Current state and guidance on arterial spin labeling perfusion MRI in clinical neuroimaging.

This article focuses on clinical applications of arterial spin labeling (ASL) and is part of a wider effort from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group to update and expand on the recommendations provided in the 2015 ASL consensus paper. Although the 2015 consensus paper provided general guidelines for clinical applications of ASL MRI, there was a lack of guidance on disease-specific parameters. Since that time, the clinical availability and clinical demand for ASL MRI has increased. This position paper provides guidance on using ASL in specific clinical scenarios, including acute ischemic stroke and steno-occlusive disease, arteriovenous malformations and fistulas, brain tumors, neurodegenerative disease, seizures/epilepsy, and pediatric neuroradiology applications, focusing on disease-specific considerations for sequence optimization and interpretation. We present several neuroradiological applications in which ASL provides unique information essential for making the diagnosis. This guidance is intended for anyone interested in using ASL in a routine clinical setting (i.e., on a single-subject basis rather than in cohort studies) building on the previous ASL consensus review.

Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

C9orf72 and intracerebral hemorrhage.

The chromosome 9 open reading frame 72 (C9orf72) GGGGCC repeat expansion has been associated with several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. It has also been associated with increased white matter changes in frontotemporal dementia and risk of cognitive impairment in ALS. Dementia is common both before and after intracerebral hemorrhage (ICH). Because the mechanisms of cognitive impairment in patients with ICH are uncertain, we investigated whether C9orf72 could influence dementia risk in this patient group. Therefore, we genotyped 1010 clinically characterized ICH cases and 2147 population controls in comparison with prior data of dementia and ALS cases. We did not find any association between C9orf72 repeat expansion and repeat size with ICH compared with controls or with dementia when assessing ICH patients only. The frequency of C9orf72 expansions in our series of individuals born in 1946 (2/2147) and other U.K. controls was age dependent, decreasing with increasing age, highlighting the high age-dependent penetrance of this expansion.

Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19-2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20-1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82-3·29) for intracranial haemorrhage and 1·23 (1·08-1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08-6·72] for intracranial haemorrhage vs 1·47 [1·19-1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36-9·05] vs 1·43 [1·07-1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69-15·81] vs 1·86 [1·23-1·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Cerebral Blood Flow and Cognitive Functioning in a Community-Based, Multi-Ethnic Cohort: The SABRE Study.

Introduction: Lower cerebral blood flow (CBF) is associated with cardiovascular disease and vascular risk factors, and is increasingly acknowledged as an important contributor to cognitive decline and dementia. In this cross-sectional study, we examined the association between CBF and cognitive functioning in a community-based, multi-ethnic cohort. Methods: From the SABRE (Southall and Brent Revisited) study, we included 214 European, 151 South Asian and 87 African Caribbean participants (71 ± 5 years; 39%F). We used 3T pseudo-continuous arterial spin labeling to estimate whole-brain, hematocrit corrected CBF. We measured global cognition and three cognitive domains (memory, executive functioning/attention and language) with a neuropsychological test battery. Associations were investigated using linear regression analyses, adjusted for demographic variables, vascular risk factors and MRI measures. Results: Across groups, we found an association between higher CBF and better performance on executive functioning/attention (standardized ß [stß] = 0.11, p < 0.05). Stratification for ethnicity showed associations between higher CBF and better performance on memory and executive functioning/attention in the white European group (stß = 0.14; p < 0.05 and stß = 0.18; p < 0.01 respectively), associations were weaker in the South Asian and African Caribbean groups. Conclusions: In a multi-ethnic community-based cohort we showed modest associations between CBF and cognitive functioning. In particular, we found an association between higher CBF and better performance on executive functioning/attention and memory in the white European group. The observations are consistent with the proposed role of cerebral hemodynamics in cognitive decline.

Neuroimaging and clinical outcomes of oral anticoagulant-associated intracerebral hemorrhage.

OBJECTIVE: Whether intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOAC-ICH) has a better outcome compared to ICH associated with vitamin K antagonists (VKA-ICH) is uncertain. METHODS: We performed a systematic review and individual patient data meta-analysis of cohort studies comparing clinical and radiological outcomes between NOAC-ICH and VKA-ICH patients. The primary outcome measure was 30-day all-cause mortality. All outcomes were assessed in multivariate regression analyses adjusted for age, sex, ICH location, and intraventricular hemorrhage extension. RESULTS: We included 7 eligible studies comprising 219 NOAC-ICH and 831 VKA-ICH patients (mean age = 77 years, 52.5% females). The 30-day mortality was similar between NOAC-ICH and VKA-ICH (24.3% vs 26.5%; hazard ratio = 0.94, 95% confidence interval [CI] = 0.67-1.31). However, in multivariate analyses adjusting for potential confounders, NOAC-ICH was associated with lower admission National Institutes of Health Stroke Scale (NIHSS) score (linear regression coefficient = -2.83, 95% CI = -5.28 to -0.38), lower likelihood of severe stroke (NIHSS > 10 points) on admission (odds ratio [OR] = 0.50, 95% CI = 0.30-0.84), and smaller baseline hematoma volume (linear regression coefficient = -0.24, 95% CI = -0.47 to -0.16). The two groups did not differ in the likelihood of baseline hematoma volume < 30cm3 (OR = 1.14, 95% CI = 0.81-1.62), hematoma expansion (OR = 0.97, 95% CI = 0.63-1.48), in-hospital mortality (OR = 0.73, 95% CI = 0.49-1.11), functional status at discharge (common OR = 0.78, 95% CI = 0.57-1.07), or functional status at 3 months (common OR = 1.03, 95% CI = 0.75-1.43). INTERPRETATION: Although functional outcome at discharge, 1 month, or 3 months was comparable after NOAC-ICH and VKA-ICH, patients with NOAC-ICH had smaller baseline hematoma volumes and less severe acute stroke syndromes. Ann Neurol 2018;84:702-712.

Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis.

OBJECTIVE: We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity). METHODS: This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2-4, 5-10, and >10 CMBs), using random effects models. RESULTS: We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2-12.6 vs 1.1%, 95% CI 0.5-1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1-3 years): OR 3.1 (95% CI 1.4-6.8; p = 0.006), 4.3 (95% CI 1.8-10.3; p = 0.001), and 3.4 (95% CI 1.4-8.3; p = 0.007) for 2-4, 5-10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1-15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts. CONCLUSIONS: CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.

Investigations of Carotid Stenosis to Identify Vulnerable Atherosclerotic Plaque and Determine Individual Stroke Risk.

Selection of patients with atherosclerotic carotid stenosis for revascularization is mainly based on the degree of luminal narrowing of the carotid artery. However, identification of other features of plaque apart from the degree of stenosis could enable better selection for intervention if they are also associated with the occurrence of stroke. Before these risk factors can possibly play a role in treatment decisions, their prognostic value needs to be proven. The purpose of this narrative review is to summarize current knowledge regarding the risk factors for stroke in patients with carotid stenosis, how they can be determined, and to what extent they predict stroke, based on recent literature. References for this review were identified by searches of PubMed between 1995 and October, 2016 and references from relevant articles. For each topic in this review different relevant search terms were used. The main search terms were 'carotid stenosis', 'atherosclerosis', 'stroke risk', and 'vulnerable plaque'. Language was restricted to English. The final reference list was generated on the basis of relevance to the topics covered in this review.

Outcome of intracerebral hemorrhage associated with different oral anticoagulants.

OBJECTIVE: In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non-vitamin K antagonist oral anticoagulation-related ICH (NOAC-ICH) and vitamin K antagonist-associated ICH (VKA-ICH). METHODS: We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score ≤2 and investigated in multivariable logistic regression. ICH volume was measured by ABC/2 or a semiautomated planimetric method. HE was defined as an ICH volume increase >33% or >6 mL from baseline within 72 hours. RESULTS: We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6-38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0-27.9) for VKA-ICH (p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52-1.64] [p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18-1.19 [p = 0.11]). CONCLUSIONS: In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH.

Developing an algorithm to identify patients with intracerebral haemorrhage secondary to a macrovascular cause.

INTRODUCTION: Determining the cause of spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is critical to guide treatment and prognosis. We investigated whether small vessel disease (SVD) in addition to clinical and other radiological findings on acute neuroimaging predicts a low risk of a macrovascular cause (e.g. an arterio-venous malformation, aneurysm or dural arteriovenous fistula). PATIENTS AND METHODS: We identified patients with acute spontaneous ICH who underwent acute non-contrast CT, CT angiography (CTA) and intra-arterial digital subtraction angiography (IADSA) at our institution from January 2010 to April 2014. Logistic regression including CTA result, SVD, age, pre-ICH hypertension and ICH location was used to derive a prediction model, validated using bootstrapping. RESULTS: 173 patients (46% female, median age 49) of whom 78 had a macrovascular cause on IADSA were included. Predictors of a macrovascular cause were: abnormal CTA (OR 67.4; p < 0.001); absence of SVD (OR 5.0; p = 0.019); and absence of pre-ICH hypertension (OR 3.4; p = 0.05). In our internally derived prediction model, the combination of CTA, SVD and pre-ICH hypertension predicted the likelihood of an underlying macrovascular cause (optimism-adjusted ROC area 0.919). Patients with negative CTA, SVD and pre-ICH hypertension have a low likelihood of an underlying macrovascular cause (1.8%). DISCUSSION AND CONCLUSION: A combination of CTA, SVD and pre-ICH hypertension predict the likelihood of finding a macrovascular cause in patients with acute spontaneous ICH, allowing informed decisions regarding the likely benefit and risk of IADSA.

The Cerebral Haemorrhage Anatomical RaTing inStrument (CHARTS): Development and assessment of reliability.

PURPOSE: The causes, risk factors and prognosis of spontaneous intracerebral haemorrhage (ICH) are partly determined by anatomical location (specifically, lobar vs. non-lobar (deep and infratentorial) regions). We systematically developed a rating instrument to reliably classify ICH location. METHODS: We used a two-stage iterative Delphi-style method for instrument development. The resultant Cerebral Haemorrhage Anatomical RaTing inStrument (CHARTS) was validated on CT and MRI scans from a cohort of consecutive patients with acute spontaneous symptomatic ICH by three independent raters. We tested interrater and intrarater reliability using kappa statistics. RESULTS: Our validation cohort included 227 patients (58% male; median age: 72.4 (IQR: 67.1-74.6)). The interrater reliability for the main analyses (i.e. including any lobar ICH; all deep and infratentorial anatomical categories (lentiform, caudate thalamus; brainstem; cerebellum); and uncertain location) was excellent (all kappa values>0.80) both in pair-wise between-rater comparisons and across all raters. The intrarater reliability was substantial to almost perfect (k=0.83; 95%CI: 0.77-0.88 and k=0.95; 95%CI: 0.92-0.96 respectively). All kappa statistics remained consistent for individual cerebral lobar regions. CONCLUSIONS: The CHARTS instrument can be used to reliably and comprehensively map the anatomical location of spontaneous ICH, and may be helpful for studying important questions regarding causes, risk factors, prognosis, and for stratification in clinical trials.

Impaired renal function is related to deep and mixed, but not strictly lobar cerebral microbleeds in patients with ischaemic stroke and TIA.

The vasculature of the brain and kidneys are similarly vulnerable to hypertension, so their microvascular damage may be correlated. We investigated the relationship of renal function to the anatomical distribution of cerebral microbleeds (CMBs), a marker of underlying cerebral small vessel disease (hypertensive arteriopathy or cerebral amyloid angiopathy), in a Western patient cohort. This was a retrospective study of referrals to a hospital stroke service. All patients with clinical data and a T2*-weighted gradient-recalled echo (T2*-GRE) MRI were included. MRI scans were rated for CMBs using the Microbleed Anatomical Rating Scale. Renal function was assessed by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula. We included 202 patients, 39 with CMBs (19.3 %); 15 had "strictly lobar", 12 had "strictly deep" and 12 had "mixed" CMBs. Patients without CMBs had a higher eGFR than those with CMBs (mean difference 6.50 ml/min/1.73 m(2), 95 % CI -14.73 to 1.72 ml/min/1.73 m(2), p = 0.121). Multivariable analysis found that those with deep and mixed CMBs had a lower eGFR than those without CMBs (mean difference -10.70 ml/min/1.73 m(2), 95 % CI -20.35 to -1.06 ml/min/1.73 m(2), p = 0.030). There was no difference in eGFR found between those with strictly lobar CMBs and those without CMBs (mean difference -1.59 ml/min/1.73 m(2), 95 % CI -13.08 to 9.89 ml/min/1.73 m(2), p = 0.79). In a Western patient cohort, there appears to be an association between eGFR and the presence of deep and mixed CMBs, but not strictly lobar CMBs. This suggests a shared vulnerability of renal afferent and cerebral deep and superficial perforating arterioles to systemic hypertension. The arteriopathy underlying strictly lobar CMBs (i.e. cerebral amyloid angiopathy), appears to be less related to renal impairment.

Evolution of Diffusion-Weighted Magnetic Resonance Imaging Signal Abnormality in Sporadic Creutzfeldt-Jakob Disease, With Histopathological Correlation.

IMPORTANCE: Prion diseases represent the archetype of brain diseases caused by protein misfolding, with the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. Diffusion-weighted imaging (DWI) has emerged as the most sensitive magnetic resonance imaging (MRI) sequence for the diagnosis of sCJD, but few studies have assessed the evolution of MRI signal as the disease progresses. OBJECTIVES: To assess the natural history of the MRI signal abnormalities on DWI in sCJD to improve our understanding of the pathogenesis and to investigate the potential of DWI as a biomarker of disease progression, with histopathological correlation. DESIGN, SETTING, AND PARTICIPANTS: Gray matter involvement on DWI was assessed among 37 patients with sCJD in 26 cortical and 5 subcortical subdivisions per hemisphere using a semiquantitative scoring system of 0 to 2 at baseline and follow-up. A total brain score was calculated as the summed scores in the individual regions. In 7 patients, serial mean diffusivity measurements were obtained. Age at baseline MRI, disease duration, atrophy, codon 129 methionine valine polymorphism, Medical Research Council Rating Scale score, and histopathological findings were documented. The study setting was the National Prion Clinic, London, England. All participants had a probable or definite diagnosis of sCJD and had at least 2 MRI studies performed during the course of their illness. The study dates were October 1, 2008 to April 1, 2012. The dates of our analysis were January 19 to April 20, 2012. MAIN OUTCOMES AND MEASURES: Correlation of regional and total brain scores with disease duration. RESULTS: Among the 37 patients with sCJD in this study there was a significant increase in the number of regions demonstrating signal abnormality during the study period, with 59 of 62 regions showing increased signal intensity (SI) at follow-up, most substantially in the caudate and putamen (P < .001 for both). The increase in the mean (SD) total brain score from 30.2 (17.3) at baseline to 40.5 (20.6) at follow-up (P = .001) correlated with disease duration (r = 0.47, P = .003 at baseline and r = 0.35, P = .03 at follow-up), and the left frontal SI correlated with the degree of spongiosis (r = 0.64, P = .047). Decreased mean diffusivity in the left caudate at follow-up was seen (P < .001). Eight patients demonstrated decreased SI in cortical regions, including the left inferior temporal gyrus and the right lingual gyrus. CONCLUSIONS AND RELEVANCE: Magnetic resonance images in sCJD show increased extent and degree of SI on DWI that correlates with disease duration and the degree of spongiosis. Although cortical SI may fluctuate, increased basal ganglia SI is a consistent finding and is due to restricted diffusion. Diffusion-weighted imaging in the basal ganglia may provide a noninvasive biomarker in future therapeutic trials.

Novel imaging techniques in cerebral small vessel diseases and vascular cognitive impairment.

Dementia is a global growing concern, affecting over 35 million people with a global economic impact of over $604 billion US. With an ageing population the number of people affected is expected double over the next two decades. Vascular cognitive impairment can be caused by various types of cerebrovascular disease, including cortical and subcortical infarcts, and the more diffuse white matter injury due to cerebral small vessel disease. Although this type of cognitive impairment is usually considered the second most common form of dementia after Alzheimer's disease, there is increasing recognition of the vascular contribution to neurodegeneration, with both pathologies frequently coexisting. The aim of this review is to highlight the recent advances in the understanding of vascular cognitive impairment, with a focus on small vessel diseases of the brain. We discuss recently identified small vessel imaging markers that have been associated with cognitive impairment, namely cerebral microbleeds, enlarged perivascular spaces, cortical superficial siderosis, and microinfarcts. We will also consider quantitative techniques including diffusion tensor imaging, magnetic resonance perfusion imaging with arterial spin labelling, functional magnetic resonance imaging and positron emission tomography. As well as potentially shedding light on the mechanism by which cerebral small vessel diseases cause dementia, these novel imaging biomarkers are also of increasing relevance given their ability to guide diagnosis and reflect disease progression, which may in the future be useful for therapeutic interventions. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

The Clinical Relevance of Microbleeds in Stroke study (CROMIS-2): rationale, design, and methods.

BACKGROUND AND RATIONALE: The increasing use of oral anticoagulants, mostly to prevent ischemic stroke due to atrial fibrillation in an ageing population, has been associated with a fivefold increased incidence of oral anticoagulant-associated intracerebral hemorrhage: a rare, serious, and unpredictable complication. We hypothesize that cerebral microbleeds and other markers of cerebral small vessel disease on magnetic resonance imaging, and genetic polymorphisms (e.g. influencing cerebral small vessel integrity or anticoagulation stability), are associated with an increased risk of oral anticoagulant-associated intracerebral hemorrhage, with potential to improve risk prediction. AIMS: (1) To determine the incidence, clinical, radiological, and genetic associations of oral anticoagulant-associated intracerebral hemorrhage in a prospective, multicentre cohort study of patients with atrial fibrillation-related ischemic stroke or transient ischemic attack started on oral anticoagulants; (2) To investigate characteristics of oral anticoagulant-associated intracerebral hemorrhage compared with non-oral anticoagulants related intracerebral hemorrhage in a prospective study. DESIGN AND METHODS: Study 1: Prospective, multicentre, inception cohort study of 1425 adults started on oral anticoagulants (including vitamin K antagonists and the nonvitamin K oral anticoagulants) after recent ischemic stroke and concurrent atrial fibrillation. Participants will have standardized brain magnetic resonance imaging (including a T2*-weighted gradient-recalled echo sequence) and DNA sample collection at baseline, with two-year follow-up by postal questionnaire and medical records surveillance for symptomatic intracranial hemorrhage, other serious vascular events, and death. We will compare the rates of symptomatic intracranial hemorrhage (primary outcome; subclassified as intracerebral, subdural, extradural, intraventricular), other vascular events, and death (secondary outcomes) in participants with one or more cerebral microbleeds to the rates in those without cerebral microbleeds. STUDY: Prospective case-control study of oral anticoagulant-associated intracerebral hemorrhage compared with non-oral anticoagulant-associated intracerebral hemorrhage to investigate genetic, clinical, and radiological associations with oral anticoagulant-associated intracerebral hemorrhage. In participants with intracerebral hemorrhage (including at least 300 with oral anticoagulant-associated intracerebral hemorrhage), we will collect a DNA sample, standardized clinical data and routine brain imaging (magnetic resonance imaging or computed tomography), and information on functional outcome. EXPECTED OUTCOMES: We will identify the factors associated with increased intracranial hemorrhage risk after oral anticoagulants for secondary prevention after ischemic stroke due to atrial fibrillation. We will determine clinical, radiological and genetic factors, and clinical outcomes associated with oral anticoagulant-associated intracerebral hemorrhage.

Prevalence and cognitive impact of medial temporal atrophy in a hospital stroke service: retrospective cohort study.

BACKGROUND: Cerebrovascular disease and neurodegeneration cause cognitive impairment and frequently coexist. AIMS: Our objectives were to investigate the prevalence and cognitive impact of medial temporal lobe atrophy - a radiological marker often associated with Alzheimer's disease - in a hospital stroke service. METHODS: Retrospective cohort study of patients from a hospital stroke service. Patients assessed for suspected ischemic stroke or transient ischemic attack, irrespective of final diagnosis, underwent neuropsychological testing and magnetic resonance imaging. medial temporal lobe atrophy, white matter hyperintensities, lacunes, and cerebral microbleeds were rated using established criteria and validated scales. The associations between medial temporal lobe atrophy and cognition were tested using multivariable logistic regression analyses, adjusted for age and imaging markers of cerebrovascular disease. RESULTS: Three hundred and ninety-three patients were included, of whom 169 (43%; 95% confidence interval: 38·1-48·1%) had medial temporal lobe atrophy; in 38 patients (9·7%), medial temporal lobe atrophy was severe (mean score ≥2). In unadjusted logistic regression analyses in the whole cohort, mean medial temporal lobe atrophy score was associated with verbal memory, nominal and perceptual skills, executive function, and speed and attention. After adjustment for age, white matter hyperintensities, number of lacunes, presence of cerebral microbleeds, previous ischemic stroke or transient ischemic attack, and premorbid intelligence quotient, mean medial temporal lobe atrophy score remained associated with impairment in verbal memory (odds ratio: 1·64; 95% confidence interval 1·04-2·58) and nominal skills (odds ratio: 1·61; 95% confidence interval 1·04-2·48). CONCLUSIONS: Medial temporal lobe atrophy is common and has an independent impact on cognitive function in a stroke service population, independent of confounding factors including age and magnetic resonance imaging markers of cerebrovascular disease. Medial temporal lobe atrophy is independently related to verbal memory and nominal skills, while small vessel pathology also contributes to speed and attention, and executive and perceptual functions.

White matter perivascular spaces on magnetic resonance imaging: marker of cerebrovascular amyloid burden?

BACKGROUND AND PURPOSE: We investigated the relationship between magnetic resonance imaging-visible centrum semiovale perivascular spaces (CSO-PVS), a biomarker of impaired interstitial fluid drainage, and positron emission tomography-based amyloid-ß burden across a wide range of cerebrovascular amyloid deposition. METHODS: Thirty-one nondemented subjects (11 probable cerebral amyloid angiopathy patients and 10 healthy subjects≥60 years; 10 older individuals, <60 years) had brain magnetic resonance imaging and Pittsburgh compound B-positron emission tomography. CSO-PVS was evaluated on T2-magnetic resonance imaging using a 4-point scale. The association between Pittsburgh compound B and CSO-PVS was assessed in linear regression. RESULTS: In multivariable analyses adjusted for age, microbleeds and white matter hyperintensities, whole cortex Pittsburgh compound B binding was associated with CSO-PVS degree both as continuous (coefficient, 0.11; 95% confidence interval, 0.01-0.22; P=0.040) and as dichotomous variable (coefficient, 0.27; 95% confidence interval, 0.11-0.44; P=0.002). The median Pittsburgh compound B retention was higher in high versus low CSO-PVS degree (P=0.0007). CONCLUSIONS: This pilot study suggests a possible association between cerebrovascular amyloid deposition and CSO-PVS, with potential pathophysiological implications.

The midbrain to pons ratio: a simple and specific MRI sign of progressive supranuclear palsy.

OBJECTIVES: MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP. METHODS: Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n = 12), Parkinson disease (n = 2), and multiple system atrophy (MSA) (n = 7), and in controls (n = 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n = 21), Parkinson disease (n = 10), MSA (n = 10), and controls (n = 21). RESULTS: The mean midbrain measurement of 8.1 mm was reduced in PSP (p < 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p < 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was <52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of <9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of <9.35 mm. CONCLUSIONS: We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic.

Strictly lobar microbleeds are associated with executive impairment in patients with ischemic stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are a marker of small vessel diseases, including hypertensive arteriopathy and cerebral amyloid angiopathy, and may be associated with cognitive impairment. The relationship between CMBs and cognitive function in ischemic cerebrovascular disease remains uncertain. We, therefore, investigated the cognitive impact of CMBs in a cohort of patients with ischemic stroke or transient ischemic attack. METHODS: All patients underwent detailed and comprehensive neuropsychological testing and standardized MRI, including fluid attenuation inversion recovery, T1, T2, and gradient-recalled echo T2*-weighted sequences. CMBs, white matter changes, lacunes, and territorial cortical infarcts (defined by standardized criteria) were identified, and associations with cognition assessed. RESULTS: Three hundred twenty patients with a diagnosis of ischemic stroke or transient ischemic attack were included. Of these, 72 (22.5%) had at least 1 CMB. Of all the cognitive domains tested, only executive impairment was more prevalent in patients with CMBs than without (38% versus 25%; P=0.039). In univariate analysis, the presence of strictly lobar (but not deep) CMBs was associated with executive impairment (odds ratio, 2.49; 95% confidence interval, 1.16-5.36; P=0.019). In adjusted multivariate analyses, the presence (OR, 2.34; 95% confidence interval, 1.08-5.09; P=0.031) and number (OR, 1.33; 95% confidence interval, 1.04-1.69; P=0.022) of strictly lobar CMBs were significantly associated with executive impairment. CMBs were not associated with impairment in other cognitive domains. CONCLUSIONS: Strictly lobar CMBs are independently associated with executive dysfunction in patients with ischemic stroke or transient ischemic attack. Our findings suggest that a microangiopathy related to strictly lobar CMBs (eg, cerebral amyloid angiopathy) contributes to cognitive impairment in this population.

Cerebral microbleed detection and mapping: principles, methodological aspects and rationale in vascular dementia.

Cerebral microbleeds (CMBs) have emerged as an important new imaging manifestation of sporadic cerebral small vessel diseases - mainly hypertensive arteriopathy and cerebral amyloid angiopathy - which are highly prevalent in the elderly and have a critical role in vascular cognitive impairment and dementia. With the development of MRI techniques that are exquisitely sensitive to the products of bleeding, including T2*-weighted gradient-recalled echo (T2*-GRE) and susceptibility-weighted imaging (SWI), CMBs have been detected in ever-increasing numbers of patients, including those with vascular cognitive impairment and dementia, as well as in population-based samples of healthy elderly people. Our increased ability to image CMBs and hence to see the development and progression of cerebral small vessel disease raises many clinical and pathophysiological questions about the mechanisms, diagnosis and monitoring of cognitive impairment. In order to tackle these questions, it is important to be able to reliably detect, define and map CMBs in the brains of elderly people. In this review, we consider radiological detection methods, criteria for defining CMBs (including a practical approach to the identification of CMB "mimics"), and the use of standardised rating scales. We also briefly discuss the potential for automatically detecting and quantitatively mapping CMBs in future.