Symptomatic Small Vessel Disease Research Articles

Are central and systemic inflammation associated with fatigue in cerebral small vessel disease?

Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET-MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (β = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. Data for this study are available from the corresponding author upon reasonable request.

Immune regulation and blood–brain barrier permeability in cerebral small vessel disease: study protocol of the INflammation and Small Vessel Disease (INSVD) study – a multicentre prospective cohort study

IntroductionThe INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood–brain barrier (BBB) permeability relate to disease progression in cerebral small vessel disease...

How often does white matter hyperintensity volume regress in cerebral small vessel disease?

It has been suggested that white matter hyperintensity lesions (WMHs), which typically progress over time, can also regress, and that this might be associated with favorable cognitive performance. We determined the prevalence of WMH regression in patients with cerebral small vessel disease (SVD) and examined which demographic, clinical, and radiological markers were associated with this regression. We used semi-automated lesion marking methods to quantify WMH volume at multiple timepoints in three cohorts with symptomatic SVD; two with moderate-to-severe symptomatic SVD (the SCANS observational cohort and the control arm of the PRESERVE interventional trial) and one with mild-to-moderate SVD (the RUN DMC observational cohort). Mixed-effects ordered logistic regression models were used to test which factors predicted participants to show WMH regression. No participants (0/98) in SCANS, 6/42 (14.3%) participants in PRESERVE, and 6/276 (2.2%) in RUN DMC showed WMH regression. On multivariate analysis, only lower WMH volume (OR: 0.36, 95% CI: 0.23-0.56) and better white matter microstructural integrity assessed by fractional anisotropy using diffusion tensor imaging (OR: 1.55, 95% CI: 1.07-2.24) predicted participant classification as regressor versus stable or progressor. Only a small proportion of participants demonstrated WMH regression across the three cohorts, when a blinded standardized assessment method was used. Subjects who showed regression had less severe imaging markers of disease at baseline. Our results show that lesion regression is uncommon in SVD and unlikely to be a major factor affecting the use of WMH quantification as an outcome for clinical trials.

Does tadalafil increase brain blood flow? The PASTIS trial

AbstractBackgroundThis trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely‐used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of vascular cognitive impairment.MethodIn a double‐blinded, placebo‐controlled, cross‐over trial, female and male participants received tadalafil (20mg) and placebo on two visits at least 7 days apart (randomized to order of treatment). The primary endpoint was change in subcortical CBF, with secondary outcome measures including change in cortical CBF and a panel of neuropsychological assays of cognition. The Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease (PASTIS) trial was funded by the ADDF and the UK Alzheimer’s Society (Clinical trial registration: clinicaltrials.gov/ct2/show/NCT02450253; eudract.ema.europa.eu/2015‐001235‐20).ResultTadalafil increased CBF non‐significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = 0.0960). There were incidental treatment effects on systolic and diastolic blood pressure (‐7.8, ‐4.9 mmHg respectively; P<0.001). No serious adverse events were observed.ConclusionThe PASTIS trial did not identify a significant treatment effect of single‐administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens.

Cognitive impact of cerebral microbleeds in patients with symptomatic small vessel disease.

Whether cerebral microbleeds cause cognitive impairment remains uncertain. We analyzed whether cerebral microbleeds are associated with cognitive dysfunction in patients with symptomatic cerebral small vessel disease, and whether this association is independent of other neuroimaging markers of cerebral small vessel disease. We analyzed consecutive patients with MRI-confirmed lacunar stroke included in DNA-Lacunar-2 multicenter study. Cerebral microbleeds were graded using the Brain Observer Microbleed Rating Scale (BOMBS). Neuropsychological assessment was performed using the Brief Memory and Executive Test (BMET). We analyzed the association between cerebral microbleeds, BMET, and the following subdomains: executive function/processing speed and orientation/memory. We also searched for an independent association between cerebral microbleeds and vascular cognitive impairment, defined as BMET ≤ 13. Out of 688 included patients, cerebral microbleeds were detected in 192 (27.9%). After adjusting for white matter hyperintensities severity, lacune count, and other confounders, both the presence and the number of cerebral microbleeds were significantly associated with impaired cognitive performance [β = -13.0; 95% CI = (-25.3, -0.6) and β = -13.1; 95% CI = (-19.8, -6.4), respectively]. On analysis of specific cognitive domains, associations were present for executive function/processing speed [β = -5.8; 95% CI = (-9.3, -2.2) and β = -4.3; 95% CI = (-6.2, -2.4), respectively] but not for orientation/memory [β = -0.4; 95% CI = (-4.0, 3.2) and β = -2.1; 95% CI = (-4.0, 0.1), respectively]. We also found an independent association between the presence and the number of cerebral microbleeds and vascular cognitive impairment [adjusted OR = 1.48; 95% CI = (1.01, 2.18) and OR = 1.43; 95% CI = (1.15, 1.79), respectively]. In a large cohort of symptomatic cerebral small vessel disease patients, after controlling for other neuroimaging markers of cerebral small vessel disease severity, cerebral microbleeds were associated with cognitive dysfunction. Executive function and processing speed were predominantly impaired. This might suggest a causal role of cerebral microbleeds in determining vascular cognitive impairment.

Do cerebral microbleeds affect cognition in patients with symptomatic small vessel disease?

BackgroundDementia and cognitive impairment are becoming increasingly a major health problem, pronounced by increased life expectancy. Cerebral small vessel disease (cSVD) is among the major causes of cognitive deterioration, yet cerebral microbleeds (CMBs) which are a common association of cSVD are still not sure to be related to cognition.Aim of the studyThe study aims to determine whether the number and localization of CMBs correlate with cognition in patients with symptomatic small vessel disease (SVD), according to Montreal Cognitive Assessment (MoCA) test.Subjects and methodsThis cross-sectional study included 85 Egyptian patients with symptomatic SVD, from the neuropsychiatry clinic of the Main Suez Hospital in Suez City, in the period between February 2017 and February 2018. Subjects were classified according to CMB presence into CMB-positive and CMB-negative groups. Both groups are assessed using MRI imaging and MoCA test for cognitive function.ResultsIn our study, CMBs recorded a high prevalence rate of SVD patients. Subjects with MBs were mainly males and significantly older, with higher white matter lesion volume and more lacunar infarcts. MoCA test detected significant impairment in visuospatial/executive function, attention, and total scores in CMB-positive group. Both frontal and parietal MBs showed independent association with visuospatial/executive impairment. Deep MBs in the basal ganglia were proved to be independent risk factor for attention affection.ConclusionNumber and localization of MBs proved to be important in determining cognitive consequences. The relations with cognitive performance were mainly driven by frontal, parietal, and deep located MBs in the basal ganglia. Memory affection in frontal MBs was dependent to severe white matter intensities and lacunes.

Texture Analysis of T1-Weighted and Fluid-Attenuated Inversion Recovery Images Detects Abnormalities That Correlate With Cognitive Decline in Small Vessel Disease.

Magnetic resonance imaging may be useful to assess disease severity in cerebral small vessel disease (SVD), identify those individuals who are most likely to progress to dementia, monitor disease progression, and act as surrogate markers to test new therapies. Texture analysis extracts information on the relationship between signal intensities of neighboring voxels. A potential advantage over techniques, such as diffusion tensor imaging, is that it can be used on clinically obtained magnetic resonance sequences. We determined whether texture parameters (TP) were abnormal in SVD, correlated with cognitive impairment, predicted cognitive decline, or conversion to dementia. In the prospective SCANS study (St George's Cognition and Neuroimaging in Stroke), we assessed TP in 121 individuals with symptomatic SVD at baseline, 99 of whom attended annual cognitive testing for 5 years. Conversion to dementia was recorded for all subjects during the 5-year period. Texture analysis was performed on fluid-attenuated inversion recovery and T1-weighted images. The TP obtained from the SVD cohort were cross-sectionally compared with 54 age-matched controls scanned on the same magnetic resonance imaging system. There were highly significant differences in several TP between SVD cases and controls. Within the SVD population, TP were highly correlated to other magnetic resonance imaging parameters (brain volume, white matter lesion volume, lacune count). TP correlated with executive function and global function at baseline and predicted conversion to dementia, after controlling for age, sex, premorbid intelligence quotient, and magnetic resonance parameters. TP, which can be obtained from routine clinical images, are abnormal in SVD, and the degree of abnormality correlates with executive dysfunction and global cognition at baseline and decline during 5 years. TP may be useful to assess disease severity in clinically collected data. This needs testing in data clinically acquired across multiple sites.

Involvement of the reward network is associated with apathy in cerebral small vessel disease

IntroductionApathy is a common yet under-recognised feature of cerebral small vessel disease (SVD), but its underlying neurobiological basis is not yet understood. We hypothesized that damage to the reward network is associated with an increase of apathy in patients with SVD. MethodsIn 114 participants with symptomatic SVD, defined as a magnetic resonance imaging confirmed lacunar stroke and confluent white matter hyperintensities, we used diffusion tensor imaging tractography to derive structural brain networks and graph theory to determine network efficiency. We determined which parts of the network correlated with apathy symptoms. We tested whether apathy was selectively associated with involvement of the reward network, compared with two “control networks” (visual and motor). ResultsApathy symptoms negatively correlated with connectivity in network clusters encompassing numerous areas of the brain. Network efficiencies within the reward network correlated negatively with apathy scores; (r = − 0.344, p < 0.001), and remained significantly correlated after co-varying for the two control networks. Of the three networks tested, only variability in the reward network independently explained variance in apathetic symptoms, whereas this was not observed for the motor or visual networks. LimitationsThe analysis refers only to cerebrum and not cerebellum. The apathy measure is derivative of depression measure. DiscussionOur results suggest that reduced neural efficiency, particularly in the reward network, is associated with increased apathy in patients with SVD. Treatments which improve connectivity in this network may improve apathy in SVD, which in turn may improve psychiatric outcome after stroke.

Identifying preclinical vascular dementia in symptomatic small vessel disease using MRI.

Sporadic cerebral small vessel disease is an important cause of vascular dementia, a syndrome of cognitive impairment together with vascular brain damage. At post-mortem pure vascular dementia is rare, with evidence of co-existing Alzheimer's disease pathology in 95% of cases. This work used MRI to characterize structural abnormalities during the preclinical phase of vascular dementia in symptomatic small vessel disease.121 subjects were recruited into the St George's Cognition and Neuroimaging in Stroke study and followed up longitudinally for five years. Over this period 22 individuals converted to dementia. Using voxel-based morphometry, we found structural abnormalities present at baseline in those with preclinical dementia, with reduced grey matter density in the left striatum and hippocampus, and more white matter hyperintensities in the frontal white-matter. The lacunar data revealed that some of these abnormalities may be due to lesions within the striatum and centrum semiovale.Using support vector machines, future dementia could be best predicted using hippocampal and striatal Jacobian determinant data, achieving a balanced classification accuracy of 73%. Using cluster ward linkage we identified four anatomical subtypes. Successful predictions were restricted to groups with lower levels of vascular damage. The subgroup that could not be predicted were younger, further from conversion, had the highest levels of vascular damage, with milder cognitive impairment at baseline but more rapid deterioration in processing speed and executive function, consistent with a primary vascular dementia. In contrast, the remaining groups had decreasing levels of vascular damage and increasing memory impairment consistent with progressively more Alzheimer's-like pathology. Voxel-wise rates of hippocampal atrophy supported these distinctions, with the vascular group closely resembling the non-dementing cohort, whereas the Alzheimer's like group demonstrated global hippocampal atrophy.This work reveals distinct anatomical endophenotypes in preclinical vascular dementia, forming a spectrum between vascular and Alzheimer's like pathology. The latter group can be identified using baseline MRI, with 73% converting within 5 years. It was not possible to predict the vascular dominant dementia subgroup, however 19% of negative predictions with high levels of vascular disease would ultimately develop dementia. It may be that techniques more sensitive to white matter damage, such as diffusion weighted imaging, may prove more useful for this vascular dominant subgroup in the future.This work provides a way to accurately stratify patients using a baseline MRI scan, and has utility in future clinical trials designed to slow or prevent the onset of dementia in these high-risk cohorts.

Prevention of Cerebral Small Vessel Disease.

AbstractCerebral small vessel disease can cause either ischemic stroke or intracerebral hemorrhage. Accounting for up to 25% of all strokes, it is also the second biggest contributor to the risk of dementia, and is the most common incidentally discovered finding on brain imaging. There are two main causes of cerebral small vessel disease: arteriolosclerotic small vessel disease (with hypertension as the main modifiable risk factor) and cerebral amyloid angiopathy (predominantly caused by β-amyloid deposits limited to the cerebral small arteries, arterioles, and capillaries). Prevention should include the treatment of hypertension and diabetes, if present, and the modification of lifestyle factors such as obesity and poor nutrition. Patients with small subcortical ischemic strokes should be treated with antithrombotics; dual antiplatelet therapy may be more effective than aspirin for the first 3 weeks following acute stroke, but is not more effective than aspirin for long-term prevention. Unresolved questions include the effectiveness of nonaspirin prevention strategies to prevent early recurrence or stroke extension in small subcortical ischemic stroke, and whether symptomatic or silent small vessel disease should influence decisions regarding selection for carotid revascularization or anticoagulation for atrial fibrillation. There is an unmet need for disease-modifying preventive therapies for cerebral amyloid angiopathy, the second most-common cause of spontaneous intracerebral hemorrhage.

Use of MRI to identify preclinical vascular dementia in symptomatic small vessel disease

BackgroundSporadic cerebral small vessel disease is an important cause of vascular dementia, and is a syndrome of cognitive impairment with evidence of vascular brain damage. At post-mortem examination pure vascular dementia is rare, with coexisting Alzheimer's disease pathology in 95% of cases. We aimed to use MRI to characterise the structural abnormalities during the preclinical phase of vascular dementia in symptomatic small vessel disease, and use these characteristics to accurately predict the development of future dementia. Methods121 adults with symptomatic small vessel disease were initially recruited to the St George's Cognition and Neuroimaging in Stroke (SCANS) study and followed up longitudinally for 5 years, with 22 individuals converting to dementia. Baseline T1-weighted MRI data were acquired for all 121 partcipants. Voxel-based morphometry was used to identify differences in patients with preclinical vascular dementia. Support vector machines were then used to predict future dementia from the baseline scans. Anatomical endophenotypes were defined using cluster ward linkage. FindingsWe found reduced grey matter density in the left striatum and hippocampus, and more white matter hyperintensities in the frontal white matter, in preclinical dementia. Future dementia could be predicted with a balanced accuracy of 73%. Four anatomical subtypes were identified. In one of them, patients were younger than those in the other three groups and had the highest levels of vascular damage; they also had milder cognitive impairment but rapid deterioration in processing speed and executive function, consistent with primary vascular dementia. The other groups had progressively less vascular damage and increasing memory impairment consistent with more Alzheimer's like pathology. The rates of hippocampal atrophy supported these groupings, with the vascular group resembling the cohort that did not develop dementia, and the Alzheimer's like group demonstrating more global hippocampal atrophy. InterpretationWe show that baseline MRI can reliably predict preclinical vascular dementia, with 73% of patients converting to dementia within 5 years. MRI can identify distinct anatomical endophenotypes representing a spectrum between vascular and Alzheimer's like pathology. This work provides a way to accurately stratify patients by use of a baseline MRI scan, and has utility in future clinical trials designed to slow or prevent the onset of dementia in these high-risk cohorts. FundingThe SCANS study was supported by the Wellcome Trust (grant 081589). Patient recruitment was supported by the National Institute for Health Research (NIHR) Clinical Stroke Research Network.

Abstract TP407: Effects of Remote Ischemic Conditioning on Cerebral Small Vessel Disease Outcomes

Objective: To evaluate the preliminary efficacy of remote ischemic conditioning (RIC) on patients with cerebral small vessel disease (SVD). Methods: Thirty patients diagnosed with symptomatic SVD within 30 days of onset were enrolled in this prospectively randomized controlled study for 1 year. All patients received routine medical treatment including treating vascular risk factors according to the guideline. Patients in the experimental group (n=14) were administered 5 cycles consisting of ischemia followed by reperfusion for 5 minutes on bilateral upper limbs twice daily for 1 year. Those in the control group (n=16) underwent sham ischemia-reperfusion cycles. Primary outcome was the change of cognitive function measured by mini-mental state examination (MMSE) and montreal cognitive assessment scale (MoCA), and secondary outcomes were changes of plasma biomarkers, cerebral hemodynamic parameters measured by vascular ultrasound and brain lesions measured by MRI FLAIR both at baseline and at the end of 1 year visit. Results: Compared with patients in the control group, patients in the RIC group had higher flow velocity (FV), and lower pulsatility index (PI), but without statistical difference. Patients in the RIC group had improvement in visuospatial and executive abilities (3.86±1.03 vs. 4.43±0.85, p=0.026), reduced plasma triglyceride (1.60±0.74 vs. 1.25±0.38, p=0.019), low density lipoprotein (2.89±0.81 vs. 2.26±0.67, p=0.003) and homocysteine (15.66±10.11 vs. 13.66±9.80 p=0.017). Similarly in the RIC group, the diastolic flow velocity (DFV) of middle cerebral artery (MCA) (right: 33.93±7.67 vs. 36.93±6.12, p=0.032; left: 33.93±7.67 vs. 36.93± 6.12, p=0.032) and the mean flow velocity (MFV) of left MCA (35.00±5.04 vs. 39.50±5.59, p=0.003) increased, and the PI of MCA (right: 1.11±0.19 vs. 1.02±0.14 p=0.030; left: 1.10±0.22 vs. 0.99±0.14, p=0.037) decreased. Conclusion: RIC appears to be potentially effective for improving cognition, enhancing cerebral perfusion, and modifying vascular risk factors in SVD patients. Further studies focusing on long-term neurological outcomes and potential mechanisms underlying RIC on SVD patients are needed.

Cerebral blood flow and metabolism associated with cerebral microbleeds in small vessel disease.

Cerebral microbleeds (CMBs), probably reflecting microangiopathy, have not yet sufficiently been examined in association with cerebral blood flow (CBF) and metabolism. We investigated the relationships between CMBs, and CBF and metabolism in symptomatic small vessel disease. We enrolled 22 patients with symptomatic small vessel disease without severe stenosis (>50%) in major cerebral arteries. Volumes of white matter lesions (WMLs) and number of CMBs were assessed on images of fluid-attenuated inversion recovery and gradient-echo T2*-weighted magnetic resonance imaging, respectively. Patients were divided into two groups according to the median number of CMBs (group I <5, n=10; group II ≥5, n=12). Parametric images of CBF, cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction and cerebral blood volume were estimated using positron emission tomography and (15)O-labeled gases. The functional values in the cortex-subcortex, basal ganglia, and centrum semiovale were compared between the two groups. Volumes of WMLs of group II were larger than those of group I (median: 38.4; range: 25.1-91.5mL vs. median: 11.3; range: 4.2-73.4mL, p=0.01). In the centrum semiovale, the mean CBF of group II was significantly lower than that of groupI (12.6±2.6 vs. 15.6±3.3mL/100g/min, p=0.04). In the other regions, there were no significant differences in either CBF or CMRO2 between the two groups. Our study indicated that increases in the number of CMBs with larger volumes of WMLs were associated with cerebral ischemia in the deep white matter in patients with symptomatic small vessel disease.

Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease.

Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson's R = -0.69, P < 1 × 10(-7)), and significant grey matter loss and whole brain atrophy occurs annually (P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity progression is associated with increases in cortical grey matter atrophy rates, in the medial-frontal, orbito-frontal, parietal and occipital regions. Conversely, increased rates of global grey matter atrophy are significantly associated with faster white matter hyperintensity growth in the frontal and parietal regions. Together, these results link the progression of white matter hyperintensities with increasing rates of regional grey matter atrophy, and demonstrate that grey matter atrophy is the major contributor to whole brain atrophy in symptomatic cerebral small vessel disease. These measures provide novel insights into the longitudinal pathogenesis of small vessel disease, and imply that therapies aimed at reducing progression of white matter hyperintensities via end-arteriole damage may protect against secondary brain atrophy and consequent functional morbidity.

Application of Diffusion Tensor Imaging Parameters to Detect Change in Longitudinal Studies in Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) is the major cause of vascular cognitive impairment, resulting in significant disability and reduced quality of life. Cognitive tests have been shown to be insensitive to change in longitudinal studies and, therefore, sensitive surrogate markers are needed to monitor disease progression and assess treatment effects in clinical trials. Diffusion tensor imaging (DTI) is thought to offer great potential in this regard. Sensitivity of the various parameters that can be derived from DTI is however unknown. We aimed to evaluate the differential sensitivity of DTI markers to detect SVD progression, and to estimate sample sizes required to assess therapeutic interventions aimed at halting decline based on DTI data. We investigated 99 patients with symptomatic SVD, defined as clinical lacunar syndrome with MRI confirmation of a corresponding infarct as well as confluent white matter hyperintensities over a 3 year follow-up period. We evaluated change in DTI histogram parameters using linear mixed effect models and calculated sample size estimates. Over a three-year follow-up period we observed a decline in fractional anisotropy and increase in diffusivity in white matter tissue and most parameters changed significantly. Mean diffusivity peak height was the most sensitive marker for SVD progression as it had the smallest sample size estimate. This suggests disease progression can be monitored sensitively using DTI histogram analysis and confirms DTI’s potential as surrogate marker for SVD.

Carotid artery wall stiffness is increased in patients with small vessel disease: A case-control study

Cerebral ischemic small-vessel disease (SVD), causing lacunar infarcts and white matter hyperintensities on brain magnetic resonance imaging (MRI), is a progressive disease associated with an increased risk of stroke, dementia and death. Increased arterial stiffness has been associated with ischemic stroke and cerebral SVD independently of common vascular risk factors. The aim of the study was to analyze arterial stiffness in our patients with symptomatic SVD. In a cross-sectional study design we included 30 patients with clinical and MRI evidence of cerebral SVD and 30 age-, gender- and risk factor-matched control subjects with no neurological diseases. Patients were evaluated at the Ultrasound Laboratory at the Neurology Clinic, Clinical Center of Serbia in Belgrade, during a three-month period (from September 1st to December 1st 2012). Baseline demographic and vascular risk factors were recorded. All patients underwent standard carotid ultrasound scans with measuring of intima-media thickness (IMT) and analysis of atheromatous plaques. Internal carotid artery stiffness was evaluated with the use of e-tracking option as beta stiffness index (BSI) value. There were no differences between study groups in regard to degree of carotid stenosis and type of carotid plaques (p > 0.05). Patients in SVD group had significantly higher mean IMT (p = 0.0093) and mean BSI (p < 0.0001) than subjects in the control group. No significant correlation was detected between IMT and BSI in SVD group (r = 0.168; p = 0.376). Brain lesions severity correlated with BSI (r = 0.733; p < 0.0001). Arterial stiffness is increased in symptomatic patients with SVD, independently of vascular risk factors and IMT.

Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.

We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

Letter by Huijts et al Regarding Article, “Cerebral Microbleeds and Cognition in Patients With Symptomatic Small Vessel Disease”

With interest we read the article by Patel et al1 about the effect of cerebral microbleeds (CMBs) on several cognitive domains in patients with symptomatic cerebral small vessel disease. The purpose of the study was to determine associations between cognition and presence, number and location of CMBs, and whether associations were independent of other imaging markers of cerebral small vessel disease. A homogeneous group of patients with lacunar stroke with white matter lesions was included. The results showed that the number of CMBs was weakly related to executive function, but not to other cognitive domains. Strikingly, the relationship between CMBs and cognition has not been studied before in patients with lacunar stroke, so this study really adds to the existing literature. However, there are some issues we would …

Cerebral Microbleeds and Cognition in Patients With Symptomatic Small Vessel Disease

Cerebral microbleeds (CMBs) are common in cerebral small vessel disease. They may cause cognitive impairment, possibly via white matter tract disruption but previous studies have produced inconsistent results. We determined whether CMB number and location are associated with impaired cognition in symptomatic small vessel disease and whether any association was independent of other magnetic resonance imaging markers of small vessel disease. One hundred sixteen patients with lacunar stroke and radiological leukoaraiosis were studied. Neuropsychological assessment was performed. CMBs on gradient echo images were assessed using the Brain Observer Microbleed Rating Scale criteria. Magnetic resonance imaging measures, including diffusion tensor imaging, were also analyzed. Associations between cognitive function and the presence, number, and location of CMBs were determined. CMBs were present in 46 (39.7%) patients. CMB number correlated weakly with executive function (r=0.22; P=0.022) but not with other cognitive indices. CMBs count in the top decile (≥ 9 CMB, N=12) was more strongly associated with poor executive function; this association remained significant after controlling for T2-lesion load, brain volume, lacune count, and mean diffusivity (b=-0.51; P=0.043). In symptomatic small vessel disease, CMB number was weakly associated with executive dysfunction. There seemed to be a threshold effect with the association being largely accounted for by an association of impaired executive function with high CMB count. No association of CMBs with other cognitive domains, including processing speed, was found.

What are the differences between younger and older patients with symptomatic small vessel disease?

Objective Although typically linked to aging, small vessel disease (SVD) is also observed in younger adult patients, with common vascular risk factors (RF). We aimed to investigate features of SVD occurrence at an early adult age. Patients and methods Vascular RF, functional and cognitive status and severity of lesions on MRI expressed as total score on Age-Related White Matter Changes (ARWMC) scale were analyzed in 200 consecutive patients with cerebral SVD admitted to a tertiary neurological hospital. Variables were compared between younger (35–55 years) and older (>56 years) patients. Results In this study, 63 (31.5%) of patients were 55 years or younger. Both age groups had comparable RF profiles, but smoking emerged as an independent predictor for SVD at a younger age (OR 2.9; 95% CI 1.5–5.5; p = 0.002). Younger patients had better functional (OR 1.8; 95% CI 1.3–2.5; p = 0.0001) and cognitive ( χ 2 13.94; p = 0.0009) status compared to older patients. However, two thirds of younger patients had some degree of cognitive deficit. Total score on ARWMC scale was lower in younger patients (mean 12.3 in younger versus 15.2 in older, OR 1.11; 95% CI 1.0–1.18; p = 0.001). There was a strong correlation in both groups between functional score, cognitive status and ARWMC score ( p < 0.0001). Conclusion In our dataset, younger patients with SVD shared common vascular RF with older patients. In the group aged ≤55, better functional and cognitive status and less severe MRI changes were noted. However, a substantial number of younger SVD patients presenting with TIA or ischemic stroke had various deficits.