White Matter Microstructural Damage on Diffusion Tensor Imaging in Cerebral Small Vessel Disease

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Apathy, but not depression, predicts all-cause dementia in cerebral small vessel disease

Objective: To determine whether apathy or depression predicts all-cause dementia in small vessel disease (SVD) patients. Methods: Analyses used two prospective cohort studies of SVD: St. George’s Cognition and Neuroimaging in Stroke (SCANS; n=121) and Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC; n=352). Multivariate Cox regressions were used to predict dementia using baseline apathy and depression scores in both datasets. Change in apathy and depression was used to predict dementia in a subset of 104 participants with longitudinal data from SCANS. All models were controlled for age, education and cognitive function. Results: Baseline apathy scores predicted dementia in SCANS (HR 1.49, 95% CI 1.05 to 2.11, p=0.024) and RUN DMC (HR 1.05, 95% CI 1.01 to 1.09, p=0.007). Increasing apathy was associated with dementia in SCANS (HR 1.53, 95% CI 1.08 to 2.17, p=0.017). In contrast, baseline depression and change in depression did not predict dementia in either dataset. Including apathy in predictive models of dementia improved model fit. Conclusions: Apathy, but not depression, may be a prodromal symptom of dementia in SVD, and may be useful in identifying at-risk individuals

Updated Stroke Gene Panels : Rapid evolution of knowledge on monogenic causes of stroke

This article updates our previous Stroke Gene Panels (SGP) from 2017. Online Mendelian Inheritance in Man and PubMed were searched. We divided detected genes into two SGP groups, SGP1: genes reported in at least one person with stroke and associated with one or more clinical subgroups: large artery atherosclerotic, large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection or occlusion), cerebral small vessel diseases, cardio-embolic (arrhythmia, heart defect, cardiomyopathy), coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), intracerebral hemorrhage, vascular malformations (cavernoma, arteriovenous malformations) and metabolism disorders; and SGP2: genes related to diseases that may predispose to stroke. We identified 168 SGP1 genes, 70 of these were validated for clinical practice. We also detected 72 SGP2 genes. Nine genes were removed because of conflicting evidence. The number of genes increased from 168 to 240 during 4.5-years, reflecting a dynamic evolution and the need for regular updates for research and clinical use.Peer reviewe

Determinants of extended door-to-needle time in acute ischemic stroke and its influence on in-hospital mortality:results of a nationwide Dutch clinical audit

Background Intravenous thrombolysis (IVT) plays a prominent role in the treatment of acute ischemic stroke (AIS). The sooner IVT is administered, the higher the odds of a good outcome. Therefore, registering the in-hospital time to treatment with IVT, i.e. the door-to-needle time (DNT), is a powerful way to measure quality improvement. The aim of this study was to identify determinants that are associated with extended DNT. Methods Patients receiving IVT in 2015 and 2016 registered in the Dutch Acute Stroke Audit were included. DNT and onset-to-door time (ODT) were dichotomized using the median (i.e. extended DNT) and the 90th percentile (i.e. severely extended DNT). Logistic regression was performed to identify determinants associated with (severely) extended DNT/ODT and its effect on in-hospital mortality. A linear model with natural spline was used to investigate the association between ODT and DNT. Results Included were 9518 IVT treated patients from 75 hospitals. Median DNT was 26 min (IQR 20-37). Determinants associated with a higher likelihood of extended DNT were female sex (OR 1.17, 95% CI 1.05-1.31) and admission during off-hours (OR 1.12, 95% CI 1.01-1.25). Short ODT correlated with longer DNT, whereas longer ODT correlated with shorter DNT. Young age (OR 1.38, 95% CI 1.07-1.76) and admission to a comprehensive stroke center (OR 1.26, 1.10-1.45) were associated with severely extended DNT, which was associated with in-hospital mortality (OR 1.54, 95%CI 1.19-1.98). Conclusions Even though DNT in the Netherlands is short compared to other countries, lowering the DNT may be achievable by focusing on specific subgroups

Brain atrophy in cerebral small vessel diseases: Extent, consequences, technical limitations and perspectives: The HARNESS initiative

Brain atrophy is increasingly evaluated in cerebral small vessel diseases. We aim at systematically reviewing the available data regarding its extent, correlates and cognitive consequences. Given that in this context, brain atrophy measures might be biased, the first part of the review focuses on technical aspects. Thereafter, data from the literature are analyzed in light of these potential limitations, to better understand the relationships between brain atrophy and other MRI markers of cerebral small vessel diseases. In the last part, we review the links between brain atrophy and cognitive alterations in patients with cerebral small vessel diseases

Use of antihypertensive medication after ischemic stroke in young adults and its association with long-term outcome

Background: Knowledge on the use of secondary preventive medication in young adults is limited. Methods: We included 936 first-ever ischemic stroke 30-day survivors aged 15-49, enrolled in the Helsinki Young Stroke Registry, 1994-2007. Follow-up data until 2012 came from Finnish Care Register, Statistics Finland, and Social Insurance Institution of Finland. Usage thresholds were defined as non-users, low (prescription coverage 80%). Adjusted Cox regression allowed assessing the association of usage with all-cause mortality and recurrent vascular events. Results: Of our patients, 40.5% were non-users, 7.8% had low usage, 11.8% intermediate usage and 40.0% high usage. Median follow-up was 8.3 years. Compared to non-users, risk of mortality and recurrent stroke or TIA was lower for patients with low-intermediate (HR 0.40, 95% CI 0.22-0.65; HR 0.31, 95% CI 0.18-0.53) and high usage (HR 0.25, 95% CI 0.15-0.42; HR 0.30, 95% CI 0.19-0.46), after adjustment for confounders. Conclusions: Use of antihypertensives was suboptimal in one-third of patients in whom antihypertensives were initially prescribed. Users were at lower risk of mortality and recurrent stroke or TIA compared to non-users.Key Messages The use of antihypertensive medication is suboptimal in one-third of patients in whom antihypertensive medication was initially prescribed after ischemic stroke at young age. The risk of mortality and recurrent stroke or TIA is lower for users of antihypertensive medication after ischemic stroke at young age compared to non-users, after adjustment for relevant confounders including pre-existing hypertension and prior use of antihypertensive medication. Specific guidelines on antihypertensive medication use after ischemic stroke at young age are lacking. However, our results may motivate doctors and patients in gaining better usage of antihypertensive medication, since better usage was associated with more favorable outcome in this study.Peer reviewe

Temporal Dynamics of Cortical Microinfarcts in Cerebral Small Vessel Disease

Question: What are the cumulative incidence and temporal dynamics of acute cortical microinfarcts? Findings In this cohort study of 54 participants with cerebral small vessel disease who were recruited to undergo 10 monthly 3-T magnetic resonance imaging (MRI) scans, including high-resolution diffusion-weighted imaging, 21 acute cortical microinfarcts were observed in 7 of 54 participants (13%). All acute cortical microinfarcts disappeared on follow-up MRI. Meaning We show that incident acute cortical microinfarcts never evolved into chronically MRI-detectable lesions and suggest that these acute microinfarcts underlie part of the submillimeter cortical microinfarcts visible only on neuropathology, thereby providing a source for the high microinfarct burden encountered on neuropathology. Importance Neuropathology studies show a high prevalence of cortical microinfarcts (CMIs) in aging individuals, especially in patients with cerebrovascular disease and dementia. However, most, are invisible on T1- and T2-weighted magnetic resonance imaging (MRI), raising the question of how to explain this mismatch. Studies on small acute infarcts, detected on diffusion-weighted imaging (DWI), suggest that infarcts are largest in their acute phase and reduce in size thereafter. Therefore, we hypothesized that a subset of the CMI that are invisible on MRI can be detected on MRI in their acute phase. However, to our knowledge, a serial imaging study investigating the temporal dynamics of acute CMI (A-CMI) is lacking. Objective: To determine the prevalence of chronic CMI (C-CMI) and the cumulative incidence and temporal dynamics of A-CMI in individuals with cerebral small vessel disease (SVD). Design, Setting, Participants and Exposures The RUN DMC-Intense study is a single-center hospital-based prospective cohort study on SVD performed between March 2016 and November 2017 and comprising 10 monthly 3-T MRI scans, including high-resolution DWI, 3-dimensional T1, 3-dimensional fluid-attenuated inversion recovery, and T2. One hundred six individuals from the previous longitudinal RUN DMC study were recruited based on the presence of progression of white matter hyperintensities on MRI between 2006 and 2015 and exclusion of causes of cerebral ischemia other than SVD. Fifty-four individuals (50.9%) participated. The median total follow-up duration was 39.5 weeks (interquartile range, 37.8-40.3). Statistical data analysis was performed between May and October 2019. Main Outcomes and Measures: We determined the prevalence of C-CMI using the baseline T1, fluid-attenuated inversion recovery, and T2 scans. Monthly high-resolution DWI scans (n = 472) were screened to determine the cumulative incidence of A-CMI. The temporal dynamics of A-CMI were determined based on the MRI scans collected during the first follow-up visit after A-CMI onset and the last available follow-up visit. Results The median age of the cohort at baseline MRI was 69 years (interquartile range, 66-74 years) and 34 participants (63%) were men. The prevalence of C-CMI was 35% (95% CI, 0.24-0.49). Monthly DWI detected 21 A-CMI in 7 of 54 participants, resulting in a cumulative incidence of 13% (95% CI, 0.06-0.24). All A-CMI disappeared on follow-up MRI. Conclusions and Relevance: Acute CMI never evolved into chronically MRI-detectable lesions. We suggest that these A-CMI underlie part of the submillimeter C-CMI encountered on neuropathological examination and thereby provide a source for the high CMI burden on neuropathology. This cohort study examines the prevalence of chronic cortical microinfarcts and the cumulative incidence and temporal dynamics of acute cortical microinfarcts in Finnish individuals with cerebral small vessel disease

White Matter Lesions Are Not Related to β-Amyloid Deposition in an Autopsy-Based Study

Population-based studies have investigated the relation between β-amyloid levels in cerebrospinal fluid or plasma and white matter lesions (WMLs). However, these circulating levels of β-amyloid in cerebrospinal fluid or plasma may not reliably reflect the actual degree of amyloid present in the brain. Therefore, we investigated the relation between WMLs and β-amyloid plaques and amyloid angiopathy in brain tissue. WML on MRI or CT were rated in 28 nondemented patients whose neuroimaging was available prior to death. β-amyloid in plaques and arterioles were immunohistochemically stained and quantified in postmortem brain necropsies. WMLs were present in 43% of the total population. Both cortex and periventricular region showed no differences for β-amyloid deposition in either plaques or blood vessel walls in patients with WMLs compared to those without WMLs. Thus, our results indicate that there is no relation between the degree of WMLs and β-amyloid deposition in the brain