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Background and Purpose: The frequency of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) varies in the current literature, and risk factors are unknown. We assessed the incidence, risk factors, and outcomes of acute ischemic stroke in hospitalized patients with COVID-19. Methods: We included patients with a laboratory-confirmed SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection admitted in 16 Dutch hospitals participating in the international CAPACITY-COVID registry between March 1 and August 1, 2020. Patients were screened for the occurrence of acute ischemic stroke. We calculated the cumulative incidence of ischemic stroke and compared risk factors, cardiovascular complications, and in-hospital mortality in patients with and without ischemic stroke. Results: We included 2147 patients with COVID-19, of whom 586 (27.3%) needed treatment at an intensive care unit. Thirty-eight patients (1.8%) had an ischemic stroke. Patients with stroke were older but did not differ in sex or cardiovascular risk factors. Median time between the onset of COVID-19 symptoms and diagnosis of stroke was 2 weeks. The incidence of ischemic stroke was higher among patients who were treated at an intensive care unit (16/586; 2.7% versus nonintensive care unit, 22/1561; 1.4%; P =0.039). Pulmonary embolism was more common in patients with (8/38; 21.1%) than in those without stroke (160/2109; 7.6%; adjusted risk ratio, 2.08 [95% CI, 1.52–2.84]). Twenty-seven patients with ischemic stroke (71.1%) died during admission or were functionally dependent at discharge. Patients with ischemic stroke were at a higher risk of in-hospital mortality (adjusted risk ratio, 1.56 [95% CI, 1.13–2.15]) than patients without stroke. Conclusions: In this multicenter cohort study, the cumulative incidence of acute ischemic stroke in hospitalized patients with COVID-19 was ≈2%, with a higher risk in patients treated at an intensive care unit. The majority of stroke patients had a poor outcome. The association between ischemic stroke and pulmonary embolism warrants further investigation.

Introduction Recent studies have shown that neuroimaging markers of cerebral small vessel disease can also regress over time. We investigated the cognitive consequences of regression of small vessel disease markers. Patients and methods Two hundred and seventy-six participants of the RUNDMC study underwent neuroimaging and cognitive assessments at three time-points over 8.7 years. We semi-automatically assessed white matter hyperintensities volumes and manually rated lacunes and microbleeds. We analysed differences in cognitive decline and accompanying brain atrophy between participants with regression, progression and stable small vessel disease by analysis of variance. Results Fifty-six participants (20.3%) showed regression of small vessel disease markers: 31 (11.2%) white matter hyperintensities regression, 10 (3.6%) vanishing lacunes and 27 (9.8%) vanishing microbleeds. Participants with regression showed a decline in overall cognition, memory, psychomotor speed and executive function similar to stable small vessel disease. Participants with small vessel disease progression showed more cognitive decline compared with stable small vessel disease (p Discussion Regression of small vessel disease markers was associated with similar cognitive decline compared to stable small vessel disease and did not accompany brain atrophy, suggesting that small vessel disease regression follows a relatively benign clinical course. Future studies are required to validate these findings and to assess the role of vascular risk factor control on small vessel disease regression and possible recovery of clinical symptoms. Conclusion Our findings of comparable cognitive decline between participants with regression and stable small vessel disease might suggest that small vessel disease regression has a relative benign cognitive outcome.

ObjectivesTo investigate whether longitudinal structural network efficiency is associated with cognitive decline and whether baseline network efficiency predicts mortality in cerebral small vessel disease (SVD).MethodsA prospective, single-centre cohort consisting of 277 non-demented individuals with SVD was conducted. In 2011 and 2015, all participants were scanned with MRI and underwent neuropsychological assessment. We computed network properties using graph theory from probabilistic tractography and calculated changes in psychomotor speed and overall cognitive index. Multiple linear regressions were performed, while adjusting for potential confounders. We divided the group into mild-to-moderate white matter hyperintensities (WMH) and severe WMH group based on median split on WMH volume.ResultsThe decline in global efficiency was significantly associated with a decline in psychomotor speed in the group with severe WMH (β=0.18, p=0.03) and a trend with change in cognitive index (β=0.14, p=0.068), which diminished after adjusting for imaging markers for SVD. Baseline global efficiency was associated with all-cause mortality (HR per decrease of 1 SD 0.43, 95% CI 0.23 to 0.80, p=0.008, C-statistic 0.76).ConclusionDisruption of the network efficiency, a metric assessing the efficiency of network information transfer, plays an important role in explaining cognitive decline in SVD, which was however not independent of imaging markers of SVD. Furthermore, baseline network efficiency predicts risk of mortality in SVD that may reflect the global health status of the brain in SVD. This emphasises the importance of structural network analysis in the context of SVD research and the use of network measures as surrogate markers in research setting.

Objective:To investigate the temporal dynamics of cerebral small vessel disease (SVD) by 3 consecutive assessments over a period of 9 years, distinguishing progression from regression.Methods:Changes in SVD markers of 276 participants of the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) cohort were assessed at 3 time points over 9 years. We assessed white matter hyperintensities (WMH) volume by semiautomatic segmentation and rated lacunes and microbleeds manually. We categorized baseline WMH severity as mild, moderate, or severe according to the modified Fazekas scale. We performed mixed-effects regression analysis including a quadratic term for increasing age.Results:Mean WMH progression over 9 years was 4.7 mL (0.54 mL/y; interquartile range 0.95–5.5 mL), 20.3% of patients had incident lacunes (2.3%/y), and 18.9% had incident microbleeds (2.2%/y). WMH volume declined in 9.4% of the participants during the first follow-up interval, but only for 1 participant (0.4%) throughout the whole follow-up. Lacunes disappeared in 3.6% and microbleeds in 5.7% of the participants. WMH progression accelerated over time: including a quadratic term for increasing age during follow-up significantly improved the model (p < 0.001). SVD progression was predominantly seen in participants with moderate to severe WMH at baseline compared to those with mild WMH (odds ratio [OR] 35.5, 95% confidence interval [CI] 15.8–80.0, p < 0.001 for WMH progression; OR 5.7, 95% CI 2.8–11.2, p < 0.001 for incident lacunes; and OR 2.9, 95% CI 1.4–5.9, p = 0.003 for incident microbleeds).Conclusions:SVD progression is nonlinear, accelerating over time, and a highly dynamic process, with progression interrupted by reduction in some, in a population that on average shows progression.

Background Cerebral small vessel disease (SVD) is cross-sectionally associated with gait disturbances, however, the relation between baseline SVD and gait decline over time is uncertain. Furthermore, diffusion tensor imaging (DTI) studies on gait decline are currently lacking. Objective To investigate the association between baseline imaging SVD markers and gait decline. Methods In 2006, 310 participants from the RUN DMC cohort, a prospective cohort with older adults aged 50–85 years with SVD, were included. Gait variables were assessed using a computerized walkway during baseline and follow-up. Linear and logistic regression analyses were used to investigate the relation between imaging measures and gait decline and incident gait impairment (speed ≤ 1.0 m/s). Tract-based spatial statistics (TBSS) was used to identify possible differences in DTI measures of white matter tracts between participants with and without incident gait impairment. Results Mean age was 63.3 years (SD: 8.4) and mean follow-up duration 5.4 years (SD: 0.2). No significant associations between imaging measures and gait decline were found. TBSS analysis revealed no significant differences in DTI measures between participants with and without incident gait impairment after additional adjustment for SVD. In sub-analyses, a high total WMH volume (OR: 2.8 for highest quartile, 95% CI: 1.1–7.1) and high infratentorial WMH volume (OR: 1.8 per SD increase, 95% CI: 1.1–2.9) were associated with an increased 5-year risk of gait impairment, although this was not significant after correction for multiple testing. Conclusion Baseline imaging SVD markers were not associated with gait decline or incident gait impairment after 5 years. Future studies should investigate if SVD progression is related to gait deterioration.

ObjectiveTo investigate the prevalence of asymptomatic diffusion-weighted imaging–positive (DWI+) lesions in individuals with cerebral small vessel disease (SVD) and identify their role in the origin of SVD markers on MRI.MethodsWe included 503 individuals with SVD from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) study (mean age 65.6 years [SD 8.8], 56.5% male) with 1.5T MRI in 2006 and, if available, follow-up MRI in 2011 and 2015. We screened DWI scans (n = 1,152) for DWI+ lesions, assessed lesion evolution on follow-up fluid-attenuated inversion recovery, T1 and T2* images, and examined the association between DWI+ lesions and annual SVD progression (white matter hyperintensities [WMH], lacunes, microbleeds).ResultsWe found 50 DWI+ lesions in 39 individuals on 1,152 DWI (3.4%). Individuals with DWI+ lesions were older (p = 0.025), more frequently had a history of hypertension (p = 0.021), and had a larger burden of preexisting SVD MRI markers (WMH, lacunes, microbleeds: all p < 0.001) compared to individuals without DWI+ lesions. Of the 23 DWI+ lesions with available follow-up MRI, 14 (61%) evolved into a WMH, 8 (35%) resulted in a cavity, and 1 (4%) was no longer visible. Presence of DWI+ lesions was significantly associated with annual WMH volume increase and yearly incidence of lacunes and microbleeds (all p < 0.001).ConclusionOver 3% of individuals with SVD have DWI+ lesions. Although DWI+ lesions play a role in the progression of SVD, they may not fully explain progression of SVD markers on MRI, suggesting that other factors than acute ischemia are at play.

Incident parkinsonism in patients with comparable cerebral small vessel disease (SVD) burden is not fully explained by presence of SVD alone. We therefore investigated if severity of SVD, SVD location, incidence of SVD and/or brain atrophy plays a role in this distinct development of parkinsonism.Participants were from the RUN DMC study, a prospective cohort of 503 individuals with SVD. Parkinsonism was diagnosed according to the UKPDS brain bank criteria. Fine and Gray method was used to assess the association between SVD and incident parkinsonism. Differences in white matter hyperintensities (WMH) progression and brain atrophy were calculated with a linear mixed effect analysis.After a median follow-up of 8.6 years, 32 of 501 participants developed parkinsonism (6.4%). The highest WMH load was found in the frontal lobe for both groups. Presence of more than one lacune at baseline was higher in the group who developed parkinsonism, especially in the frontal lobe (22% versus 3%, p 0.001) and basal ganglia (12.5% versus 1%, p-value0.001). The annual rate of total brain atrophy was significantly higher for those who developed parkinsonism compared to those who did not (8.7 ml [95%CI 7.1-10.3] and 4.9 ml [95%CI 4.5-5.3], respectively). While WMH progression was not different, incidence of lacunes and microbleeds was higher in the group with parkinsonism.The risk of parkinsonism in patients with SVD is especially increased when WMH and lacunes are present in the frontal lobe. A higher brain atrophy rate might further increase this risk.

Cerebral small vessel disease (SVD) is considered the most important vascular contributor to the development of cognitive impairment and dementia. There is increasing awareness that SVD exerts its clinical effects by disrupting white matter connections, predominantly disrupting connections between rich club nodes, a set of highly connected and interconnected regions. Here we examined the progression of disturbances in rich club organization in older adults with SVD and their associations with conventional SVD markers and cognitive decline. We additionally investigated associations of baseline network measures with dementia. In 270 participants of the RUN DMC study, we performed diffusion tensor imaging (DTI) and cognitive assessments longitudinally. Rich club organization was examined in structural networks derived from DTI followed by deterministic tractography. Global efficiency (p

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

Background and Purpose— White matter hyperintensities (WMH) are frequently seen on neuroimaging of elderly and are associated with cognitive decline and the development of dementia. Yet, the temporal dynamics of conversion of normal-appearing white matter (NAWM) into WMH remains unknown. We examined whether and when progression of WMH was preceded by changes in fluid-attenuated inversion recovery and diffusion tensor imaging values, thereby taking into account differences between participants with mild versus severe baseline WMH. Methods— From 266 participants of the RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort), we semiautomatically segmented WMH at 3 time points for 9 years. Images were registered to standard space through a subject template. We analyzed differences in baseline fluid-attenuated inversion recovery, fractional anisotropy, and mean diffusivity (MD) values and changes in MD values over time between 4 regions: (1) remaining NAWM, (2) NAWM converting into WMH in the second follow-up period, (3) NAWM converting into WMH in the first follow-up period, and (4) WMH. Results— NAWM converting into WMH in the first or second time interval showed higher fluid-attenuated inversion recovery and MD values than remaining NAWM. MD values in NAWM converting into WMH in the first time interval were similar to MD values in WMH. When stratified by baseline WMH severity, participants with severe WMH had higher fluid-attenuated inversion recovery and MD and lower fractional anisotropy values than participants with mild WMH, in all areas including the NAWM. MD values in WMH and in NAWM that converted into WMH continuously increased over time. Conclusions— Impaired microstructural integrity preceded conversion into WMH and continuously declined over time, suggesting a continuous disease process of white matter integrity loss that can be detected using diffusion tensor imaging even years before WMH become visible on conventional neuroimaging. Differences in microstructural integrity between participants with mild versus severe WMH suggest heterogeneity of both NAWM and WMH, which might explain the clinical variability observed in patients with similar small vessel disease severity.

Background and Purpose— Cerebral small vessel disease (SVD) is a frequent pathology in aging and contributor to the development of dementia. Plasma Aβ (amyloid β) levels may be useful as early biomarker, but the role of plasma Aβ in SVD remains to be elucidated. We investigated the association of plasma Aβ levels with severity and progression of SVD markers. Methods— We studied 487 participants from the RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort) of whom 258 participants underwent 3 MRI assessments during 9 years. We determined baseline plasma Aβ38, Aβ40, and Aβ42 levels using ELISAs. We longitudinally assessed volume of white matter hyperintensities semiautomatically and manually rated lacunes and microbleeds. We analyzed associations between plasma Aβ and SVD markers by ANCOVA adjusted for age, sex, and hypertension. Results— Cross-sectionally, plasma Aβ40 levels were elevated in participants with microbleeds (mean, 205.4 versus 186.4 pg/mL; P P P P P P P P Conclusions— Plasma Aβ levels are associated with both presence and progression of SVD markers, suggesting that Aβ pathology might contribute to the development and progression of SVD. Plasma Aβ levels might thereby serve as inexpensive and noninvasive measure for identifying individuals with increased risk for progression of SVD.

Contains fulltext : 167794.pdf (Publisher’s version ) (Closed access) IMPORTANCE: Gait and cognition have been related to mortality in population-based studies. This association is possibly mediated by cerebral small vessel disease (SVD), which has been associated with mortality as well. It is unknown which factors can predict mortality in individuals with SVD. Identification of high-risk patients may provide insight into factors that reflect their vital health status. OBJECTIVES: To assess mortality in patients with cerebral SVD and identify potential clinical and/or imaging factors associated with mortality. DESIGN, SETTING, AND PARTICIPANTS: A prospective, single-center cohort study was conducted. The present investigation is embedded in the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study. Between January 17, 2006, and February 27, 2007, all participants underwent a cognitive and motor assessment and cerebral magnetic resonance imaging (MRI) including a diffusion tensor imaging sequence to assess microstructural integrity of the white matter. Participants were followed up until their death or November 24, 2014. Participants included 503 older adults with SVD noted on brain imaging. Data analysis was performed from November 26, 2014, to February 2, 2015. MAIN OUTCOMES AND MEASURES: Eight-year all-cause mortality. RESULTS: Of 503 participants (mean [SD] age, 65.7 [8.8] years; range, 50-85 years; 284 [56.5%] were male), 80 individuals (15.9%) died during a mean (SD) follow-up of 7.8 (1.5) years. In the final analysis, 494 (98.2%) were included, of whom 78 (15.8%) died. Gait speed, cognitive index, conventional MRI markers of SVD (white matter hyperintensity volume, brain volume, and lacunes), and diffusion measures of the white matter were associated with an 8-year risk of mortality independent of age, sex, and vascular risk factors. The prediction of mortality was determined using Cox proportional hazards models with backward stepwise selection and including age, sex, vascular risk factors, gait speed, cognitive index, MRI, and diffusion measures. Results are reported as hazard ratios (HRs) (95% CI). Older age (1.05 per 1-year increase [1.01-1.08]), lower gait speed (1.15 per 0.1-m/s slower gait [1.06-1.24]), lower gray matter volume (0.72 per 1-SD increase [0.55-0.95]), and greater global mean diffusivity of the white matter (1.51 per 1-SD increase [1.19-1.92]) were identified as the main factors associated with mortality. Cognitive index and other conventional SVD markers were not retained in the prediction model. CONCLUSIONS AND RELEVANCE: Gait, cognition, and imaging markers of SVD are associated with 8-year risk of mortality. In the prediction of mortality, an older age, lower gait speed, lower gray matter volume, and greater global mean diffusivity of white matter at baseline best predicted mortality in our population. Further research is needed to investigate the reproducibility of this prediction model and to elucidate the association between the factors identified and mortality. 8 p.

Contains fulltext : 168158.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To examine whether structural network connectivity at baseline predicts incident all-cause dementia in a prospective hospital-based cohort of elderly participants with MRI evidence of small vessel disease (SVD). METHODS: A total of 436 participants from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC), a prospective hospital-based cohort of elderly without dementia with cerebral SVD, were included in 2006. During follow-up (2011-2012), dementia was diagnosed. The structural network was constructed from baseline diffusion tensor imaging followed by deterministic tractography and measures of efficiency using graph theory were calculated. Cox proportional regression analyses were conducted. RESULTS: During 5 years of follow-up, 32 patients developed dementia. MRI markers for SVD were strongly associated with network measures. Patients with dementia showed lower total network strength and global and local efficiency at baseline as compared with the group without dementia. Lower global network efficiency was independently associated with increased risk of incident all-cause dementia (hazard ratio 0.63, 95% confidence interval 0.42-0.96, p = 0.032); in contrast, individual SVD markers including lacunes, white matter hyperintensities volume, and atrophy were not independently associated. CONCLUSIONS: These results support a role of network disruption playing a pivotal role in the genesis of dementia in SVD, and suggest network analysis of the connectivity of white matter has potential as a predictive marker in the disease. 8 p.

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.

Contains fulltext : 165751.pdf (Publisher’s version ) (Open Access) Progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain, is typically diagnosed in immunocompromised persons. Here, we describe the diagnostic challenge of PML in an apparently immunocompetent patient. Thorough analyses, including cytokine release assays and whole exome sequencing, revealed a deficit in the antiviral interferon gamma production capacity of this patient and compound heterozygous mutations in BCL-2-associated athanogene 3. Interestingly, both factors are associated with reduced expression of John Cunningham virus T-antigen, a protein that plays a key role in viral replication in infected cells. After validation in other patients, our findings may contribute to novel insights into the etiology and possibly treatment of PML.

Contains fulltext : 152941.pdf (Publisher’s version ) (Closed access) BACKGROUND: The relationship between cerebral small vessel disease (SVD) and dementia has been studied without considering white matter (WM) volume, the microstructural integrity of the WM surrounding the SVD, and grey matter (GM). OBJECTIVE: We prospectively investigated the relationship between these structures and the risk of dementia, and formed a prediction model to investigate which characteristics (macro- or microstructural) explained most of the variance. METHODS: The RUN DMC study is a prospective cohort study among 503 non-demented participants with an age between 50 and 85 years at baseline, with baseline assessment in 2006 and follow-up assessment in 2012. Two were lost to follow-up (yielding a 99.6% response-rate). Cox regression analysis was used, to calculate hazard ratios for dementia, of baseline MRI characteristics. Tract-Based Spatial Statistics (TBSS) analysis was used to assess the added value of microstructural integrity of the WM. RESULTS: Mean age at baseline was 65.6 years (SD 8.8) and 56.8% was male. 43 participants developed dementia (8.6% ), resulting in a 5.5-year cumulative risk of 11.1% (95% CI 7.7-14.6). Low WM and hippocampal volume are significant predictors for dementia. WM, WM hyperintensities, and hippocampal volume explained most of the variance. TBSS analyses showed no additional value of diffusion parameters. CONCLUSIONS: WM and hippocampal volume were the main predictors for the development of incident dementia at 5-year follow-up in elderly with SVD. There was no additional diagnostic value of the diffusion tensor imaging parameters on top of the macrostructural characteristics. 11 p.

Contains fulltext : 144567.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Depressive symptoms are common in elderly with cerebral small vessel disease (SVD). As not every individual with SVD experiences depressive symptoms, other factors might play a role. We therefore investigated the white matter (WM) integrity of the white matter tracts in elderly with depressive symptoms, independent of global cognitive function, by applying the tract-based spatial statistics (TBSS). DESIGN: Prospective cohort study with cross-sectional baseline data. SETTING: Radboud University Nijmegen Medical Centre, The Netherlands. PARTICIPANTS: 438 individuals aged between 50-85 years, with SVD without dementia. MEASUREMENTS: Diffusion tensor imaging parameters and depressive symptoms, assessed with the Center for Epidemiologic Studies Depression Scale. RESULTS: Compared with non-depressed participants (N = 287), those with depressive symptoms (N = 151) had lower fractional anisotropy in the genu and body of the corpus callosum, bilateral inferior fronto-occipital fasciculus, uncinate fasciculus, and corona radiata. These differences disappeared after adjustment for white matter hyperintensities (WMH) and lacunar infarcts. Mean-, axial- and radial diffusivity were higher in these areas in participants with depressive symptoms. After additional adjustment for WMH and lacunar infarcts, the changes observed in radial diffusivity also disappeared. Adding global cognition as confounding variable altered the diffusion parameters only slightly. CONCLUSION: This study indicates that elderly with depressive symptoms show a lower WM integrity, independent of global cognitive function, and that the presence of SVD is mostly responsible, affecting the fronto-subcortical regions and hereby disrupting the neural circuitry involved in mood regulation. 11 p.