Project description:Background and purposeSerum neurofilament light (NfL)-chain is a circulating marker for neuroaxonal injury and is also associated with severity of cerebral small vessel disease (SVD) cross-sectionally. Here we explored the association of serum-NfL with imaging and cognitive measures in SVD longitudinally.MethodsFrom 503 subjects with SVD, baseline and follow-up magnetic resonance imaging (MRI) was available for 264 participants (follow-up 8.7±0.2 years). Baseline serum-NfL was measured by an ultrasensitive single-molecule-assay. SVD-MRI-markers including white matter hyperintensity (WMH)-volume, mean diffusivity (MD), lacunes, and microbleeds were assessed at both timepoints. Cognitive testing was performed in 336 participants, including SVD-related domains as well as global cognition and memory. Associations with NfL were assessed using linear regression analyses and analysis of covariance (ANCOVA).ResultsSerum-NfL was associated with baseline WMH-volume, MD-values and presence of lacunes and microbleeds. SVD-related MRI- and cognitive measures showed progression during follow-up. NfL-levels were associated with future MRI-markers of SVD, including WMH, MD and lacunes. For the latter, this association was independent of baseline lacunes. Furthermore, NfL was associated with incident lacunes during follow-up (P=0.040). NfL-levels were associated with future SVD-related cognitive impairment (processing speed: β=-0.159; 95% confidence interval [CI], -0.242 to -0.068; P=0.001; executive function β=-0.095; 95% CI, -0.170 to -0.007; P=0.033), adjusted for age, sex, education, and depression. Dementia-risk increased with higher NfL-levels (hazard ratio, 5.0; 95% CI, 2.6 to 9.4; P<0.001), however not after adjusting for age.ConclusionsLongitudinally, serum-NfL is associated with markers of SVD, especially with incident lacunes, and future cognitive impairment affecting various domains. NfL may potentially serve as an additional marker for disease monitoring and outcome in SVD, potentially capturing both vascular and neurodegenerative processes in the elderly.
Project description:ObjectiveTo evaluate whether the burden of deep and lobar lacunes differs between patients with intracerebral hemorrhage (ICH) with definite/probable cerebral amyloid angiopathy (CAA) per the Boston criteria and hypertensive small vessel disease (HTN-SVD; ICH in basal ganglia, thalami, brainstem).MethodsWe defined lobar and deep lacunes similar to the topographic distribution used for ICH and cerebral microbleeds (CMBs). We then compared their distribution between patients with CAA-ICH and those with strictly deep CMB and ICH (HTN-ICH). The independent associations of lacune location with the diagnosis of CAA-ICH and HTN-ICH were evaluated with multivariable models. The relationship between lobar lacunes and white matter hyperintensity (WMH) volume was evaluated by means of partial correlation analyses adjusted for age and a validated visual scale.ResultsIn our final cohort of 316 patients with ICH, lacunes were frequent (24.7%), with similar rates in 191 patients with CAA and 125 with HTN-ICH (23% vs 27.2%, p = 0.4). Lobar lacunes were more commonly present in CAA (20.4% vs 5.7%, p < 0.001), while deep lacunes were more frequent in HTN-ICH (15.2% vs 2.1%, p < 0.001). After correction for demographics and clinical and neuroimaging markers of SVD, lobar lacunes were associated with CAA (p = 0.003) and deep lacunes with HTN-ICH (p < 0.001). Lobar lacunes in 80% of the cases were at least in contact with WMH, and after adjustment for age, they were highly correlated to WMH volume (r = 0.42, p < 0.001).ConclusionsLobar lacunes are associated with CAA, whereas deep lacunes are more frequent in HTN-SVD. Lobar lacunes seem to have a close relationship with WMH, suggesting a possible common origin.
Project description:Lacunes are an important disease feature of cerebral small vessel disease (SVD) but their relationship to cognitive impairment is not fully understood. To investigate this we determined (1) the relationship between lacune count and total lacune volume with cognition, (2) the spatial distribution of lacunes and the cognitive impact of lacune location, and (3) the whole brain anatomical covariance associated with these strategically located regions of lacune damage.One hundred and twenty one patients with symptomatic lacunar stroke and radiological leukoaraiosis were recruited and multimodal MRI and neuropsychological data acquired. Lacunes were mapped semi-automatically and their volume calculated. Lacune location was automatically determined by projection onto atlases, including an atlas which segments the thalamus based on its connectivity to the cortex. Lacune locations were correlated with neuropsychological results. Voxel based morphometry was used to create anatomical covariance maps for these 'strategic' regions.Lacune number and lacune volume were positively associated with worse executive function (number p < 0.001; volume p < 0.001) and processing speed (number p < 0.001; volume p < 0.001). Thalamic lacunes, particularly those in regions with connectivity to the prefrontal cortex, were associated with impaired processing speed (Bonferroni corrected p = 0.016). Regions of associated anatomical covariance included the medial prefrontal, orbitofrontal, anterior insular cortex and the striatum.Lacunes are important predictors of cognitive impairment in SVD. We highlight the importance of spatial distribution, particularly of anteromedial thalamic lacunes which are associated with impaired information processing speed and may mediate cognitive impairment via disruption of connectivity to the prefrontal cortex.
Project description:Multiple sclerosis (MS) is a condition that affects the veins and small blood vessels. Previous research suggests that individuals with MS have an increased risk of vascular events and higher mortality rates. However, the relationship between MS and cerebral small vessel disease (CSVD) remains uncertain. This study aims to investigate the association between MS and lacunes. A prospective observational study was conducted, including a total of 112 participants, of which 46 had MS and 66 had CSVD. All participants underwent an MRI scan and a battery of neurological functional assessments. The presence of definite lacunes and black holes was determined through the analysis of T2-weighted, T1-weighted, and FLAIR images. The occurrence of lacunes in MS patients was found to be 19.6%. Notably, the duration of MS was identified as the sole risk factor for the development of lacune lesions in MS patients [odds ratio (OR) = 1.3, 95% confidence interval (CI) = 1.1-1.6, p = 0.008]. Comparatively, MS patients with lacunes exhibited a higher frequency of attacks and larger volumes of T2 lesions compared to MS patients without lacunes. Further analysis using receiver operating characteristic (ROC) curves showed that lacune lesions had limited ability to discriminate between MS and CSVD when disease duration exceeded 6 years. The presence of small arterial lesions in the brain of individuals with MS, along with the duration of the disease, contributes to the development of lacunes in MS patients.
Project description:ObjectiveTo 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.MethodsIn 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.ResultsFollow-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.ConclusionsSVD 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.
Project description:Cerebral microbleeds (CMBs) are MRI markers attributed to the most common cerebral angiopathies in the elderly and in patients with dementia: hypertensive and cerebral amyloid angiopathy. CMB detection in asymptomatic persons may help identify those at risk for dementia and may influence preventive strategies and design of clinical trials testing treatments for dementia. We studied the association of CMB with risk of incident dementia in community dwelling individuals. A total of 1296 dementia-free Framingham Heart Study participants (mean age 72 years; 54% women) with available brain MRI and incident dementia data during a mean follow-up period of 6.7 years were included. Using Cox proportional hazards models, we related CMB presence to incident dementia. Multivariable models were adjusted for age, sex, APOE status, and education, with additional models adjusting for vascular risk factors and MRI markers of ischemic brain injury. CMBs were observed in 10.8% and incident dementia in 85 participants (6.6% over study period). Participants with any CMB had 1.74 times higher risk of dementia (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.00-3.01), whereas those with deep and mixed CMB had a three-fold increased risk (HR 2.99, 95% CI 1.52-5.90). The associations were independent of vascular risk factors, and for deep and mixed CMB also independent of MRI markers of ischemia (HR 2.44, 95% CI 1.22-4.88). Purely lobar CMBs were not associated with incident dementia. Our findings support a role for hypertensive vasculopathy and the interplay of hypertensive and cerebral amyloid angiopathy in risk of dementia and suggest that CMB presence can identify individuals at risk of dementia.
Project description:MRI features of cerebral small vessel disease (CSVD), i.e. white matter hyperintensities, lacunes, microbleeds, perivascular spaces, and cerebral atrophy, may be associated with clinical events, but the strength of these associations remains unclear. We conducted a systematic review and meta-analysis on the association between these features and incident ischaemic and haemorrhagic stroke, all-cause dementia and depression, and all-cause mortality. For the association with stroke, 36 studies were identified (number of individuals/events [n] = 38,432/4,136), for dementia 28 (n = 16,458/1,709), for depression nine (n = 9,538/1,746), and for mortality 28 (n = 23,031/2,558). Only two studies evaluated perivascular spaces; these results were not pooled. Pooled analyses showed that all other features were associated with all outcomes (hazard ratios ranged 1.22-2.72). Combinations of two features were more strongly associated with stroke than any individual feature. Individual features and combinations of CSVD features are strongly associated with incident ischaemic and haemorrhagic stroke, all-cause dementia and depression, and all-cause mortality. If these associations are causal, the strength of these associations suggests that a substantial burden of disease is attributable to CSVD.
Project description:BackgroundTo investigate whether structural network disconnectivity is associated with parkinsonian signs and their progression, as well as with an increased risk of incident parkinsonism.MethodsIn a prospective cohort (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study) consisting of 293 participants with small vessel disease (SVD), we assessed parkinsonian signs and incident parkinsonism over an 8-year follow-up. In addition, we reconstructed the white matter network followed by graph-theoretical analyses to compute the network metrics. Conventional magnetic resonance imaging markers for SVD were assessed.ResultsWe included 293 patients free of parkinsonism at baseline (2011), with a mean age 68.8 (standard deviation [SD] 8.4) years, and 130 (44.4%) were men. Nineteen participants (6.5%) developed parkinsonism during a median (SD) follow-up time of 8.3 years. Compared with participants without parkinsonism, those with all-cause parkinsonism had higher Unified Parkinson's Disease Rating scale (UPDRS) scores and lower global efficiency at baseline. Baseline global efficiency was associated with UPDRS motor scores in 2011 (β = -0.047, p < .001) and 2015 (β = -0.84, p < .001), as well as with the changes in UPDRS scores during the 4-year follow-up (β = -0.63, p = .004). In addition, at the regional level, we identified an inter-hemispheric disconnected network associated with an increased UPDRS motor score. Besides, lower global efficiency was associated with an increased risk of all-cause and vascular parkinsonism independent of SVD markers.ConclusionsOur findings suggest that global network efficiency is associated with a gradual decline in motor performance, ultimately leading to incident parkinsonism in the elderly with SVD. Global network efficiency may have the added value to serve as a useful marker to capture changes in motor signs.