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Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is associated with early-onset stroke and dementia. Whether its clinical phenotype is becoming milder with better risk factor treatments and other care improvements is unknown. In a large longitudinal CADASIL cohort, we determined whether the prognosis has changed over 23 years., Methods: Patients were identified from the Cambridge CADASIL register and the UK Familial stroke study. Change in age at stroke over the time of recruitment was determined using linear mixed-effects model, and the impact of genetic and vascular risk factors on stroke and dementia risk was further evaluated using Cox proportional hazard regression., Results: A total of 555 patients with CADASIL were recruited between 2001 and 2023. The age of stroke onset significantly increased over time (p<0.001), with the mean age of stroke onset for patients recruited before 2016 (n=265) at 46.7±9.2 years and 51.6±9.5 years for those recruited since 2016 (n=290). Patients recruited since 2016 had lower risks of both stroke (HR 0.36, 95% CI 0.26 to 0.50, p<0.001) and dementia (HR 0.43, 95% CI 0.19 to 0.99, p=0.046) after adjusting for sex, hypertension history, smoking status, epidermal growth factor-like repeat position and calendar effect., Conclusions: The clinical phenotype of CADASIL is improving. While this may be partly explained by reduced vascular risk factors such as smoking and the identification of milder cases, differences persisted after controlling for risk factors and mutation sites. These updated risk estimates should be used when counselling patients with CADASIL on prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD., Methods: Cognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen., Results: At baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p<0.001), periventricular (p<0.001) and deep (p=0.012) WMH progression, and increased CRP (p=0.017). Assessment of individual CAIDE components suggested that markers were driven by different risk factors (WMH/EPVS: age/hypertension, lacunes/deep microbleeds: hypertension/obesity). Interaction analyses demonstrated that higher CAIDE scores amplified the effect of age on SVD, and the effect of WMH on poorer memory., Conclusion: Higher CAIDE scores, indicating greater risk of dementia, predicts future progression of both WMH and systemic inflammation. Findings highlight the CAIDE score's potential as both a prognostic and predictive marker in the context of cerebrovascular disease, identifying at-risk individuals who might benefit most from managing modifiable risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: It has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but also in mild cognitive impairment. To determine whether DTI measures were associated with cognition cross-sectionally and predicted future dementia risk across the full range of SVD severity, we established the International OPtimising mulTImodal MRI markers for use as surrogate markers in trials of Vascular Cognitive Impairment due to cerebrAl small vesseL disease collaboration which included six cohorts., Methods: Among the six cohorts, prospective data with dementia incidences were available for three cohorts. The associations between six different DTI measures and cognition or dementia conversion were tested. The additional contribution to prediction of other MRI markers of SVD was also determined., Results: The DTI measure mean diffusivity (MD) median correlated with cognition in all cohorts, demonstrating the contribution of WM damage to cognition. Adding MD median significantly improved the model fit compared to the clinical risk model alone and further increased in all single-centre SVD cohorts when adding conventional MRI measures. Baseline MD median predicted dementia conversion. In a study with severe SVD (SCANS) change in MD median also predicted dementia conversion. The area under the curve was best when employing a multimodal MRI model using both DTI measures and other MRI measures., Conclusions: Our results support a central role for WM alterations in dementia pathogenesis in all cohorts. DTI measures such as MD median may be a useful clinical risk predictor. The contribution of other MRI markers varied according to disease severity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: White matter hyperintensities (WMHs) are a highly prevalent MRI marker of cerebral small vessel disease (SVD), which predict stroke and dementia risk, and are being increasingly used as a surrogate marker in clinical trials. However, the influence of study population selection on WMH progression rate has not been studied and the effect of individual patient factors for WMH growth are not fully understood., Methods: We performed a systematic review and meta-analysis of the literature on progression of WMHs in longitudinal studies to determine rates of WMH growth, and how these varied according to population characteristics and cardiovascular risk factors. We used these data to calculate necessary sample sizes for clinical trials using WMH as an endpoint., Results: WMH growth rate was highest in SVD (2.50cc/year), intermediate in unselected stroke patients (1.29cc/year) and lower in patients with non-stroke cardiovascular disease, and with cognitive impairment. Age was significantly associated with progression (correlation coefficient 0.15cc/year, 95% CI 0.02 to 0.28cc/year) as was baseline lesion volume (0.6cc/year, 95% CI 0.13 to 1.06 cc/year). Both hypertension (OR 1.72, 95% CI 1.19 to 2.46) and current smoking (OR 1.48, 95% CI 1.02 to 2.16) were associated with WMH growth. Sample sizes for a clinical trial varied greatly with patient population selection and baseline lesion volume; estimates are provided., Conclusions: WMH progression varies markedly according to the characteristics of the population being studied and this will have a major impact on sample sizes required in a clinical trial. Our sample size estimates provide data for planning clinical trials using WMH as an outcome measure., Prospero Registration Number: CRD42020191781., Competing Interests: Competing interests: The authors declare that the research was conducted in the absence of any personal, professional or financial relationships that would constitute a potential conflict of interest., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remain unclear., Methods: Cysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls., Results: Of 200 632 participants with exome sequencing data available, 443 (~1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjustment for various covariates, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0004) and vascular dementia (OR: 5.00, p=0.007), and increased white matter hyperintensity volume (standardised difference: 0.52, p<0.001) and white matter ultrastructural damage on diffusion MRI (standardised difference: 0.72, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 5.97, p<0.001) and cerebral microbleeds (OR: 4.38, p<0.001). White matter hyperintensity prevalence was most increased in the anterior temporal lobes (OR: 7.65, p<0.001) and external capsule (OR: 13.32, p<0.001)., Conclusions: Cysteine-changing NOTCH3 variants are more common in the general population than expected from CADASIL prevalence and are risk factors for apparently 'sporadic' stroke and vascular dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Serum neurofilament light chain (NfL) has been proposed as prognostic markers in neurogenerative disease. A cross-sectional study in cerebral small vessel disease (SVD) reported an association with cognition and disability. If NfL is to be used to predict outcome, studies are required to demonstrate baseline NfL predicts future dementia risk. Furthermore, if it is to be used as a surrogate marker in clinical trials, change in NfL over time periods typical of a clinical trial must be linked to clinical progression. In a longitudinal study of patients with lacunar stroke and confluent white matter hyperintensities, we determined whether both baseline, and change, in NfL levels were linked to changes in MRI markers, cognitive decline and dementia risk., Methods: Patients underwent MRI, cognitive testing and blood taking at baseline and annually for 3 years. Clinical and cognitive follow-up continued for 5 years., Results: NfL data were available for 113 subjects for baseline analysis, and 90 patients for the longitudinal analysis. Baseline NfL predicted cognitive decline (global cognition β = -0.335, SE=0.094, p=0.001) and risk of converting to dementia (HR=1.676 (95% CI 1.183 to 2.373), p=0.004). In contrast to imaging, there was no change in NfL values over the follow-up period., Conclusions: Baseline NfL predicts changes in MRI markers, cognitive decline and dementia rate over a 5 years follow-up period in SVD, suggesting NfL may be a useful prognostic marker. However, change in NfL values was not detected, and therefore NfL may not be a useful surrogate marker in clinical trials in SVD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [ 11 C]PK11195 positron emission tomography (PET) imaging., Methods: Forty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer's disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [ 11 C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [ 11 C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [ 11 C]PK11195., Results: Global [ 11 C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [ 11 C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66-0.76, t=3.90-5.58, FDR-corrected p (p FDR )=<0.001-0.002) and orbitofrontal cortex (β=0.51-0.57, t=3.53-4.30, p FDR =0.001-0.004)., Conclusion: Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: To determine whether apathy or depression predicts all-cause dementia in small vessel disease (SVD) patients., Methods: Analyses used two prospective cohort studies of SVD: St. George's Cognition and Neuroimaging in Stroke (SCANS; n=121) and Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC; n=352). Multivariate Cox regressions were used to predict dementia using baseline apathy and depression scores in both datasets. Change in apathy and depression was used to predict dementia in a subset of 104 participants with longitudinal data from SCANS. All models were controlled for age, education and cognitive function., Results: Baseline apathy scores predicted dementia in SCANS (HR 1.49, 95% CI 1.05 to 2.11, p=0.024) and RUN DMC (HR 1.05, 95% CI 1.01 to 1.09, p=0.007). Increasing apathy was associated with dementia in SCANS (HR 1.53, 95% CI 1.08 to 2.17, p=0.017). In contrast, baseline depression and change in depression did not predict dementia in either dataset. Including apathy in predictive models of dementia improved model fit., Conclusions: Apathy, but not depression, may be a prodromal symptom of dementia in SVD, and may be useful in identifying at-risk individuals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To investigate whether longitudinal structural network efficiency is associated with cognitive decline and whether baseline network efficiency predicts mortality in cerebral small vessel disease (SVD)., Methods: A prospective, single-centre cohort consisting of 277 non-demented individuals with SVD was conducted. In 2011 and 2015, all participants were scanned with MRI and underwent neuropsychological assessment. We computed network properties using graph theory from probabilistic tractography and calculated changes in psychomotor speed and overall cognitive index. Multiple linear regressions were performed, while adjusting for potential confounders. We divided the group into mild-to-moderate white matter hyperintensities (WMH) and severe WMH group based on median split on WMH volume., Results: The decline in global efficiency was significantly associated with a decline in psychomotor speed in the group with severe WMH (β=0.18, p=0.03) and a trend with change in cognitive index (β=0.14, p=0.068), which diminished after adjusting for imaging markers for SVD. Baseline global efficiency was associated with all-cause mortality (HR per decrease of 1 SD 0.43, 95% CI 0.23 to 0.80, p=0.008, C-statistic 0.76)., Conclusion: Disruption of the network efficiency, a metric assessing the efficiency of network information transfer, plays an important role in explaining cognitive decline in SVD, which was however not independent of imaging markers of SVD. Furthermore, baseline network efficiency predicts risk of mortality in SVD that may reflect the global health status of the brain in SVD. This emphasises the importance of structural network analysis in the context of SVD research and the use of network measures as surrogate markers in research setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The overall population benefit of intravascular recombinant tissue plasminogen activator (rtPA) on functional outcome in ischaemic stroke is clear, but there are some treated patients who are harmed by early symptomatic intracranial haemorrhage (ICH). Although several clinical and radiological factors increase the risk of rtPA-related ICH, none of the currently available risk prediction tools are yet useful for practical clinical decision-making, probably reflecting our limited understanding of the underlying mechanisms. Finding new methods to identify patients at highest risk of rtPA-related ICH, or new measures to limit risk, are urgent challenges in acute stroke therapy research. In this article, we focus on the potential underlying mechanisms of rtPA-related ICH, highlight promising candidate risk biomarkers and suggest future research directions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Aim: The pathogenesis of cerebral small-vessel disease (SVD) is incompletely understood. Endothelial dysfunction has been implicated and may result in increased blood-brain barrier (BBB) permeability with leakage of blood constituents into the vessel wall and white matter. We used contrast-enhanced MRI to determine whether there was any evidence for BBB permeability in the white matter of patients with SVD, and whether this was present not only in areas of leucoaraiosis (white-matter lesions) but also in normal-appearing white matter (NAWM)., Methods: Subjects underwent T1 volumetric MRI before and after bolus injection of contrast. Scanning was continued for 30 min postinjection to determine the contrast-enhancement time course. The mean signal intensity change was plotted against time to calculate the area under the curve values, a parameter related to BBB permeability. Automated brain segmentation and regions of interest analysis were performed to determine 'permeability' in different brain compartments., Results: Compared with controls (n=15), the SVD patient group (n=24) had signal changes consistent with increased BBB permeability in NAWM (p=0.033). Multivariate regression analyses identified leucoaraiosis grade as an independent predictor of these permeability related signal changes in NAWM after adjustment for age, gender, weight, brain volume, area under the curve in the internal carotid arteries and cardiovascular risk factors., Conclusion: This study provides evidence for increased BBB permeability in SVD, and this is particularly seen in SVD with leucoaraiosis. Its presence in NAWM would be consistent with it playing a causal role in disease pathophysiology.

Background: Diffusion tensor imaging (DTI) is a sensitive method for detecting white matter damage, and in cross sectional studies DTI measures correlate with age related cognitive decline. However, there are few data on whether DTI can detect age related changes over short time periods and whether such change correlates with cognitive function., Methods: In a community sample of 84 middle-aged and elderly adults, MRI and cognitive testing were performed at baseline and after 2 years. Changes in DTI white matter histograms, white matter hyperintensity (WMH) volume and brain volume were determined. Change over time in performance on tests of executive function, working memory and information processing speed were also assessed., Results: Significant change in all MRI measures was detected. For cognition, change was detected for working memory and this correlated with change in DTI only. In a stepwise regression, with change in working memory as the dependent variable, a DTI histogram measure explained 10.8% of the variance in working memory. Change in WMH or brain volume did not contribute to the model., Conclusions: DTI is sensitive to age related change in white matter ultrastructure and appears useful for monitoring age related white matter change even over short time periods.

Background: It has been suggested that impaired cerebral autoregulation and vasodilatory capacity may play in role in the pathogenesis of the leukoaraiosis seen in small vessel disease. Adequate perfusion of the deep white matter of the brain depends on the relationships between blood pressure (BP), cerebral vasoreactivity and autoregulation., Methods: 24 h ambulatory BP measurement, quantitative volumetric MRI analysis of white matter lesion (WML) volume and transcranial Doppler ultrasound assessments of CO(2) reactivity in response to hypercapnia and dynamic cerebral autoregulatory index (ARI) were undertaken in 64 patients with cerebral small vessel disease., Results: Subjects had mean 24 h BP 133/76 mm Hg (SD 13/9), median WML volume 7169 (IQR 20497) mm(3), mean CO(2) reactivity 83.6 (SD 37.4)% and mean ARI 5.6 (SD 1.4) (range 0-9). In multivariate models, after adjusting for age, gender, vascular risk profile and WML volume, ARI correlated with 24 h mean BP levels (R(2) = 0.127, t = 2.440, p = 0.019) and CO(2) reactivity correlated with duration of hypertension (R(2) = 0.085, t = -2.244, p = 0.029). In individuals with hypertension for more than 10 years, ARI also correlated with nocturnal BP dipping (r = 0.806, p = 0.002). ARI and CO(2) reactivity were unaffected by WML volumes, and ARI and CO(2) reactivity were unrelated., Conclusion: Cerebral autoregulation and CO(2) reactivity are two distinct processes which are not related to WML volume but are related to BP levels and duration of hypertension, respectively. Greater nocturnal dipping was associated with higher ARI values, suggesting preservation of autoregulation in patients with increased vulnerability to reduced cerebral perfusion.

Background and Purpose: Cervical dissection is an important cause of stroke in the young. This paper presents a systematic review and a meta-analysis to assess the effectiveness of different treatment approaches: antithrombotic drugs, thrombolysis and stenting., Methods: Medline and PubMed were searched from 1966 to 8 April 2007. Reference lists were reviewed. Separate searches were performed for treatment with anticoagulation and antiplatelet therapy during the acute phase (within 1 month of symptoms), thrombolysis and stenting., Results: There were only sufficient data for meta-analysis for the comparison of antiplatelet versus anticoagulation therapy. No randomised trials were identified. 34 non-randomised studies included 762 patients. There was no significant difference in risk of death (antiplatelet 5/268 (1.8%), anticoagulation 9/494 (1.8%), p = 0.88); stroke (antiplatelet 5/268 (1.9%), anticoagulant 10/494 (2.0%), p = 0.66), or stroke and death. Four non-randomised studies of thrombolysis provided insufficient data for assessment of efficacy but complication rates were no greater than thrombolysis for other ischaemic stroke. Six studies included 96 patients undergoing stenting for both acute dissection and chronic complications, providing insufficient data for assessment of efficacy, although complication rates appeared similar to those published for carotid atherosclerosic stenosis., Conclusions: There are no data to support the therapeutic superiority of anticoagulants over antiplatelet agents. Thrombolysis in dissection appears safe but more data on efficacy are required. Stenting is technically possible but there are no data to demonstrate efficacy. There is little evidence to support current treatment approaches in cervical dissection. Randomised controlled prospective trials, particularly assessing anticoagulation versus antiplatelet agents, are required.

Background and Purpose: Posterior circulation stroke accounts for 20% of ischaemic strokes. Recent data suggest that the early stroke recurrence risk is high and comparable with carotid artery disease. Vertebral artery stenosis accounts for approximately 20% of posterior circulation stroke, and with endovascular treatment available accurate diagnostic imaging is important. We performed a systematic literature review to validate the accuracy of the non-invasive imaging techniques Duplex ultrasound (DUS), magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) in detecting severe vertebral artery stenosis, with intra-arterial angiography (IAA) as the reference standard., Methods: We identified studies that used non-invasive imaging and IAA as the reference standard to determine vertebral artery stenosis and provided adequate data to calculate sensitivity and specificity. We analysed the quality of these studies, looked for evidence of heterogeneity and performed subgroup analysis for different degrees of stenosis., Results: 11 studies categorised stenosis into 50-99%. The sensitivity of CTA (single study) and pooled sensitivities of contrast enhanced MRA (CE-MRA) and colour duplex were 100% (95% CI 15.8 to 100), 93.9% (79.8 to 99.3) and 70.2% (54.2 to 83.3), respectively. The specificities for CTA, CE-MRA and colour duplex were 95.2% (83.8 to 99.4), 94.8% (91.1 to 97.3) and 97.7% (95.2 to 99.1). However, specificities for CE-MRA and colour duplex demonstrated significant heterogeneity (p = 0.003 and p = 0.002, respectively)., Conclusions: CE-MRA and possibly CTA may be more sensitive in diagnosing vertebral artery stenosis than DUS. However, data are limited and further high quality studies comparing DUS, MRA and CTA with IAA are required.

Background: The mechanisms of cerebral small vessel disease (SVD) are unclear. Both atherosclerosis and a non-atherosclerotic diffuse arteriopathy have been reported pathologically. Two pathological and radiological subtypes have been suggested: localised atherosclerotic disease in larger perforating arteries causing larger lacunar infarcts without leukoaraiosis, and diffuse disease in smaller arterioles causing multiple smaller lacunar infarcts with leukoaraiosis. If atherosclerosis were important in SVD as a whole or in one particular subtype, one would expect the risk factor profile to be similar to that of cerebral large vessel disease (LVD)., Methods: Risk factor profiles were compared in Caucasian stroke patients with SVD (n = 414), LVD (n = 471) and 734 stroke-free Caucasian population controls. Patients with SVD were subdivided according to the presence or absence of confluent leukoaraiosis, into isolated lacunar infarction (ILI) and ischaemic leukoaraiosis (ILA)., Results: Hypertension was commoner in SVD than LVD (odds ratio (OR) 3.43 (2.32 to 5.07); p<0.001) whereas hypercholesterolaemia (OR 0.34 (0.24 to 0.48); p<0.001), smoking (OR 0.63 (0.44 to 0.91); p = 0.012), myocardial infarction (OR 0.35 (0.20 to 0.59); p<0.001) and peripheral vascular disease (OR 0.32 (0.20 to 0.50); p<0.001) were commoner in LVD. Among SVD patients, age (OR 1.11 (1.09 to 1.14); p<0.001) and hypertension (OR 3.32 (1.56 to 7.07); p = 0.002) were associated with ILA and hypercholesterolaemia (OR 0.45 (0.28 to 0.74); p = 0.002), diabetes (OR 0.42 (0.21 to 0.84); p = 0.014) and myocardial infarction (OR 0.18 (0.06 to 0.52); p = 0.001) with ILI., Conclusion: SVD has a different risk factor profile from the typical atherosclerotic profile found in LVD, with hypertension being important. There are differences in the risk factor profile between the SVD subtypes; the association of ILI with hypercholesterolaemia, diabetes and myocardial infarction may be consistent with a more atherosclerotic aetiology.

Background: Cerebral small vessel disease is a common cause of cognitive impairment and vascular dementia. The cognitive deficit differs from that in Alzheimer's disease, with greater executive/attentional dysfunction and relatively intact episodic memory., Objective: To develop brief assessment tools that are better adapted to the neuropsychological profile of cerebral small vessel disease., Methods: 32 subjects with ischaemic leukoaraiosis (history of lacunar stroke and leukoaraiosis on MRI), aged 50 to 84 years, and 17 age and education matched controls had a brief executive assessment, which took 20 minutes to administer, and a wide range of additional tests. The ability of the brief executive assessment to discriminate between groups-both individually and in combination-was evaluated and compared with that of the whole battery., Results: The brief executive assessment provided good sensitivity and specificity for identifying subjects with ischaemic leukoaraiosis (sensitivity 88%, specificity 88%, using the optimal combination of scores). The best individual tests were trail making and digit symbol, which were both far more sensitive than the mini-mental state examination (MMSE). The ability to discriminate between groups was maintained in subjects with MMSE > 27 and across the whole age range. The brief executive assessment performed well compared with the whole battery, with additional tests accounting for only a further 12% of between-group variance., Conclusions: The brief executive assessment was sensitive to deficits found in ischaemic leukoaraiosis and discriminated them from the cognitive effects of healthy aging. The assessment has potential for bedside use and as a cognitive end point for clinical trials.

Stroke is a heterogeneous syndrome caused by multiple disease mechanisms, but all result in a disruption of cerebral blood flow with subsequent tissue damage. This review covers the mechanisms responsible for regulation of the normal cerebral circulation, and how they are disrupted in disease states. A central concept in treating patients with acute ischaemic stroke is the existence of an ischaemic penumbra of potentially salvageable tissue, and the evidence for its existence in humans is reviewed.

Background: Cerebral small vessel disease is a common cause of vascular dementia. Both discrete lacunar infarcts and more diffuse ischaemic changes, seen as confluent high signal (leukoaraiosis) on T2 weighted magnetic resonance imaging (MRI), occur. However, there is a weak correlation between T2 lesion load and cognitive impairment. Diffusion tensor MRI (DTI) is a new technique that may provide a better index of white matter damage., Objectives: To determine whether DTI measures are correlated more strongly with cognitive performance than lesion load on T2 weighted images, and whether these correlations are independent of conventional MRI parameters., Methods: 36 patients with ischaemic leukoaraiosis (leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment., Results: On DTI, diffusivity was increased both within lesions and in normal appearing white matter. Mean diffusivity of normal appearing white matter correlated with full scale IQ (r = -0.46, p = 0.009) and tests of executive function. These correlations remained significant after controlling for age, sex, brain volume, and T1/T2 lesion volumes. No significant correlation was identified between T2 lesion load and IQ or neuropsychological scores. Of conventional measures, brain volume correlated best with cognitive function., Conclusions: Diffusion tensor measurements correlate better with cognition than conventional MRI measures. They may be useful in monitoring disease progression and as a surrogate marker for treatment trials. The findings support the role of white matter damage and disruption of white matter connections in the pathogenesis of cognitive impairment in cerebral small vessel disease.

Objectives: To report a single centre ongoing experience of endovascular treatment for atherosclerotic vertebral artery origin stenosis in a series of symptomatic patients, with follow up imaging to determine the incidence of restenosis., Methods: 14 patients with vertebral artery origin stenosis on catheter angiography were treated. Angioplasty without stenting was undertaken in the first four patients, all of whom had follow up catheter angiography at one year. Subsequently, patients were treated by primary stenting and followed up with colour Doppler ultrasound examination., Results: The procedure was technically successful in all treated arteries, with no immediate complications. The degree of stenosis was reduced from (mean (SD)) 73 (18)% before treatment to 21 (26)% immediately after treatment in the angioplasty alone group (p = 0.059). In the primary stenting patients, the severity of stenosis was reduced from 82 (8)% to 13 (13)% immediately after treatment (p < 0.001). Restenosis to 70% or greater occurred at one year in all four patients initially treated by angioplasty without stenting. One patient subsequently developed further symptoms and was retreated by stenting. One of the 10 patients treated by primary stenting developed restenosis. None of the remaining patients had further posterior circulation ischaemic symptoms during a mean follow up period of 33.6 months (range 1 to 72 months)., Conclusions: Restenosis occurs often after vertebral artery origin balloon angioplasty without stenting but is uncommon after stenting. Primary stenting is therefore recommended to maintain patency at this site, and had a low complication rate in this series.

The main clinical features of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) are stroke, dementia, and migraine. A reversible acute encephalopathy was the principal presentation in six of 70 patients in a British prevalence study. The episodes lasted seven to 14 days, presenting with fever, acute confusion, coma, and fits; there was full recovery but in two cases identical episodes recurred some years later. All patients had a previous history of migraine with aura and were originally misdiagnosed as viral encephalitis. CADASIL should be considered in acute unexplained encephalopathies. MRI white matter changes, previous migraine with aura, and a family history of stroke and dementia may be useful pointers to the diagnosis.

Objectives: Better methods of identifying patients with asymptomatic carotid artery stenosis who are at high risk of stroke are required. It has been suggested that proton magnetic resonance spectroscopy (MRS) may allow the identification of ongoing ischaemia in this patient group by the detection of a potentially reversible reduction of N-acetyl aspartate (NAA), a presumed marker of neuronal integrity, and the presence of lactate, a marker of anaerobic metabolism. Previous studies have reported metabolite ratios rather than absolute concentrations. This study was performed to determine if NAA was reduced ipsilateral to carotid stenosis or occlusion, and if its concentration was related to carbon dioxide reactivity, a marker of cerebrovascular reserve., Methods: Twenty one patients with unilateral carotid stenosis (>70%) or occlusion were studied. Single voxel proton MRS was performed in the ipsilateral and contralateral hemispheres, with the voxel positioned in the arterial borderzone region between the middle and anterior cerebral artery territories. Absolute quantification of metabolite concentrations was performed. Cerebrovascular reactivity to 6% carbon dioxide was determined in both middle cerebral artery territories using transcranial Doppler ultrasonography., Results: Mean (SD) cerebrovascular reactivity was significantly lower in the stenosed compared with the contralateral hemisphere (13.3 (7.7) v 19.2 (8.2)%/kPa, p=0.002). There were no significant differences in the absolute concentrations of NAA, choline, or creatine between the ipsilateral and contralateral hemispheres (for example, NAA 10.1 (1.1) v 10.5 (1.1) mmol/l, p=0.1). No lactate peak was seen in any spectra. For each metabolite measured, there was no correlation between the absolute concentration and cerebrovascular reactivity for either hemisphere., Conclusions: In patients with carotid stenosis and occlusion we found no evidence that chronic hypoperfusion is associated with a reduction in NAA or the presence of lactate. Magnetic resonance spectroscopy is unlikely to help in the selection of patients with asymptomatic carotid stenosis for endarterectomy.

Objective: White matter hypoperfusion may play a part in the pathogenesis of ischaemic leukoaraiosis, but demonstration of this requires a high resolution quantitative method of cerebral blood flow (CBF) measurement. Initial exogenous contrast based MRI methods only allowed measurement of relative cerebral blood volume (CBV) values, but more recently a mathematical approach has been developed which enables absolute regional CBF and CBV to be determined. This technique was applied to patients with ischaemic leukoaraiosis to determine whether reduced white matter CBF in this patient group could be demonstrated., Methods: Eight patients with ischaemic leukoaraiosis (radiological leukoaraiosis and clinical lacunar stroke), and nine age matched controls were studied. A spin echo echoplanar image sequence was used on a 1.5 Tesla MR system. An arterial input function was obtained from voxels placed over the middle cerebral arteries. Cerebral blood flow, CBV, and mean transit (MTT) maps were derived. Regions of interest were placed at standard positions in the white and grey matter and mean values of CBF, CBV, and MTT were compared between the two groups., Results: Mean (SD) white matter CBF was significantly reduced in patients by 38% (13.40 (4.87) v 21.74 (3.53) ml/min/ 100 g, p=0.002). Significant reductions in CBF were seen in all white matter regions. By contrast there was no reduction in CBF in any grey matter region. There was no significant difference in white matter CBV between cases and controls; mean values were lower in all white matter regions for patients but this did not reach significance for any region. By contrast mean grey matter CBV was significantly higher in patients than in controls. Mean MTT values were higher in all regions of grey and white matter in the patient group, but this only achieved significance for the superior white matter., Conclusion: A quantitative MR perfusion method showed reduced white matter CBF in patients with ischaemic leukoaraiosis, but normal grey matter CBF. This is consistent with hypoperfusion playing a part in the pathogenesis of ischaemic leukoaraiosis. The absolute values of white matter and grey matter CBF obtained in the patient groups were very similar to those in previous PET studies, providing further evidence for the validity of the regional CBF measurements obtained using this quantitative MR perfusion technique. The high spatial resolution and lack of radioactive administration makes such techniques ideal for longitudinal studies in this condition.

Objectives: Chronic Helicobacter pylori infection has been associated with ischaemic heart disease although the mechanism by which it mediates this effect remains unclear. The objective was to determine whether it is also a risk factor for ischaemic cerebrovascular disease, Methods: A total of 238 patients and 119 controls were studied. Patients were characterised into stroke subtypes based on pathogenic mechanisms and carotid atheroma load was estimated using duplex ultrasound. H pylori seropositivity was determined on serum samples., Results: H pylori seropositivity was more common in cases (58.8% v 44.5%, p=0.01). The odds ratio for cerebrovascular disease associated with seropositivity was 1.78 (95% confidence interval (95% CI) 1.14-2.77), and this remained significant after controlling for other risk factors including socioeconomic status (1.63 (95% CI 1.02-2.60). H pylori seropositivity was associated with large vessel disease (odds ratio 2.58 (95% CI 1.44-4.63), p=0.001) and lacunar stroke (odds ratio 2.21 (95% CI 1.12-4.38), p=0.02) but not stroke due to cardioembolism or unknown aetiology (odds ratio 1.16 (95% CI 0.66-2.02), p=0.5). Mean (SD) carotid stenosis was greater in patients seropositive for H pylori (37.3 (29.7) v 27.9 (26.2)%, p=0.01). There was no difference in the prevalence of seropositivity between patients with stroke and transient ischaemic attack (59.6% v 58.6%, p=0.9), Conclusion: Chronic H pylori infection is an independent risk factor for ischaemic cerebrovascular disease and may act, at least in part, by increasing atherosclerosis.

Regional cerebral perfusion was evaluated by SPECT with technetium 99m hexamethylpropyleneamine oxime (99mTc HMPAO) as a tracer in 21 patients presenting with Parkinson's disease and in 11 normal controls. In the parkinsonian patients, scans were performed both off treatment, and after levodopa, and clinical dopaminergic responsiveness was evaluated. Uptake of HMPAO by the basal ganglia was significantly decreased in the parkinsonian subjects, compared with normal controls. This reduction was seen in both responders (n = 14) and non-responders (n = 7) to dopaminergic treatment. Uptake of HMPAO by the basal ganglia rose after treatment with levodopa, but the change was similar in both responders and non-responders. By contrast a striking difference in cortical HMPAO uptake was found between responders and non-responders, with significantly lower uptake in the medial temporal and posterior parietal cortex in the non-responders. This reduction was symmetrical. Basal ganglia perfusion assessed by this technique is unlikely to be of use in the diagnosis of Parkinson's disease that is responsive to dopaminergic treatment. The presence of extensive cortical involvement on a baseline scan correlates with a lack of dopaminergic responsiveness, however, and this may be useful diagnostically.