging. Vascular risk factors and cognitive tests results were collected. The ePVS in the BG and CSO, SVD markers and the volume of white matter hyperintensities were measured.Results: There were no significant differences in the severity and distribution of ePVS among clinical syndromes. Both BG- and CSO-ePVS were not related to cognitive function. Patients with lacunes were more likely to have high-degree BG-ePVS. High degree CSO-ePVS had an odds ratio (OR) for amyloid positive of 2.351, while BG-ePVS was a negative predictor for amyloid pathology (OR, 0.336).Conclusions: Our findings support that ePVS has different underlying pathologies according to the cerebral topography. BG-ePVS would be attributed to hypertensive angiopathy considering the relation with SVD markers, whereas and CSO-ePVS would be attributed to CAA considering the association with amyloid pathology.

Abstract 072: Risk Factors for Developing Ischemic Strokes While Taking Non‐Vitamin K Antagonist Oral Anticoagulants

Introduction Over the past decade, non‐vitamin K antagonist oral anticoagulants (NOACs) have replaced warfarin as the initial strategy for stroke prevention in non‐valvular atrial fibrillation. However, ischemic strokes occurring in patients taking NOACs are becoming increasingly more frequent. In this study, we aimed to determine the clinical, echocardiographic, and neuroimaging markers associated with developing ischemic strokes in patients taking NOACs for atrial fibrillation. Methods Among atrial fibrillation patients on NOACs with and without ischemic stroke, brain MRIs were reviewed for the presence of neuroimaging markers of small vessel disease. Transthoracic echocardiography reports were reviewed to obtain left atrial volumes, presence of left ventricular hypertrophy, ejection fractions, and presence of wall motion abnormalities. Clinical and radiologic variables with significant differences between groups were entered into a multivariable regression model to determine predictors of ischemic stroke. In the ischemic stroke group, a Cox regression analysis was constructed to determine predictors of ischemic stroke recurrence during follow‐up. Results 112 patients with ischemic stroke and 94 controls (free of ischemic stroke) were included in the study. The mean age (77±9 years vs. 74±11 years, p = 0.13) and proportion of patients with CHA2DS2‐VASc>2 were similar between controls and ischemic stroke patients (82% vs. 83%, p = 0.86). The variables that were significantly different between groups included apixaban use, dabigatran use, prior cerebrovascular events, hemoglobin A1c (HbA1c), left ventricular hypertrophy, left atrial volume index, and severe white matter hyperintensities. After multivariable adjustment, prior cerebrovascular events (aOR 23.86, 95% CI [6.02–94.48]), HbA1c levels (aOR 2.36, 95% CI [1.39–3.99]), left ventricular hypertrophy (aOR 2.73, 95% CI [1.11–6.71]) and left atrial volume index (aOR 1.05, 95% CI [1.01–1.08]) increased the risk of stroke, whereas apixaban use appeared to decrease the risk (aOR 0.38, 95% CI [0.16–0.92]). Among patients with ischemic stroke, there were 103 survivors, 82 (80%) of which had follow‐up data. The median follow‐up duration for these patients was 2.6 (0.5–4.7) years. Of these 82 patients, 11 (13%) experienced an ischemic stroke during the follow‐up period. Malignancy was associated with ischemic stroke recurrence (aHR 4.90, 95% CI [1.35–18.42]) after adjustment for age and chronic renal failure. Conclusion Prior cerebrovascular events, diabetes, left ventricular hypertrophy, and left atrial size are associated with the development of ischemic stroke among NOAC users. Future studies should aim to investigate nonpharmacological stroke prevention strategies in patients with the vascular risk factors and echocardiographic risk markers identified in the present study.

Association of Baseline Cerebrovascular Reactivity and Longitudinal Development of Enlarged Perivascular Spaces in the Basal Ganglia.

Increasing evidence suggests that enlarged perivascular spaces (ePVS) are associated with cognitive dysfunction in aging. However, the pathogenesis of ePVS remains unknown. Here, we tested the possibility that baseline cerebrovascular dysfunction, as measured by a magnetic resonance imaging measure of cerebrovascular reactivity, contributes to the later development of ePVS. Fifty cognitively unimpaired, older adults (31 women; age range, 60-84 years) underwent magnetic resonance imaging scanning at baseline and follow-up separated by ≈2.5 years. ePVS were counted in the basal ganglia, centrum semiovale, midbrain, and hippocampus. Cerebrovascular reactivity, an index of the vasodilatory capacity of cerebral small vessels, was assessed using carbon dioxide inhalation while acquiring blood oxygen level-dependent magnetic resonance images. Low baseline cerebrovascular reactivity values in the basal ganglia were associated with increased follow-up ePVS counts in the basal ganglia after controlling for age, sex, and baseline ePVS values (estimate [SE]=-3.18 [0.96]; P=0.002; [95% CI, -5.11 to -1.24]). This effect remained significant after accounting for self-reported risk factors of cerebral small vessel disease (estimate [SE]=-3.10 [1.00]; P=0.003; [CI, -5.11 to -1.09]) and neuroimaging markers of cerebral small vessel disease (estimate [SE]=-2.72 [0.99]; P=0.009; [CI, -4.71 to -0.73]). Our results demonstrate that low baseline cerebrovascular reactivity is a risk factor for later development of ePVS.

Association of Plasma Lipids with White Matter Hyperintensities in Patients with Acute Ischemic Stroke.

White matter hyperintensities (WMH) are the common marker of cerebral small vessel disease (CSVD). Dyslipidemia plays a notable role in the pathogenesis of CSVD. However, the relationship between dyslipidemia and WMH is poorly elucidated. This study aims to investigate the association between serum lipid fractions and WMH in patients with acute ischemic stroke (AIS). A total of 901 patients with AIS were included in this study. The burden of WMH, including deep white matter hyperintensities (DWMH), periventricular white matter hyperintensities (PVWMH), and total WMH load, were evaluated on magnetic resonance imaging (MRI) by the Fazekas scale. All the WMH burden were set as dichotomous variables. Serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) were collected. The association of serum lipid fractions with WMH burden was analyzed using univariate and multivariate logistic regression models. The average age of the participants was 67.6±11.6 years, and 584 cases (64.8%) were male. About 33.5% (n = 302) patients were smoker, and 23.5% (n = 212) patients had a history of alcohol consumption. The proportion of previous diabetes, ischemic cardiomyopathy and hypertension was 39.0% (n = 351), 21.2% (n = 191) and 75.9% (n = 684), respectively. The average of serum HDL-c, TC, TG, LDL-c levels for all participants were 1.26 ± 0.28 mmol/l, 4.54 ± 1.06 mmol/l, 1.67 ± 1.09 mmol/l, 3.08 ± 0.94 mmol/l. There were no statistical associations between HDL-c, TG, TC, LDL-c and each type of WMH burden (P > 0.05) in multivariate logistic regression analysis. Similar findings were found in subgroup analysis based on gender classification. Serum lipid levels were not associated with the presence of any type of WMH in patients with AIS.

Angiotensin-converting enzyme insertion/deletion gene polymorphism and the progression of cerebral microbleeds.

The angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism has been studied as a genetic candidate for cerebral small vessel disease (CSVD). However, no previous study has evaluated the relationship between the ACE I/D polymorphism and cerebral microbleed (CMB), an important CSVD marker. We evaluated the association between ACE I/D polymorphisms and 2-year changes in CMBs. The CHALLENGE (Comparison Study of Cilostazol and Aspirin on Changes in Volume of Cerebral Small Vessel Disease White Matter Changes) database was analyzed. Of 256 subjects, 186 participants who underwent a 2-year follow-up brain scan and ACE genotyping were included. Our analysis was conducted by dividing the ACE genotype into two groups (DD vs. ID/II) under the assumption of the recessive effects of the D allele. A linear mixed-effect model was used to compare the 2-year changes in the number of CMBs between the DD and combined ID/II genotypes. Among 186 patients included in this study, 24 (12.9%) had the DD genotype, 91 (48.9%) had the ID genotype, and 71 (38.2%) had the II genotype. Baseline clinical characteristics and cerebral small vessel disease markers were not different between the two groups (DD vs. ID/II) except for the prevalence of hypertension (DD 66.7% vs. ID/II 84.6%; p = 0.04). A multivariate linear mixed-effects model showed that the DD carriers had a greater increase in total CMB counts than the ID/II carriers after adjusting for the baseline number of CMBs, age, sex, and hypertension (estimated mean of difference [standard error (SE)] = 1.33 [0.61]; p = 0.03). When we performed an analysis of cases divided into deep and lobar CMBs, only lobar CMBs were significantly different between the two groups (estimated mean of difference [SE] = 0.94 [0.42]; p = 0.02). The progression of CMBs over 2 years was greater in the ACE DD carriers compared with the combined II/ID carriers. The results of our study indicate a possible association between the ACE I/D polymorphism and CMB. A study with a larger sample size is needed to confirm this association.

Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-0.0048 [95% CI, -0.0075 to -0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (BNAWM=0.00065 [95% CI, -0.00007 to 0.00137] %/mm Hg per score point increase). Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

Brain-derived neurotrophic factor gene polymorphism affects cognitive function and neurofilament light chain level in patients with subcortical ischaemic vascular dementia.

To investigate the effects of brain-derived neurotrophic factor (BDNF) gene polymorphism on cognitive function, neuroimaging and blood biological markers in patients with subcortical ischaemic vascular dementia (SIVD). A total of 81 patients with SIVD were included. According to their BDNF gene polymorphism, the participants were divided into the Val/Val (n = 26), Val/Met (n = 35), and Met/Met (n = 20) groups. A comprehensive neuropsychological evaluation and multimodal brain MRI scan were performed. MRI markers for small vessel disease were visually rated or quantitatively analysed. Moreover, 52 patients were further evaluated with blood marker assays, including amyloid beta (Aβ), phosphorylated tau at threonine-181 (P-tau181), glial fibrillary acidic protein (GFAP), total tau (T-tau) and neurofilament light chain (NfL). There were no significant differences in demographics, disease duration or MRI markers of small vessel disease between the three groups. Compared with the Val/Val and Val/Met groups, the Met/Met group showed worse performance in the verbal fluency test and higher levels of plasma NfL. The rs6265 polymorphism of the BDNF gene is associated with semantic language fluency in patients with SIVD. The Met genotype may be a risk factor for cognitive impairment and neuronal injury.

Hemodynamic significance of intracranial atherosclerotic disease and ipsilateral imaging markers of cerebral small vessel disease.

Cerebral small vessel disease (CSVD) commonly exists in patients with symptomatic intracranial atherosclerotic disease (sICAD). We aimed to investigate the associations of hemodynamic features of sICAD lesions with imaging markers and overall burden of CSVD. Patients with anterior-circulation sICAD (50%-99% stenosis) were analyzed in this cross-sectional study. Hemodynamic features of a sICAD lesion were quantified by translesional pressure ratio (PR = Pressurepost-stenotic/Pressurepre-stenotic) and wall shear stress ratio (WSSR = WSSstenotic-throat/WSSpre-stenotic) via CT angiography-based computational fluid dynamics modeling. PR ⩽median was defined as low ("abnormal") PR, and WSSR ⩾ fourth quartile as high ("abnormal") WSSR. For primary analyses, white matter hyperintensities (WMHs), lacunes, and cortical microinfarcts (CMIs) were assessed in MRI and summed up as overall CSVD burden, respectively in ipsilateral and contralateral hemispheres to sICAD. Enlarged perivascular spaces (EPVSs) and cerebral microbleeds (CMBs) were assessed for secondary analyses. Among 112 sICAD patients, there were more severe WMHs, more lacunes and CMIs, and more severe overall CSVD burden ipsilaterally than contralaterally (all p < 0.05). Abnormal PR and WSSR (vs normal PR and WSSR) was significantly associated with moderate-to-severe WMHs (adjusted odds ratio = 10.12, p = 0.018), CMI presence (5.25, p = 0.003), and moderate-to-severe CSVD burden (12.55; p = 0.033), ipsilaterally, respectively independent of contralateral WMHs, CMI(s), and CSVD burden. EPVSs and CMBs were comparable between the two hemispheres, with no association found with the hemodynamic metrics. There are more severe WMHs and CMI(s) in the hemisphere ipsilateral than contralateral to sICAD. The hemodynamic significance of sICAD lesions was independently associated with severities of WMHs and CMI(s) ipsilaterally.

Longitudinal Progression of White Matter Hyperintensity Severity in Chronic Stroke Aphasia

ObjectiveTo determine whether longitudinal progression of small vessel disease in chronic stroke survivors is associated with longitudinal worsening of chronic aphasia severity. DesignA longitudinal retrospective study. Severity of white matter hyperintensities (WMHs) as a marker for small vessel disease was assessed on fluid-attenuated inversion recovery (FLAIR) scans using the Fazekas scale, with ratings for deep WMHs (DWMHs) and periventricular WMHs (PVHs). SettingUniversity research laboratories. ParticipantsThis study includes data from 49 chronic stroke survivors with aphasia (N=49; 15 women, 34 men, age range=32-81 years, >6 months post-stroke, stroke type: [46 ischemic, 3 hemorrhagic], community dwelling). All participants completed the Western Aphasia Battery-Revised (WAB) and had FLAIR scans at 2 timepoints (average years between timepoints: 1.87 years, SD=3.21 years). InterventionsNot applicable. Main Outcome MeasuresChange in white matter hyperintensity severity (calculated using the Fazekas scale) and change in aphasia severity (difference in Western Aphasia Battery scores) were calculated between timepoints. Separate stepwise regression models were used to identify predictors of WMH severity change, with lesion volume, age, time between timepoints, body mass index (BMI), and presence of diabetes as independent variables. Additional stepwise regression models investigated predictors of change in aphasia severity, with PVH change, DWMH change, lesion volume, time between timepoints, and age as independent predictors. Results22.5% of participants (11/49) had increased WMH severity. Increased BMI was associated with increases in PVH severity (P=.007), whereas the presence of diabetes was associated with increased DWMH severity (P=.002). Twenty-five percent of participants had increased aphasia severity which was significantly associated with increased severity of PVH (P<.001, 16.8% variance explained). ConclusionIncreased small vessel disease burden is associated with contributing to chronic changes in aphasia severity. These findings support the idea that good cardiovascular risk factor control may play an important role in the prevention of long-term worsening of aphasic symptoms.

Domain-specific neuropsychological investigation of CAA with and without intracerebral haemorrhage

BackgroundCerebral amyloid angiopathy (CAA) is associated with cognitive impairment, but the contributions of lobar intracerebral haemorrhage (ICH), underlying diffuse vasculopathy, and neurodegeneration, remain uncertain. We investigated the domain-specific neuropsychological profile of CAA with and without ICH, and their associations with structural neuroimaging features.MethodsData were collected from patients with possible or probable CAA attending a specialist outpatient clinic. Patients completed standardised neuropsychological assessment covering seven domains. MRI scans were scored for markers of cerebral small vessel disease and neurodegeneration. Patients were grouped into those with and without a macro-haemorrhage (CAA-ICH and CAA-non-ICH).ResultsWe included 77 participants (mean age 72, 65% male). 26/32 (81%) CAA-non-ICH patients and 41/45 (91%) CAA-ICH patients were impaired in at least one cognitive domain. Verbal IQ and non-verbal IQ were the most frequently impaired, followed by executive functions and processing speed. We found no significant differences in the frequency of impairment across domains between the two groups. Medial temporal atrophy was the imaging feature most consistently associated with cognitive impairment (both overall and in individual domains) in both univariable and multivariable analyses.DiscussionCognitive impairment is common in CAA, even in the absence of ICH, suggesting a key role for diffuse processes related to small vessel disease and/or neurodegeneration. Our findings indicate that neurodegeneration, possibly due to co-existing Alzheimer’s disease pathology, may be the most important contributor. The observation that general intelligence is the most frequently affected domain suggests that CAA has a generalised rather than focal cognitive impact.

Methods of a Study to Assess the Contribution of Cerebral Small Vessel Disease and Dementia Risk Alleles to Racial Disparities in Vascular Cognitive Impairment and Dementia.

Background Non-Hispanic Black adults have a higher proportion of vascular cognitive impairment and Alzheimer's disease and related dementias compared with non-Hispanic White adults that may be due to differences in the burden of cerebral small vessel disease and risk alleles for Alzheimer's disease and related dementias. We describe here the methods of an ancillary study to the REGARDS (Reason for Geographic and and Racial Difference in Stroke) study, which will examine the role of magnetic resonance imaging markers of cerebral small vessel disease and vascular as well as genetic risk factors for Alzheimer's disease and related dementias in racial disparity in the prevalence and trajectory of vascular cognitive impairment and dementia in non-Hispanic White and non-Hispanic Black participants. Methods In participants with no prior history of stroke who had an incident stroke or transient ischemic attack after enrollment in the study, magnetic resonance imaging scans will be evaluated using the Standards for Reporting Vascular Changes on Neuroimaging international consensus criteria and automated analysis pipelines for quantification of cerebral small vessel disease. Participants will be genotyped for APOE ε4 and TREM2 risk alleles for Alzheimer's disease and related dementias. The 6-item screener will define global cognitive function and be the primary cognitive outcome. Conclusions With at least 426 non-Hispanic Black and 463 non-Hispanic White participants who have at least 2 prior and 2 poststroke or transient ischemic attack cognitive assessments, we will have at least 80% power to detect a minimum effect size of 0.09 SD change in Z score, with correction for as many as 20 tests (ie, at P<0.0025, after adjusting for up to 20 covariates) for cognitive decline.

Small vessel disease burden and risk of recurrent cerebrovascular events in patients with lacunar stroke and intracerebral haemorrhage attributable to deep perforator arteriolopathy.

Deep perforator arteriolopathy (DPA) causes intracerebral haemorrhage (ICH) and lacunar strokes (LS). We compare patient characteristics, MRI findings and clinical outcomes among patients with deep ICH and LS. We included patients with MRI-confirmed LS or ICH in the basal ganglia, thalamus, internal capsule or brainstem from the Bernese Stroke Registry. We assessed MRI small vessel disease (SVD) markers, SVD burden score, modified Rankin Scale (mRS) and ischaemic stroke or ICH at 3 months. We included 716 patients, 117 patients (16.3%) with deep ICH (mean age (SD) 65.1 (±15.2) years, 37.1% female) and 599 patients (83.7%) with LS (mean age (SD) 69.7 (±13.6) years, 39.9% female). Compared to LS, deep ICH was associated with a higher SVD burden score (median (IQR) 2 (1-2) vs 1 (0-2)), aORshift 3.19, 95%CI 2.15-4.75). Deep ICH patients had more often cerebral microbleeds (deep ICH: 71.6% vs LS: 29.2%, p < 0.001, median count (IQR) 4(2-12) vs 2(1-6)) and a higher prevalence of lacunes (deep ICH: 60.5% vs LS: 27.4% p < 0.001). At 3 months, deep ICH was associated with higher mRS (aORshift 2.16, 95%CI 1.21-3.87). Occurrence of ischaemic stroke was numerically but not significantly higher in deep ICH (4.3% vs 2.9%; p = 0.51). One patient (1.1%) with ICH but none with LS suffered ICH recurrence. DPA manifesting as ICH is associated with more severe MRI SVD burden and worse outcome compared to LS. The short-term risks of subsequent ischaemic stroke and recurrent ICH are similar in ICH and LS patients. This implies potential consequences for future secondary prevention strategies.

Cerebral small vessel disease burden is associated with decreased abundance of gut Barnesiella intestinihominis bacterium in the Framingham Heart Study

A bidirectional communication exists between the brain and the gut, in which the gut microbiota influences cognitive function and vice-versa. Gut dysbiosis has been linked to several diseases, including Alzheimer's disease and related dementias (ADRD). However, the relationship between gut dysbiosis and markers of cerebral small vessel disease (cSVD), a major contributor to ADRD, is unknown. In this cross-sectional study, we examined the connection between the gut microbiome, cognitive, and neuroimaging markers of cSVD in the Framingham Heart Study (FHS). Markers of cSVD included white matter hyperintensities (WMH), peak width of skeletonized mean diffusivity (PSMD), and executive function (EF), estimated as the difference between the trail-making tests B and A. We included 972 FHS participants with MRI scans, neurocognitive measures, and stool samples and quantified the gut microbiota composition using 16S rRNA sequencing. We used multivariable association and differential abundance analyses adjusting for age, sex, BMI, and education level to estimate the association between gut microbiota and WMH, PSMD, and EF measures. Our results suggest an increased abundance of Pseudobutyrivibrio and Ruminococcus genera was associated with lower WMH and PSMD (p values < 0.001), as well as better executive function (p values < 0.01). In addition, in both differential and multivariable analyses, we found that the gram-negative bacterium Barnesiella intestinihominis was strongly associated with markers indicating a higher cSVD burden. Finally, functional analyses using PICRUSt implicated various KEGG pathways, including microbial quorum sensing, AMP/GMP-activated protein kinase, phenylpyruvate, and β-hydroxybutyrate production previously associated with cognitive performance and dementia. Our study provides important insights into the association between the gut microbiome and cSVD, but further studies are needed to replicate the findings.

Left ventricular hypertrophy and left atrial size are associated with ischemic strokes among non-vitamin K antagonist oral anticoagulant users.

Ischemic strokes (IS) occurring in patients taking non-vitamin K antagonist oral anticoagulants (NOACs) are becoming increasingly more frequent. We aimed to determine the clinical, echocardiographic, and neuroimaging markers associated with developing IS in patients taking NOACs for atrial fibrillation. From a quaternary care center, clinical/radiologic data were collected from consecutive NOAC users with IS and age-matched controls without IS. Brain MRIs were reviewed for markers of cerebral small vessel disease. Variables with significant differences between groups were entered into a multivariable regression model to determine predictors of IS. Among IS patients, a Cox regression analysis was constructed to determine predictors of IS recurrence during follow-up. 112 patients with IS and 94 controls were included in the study. Variables significantly different between groups included apixaban use, dabigatran use, prior cerebrovascular events, hemoglobin A1c (HbA1c), left ventricular hypertrophy, left atrial volume index, and severe white matter hyperintensities. After multivariable adjustment, prior cerebrovascular events (aOR 23.86, 95% CI [6.02-94.48]), HbA1c levels (aOR 2.36, 95% CI [1.39-3.99]), left ventricular hypertrophy (aOR 2.73, 95% CI [1.11-6.71]) and left atrial volume index (aOR 1.05, 95% CI [1.01-1.08]) increased the risk of stroke, whereas apixaban use appeared to decrease the risk (aOR 0.38, 95% CI [0.16-0.92]). Malignancy was associated with IS recurrence (aHR 4.90, 95% CI [1.35-18.42]) after adjustment for age and chronic renal failure. Prior cerebrovascular events, diabetes, left ventricular hypertrophy, and increased left atrial size are risk factors for developing an IS among NOAC users.

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.

Associations of plasma NfL, GFAP, and t-tau with cerebral small vessel disease and incident dementia: longitudinal data of the AGES-Reykjavik Study

We investigated the associations of plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (t-tau) with markers of cerebral small vessel disease (SVD) and with incident dementia. We also investigated whether associations of NfL, GFAP, and t-tau with incident dementia were explained by SVD. Data are from a random subsample (n = 1069) of the population-based AGES-Reykjavik Study who underwent brain MRI and in whom plasma NfL, GFAP, and t-tau were measured at baseline (76.1 ± 5.4 years/55.9% women/baseline 2002–2006/follow-up until 2015). A composite SVD burden score was calculated using white matter hyperintensity volume (WMHV), subcortical infarcts, cerebral microbleeds, and large perivascular spaces. Dementia was assessed in a 3-step process and adjudicated by specialists. Higher NfL was associated with a higher SVD burden score. Dementia occurred in 225 (21.0%) individuals. The SVD burden score significantly explained part of the association between NfL and incident dementia. WMHV mostly strongly contributed to the explained effect. GFAP was not associated with the SVD burden score, but was associated with WMHV, and WMHV significantly explained part of the association between GFAP and incident dementia. T-tau was associated with WMHV, but not with incident dementia. In conclusion, the marker most strongly related to SVD is plasma NfL, for which the association with WMHV appeared to explain part of its association with incident dementia. This study suggests that plasma NfL may reflect the contribution of co-morbid vascular disease to dementia. However, the magnitude of the explained effect was relatively small, and further research is required to investigate the clinical implications of this finding.

Deep medullary veins as an important imaging indicator of poor prognosis in acute ischemic stroke: a retrospective cohort survey.

The deep medullary veins (DMVs), which constitute a component of the intracerebral venous circulation system and are part of intracerebral reperfusion mechanisms, have been suggested as a novel imaging marker for cerebral white matter hypersignal and cerebral small vessel disease based on their discontinuous and reduced visual representation. However, the correlation between the number and continuity of visible DMVs and the poor prognosis of acute ischemic stroke (AIS) remains undefined. Magnetic susceptibility-weighted imaging was applied in this study to assess the distribution and structural characteristics of DMVs in patients with AIS and to investigate its relationship with the poor prognosis of those with AIS. This retrospective study included 90 patients diagnosed with AIS in the middle cerebral artery region by the Neurology Department of Liaoning Provincial People's Hospital. Clinical, laboratory, and cranial magnetic resonance imaging data were collected. After the 3-month follow-up visit, patients were dichotomized into good (0-2 points) and poor (≥3 points) prognosis groups based on the modified Rankin Scale score, and the DMV imaging characteristics were evaluated using a 3-level visual rating scale. The association between DMV and AIS prognosis was determined through Mann-Whitney test and multivariate logistic regression analysis. In univariate analysis, factors that were statistically significant between the different prognostic groups were DMV score (P=0.007), DMV symmetry (P=0.016), infarct size (P=0.029), and admission National Institutes of Health Stroke Scale (NIHSS) score (P<0.001). DMV score had a positive correlation with NIHSS score, (rs=0.209; P=0.048). Logistic regression analysis showed that the DMV score [odds ratio (OR), 1.356; 95% confidence interval (CI): 1.114-1.650; P=0.002], NIHSS score (OR, 1.280; 95% CI: 1.117-1.466; P<0.001), and fasting glucose (OR, 1.220; 95% CI: 1.023-1.456; P=0.027) were risk factors for poor prognosis in those with AIS. Discontinuity in DMV visualization was found to be associated with an unfavorable prognosis for patients AIS. The visual assessment of DMV through susceptibility-weighted imaging has the potential to predict AIS prognosis and furnish valuable insights for clinical treatment.

Effects of the APOEɛ4 Allele on the Relationship Between Tau and Amyloid-β in Early- and Late-Onset Alzheimer's Disease.

Little is known regarding the differential effects of the apolipoprotein E (APOE) ɛ4 on the regional topography of amyloid and tau in patients with both early-onset (EOAD) and late-onset Alzheimer's disease (LOAD). To compare the distribution and association of tau, amyloid, and cortical thickness among groups classified by the presence of APOEɛ4 allele and onset age. A total of 165 participants including 54 EOAD patients (29 ɛ4-; 25 ɛ4+), 45 LOAD patients (21 ɛ4-; 24 ɛ4+), and 66 age-matched controls underwent 3T MRI, 18F-THK5351 (THK) and 18F-flutemetamol (FLUTE) PET scans, APOE genotyping, and neuropsychological tests. Data for voxel-wise and standardized uptake values from PET scans were analyzed in the context of APOE and age at onset. EOAD ɛ4- patients showed greater THK retention in the association cortices, whereas their EOAD ɛ4+ counterparts had more retention in medial temporal areas. THK topography of LOAD ɛ4+ was similar to EOAD ɛ4 + . THK correlated positively with FLUTE and conversely with mean cortical thickness, being lowest in EOAD ɛ4-, highest in LOAD ɛ4-, and modest in ɛ4+ groups. Even in the APOEɛ4+ groups, THK tended to correlate with FLUTE and mean cortical thickness in the inferior parietal region in EOAD and in the medial temporal region in LOAD. LOAD ɛ4- manifested with prevalent small vessel disease markers and the lowest correlation between THK retention and cognition. Our observations suggest the differential effects of the APOEɛ4 on the relationship between tau and amyloid in EOAD and LOAD.

Structural Network Efficiency Predicts Conversion to Incident Parkinsonism in Patients With Cerebral Small Vessel Disease.

To investigate whether structural network disconnectivity is associated with parkinsonian signs and their progression, as well as with an increased risk of incident parkinsonism. In a prospective cohort (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study) consisting of 293 participants with small vessel disease (SVD), we assessed parkinsonian signs and incident parkinsonism over an 8-year follow-up. In addition, we reconstructed the white matter network followed by graph-theoretical analyses to compute the network metrics. Conventional magnetic resonance imaging markers for SVD were assessed. We included 293 patients free of parkinsonism at baseline (2011), with a mean age 68.8 (standard deviation [SD] 8.4) years, and 130 (44.4%) were men. Nineteen participants (6.5%) developed parkinsonism during a median (SD) follow-up time of 8.3 years. Compared with participants without parkinsonism, those with all-cause parkinsonism had higher Unified Parkinson's Disease Rating scale (UPDRS) scores and lower global efficiency at baseline. Baseline global efficiency was associated with UPDRS motor scores in 2011 (β = -0.047, p < .001) and 2015 (β = -0.84, p < .001), as well as with the changes in UPDRS scores during the 4-year follow-up (β = -0.63, p = .004). In addition, at the regional level, we identified an inter-hemispheric disconnected network associated with an increased UPDRS motor score. Besides, lower global efficiency was associated with an increased risk of all-cause and vascular parkinsonism independent of SVD markers. Our findings suggest that global network efficiency is associated with a gradual decline in motor performance, ultimately leading to incident parkinsonism in the elderly with SVD. Global network efficiency may have the added value to serve as a useful marker to capture changes in motor signs.

A Neuro-Informatics Pipeline for Cerebrovascular Disease: Research Registry Development.

Although stroke is well recognized as a critical disease, treatment options are often limited. Inpatient stroke encounters carry critical information regarding the mechanisms of stroke and patient outcomes; however, these data are typically formatted to support administrative functions instead of research. To support improvements in the care of patients with stroke, a substantive research data platform is needed. To advance a stroke-oriented learning health care system, we sought to establish a comprehensive research repository of stroke data using the Houston Methodist electronic health record (EHR) system. Dedicated processes were developed to import EHR data of patients with primary acute ischemic stroke, intracerebral hemorrhage (ICH), transient ischemic attack, and subarachnoid hemorrhage under a review board-approved protocol. Relevant patients were identified from discharge diagnosis codes and assigned registry patient identification numbers. For identified patients, extract, transform, and load processes imported EHR data of primary cerebrovascular disease admissions and available data from any previous or subsequent admissions. Data were loaded into patient-focused SQL objects to enable cross-sectional and longitudinal analyses. Primary data domains (admission details, comorbidities, laboratory data, medications, imaging data, and discharge characteristics) were loaded into separate relational tables unified by patient and encounter identification numbers. Computed tomography, magnetic resonance, and angiography images were retrieved. Imaging data from patients with ICH were assessed for hemorrhage characteristics and cerebral small vessel disease markers. Patient information needed to interface with other local and national databases was retained. Prospective patient outreach was established, with patients contacted via telephone to assess functional outcomes 30, 90, 180, and 365 days after discharge. Dashboards were constructed to provide investigators with data summaries to support access. The Registry of Neurological Endpoint Assessments among Patients with Ischemic and Hemorrhagic Stroke (REINAH) database was constructed as a series of relational category-specific SQL objects. Encounter summaries and dashboards were constructed to draw from these objects, providing visual data summaries for investigators seeking to build studies based on REINAH data. As of June 2022, the database contains 18,061 total patients, including 1809 (10.02%) with ICH, 13,444 (74.43%) with acute ischemic stroke, 1221 (6.76%) with subarachnoid hemorrhage, and 3165 (17.52%) with transient ischemic attack. Depending on the cohort, imaging data from computed tomography are available for 85.83% (1048/1221) to 98.4% (1780/1809) of patients, with magnetic resonance imaging available for 27.85% (340/1221) to 85.54% (11,500/13,444) of patients. Outcome assessment has successfully contacted 56.1% (240/428) of patients after ICH, with 71.3% (171/240) of responders providing consent for assessment. Responders reported a median modified Rankin Scale score of 3 at 90 days after discharge. A highly curated and clinically focused research platform for stroke data will establish a foundation for future research that may fundamentally improve poststroke patient care and outcomes.