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Contains fulltext : 306038.pdf (Author’s version preprint ) (Open Access), Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD.In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA).Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among t, 06 mei 2024

Item does not contain fulltext, Alzheimer's disease and cerebral small vessel disease are the two leading causes of cognitive decline and dementia and coexist in most memory clinic patients. White matter damage as assessed by diffusion MRI is a key feature in both Alzheimer's and cerebral small vessel disease. However, disease-specific biomarkers of white matter alterations are missing. Recent advances in diffusion MRI operating on the fixel level (fibre population within a voxel) promise to advance our understanding of disease-related white matter alterations. Fixel-based analysis allows derivation of measures of both white matter microstructure, measured by fibre density, and macrostructure, measured by fibre-bundle cross-section. Here, we evaluated the capacity of these state-of-the-art fixel metrics to disentangle the effects of cerebral small vessel disease and Alzheimer's disease on white matter integrity. We included three independent samples (total n = 387) covering genetically defined cerebral small vessel disease and age-matched controls, the full spectrum of biomarker-confirmed Alzheimer's disease including amyloid- and tau-PET negative controls and a validation sample with presumed mixed pathology. In this cross-sectional analysis, we performed group comparisons between patients and controls and assessed associations between fixel metrics within main white matter tracts and imaging hallmarks of cerebral small vessel disease (white matter hyperintensity volume, lacune and cerebral microbleed count) and Alzheimer's disease (amyloid- and tau-PET), age and a measure of neurodegeneration (brain volume). Our results showed that (i) fibre density was reduced in genetically defined cerebral small vessel disease and strongly associated with cerebral small vessel disease imaging hallmarks; (ii) fibre-bundle cross-section was mainly associated with brain volume; and (iii) both fibre density and fibre-bundle cross-section were reduced in the presence of amyloid, but not further exacerbated by abno

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Item does not contain fulltext, BACKGROUND AND OBJECTIVES: Causes of stroke in young adults differ from those in the elderly individuals, and in a larger percentage, no cause can be determined. To gain more insight into the etiology of (cryptogenic) stroke in the young population, we investigated whether trigger factors, such as short-lasting exposure to toxins or infection, may play a role. METHODS: Patients aged 18-49 years with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) in 17 participating centers in the Netherlands completed a questionnaire about exposure to 9 potential trigger factors in hazard periods and on a regular yearly basis. A case-crossover design was used to assess relative risks (RRs) with 95% confidence intervals (95% CIs) by the Mantel-Haenszel case-crossover method, for any stroke (ischemic stroke and ICH combined) and for different etiologic subgroups of ischemic stroke. RESULTS: One thousand one hundred forty-six patients completed the questionnaire (1,043 patients with an ischemic stroke and 103 with an ICH, median age 44.0 years, 52.6% men). For any stroke, an increased risk emerged within 1 hour of cola consumption (RR 2.0, 95% CI 1.5-2.8) and vigorous physical exercise (RR 2.6, 95% CI 2.2-3.0), within 2 hours after sexual activity (RR 2.4, 95% CI 1.6-3.5), within 4 hours after illicit drug use (RR 2.8, 95% CI 1.7-4.9), and within 24 hours after fever or flu-like disease (RR 14.1, 95% CI 10.5-31.2; RR 13.9, 95% CI 8.9-21.9). Four trigger factors increased the risk of other determined and cryptogenic ischemic stroke, 3 that of cardioembolic stroke, 2 that of large vessel atherosclerosis and likely atherothrombotic stroke combined and stroke with multiple causes, and none that of stroke due to small vessel disease. DISCUSSION: We identified cola consumption, vigorous physical exercise, sexual activity, illicit drug use, fever, and flu-like disease as potential trigger factors for stroke in the young population and found differences in the type and number o

01 juni 2023, Contains fulltext : 293219.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Cerebral small vessel disease (SVD) is associated with motor impairments and parkinsonian signs cross-sectionally, however, there are little longitudinal data on whether SVD increases risk of incident parkinsonism itself. We investigated the relation between baseline SVD severity as well as SVD progression, and incident parkinsonism over a follow-up of 14 years. METHODS: This study included 503 participants with SVD, and without parkinsonism at baseline, from the RUN DMC prospective cohort study. Baseline inclusion was performed in 2006 and follow-up took place in 2011, 2015, and 2020, including magnetic resonance imaging (MRI) and motor assessments. Parkinsonism was diagnosed according to the UK Brain Bank criteria, and stratified into vascular parkinsonism (VaP) and idiopathic Parkinson's disease (IPD). Linear mixed-effect models were constructed to estimate individual rate changes of MRI-characteristics. RESULTS: Follow-up for incident parkinsonism was near-complete (99%). In total, 51 (10.2%) participants developed parkinsonism (33 VaP, 17 IPD, and 1 progressive supranuclear palsy). Patients with incident VaP had higher SVD burden compared with patients with IPD. Higher baseline white matter hyperintensities (hazard ratio [HR] = 1.46 per 1-SD increase, 95% confidence interval [CI] = 1.21-1.78), peak width of skeletonized mean diffusivity (HR = 1.66 per 1-SD increase, 95% CI = 1.34-2.05), and presence of lacunes (HR = 1.84, 95% CI = 0.99-3.42) were associated with increased risk of all-cause parkinsonism. Incident lacunes were associated with incident VaP (HR = 4.64, 95% CI = 1.32-16.32). INTERPRETATION: Both baseline SVD severity and SVD progression are independently associated with long-term parkinsonism. Our findings indicate a causal role of SVD in parkinsonism. Future studies are needed to examine the underlying pathophysiology of this relation. ANN NEUROL 2023;93:1130-1141.

01 juli 2023, Contains fulltext : 293781.pdf (Publisher’s version ) (Open Access), The acquisition of intravoxel incoherent motion (IVIM) data and diffusion tensor imaging (DTI) data from the brain can be integrated into a single measurement, which offers the possibility to determine orientation-dependent (tensorial) perfusion parameters in addition to established IVIM and DTI parameters. The purpose of this study was to evaluate the feasibility of such a protocol with a clinically feasible scan time below 6 min and to use a model-selection approach to find a set of DTI and IVIM tensor parameters that most adequately describes the acquired data. Diffusion-weighted images of the brain were acquired at 3 T in 20 elderly participants with cerebral small vessel disease using a multiband echoplanar imaging sequence with 15 b-values between 0 and 1000 s/mm(2) and six non-collinear diffusion gradient directions for each b-value. Seven different IVIM-diffusion models with 4 to 14 parameters were implemented, which modeled diffusion and pseudo-diffusion as scalar or tensor quantities. The models were compared with respect to their fitting performance based on the goodness of fit (sum of squared fit residuals, chi(2) ) and their Akaike weights (calculated from the corrected Akaike information criterion). Lowest chi(2) values were found using the model with the largest number of model parameters. However, significantly highest Akaike weights indicating the most appropriate models for the acquired data were found with a nine-parameter IVIM-DTI model (with isotropic perfusion modeling) in normal-appearing white matter (NAWM), and with an 11-parameter model (IVIM-DTI with additional pseudo-diffusion anisotropy) in white matter with hyperintensities (WMH) and in gray matter (GM). The latter model allowed for the additional calculation of the fractional anisotropy of the pseudo-diffusion tensor (with a median value of 0.45 in NAWM, 0.23 in WMH, and 0.36 in GM), which is not accessible with the usually performed IVIM acquisitions based on three orthogonal diffusio

Item does not contain fulltext, BACKGROUND: Cerebral small vessel disease is a leading cause of cognitive decline and vascular dementia. Small vessel disease pathology changes structural brain networks, but its impact on functional networks remains poorly understood. Structural and functional networks are closely coupled in healthy individuals, and decoupling is associated with clinical symptoms in other neurological conditions. We tested the hypothesis that structural-functional network coupling is related to neurocognitive outcomes in 262 small vessel disease patients. METHODS: Participants underwent multimodal magnetic resonance imaging and cognitive assessment in 2011 and 2015. Structural connectivity networks were reconstructed using probabilistic diffusion tractography, while functional connectivity networks were estimated from resting-state functional magnetic resonance imaging. Structural and functional networks were then correlated to calculate a measure of structural-functional network coupling for each participant. RESULTS: Lower whole-brain coupling was associated with reduced processing speed and greater apathy both cross-sectionally and longitudinally. In addition, coupling within the cognitive control network was associated with all cognitive outcomes, suggesting that neurocognitive outcomes in small vessel disease may be related to the functioning of this intrinsic connectivity network. CONCLUSIONS: Our work demonstrates the influence of structural-functional connectivity network decoupling in small vessel disease symptomatology. Cognitive control network function may be investigated in future studies.

Contains fulltext : 284228.pdf (Publisher’s version ) (Open Access), Introduction: We aimed to investigate the prevalence of cognitive impairment in the subacute phase after transient ischemic attack (TIA) and ischemic stroke (IS), factors associated with a vascular cognitive disorder, and the prevalence of subjective cognitive complaints and their relation with objective cognitive performance.Patients and methods: In this multicenter prospective cohort study, we recruited patients with first-ever TIA and IS, aged 18-49 years, between 2013 and 2021 for cognitive assessment up to 6 months after index event. We calculated composite Z-scores for seven cognitive domains. We defined cognitive impairment as a composite Z-score < -1.5. We defined major vascular cognitive disorder as a Z-score < -2.0 in one or more cognitive domains. Results: Fifty three TIA and 545 IS patients completed cognitive assessment with mean time to assessment of 89.7 (SD 40.7) days. The median NIHSS at admission was 3 (interquartile range, 1-5). Cognitive impairment was common in five domains (up to 37%), with similar proportion in TIA and IS patients. Patients with major vascular cognitive disorder had a lower education level, higher NIHSS scores and more frequent lesions in the left frontotemporal lobe than without vascular cognitive disorder (p < 0.05 FDR-corrected). Subjective memory and executive cognitive complaints were present in about two-thirds of the patients, but were weakly associated with objective cognitive performance (ß: -0.32 and -0.21, respectively). Discussion and conclusion: In the subacute phase after TIA or stroke in young adults, cognitive impairment and subjective cognitive complaints are prevalent, but they are weakly associated with each other.

19 april 2023, Item does not contain fulltext, Objective: Cerebral small vessel disease (SVD) is considered the most important vascular contributor to cognitive decline and dementia, although a causal relation between its MRI markers and dementia still needs to be established. The authors investigated the relation between baseline SVD severity as well as SVD progression on MRI markers and incident dementia, by subtype, in individuals with sporadic SVD over a follow-up period of 14 years. Methods: The study included 503 participants with sporadic SVD, and without dementia, from the prospective Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, with screening for baseline inclusion conducted in 2006. Follow-ups in 2011, 2015, and 2020 included cognitive assessments and MRI scans. Dementia was diagnosed according to DSM-5 criteria and stratified into Alzheimer's dementia and vascular dementia. Results: Dementia as an endpoint was available for 498 participants (99.0%) and occurred in 108 participants (21.5%) (Alzheimer's dementia, N=38; vascular dementia, N=34; mixed-etiology Alzheimer’s dementia/vascular dementia, N=26), with a median follow-up time of 13.2 years (interquartile range, 8.8-13.8). Higher baseline white matter hyperintensity (WMH) volume (hazard ratio=1.31 per 1-SD increase, 95% CI=1.02-1.67), presence of diffusion-weighted-imaging-positive lesions (hazard ratio=2.03, 95% CI=1.01-4.04), and higher peak width of skeletonized mean diffusivity (hazard ratio=1.24 per 1-SD increase, 95% CI=1.02-1.51) were independently associated with all-cause dementia and vascular dementia. WMH progression predicted incident all-cause dementia (hazard ratio=1.76 per 1-SD increase, 95% CI=1.18-2.63). Conclusions: Both baseline SVD severity and SVD progression were independently associated with an increase in risk of all-cause dementia over a follow-up of 14 years. The results suggest that SVD progression precedes dementia and may causally contribute to its development. Slowing SVD

Contains fulltext : 295930.pdf (Publisher’s version ) (Open Access), BACKGROUND: Cerebral small vessel disease (SVD) contributes to 45% of dementia cases worldwide, yet we lack a reliable model for predicting dementia in SVD. Past attempts largely relied on traditional statistical approaches. Here, we investigated whether machine learning (ML) methods improved prediction of incident dementia in SVD from baseline SVD-related features over traditional statistical methods. METHODS: We included three cohorts with varying SVD severity (RUN DMC, n = 503; SCANS, n = 121; HARMONISATION, n = 265). Baseline demographics, vascular risk factors, cognitive scores, and magnetic resonance imaging (MRI) features of SVD were used for prediction. We conducted both survival analysis and classification analysis predicting 3-year dementia risk. For each analysis, several ML methods were evaluated against standard Cox or logistic regression. Finally, we compared the feature importance ranked by different models. RESULTS: We included 789 participants without missing data in the survival analysis, amongst whom 108 (13.7%) developed dementia during a median follow-up of 5.4 years. Excluding those censored before three years, we included 750 participants in the classification analysis, amongst whom 48 (6.4%) developed dementia by year 3. Comparing statistical and ML models, only regularised Cox/logistic regression outperformed their statistical counterparts overall, but not significantly so in survival analysis. Baseline cognition was highly predictive, and global cognition was the most important feature. CONCLUSIONS: When using baseline SVD-related features to predict dementia in SVD, the ML survival or classification models we evaluated brought little improvement over traditional statistical approaches. The benefits of ML should be evaluated with caution, especially given limited sample size and features.

Contains fulltext : 296795.pdf (Publisher’s version ) (Open Access), BACKGROUND AND OBJECTIVES: It has been suggested that white matter hyperintensity lesions (WMHs), which typically progress over time, can also regress, and that this might be associated with favorable cognitive performance. We determined the prevalence of WMH regression in patients with cerebral small vessel disease (SVD) and examined which demographic, clinical, and radiological markers were associated with this regression. METHODS: We used semi-automated lesion marking methods to quantify WMH volume at multiple timepoints in three cohorts with symptomatic SVD; two with moderate-to-severe symptomatic SVD (the SCANS observational cohort and the control arm of the PRESERVE interventional trial) and one with mild-to-moderate SVD (the RUN DMC observational cohort). Mixed-effects ordered logistic regression models were used to test which factors predicted participants to show WMH regression. RESULTS: No participants (0/98) in SCANS, 6/42 (14.3%) participants in PRESERVE, and 6/276 (2.2%) in RUN DMC showed WMH regression. On multivariate analysis, only lower WMH volume (OR: 0.36, 95% CI: 0.23-0.56) and better white matter microstructural integrity assessed by fractional anisotropy using diffusion tensor imaging (OR: 1.55, 95% CI: 1.07-2.24) predicted participant classification as regressor versus stable or progressor. DISCUSSION: Only a small proportion of participants demonstrated WMH regression across the three cohorts, when a blinded standardized assessment method was used. Subjects who showed regression had less severe imaging markers of disease at baseline. Our results show that lesion regression is uncommon in SVD and unlikely to be a major factor affecting the use of WMH quantification as an outcome for clinical trials.

01 juli 2023, Contains fulltext : 294348.pdf (Publisher’s version ) (Open Access), 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;94:61-74.

Contains fulltext : 297148.pdf (Publisher’s version ) (Closed access), It remains unknown which factors influence how brain disconnectivity derived from White Matter Hyperintensity (WMH) lesions leads to psychomotor speed dysfunction, one of the earliest and most common cognitive manifestations in the cerebral Small Vessel Disease (cSVD) population. While the burden of WMH has been strongly linked to psychomotor speed performance, the effect that different locations and volumes of WMH may have on cSVD-related cognitive impairment remains unclear. Therefore, we aimed to explore (1) whether global WMH, deep WMH (DWMH), and periventricular (PVWMH) volumes display different psychomotor speed associations; (2) whether tract-specific WMH volume shows stronger cognitive associations compared with global measures of WMH volume; (3) whether specific patterns of WMH location lead to different degrees of disconnectivity. Using the BCBToolkit, we investigated which pattern of distribution and which locations of WMH lesion result in impaired psychomotor speed in a well-characterized sample (n = 195) of cSVD patients without dementia. Two key findings emerge from our study. First, global (and not tract-specific) measures of WMH volume were associated with psychomotor speed performance. Second, disconnection maps revealed the involvement of callosal tracts, association and projection fibers, and frontal and parietal cortical brain areas related to psychomotor speed, while the lesion location influenced such associations. In conclusion, psychomotor deficits are affected differently by WMH burden and topographic distribution through brain disconnection in non-demented cSVD patients.

Contains fulltext : 297147.pdf (Publisher’s version ) (Closed access), White matter hyperintensities of presumed vascular origin (WMH) are the most common imaging feature of cerebral small vessel disease (cSVD) and are associated with cognitive impairment, especially information processing speed (IPS) deficits. However, it is unclear how WMH can directly impact IPS or whether the cortical thickness and brain connectivity mediate such association. In this study, it was evaluated the possible mediating roles of cortical thickness and brain (structural and functional) connectivity on the relationship between WMH (also considering its topography distribution) and IPS in 389 patients with cSVD from the RUN-DMC (Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort) database. Significant (p < 0.05 after multiple comparisons correction) associations of WMH volume and topography with cortical thickness, brain connectivity, and IPS performance in cSVD individuals were found. Additionally, cortical thickness and brain structural and functional connectivity were shown to mediate the association of WMH volume and location with IPS scores. More specifically, frontal cortical thickness, functional sensorimotor network, and posterior thalamic radiation tract were the essential mediators of WMH and IPS in this clinical group. This study provided insight into the mechanisms underlying the clinical relevance of white matter hyperintensities in information processing speed deficits in cSVD through cortical thinning and network disruptions.

Contains fulltext : 298145.pdf (Publisher’s version ) (Open Access), Approximately 1 in 10 young stroke patients (18-50 years) will develop post-stroke epilepsy, which is associated with cognitive impairment. While previous studies have shown altered brain connectivity in patients with epilepsy, little is however known about the changes in functional brain connectivity in young stroke patients with post-stroke epilepsy and their relationship with cognitive impairment. Therefore, we aimed to investigate whether young ischaemic stroke patients have altered functional networks and whether this alteration is related to cognitive impairment. We included 164 participants with a first-ever cerebral infarction at young age (18-50 years), along with 77 age- and sex-matched controls, from the Follow-Up of Transient Ischemic Attack and Stroke patients and Unelucidated Risk Factor Evaluation study. All participants underwent neuropsychological testing and resting-state functional MRI to generate functional connectivity networks. At follow-up (10.5 years after the index event), 23 participants developed post-stroke epilepsy. Graph theoretical analysis revealed functional network reorganization in participants with post-stroke epilepsy, in whom a weaker (i.e. network strength), less-integrated (i.e. global efficiency) and less-segregated (i.e. clustering coefficient and local efficiency) functional network was observed compared with the participants without post-stroke epilepsy group and the controls (P < 0.05). Regional analysis showed a trend towards decreased clustering coefficient, local efficiency and nodal efficiency in contralesional brain regions, including the caudal anterior cingulate cortex, posterior cingulate cortex, precuneus, superior frontal gyrus and insula in participants with post-stroke epilepsy compared with those without post-stroke epilepsy. Furthermore, participants with post-stroke epilepsy more often had impairment in the processing speed domain than the group without post-stroke epilepsy, in whom the network properties o, 12 p.

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Contains fulltext : 247521.pdf (Publisher’s version ) (Open Access), Background: With a growing, younger population of head and neck cancer survivors, attention to long-term side-effects of prior, often radiotherapeutic, treatment is warranted. Therefore, we studied the long-term cognitive effects in young adult patients irradiated for head and neck neoplasms (HNN). Methods: Young to middle-aged adults with HNN (aged 18-40 years) and treated with unilateral neck irradiation >= 5 years before inclusion underwent cardiovascular risk and neuropsychological assessments and answered validated questionnaires regarding subjective cognitive complaints, fatigue, depression, quality of life, and cancer-specific distress. Additionally, magnetic resonance imaging (MRI) of the brain was performed to assess white matter hyperintensities (WMH), infarctions, and atrophy. Results: Twenty-nine patients (aged 24-61, 13 men) median 9.2 [7.3-12.9] years post-treatment were included. HNN patients performed worse in episodic memory (Z-score = -1.16 [-1.58-0.34], p < 0.001) and reported more fatigue symptoms (Z-score = 1.75 [1.21-2.00], p < 0.001) compared to normative data. Furthermore, patients had a high level of fear of tumor recurrence (13 patients [44.8%]) and a heightened speech handicap index (13 patients [44.8%]). Only a small number of neurovascular lesions were found (3 infarctions in 2 patients and 0.11 [0.00-0.40] mL WMH), unrelated to the irradiated side. Cognitive impairment was not associated with WMH, brain atrophy, fatigue, or subjective speech problems. Conclusions: HNN patients showed impairments in episodic memory and an increased level of fatigue >= 5 years after radiotherapy compared to normative data. Cognitive impairments could not be explained by WMH or brain atrophy on brain MRI or psychological factors.

Contains fulltext : 248974.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, BACKGROUND AND OBJECTIVES: There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide. METHODS: We performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18-50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression. RESULTS: We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas "other determined stroke" and "undetermined stroke" were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42-4.36). DISCUSSION: Ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve h

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12 mei 2022, Item does not contain fulltext, Background: Neuroimaging markers of cerebral small vessel disease (SVD) are common in older individuals, but the pathophysiological mechanisms causing these lesions remain poorly understood. Although hypertension is a major risk factor for SVD, the direct causal effects of increased blood pressure are unknown. The Hyperintense study is designed to examine cerebrovascular and structural abnormalities, possibly preceding SVD, in young adults with hypertension. These patients undergo a diagnostic work-up that requires patients to temporarily discontinue their antihypertensive agents, often leading to an increase in blood pressure followed by a decrease once effective medication is restarted. This allows examination of the effects of blood pressure increase and decrease on the cerebral small vessels. Methods: Hyperintense is a prospective observational cohort study in 50 hypertensive adults (18–55 years) who will temporarily discontinue antihypertensive medication for diagnostic purposes. MRI and clinical data is collected at four timepoints: before medication withdrawal (baseline), once antihypertensives are largely or completely withdrawn (T = 1), when patients have restarted medication (T = 2) and reached target blood pressure and 1 year later (T = 3). The 3T MRI protocol includes conventional structural sequences and advanced techniques to assess various aspects of microvascular integrity, including blood-brain barrier function using Dynamic Contrast Enhanced MRI, white matter integrity, and microperfusion. Clinical assessments include motor and cognitive examinations and blood sampling.Discussion: The Hyperintense study will improve the understanding of the pathophysiological mechanisms following hypertension that may cause SVD. This knowledge can ultimately help to identify new targets for treatment of SVD, aimed at prevention or limiting disease progression.

Item does not contain fulltext, Introduction: Post-stroke fatigue is frequently present in young adults, but its underlying mechanism is still unclear. The aim of the study was to investigate the association between lesion location, network efficiency and chronic post-stroke fatigue based on voxel-based lesion-symptom mapping and structural network connectivity analysis. Patients and Methods: One hundred and thirty five young patients, aged 18-50 years, with a first-ever transient ischemic attack or cerebral infarction from the Follow-Up of Transient ischemic attack and stroke patients and Unelucidated Risk factor Evaluation (FUTURE) study, underwent 1.5T MRI and were assessed for fatigue using the self-report Checklist Individual Strength. Stroke lesions were manually segmented, and structural network efficiency was calculated using the diffusion MRI-based brain networks and graph theory for each patient. Univariate and multivariate analyses was performed to study the associations between MRI parameters and chronic post-stroke fatigue. In addition, we used voxel-based lesion-symptom mapping to analyze the relationship between the lesion location and chronic post-stroke fatigue. Results: Mean age at index event was 39.0 years (SD ± 8.2), and mean follow-up duration was 11.0 years (SD ± 8.0). 50 patients (37%) had post-stroke fatigue. Voxel-based lesion-symptom mapping showed no significant relation between stroke lesions and the presence of chronic post-stroke fatigue. Furthermore, there were no significant associations between the lesion size or network efficiency, and the presence of chronic post-stroke fatigue. Discussion: We did not find any association between stroke characteristics (lesion location and size) and chronic post-stroke fatigue (CIS20-R), nor associations between structural brain network connectivity and post-stroke fatigue on the long term in young stroke patients.

Radboud University, 19 april 2022, Promotores : Leeuw, H.F. de, Düring, M.H. Co-promotor : Tuladhar, A.M., Contains fulltext : 247708.pdf (Publisher’s version ) (Closed access)

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Contains fulltext : 252082.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 252107.pdf (Publisher’s version ) (Open Access), Cerebral small vessel disease (SVD) is considered a disconnection syndrome, which can be quantified using structural brain network analysis obtained from diffusion MRI. Network analysis is a demanding analysis approach and the added benefit over simpler diffusion MRI analysis is largely unexplored in SVD. In this pre-registered study, we assessed the clinical and technical validity of network analysis in two non-overlapping samples of SVD patients from the RUN DMC study (n = 52 for exploration and longitudinal analysis and n = 105 for validation). We compared two connectome pipelines utilizing single-shell or multi-shell diffusion MRI, while also systematically comparing different node and edge definitions. For clinical validation, we assessed the added benefit of network analysis in explaining processing speed and in detecting short-term disease progression. For technical validation, we determined test-retest repeatability.Our findings in clinical validation show that structural brain networks provide only a small added benefit over simpler global white matter diffusion metrics and do not capture short-term disease progression. Test-retest reliability was excellent for most brain networks. Our findings question the added value of brain network analysis in clinical applications in SVD and highlight the utility of simpler diffusion MRI based markers.

Contains fulltext : 248974.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, OBJECTIVES: It has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but also in mild cognitive impairment. To determine whether DTI measures were associated with cognition cross-sectionally and predicted future dementia risk across the full range of SVD severity, we established the International OPtimising mulTImodal MRI markers for use as surrogate markers in trials of Vascular Cognitive Impairment due to cerebrAl small vesseL disease collaboration which included six cohorts. METHODS: Among the six cohorts, prospective data with dementia incidences were available for three cohorts. The associations between six different DTI measures and cognition or dementia conversion were tested. The additional contribution to prediction of other MRI markers of SVD was also determined. RESULTS: The DTI measure mean diffusivity (MD) median correlated with cognition in all cohorts, demonstrating the contribution of WM damage to cognition. Adding MD median significantly improved the model fit compared to the clinical risk model alone and further increased in all single-centre SVD cohorts when adding conventional MRI measures. Baseline MD median predicted dementia conversion. In a study with severe SVD (SCANS) change in MD median also predicted dementia conversion. The area under the curve was best when employing a multimodal MRI model using both DTI measures and other MRI measures. CONCLUSIONS: Our results support a central role for WM alterations in dementia pathogenesis in all cohorts. DTI measures such as MD median may be a useful clinical risk predictor. The contribution of other MRI markers varied according to disease severity.

31 oktober 2022, Contains fulltext : 284228.pdf (Publisher’s version ) (Open Access), Introduction: We aimed to investigate the prevalence of cognitive impairment in the subacute phase after transient ischemic attack (TIA) and ischemic stroke (IS), factors associated with a vascular cognitive disorder, and the prevalence of subjective cognitive complaints and their relation with objective cognitive performance.Patients and methods: In this multicenter prospective cohort study, we recruited patients with first-ever TIA and IS, aged 18-49 years, between 2013 and 2021 for cognitive assessment up to 6 months after index event. We calculated composite Z-scores for seven cognitive domains. We defined cognitive impairment as a composite Z-score < -1.5. We defined major vascular cognitive disorder as a Z-score < -2.0 in one or more cognitive domains. Results: Fifty three TIA and 545 IS patients completed cognitive assessment with mean time to assessment of 89.7 (SD 40.7) days. The median NIHSS at admission was 3 (interquartile range, 1-5). Cognitive impairment was common in five domains (up to 37%), with similar proportion in TIA and IS patients. Patients with major vascular cognitive disorder had a lower education level, higher NIHSS scores and more frequent lesions in the left frontotemporal lobe than without vascular cognitive disorder (p < 0.05 FDR-corrected). Subjective memory and executive cognitive complaints were present in about two-thirds of the patients, but were weakly associated with objective cognitive performance (ß: -0.32 and -0.21, respectively). Discussion and conclusion: In the subacute phase after TIA or stroke in young adults, cognitive impairment and subjective cognitive complaints are prevalent, but they are weakly associated with each other.

Item does not contain fulltext, We aimed to provide practical recommendations for the screening of subclinical atrial fibrillation (AF) in patients with ischaemic stroke or transient ischaemic attack (TIA) of undetermined origin. These guidelines are based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Five relevant Population, Intervention, Comparator, Outcome questions were defined by a multidisciplinary module working group (MWG). Longer duration of cardiac rhythm monitoring increases the detection of subclinical AF, but the optimal monitoring length is yet to be defined. We advise longer monitoring to increase the rate of anticoagulation, but whether longer monitoring improves clinical outcomes needs to be addressed. AF detection does not differ from in- or out-patient ECG-monitoring with similar monitoring duration, so we consider it reasonable to initiate in-hospital monitoring as soon as possible and continue with outpatient monitoring for more than 48 h. Although insertable loop recorders (ILR) increase AF detection based on their longer monitoring duration, comparison with non-implantable ECG devices for similar monitoring time is lacking. We suggest the use of implantable devices, if feasible, for AF detection instead of non-implantable devices to increase the detection of subclinical AF. There is weak evidence of a useful role for blood, ECG and brain imaging biomarkers for the identification of patients at high risk of AF. In patients with patent foramen ovale, we found insufficient evidence from RCT, but prolonged cardiac monitoring in patients >55 years is advisable for subclinical AF detection. To conclude, in adult patients with ischaemic stroke or TIA of undetermined origin, we recommend longer duration of cardiac rhythm monitoring of more than 48 h and if feasible with IRL to increase the detection of subclinical AF.

Item does not contain fulltext, Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

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Contains fulltext : 251916.pdf (Publisher’s version ) (Open Access), BACKGROUND: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of silent cerebral ischemia, and the long-term functional outcome in these patients are currently unknown. PATIENTS AND METHODS: CORONavirus and Ischemic Stroke (CORONIS) is a multicentre prospective cohort study investigating the prevalence, risk factors and long-term incidence of (silent) cerebral ischemia, and the long-term functional outcome among patients with COVID-19. We aim to include 200 adult patients hospitalized with COVID-19 without symptomatic ischemic stroke to investigate the prevalence of silent cerebral ischemia compared with 60 (matched) controls with MRI. In addition, we will identify potential risk factors and/or causes of cerebral ischemia in COVID-19 patients with (n = 70) or without symptomatic stroke (n = 200) by means of blood sampling, cardiac workup and brain MRI. We will measure functional outcome and cognitive function after 3 and 12 months with standardized questionnaires in all patients with COVID-19. Finally, the long-term incidence of (new) silent cerebral ischemia in patients with COVID-19 will be assessed with follow up MRI (n = 120). SUMMARY: The CORONIS study is designed to add further insight into the prevalence, long-term incidence and risk factors of cerebral ischemia, and the long-term functional outcome in hospitalized adult patients with COVID-19.

Item does not contain fulltext, BACKGROUND: The underlying mechanisms of incident lacunes regarding their spatial distribution remain largely unknown. We investigated the spatial distribution pattern and MRI predictors of incident lacunes in relation to white matter hyperintensity (WMH) over 14 years follow-up in sporadic small vessel disease. METHODS: Five hundred three participants from the ongoing prospective single-center Radboud University Nijmegen Diffusion Tensor and Magnetic resonance Cohort (RUN DMC) were recruited with baseline assessment in 2006 and follow ups in 2011, 2015, and 2020. Three hundred eighty-two participants who underwent at least 2 available brain MRI scans were included. Incident lacunes were systematically identified, and the spatial relationship between incident lacunes located in subcortical white matter and WMH were determined using a visual rating scale. Adjusted multiple logistic regression and linear mixed-effect regression models were used to assess the association between baseline small vessel disease markers, WMH progression, and incident lacunes. Participants with atrial fibrillation were excluded in multivariable analysis. RESULTS: Eighty incident lacunes were identified in 43 patients (mean age 66.5±8.2 years, 37.2% women) during a mean follow-up time of 11.2±3.3 years (incidence rate 10.0/1000 person-year). Sixty percent of incident lacunes were in the white matter, of which 48.9% showed no contact with preexisting WMH. Baseline WMH volume (odds ratio=2.5 [95% CI, 1.6-4.2]) predicted incident lacunes after adjustment for age, sex, and vascular risk factors. WMH progression was associated with incident lacunes independent of age, sex, baseline WMH volume, and vascular risk factors (odds ratio, 3.2 [95% CI, 1.5-6.9]). Baseline WMH volume and progression rate were higher in participants with incident lacunes in contact with preexisting WMH. No difference in vascular risk factors was observed regarding location or relation with preexisting WMH. CONCLUSIONS: The

Item does not contain fulltext, Cerebral small vessel disease is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of the underlying pathophysiology. Metabolomics can be used to identify novel risk factors to better understand pathogenesis and to predict disease progression and severity. We analysed data from 624 patients with symptomatic cerebral small vessel disease from two prospective cohort studies. Serum samples were collected at baseline and patients underwent MRI scans and cognitive testing at regular intervals with up to 14 years of follow-up. Using ultra-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy, we obtained metabolic and lipidomic profiles from 369 annotated metabolites and 54 764 unannotated features and examined their association with respect to disease severity, assessed using MRI small vessel disease markers, cognition and future risk of all-cause dementia. Our analysis identified 28 metabolites that were significantly associated with small vessel disease imaging markers and cognition. Decreased levels of multiple glycerophospholipids and sphingolipids were associated with increased small vessel disease load as evidenced by higher white matter hyperintensity volume, lower mean diffusivity normalized peak height, greater brain atrophy and impaired cognition. Higher levels of creatine, FA(18:2(OH)) and SM(d18:2/24:1) were associated with increased lacune count, higher white matter hyperintensity volume and impaired cognition. Lower baseline levels of carnitines and creatinine were associated with higher annualized change in peak width of skeletonized mean diffusivity, and 25 metabolites, including lipoprotein subclasses, amino acids and xenobiotics, were associated with future dementia incidence. Our results show multiple distinct metabolic signatures that are associated with imaging markers of small vessel disease, cognition and conversion to dementia. F

Item does not contain fulltext, Recent studies suggest that a subset of cortical microinfarcts may be identifiable on T2* but invisible on T1 and T2 follow-up images. We aimed to investigate whether cortical microinfarcts are associated with iron accumulation after the acute stage. The RUN DMC - InTENse study is a serial MRI study including individuals with cerebral small vessel disease (SVD). 54 Participants underwent 10 monthly 3 T MRIs, including diffusion-weighted imaging, quantitative R1 (=1/T1), R2 (=1/T2), and R2* (=1/T2*) mapping, from which MRI parameters within areas corresponding to microinfarcts and control region of interests (ROIs) were retrieved within 16 participants. Finally, we compared pre- and post-lesional values with repeated measures ANOVA and post-hoc paired t-tests using the mean difference between lesion and control ROI values. We observed 21 acute cortical microinfarcts in 7 of the 54 participants (median age 69 years [IQR 66-74], 63% male). R2* maps demonstrated an increase in R2* values at the moment of the last available follow-up MRI (median [IQR], 5 [5-14] weeks after infarction) relative to prelesional values (p = .08), indicative of iron accumulation. Our data suggest that cortical microinfarcts are associated with increased R2* values, indicative of iron accumulation, possibly due to microhemorrhages, neuroinflammation or neurodegeneration, awaiting histopathological verification.

Item does not contain fulltext, BACKGROUND AND AIMS: Given the unexplored potential of physical activity to reduce the progression of cerebral small vessel disease (cSVD, the purpose of this study was to prospectively (across nine-year follow-up) examine the relation between (baseline) physical activity and the (clinical and imaging) consequences of the whole spectrum of cerebral small vessel disease. METHODS: Five hundred and three patients with cerebral small vessel disease from the RUNDMC study were followed for nine years. Physical activity was assessed using a questionnaire in 2006, 2011, and 2015. Clinical events (i.e. all-cause mortality, cerebrovascular events (by stroke subtype)) were collected with a structured questionnaire. Patients underwent magnetic resonance imaging scanning for the assessment of magnetic resonance imaging markers of cerebral small vessel disease (i.e. white matter hyperintensities, lacunes, and microbleeds) and microstructural integrity of the white matter at three timepoints. RESULTS: The mean age at baseline was 66 (SD 9.0) years; 44% were women. A higher baseline physical activity level was independently associated with a lower all-cause mortality (HR: 0.69, 95%CI: 0.49-0.98, p = 0.03) and incidence of cerebrovascular disease (HR: 0.58, 95%CI: 0.36-0.96, p = 0.03). However, we found no relation between physical activity and incident lacunar stroke or progression of magnetic resonance imaging markers of cerebral small vessel disease. CONCLUSIONS: Whilst regular physical activity was not related to the progression of magnetic resonance imaging markers of cerebral small vessel disease across a nine-year follow-up, results from our study prove that high levels of physical activity in patients with cerebral small vessel disease are associated with a lower all-cause mortality and lower incidence of cerebrovascular events.

Contains fulltext : 242453.pdf (Publisher’s version ) (Open Access), The endeavor to understand the human brain has seen more progress in the last few decades than in the previous two millennia. Still, our understanding of how the human brain relates to behavior in the real world and how this link is modulated by biological, social, and environmental factors is limited. To address this, we designed the Healthy Brain Study (HBS), an interdisciplinary, longitudinal, cohort study based on multidimensional, dynamic assessments in both the laboratory and the real world. Here, we describe the rationale and design of the currently ongoing HBS. The HBS is examining a population-based sample of 1,000 healthy participants (age 30-39) who are thoroughly studied across an entire year. Data are collected through cognitive, affective, behavioral, and physiological testing, neuroimaging, bio-sampling, questionnaires, ecological momentary assessment, and real-world assessments using wearable devices. These data will become an accessible resource for the scientific community enabling the next step in understanding the human brain and how it dynamically and individually operates in its bio-social context. An access procedure to the collected data and bio-samples is in place and published on https://www.healthybrainstudy.nl/en/data-and-methods. https://www.trialregister.nl/trial/7955

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Contains fulltext : 241229.pdf (Publisher’s version ) (Open Access), Introduction: Cerebral hypoperfusion is thought to play an important role in the etiology of cerebral small vessel disease (SVD). Orthostatic hypotension (OH) is assumed to be a cause of cerebral hypoperfusion by causing recurrent hypoperfusion episodes, and might thus be related to progression of SVD. Here, we investigated whether presence of OH is associated with the progression of SVD MRI-markers and cognitive decline over a time period of 9 years in a cohort of sporadic SVD patients. Methods: This study included SVD patients from the RUN DMC study, a prospective longitudinal single-center cohort study. In total, 503 patients were included at baseline (2006), from whom 351 participated at first follow-up (2011), and 293 at second follow-up (2015). During all visits, patients underwent MRI and cognitive testing. Association between presence of OH at baseline and progression of SVD-markers on MRI and cognitive decline over time was estimated using linear mixed-effects models. Results: Of the 503 patients who participated at baseline, 46 patients (9.1%) had OH. Cross-sectional analysis of the baseline data showed that OH was associated with higher white matter hyperintensity (WMH) volume (ß = 0.18, p = 0.03), higher mean diffusivity (MD; ß = 0.02, p = 0.002), and with presence of microbleeds (OR 2.37 95% CI 1.16-4.68). Longitudinally, OH was however not associated with a progression of total WMH volume (ß = -0.17, p = 0.96) or with higher MD (ß = -0.001, p = 0.49). There was no association between OH and cognitive performance, both at baseline and over time. Conclusion: In this longitudinal observational study, there was no evidence that presence of OH is associated with progression of SVD-markers or cognitive decline over time. Our findings indicate that OH may not be causally related to SVD progression over time.

Item does not contain fulltext, BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with