Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.
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ABSTRACT:
SUBMITTER: Duperron MG
PROVIDER: S-EPMC10115645 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.
Duperron Marie-Gabrielle MG Knol Maria J MJ Le Grand Quentin Q Evans Tavia E TE Mishra Aniket A Tsuchida Ami A Roshchupkin Gennady G Konuma Takahiro T Trégouët David-Alexandre DA Romero Jose Rafael JR Frenzel Stefan S Luciano Michelle M Hofer Edith E Bourgey Mathieu M Dueker Nicole D ND Delgado Pilar P Hilal Saima S Tankard Rick M RM Dubost Florian F Shin Jean J Saba Yasaman Y Armstrong Nicola J NJ Bordes Constance C Bastin Mark E ME Beiser Alexa A Brodaty Henry H Bülow Robin R Carrera Caty C Chen Christopher C Cheng Ching-Yu CY Deary Ian J IJ Gampawar Piyush G PG Himali Jayandra J JJ Jiang Jiyang J Kawaguchi Takahisa T Li Shuo S Macalli Melissa M Marquis Pascale P Morris Zoe Z Muñoz Maniega Susana S Miyamoto Susumu S Okawa Masakazu M Paradise Matthew M Parva Pedram P Rundek Tatjana T Sargurupremraj Muralidharan M Schilling Sabrina S Setoh Kazuya K Soukarieh Omar O Tabara Yasuharu Y Teumer Alexander A Thalamuthu Anbupalam A Trollor Julian N JN Valdés Hernández Maria C MC Vernooij Meike W MW Völker Uwe U Wittfeld Katharina K Wong Tien Yin TY Wright Margaret J MJ Zhang Junyi J Zhao Wanting W Zhu Yi-Cheng YC Schmidt Helena H Sachdev Perminder S PS Wen Wei W Yoshida Kazumichi K Joutel Anne A Satizabal Claudia L CL Sacco Ralph L RL Bourque Guillaume G Lathrop Mark M Paus Tomas T Fernandez-Cadenas Israel I Yang Qiong Q Mazoyer Bernard B Boutinaud Philippe P Okada Yukinori Y Grabe Hans J HJ Mather Karen A KA Schmidt Reinhold R Joliot Marc M Ikram M Arfan MA Matsuda Fumihiko F Tzourio Christophe C Wardlaw Joanna M JM Seshadri Sudha S Adams Hieab H H HHH Debette Stéphanie S
Nature medicine 20230417 4
Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in ...[more]
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Project description:BackgroundRecent studies, using diffusion tensor image analysis along the perivascular space (DTI-ALPS), suggest impaired perivascular space (PVS) function in cerebral small vessel disease, but they were cross-sectional, making inferences on causality difficult. We determined associations between impaired PVS, measured using DTI-ALPS and PVS volume, and cognition and incident dementia.MethodsIn patients with lacunar stroke and confluent white matter hyperintensities, without dementia at baseline, recruited prospectively in a single center, magnetic resonance imaging was performed annually for 3 years, and cognitive assessments, including global, memory, executive function, and processing speed, were performed annually for 5 years. We determined associations between DTI-ALPS and PVS volume with cerebral small vessel disease imaging markers (white matter hyperintensity volume, lacunes, and microbleeds) at baseline and with changes in imaging markers. We determined whether DTI-ALPS and PVS volume at baseline and change over 3 years predicted incident dementia. Analyses were controlled for conventional diffusion tensor image metrics using 2 markers (median mean diffusivity [MD] and peak width of skeletonized MD) and adjusted for age, sex, and vascular risk factors.ResultsA total of 120 patients, mean age 70.0 years and 65.0% male, were included. DTI-ALPS declined over 3 years, while no change in PVS volume was found. Neither DTI-ALPS nor PVS volume was associated with cerebral small vessel disease imaging marker progression. Baseline DTI-ALPS was associated with changes in global cognition (β=0.142, P=0.032), executive function (β=0.287, P=0.027), and long-term memory (β=0.228, P=0.027). Higher DTI-ALPS at baseline predicted a lower risk of dementia (hazard ratio, 0.328 [0.183-0.588]; P<0.001), and this remained significant after including median MD as a covariate (hazard ratio, 0.290 [0.139-0.602]; P<0.001). Change in DTI-ALPS predicted dementia conversion (hazard ratio, 0.630 [0.428-0.964]; P=0.048), but when peak width of skeletonized MD and median MD were entered as covariates, the association was not significant. There was no association between baseline PVS volume, or PVS change over 3 years, and conversion to dementia.ConclusionsDTI-ALPS predicts future dementia risk in patients with lacunar strokes and confluent white matter hyperintensities. However, the weakening of the association between change in DTI-ALPS and incident dementia after controlling for peak width of skeletonized MD and median MD suggests part of the signal may represent conventional diffusion tensor image metrics. PVS volume is not a predictor of future dementia risk.
| S-EPMC10962441 | biostudies-literature
Project description:Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18-35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30-40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45-82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention.
| S-EPMC11541005 | biostudies-literature
Project description:Background and aimsEnlarged perivascular spaces (also known as Virchow-Robin spaces) on T2-weighted brain magnetic resonance imaging are common, but their etiology, and specificity to small vessel as opposed to general cerebrovascular disease or ageing, is unclear. We tested the association between enlarged perivascular spaces and ischemic stroke subtype, other markers of small vessel disease, and common vascular risk factors.MethodsWe prospectively recruited patients with acute stroke, diagnosed and subtyped by a stroke physician using clinical features and brain magnetic resonance imaging. A neuroradiologist rated basal ganglia and centrum semiovale enlarged perivascular spaces on a five-point scale, white matter lesions, recent and old infarcts, and cerebral atrophy. We assessed associations between basal ganglia-, centrum semiovale- and total (combined basal ganglia and centrum semiovale) enlarged perivascular spaces, stroke subtype, white matter lesions, atrophy, and vascular risk factors.ResultsAmong 298 patients (mean age 68 years), after adjusting for vascular risk factors and white matter lesions, basal ganglia-enlarged perivascular spaces were associated with increasing age (P = 0.001), centrum semiovale-enlarged perivascular spaces (P < 0.001), cerebral atrophy (P = 0.03), and lacunar stroke subtype (P = 0.04). Centrum semiovale-enlarged perivascular spaces were associated mainly with basal ganglia-enlarged perivascular spaces. Total enlarged perivascular spaces were associated with increasing age (P = 0.01), deep white matter lesions (P = 0.005), and previous stroke (P = 0.006).ConclusionsEnlarged perivascular spaces are associated with age, lacunar stroke subtype and white matter lesions and should be considered as another magnetic resonance imaging marker of cerebral small vessel disease. Further evaluation of enlarged perivascular spaces in studies of ageing, stroke, and dementia is needed to determine their pathophysiological importance.
| S-EPMC4463944 | biostudies-literature
Project description:Studies aiming to identify the significance of the carotid artery perivascular fat density are limited. The present study investigated the distribution pattern of pericarotid fat and its association with imaging markers of cerebral small vessel disease (CSVD). In total, 572 subjects who underwent both neck computed tomography angiography and cranial magnetic resonance imaging were analyzed. The pericarotid fat density near the origin of the internal carotid artery (ICA) and imaging markers of CSVD, such as lacunes, white matter hyperintensities (WMHs) and dilated perivascular spaces (PVSs), were assessed. We found that an increased pericarotid fat density was associated with the presence of lacunes and a higher WMH grade in all subjects, but in the patients with acute ischemic stroke, there was a difference only among the WMH grades. There was no significant difference in the pericarotid fat density in different grades of PVSs. The patients with acute ischemic stroke had a significantly higher mean pericarotid fat density than those without stroke. In conclusion, our study provides evidence suggesting that an increased pericarotid fat density is associated with the presence and degree of WMHs and lacunes. Our findings suggested that features that appear to extend beyond the vessel lumen of the ICA may be linked to CSVD.
| S-EPMC8351687 | biostudies-literature
Project description:One of the most common causes of dementia is cerebral small vessel disease (SVD), which is associated with enlarged perivascular spaces (PVS). Clinically, PVS are visible as hyperintensities on T2-weighted (T2w) magnetic resonance images (MRI). While rodent SVD models exhibit arteriolosclerosis, PVS have not been robustly documented by MRI casting doubts on their clinical relevance. Here we established that the severity of SVD in spontaneously hypertensive stroke prone (SHRSP) rats correlated to 'moderate' SVD in human post-mortem tissue. We then developed two approaches for detecting PVS in SHRSP rats: 1) T2w imaging and 2) T1-weighted imaging with administration of gadoteric acid into cerebrospinal fluid. We applied the two protocols to six Wistar-Kyoto (WKY) control rats and thirteen SHRSP rats at ∼12 month of age. The primary endpoint was the number of hyperintense lesions. We found more hyperintensities on T2w MRI in the SHRSP compared to WKY rats (p-value = 0.023). CSF enhancement with gadoteric acid increased the visibility of PVS-like lesions in SHRSP rats. In some of the SHRSP rats, the MRI hyperintensities corresponded to enlarged PVS on histopathology. The finding of PVS-like hyperintensities on T2w MRI support the SHRSP rat's clinical relevance for studying the underlying pathophysiology of SVD.
| S-EPMC9536121 | biostudies-literature
Project description:Perivascular space (PVS) is associated with neurodegenerative diseases, while its effect on Parkinson's disease (PD) remains unclear. We aimed to investigate the clinical and neuroimaging significance of PVS in basal ganglia (BG) and midbrain in early-stage PD. We recruited 40 early-stage PD patients and 41 healthy controls (HCs). Both PVS number and volume were calculated to evaluate PVS burden on 7 T magnetic resonance imaging images. We compared PVS burden between PD and HC, and conducted partial correlation analysis between PVS burden and clinical and imaging features. PD patients had a significantly more serious PVS burden in BG and midbrain, and the PVS number in BG was significantly correlated to the PD disease severity and L-dopa equivalent dosage. The fractional anisotropy and mean diffusivity values of certain subcortical nuclei and white matter fibers within or nearby the BG and midbrain were significantly correlated with the ipsilateral PVS burden indexes. Regarding to the midbrain, the difference between bilateral PVS burden was, respectively, correlated to the difference between fiber counts of white fiber tract passing through bilateral substantia nigra in PD. Our study suggests that PVS burden indexes in BG are candidate biomarkers to evaluate PD motor symptom severity and aid in predicting medication dosage. And our findings also highlight the potential correlations between PVS burden and both grey and white matter microstructures.
| S-EPMC7864928 | biostudies-literature
Project description:White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
| S-EPMC7722866 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) increases stroke risk, but the mechanism is uncertain. This study aimed to determine the association between SLE and features on neuroimaging of cerebral small vessel disease (SVD), a risk factor for stroke.Consecutive patients attending a clinic for SLE were recruited. All patients underwent brain magnetic resonance imaging; had blood samples taken for markers of inflammation, endothelial dysfunction, cholesterol, and autoantibodies; and underwent cognitive and psychiatric testing. The data were compared with sex- and age-matched healthy controls and patients with minor stroke. Features of SVD were measured, a total SVD score calculated, and associations sought with vascular risk factors, cognition, SLE activity, and disease duration.Fifty-one SLE patients (age: 48.8 years; SD: 14.3 years) had a greater total SVD score compared with healthy controls (1 versus 0; P<0.0001) and stroke patients (1 versus 0; P=0.02). There were higher perivascular spaces and deep white matter hyperintensity scores and more superficial brain atrophy in SLE patients versus healthy controls. Despite fewer vascular risk factors than similarly aged stroke patients, SLE patients had similar or more of some SVD features. The total SVD score was not associated with SLE activity, cognition, disease duration, or any blood measure.In this data set, SLE patients had a high burden of SVD features on magnetic resonance imaging, particularly perivascular spaces. A larger longitudinal study is warranted to determine the causes of SVD features in SLE and clinical implications.
| S-EPMC5079231 | biostudies-literature
Project description:ObjectiveCerebral amyloid angiopathy (CAA) is a common age-related small vessel disease (SVD). Patients without intracerebral hemorrhage (ICH) typically present with transient focal neurologic episodes (TFNEs) or cognitive symptoms. We sought to determine if SVD lesion burden differed between patients with CAA first presenting with TFNEs vs cognitive symptoms.MethodsA total of 647 patients presenting either to a stroke department (n = 205) or an outpatient memory clinic (n = 442) were screened for eligibility. Patients meeting modified Boston criteria for probable CAA were included and markers of SVD were quantified, including cerebral microbleeds (CMBs), perivascular spaces, cortical superficial siderosis (cSS), and white matter hyperintensities (WMHs). Patients were classified according to presentation symptoms (TFNEs vs cognitive). Total CAA-SVD burden was assessed using a validated summary score. Individual neuroimaging markers and total SVD burden were compared between groups using univariable and multivariable models.ResultsThere were 261 patients with probable CAA included. After adjustment for confounders, patients first seen for TFNEs (n = 97) demonstrated a higher prevalence of cSS (p < 0.0001), higher WMH volumes (p = 0.03), and a trend toward higher CMB counts (p = 0.09). The total SVD summary score was higher in patients seen for TFNEs (adjusted odds ratio per additional score point 1.46, 95% confidence interval 1.16-1.84, p = 0.013).ConclusionsPatients with probable CAA without ICH first evaluated for TFNEs bear a higher burden of structural MRI SVD-related damage compared to those first seen for cognitive symptoms. This study sheds light on neuroimaging profile differences across clinical phenotypes of patients with CAA without ICH.
| S-EPMC5331873 | biostudies-literature
Project description:The term cerebral small vessel disease (SVD) describes a range of neuroimaging, pathological, and associated clinical features. Clinical features range from none, to discrete focal neurological symptoms (eg, stroke), to insidious global neurological dysfunction and dementia. The burden on public health is substantial. The pathogenesis of SVD is largely unknown. Although the pathological processes leading to the arteriolar disease are associated with vascular risk factors and are believed to result from an intrinsic cerebral arteriolar occlusive disease, little is known about how these processes result in brain disease, how SVD lesions contribute to neurological or cognitive symptoms, and the association with risk factors. Pathology often shows end-stage disease, which makes identification of the earliest stages difficult. Neuroimaging provides considerable insights; although the small vessels are not easily seen themselves, the effects of their malfunction on the brain can be tracked with detailed brain imaging. We discuss potential mechanisms, detectable with neuroimaging, that might better fit the available evidence and provide testable hypotheses for future study.
| S-EPMC3836247 | biostudies-literature