Small Vessel Disease Markers Research Articles

Detectability and accuracy of computational measurements of in-silico and physical representations of enlarged perivascular spaces from magnetic resonance images

BackgroundMagnetic Resonance Imaging (MRI) visible perivascular spaces (PVS) have been associated with age, decline in cognitive abilities, interrupted sleep, and markers of small vessel disease. But the limits of validity of their quantification have not been established. New methodWe use a purpose-built digital reference object to construct an in-silico phantom for addressing this need, and validate it using a physical phantom. We use cylinders of different sizes as models for PVS. We also evaluate the influence of ‘PVS’ orientation, and different sets of parameters of the two vesselness filters that have been used for enhancing tubular structures, namely Frangi and RORPO filters, in the measurements’ accuracy. ResultsPVS measurements in MRI are only a proxy of their true dimensions, as the boundaries of their representation are consistently overestimated. The success in the use of the Frangi filter relies on a careful tuning of several parameters. Alpha= 0.5, beta= 0.5 and c= 500 yielded the best results. RORPO does not have these requirements and allows detecting smaller cylinders in their entirety more consistently in the absence of noise and confounding artefacts. The Frangi filter seems to be best suited for voxel sizes equal or larger than 0.4 mm-isotropic and cylinders larger than 1 mm diameter and 2 mm length. ‘PVS’ orientation did not affect measurements in data with isotropic voxels. Comparison with existent methodsDoes not apply. ConclusionsThe in-silico and physical phantoms presented are useful for establishing the validity of quantification methods of tubular small structures.

Cerebral microbleeds and asundexian in non-cardioembolic ischemic stroke: Secondary analyses of the PACIFIC-STROKE randomized trial.

Cerebral microbleeds are magnetic imaging resonance (MRI) markers of hemorrhage-prone cerebral small vessel disease that predict future risk of ischemic stroke and intracranial hemorrhage (ICrH). There exist concerns about the net benefit of antithrombotic therapy in patients with microbleeds. We aimed to investigate the effects of an oral factor-XIa inhibitor (asundexian), that is hypothesized to inhibit thrombosis without compromising hemostasis, on the development of new microbleeds over time and interactions between microbleeds and asundexian treatment on clinical outcomes. We additionally assessed associations between baseline microbleeds and the risks of clinical and neuroimaging outcomes in patients with non-cardioembolic ischemic stroke. This is a secondary analysis of the PACIFIC-STROKE, international, multi-center Phase 2b double-blind, randomized clinical trial. PACIFIC-STROKE enrolled patients aged ⩾ 45 years with mild-to-moderate non-cardioembolic ischemic stroke who presented within 48 h of symptom onset for whom antiplatelet therapy was intended. Microbleeds were centrally adjudicated, and participants with an interpretable T2*-weighted sequence at their baseline MRI were included in this analysis. Patients were randomized to asundexian (10/20/50 mg daily) versus placebo plus standard antiplatelet treatment. Regression models were used to estimate the effects of (1) all pooled asundexian doses and (2) asundexian 50 mg daily on new microbleed formation on 26-week MRIs. Cox proportional hazards or regression models were additionally used to estimate interactions between treatment assignment and microbleeds for ischemic stroke/transient ischemic attack (TIA) (primary outcome), and ICrH, all-cause mortality, hemorrhagic transformation (HT), and new microbleeds (secondary outcomes). Of 1746 participants (mean age, 67.0 ± 10.0; 34% female) with baseline MRIs, 604 (35%) had microbleeds. During a median follow-up of 10.6 months, 7.0% (n = 122) had ischemic stroke/TIA, 0.5% (n = 8) ICrH, and 2.1% (n = 37) died. New microbleeds developed in 10.3% (n = 155) of participants with adequate follow-up MRIs and HT in 31.4% (n = 345). In the total sample of patients with adequate baseline and 26-week follow-up MRIs (n = 1507), new microbleeds occurred in 10.2% of patients assigned to any asundexian dose and 10.5% of patients assigned to placebo (OR, 0.96; 95% CI, 0.66-1.41). There were no interactions between microbleeds and treatment assignment for any of the outcomes (p for interaction > 0.05). The rates of new microbleeds, HT, and ICrH were numerically less in patients with microbleeds assigned to asundexian relative to placebo. The presence of microbleeds was associated with a higher risk of HT (aOR, 1.6; 95% CI, 1.2-2.1) and new microbleeds (aOR, 4.4; 95% CI, 3.0-6.3). Factor XIa inhibition with asundexian appears safe in patients with non-cardioembolic ischemic stroke and hemorrhage-prone cerebral small vessel disease marked by microbleeds on MRI. These preliminary findings will be confirmed in the ongoing OCEANIC-STROKE randomized trial. ClinicalTrials.gov Identifier: NCT04304508.

Risk factors for cognitive impairment and dementia after stroke: a systematic review and meta-analysis

Cognitive impairment and dementia are highly prevalent among stroke survivors and represent a major burden for patients, carers, and health-care systems. We studied the risk factors for post-stroke cognitive impairment (PSCI) and dementia (PSD) beyond the well established risk factors of age and stroke severity. In this systematic review and meta-analysis we conducted a systematic literature search from database inception until Sept 15, 2023. We selected prospective and retrospective cohort studies, post-hoc analyses from randomised controlled trials, and nested case-control studies of patients with acute stroke (ischaemic, haemorrhagic, and transient ischaemic attack), exploring associations between risk factors at baseline and PSCI or PSD over a follow-up period of at least 3 months. Study quality was assessed using the Newcastle-Ottawa quality assessment scale. We calculated pooled relative risks (RRs) with random-effects meta-analyses and performed subgroup, meta-regression, and sensitivity analyses. This study was preregistered with PROSPERO, CRD42020164959. We identified 162 eligible articles for our systematic review, of which 113 articles (89 studies, 160 783 patients) were eligible for meta-analysis. Baseline cognitive impairment was the strongest risk factor for PSCI (RR 2·00, 95% CI 1·66-2·40) and PSD (3·10, 2·77-3·47). We identified diabetes (1·29, 1·14-1·45), presence or history of atrial fibrillation (1·29, 1·04-1·60), presence of moderate or severe white matter hyperintensities (WMH; 1·51, 1·20-1·91), and WMH severity (1·30, 1·10-1·55, per SD increase) as treatable risk factors for PSCI, independent of age and stroke severity. For PSD, we identified diabetes (1·38, 1·10-1·72), presence of moderate or severe WMH (1·55, 1·01-2·38), and WMH severity (1·61, 1·20-2·14, per SD increase) as treatable risk factors. Additional risk factors included lower educational attainment, previous stroke, left hemisphere stroke, presence of three or more lacunes, brain atrophy, and low baseline functional status. Associations of risk factors with PSD were weaker in studies conducted and published more recently. We found substantial interstudy heterogeneity and evidence of reporting bias. Our results highlight the importance of cognitive impairment in the acute phase after stroke for long-term prediction of PSCI and PSD. Treatable risk factors include diabetes, atrial fibrillation, and markers of cerebral small vessel disease (ie, white matter hyperintensities and lacunes). Future trials should explore these risk factors as potential targets for prevention of PSCI and PSD. German Research Foundation.

Early detection of white matter hyperintensities using SHIVA-WMH detector.

White matter hyperintensities (WMHs) are well-established markers of cerebral small vessel disease, and are associated with an increased risk of stroke, dementia, and mortality. Although their prevalence increases with age, small and punctate WMHs have been reported with surprisingly high frequency even in young, neurologically asymptomatic adults. However, most automated methods to segment WMH published to date are not optimized for detecting small and sparse WMH. Here we present the SHIVA-WMH tool, a deep-learning (DL)-based automatic WMH segmentation tool that has been trained with manual segmentations of WMH in a wide range of WMH severity. We show that it is able to detect WMH with high efficiency in subjects with only small punctate WMH as well as in subjects with large WMHs (i.e., with confluency) in evaluation datasets from three distinct databases: magnetic resonance imaging-Share consisting of young university students, MICCAI 2017 WMH challenge dataset consisting of older patients from memory clinics, and UK Biobank with community-dwelling middle-aged and older adults. Across these three cohorts with a wide-ranging WMH load, our tool achieved voxel-level and individual lesion cluster-level Dice scores of 0.66 and 0.71, respectively, which were higher than for three reference tools tested: the lesion prediction algorithm implemented in the lesion segmentation toolbox (LPA: Schmidt), PGS tool, a DL-based algorithm and the current winner of the MICCAI 2017 WMH challenge (Park et al.), and HyperMapper tool (Mojiri Forooshani et al.), another DL-based method with high reported performance in subjects with mild WMH burden. Our tool is publicly and openly available to the research community to facilitate investigations of WMH across a wide range of severity in other cohorts, and to contribute to our understanding of the emergence and progression of WMH.

Small vessel disease burden and functional brain connectivity in mild cognitive impairment

BackgroundThe role of small vessel disease in the development of dementia is not yet completely understood. Functional brain connectivity has been shown to differ between individuals with and without cerebral small vessel disease. However, a comprehensive measure of small vessel disease quantifying the overall damage on the brain is not consistently used and studies using such measure in mild cognitive impairment individuals are missing. MethodFunctional brain connectivity differences were analyzed between mild cognitive impairment individuals with absent or low (n = 34) and high (n = 34) small vessel disease burden using data from the Parelsnoer Institute, a Dutch multicenter study. Small vessel disease was characterized using an ordinal scale considering: lacunes, microbleeds, perivascular spaces in the basal ganglia, and white matter hyperintensities. Resting state functional MRI data using 3 Tesla scanners was analyzed with group-independent component analysis using the CONN toolbox. ResultsFunctional connectivity between areas of the cerebellum and between the cerebellum and the thalamus and caudate nucleus was higher in the absent or low small vessel disease group compared to the high small vessel disease group. ConclusionThese findings might suggest that functional connectivity of mild cognitive impairment individuals with low or absent small vessel disease burden is more intact than in mild cognitive impairment individuals with high small vessel disease. These brain areas are mainly responsible for motor, attentional and executive functions, domains which in previous studies were found to be mostly associated with small vessel disease markers. Our results support findings on the involvement of the cerebellum in cognitive functioning.

Relationship between white matter lesion coalescence and plasma cystatin C in an ethnically diverse population

AbstractBackgroundBrain and kidney share anatomical similarities in terms of the small vessels serving their irrigation. Previous work have shown associations between markers of cerebral small vessel disease (CSVD) e.g. white matter hyperintensities (WMH) and markers of renal function e.g. cystatin C. Few studies have however investigated the relationship between renal function and more detailed descriptions of lesion shape and distributionMethod768 individuals from the tri‐ethnic SABRE cohort underwent brain MRI including T1w and FLAIR sequences. WMH were automatically segmented and an overall measure of coalescence was derived from the lesion map ranging from 0 (only punctuate lesions) to 4 (high level of coalescence). Regional coalescence measures according to distance from the ventricles were further derived in 4 equidistant layers. Clinic blood samples were available for 731 individuals (45% female, mean age 71.3 (SD 6.4) years) including from 311 European; 172 African Caribbean; and 248 South Asian ethnicity. Blood measures include plasma cystatin C, a marker of glomerular filtration rate, white blood cell count (WBC) and HbA1c. Associations between cystatin C and coalescence score or lesion volume expressed as percentage of total intracranial volume were investigated using robust linear regression adjusting for age, ethnicity, sex, HbA1c and WBC; all factors known to be associated with cystatin C levels and WMH.ResultCystatin C was positively associated with male sex, WBC and HbA1c, and differed across ethnicities being highest in South Asians and lowest in African Caribbeans. After adjusting for potential confounders, cystatin C was positively associated with overall coalescence score (b = 0.026 [0.004;0.047], p = 0.018) despite unconvincing evidence of an association with overall lesion volume (b = 0.003 [‐0.0003; 0.007], p = 0.066). Associations between cystatin C and coalescence score were stronger in the South Asian group (b = 0.066 [0.027;0.105], p interaction = 0.001). Associations between cystatin C and coalescence score were similar across different layers.ConclusionShape patterns of WMH, rather than overall WMH volume, may provide a more sensitive measure to assess the relationship with markers of small vessel disease in the kidneys.

Relationship between white matter lesion coalescence and plasma cystatin C in an ethnically diverse population.

AbstractBackground: Brain and kidney share anatomical similarities in terms of the small vessels serving their irrigation. Previous work have shown associations between markers of cerebral small vessel disease (CSVD) e.g. white matter hyperintensities (WMH) and markers of renal function e.g. cystatin C. Few studies have however investigated the relationship between renal function and more detailed descriptions of lesion shape and distributionMethod768 individuals from the tri‐ethnic SABRE cohort underwent brain MRI including T1w and FLAIR sequences. WMH were automatically segmented and an overall measure of coalescence was derived from the lesion map ranging from 0 (only punctuate lesions) to 4 (high level of coalescence). Regional coalescence measures according to distance from the ventricles were further derived in 4 equidistant layers. Clinic blood samples were available for 731 individuals (45% female, mean age 71.3 (SD 6.4) years) including from 311 European; 172 African Caribbean; and 248 South Asian ethnicity. Blood measures include plasma cystatin C, a marker of glomerular filtration rate, white blood cell count (WBC) and HbA1c. Associations between cystatin C and coalescence score or lesion volume expressed as percentage of total intracranial volume were investigated using robust linear regression adjusting for age, ethnicity, sex, HbA1c and WBC; all factors known to be associated with cystatin C levels and WMH.ResultCystatin C was positively associated with male sex, WBC and HbA1c, and differed across ethnicities being highest in South Asians and lowest in African Caribbeans. After adjusting for potential confounders, cystatin C was positively associated with overall coalescence score (b = 0.026 [0.004;0.047], p = 0.018) despite unconvincing evidence of an association with overall lesion volume (b = 0.003 [‐0.0003; 0.007], p = 0.066). Associations between cystatin C and coalescence score were stronger in the South Asian group (b = 0.066 [0.027;0.105], p interaction = 0.001). Associations between cystatin C and coalescence score were similar across different layers.ConclusionShape patterns of WMH, rather than overall WMH volume, may provide a more sensitive measure to assess the relationship with markers of small vessel disease in the kidneys.

Impact of White Matter Hyperintensities on domain‐specific cognition in Southeast Asians

AbstractBackgroundDementia affects 55 million people worldwide, with 60% of the burden in Asia. White Matter Hyperintensities (WMH) is a key marker of small vessel disease, with high prevalence in Asian populations with prodromal and clinical dementia. WMH is described as: Deep White Matter Hyperintensities (DWMH), Periventricular Hyperintensities (PVH) or Fazekas‐Total (DWMH and PVH).However, association between WMH topography and performance in specific cognitive domains remains unexplored. Thus, this study aims to characterise the impact of Fazekas‐Total, DWMH and PVH on different cognitive domains.Method304 participants (mean age 60.6, mean education years 14.2, mean Montreal Cognitive Assessment 25.99, 43.8% males) from Biomarkers and Cognition Study, Singapore (Dementia Research Centre (Singapore)) met the inclusion criteria.Eight domains of cognition were tested: global cognition, learning and memory, language, executive function, complex‐attention, perceptual‐motor, social‐cognition, and processing speed.Normality tests, correlation analysis and stepwise regression (with Benjamini and Hochberg False Discovery Rate correction) were performed to understand association between Fazekas‐Total, DWMH, PVH on domains of cognition tested, accounting for age, education, and gender.Two approaches were used for data analysis: (1) by grouping participants as Mild Cognitive Impairment (MCI), Subjective Cognitive Decline (SCD) and Cognitively Normal (CN) as per the National Institute on Aging‐Alzheimer’s Association (NIA‐AA) criteria and (2) by grouping participants’ WMH as confluent (DWMH ≥2 and PVH ≥3) and non‐confluent.ResultHigher Fazekas‐Total was associated with slower processing speed (p = 0.0255, R = ‐0.039) in prodromal participants (MCI and SCD). Higher PVH was associated with slower processing speed in MCI (p = 0.017, R = ‐0.32) and CN (p = 0.017, R = ‐0.663) participants. Higher PVH was significantly associated with poorer learning and memory (p = 0.045, R = ‐0.043) in SCD participants. Higher DWMH was significantly associated with poorer learning and memory (p = 0.017, R = ‐0.765) in CN participants.ConclusionThese results demonstrate differential association between PVH, DWMH and cognitive domains, thus the location of WMH determines the affected cognitive domains. Therefore, it is worthwhile to assess PVH and DWMH in clinical cognitive outcomes separately and to understand the upstream pathobiology of DWMH and PVH.Furthermore, higher Fazekas‐Total was strongly associated with slower processing speed in prodromal participants and could be a marker of cognitive decline.

Arterial spin‐labeling spatial coefficient of variation is associated with cerebral small vessel disease

AbstractBackgroundCerebral small vessel disease (SVD) is the most common pathology to co‐occur with Alzheimer’s disease but pathophysiologic mechanisms leading to SVD are poorly understood. The arterial spin‐labeling (ASL) spatial coefficient of variation (sCoV), a proxy marker of arterial transit time (ATT), may better reflect SVD‐related hemodynamic disturbances than ASL‐derived cerebral blood flow (CBF). We investigated whether grey matter CBF and grey matter sCoV each related to neuroimaging markers of SVD, including white matter hyperintensities (WMHs), basal ganglia enlarged perivascular spaces (ePVS), cerebral microbleeds (CMBs), and lacunes.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia and stroke at study entry (n = 312, 73±7 years, 39% mild cognitive impairment, 41% female) underwent multimodal 3T brain magnetic resonance imaging to quantify ASL parameters and SVD burden. Pseudo‐continuous ASL assessed CBF in total grey matter. Grey matter sCoV was calculated as σ(CBFGrey Matter)/μ(CBFGrey Matter). WMHs and ePVS volumes were quantified using automated methods and ePVS volumes were standardized to basal ganglia volume. CMBs and lacune counts were quantified by an expert rater. Ordinary least squares regression models cross‐sectionally related grey matter CBF and sCoV individually to log‐transformed burden of each SVD marker. Models were adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), intracranial volume, grey matter volume, and apolipoprotein E‐ε4 status.ResultsGrey matter CBF was unrelated to all SVD outcomes (p‐values>0.25). Higher grey matter sCoV was associated with greater WMHs (β = 2.1, p = 0.001), ePVS (β = 0.004, p = 0.0003), and lacunar infarcts (β = 1.4, p = 0.0006) but not CMBs (β = 1.0, p = 0.06).ConclusionsOur findings align with previous results showing that grey matter sCoV is a valuable marker of SVD. In contrast to previous work, we found an association between higher grey matter sCoV and higher basal ganglia ePVS burden. Potentially, our use of volumetric ePVS quantification rather than qualitative ePVS burden increased our ability to detect this association. As sCoV is a proxy marker of ATT, future work should consider quantifying sCoV or ATT in addition to CBF to better characterize SVD‐related hemodynamic disturbances. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, P20‐AG068082

Functional Brain Activation in Mild Cognitive Impairment With Defined Small Vessel Disease Burden

AbstractBackgroundVascular dysregulations and changes in functional brain network integrity play a fundamental role in the pathogenesis of dementia. While often identified in individuals with dementia, the role of small vessel disease (SVD) in the development of dementia is not completely understood yet. Previously, structural and functional brain connectivity was shown to be different between individuals with and without cerebral SVD, but a comprehensive measure of SVD has not been used consistently. We aim to analyze functional brain activation differences in mild cognitive impairment (MCI) individuals with defined SVD burden.MethodFunctional brain activation differences were analyzed in MCI individuals with absent or low (n = 34) or high (n = 34) SVD burden using data from the Parelsnoer Institute, a multicenter study involving eight Dutch medical centers. SVD burden was characterized using an ordinal scale ranging from 0 to 4 (Klarenbeek et al., 2013) considering the following markers: lacunes; microbleeds; perivascular spaces in the basal ganglia; white matter hyperintensities based on the Fazekas score. Two groups were identified: the absent or low SVD burden group with a score of 0 or 1 and the high SVD group with a score between 2 and 4. Activation differences were calculated using resting state fMRI data acquired using 3Tesla scanners and analyzed with group‐independent component analysis using the CONN toolbox.ResultActivation of two clusters in the high SVD burden group was lower than in the absent or low SVD group: the cerebellum (p‐FDR >. 001, F = 1.49) and the brainstem (p‐FDR >. 001, F = 2.79). The cerebellar cluster (4541 voxels, +20 ‐74 ‐38) consisted of the left cerebellum crus II, right cerebellum crus II, and left cerebellum lobule VIII. The brainstem cluster (218 voxels, +22 ‐28 +20) involved the right thalamus and the right caudate nucleus.ConclusionBrain activation differences between groups of individuals with MCI and absent or low or high SVD burden were found in the cerebellum and brainstem. These brain areas are mainly responsible for motor, attentional and executive functions, domains which were found in previous studies to be mostly associated with SVD markers.

Neighborhood disadvantage is associated with changes in cerebrovascular function among older adults over a 9 year follow‐up period

AbstractBackgroundStressful social environments exert a strong influence on unhealthy aging, both in greater magnitude and independent of individual socioeconomic and lifestyle factors. Neighborhood disadvantage specifically has been linked to accelerated biological aging, cognitive decline, and core Alzheimer’s disease (AD) neuropathology, but little is known about whether neighborhood disadvantage contributes to cerebrovascular dysfunction commonly observed in aging and AD. We examine whether neighborhood disadvantage relates to changes in cerebrovascular outcomes over time, including blood‐brain barrier (BBB) integrity, cerebral blood flow (CBF), and small vessel disease (SVD) biomarkers.MethodsVanderbilt Memory and Aging Project participants (n = 296, 73±7 years, 40% female) underwent fasting blood and cerebrospinal fluid (CSF) acquisition serially over a 9‐year follow‐up period (mean follow‐up = 5.5 years). Area Deprivation Index (ADI), representing neighborhood disadvantage, was quantified at baseline based on 17 components [e.g., housing, income, education, and household characteristics (Kind & Buckingham, 2018)]. BBB markers (MMP‐2, MMP‐3, MMP‐9, TIMP‐1, TIMP‐2, PDGFRβ) were quantified from CSF and CSF/plasma albumin ratio was quantified from both CSF and plasma. 3T multimodal MRI images were used to quantify grey matter CBF and SVD markers, including white matter hyperintensities (WMHs), perivascular spaces (PVS), and lacunes. Linear mixed effects regression models related time x ADI to longitudinal BBB, CBF, and SVD outcomes adjusting for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), apolipoprotein ε4 status, and follow‐up time. CBF models additionally adjusted for corresponding grey matter volume while SVD models adjusted for T1‐weighted intracranial volume.ResultsBaseline ADI related to increased MMP‐9 (β = 0.03, p‐value = 0.01) and decreased PDGFRβ (β = ‐0.1407, p‐value<0.05) over time but unrelated to longitudinal changes in CBF (p‐values>0.35), SVD (p‐values>0.36), or other BBB outcomes (p‐values>0.07).ConclusionsNeighborhood socioeconomic disadvantage relates to changes in BBB integrity among older adults over time, particularly molecular markers of barrier disruption and pericyte damage. Findings support the hypothesis that adverse environmental conditions, including low quality housing and community‐wide resource constraints, may contribute to early‐stage cerebrovascular dysfunction beyond individual socioeconomic and lifestyle factors.FundingHHMI James H. Gilliam Fellowship for Advanced Study; IIRG‐08‐88733; R01‐AG034962; R01‐AG056534; K24‐AG046373; P20‐AG068

Etiology of Primary Cerebellar Intracerebral Hemorrhage Based on Topographic Localization.

Cerebellar intracerebral hemorrhage (cICH) is often attributed to hypertension or cerebral amyloid angiopathy (CAA). However, deciphering the exact etiology can be challenging. A recent study reported a topographical etiologic relationship with superficial cICH secondary to CAA. We aimed to reexamine this relationship between topography and etiology in a separate cohort of patients and using the most recent Boston criteria version 2.0. We performed a retrospective analysis of consecutive patients with primary cICH admitted to a tertiary academic center between 2000 and 2022. cICH location on brain computed tomography/magnetic resonance imaging scan(s) was divided into strictly superficial (cortex, surrounding white matter, vermis) versus deep (cerebellar nuclei, deep white matter, peduncular region) or mixed (both regions). Magnetic resonance imaging was rated for markers of cerebral small vessel disease. We assigned possible/probable versus absent CAA using Boston criteria 2.0. We included 197 patients; 106 (53.8%) were females, median age was 74 (63-82) years. Fifty-six (28%) patients had superficial cICH and 141 (72%) deep/mixed cICH. Magnetic resonance imaging was available for 112 (57%) patients (30 [26.8%] with superficial and 82 [73.2%] with deep/mixed cICH). Patients with superficial cICH were more likely to have possible/probable CAA (48.3% versus 8.6%; odds ratio [OR], 11.43 [95% CI, 3.26-40.05]; P<0.001), strictly lobar cerebral microbleeds (51.7% versus 6.2%; OR, 14.18 [95% CI, 3.98-50.50]; P<0.001), and cortical superficial siderosis (13.8% versus 1.2%; OR, 7.70 [95% CI, 0.73-80.49]; P=0.08). Patients with deep/mixed cICH were more likely to have deep/mixed cerebral microbleeds (59.2% versus 3.4%; OR, 41.39 [95% CI, 5.01-341.68]; P=0.001), lacunes (54.9% versus 17.2%; OR, 6.14 [95% CI, 1.89-19.91]; P=0.002), severe basal ganglia enlarged perivascular spaces (36.6% versus 7.1%; OR, 7.63 [95% CI, 1.58-36.73]; P=0.01), hypertension (84.4% versus 62.5%; OR, 3.43 [95% CI, 1.61 to -7.30]; P=0.001), and higher admission systolic blood pressure (172 [146-200] versus 146 [124-158] mm Hg, P<0.001). Our results suggest that superficial cICH is strongly associated with CAA whereas deep/mixed cICH is strongly associated with hypertensive arteriopathy.

Associations of anemia and cardiovascular disease with longitudinal changes in brain MRI markers and cognitive decline in older adults: A cohort study

AbstractBackgroundAnemia and cardiovascular disease (CVD) are two prevalent chronic conditions causing cerebral hypoxia in older adults. Although anemia and CVD often coexist in older people and potentially share underlying mechanisms, the independent effects of these two diseases with cognitive decline are largely unknown. The objective of this cohort study is to investigate the independent associations of anemia and CVD with cognitive decline in older adults, and further explore their associations with changes in MRI markers of brain aging using longitudinal MRI data.MethodThis cohort study used data from 2244 dementia‐ and stroke‐free participants in the population‐based Swedish National study on Aging and Care in Kungsholmen (age ≥60 years, female 62%). Participants were regularly followed from 2001‐2004 (baseline) through 2013‐2016. Anemia (WHO criteria) and CVD were determined at baseline. Cognitive function was assessed using a neuropsychological test battery across 12 years. A subset of participants (N = 503) underwent brain MRI examinations at baseline, and 327undertook follow‐up MRI scans after 3 and/or 6 years. Brain volumetric measures and markers of cerebral small vessel disease (cSVD) were assessed following standard methods. The associations of anemia or/and CVD with cognitive decline and changes in brain volume and cSVD markers were investigated using linear mixed‐effects models, while controlling for age, sex, lifestyle, vascular risk factors, chronic kidney disease, cancer, serum c‐reactive protein, and APOE genotype.ResultOf the 2244 participants, 5% had only anemia and 17% had only CVD. Both anemia and CVD were independently associated with a steeper decline in global cognitive composite score (anemia ‐0.01/year; 95%CI ‐0.03 to ‐0.00, CVD ‐0.02/year; 95%CI ‐0.03 to ‐0.02). Anemia was associated with faster decline in category fluency and perceptual speed, while CVD was significantly associated with an accelerated decline in all examined cognitive domains. Both anemia and CVD at baseline were associated with a steeper decline in total brain tissue volume, while CVD was additionally associated with steeper decline in volumes of hippocampus (P&lt;0.05). Neither was significantly associated with changes in cSVD markers (i.e., white‐matter hyperintensities, lacunes).ConclusionBoth anemia and CVD are risk factors for accelerated cognitive decline and brain atrophy in older adults.

Mechanistic Evaluation of Diffusion Weighted Hyperintense Lesions After Large Spontaneous Intracerebral Hemorrhage: A Subgroup Analysis of MISTIE III.

Ischemic lesions on diffusion weighted imaging (DWI) are common after acute spontaneous intracerebral hemorrhage (ICH) but are poorly understood for large ICH volumes (> 30mL). We hypothesized that large blood pressure drops and effect modification by cerebral small vessel disease markers on magnetic resonance imaging (MRI) are associated with DWI lesions. This was an exploratory analysis of participants in the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial with protocolized brain MRI scans within 7days from ICH. Multivariable logistic regression analysis was performed to assess biologically relevant factors associated with DWI lesions, and relationships between DWI lesions and favorable ICH outcomes (modified Rankin Scale 0-3). Of 499 enrolled patients, 300 had MRI at median 7.5days (interquartile range 7-8), and 178 (59%) had DWI lesions. The incidence of DWI lesions was higher in patients with systolic blood pressure (SBP) reduction ≥ 80mm Hg in first 24h (76%). In adjusted models, factors associated with DWI lesions were as follows: admission intraventricular hematoma volume (p = 0.03), decrease in SBP ≥ 80mm Hg from admission to day 1 (p = 0.03), and moderate-to-severe white matter disease (p = 0.01). Patients with DWI lesions had higher odds of severe disability at 1month (p = 0.04), 6months (p = 0.036), and 12months (p < 0.01). No evidence of effect modification by cerebral small vessel disease on blood pressure was found. In patients with large hypertensive ICH, white matter disease, intraventricular hemorrhage volume, and large reductions in SBP over the first 24h were independently associated with DWI lesions. Further investigation of potential hemodynamic mechanisms of ischemic injury after large ICH is warranted.

Can exercise benefit cerebral white matter myelin? Findings from a 12‐month randomized controlled trial in older adults with vascular cognitive impairment

AbstractBackgroundCerebral small vessel disease is a major underlying cause of subcortical ischemic vascular cognitive impairment (SIVCI). Myelin loss is a feature of cerebral small vessel disease, which may underly cognitive and functional decline in older adults living with SIVCI. Resistance training (RT) is a form of exercise associated with slower progression of white matter lesions, a cerebral small vessel disease marker. However, it remains to be determined whether RT can counteract myelin loss in individuals living with SIVCI. Thus, we examined the impact of a 12‐month, twice‐weekly progressive RT program on myelin content in those with SIVCI.MethodThis was a sub‐study of a 12‐month single‐blinded, randomized controlled trial. Participants (n = 91) were randomized to RT or an active control group (balance and tone exercises [BAT]). Study eligibility included: 1) age 55 years and older; 2) magnetic resonance imaging (MRI) evidence of cerebral small vessel disease; 3) mild cognitive impairment; and 4) the absence of dementia. Myelin was measured using a multi‐echo gradient and spin echo T2 relaxation MRI sequence, indexed as myelin water fraction (MWF). Differences between groups at 12 months were assessed via analysis of covariance adjusting for baseline MWF and estimated intracranial volume. MWF data from fifteen white matter tracts were analyzed. Post‐hoc regressions were conducted to determine if changes in MWF were associated with changes in mobility measured with the Short Physical Performance Battery (SPPB).ResultSeventy‐three participants (RT = 36) aged 74.1 (SD = 5.7), 64% females with high‐quality MRI data were included in the analyses. At 12 months, RT showed lower MWF levels compared with BAT in the genu of the corpus callosum (estimated mean difference [RT – BAT]: ‐0.610, 95% CI: ‐1.041 to ‐0.178, p = 0.006), fornix (‐0.883, 95% CI: ‐1.570 to ‐0.197, p = 0.012), and combined white matter tracts (‐0.326, 95% CI: ‐0.643 to ‐0.009, p = 0.044). Changes in MWF in the combined white matter tracs were positively associated with changes in SPPB (Unstandardized B = 0.124, SE = 0.061, p = 0.047).ConclusionContrary to our expectations, 12 months of balance and tone exercises, but not RT, showed positive changes in myelin. These improvements may result in better mobility in older adults with SIVCI.

Heart rate fragmentation and brain MRI markers of small vessel disease in MESA.

Heart rate (HR) fragmentation indices quantify breakdown of HR regulation and are associated with atrial fibrillation and cognitive impairment. Their association with brain magnetic resonance imaging (MRI) markers of small vessel disease is unexplored. In 606 stroke-free participants of the Multi-Ethnic Study of Atherosclerosis (mean age 67), HR fragmentation indices including percentage of inflection points (PIP) were derived from sleep study recordings. We examined PIP in relation to white matter hyperintensity (WMH) volume, total white matter fractional anisotropy (FA), and microbleeds from 3-Tesla brain MRI completed 7 years later. In adjusted analyses, higher PIP was associated with greater WMH volume (14% per standard deviation [SD], 95% confidence interval [CI]: 2, 27%, P=0.02) and lower WM FA (-0.09 SD per SD, 95% CI: -0.16, -0.01, P=0.03). HR fragmentation was associated with small vessel disease. HR fragmentation can be measured automatically from ambulatory electrocardiogram devices and may be useful as a biomarker of vascular brain injury.

Correlation between migraine and cerebral small vessel disease: A case-control study.

Microcirculatory pathology is one of the pathophysiological theories of migraine, which may present as visually subclinical lesions. Image markers of cerebral small vessel disease (CSVD) have been investigated in elderly migraineurs. However, past studies looked at only part of image features, and the conclusions may have been hindered by confounding factors. The relationship between migraine and CSVD signs needs reliable demonstrations. We conducted a case-control study by recruiting episodic young migraineurs from a tertiary headache centre, with tension-type headache (TTH) and healthy controls. Distinct image features of microvascular damage and baseline characteristics across groups were assessed, and multivariate linear regression was performed to evaluate the risk factors for image abnormalities in migraineurs. Forty-eight migraineurs, 32 TTHs and 49 healthy controls were included. The median age was 32 year-old. 58.7% of the participants were female. The Scheltens score and volume of white matter hyperintensities (WMHs) in migraineurs, and the number of Virchow-Robin spaces (VRSs) in both migraineurs and TTHs were different from those in normal controls. No lacunar infarct-like lesions (ILLs) or cerebral microbleeds (CMBs) were found. Age, education level (high level: β = -2.23, lobar WMHs), attack duration (long duration: β = 3.81, lobar WMHs) and attack frequency were independent risk factors for Scheltens score and volume of WMH in migraineurs. Migraine aura (β = -2.389), attack frequency and education level were correlated with the number of VRSs. Migraine was associated with WMHs and VRSs. Aura, attack duration, attack frequency, age and education level were risk factors for image abnormalities of CVSD in migraineurs. This study provides a novel and comprehensive landscape of CSVD MRI features in young migraineurs, and it fills the blank of CMBs and VRSs which received less attention, with more persuasive, more reliable and stronger evidence of the association between CSVD and migraine. Our results also imply some new feature of TTH and the possible pathophysiology of the migraine course as well as new clues for the early management of migraine in terms of visual brain damage.

Where is VALDO? VAscular Lesions Detection and segmentatiOn challenge at MICCAI 2021

Imaging markers of cerebral small vessel disease provide valuable information on brain health, but their manual assessment is time-consuming and hampered by substantial intra- and interrater variability. Automated rating may benefit biomedical research, as well as clinical assessment, but diagnostic reliability of existing algorithms is unknown. Here, we present the results of the VAscular Lesions DetectiOn and Segmentation (Where is VALDO?) challenge that was run as a satellite event at the international conference on Medical Image Computing and Computer Aided Intervention (MICCAI) 2021. This challenge aimed to promote the development of methods for automated detection and segmentation of small and sparse imaging markers of cerebral small vessel disease, namely enlarged perivascular spaces (EPVS) (Task 1), cerebral microbleeds (Task 2) and lacunes of presumed vascular origin (Task 3) while leveraging weak and noisy labels. Overall, 12 teams participated in the challenge proposing solutions for one or more tasks (4 for Task 1-EPVS, 9 for Task 2-Microbleeds and 6 for Task 3-Lacunes). Multi-cohort data was used in both training and evaluation. Results showed a large variability in performance both across teams and across tasks, with promising results notably for Task 1-EPVS and Task 2-Microbleeds and not practically useful results yet for Task 3-Lacunes. It also highlighted the performance inconsistency across cases that may deter use at an individual level, while still proving useful at a population level.

Retinal ganglion cell-inner plexiform layer, white matter hyperintensities, and their interaction with cognition in older adults.

We explored the interaction of optical coherence tomography (OCT) parameters and white matter hyperintensities with cognitive measures in our older adult cohort. This observational study enrolled participants who underwent a comprehensive neuropsychological battery, structural 3-T brain magnetic resonance imaging (MRI), visual acuity examination, and OCT imaging. Cerebral small vessel disease (CSVD) markers were read on MR images; lacune, cerebral microbleeds (CMB), white matter hyperintensities (WMH), and enlarged perivascular spaces (EPVS), were defined according to the STRIVE standards. Retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thicknesses (μm) were measured on the OCT tool. Older adults with cognitive impairment (CI) showed lower RNFL (p = 0.001), GCIPL (p = 0.009) thicknesses, and lower hippocampal volume (p = 0.004) when compared to non-cognitively impaired (NCI). RNFL (p = 0.006) and GCIPL thicknesses (p = 0.032) correlated with MoCA scores. GCIPL thickness (p = 0.037), total WMH (p = 0.003), PWMH (p = 0.041), and DWMH (p = 0.001) correlated with hippocampal volume in our older adults after adjusting for covariates. With hippocampal volume as the outcome, a significant interaction (p < 0.05) between GCIPL and PWMH and total WMH was observed in our older adults. Both GCIPL thinning and higher WMH burden (especially PWMH) are associated with hippocampal volume and older adults with both pathologies are more susceptible to subclinical cognitive decline.

Serum immunoglobulins and biomarkers of dementia: a population-based study

BackgroundInflammation plays a key role in the development of dementia, but its link to early biomarkers, particularly those in plasma or neuroimaging, remains elusive. This study aimed to investigate the association between serum immunoglobulins and biomarkers of dementia.MethodsBetween 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in dementia-free participants of the population-based Rotterdam Study. A random subset of participants had assessment of biomarkers in plasma (total tau (t-tau), neurofilament light chain (NfL), amyloid-β40 (Aβ-40), amyloid-β42 (Aβ-42), while another subset of participants underwent neuroimaging to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. Linear regression models were constructed to determine cross-sectional associations between IgA, IgG, IgM and biomarkers of dementia, with adjustment for potential confounders. Multiple testing correction was applied using the false discovery rate. As a sensitivity analysis, we re-ran the models for participants within the reference range of immunoglobulins, excluding those using immunomodulating drugs, and conducted a stratified analysis by APOE-ε4 carriership and sex.ResultsOf 8,768 participants with serum immunoglobulins, 3,455 participants (65.8 years [interquartile range (IQR): 61.5–72.0], 57.2% female) had plasma biomarkers available and 3,139 participants (57.4 years [IQR: 52.7–60.7], 54.4% female) had neuroimaging data. Overall, no associations between serum immunoglobulins and biomarkers of dementia remained significant after correction for multiple testing. However, several suggestive associations were noted: higher serum IgA levels concurred with lower plasma levels of Aβ-42 (standardized adjusted mean difference: -0.015 [95% confidence interval (CI): -0.029−-0.002], p = 2.8 × 10–2), and a lower total brain volume, mainly driven by less gray matter (-0.027 [-0.046−-0.008], p = 6.0 × 10–3) and more white matter hyperintensities (0.047 [0.016 – 0.077], p = 3.0 × 10–3). In sensitivity analyses, higher IgM was linked to lower t-tau, Aβ-40, and Aβ-42, but also a loss of white matter microstructural integrity. Stratified analyses indicate that these associations potentially differ between carriers and non-carriers of the APOE-ε4 allele and men and women.ConclusionsWhile associations between serum immunoglobulins and early markers of dementia could not be established in this population-based sample, it may be valuable to consider factors such as APOE-ε4 allele carriership and sex in future investigations.