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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

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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

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

10 februari 2023, Item does not contain fulltext, Background: Information about cognitive functioning is vital in the management of stroke, but the literature is mostly based on data from individuals older than 50 years of age who make up the majority of the stroke population. As cognitive functioning is subject to change due to aging, it is unclear whether such cognitive impairment patterns from the general stroke literature apply to the growing population of younger people with a stroke. Aim: The aim of the study was to conduct a systematic review and meta-analysis of the proportion and severity of cognitive impairment in young-stroke patients. Summary of review: MEDLINE, Embase, PsycINFO, and Web of Science were systematically searched up to 11 October 2022. Studies were included if they reported on a population of young-stroke patients, evaluated cognitive functioning as an outcome measure, and reported original data. We estimated the pooled prevalence rates for cognitive impairment and for aphasia. In addition, we calculated the pooled estimates for the severity of impairment per cognitive domain in the chronic phase (defined as >6 months post-stroke). Six hundred thirty-five articles were identified, of which 29 were eligible for inclusion. The pooled prevalence of cognitive impairment was 44% (k = 10; 95% confidence interval (CI): 34-54%) and of aphasia 22% (k = 13; 95% CI: 12-39%). Young-stroke patients in the chronic phase performed worse than stroke-free healthy age-appropriate controls across all cognitive domains examined, with Hedges’ g effect sizes ranging from -0.49 to -1.64. Conclusion: Around half of all young-stroke patients present with cognitive impairment and around a quarter with aphasia. Our data suggest that patterns of impairment in young-stroke patients follow those in the general stroke literature.

Contains fulltext : 297911.pdf (Publisher’s version ) (Open Access), Cognitive and affective sequelae of cerebellar disease are receiving increased attention, but their actual rate of occurrence remains unclear. Complaints may have a significant impact on patients, affecting social behavior and psychological well-being. This study aims to explore the extent of subjective cognitive and affective symptoms in patients with degenerative ataxias in the Netherlands. An explorative study was set up in a heterogeneous group of degenerative ataxia patients. Self-reported cognition was evaluated in terms of executive functioning and affect (Dysexecutive Questionnaire/DEX), and memory/attention (Cognitive Failures Questionnaire/CFQ). The Daily Living Questionnaire (DLQ) was administered to quantify the impact on daily life. Furthermore, informants completed questionnaires to obtain insight into patients' self-awareness and social cognition (Observable Social Cognition Rating Scale/OSCARS). This study shows that subjective complaints in the domains of (1) executive functioning and/or (2) memory and attention were reported by 29% of all patients (n = 24/84). In addition, more difficulties in daily life in terms of language/comprehension and community/participation were reported, and this was more common for patients with cognitive complaints than those without. Discrepancies between patients and informants about executive functioning were present in both directions. Deficits in social cognition were not identified at the group level, but more social-cognitive problems were observed in patients with more executive problems rated by informants. Taken together, our findings indicate that cognitive complaints are common in patients with degenerative cerebellar disorders and have an impact on daily life functioning. These results may help to increase awareness of cognitive symptoms and their impact in patients with cerebellar ataxia, their significant others, and professional caregivers., 02 oktober 2023, 11 p.

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.

Item does not contain fulltext, We characterize the associations of total cerebral small vessel disease (SVD) burden with brain structure, trajectories of vascular risk factors, and cognitive functions in mid-to-late life. Participants were 623 community-dwelling adults from the Whitehall II Imaging Sub-study with multi-modal MRI (mean age 69.96, SD = 5.18, 79% men). We used linear mixed-effects models to investigate associations of SVD burden with up to 25-year retrospective trajectories of vascular risk and cognitive performance. General linear modelling was used to investigate concurrent associations with grey matter (GM) density and white matter (WM) microstructure, and whether these associations were modified by cognitive status (Montreal Cognitive Asessment [MoCA] scores of < 26 vs. >= 26). Severe SVD burden in older age was associated with higher mean arterial pressure throughout midlife (ß = 3.36, 95% CI [0.42-6.30]), and faster cognitive decline in letter fluency (ß = -0.07, 95% CI [-0.13 - -0.01]), and verbal reasoning (ß = -0.05, 95% CI [-0.11- -0.001]). Moreover, SVD burden was related to lower GM volumes in 9.7% of total GM, and widespread WM microstructural decline (FWE-corrected p < 0.05). The latter association was most pronounced in individuals who demonstrated cognitive impairments on MoCA (MoCA < 26; F3,608 = 2.14, p = 0.007). These findings highlight the importance of managing midlife vascular health to preserve brain structure and cognitive function in old age.

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.

Radboud University, 28 juni 2022, Promotores : Thijssen, D.H.J., Leeuw, H.F. de, Schoon, Y. Co-promotor : Warle, M.C., Item does not contain fulltext

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)

Radboud University, 27 september 2022, Promotores : Leeuw, H.F. de, Klijn, C.J.M., Contains fulltext : 252885.pdf (Publisher’s version ) (Open Access)

Radboud University, 27 september 2022, Promotores : Kessels, R.P.C., Leeuw, H.F. de Co-promotor : Piai, V., Contains fulltext : 252729.pdf (Publisher’s version ) (Open Access), Aging is an inevitable process that leads to changes in the structure of the brain. A main contributor of the increase of structural changes occurring in the aging brain is cerebral small vessel disease (SVD). The most common consequences of SVD, visible on neuroimaging scans of nearly all individuals older than 60 year old are white matter hyperintensities (WMH). Although the association between WMH and decline in general cognition is well established, there is high variability in the type and severity of clinical symptoms. Large amount of studies are focused on investigating the association between brain related pathology and executive functions in people with SVD. It is hypothesized that decline in cognition and executive functions, in particular, could be attributed to the disconnection between frontal and subcortical areas due to SVD related pathology in frontal-subcortical white matter pathways. Yet, little attention has been paid to language production abilities in people with SVD. The aim of this thesis is to investigate word production abilities in different pathologies of the basal ganglia such as SVD, stroke, Parkinson’s disease, and Huntington’s disease. Additionally the goal of this thesis is to explore the integrity of frontal white matter tracts and their association with performance in language production tasks in older people with SVD and in participants with a left hemisphere stroke. Word production abilities, although mildly, are affected by cerebrovascular lesions (either WMH or stroke) in areas that are not classically associated with language function, that is, a frontal white matter pathways and the basal ganglia.

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.

24 december 2022, Item does not contain fulltext, Clinical populations with basal ganglia pathologies may present with language production impairments, which are often described in combination with comprehension measures or attributed to motor, memory, or processing-speed problems. In this systematic review and meta-analysis, we studied word production in four (vascular and non-vascular) pathologies of the basal ganglia: stroke affecting the basal ganglia, small vessel disease, Parkinson's disease, and Huntington's disease. We compared scores of these clinical populations with those of matched cognitively unimpaired adults on four well-established production tasks, namely picture naming, category fluency, letter fluency, and past-tense verb inflection. We conducted a systematic search in PubMed and PsycINFO with terms for basal ganglia structures, basal ganglia disorders and language production tasks. A total of 114 studies were included, containing results for one or more of the tasks of interest. For each pathology and task combination, effect sizes (Hedges' g) were extracted comparing patient versus control groups. For all four populations, performance was consistently worse than that of cognitively unimpaired adults across the four language production tasks (p-values < 0.010). Given that performance in picture naming and verb inflection across all pathologies was quantified in terms of accuracy, our results suggest that production impairments cannot be fully explained by motor or processing-speed deficits. Our review shows that while language production difficulties in these clinical populations are not negligible, more evidence is necessary to determine the exact mechanism that leads to these deficits and whether this mechanism is the same across different pathologies.

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.

Contains fulltext : 234088.pdf (Publisher’s version ) (Open Access), Working memory and episodic memory are two different processes, although the nature of their interrelationship is debated. As these processes are predominantly studied in isolation, it is unclear whether they crucially rely on different neural substrates. To obtain more insight in this, 81 adults with sub-acute ischemic stroke and 29 elderly controls were assessed on a visual working memory task, followed by a surprise subsequent memory test for the same stimuli. Multivariate, atlas- and track-based lesion-symptom mapping (LSM) analyses were performed to identify anatomical correlates of visual memory. Behavioral results gave moderate evidence for independence between discriminability in working memory and subsequent memory, and strong evidence for a correlation in response bias on the two tasks in stroke patients. LSM analyses suggested there might be independent regions associated with working memory and episodic memory. Lesions in the right arcuate fasciculus were more strongly associated with discriminability in working memory than in subsequent memory, while lesions in the frontal operculum in the right hemisphere were more strongly associated with criterion setting in subsequent memory. These findings support the view that some processes involved in working memory and episodic memory rely on separate mechanisms, while acknowledging that there might also be shared processes.

Contains fulltext : 230769.pdf (Publisher’s version ) (Open Access), Visual memory for objects involves the integration, or binding, of individual features into a coherent representation. We used a novel approach to assess feature binding, using a delayed-reproduction task in combination with computational modeling and lesion analysis. We assessed stroke patients and neurotypical controls on a visual working memory task in which spatial arrays of colored disks were presented. After a brief delay, participants either had to report the color of one disk cued by its location or the location of one disk cued by its color. Our results demonstrate that, in the controls, report imprecision and swap errors (non-target reports) can be explained by a single source of variability. Stroke patients showed an overall decrease in memory precision for both color and location, with only limited evidence for deviations from the predicted relationship between report precision and swap errors. These deviations were primarily deficits in reporting items rather than selecting items based on the cue. Atlas-based lesion-symptom mapping showed that selection and reporting deficits, precision in reporting color, and precision in reporting location were associated with different lesion profiles. Deficits in binding are associated with lesions in the left somatosensory cortex, deficits in the precision of reporting color with bilateral fronto-parietal regions, and no anatomical substrates were identified for precision in reporting location. Our results converge with previous reports that working memory representations are widely distributed in the brain and can be found across sensory, parietal, temporal, and prefrontal cortices. Stroke patients demonstrate mostly subtle impairments in visual working memory, perhaps because representations from different areas in the brain can partly compensate for impaired encoding in lesioned areas. These findings contribute to understanding of the relation between memorizing features and their bound representations.

Radboud University, 16 september 2021, Promotores : Leeuw, H.F. de, Klijn, C.J.M. Co-promotores : Tuladhar, A.M., Schreuder, F.H.B.M., Contains fulltext : 236298.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 236999.pdf (Publisher’s version ) (Open Access), Introduction: It is unclear why cerebral small vessel disease (SVD) leads to lacunar stroke in some and to non–lobar intracerebral hemorrhage (ICH) in others. We investigated differences in MRI markers of SVD in patients with lacunar stroke or non–lobar ICH.Patients and methodsWe included patients from two prospective cohort studies with either lacunar stroke (RUN DMC) or non–lobar ICH (FETCH). Differences in SVD markers (white matter hyperintensities [WMH], lacunes, cerebral microbleeds [CMB]) between groups were investigated with univariable tests; multivariable logistic regression analysis, adjusted for age, sex, and vascular risk factors; spatial correlation analysis and voxel-wise lesion symptom mapping. Results: We included 82 patients with lacunar stroke (median age 63, IQR 57-72) and 54 with non-lobar ICH (66, 59-75). WMH volumes and distribution were not different between groups. Lacunes were more frequent in patients with a lacunar stroke (44% vs. 17%, adjusted odds ratio [aOR] 5.69, 95% CI [1.66-22.75]) compared to patients with a non–lobar ICH. CMB were more frequent in patients with a non-lobar ICH (71% vs. 23%, aOR for lacunar stroke vs non-lobar ICH 0.08 95% CI [0.02–0.26]), and more often located in non-lobar regions compared to CMB in lacunar stroke. Discussion: Although we obserd different types of MRI markers of SVD within the same patient, ischemic markers of SVD were more frequent in the ischemic type of lacunar stroke, and hemorrhagic markers were more prevalent in the hemorrhagic phenotype of non-lobar ICH.Conclusion: There are differences between MRI markers of SVD between patients with a lacunar stroke and those with a non-lobar ICH.

Contains fulltext : 226541.pdf (publisher's version ) (Open Access), This review investigates the severity and nature of post-stroke working memory deficits with reference to the multi-component model of working memory. We conducted a systematic search in PubMed up to March 2019 with search terms for stroke and memory. Studies on adult stroke patients, that included a control group, and assessed working memory function, were selected. Effect sizes (Hedges' g) were extracted from 50 studies (in total 3,084 stroke patients) based on the sample size, mean and standard deviation of patients and controls. Performance of stroke patients was compared to healthy controls on low-load (i.e. capacity) and high-load (executively demanding) working memory tasks, grouped by modality (verbal, non-verbal). A separate analysis compared patients in the sub-acute and the chronic stage. Longitudinal studies and effects of lesion location were systematically reviewed. Stroke patients demonstrated significant deficits in working memory with a moderate effect size for both low-load (Hedges' g = -.58 [-.82 to -.43]) and high-load (Hedges' g = -.59 [-.73 to -.45]) tasks. The effect sizes were comparable for verbal and non-verbal material. Systematically reviewing the literature showed that working memory deficits remain prominent in the chronic stage of stroke. Lesions in a widespread fronto-parietal network are associated with working memory deficits. Stroke patients show decrements of moderate magnitude in all subsystems of working memory. This review clearly demonstrates the global nature of the impairment in working memory post-stroke.

Contains fulltext : 226145.pdf (publisher's version ) (Open Access)

Radboud University, 09 juni 2020, Promotor : Leeuw, H.F. de Co-promotores : Tuladhar, A.M., Düring, M.H., Contains fulltext : 219047.pdf (publisher's version ) (Open Access)

Contains fulltext : 220281.pdf (publisher's version ) (Open Access), Cerebral small vessel disease (SVD) is a common disease in older adults and a major contributor to vascular cognitive impairment and dementia. White matter network damage is a potentially important mechanism by which SVD causes cognitive impairment. Earlier studies showed that a higher degree of white matter network damage, indicated by lower global efficiency (a graph-theory measure assessing efficiency of network information transfer), was associated with lower scores on cognitive performance independent of MRI markers for SVD. However, it is unknown whether this global efficiency index is the strongest predictor for cognitive impairment, as there is a wide range of network measures. Here, we investigate which network measure is the most informative in explaining baseline cognitive performance and decline over a period of 8.7 years in SVD. We used data from the Radboud University Nijmegen Diffusion tensor and MRI Cohort (RUN DMC), which included 436 participants without dementia (65.2 ± 8.8 years) but with evidence of SVD on neuroimaging. Binarized and weighted structural brain networks were reconstructed using diffusion tensor imaging and deterministic streamlining. Using graph-theory, we calculated 21 global network measures and performed linear regression analyses, elastic net analysis and linear mixed effect models to compare these measures. All analyses were adjusted for potential confounders (age, sex, educational level, depressive symptoms and conventional SVD MRI-markers (e.g. white matter hyperintensities (WMH), lacunes of presumed vascular origin and microbleeds). The elastic net analyses showed that, at baseline, global efficiency had the strongest association with cognitive index (CI), while characteristic path length showed the strongest association with psychomotor speed (PMS) and memory. Binary local efficiency showed the strongest association with attention & executive function (A&EF). In addition, linear mixed-effect models demonstrated that basel

University of Amsterdam, 25 september 2020, Promotores : Haan, E.H.F. de, Kessels, R.P.C., Leeuw, H.F. de Co-promotor : Geerligs, L., Item does not contain fulltext, Our surroundings consist of scenes and objects that have a multitude of visual features: shape, color, texture, size, orientation, and location. We are able to remember which object was where and what features belong to it by forming an internal representation of features and their conjunctions. Some representations only last for a brief period, they are kept in working memory, while other representations remain over a longer period of time, known as episodic memory. The aim of this thesis was to investigate how memory subsystems relate at a behavioral and neural level using novel behavioral paradigms, lesion-symptom mapping, and computational modeling, in healthy adults and stroke patients. Lesions studies in this thesis support the notion of a widely distributed frontoparietal network underlying memory, with a suggestion of specialization for memory subsystems (working memory and episodic memory; feature reporting and binding) and multiple visual representations in the brain. Representations in different areas might compensate for impaired encoding in lesioned areas explaining mostly subtle visual memory impairments following stroke. Experimental studies in this thesis showed that, at a group level, controls outperform patients and younger adults perform better than older adults. At the same time, selective deficits in different subsystems of visual memory are prevalent. This indicates that different neural mechanisms may be involved. It also stresses the need for broad memory examination, as selective memory deficits might easily be missed in standard clinical assessment where testing mainly with verbal materials and with a maximum delay of 30 minutes is the standard.

Contains fulltext : 203300.pdf (publisher's version ) (Closed access)

Contains fulltext : 203440.pdf (publisher's version ) (Open Access), Background: White matter hyperintensities (WMH) constitute the visible spectrum of cerebral small vessel disease (SVD) markers and are associated with cognitive decline, although they do not fully account for memory decline observed in individuals with SVD. We hypothesize that WMH might exert their effect on memory decline indirectly by affecting remote brain structures such as the hippocampus. We investigated the temporal interactions between WMH, hippocampal atrophy and memory decline in older adults with SVD. Methods: 503 participants of the RUNDMC study underwent neuroimaging and cognitive assessments up to 3 times over 8.7 years. We assessed WMH volumes semi-automatically and calculated hippocampal volumes (HV) using FreeSurfer. We used linear mixed effects models and causal mediation analyses to assess both interaction and mediation effects of hippocampal atrophy in the associations between WMH and memory decline, separately for working memory (WM) and episodic memory (EM). Results: Linear mixed effect models revealed that the interaction between WMH and hippocampal volumes explained memory decline (WM: beta=0.067; 95%CI[0.024–0.111]; p<0.01; EM: beta=0.061; 95%CI[0.025–0.098]; p<0.01), with better model fit when the WMH*HV interaction term was added to the model, for both WM (likelihood ratio test, X2(1)=9.3, p<0.01) and for EM (likelihood ratio test, X2(1)=10.7, p<0.01). Mediation models showed that both baseline WMH volume (beta=-0.170; p=0.001) and hippocampal atrophy (beta=0.126; p=0.009) were independently related to EM decline, but the effect of baseline WMH on EM decline was not mediated by hippocampal atrophy (p-value indirect effect: 0.572). Conclusions: Memory decline in elderly with SVD was best explained by the interaction of WMH and hippocampal volumes. The relationship between WMH and memory was not causally mediated by hippocampal atrophy, suggesting that memory decline during aging is a heterogeneous condition in which different pathologies co

Radboud University, 18 oktober 2019, Promotor : Leeuw, H.F. de Co-promotor : Tuladhar, A.M., Contains fulltext : 207774.pdf (publisher's version ) (Open Access)

Contains fulltext : 203075.pdf (publisher's version ) (Open Access)

Radboud University, 19 november 2018, Promotor : Leeuw, H.F. de Co-promotores : Verbeek, M.M., Tuladhar, A.M., Contains fulltext : 196856.pdf (publisher's version ) (Open Access)

Radboud University, 14 juni 2018, Promotores : Leeuw, H.F. de, Klijn, C.J.M. Co-promotor : Dijk, E.J. van, Contains fulltext : 191612.pdf (publisher's version ) (Open Access), The diagnosis of transient ischemic attack (TIA) is often difficult to establish. Early diffusion-weighted imaging (DWI) may show signs of recent ischemia. In the absence of focal neurological symptoms, an attack of short-lasting neurological symptoms is often referred to as a transient neurological attack (TNA). Although both TIA and TNA harbor the term transient, many patients report cognitive and other complaints well beyond the point of initial symptom resolution. This thesis was dedicated to TIA and TNA and aimed to unravel the etiology and prognosis of this spectrum of transient episodes of neurological dysfunction. In the first part we showed that clinically diagnosing TIA fails to adequately identify those patients with proven cerebral ischemia. In the second part we focused on possible lasting cognitive effects of TIA or TNA and found that cognitive impairment was present in more than a third of patients and mostly affected the cognitive domain of executive function. An initial DWI lesion, but not other markers for cerebrovascular macrostructural damage, was associated with worse cognitive function in the first 6 months after TIA or TNA. Also, fatigue and subjective cognitive impairment increased in severity after TIA or TNA, but only in those individuals with an initial DWI lesion. As a first step in establishing a ground for the hypothesis that microstructural damage after TIA or TNA may cause lasting cognitive symptoms afterwards, we used diffusion tensor imaging (DTI) in the third part of this thesis. We identified marginal but significant differences suggesting a worse cerebral microstructure in DWI-positive patients >6 months after the initial event. The studies in this thesis show that the diagnosis of TIA remains difficult, and distinguishing vascular form nonvascular events seems most important. Neuroimaging, especially DWI, can help in determining which patients deserve vascular work-up and secondary prevention. Finally, although the word transien

Contains fulltext : 191933.pdf (publisher's version ) (Closed access)

Contains fulltext : 197971.pdf (publisher's version ) (Open Access), Background: Neuroimaging in older adults commonly reveals signs of cerebral small vessel disease (SVD). SVD is believed to be caused by chronic hypoperfusion based on animal models and longitudinal studies with inter-scan intervals of years. Recent imaging evidence, however, suggests a role for acute ischaemia, as indicated by incidental diffusion-weighted imaging lesions (DWI+ lesions), in the origin of SVD. Furthermore, it becomes increasingly recognised that focal SVD lesions likely affect the structure and function of brain areas remote from the original SVD lesion. However, the temporal dynamics of these events are largely unknown. Aims: (1) To investigate the monthly incidence of DWI+ lesions in subjects with SVD; (2) to assess to which extent these lesions explain progression of SVD imaging markers; (3) to investigate their effects on cortical thickness, structural and functional connectivity and cognitive and motor performance; and (4) to investigate the potential role of the innate immune system in the pathophysiology of SVD. Design/methods: The RUN DMC -InTENse study is a longitudinal observational study among 54 non-demented RUN DMC survivors with mild to severe SVD and no other presumed cause of ischaemia. We performed MRI assessments monthly during 10 consecutive months (totalling up to 10 scans per subject), complemented with clinical, motor and cognitive examinations. Discussion: Our study will provide a better understanding of the role of DWI+ lesions in the pathophysiology of SVD and will further unravel the structural and functional consequences and clinical importance of these lesions, with an unprecedented temporal resolution. Understanding the role of acute, potentially ischaemic, processes in SVD may provide new strategies for therapies.

Contains fulltext : 178842.pdf (publisher's version ) (Open Access), Introduction. Subjective cognitive impairment (SCI), depressive symptoms, and fatigue are common after stroke and are associated with reduced quality of life. We prospectively investigated their prevalence and course after a transient ischemic attack (TIA) or nonfocal transient neurological attack (TNA) and the association with diffusion-weighted imaging (DWI) lesions. Methods. The Cognitive Failures Questionnaire, Hospital Anxiety and Depression Scale, and Subjective Fatigue subscale from the Checklist Individual Strength were used to assess subjective complaints shortly after TIA or TNA and six months later. With repeated measure analysis, the associations between DWI lesion presence or clinical diagnosis (TIA or TNA) and subjective complaints over time were determined. Results. We included 103 patients (28 DWI positive). At baseline, SCI and fatigue were less severe in DWI positive than in DWI negative patients, whereas at follow-up, there were no differences. SCI () and fatigue () increased in severity only in DWI positive patients. There were no differences between TIA and TNA. Conclusions. Subjective complaints are highly prevalent in TIA and TNA patients. The short-term prognosis is not different between DWI-positive and DWI negative patients, but SCI and fatigue increase in severity within six months after the event when an initial DWI lesion is present.

Radboud University, 14 februari 2017, Promotores : Klijn, C.J.M., Leeuw, H.F. de Co-promotor : Dijk, E.J. van, Contains fulltext : 165628.pdf (publisher's version ) (Open Access)

Item does not contain fulltext, Objectives: The extent of vascular cognitive impairment (VCI) after stroke varies greatly across individuals, even when the same amount of brain damage is present. Education level is a potentially protective factor explaining these differences, but results on its effects on VCI are inconclusive. Methods: First, we performed a meta-analysis on formal education and VCI, identifying 21 studies (N=7770). Second, we examined the effect of formal education on VCI in young-stroke patients who were cognitively assessed on average 11.0 (SD=8.2) years post-stroke (the FUTURE study cohort). The total sample consisted of 277 young-stroke patients with a mean age at follow-up 50.9 (SD=10.3). Age and education-adjusted expected scores were computed using 146 matched stroke-free controls. Results: The meta-analysis showed an overall effect size (z') of 0.25 (95% confidence interval [0.18-0.31]), indicating that formal education level had a small to medium effect on VCI. Analyses of the FUTURE data showed that the effect of education on post-stroke executive dysfunction was mediated by age (beta age -0.015; p<.05). Below-average performance in the attention domain was more frequent for low-education patients (x2(2)=9.8; p<.05). Conclusions: While education level was found to be related to post-stroke VCI in previous research, the effects were small. Further analysis in a large stroke cohort showed that these education effects were fully mediated by age, even in relatively young stroke patients. Education level in and of itself does not appear to be a valid indicator of cognitive reserve. Multi-indicator methods may be more valid, but have not been studied in relation to VCI. (JINS, 2017, 22, 1–16)

Radboud University, 24 januari 2017, Promotores : Leeuw, H.F. de, Kessels, R.P.C., Contains fulltext : 162529.pdf (publisher's version ) (Open Access)

Radboud University, 5 april 2017, Promotores : Leeuw, H.F. de, Klijn, C.J.M. Co-promotores : Tuladhar, A.M., Dijk, E.J. van, Contains fulltext : 169056.pdf (publisher's version ) (Open Access)

Radboud University, 16 februari 2017, Promotores : Leeuw, H.F. de, Klijn, C.J.M. Co-promotor : Dijk, E.J. van, Contains fulltext : 165609.pdf (publisher's version ) (Open Access)

Contains fulltext : 166301.pdf (publisher's version ) (Open Access), OBJECTIVE: We prospectively investigated the role of depressive symptoms (DS) on all-cause dementia in a population with small vessel disease (SVD), considering onset age of DS and cognitive performance. METHODS: The RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort) is a prospective cohort study among 503 older adults with SVD on MRI without dementia at baseline (2006), with a follow-up of 5 years (2012). Kaplan-Meier curves stratified for DS and dementia risk were compared using log-rank test. We calculated hazard ratios using Cox regression analyses. RESULTS: Follow-up was available for 496 participants (mean baseline age 65.6 years [SD 8.8]; mean follow-up time 5.2 years). All-cause dementia developed in 41 participants. The 5.5-year dementia risk was higher in those with DS (hazard ratio 2.7, 95% confidence interval 1.4-5.2), independent of confounders. This was driven by those with late-onset DS. Five-year cumulative risk difference for dementia was higher in participants with depressive symptoms who had high baseline cognitive performance (no DS 0.0% vs DS 6.9%, log-rank p < 0.001) compared with those who had low cognitive performance at baseline. CONCLUSIONS: Late-onset DS increases dementia risk, independent of SVD. Especially in those with relatively high cognitive performance, DS indicate a higher risk. In contrast to current practice, clinicians should monitor those with DS who also show relatively good cognitive test scores.

RU Radboud Universiteit, 4 oktober 2016, Promotores : Klijn, C.J.M., Norris, D.G. Co-promotores : Leeuw, H.F. de, Dijk, E.J. van, Item does not contain fulltext

Contains fulltext : 167667.pdf (publisher's version ) (Open Access), BACKGROUND: Although by definition a transient ischemic attack (TIA) lasts less than 24 h, many patients experience cognitive complaints beyond focal symptom resolution. However, their prevalence, causes and profile are unclear. We therefore performed a systematic review on cognitive impairment after TIA. SUMMARY: Medline and Embase were searched for relevant studies. Risk of bias was assessed, and data synthesis was performed according to the severity of cognitive impairment. Thirteen studies were included, with considerable heterogeneity concerning methods and timing of cognitive testing. Confounding, detection bias and attrition were the main causes of a high risk of bias in several studies. The prevalence of post-TIA mild cognitive impairment ranged from 29 to 68%. Severe cognitive impairment was found in 8-22% of patients. Studies using a cognitive screening instrument and those performed shortly after TIA or several years later, reported the highest frequencies of impairment. Patients evaluated with a screening tool were substantially older than those who underwent a full neuropsychological assessment (weighted mean age difference 10.9 years). Based on limited data, the post-TIA cognitive profile showed prominent executive function deficits. Insufficient data refrained us from drawing conclusions on causality. The few studies that reported neuroimaging results found a minor correlation with cognitive impairment. KEY MESSAGES: Mild cognitive impairment is present in more than a third of the TIA patients and has a profile comparable with vascular cognitive impairment. Reported rates of post-TIA cognitive impairment are highly variable and higher frequencies are found with cognitive screening tools. Considerable heterogeneity and insufficient data limit further conclusions about potential causative factors.

RU Radboud Universiteit, 28 september 2016, Promotores : Klijn, C.J.M., Leeuw, H.F. de Co-promotor : Kort, P.L.M. de, Contains fulltext : 159469.pdf (publisher's version ) (Open Access), The long-term outcome in young stroke patients is not favourable. This is in contrast with the general opinion in neurologists, which is based on studies describing lower short-term mortality rates in young stroke patients compared to older patients. A substantial proportion of patients, even in the long run after stroke (on average 14 years after stroke), stays dependent in daily living, despite their young age. This especially holds true for women and patients with severe neurological deficits at admission. Fatigue and depression after stroke are associated with a lower quality of life. Therefore, it is important that health care professionals actively assess the presence of these symptoms. Unexpectedly, in contrast, the effect of post-stroke cognitive disorders on the daily life after a stroke at young age is less clear. A new, preliminary insight is the association between kidney dysfunction and the occurrence of recurrent strokes after a young stroke. The results of these studies enable health care professionals to give patients and their relatives more accurate information on the long-term functional prognosis after a stroke at young age.

Contains fulltext : 151429.pdf (publisher's version ) (Open Access), OBJECTIVE: To investigate the relation between baseline cerebral small vessel disease (SVD) and the risk of incident parkinsonism using different MRI and diffusion tensor imaging (DTI) measures. METHODS: In the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, a prospective cohort study, 503 elderly participants with SVD and without parkinsonism were included in 2006. During follow-up (2011-2012), parkinsonism was diagnosed according to UK Brain Bank criteria. Cox regression analysis was used to investigate the association between baseline imaging measures and incident all-cause parkinsonism and vascular parkinsonism (VP). Tract-based spatial statistics analysis was used to identify differences in baseline DTI measures of white matter (WM) tracts between participants with VP and without parkinsonism. RESULTS: Follow-up was available from 501 participants (mean age 65.6 years; mean follow-up duration 5.2 years). Parkinsonism developed in 20 participants; 15 were diagnosed with VP. The 5-year risk of (any) parkinsonism was increased for those with a high white matter hyperintensity (WMH) volume (hazard ratio [HR] 1.8 per SD increase, 95% confidence interval [CI] 1.3-2.4) and a high number of lacunes (HR 1.4 per number increase, 95% CI 1.1-1.8) at baseline. For VP, this risk was also increased by the presence of microbleeds (HR 5.7, 95% CI 1.9-16.8) and a low gray matter volume (HR 0.4 per SD increase, 95% CI 0.2-0.8). Lower fractional anisotropy values in bifrontal WM tracts involved in movement control were observed in participants with VP compared to participants without parkinsonism. CONCLUSIONS: SVD at baseline, especially a high WMH volume and a high number of lacunes, is associated with incident parkinsonism. Our findings favor a role of SVD in the etiology of parkinsonism.

Radboud Universiteit Nijmegen, 12 juni 2015, Promotor : Willemsen, M.A.A.P. Co-promotores : Leeuw, H.F. de, Dijk, E.J. van, Contains fulltext : 141370.pdf (publisher's version ) (Open Access)