Assessment of Small Vessel Function Using 7T MRI in Patients With Sporadic Cerebral Small Vessel Disease: The ZOOM@SVDs Study.

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia, but little is known about disease mechanisms at the level of the small vessels. 7T-MRI allows assessing small vessel function in vivo in different vessel populations. We hypothesized that multiple aspects of small vessel function are altered in patients with cSVD and that these abnormalities relate to disease burden. METHODS: Patients and controls participated in a prospective observational cohort study, the ZOOM@SVDs study. Small vessel function measures on 7T-MRI included perforating artery blood flow velocity and pulsatility index in the basal ganglia and centrum semiovale, vascular reactivity to visual stimulation in the occipital cortex, and reactivity to hypercapnia in the gray and white matter. Lesion load on 3T-MRI and cognitive function were used to assess disease burden. RESULTS: Forty-six patients with sporadic cSVD (mean age ± SD 65 ± 9 years) and 22 matched controls (64 ± 7 years) participated in the ZOOM@SVDs study. Compared with controls, patients had increased pulsatility index (mean difference 0.09, p = 0.01) but similar blood flow velocity in basal ganglia perforating arteries and similar flow velocity and pulsatility index in centrum semiovale perforating arteries. The duration of the vascular response to brief visual stimulation in the occipital cortex was shorter in patients than in controls (mean difference -0.63 seconds, p = 0.02), whereas reactivity to hypercapnia was not significantly affected in the gray and total white matter. Among patients, reactivity to hypercapnia was lower in white matter hyperintensities compared with normal-appearing white matter (blood-oxygen-level dependent mean difference 0.35%, p = 0.001). Blood flow velocity and pulsatility index in basal ganglia perforating arteries and reactivity to brief visual stimulation correlated with disease burden. DISCUSSION: We observed abnormalities in several aspects of small vessel function in patients with cSVD indicative of regionally increased arteriolar stiffness and decreased reactivity. Worse small vessel function also correlated with increased disease burden. These functional measures provide new mechanistic markers of sporadic cSVD.

Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial.

Background: Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130-140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018. Methods: All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24-36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24-36 h. Mean achieved systolic blood pressures over 1-24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24-36 h (0.3 [IQR 0.0-16.6] in the intensive group and 0.9 [0.0-12.5] in the guideline group; log Δmean -0.17, 95% CI -0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Interpretation: Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Assessment of perivascular space filtering methods using a three-dimensional computational model.

Growing interest surrounds the assessment of perivascular spaces (PVS) on magnetic resonance imaging (MRI) and their validation as a clinical biomarker of adverse brain health. Nonetheless, the limits of validity of current state-of-the-art segmentation methods are still unclear. Here, we propose an open-source three-dimensional computational framework comprising 3D digital reference objects and evaluate the performance of three PVS filtering methods under various spatiotemporal imaging considerations (including sampling, motion artefacts, and Rician noise). Specifically, we study the performance of the Frangi, Jerman and RORPO filters in enhancing PVS-like structures to facilitate segmentation. Our findings were three-fold. First, as long as voxels are isotropic, RORPO outperforms the other two filters, regardless of imaging quality. Unlike the Frangi and Jerman filters, RORPO's performance does not deteriorate as PVS volume increases. Second, the performance of all "vesselness" filters is heavily influenced by imaging quality, with sampling and motion artefacts being the most damaging for these types of analyses. Third, none of the filters can distinguish PVS from other hyperintense structures (e.g. white matter hyperintensities, stroke lesions, or lacunes) effectively, the area under precision-recall curve dropped substantially (Frangi: from 94.21 [IQR 91.60, 96.16] to 43.76 [IQR 25.19, 63.38]; Jerman: from 94.51 [IQR 91.90, 95.37] to 58.00 [IQR 35.68, 64.87]; RORPO: from 98.72 [IQR 95.37, 98.96] to 71.87 [IQR 57.21, 76.63] without and with other hyperintense structures, respectively). The use of our computational model enables comparing segmentation methods and identifying their advantages and disadvantages, thereby providing means for testing and optimising pipelines for ongoing and future studies.

Towards equality: gender representation at the Royal College of Radiologists' Annual Scientific Meeting 2014-2021.

Background: Conferences facilitate career advancement, but gender imbalances in public fora may negatively impact both women and men, and society. We aimed to describe the gender distribution of presenters at the UK's 2014-2021 Royal College of Radiologists' (RCR) Annual Scientific Meeting. Methods: We extracted data on presenter name, role and session type from meeting programmes. We classified gender as male or female using names, records or personal pronouns, accepting the limitations of these categories. We classified roles by prestige: lead, other (speakers and workshop faculty), proffered paper or poster presenters. We calculated odds ratios (OR) and 95% confidence intervals (CI) for associations between gender and binary outcomes using logistic regression.  Results: Women held 1,059 (37.5%) of 2,826 conference roles and presented 9/27 keynotes. Compared to men, women were less likely to hold other roles such as speakers and workshop faculty (OR 0.72 95% CI 0.61-0.83), and more likely to present posters (OR 1.49 95% CI 1.27-1.76). There were 60 male-only and eight women-only multi-presenter sessions. Sessions led by women had higher proportions of women speakers. The odds of roles being held by women increased during online meetings during COVID in 2020 and 2021 (OR 1.61, 95% CI 1.36-1.91) compared to earlier years. Conclusion: The proportion of women presenters and keynote speakers reflects that of RCR membership, but not of wider society. Disadvantage starts from the earliest career stages, prejudicing career opportunities. Efforts to improve inclusion and diversity are needed; focusing on lead roles and hybrid online/in-person formats may accelerate change.

Tracer kinetic assessment of blood-brain barrier leakage and blood volume in cerebral small vessel disease: Associations with disease burden and vascular risk factors.

Subtle blood-brain barrier (BBB) permeability increases have been shown in small vessel disease (SVD) using various analysis methods. Following recent consensus recommendations, we used Patlak tracer kinetic analysis, considered optimal in low permeability states, to quantify permeability-surface area product (PS), a BBB leakage estimate, and blood plasma volume (vP) in 201 patients with SVD who underwent dynamic contrast-enhanced MRI scans. We ran multivariable regression models with a quantitative or qualitative metric of white matter hyperintensity (WMH) severity, demographic and vascular risk factors. PS increased with WMH severity in grey (B = 0.15, Confidence Interval (CI): [0.001,0.299], p = 0.049) and normal-appearing white matter (B = 0.015, CI: [-0.008,0.308], p = 0.062). Patients with more severe WMH had lower vP in WMH (B = -0.088, CI: [-0.138,-0.039], p < 0.001), but higher vP in normal-appearing white matter (B = 0.031, CI: [-0.004,0.065], p = 0.082). PS and vP were lower at older ages in WMH, grey and white matter. We conclude higher PS in normal-appearing tissue with more severe WMH suggests impaired BBB integrity beyond visible lesions indicating that the microvasculature is compromised in normal-appearing white matter and WMH. BBB dysfunction is an important mechanism in SVD, but associations with clinical variables are complex and underlying damage affecting vascular surface area may alter interpretation of tracer kinetic results.

Early life predictors of late life cerebral small vessel disease in four prospective cohort studies.

Development of cerebral small vessel disease, a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socio-economic status or of vascular risk factor exposures. We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, socio-economic status), adult small vessel disease, and brain volumes, using data from four prospective cohort studies: STratifying Resilience And Depression Longitudinally (STRADL) (n = 1080; mean age = 59 years); the Dutch Famine Birth Cohort (n = 118; mean age = 68 years); the Lothian Birth Cohort 1936 (LBC1936; n = 617; mean age = 73 years), and the Simpson's cohort (n = 110; mean age = 78 years). We analysed each small vessel disease feature individually and summed to give a total small vessel disease score (range 1-4) in each cohort separately, then in meta-analysis, adjusted for vascular risk factors and adult socio-economic status. Higher birth weight was associated with fewer lacunes [odds ratio (OR) per 100 g = 0.93, 95% confidence interval (CI) = 0.88 to 0.99], fewer infarcts (OR = 0.94, 95% CI = 0.89 to 0.99), and fewer perivascular spaces (OR = 0.95, 95% CI = 0.91 to 0.99). Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point = 0.99, 95% CI 0.98 to 0.998), fewer infarcts (OR = 0.98, 95% CI = 0.97 to 0.998), fewer lacunes (OR = 0.98, 95% CI = 0.97 to 0.999), and lower total small vessel disease burden (OR = 0.98, 95% CI = 0.96 to 0.999). Low education was associated with more microbleeds (OR = 1.90, 95% CI = 1.33 to 2.72) and lower total brain volume (mean difference = -178.86 cm3, 95% CI = -325.07 to -32.66). Low childhood socio-economic status was associated with fewer lacunes (OR = 0.62, 95% CI = 0.40 to 0.95). Early life factors are associated with worse small vessel disease in later life, independent of each other, vascular risk factors and adult socio-economic status. Risk for small vessel disease may originate in early life and provide a mechanistic link between early life factors and risk of stroke and dementia. Policies investing in early child development may improve lifelong brain health and contribute to the prevention of dementia and stroke in older age.

Neuropsychiatric symptoms associated with cerebral small vessel disease: a systematic review and meta-analysis.

BACKGROUND: Cerebral small vessel disease, a common cause of vascular dementia, is often considered clinically silent before dementia or stroke become apparent. However, some individuals have subtle symptoms associated with acute MRI lesions. We aimed to determine whether neuropsychiatric and cognitive symptoms vary according to small vessel disease burden. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, and PsycINFO for articles published in any language from database inception to Jan 24, 2020. We searched for studies assessing anxiety, apathy, delirium, emotional lability, fatigue, personality change, psychosis, dementia-related behavioural symptoms or cognitive symptoms (including subjective memory complaints), and radiological features of cerebral small vessel disease. We extracted reported odds ratios (OR), standardised mean differences (SMD), and correlations, stratified outcomes by disease severity or symptom presence or absence, and pooled data using random-effects meta-analyses, reporting adjusted findings when possible. We assessed the bias on included studies using the Risk of Bias for Non-randomized Studies tool. This study is registered with PROSPERO, CRD42018096673. FINDINGS: Of 7119 papers identified, 81 studies including 79 cohorts in total were eligible for inclusion (n=21 730 participants, mean age 69·2 years). Of these 81 studies, 45 (8120 participants) reported effect estimates. We found associations between worse white matter hyperintensity (WMH) severity and apathy (OR 1·41, 95% CI 1·05-1·89) and the adjusted SMD in apathy score between WMH severities was 0·38 (95% CI 0·15-0·61). Worse WMH severity was also associated with delirium (adjusted OR 2·9, 95% CI 1·12-7·55) and fatigue (unadjusted OR 1·63, 95% CI 1·20-2·22). WMHs were not consistently associated with subjective memory complaints (OR 1·34, 95% CI 0·61-2·94) and unadjusted SMD for WMH severity between these groups was 0·08 (95% CI -0·31 to 0·47). Anxiety, dementia-related behaviours, emotional lability, and psychosis were too varied or sparse for meta-analysis; these factors were reviewed narratively. Overall heterogeneity varied from 0% to 79%. Only five studies had a low risk of bias across all domains. INTERPRETATION: Apathy, fatigue, and delirium associated independently with worse WMH, whereas subjective cognitive complaints did not. The association of anxiety, dementia-related behaviours, emotional lability, and psychosis with cerebral small vessel disease require further investigation. These symptoms should be assessed longitudinally to improve early clinical detection of small vessel disease and enable prevention trials to happen early in the disease course, long before cognition declines. FUNDING: Chief Scientist Office of the Scottish Government, UK Dementia Research Institute, Fondation Leducq, Stroke Association Garfield-Weston Foundation, Alzheimer's Society, and National Health Service Research Scotland.

Pharmacokinetic modelling for the simultaneous assessment of perfusion and 18F-flutemetamol uptake in cerebral amyloid angiopathy using a reduced PET-MR acquisition time: Proof of concept.

PURPOSE: Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease associated with perivascular ß-amyloid deposition. CAA is also associated with strokes due to lobar intracerebral haemorrhage (ICH). 18F-flutemetamol amyloid ligand PET may improve the early detection of CAA. We performed pharmacokinetic modelling using both full (0-30, 90-120 min) and reduced (30 min) 18F-flutemetamol PET-MR acquisitions, to investigate regional cerebral perfusion and amyloid deposition in ICH patients. METHODS: Dynamic18F-flutemetamol PET-MR was performed in a pilot cohort of sixteen ICH participants; eight lobar ICH cases with probable CAA and eight deep ICH patients. A model-based input function (mIF) method was developed for compartmental modelling. mIF 1-tissue (1-TC) and 2-tissue (2-TC) compartmental modelling, reference tissue models and standardized uptake value ratios were assessed in the setting of probable CAA detection. RESULTS: The mIF 1-TC model detected perfusion deficits and 18F-flutemetamol uptake in cases with probable CAA versus deep ICH patients, in both full and reduced PET acquisition time (all P < 0.05). In the reduced PET acquisition, mIF 1-TC modelling reached the highest sensitivity and specificity in detecting perfusion deficits (0.87, 0.77) and 18F-flutemetamol uptake (0.83, 0.71) in cases with probable CAA. Overall, 52 and 48 out of the 64 brain areas with 18F-flutemetamol-determined amyloid deposition showed reduced perfusion for 1-TC and 2-TC models, respectively. CONCLUSION: Pharmacokinetic (1-TC) modelling using a 30 min PET-MR time frame detected impaired haemodynamics and increased amyloid load in probable CAA. Perfusion deficits and amyloid burden co-existed within cases with CAA, demonstrating a distinct imaging pattern which may have merit in elucidating the pathophysiological process of CAA.

Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy.

Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aß deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.

Limited One-time Sampling Irregularity Map (LOTS-IM) for Automatic Unsupervised Assessment of White Matter Hyperintensities and Multiple Sclerosis Lesions in Structural Brain Magnetic Resonance Images.

We present the application of limited one-time sampling irregularity map (LOTS-IM): a fully automatic unsupervised approach to extract brain tissue irregularities in magnetic resonance images (MRI), for quantitatively assessing white matter hyperintensities (WMH) of presumed vascular origin, and multiple sclerosis (MS) lesions and their progression. LOTS-IM generates an irregularity map (IM) that represents all voxels as irregularity values with respect to the ones considered "normal". Unlike probability values, IM represents both regular and irregular regions in the brain based on the original MRI's texture information. We evaluated and compared the use of IM for WMH and MS lesions segmentation on T2-FLAIR MRI with the state-of-the-art unsupervised lesions' segmentation method, Lesion Growth Algorithm from the public toolbox Lesion Segmentation Toolbox (LST-LGA), with several well established conventional supervised machine learning schemes and with state-of-the-art supervised deep learning methods for WMH segmentation. In our experiments, LOTS-IM outperformed unsupervised method LST-LGA on WMH segmentation, both in performance and processing speed, thanks to the limited one-time sampling scheme and its implementation on GPU. Our method also outperformed supervised conventional machine learning algorithms (i.e., support vector machine (SVM) and random forest (RF)) and deep learning algorithms (i.e., deep Boltzmann machine (DBM) and convolutional encoder network (CEN)), while yielding comparable results to the convolutional neural network schemes that rank top of the algorithms developed up to date for this purpose (i.e., UResNet and UNet). LOTS-IM also performed well on MS lesions segmentation, performing similar to LST-LGA. On the other hand, the high sensitivity of IM on depicting signal change deems suitable for assessing MS progression, although care must be taken with signal changes not reflective of a true pathology.

Mechanical thrombectomy in patients with acute ischemic stroke: A cost-effectiveness and value of implementation analysis.

BACKGROUND: Recent clinical trials have demonstrated the efficacy of mechanical thrombectomy in acute ischemic stroke. AIMS: To determine the cost-effectiveness, value of future research, and value of implementation of mechanical thrombectomy. METHODS: Using UK clinical and cost data from the Pragmatic Ischemic Stroke Thrombectomy Evaluation (PISTE) trial, we estimated the cost-effectiveness of mechanical thrombectomy over time horizons of 90-days and lifetime, based on a decision-analytic model, using all existing evidence. We performed a meta-analysis of seven clinical trials to estimate treatment effects. We used sensitivity analysis to address uncertainty. Value of implementation analysis was used to estimate the potential value of additional implementation activities to support routine delivery of mechanical thrombectomy. RESULTS: Over the trial period (90 days), compared with best medical care alone, mechanical thrombectomy incurred an incremental cost of £5207 and 0.025 gain in QALY (incremental cost-effectiveness ratio (ICER) £205,279), which would not be considered cost-effective. However, mechanical thrombectomy was shown to be cost-effective over a lifetime horizon, with an ICER of £3466 per QALY gained. The expected value of perfect information per patient eligible for mechanical thrombectomy in the UK is estimated at £3178. The expected value of full implementation of mechanical thrombectomy is estimated at £1.3 billion over five years. CONCLUSION: Mechanical thrombectomy was cost-effective compared with best medical care alone over a patient's lifetime. On the assumption of 30% implementation being achieved throughout the UK healthcare system, we estimate that the population health benefits obtained from this treatment are greater than the cost of implementation. TRIAL REGISTRATION: NCT01745692.

Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial.

BACKGROUND: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. METHODS: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. FINDINGS: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. INTERPRETATION: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. FUNDING: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Brain structural differences between 73- and 92-year olds matched for childhood intelligence, social background, and intracranial volume.

Fully characterizing age differences in the brain is a key task for combating aging-related cognitive decline. Using propensity score matching on 2 independent, narrow-age cohorts, we used data on childhood cognitive ability, socioeconomic background, and intracranial volume to match participants at mean age of 92 years (n = 42) to very similar participants at mean age of 73 years (n = 126). Examining a variety of global and regional structural neuroimaging variables, there were large differences in gray and white matter volumes, cortical surface area, cortical thickness, and white matter hyperintensity volume and spatial extent. In a mediation analysis, the total volume of white matter hyperintensities and total cortical surface area jointly mediated 24.9% of the relation between age and general cognitive ability (tissue volumes and cortical thickness were not significant mediators in this analysis). These findings provide an unusual and valuable perspective on neurostructural aging, in which brains from the 8th and 10th decades of life differ widely despite the same cognitive, socioeconomic, and brain-volumetric starting points.

Education, Socioeconomic Status, and Intelligence in Childhood and Stroke Risk in Later Life: A Meta-analysis.

BACKGROUND: Stroke is the second most common cause of death, and a common cause of dependency and dementia. Adult vascular risk factors and socioeconomic status (SES) are associated with increased risk, but less is known about early life risk factors, such as education, childhood SES, or intelligence (IQ). METHODS: We comprehensively searched Medline, PsycINFO, and EMBASE from inception to November 2015. We included all studies reporting data on >50 strokes examining childhood/premorbid IQ, SES, and education. Two reviewers independently screened full texts and extracted and cross-checked data, including available risk factor adjustments. We meta-analyzed stroke risk using hazard ratios (HR), odds ratios (OR), and mean differences (MD). We tested effects of study and participant characteristics in sensitivity analyses and meta-regression, and assessed heterogeneity and publication bias. RESULTS: We identified 90 studies examining stroke risk and education (79), SES (10), or IQ (nine) including approximately 164,683 stroke and over 5 million stroke-free participants. Stroke risk increased with lower education (OR = 1.35, 95% CI = 1.24, 1.48), SES (OR = 1.28, 95% CI = 1.12, 1.46), and IQ (HR = 1.17, 95% CI = 1.00, 1.37) in studies reporting point estimates, with similar associations for MD. We found minimal publication bias. Between-study heterogeneity was partly explained by participant age and case ascertainment method. CONCLUSIONS: Education, childhood SES, and intelligence have modest but important associations with lifetime stroke, and hence dementia, risks. Future studies distinguishing between the individual and combined effects of education, childhood SES and intelligence are needed to determine the independent contribution of each factor to stroke risk. See video abstract at, http://links.lww.com/EDE/B210.

Risk and protective factors for structural brain ageing in the eighth decade of life.

Individuals differ markedly in brain structure, and in how this structure degenerates during ageing. In a large sample of human participants (baseline n = 731 at age 73 years; follow-up n = 488 at age 76 years), we estimated the magnitude of mean change and variability in changes in MRI measures of brain macrostructure (grey matter, white matter, and white matter hyperintensity volumes) and microstructure (fractional anisotropy and mean diffusivity from diffusion tensor MRI). All indices showed significant average change with age, with considerable heterogeneity in those changes. We then tested eleven socioeconomic, physical, health, cognitive, allostatic (inflammatory and metabolic), and genetic variables for their value in predicting these differences in changes. Many of these variables were significantly correlated with baseline brain structure, but few could account for significant portions of the heterogeneity in subsequent brain change. Physical fitness was an exception, being correlated both with brain level and changes. The results suggest that only a subset of correlates of brain structure are also predictive of differences in brain ageing.

Early life characteristics and late life burden of cerebral small vessel disease in the Lothian Birth Cohort 1936.

It is unknown whether relations between early-life factors and overall health in later life apply to burden of cerebral small vessel disease (cSVD), a major cause of stroke and dementia. We explored relations between early-life factors and cSVD in the Lothian Birth Cohort, a healthy aging cohort. Participants were recruited at age 70 (N = 1091); most had completed a test of cognitive ability at age 11 as part of the Scottish Mental Survey of 1947. Of those, 700 participants had brain MRI that could be rated for cSVD conducted at age 73. Presence of lacunes, white matter hyperintensities, microbleeds, and perivascular spaces were summed in a score of 0-4 representing all MRI cSVD features. We tested associations with early-life factors using multivariate logistic regression. Greater SVD score was significantly associated with lower age-11 IQ (OR higher SVD score per SD age-11 IQ = .78, 95%CI 0.65-.95, p=.01). The associations between SVD score and own job class (OR higher job class, .64 95%CI .43-.95, p=.03), age-11 deprivation index (OR per point deprivation score, 1.08, 95%CI 1.00-1.17, p=.04), and education (OR some qualifying education, .60 95%CI .37-.98, p=.04) trended towards significance (p<.05 for all) but did not meet thresholds for multiple testing. No early-life factor was significantly associated with any one individual score component. Early-life factors may contribute to age-73 burden of cSVD. These relations, and the potential for early social interventions to improve brain health, deserve further study.

On the computational assessment of white matter hyperintensity progression: difficulties in method selection and bias field correction performance on images with significant white matter pathology.

INTRODUCTION: Subtle inhomogeneities in the scanner's magnetic fields (B0 and B1) alter the intensity levels of the structural magnetic resonance imaging (MRI) affecting the volumetric assessment of WMH changes. Here, we investigate the influence that (1) correcting the images for the B1 inhomogeneities (i.e. bias field correction (BFC)) and (2) selection of the WMH change assessment method can have on longitudinal analyses of WMH progression and discuss possible solutions. METHODS: We used brain structural MRI from 46 mild stroke patients scanned at stroke onset and 3 years later. We tested three BFC approaches: FSL-FAST, N4 and exponentially entropy-driven homomorphic unsharp masking (E(2)D-HUM) and analysed their effect on the measured WMH change. Separately, we tested two methods to assess WMH changes: measuring WMH volumes independently at both time points semi-automatically (MCMxxxVI) and subtracting intensity-normalised FLAIR images at both time points following image gamma correction. We then combined the BFC with the computational method that performed best across the whole sample to assess WMH changes. RESULTS: Analysis of the difference in the variance-to-mean intensity ratio in normal tissue between BFC and uncorrected images and visual inspection showed that all BFC methods altered the WMH appearance and distribution, but FSL-FAST in general performed more consistently across the sample and MRI modalities. The WMH volume change over 3 years obtained with MCMxxxVI with vs. without FSL-FAST BFC did not significantly differ (medians(IQR)(with BFC) = 3.2(6.3) vs. 2.9(7.4)ml (without BFC), p = 0.5), but both differed significantly from the WMH volume change obtained from subtracting post-processed FLAIR images (without BFC)(7.6(8.2)ml, p < 0.001). This latter method considerably inflated the WMH volume change as subtle WMH at baseline that became more intense at follow-up were counted as increase in the volumetric change. CONCLUSIONS: Measurement of WMH volume change remains challenging. Although the overall volumetric change was not significantly affected by the application of BFC, these methods distorted the image intensity distribution affecting subtle WMH. Subtracting the FLAIR images at both time points following gamma correction seems a promising technique but is adversely affected by subtle WMH. It is important to take into account not only the changes in volume but also in the signal intensity.

Magnetic resonance imaging for assessment of cerebrovascular reactivity in cerebral small vessel disease: A systematic review.

Cerebral small vessel disease (SVD) pathophysiology is poorly understood. Cerebrovascular reactivity (CVR) impairment may play a role, but evidence to date is mainly indirect. Magnetic resonance imaging (MRI) allows investigation of CVR directly in the tissues affected by SVD. We systematically reviewed the use of MRI to measure CVR in subjects with SVD. Five studies (total n = 155 SVD subjects, 84 controls) provided relevant data. The studies included different types of patients. Each study used blood oxygen level dependent (BOLD) MRI to assess CVR but a different vasoactive stimulus and method of calculating CVR. CVR decreased with increasing white matter hyperintensities in two studies (n = 17, 11%) and in the presence of microbleeds in another. Three studies (n = 138, 89%) found no association of CVR with white matter hyperintensities. No studies provided tissue-specific CVR values. CVR decreased with age in three studies, and with female gender and increasing diastolic blood pressure in one study. Safety and tolerability data were limited. Larger studies using CVR appear to be feasible and are needed, preferably with more standardized methods, to determine if specific clinical or radiological features of SVD are more or less associated with impaired CVR.

Observer reliability of CT angiography in the assessment of acute ischaemic stroke: data from the Third International Stroke Trial.

INTRODUCTION: CT angiography (CTA) is often used for assessing patients with acute ischaemic stroke. Only limited observer reliability data exist. We tested inter- and intra-observer reliability for the assessment of CTA in acute ischaemic stroke. METHODS: We selected 15 cases from the Third International Stroke Trial (IST-3, ISRCTN25765518) with various degrees of arterial obstruction in different intracranial locations on CTA. To assess inter-observer reliability, seven members of the IST-3 expert image reading panel (>5 years experience reading CTA) and seven radiology trainees (<2 years experience) rated all 15 scans independently and blind to clinical data for: presence (versus absence) of any intracranial arterial abnormality (stenosis or occlusion), severity of arterial abnormality using relevant scales (IST-3 angiography score, Thrombolysis in Cerebral Infarction (TICI) score, Clot Burden Score), collateral supply and visibility of a perfusion defect on CTA source images (CTA-SI). Intra-observer reliability was assessed using independently repeated expert panel scan ratings. We assessed observer agreement with Krippendorff's-alpha (K-alpha). RESULTS: Among experienced observers, inter-observer agreement was substantial for the identification of any angiographic abnormality (K-alpha = 0.70) and with an angiography assessment scale (K-alpha = 0.60-0.66). There was less agreement for grades of collateral supply (K-alpha = 0.56) or for identification of a perfusion defect on CTA-SI (K-alpha = 0.32). Radiology trainees performed as well as expert readers when additional training was undertaken (neuroradiology specialist trainees). Intra-observer agreement among experts provided similar results (K-alpha = 0.33-0.72). CONCLUSION: For most imaging characteristics assessed, CTA has moderate to substantial observer agreement in acute ischaemic stroke. Experienced readers and those with specialist training perform best.