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Objectives: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet).Methods: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use.Results: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years).Interpretation: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023. Objectives: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet).Methods: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use.Results: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years).Interpretation: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023.

Ischaemic stroke is a major health concern, with over two million young adults experiencing this condition annually. Despite typically being associated with older adults, approximately 10% to 20% of ischaemic stroke cases occur in individuals aged 18 to 50 years. Furthermore, recent data have shown a growing incidence of ischaemic stroke among young adults worldwide, highlighting the attention to the stroke in young adults. The socioeconomic impact of stroke in young adults is substantial, including high healthcare costs, loss of labour productivity and long-term consequences, such as cognitive impairments, vascular dementia, apathy, and depression. Despite its importance,, the underlying mechanisms of post-stroke outcomes in young adults are still largely unknown. One potential factor is lesion location, which refers to the specific location and size of brain damage resulting from stroke. Prior studies in older stroke patients have employed voxel-based lesion symptom mapping (VLSM), a technique that investigates the relationship between lesion location and behavioral measurements, to identify the strategic regions for post-stroke consequences. However, there is still a lack of evidence on how lesion location influences post-stroke outcomes in young adults. In addition to the lesion location, brain network disruption is another potential factor that may impact post-stroke outcomes in young adults. Brain networks comprise interconnected brain regions that work together to perform mormal neuropsychological functions. Stroke can damage not only a single region but also its connections with other regions, resulting in network dysfunction. To investigate this effect, researchers have employed functional or structural lesion network mapping (LNM) approach, which use data from healthy individuals to infer how stroke lesions affect brain networks. This approach has been applied to uncover the mechanism of post-stroke depression and predict short-term cognitive decline in older stroke patients. However, further studies are required to examine the association between damaged networks and clinical outcomes in young stroke patients.

While structural network analysis consolidated the hypothesis of cerebral small vessel disease (SVD) being a disconnection syndrome, little is known about functional changes on the level of brain networks. In patients with genetically defined SVD (CADASIL, n = 41) and sporadic SVD (n = 46), we independently tested the hypothesis that functional networks change with SVD burden and mediate the effect of disease burden on cognitive performance, in particular slowing of processing speed. We further determined test-retest reliability of functional network measures in sporadic SVD patients participating in a high-frequency (monthly) serial imaging study (RUN DMC-InTENse, median: 8 MRIs per participant). Functional networks for the whole brain and major subsystems (i.e., default mode network, DMN; fronto-parietal task control network, FPCN; visual network, VN; hand somatosensory-motor network, HSMN) were constructed based on resting-state multi-band functional MRI. In CADASIL, global efficiency (a graph metric capturing network integration) of the DMN was lower in patients with high disease burden (standardized beta = -.44; p [corrected] = .035) and mediated the negative effect of disease burden on processing speed (indirect path: std. beta = -.20, p = .047; direct path: std. beta = -.19, p = .25; total effect: std. beta = -.39, p = .02). The corresponding analyses in sporadic SVD showed no effect. Intraclass correlations in the high-frequency serial MRI dataset of the sporadic SVD patients revealed poor test-retest reliability and analysis of individual variability suggested an influence of age, but not disease burden, on global efficiency. In conclusion, our results suggest that changes in functional connectivity networks mediate the effect of SVD-related brain damage on cognitive deficits. However, limited reliability of functional network measures, possibly due to age-related comorbidities, impedes the analysis in elderly SVD patients.

Background and Aims:Recent studies have shown that white matter disruption, indicated by network efficiency, plays an important role in the development of cognitive impairment in cerebral small vessel disease (SVD). As wide range of network measures now exist, we investigated which network measure is the most biologically informative in explaining the cognitive deficits and we assessed the effect of hypertension on this network measure.Methods:436 non-demented participants with SVD on neuroimaging were included (mean age 65.2 years [SD: 8.8], 46% female). Weighted connectivity matrices from diffusion tensor imaging and graph-theoretical measures were calculated. To identify the most influential network measure, we performed elastic net method. We performed linear regression models and mediation analysis to assess the association between hypertension, SVD markers and network measure, adjusted for age, sex, education and other cardiovascular risk factors.Results:Global efficiency showed the strongest association with psychomotor speed and cognitive index among all network measures in SVD. Hypertension was significantly associated with lower global efficiency (u03b2=-0.15, P=0.01) and higher white matter hypertensities (WMH) volume (u03b2=0.15, P=0.01). Mediation analysis showed that hypertension was directly related to global efficiency (u03b2=-0.19, P=0.03u2009). However the effect of indirect pathway through WMH is stronger (u03b2=-0.24, Pu2009

To establish a fully automated, robust imaging marker for cerebral small vessel disease (SVD) and related cognitive impairment that is easy to implement, reflects disease burden, and is strongly associated with processing speed, the predominantly affected cognitive domain in SVD.We developed a novel magnetic resonance imaging marker based on diffusion tensor imaging, skeletonization of white matter tracts, and histogram analysis. The marker (peak width of skeletonized mean diffusivity [PSMD]) was assessed along with conventional SVD imaging markers. We first evaluated associations with processing speed in patients with genetically defined SVD (n = 113). Next, we validated our findings in independent samples of inherited SVD (n = 57), sporadic SVD (n = 444), and memory clinic patients with SVD (n = 105). The new marker was further applied to healthy controls (n = 241) and to patients with Alzheimer's disease (n = 153). We further conducted a longitudinal analysis and interscanner reproducibility study.PSMD was associated with processing speed in all study samples with SVD (p-values between 2.8 × 10(-3) and 1.8 × 10(-10) ). PSMD explained most of the variance in processing speed (R(2) ranging from 8.8% to 46%) and consistently outperformed conventional imaging markers (white matter hyperintensity volume, lacune volume, and brain volume) in multiple regression analyses. Increases in PSMD were linked to vascular but not to neurodegenerative disease. In longitudinal analysis, PSMD captured SVD progression better than other imaging markers.PSMD is a new, fully automated, and robust imaging marker for SVD. PSMD can easily be applied to large samples and may be of great utility for both research studies and clinical use. Ann Neurol 2016;80:581-592.