Enlarged Perivascular Spaces Research Articles

Assessing the effectiveness of statin therapy for alleviating cerebral small vessel disease progression in people \u226575\u2009years of age

BackgroundStatins have been recommended by several guidelines as the primary prevention medication for cardiovascular diseases. However, the benefits of statin therapy for cerebral small vessel disease (CSVD), particularly in adults ≥75 years of age, have not been fully evaluated.MethodsWe analyzed the data from a prospective population-based cohort study and a randomized, double-blind, placebo-controlled clinical trial to determine whether statin therapy might aid in slowing the progression of CSVD in adults ≥75 years of age. For the cohort study, 827 participants were considered eligible and were included in the baseline analysis. Subsequently, 781 participants were included in follow-up analysis. For the clinical trial, 227 participants were considered eligible and were used in the baseline and follow-up analyses.ResultsThe white matter hyperintensities (WMH) volume, the WMH-to-intracranial volume (ICV) ratio, the prevalence of a Fazekas scale score ≥ 2, lacunes, enlarged perivascular spaces (EPVS), and microbleeds were significantly lower in the statin group than the non-statin group at baseline in the cohort study (all P < 0.05). During the follow-up period, in both the cohort and clinical trial studies, the WMH volume and WMH-to-ICV ratio were significantly lower in the statin/rosuvastatin group than the non-statin/placebo group (all P < 0.001). Statin therapy was associated with lower risk of WMH, lacunes, and EPVS progression than the non-statin therapy group after adjustment for confounders (all P < 0.05). There was no statistically significant difference in the risk of microbleeds between the statin and non-statin therapy groups (all, P > 0.05).ConclusionsOur findings indicated that statin therapy alleviated the progression of WMH, lacunes, and EPVS without elevating the risk of microbleeds. On the basis of the observed results, we concluded that statin therapy is an efficient and safe intervention for CSVD in adults ≥75 years of age.Trial registrationChictr.org.cn: ChiCTR-IOR-17013557, date of trial retrospective registration November 27, 2017 and ChiCTR-EOC-017013598, date of trial retrospective registration November 29, 2017.

Neuropathologic and Cognitive Correlates of Enlarged Perivascular Spaces in a Community-Based Cohort of Older Adults.

Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function, and vascular dementia. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, the purpose of this study was to assess the neuropathologic correlates of EPVS in a large community-based cohort of older adults. The cognitive correlates of EPVS over and beyond those of other pathologies were also assessed. This study included 654 older deceased and autopsied participants of 3 longitudinal community-based studies of aging that had available data on cognition, ex vivo brain magnetic resonance imaging, and detailed neuropathologic examination. EPVS seen on ex vivo magnetic resonance imaging were histologically validated. Experienced observers rated EPVS burden in ex vivo magnetic resonance imaging using a semiquantitative 4-level scale. Elastic-net regularized ordinal logistic regression was used to investigate associations of EPVS burden with age-related neuropathologies. Mixed-effects models of cognition controlling for neuropathologies, demographics, and clinical factors, were used to determine whether EPVS burden has additional contributions to cognitive decline. EPVS burden in the whole group was associated with gross infarcts (odds ratio=1.67, P=0.0017) and diabetes mellitus (odds ratio=1.73, P=0.004). When considering only nondemented participants (with mild or no cognitive impairment), EPVS burden was associated with gross infarcts (odds ratio=1.74, P=0.016) and microscopic infarcts (odds ratio=1.79, P=0.013). EPVS burden was associated with faster decline in visuospatial abilities (estimate=-0.009, P=0.028), in the whole group, as well as lower levels of semantic memory (estimate=-0.13, P=0.048) and visuospatial abilities (estimate=-0.11, P=0.016) at the time of death. EPVS and infarcts may share similar neurobiological pathways regardless of dementia status. EPVS burden is linked to diabetes mellitus independently of neuropathologies, extending recent findings in animal studies implicating diabetes mellitus in impairment of the glymphatic system. Finally, EPVS burden may reflect additional brain tissue injury that may contribute to cognitive decline, not captured with traditional neuropathologic measures.

Distinct association between cerebral arterial pulsatility and subtypes of cerebral small vessel disease.

BackgroundIncreased arterial resistance is a potential pathological mechanism of cerebral small vessel disease (cSVD).AimIn this study, we aimed to investigate the association between pulsatility index (PI) representing cerebral arterial resistance and subtypes of cSVD in patients with lacunar stroke.MethodsWe included consecutive lacunar stroke patients between 2010 and 2013. White matter hyperintensity (WMH) volume was rated using semi-automated quantitative methods. Additionally, the presence of old lacunar infarct (OLI), cerebral microbleed (CMB), or enlarged perivascular space (EPVS) was also evaluated. The relationship between PI, measured in each middle cerebral artery, and the subtype/burden of cSVD was analyzed in the relevant hemisphere.ResultsA total of 206 lacunar patients were included and 412 hemispheres were analyzed (mean age: 64 years, male: 68.4%). In multivariable analysis, PI was positively associated with the WMH volume [beta = 1.372, 95% confidence interval (CI) = 0.624 to 2.120, P < 0.001] after adjusting for confounders. PI was also related to the presence of OLI (adjusted odds ratio = 11.37, 95% CI = 2.55–48.56, P = 0.001); however, this relationship was not significant in CMB or EPVS. Regarding the cSVD burden, PI increased according to the WMH tertiles (P for trend < 0.001), the burden of OLI (P for trend < 0.001), and EPVS tertiles (P for trend < 0.001), showing a quantitative relationship.ConclusionsIpsilateral PI is closely associated with cSVD in patients with lacunar stroke. Furthermore, this association is different between subtypes of cSVD, which is suggestive of underlying pathophysiological differences.

Cerebral MRI and Clinical Findings in Children with PTEN Hamartoma Tumor Syndrome: Can Cerebral MRI Scan Help to Establish an Earlier Diagnosis of PHTS in Children?

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is caused by germline autosomal-dominant mutations of the tumor suppressor gene PTEN. Subjects harbour an increased risk for tumor development, with thyroid carcinoma occurring in young children. Establishing a diagnosis is challenging, since not all children fulfill diagnostic criteria established for adults. Macrocephaly is a common feature in childhood, with cerebral MRI being part of its diagnostic workup. We asked whether distinct cMRI features might facilitate an earlier diagnosis. Methods: We retrospectively studied radiological and clinical data of pediatric patients who were presented in our hospital between 2013 and 2019 in whom PTEN gene mutations were identified. Results: We included 27 pediatric patients (18 male) in the analysis. All patients were macrocephalic. Of these, 19 patients had received at least one cMRI scan. In 18 subjects variations were detected: enlarged perivascular spaces (EPVS; in 18), white matter abnormalities (in seven) and less frequently additional pathologies. Intellectual ability was variable. Most patients exhibited developmental delay in motor skills, but normal intelligence. Conclusion: cMRI elucidates EPVS and white matter abnormalities in a high prevalence in children with PHTS and might therefore aid as a diagnostic feature to establish an earlier diagnosis of PHTS in childhood.

Weakly supervised object detection with 2D and 3D regression neural networks

Finding automatically multiple lesions in large images is a common problem in medical image analysis. Solving this problem can be challenging if, during optimization, the automated method cannot access information about the location of the lesions nor is given single examples of the lesions. We propose a new weakly supervised detection method using neural networks, that computes attention maps revealing the locations of brain lesions. These attention maps are computed using the last feature maps of a segmentation network optimized only with global image-level labels. The proposed method can generate attention maps at full input resolution without need for interpolation during preprocessing, which allows small lesions to appear in attention maps. For comparison, we modify state-of-the-art methods to compute attention maps for weakly supervised object detection, by using a global regression objective instead of the more conventional classification objective. This regression objective optimizes the number of occurrences of the target object in an image, e.g. the number of brain lesions in a scan, or the number of digits in an image. We study the behavior of the proposed method in MNIST-based detection datasets, and evaluate it for the challenging detection of enlarged perivascular spaces - a type of brain lesion - in a dataset of 2202 3D scans with point-wise annotations in the center of all lesions in four brain regions. In MNIST-based datasets, the proposed method outperforms the other methods. In the brain dataset, the weakly supervised detection methods come close to the human intrarater agreement in each region. The proposed method reaches the best area under the curve in two out of four regions, and has the lowest number of false positive detections in all regions, while its average sensitivity over all regions is similar to that of the other best methods. The proposed method can facilitate epidemiological and clinical studies of enlarged perivascular spaces and help advance research in the etiology of enlarged perivascular spaces and in their relationship with cerebrovascular diseases.

Enlarged perivascular spaces in multiple sclerosis on magnetic resonance imaging: a systematic review and meta-analysis

BackgroundPerivascular spaces can become detectable on magnetic resonance imaging (MRI) upon enlargement, referred to as enlarged perivascular spaces (EPVS) or Virchow-Robin spaces. EPVS have been linked to small vessel disease. Some studies have also indicated an association of EPVS to neuroinflammation and/or neurodegeneration. However, there is conflicting evidence with regards to their potential as a clinically relevant imaging biomarker in multiple sclerosis (MS).MethodsTo perform a systematic review and meta-analysis of EPVS as visualized by MRI in MS. Nine out of 299 original studies addressing EPVS in humans using MRI were eligible for the systematic review and meta-analysis including a total of 457 MS patients and 352 control subjects.ResultsIn MS, EPVS have been associated with cognitive decline, contrast-enhancing MRI lesions, and brain atrophy. Yet, these associations were not consistent between studies. The meta-analysis revealed that MS patients have greater EPVS prevalence (odds ratio = 4.61, 95% CI = [1.84; 11.60], p = 0.001) as well as higher EPVS counts (standardized mean difference [SMD] = 0.46, 95% CI = [0.26; 0.67], p < 0.001) and larger volumes (SMD = 0.88, 95% CI = [0.19; 1.56], p = 0.01) compared to controls.ConclusionsAvailable literature suggests a higher EPVS burden in MS patients compared to controls. The association of EPVS to neuroinflammatory or -degenerative pathology in MS remains inconsistent. Thus, there is currently insufficient evidence supporting EPVS as diagnostic and/or prognostic marker in MS. In order to benefit future comparisons of studies, we propose recommendations on EPVS assessment standardization in MS. PROSPERO No: CRD42019133946.

Cerebral perivascular spaces as an important diagnostic marker of cerebral small vessel disease and brain pathology

Objective. To assess the association of enlarged perivascular spaces (EPVS) with cerebral small vessel disease (CSVD), some basic metabolic tests, brain atrophy and clinical outcome after territorial stroke.Methods. 90 patients with acute stroke (&lt;24 hours of onset) were recruited. Modified Rankin scale and Bartel index where used to assess stroke outcome. Cerebral MRI was performed to assess white matter lesions (WML), lacunes, cerebral atrophy and EPVS in basal ganglia and cortical-subcortical area with a validated four-point visual rating scale. Total CSVD burden was calculated with summation of lacunes, WML and EPVS with a validated scale. Spearmen correlation and logistic regression were used to identified association between EPVS, total CSVD burden, CSVD features and some basic metabolic tests (creatinine, urea, cholesterol, bilirubin, fibrinogen, erythrocyte sedimentation rate).Results. There was a very strong correlation between EPVS and total CSVD burden (r = 0.9, p &lt;0.000) and with Fazekas score scale (r = 0.9, p &lt;0.000). A strong correlation was found between EPVS and global cortical atrophy (r = 0.7, p &lt;0.000), and a moderate correlation with presence of lacunes (r = 0.4, p &lt;0.05). EPVS in basal ganglia had a significant correlation with the degree of extracranial carotid stenosis (r = 0.4, p &lt;0.05). The severity of EPVS was associated with a more severe neurological deficit on the NIHSS scale (r = 0.5, p &lt;0.05) and an increased degree of disability by Bartel's index (r = 0.5, p &lt;0.05) in patients on discharge. Creatinine was associated with CSVD features.Conclusions. EPVS is highly associated with total CSVD burden and others its features as well as with stroke outcome. EPVS in different brain regions may lead to the distinguish of two main type of CSVD – hypertensive arteriolosclerosis and beta-amyloid angiopathy.

Clinical Features and Experimental Models of Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) refers to a group of disease conditions affecting the cerebral small vessels, which include the small arteries, arterioles, capillaries, and postcapillary venules in the brain. SVD is the primary cause of vascular cognitive impairment and gait disturbances in aged people. There are several types of SVD, though arteriolosclerosis, which is mainly associated with hypertension, aging, and diabetes mellitus, and cerebral amyloid angiopathy (CAA) comprise most SVD cases. The pathology of arteriolosclerosis-induced SVD is characterized by fibrinoid necrosis and lipohyalinosis, while CAA-associated SVD is characterized by progressive deposition of amyloid beta (Aβ) protein in the cerebral vessels. Brain magnetic resonance imaging (MRI) has been used for examination of SVD lesions; typical lesions are characterized by white matter hyperintensity, lacunar infarcts, enlargement of perivascular spaces (EPVS), microbleeds, cortical superficial siderosis (cSS), and cortical microinfarcts. The microvascular changes that occur in the small vessels are difficult to identify clearly; however, these consequent image findings can represent the SVD. There are two main strategies for prevention and treatment of SVD, i.e., pharmacotherapy and lifestyle modification. In this review, we discuss clinical features of SVD, experimental models replicating SVD, and treatments to further understand the pathological and clinical features of SVD.

Concomitant enlargement of perivascular spaces and decrease in glymphatic transport in an animal model of cerebral small vessel disease

ObjectivesTo observe glymphatic transport and evaluate enlarged perivascular spaces (PVSs) in spontaneously hypertensive rats (SHRs). MethodsSHRs were used as an animal model of cerebral small vessel disease, and Wistar Kyoto (WKY) rats were used as the control group. Histopathology was used to evaluate the enlargement of PVSs. A fluorescent tracer was infused into the cisterna magna of rats, and the proportion of the brain parenchyma area exposed to the fluorescent tracer was later quantified to evaluate the influx and efflux function of the glymphatic system. The global and polarized expression of aquaporin protein 4 (AQP4) was analyzed by immunofluorescence. ResultsCompared with WKY rats, SHRs exhibited obviously enlarged PVSs and significantly decreased influx and efflux function of the glymphatic system. The results showed a significant decrease in AQP4 polarity in SHRs, but a difference in global AQP4 expression was not observed between SHRs and WKY rats. ConclusionsImpaired glymphatic transport may be involved in the pathogenesis of arteriolosclerotic cerebral small vessel disease, and enlarged PVSs may be a manifestation of the impaired glymphatic system.

Continuous Hypodynamic Change of Cerebrospinal Fluid Flow as A Potential Factor Working for Experimental Scoliotic Formation

Scoliosis is often associated with syringomyelia (SM). As an important role in SM formation, the influence from abnormal cerebrospinal fluid (CSF) flow is still unclear to scoliosis. The aim of this experimental work is to explore the connection between CSF flow and scoliosis through imaging and histological analysis on the basis of a kaolin-induced scoliotic rabbit model. For imaging observation, in 40 kaolin-induced rabbits by C7 spinal cord injection, through pre- and postoperative MRI and radiography, CSF flow and scoliosis formation were detected at consecutive phases. According to the final formation of scoliosis until postoperative week 12, the kaolin-induced rabbits were divided into 2 groups. Through comparing the 2 groups, the relationship between the changes of CSF flow velocity and scoliosis formation were reviewed and analyzed. For histological observation, another 20 kaolin-induced rabbits were used for consecutive histological observations of spinal cord at postoperative 3-day, 2-week, 4-week and 6-week. After kaolin-induction, abnormal spinal coronal curve was observed from postoperative week 6 in the 37 survived rabbits. At postoperative week 12, scoliosis formation was detected in 73.0% kaolin-induced rabbits and the mean Cobb angle was 27.4°. From the comparison between scoliotic and non-scoliotic groups, the difference of the velocities of CSF flow was more obviously from postoperative week 4 to 12, especially after week 6. In the scoliotic group, the peak velocity of CSF flow was diseased gradually following scoliosis formation after induction. Moreover, the decrease of the peak velocities of CSF flow from preoperation to postoperative 12 weeks (ΔVmax), including up-flow (ΔVUmax) and down-flow (ΔVDmax), were positively correlated to the final scoliotic Cobb angle (P < 0.01). Through histological observation at different phases, the distinctive pathological changes of the spinal cord included early inflammatory reaction, adhesion and blockage in the subarachnoid space and the central canal, perivascular space enlargement, central canal expansion, which suggested the CSF flow being blocked by multiple ways after kaolin-induction. In conclusion, experimental scoliosis can be successfully induced by intraspinal kaolin injection. In this model, continuous hypodynamic change of CSF flow was correlated to the formation of scoliosis, which could be an important factor of scoliotic pathogenesis being explored furtherly.

Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System.

Most neurological disorders seemingly have heterogenous pathogenesis, with overlapping contribution of neuronal, immune and vascular mechanisms of brain injury. The perivascular space in the brain represents a crossroad where those mechanisms interact, as well as a key anatomical component of the recently discovered glymphatic pathway, which is considered to play a crucial role in the clearance of brain waste linked to neurodegenerative diseases. The pathological interplay between neuronal, immune and vascular factors can create an environment that promotes self-perpetration of mechanisms of brain injury across different neurological diseases, including those that are primarily thought of as neurodegenerative, neuroinflammatory or cerebrovascular. Changes of the perivascular space can be monitored in humans in vivo using magnetic resonance imaging (MRI). In the context of glymphatic clearance, MRI-visible enlarged perivascular spaces (EPVS) are considered to reflect glymphatic stasis secondary to the perivascular accumulation of brain debris, although they may also represent an adaptive mechanism of the glymphatic system to clear them. EPVS are also established correlates of dementia and cerebral small vessel disease (SVD) and are considered to reflect brain inflammatory activity. In this review, we describe the “perivascular unit” as a key anatomical and functional substrate for the interaction between neuronal, immune and vascular mechanisms of brain injury, which are shared across different neurological diseases. We will describe the main anatomical, physiological and pathological features of the perivascular unit, highlight potential substrates for the interplay between different noxae and summarize MRI studies of EPVS in cerebrovascular, neuroinflammatory and neurodegenerative disorders.

Peak Width of Skeletonized Mean Diffusivity as a Marker of Diffuse Cerebrovascular Damage.

BackgroundThe peak width of skeletonized mean diffusivity (PSMD) has been proposed as a fully automated imaging marker of relevance to cerebral small vessel disease (SVD). We assessed PSMD in relation to conventional SVD markers, global measures of neurodegeneration, and cognition.Methods145 participants underwent 3T brain MRI and cognitive assessment. 112 were patients with mild cognitive impairment, Alzheimer’s disease, progressive supranuclear palsy, dementia with Lewy bodies, or frontotemporal dementia. PSMD, SVD burden [white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds, lacunes], average mean diffusivity (MD), gray matter (GM), white matter (WM), and total intracranial volume were quantified. Robust linear regression was conducted to examine associations between variables. Dominance analysis assessed the relative importance of markers in predicting various outcomes. Regional analyses examined spatial overlap between PSMD and WMH.ResultsPSMD was associated with global and regional SVD measures, especially WMH and microbleeds. Dominance analysis demonstrated that among SVD markers, WMH was the strongest predictor of PSMD. Furthermore, PSMD was more closely associated to WMH than with GM and WM volumes. PSMD was associated with WMH across all regions, and correlations were not significantly stronger in corresponding regions (e.g., frontal PSMD and frontal WMH) compared to non-corresponding regions. PSMD outperformed all four conventional SVD markers and MD in predicting cognition, but was comparable to GM and WM volumes.DiscussionPSMD was robustly associated with established SVD markers. This new measure appears to be a marker of diffuse brain injury, largely due to vascular pathology, and may be a useful and convenient metric of overall cerebrovascular burden.

Association between advanced interatrial block and small vessel diseases in the brain.

The latest evidence shows the association of atrial cardiopathy with embolic strokes of undetermined source. Advanced interatrial block (aIAB) is an electrophysiological mark of atrial cardiopathy. This study investigated the relationship between aIAB and the burden of silent cerebral small vessel diseases (SVD) on magnetic resonance imaging in the absence of atrial fibrillation (AF) and atrial flutter. This cross-sectional study included 499 patients with normal left ventricular ejection fraction (LVEF), who were free of AF, atrial flutter, stroke, and acute coronary syndrome in our hospital. aIAB was ascertained by digital electrocardiograms. Left atrial diameter, LVEF, and left ventricular posterior wall thickness (LVPWT) were measured on echocardiograms. Based on the presence of 4 manifestations of SVD, including white matter hyperintensity (WMH), lacunes, microbleeds, and enlarged perivascular spaces (EPVS) on magnetic resonance imaging, an ordinal SVD score (range, 0-4) was devised to reflect the total burden of cerebral SVD. The ordinal regression model was used to explore the association of aIAB with SVD burden after adjusting for confounding factors. The mean age was 67.7 years, and 327 (65.5%) were male. A total of 23 (4.6%) patients had aIAB. The number of patients with cerebral SVD scores of 0, 1, 2, 3, and 4 was 92 (18.4%), 122 (24.4%), 190 (38.1%), 83 (16.6%), and 12 (2.4%), respectively. After adjusting for age, sex, hypertension, diabetes, hyperlipidemia, left atrial diameter, LVEF, and LVPWT, the regression model showed a significant association of aIAB with cerebral SVD score (OR =2.408, 95% CI, 1.082-5.366). Atrial cardiopathy indexed by aIAB was independently associated with a high burden of SVD in the brain.

Abstract TMP19: MRI Characteristics and Predictors of Diffusion Weighted Hyperintense Lesions After Spontaneous Intracerebral Hemorrhage: A Secondary Analysis of MISTIE-III

Introduction: Mechanisms of diffusion weighted hyperintense lesions (DWIHL) after spontaneous intracerebral hemorrhage (ICH) are controversial. We evaluated mechanism and outcome of DWIHL. Methods: Protocolized MRI scans within 7 days from ICH were reviewed from MISTIE-III trial. Imaging analysis included DWIHL, leukoariosis (Fazekas score), enlarged perivascular space (EPVS), and cerebral microbleeds. Multivariable logistic regression analysis was performed to assess predictors and outcomes of having DWIHLs. Favorable outcome was defined as modified Rankin Score 0-3 at 12 months. Results: Of 499 patients, 300 underwent DWI studies (62% lobar ICH; 38% deep ICH) and 178 (59%) had acute DWIHLs (66% lobar; 34% deep). DWIHL locations were perihematomal in 140 (79%); and remote in 96 (54%). In multivariable regression analysis, DWIHLs were associated with initial mean arterial pressure [MAP] (odds ratio [OR]: 1.004; 95% confidence interval [CI]: 1.002-1.01), initial ICH volume (OR: 1.004; 95%CI: 1.001-1.01), NIHSS at randomization (OR: 1.01; 95%CI: 1.01-1.02), hypertension history (OR: 1.41; 95%CI: 1.04-1.93), and Fazekas score (OR: 1.04; 95%CI: 1.01-1.08). Patients with DWIHLs were less likely to have favorable outcome (66% vs. 50%; OR: 0.89; 95%CI: 0.81-0.99) after adjusting for ICH severity; however, the presence of DWIHLs did not confer an independent mortality risk at 12 months. In addition, perihematomal DWIHLs were associated with ICH volume (OR: 1.003; 95%CI: 1.00-1.01), NIHSS (OR: 1.01; 95%CI: 1.00-1.02), deep location (OR: 1.25; 95%CI: 1.10-1.42), and centrum semiovale EPVS score (OR: 0.99; 95% CI: 0.99-1.00). Remote DWIHLs were associated with Fazekas score (OR: 1.17; 95%CI: 1.06-1.29), centrum semiovale EPVS score (OR: 1.01; 95%CI: 1.00-1.01), atrial fibrillation (OR: 1.40; 95%CI: 1.04-1.90), and maximal ΔMAP on first 24 hours (OR: 1.004; 95%CI: 1.001-1.006). Conclusions: DWIHLs were common (59%) in patients after spontaneous ICH, predominantly in lobar locations and were associated with unfavorable neurologic outcome. While perihematomal DWIHLs were associated with ICH severity, remote DWIHLs suggested different mechanisms including acute blood pressure reduction, cardiac emboli, and white matter disease severity.

Abstract 7: Cerebral Small Vessel Disease Burden and Association With Post-Surgical Rebleeding and Long-Term Outcome in Intracerebral Hemorrhage Patients From the Mistie III Trial

Objectives: To examine the effect of cerebral small vessel disease (CSVD) markers and CSVD burden on hematoma expansion and long-term functional outcomes in large spontaneous intracerebral hemorrhage (ICH) &gt;30 mL. Method: Retrospective analysis of 288 patients from the MISTIE III trial with qualified MRI sequences. MISTIE III evaluated minimally invasive surgery plus alteplase (vs medical management). We identified 6 CSVD markers including lacunes, cerebral microbleeds (CMB), enlarged perivascular space (EPVS), white matter hyperintensities (WMH), cortical superficial siderosis (cSS), and acute DWI positive lesions. First 5 components were reviewed on day 1 MRI and DWI lesions on day 7. The primary outcome was death or major disability at one year (modified Rankin score 4-6). Secondary outcome was post-surgical rebleeding, defined as symptomatic or asymptomatic hemorrhage expansion within 72 hours post last dose of alteplase. Result: Unfavorable outcome occurred in 65.9% at one year. Post-surgical ICH expansion occurred in 34 (22.9%) of 148 surgical patients. Mean time from symptom onset to first MRI was 0.94 (IQR 0.2-6.3) days. Most individual CSVD markers were more common in patients with unfavorable vs. favorable outcome: CMB≧5 (26.1% vs 15.0%, p=0.03), DWI lesions (65.8%vs 49.6%, p=0.006), cSS (16.8% vs 7.1%, p=0.02) severe WMH (67.7% vs 29.9%, p&lt;0.001) severe EPVS in basal ganglia (19.3% vs 10.2%, p=0.047), and lacunes (11.2% vs 6.3%, p=0.21), In the multivariable adjusted model, cumulative CSVD score (one point for each component: CMB≥5, severe EPVS in basal ganglia, lacunes, severe WMH and cSS) was independently associated with unfavorable outcome (OR 0.56, 95%CI 0.41-0.76, p&lt;0.001; AUC 0.855). We did not find a relationship between either independent CSVD markers or CSVD score with post-surgical ICH expansion. Cumulative CSVD score in multivariable analysis adjusted for predictors of hematoma expansion had OR 0.77 (95% CI 0.50-1.19, p=0.77; AUC 0.659). Conclusion: In large volume ICH patients with long-term follow-up, heavy burden of CSVD at ICH onset remains an independent predictor of unfavorable outcome, and particularly severe white matter hyperintensities. CSVD markers did not show association with post-surgical ICH expansion.

Abstract WP267: Association Between Arterial Resistance and Subtypes of Cerebral Small Vessel Disease

Introduction: Increased arterial resistance is a potential pathophysiological mechanism in the pathogenesis of cerebral small vessel disease (cSVD). In this study, we aimed to investigate the association between puslatility index (PI) representing cerebral arterial resistance and subtypes of cSVD in patients with stroke due to small vessel occlusion (SVO). Hypothesis: Pattern of increased arterial resistance may be different between individual subtypes of cSVD. Methods: We included consecutive patients with SVO between 2010 and 2013. White matter hyperintensity (WMH) volume was rated using semi-automated quantitative methods. And the presence of old lacunar infarct (OLI), cerebral microbleed (CMB), or enlarged perivascular space (EPVS) was also evaluated. The relationship between PI, measured with transcranial Doppler sonography in each middle cerebral artery, and subtypes/burden of cSVD was analyzed in the relevant hemisphere. Results: A total of 206 patients with 412 hemispheres were included (mean age: 64 years, male: 68%). In multivariable analysis, PI was positively associated with the WMH volume [beta = 1.372, 95% confidence interval (CI) = 0.624 to 2.120, P &lt; 0.001] after adjusting confounders. PI was also related to the presence of OLI (adjusted odds ratio = 11.37, 95% CI = 2.55-48.56, P = 0.001), however this relationship was not significant in CMB or EPVS. Regarding to the cSVD burden, PI increased according to the WMH tertiles ( P for trend &lt; 0.001), and burden of OLI ( P for trend = 0.004) in a dose-response manner. Conclusion: Association of cerebral arterial resistance is different between subtypes of cSVD, which is suggestive of underlying pathophysiological difference. Simple measure of PI seems to be useful to estimate the arterial resistance and the burden of cSVD.

Abstract WP417: Relevance of Lobar Cerebral Microbleeds in Patients With Deep Intracerebral Hemorrhage

Background: Markers of cerebral small vessel disease (cSVD) severity and prognosis in strictly lobar or strictly deep intracerebral hemorrhages (ICH)/cerebral microbleeds (CMB) are well defined but data are scarce for mixed-location ICH/CMB. We aimed to compare neuroimaging features and outcomes between deep ICH patients with and without lobar CMBs. Methods: Patients with first-ever deep ICH from a prospectively maintained single-center registry were analyzed. Demographics, risk factors and neuroimaging markers of cSVD including CMBs, cortical superficial siderosis, enlarged perivascular spaces (EPVS), white matter hyperintensity volumes (WMH) and brain atrophy scores (range 0-15) were compared between deep ICH patients with lobar CMBs and those without lobar CMBs. The follow-up data were analyzed for ICH recurrence, ischemic stroke (IS) and all-cause mortality. Results: Of 208 patients, 98 (47.1%) had lobar CMBs. Patients with L-CMBs were older (65.3±12.1 vs. 57.4±12.5, p&lt;0.001) and more likely to be hypertensive (98% vs. 90.9%, p=0.037) than those without L-CMBs. Deep CMBs (83.7% vs 56.4%, p&lt;0.001), lacunes (53.1% vs 31.8%, p=0.003) and severe basal ganglia EPVS (40.8% vs 17.3%, p&lt;0.001) were more common in patients with L-CMBs. Patients with L-CMBs had higher volumes of WMH (17.4 ml [IQR 9-38] vs 4.8 ml [IQR 1-13], p&lt;0.001) and atrophy scores (4 [IQR 2-7] vs 3 [IQR 0-6], p=0.007) as compared to patients without L-CMBs. During a median follow-up of 21 months, the ICH recurrence rate was similar between groups (p=0.2), but higher incident IS (3.0 vs 0.0 per 1000-person-months, p=0.016) and all-cause mortality (4.9 vs 1.5 per 1000-person-months, p=0.026) were observed in patients with L-CMBs. In a cox regression model, the presence of lobar CMBs was independently associated with a composite outcome measure (ICH/IS/mortality) after adjusting for age, hypertension, WMH volume, lacune, BG-EPVS and atrophy scores (odds ratio: 2.9, 95%CI:1.01-8.4 p=0.046). Conclusions: Presence of lobar CMBs in patients with deep ICH is associated with parenchymal markers of more severe cSVD and poor prognosis, suggesting a more advanced vasculopathy compared to patients with strictly deep ICH.

Association between Enlarged Perivascular Spaces and Internal Carotid Artery Stenosis: A Study in Patients Diagnosed by Digital Subtraction Angiography

Objective: An enlarged perivascular space (EPVS) is an imaging marker of cerebral small vessel disease, and its relationship with large artery disease is elusive. We investigated the EPVS in patients with internal carotid artery stenosis (ICAS) with the use of digital subtraction angiography (DSA) and tested the relationship between the degree of EPVS and the degree of ICAS; as well as the relationship between the degree of EPVS and white matter hyperintensity (WMH). Method: A total of 202 patients with or without ICAS diagnosed by DSA were enrolled. The maximal ICAS rates, the degrees of EPVS and WMH were measured. The patients’ clinical characteristics and laboratory parameters were recorded. Univariable analysis and multivariable regression were used to test their correlations. In a unilateral stenosis subgroup, the EPVSs in the ipsilateral hemisphere of stenosis and in the contralateral hemisphere were compared. Results: According to univariable analysis, there were significant differences in age (P = .000), Hg1bc (P = .035) and folic acid (P = .008) among the subgroups based on the degrees of EPVS in the basal ganglia (BG). Age (P = .000) and the level of fibrinogen (P = .018) differed statistically among the subgroups based on the degrees of EPVS in the white matter (WM). The correlation between the degrees of WM-EPVS and the ICAS levels was tested with a gamma test: G = .280, P = .001. The ordinal multivariable regression model showed that age was independently associated with both BG-EPVSs and WM-EPVSs. A current smoker status was also independently associated with WM-EPVSs. ICAS level was associated with the severity of WM-EPVSs after adjusting for other risk factors. The degree of BG-EPVS was not correlated with the degree of stenosis. (P = .101). In 59 patients with unilateral ICAS, as tested by the Wilcoxon signed ranks test, the WM-EPVS scores in the ipsilateral hemisphere of stenosis were higher than those in the contralateral hemisphere. (P = .004), but there was no difference in BG-EPVSs (P = .070). Both BG-EPVSs and WM-EPVSs were independently correlated with WMH. Conclusions: BG-EPVSs and WM-EPVSs have different risk factors. WM-EPVSs but not BG-EPVSs are correlated with ICAS.

Insulin Resistance Is Independently Associated With Enlarged Perivascular Space in the Basal Ganglia in Nondiabetic Healthy Elderly Population.

To investigate the association between insulin resistance (IR) and enlarged perivascular space (EPVS) in the basal gangliain nondiabetic healthy elderly population. A total of 235 nondiabetic healthy elderly population were recruited. A 3-level scale was used to evaluate the burden of EPVSs. The homeostasis model assessment-estimated insulin resistance index (HOMA-IR) was used for IR estimation. Correlation between IR and severity of EPVS was assessed using the regression model after adjusting demographics and cardiovascular risk factors. The top quartile of HOMA-IR was 2.52, and 25.11% of patients showed IR. The proportion of patients with IR was higher in the moderate to severe EPVS group than in the mild group (36.51% vs 20.93%, P = .015). In multivariate logistic analysis, IR was positively correlated with the moderate to severe EPVS (adjusted odds ratio: 3.532, 95% confidence interval: 1.633-7.636, P = .001) after adjusting classical risk factors. Insulin resistance was independently correlated with EPVS in the basal ganglia in nondiabetic healthy elderly population.

Pathological characterization of T2*-weighted MRI contrast in the striatum of Huntington’s disease patients

Previous MRI studies consistently reported iron accumulation within the striatum of patients with Huntington’s disease (HD). However, the pattern and origin of iron accumulation is poorly understood. This study aimed to characterize the histopathological correlates of iron-sensitive ex vivo MRI contrast change in HD brains. To this end, T2*-weighted 7T MRI was performed on postmortem tissue of the striatum of three control subjects and 10 HD patients followed by histological examination. In addition, formalin-fixed paraffin-embedded material of three control subjects and 14 HD patients was selected for only histology to identify the cellular localization of iron using stainings for iron, myelin, microglia and astrocytes. As expected HD striata showed prominent atrophy. Compared to controls, the striatum of HD patients was in general more hypointense on T2*-weighted high-field MRI and showed a more intense histopathological staining for iron. In addition, T2*-weighted MRI identified large focal hypointensities within the striatum of HD patients. Upon histological examination, these large focal hypointensities frequently colocalized with enlarged perivascular spaces and iron was found within the vessel wall and reactive astrocytes. In conclusion, we show that the striatum of HD patients has a distinctive phenotype on T2*-weighted MRI compared to control subjects. On ex vivo MRI, these contrast changes are heavily biased by enlarged perivascular spaces from which it is currently unknown whether this is a fixation artefact or a disease specific observation. Clinically, the observation of iron within reactive astrocytes is of importance for the interpretation and understanding of the potential underlying mechanisms of T2*-weighted MRI results in HD patients.