Cerebral small vessel disease (SVD) is a leading cause of stroke and vascular dementia. The majority of cases are sporadic, occurring in the elderly hypertensive population. However, there also exist patients with familial disease. The most common form is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene. In recent years, other genes have also been found to cause familial SVD, such as COL4A1/A2, HTRA1, FOXC1 and TREX1. Genome wide association studies (GWAS) have also revealed loci associated with sporadic SVD strokes and its related features. This thesis explores the genetic basis of SVD primarily from the angle of the 'one gene, one disease' hypothesis. We explore the phenotype of familial SVD using CADASIL as a prototype. We next adopt a candidate gene approach to rare variant discovery using high throughput sequencing (HTS) techniques in two forms: 1) a multi-gene sequencing panel to examine the presence of rare variants in a cohort of 993 presumed-sporadic, early-onset SVD stroke patients, and 2) whole genome sequencing in 118 pedigrees with suspected familial SVD. We also evaluate the prevalence of known disease-causing mutations in the general population using a cohort of whole genome sequenced non-SVD patients, and other control databases. We demonstrate that a few presumed-sporadic SVD stroke patients may in fact have familial disease that was not previously diagnosed. We show that known and novel rare variants in candidate genes are found in our cohort of familial SVD patients, and suggest a possible role for rare variants in genes associated with related phenotypes and sporadic disease in this cohort. Finally, we identify known disease-causing variants in relatively high frequencies in the population, and show that conclusions on the pathogenicity of variants based on allele frequency and functional analyses may sometimes be misguided, thus highlighting the current limitations we face in the clinical interpretation of variants identified on HTS. In recent years genetic studies have revealed that pathways in different familial diseases are likely to converge in the pathogenesis of sporadic disease. Further uncovering the genetic basis of undiagnosed cases of familial SVD may shed light on the mechanisms underlying the sporadic form of disease, and may in turn drive the identification of potential therapeutic targets.

Small vessel disease (SVD) accounts for approximately 25% of all strokes and 45% of all dementias. Although the small vessels cannot be visualised with conventional neuroimaging, the pathological changes in the cerebral white and deep grey matter secondary to SVD has been adopted as markers of SVD. These are best appreciated with magnetic resonance imaging (MRI) and includes recent small subcortical infarcts, white matter hyperintensity (WMH), lacunes, cerebral microbleeds and enlarged perivascular spaces (PVSs). There are however a number of outstanding questions regarding these surrogate neuroimaging markers of SVD and how these markers may influence clinical management. First, although a high burden of microbleeds have been associated with an increased risk of intracerebral haemorrhage (ICH) and possibly recurrent ischaemic stroke in patients with TIA or ischaemic stroke, how microbleeds should influence antithrombotic treatment use after TIA or ischaemic stroke remains uncertain. Second, the long-term prognostic implications of enlarged PVSs in patients with TIA or ischaemic stroke have not been studied. Third, although previous studies have shown possible ethnic differences in prevalence of microbleeds, whether there are any ethnic differences in prevalence of other neuroimaging markers of SVD remains unclear. Fourth, although a Total SVD Score was recently proposed to measure the global SVD burden, the prognostic value of this score in patients with TIA or ischaemic stroke has yet to be studied. Fifth, the relationships of long-term premorbid blood pressure with global SVD burden is unknown. Finally, the age and sex specific associations between renal impairment, carotid and cerebral pulsatility with burden of SVD has yet to be studied. The aim of my thesis was therefore to determine the clinical correlates, ethnic differences and long-term prognostic implications of a range of neuroimaging markers and global burden of SVD. I also aimed to determine the relationships of global SVD burden with long-term mean premorbid blood pressure, renal impairment and carotid pulsatiltiy. I have collected, collated and analysed clinical and neuroimaging data from two independent cohorts - the Oxford Vascular Study (OXVASC) and The University of Hong Kong (HKU). In particular I worked as one of the Clinical Research Fellows at OXVASC and was involved in regular recruitment, assessment and follow up of study patients. In OXVASC, 1080 predominantly Caucasians with TIA or ischaemic stroke who had a cerebral MRI performed at baseline was recruited during 2004 to 2014. I interpreted all these MRIs, specifically coding the burden of microbleeds, enlarged perivascular spaces and lacunes. I was involved in obtaining funding and developing the HKU cohort, which includes 1003 predominantly Chinese with ischaemic stroke recruited during 2008-2014 who had a cerebral MRI performed at baseline. I saw about 25% of the patients in the cohort and was involved in interpreting all of the MRIs of the cohort. All patients from both cohorts were followed-up regularly and adverse events including recurrent ischaemic stroke and ICH was determined. Presence and burden of periventricular and subcortical WMH, lacunes, microbleeds, basal ganglia and centrum semiovale PVSs was determined for all patients and the global burden of SVD estimated according to the Total SVD Score. There are several clinically relevant findings in this thesis. First, I have shown that in Caucasians and Chinese with ≥5 microbleeds, withholding antiplatelet drugs during the first year after TIA or ischaemic stroke may be inappropriate, especially early after TIA. However, the risk of ICH is likely to outweigh any benefit thereafter. Second, I have shown that TIA or ischaemic stroke patients with microbleeds on warfarin had an increased risk of subsequent ICH. However, this risk was not different from that of antiplatelet users with microbleeds. Third, I have shown that a high burden of MRI-visible basal ganglia PVSs is independently associated with an increased risk of recurrent ischaemic stroke, but not ICH. However, the prognostic value of MRI-visible centrum semiovale PVSs in the TIA or ischaemic stroke population is limited. Fourth, I demonstrated significant ethnic differences in underlying prevalence and burden of neuroimaging markers of SVD - Chinese had a greater prevalence of microbleeds, lacunes and subcortical WMH, whilst Caucasians had a greater prevalence of periventricular WMH and PVSs. Fifth, I validated the Total SVD Score and showed that the SVD Score is able to predict risk of recurrent ischaemic stroke and ICH in Caucasians and Chinese, but is unable to identify patients at high risk of ICH from those at high risk of recurrent ischaemic stroke. Sixth, I showed that mean premorbid blood pressure, especially diastolic blood pressure measurements taken 10-20 years prior to TIA or ischaemic stroke was most strongly associated with global SVD burden suggesting a latency effect of hypertension on the pathogenesis of SVD. Finally, I demonstrated age-specific associations between renal impairment, internal carotid artery pulsatility index and SVD burden.

Lacunar stroke accounts for one quarter of all ischaemic stroke and in the long term carries a greater risk of death and disability than was previously realised. Much of our current knowledge originated from neuropathological studies in the 1950s and 1960s. In the last thirty years, brain computed tomography (CT) and magnetic resonance imaging (MRI) have revolutionised our understanding of lacunar stroke and associated features of cerebral small vessel disease (SVD), namely white matter lesions (WML), enlarged perivascular spaces (EPVS) and brain microbleeds (BMB). The purpose of the projects which led to the writing of this thesis was to improve understanding of imaging characteristics of cerebral SVD. We aimed to assess (i) clinical and imaging features which might explain misclassification of lacunar infarcts as cortical infarcts and vice versa, (ii) the proportion of symptomatic lacunar infarcts progressing to lacunar cavities and associations of cavitation, (iii) completeness of reporting of lacunar lesions in the lacunar stroke literature, (iv) definitions and detection of lacunar lesions amongst SVD researchers, (v) the relationship between WML and carotid stenosis, (vi) clinical and imaging associations of EPVS and, (vii) observer variability in the assessment of EPVS and BMB, in order to develop visual rating scales. Section one describes neuroimaging of lacunar stroke. To investigate features which might explain clinical stroke subtype misclassification (‘clinical-imaging dissociation’), I used data from a stroke study. The main factor associated with clinical-imaging dissociation was diabetes, and in patients with acute lacunar infarction, proximity of the lacunar infarct to the cortex, age, diabetes and left hemisphere location. To investigate the proportion of symptomatic lacunar infarcts progressing to cavities, I used data from two stroke studies. A fifth of patients with acute lacunar ischaemic stroke showed definite cavitation on follow-up imaging at a median of 227 days; cavitation was associated with increasing time to follow-up. To assess completeness of reporting of lacunar lesions in the lacunar stroke literature, I reviewed 50 articles from three journals with a stroke focus. There was marked variation in terminology and descriptions of imaging definitions of lacunar lesions. To assess lacunar lesion definitions and detection amongst SVD researchers, I used an online survey consisting of case-based and non-case-based questions. There was marked variation in definitions and descriptions. Cavitated lesions were detected with the highest degree of confidence. Section two describes neuroimaging of associated features of cerebral SVD. Using data from two stroke studies, I examined the relationship between WML and ipsilateral carotid artery stenosis. There was no association between carotid stenosis and WML. I tested the association of EPVS with WML and lacunar stroke subtype using data from a stroke study. Total EPVS were associated with age and deep WML; basal ganglia (BG) EPVS were associated with age, centrum semiovale (CS) EPVS, cerebral atrophy and lacunar stroke subtype. Quantification of observer variability in EPVS rating was assessed on 60 MRI scans selected from a stroke study and an ageing cohort. Intrarater agreement was good and interrater agreement was moderate. Main reasons for interrater disagreement included the visualisation of very small EPVS and the presence of concomitant WML and lacunar lesions. Observer variability in BMB rating was quantified using MRI scans from a stroke study. Interrater agreement was moderate but improved following modification of the pilot rating scale (BOMBS; Brain Observer MicroBleed Scale), which had its main effect by differentiating ‘certain’ BMB from ‘uncertain’ BMB and BMB ‘mimics’. In conclusion, neuroimaging, particularly MRI, is a valuable tool for the investigation of lacunar stroke and associated features of cerebral SVD. With recent technological advances in both CT and MRI, neuroimaging will remain central to future SVD studies, hopefully leading to a much improved understanding of this important disease.

Cerebral small vessel disease (SVD) is a common cause of strokes and dementia. The pathogenesis of SVD is poorly understood, but imaging and biochemical investigations suggest that subtle blood-brain barrier (BBB) leakage may contribute to tissue damage. The most widely-used imaging method for assessing BBB integrity and other microvascular properties is dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI has primarily been applied in situations where contrast uptake in tissue is typically large and rapid (e.g. neuro-oncology); the optimal approach for quantifying BBB integrity in diseases where the BBB remains largely intact and the reliability of resulting measurements is unclear. The main purpose of this thesis was to assess and improve the reliability of quantitative assessment of subtle BBB disruption, in order to illuminate its potential role in cerebral SVD. Firstly, a systematic literature review was performed in order to provide an overview of DCE-MRI methods in the brain. This review found large variations in MRI procedures and data analysis methods, resulting in widely varying estimates of tracer kinetic parameters. Secondly, this thesis focused on the analysis of DCE-MRI data acquired in an on-site clinical study of mild stroke patients. After performing basic DCE-MRI processing (e.g. selection of a vascular input function), this work aimed to determine the tracer kinetic modelling approach most suitable for assessing subtle BBB disruption in this cohort. Using data-driven model selection and computer simulations, the Patlak model was found to provide accurate estimates of blood plasma volume and low-level BBB leakage. Thirdly, this thesis aimed to investigate two potential pitfalls in the quantification of subtle BBB disruption. Contrast-free measurements in healthy volunteers revealed that a signal drift of approximately 0.1 %/min occurs during the DCE-MRI acquisition; computer simulations showed that this drift introduces significant systematic errors when estimating low-level tracer kinetic parameters. Furthermore, tracer kinetic analysis was performed in an external patient cohort in order to investigate the inter-study comparability of DCE-MRI measurements. Due to the nature of the acquisition protocol it proved difficult to obtain reliable estimates of BBB leakage, highlighting the importance of study design. Lastly, this thesis examined the relationship between quantitative MRI parameters and clinical measurements in cerebral SVD, with a focus on the estimates of blood volume and BBB leakage obtained in the internal SVD patient cohort. This work did not provide evidence that BBB leakage in normal-appearing tissue increases with SVD burden or predicts disease progression; however, increased BBB leakage was found in white matter hyperintensities. Furthermore, this work raises the possibility of a role for blood plasma volume and dietary salt intake in cerebral SVD. The work described in this thesis has demonstrated that it is possible to estimate subtle BBB disruption using DCE-MRI, provided that the measurement and data analysis strategies are carefully optimised. However, absolute values of tracer kinetic parameters should be interpreted with caution, particularly when making comparisons between studies, and sources of error and their influence should be estimated where possible. The exact roles of BBB breakdown and other microvascular changes in SVD pathology remain to be defined; however, the work presented in this thesis contributes further insights and, together with technical advances, will facilitate improved study design in the future.

Small vessel disease (SVD) is an important cause of stroke, cognitive decline, and age-related disability. The cause of SVD is unknown, increasing evidence from neuropathology and neuroimaging suggests that failure of the blood-brain barrier (BBB) precipitates or worsens cerebral SVD progression and its failure is associated with SVD features such as white matter hyperintensities (WMH), perivascular spaces (PVS) and lacunar infarcts. The BBB change mechanism may also contribute to other common disorders of ageing such as Alzheimer's disease (AD). Magnetic resonance imaging (MRI) has revolutionised our understanding of SVD features. The MRI contributes to better understanding of the SVD pathophysiology and their clinical correlates. The purpose of this project was to better understand the pathogenesis of SVD, which involves improved understanding of BBB structures and pathophysiology and accurate measurement of cerebral SVD imaging characteristics on MRI scans. We aimed to assess (1) structures related to the BBB and factors that affect the BBB; (2) efficient and consistent WMH measurement method; (3) effect of stroke lesions on WMH and cerebral atrophy progression; (4) development and optimisation of computational PVS measurement method; (5) the relationships between PVS and SVD, blood markers, and BBB permeability. Section one describes structures and pathophysiology of the BBB. I reviewed the BBB structural and functional components from the view of neurovascular unit, PVS, and junctional proteins. The PVS part was done in a systematic search. I also reviewed some common stimuli for BBB permeability including inflammation and ischemia. Ischemic triggers for the BBB permeability were summarized systematically. Based on the literatures above, I summarized changes in junctional proteins in ischemia, inflammatory pain and AD models. Section two describes accurate measurement of WMH progression and atrophy. I used data from 100 patients who participated in a stroke study about BBB permeability changes in lacunar versus cortical stroke. To find a most efficient and consistent WMH measurement method, we tested several computational methods and effect of common processing steps including bias field correction and intensity adjustment. To avoid the effect of artefacts, I did a systematic search about artefacts and tested methods of image segmentation to avoid WMH artefacts as much as possible. To investigate the effect of stroke lesions on WMH and atrophy progression, I did the WMH, atrophy segmentation and stroke lesion measurements in a subgroup of 46 patients with follow-up scans, and showed that stroke lesions distorted measurement of WMH and atrophy progression and should be excluded. Section three describes development and optimization of a computational PVS measurement method, which measures the count and volume for PVS based on a threshold method using AnalyzeTM software. We tested the observer variability and validated it by comparison with visual rating scores. We investigated the associations between PVS results with other SVD features (WMH, atrophy), risk factors (hypertension, smoking and diabetes), blood markers, and BBB permeability. In conclusion, MRI is a valuable tool for the investigation of cerebral SVD features and BBB permeability. Exclusions of artefacts and stroke lesions are important in accurate measurement of WMH. PVS are important features of BBB abnormalities, and they correlate and share risk factors with other SVD features, and they should be considered as a marker of SVD and BBB permeability. Further systematic histological and ultrastructural studies of BBB are desirable in understanding the BBB regarding to the different parts of the cerebral vascular tree.

Cerebral small vessel disease (SVD) is a vascular neurodegenerative disease which is the leading cause of vascular dementia and causes 20% of strokes. 20-30% of those over 80 show signs of the disease as white matter hyperintensities on MRI scans, doubling their risk of stroke and trebling their risk of dementia. Sporadic SVD is thought to be caused by hypertension but 30% of sufferers are normotensive and an alternative hypothesis implicates loss of integrity of the blood brain barrier (BBB). To investigate this, I studied brains from normotensive people with early stage SVD and found reduced capillary endothelial claudin-5 (a BBB tight junction protein), more oligodendrocyte precursor cells (OPCs; the precursors to myelinating oligodendrocytes), and more microglia/macrophages compared to controls. Furthermore, in a relevant rat model of spontaneous SVD, the Stroke Prone Spontaneously Hypertensive Rat (SHRSP; disease model; DM) I found that reduced endothelial claudin-5 was the earliest change, appearing at 3 weeks of age, followed by OPC proliferation, appearing at 4 weeks, and then increased number of microglia/macrophages, appearing at 5 weeks. Importantly, all these changes occurred at a young age (< 5 weeks), before any measurable hypertension. These changes were confirmed in an ex vivo slice culture model (i.e. removing blood flow), ruling out direct damage by leakage of blood components through an impaired BBB and suggesting an inherent endothelial cell dysfunction as the primary cause, with secondary BBB defects. This hypothesis of endothelial dysfunction is supported by increased endothelial cell proliferation in both human SVD tissue and the DM rats, and lower levels of endothelial nitric oxide synthase (eNOS) in brains of DM rats. To study this further I isolated primary brain microvascular endothelial cells (BMECs) from DM and control rats and found that those from DM rats formed less mature tight junctions (less membranous claudin-5) than control BMECs. I also found that conditioned media (CM) from DM BMECs causes OPCs in culture to proliferate more and mature less. This indicates that the endothelial dysfunction is inherent to the endothelial cells, rather than induced by other cell types, and through secreted factors causes OPC changes mirroring what is seen in vivo. Using an antibody array, I identified HSP90α as a candidate secreted factor and showed that it is necessary (by blocking the protein in CM) and sufficient (by adding recombinant HSP90α) to induce the maturation phenotype in OPCs, but not the proliferation phenotype. The idea that endothelial dysfunction causes SVD begs the question of what causes endothelial dysfunction, especially in our inbred DM rat strain. To establish this, I reanalysed sequencing data of the DM and control rats from a previously published study, searching for mutations which lead to truncated proteins in genes expressed in brain endothelial cells. We confirmed the candidate gene Atp11b, a phospholipid flippase, was mutated as predicted. I found that knocking down Atp11b using siRNA in a control endothelial cell line caused endothelial dysfunction and a loss of tight junction maturity, and that CM from these cells causes OPCs to proliferate more and mature less, mirroring what we see in primary DM BMECs and suggesting that Atp11b has a key function in promoting normal endothelial function. Furthermore, I showed that knocking down Atp11b causes cells to secrete increased levels of HSP90α. I propose a mechanism whereby ATP11B regulates the retention of HSP90α within endothelial cells, which in turns regulates eNOS levels and activity, as has been shown previously. In summary, this work shows that there are many pre-symptomatic changes which occur in the brain in the development of SVD in DM rats, and that these are ultimately caused by endothelial dysfunction. As these changes are similar to those found in spontaneous human SVD, I propose that endothelial dysfunction is a key mechanism of human SVD, which may in the future lead to new therapies.

Cerebral small vessel pathology is now known to be associated with the development of cognitive impairment and mild motor impairments such as gait disturbance in a variety of neurodegenerative diseases. This dissertation explores the hypothesis that blood brain barrier dysfunction is an early event in cerebral ischemia and contributes to the development of cerebral small vessel disease (CSVD). A common rodent model of CSVD is permanent bilateral common carotid artery occlusion in the rat. This model was used to study several aspects of the progression of CSVD including the timecourse of blood brain barrier permeability changes following the onset of ischemia, gait disturbance, the expression of tight junction proteins and cytokine expression. It was determined that BBB permeability was elevated for 2 weeks following BCCAO and ischemic rats displayed lower gait velocity. There was no change in expression of TJ proteins. However, ischemic rats had higher levels of some proinflammatory cytokines and chemokines in brain tissue with no obvious changes in plasma levels. The mechanisms underlying the increase in BBB permeability were studied in vitro using artificial barriers made of confluent rat brain microvascular endothelial cells. Cerebral ischemia has been reported to cause an increase in plasma toxicity, likely by elevating the numbers of circulating microparticles (MPs). MPs isolated from the plasma of ischemic rats were applied to artificial barriers where it was found that they act mainly as vectors of TNF-α signaling. MPs induce activation of caspase-3 and the Rho/Rho kinase pathways. It is concluded that most of the increase in barrier permeability is due to apoptosis and disassembly of actin cytoskeleton and disruption of adherens junctions IV and not an increase in transcellular transport. The effects of treatment with the type III phosphodiesterase inhibitor cilostazol on dye extravasation in the brain, glial activation, white matter damage and motor performance were evaluated. It was determined that cilostazol could improve the increased BBB permeability and gait disturbance and microglial activation in optic tract following BCCAO. Also, the effects of treatment with cilostazol on plasma toxicity in vivo (24h and 14d following BCCAO) and artificial barriers (in vitro) were assessed. It was found that cilostazol could reduce plasma toxicity at 24h and improve increased endothelial barrier permeability that is induced by MP treatment respectively. In summary BBB dysfunction occurs in the rat model of chronic cerebral hypoperfusion with no differences in expression of TJ proteins. There is a mild motor disturbance in the form of lower gait velocity following BCCAO. Cytokines released in brain tissue may be associated with pathological consequences following BCCAO while there is no significant difference in plasma levels and circulating MPs may play a role in BBB dysfunction.

Balali_Pargol_MSc thesis_Neuroscience department_2023Sep / Background: Cerebral microbleeds are asymptomatic neuroimaging markers of small vessel disease (SVD), visualized as small hypointensities on blood-sensitive magnetic resonance imaging (MRI) sequences. Patients with ischemic stroke and microbleeds are at a higher risk of future ischemic stroke and intracranial hemorrhage. Antithrombotic therapies, the mainstay treatment of secondary stroke prevention, are associated with an increased risk of bleeding. This raises concerns surrounding the net benefit of antithrombotic therapies in these hemorrhage-prone patients. The overarching aim of this thesis is to determine the safety of antithrombotic treatments in patients with hemorrhage-prone SVD marked by microbleeds on MRI or prior intracerebral hemorrhage (ICH). I aimed to characterize the association between baseline microbleeds and the risk of future clinical outcomes in patients with ischemic stroke and whether there exists treatment effect modification of different anticoagulants on clinical outcomes according to microbleeds presence, location, and number. Methods: We performed post hoc analyses on two multicenter previously conducted randomized trials in patients with non-cardioembolic ischemic stroke. For the PACIFIC-STROKE trial, we used multivariable regression models to determine the contribution of microbleeds to the risk of new microbleeds, hemorrhagic transformation (HT), ischemic stroke, intracranial hemorrhage, and death. We assessed the treatment effect of asundexian, a factor XIa inhibitor, vs. placebo on these clinical outcomes, stratified by microbleeds presence, location, and number. I was trained on standardized rating of microbleeds on MRI, achieved excellent interrater reliability, and rated all DATAS-II participant MRIs. I used multivariable logistic regression models to identify the association between microbleeds and HT and 90-day excellent functional outcome. I assessed the interaction between treatment with dabigatran, a direct thrombin inhibitor, vs. aspirin and microbleeds for these outcomes. Separately, I performed a review of the literature and wrote an editorial discussing the optimum timing of antiplatelet re-initiation after ICH. Results: The PACIFIC-STROKE post hoc analyses showed that microbleeds are associated with a 1.6-fold and 4.4-fold higher risk of HT and new microbleeds, respectively. The DATAS-II exploratory analyses demonstrated no association between the risk of outcomes and microbleeds presence. We found no interaction between treatment assignment and microbleed presence for any of the clinical outcomes investigated in either of these studies. Based on the totality of evidence, we concluded that early resumption of antiplatelets in ICH survivors is likely to be safe. Conclusion: Our findings do not support existing concerns surrounding the use of anticoagulants in patients with acute ischemic stroke and microbleeds on MRI, nor for the early resumption of antiplatelets in ICH survivors. / Thesis / Master of Science (MSc) / Diseases of small brain blood vessels can lead to strokes due to blockage or bleeding. Small, asymptomatic brain bleeds on MRIs (microbleeds) are common among affected patients. Patients with clot-induced stroke and microbleeds have a higher risk of both types of strokes. Blood thinners are standard treatments to prevent future clotting events after clot-induced stroke. However, their potential to increase the risk of brain bleeding has raised concerns regarding their use in patients with microbleeds or bleeding-induced stroke. We assessed information from two large, previously completed randomized trials to evaluate the safety of strong blood thinners (anticoagulants) in patients with clot-induced stroke and microbleeds. Additionally, we evaluated the risk vs. benefit of restarting milder blood thinners (antiplatelets) early after bleeding-induced stroke. Bleeding was more prevalent in patients with microbleeds; however, the effect of the anticoagulants tested on bleeding outcomes was not modified by microbleed presence. Overall, our findings suggest that blood thinners are safe in patients with clot-induced stroke and microbleeds, and that early resumption of antiplatelets seems safe in patients with bleeding-induced stroke.

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