Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

BACKGROUND: Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. METHODS: Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. RESULTS: Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-0.0048 [95% CI, -0.0075 to -0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (BNAWM=0.00065 [95% CI, -0.00007 to 0.00137] %/mm Hg per score point increase). CONCLUSIONS: Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

The Effects of Brain Tumours upon Medical Decision-Making Capacity.

PURPOSE OF REVIEW: Informed consent is the integral part of good medical practice in patients with brain tumours. Capacity to consent may be affected by the brain disorder or its treatment. We intend to draw upon the current neuro-oncology literature to discuss the influence intracranial tumours have upon patients' capacity to consent to treatment and research. RECENT FINDINGS: We performed a systematic review of studies of capacity to consent for treatment or research in patients with intracranial tumours. The search retrieved 1597 papers of which 8 were considered eligible for review. Although there are obvious inherent limitations to solely assessing cognition, most research consistently demonstrated increased risk of incapacity in brain tumour patients with cognitive impairment. Specific items in cognitive screening batteries, for example Semantic Verbal Fluency Test (SVFT), Hopkins Verbal Learning Test (HVLT-Recall), and Trail Making Test A/B (TMT), are simple, easily applied tests that may act as significant red flags to identify patients at increased risk of incapacity and who subsequently will require additional cognitive/psychiatric evaluation or more formal tests for capacity to consent for treatment or research.

What are practitioners' views of how digital health interventions may play a role in online child sexual abuse service delivery?

Introduction: Online child sexual abuse (OCSA) affects considerable numbers of children globally and is associated with a variety of mental health problems. Existing practitioner studies suggest that young people are infrequently asked about online abuse and practitioners have a fragmented understanding of the problems experienced or how they might approach them. There are very few evidence-based interventions that guide clinical assessment or practice. Digital Health Interventions (DHIs) have the potential to be an effective option where children and young people's services are challenged, including accessibility and anonymity. The aim of this study was to explore mental health practitioners' views of how DHIs may play a role in supporting young people who have experienced OCSA, and the role they can play in healthcare delivery. Method: In-depth qualitative interviews and one focus group were conducted with 25 child mental health professionals across two sites (Manchester and Edinburgh). Data was analyzed using reflexive thematic analysis. Results: Three overarching themes and 9 sub-themes were identified: (1) feeling a little bit lost; (2) seeing potential problems; and (3) knowing what works. Practitioners expressed interest in a DHI to support this client group and saw it as a way of managing waiting lists and complementing existing therapies. They felt that many young people would see this as a preferred medium to in-person therapy, would be empowering, and offers new ways of learning how to stay safe online. However, there were concerns about how much time would be needed by staff to deliver a DHI, anxieties about safety issues in relation to content and data protection, some of which may be unique to this population of young people, and concerns about the absence of a therapeutic relationship with vulnerable children. Discussion: Our findings indicated that practitioners were uncertain about working with children subjected to OCSA but were receptive to the possibility of using a DHI to support their practice and to reduce waiting lists. Concerns were expressed about the time needed for staff training and support as well as concerns over patient safety and the lack of evidence about the effectiveness of an unsupported DHI.

Influence of threshold selection and image sequence in in-vivo segmentation of enlarged perivascular spaces.

BACKGROUND: Growing interest surrounds perivascular spaces (PVS) as a clinical biomarker of brain dysfunction given their association with cerebrovascular risk factors and disease. Neuroimaging techniques allowing quick and reliable quantification are being developed, but, in practice, they require optimisation as their limits of validity are usually unspecified. NEW METHOD: We evaluate modifications and alternatives to a state-of-the-art (SOTA) PVS segmentation method that uses a vesselness filter to enhance PVS discrimination, followed by thresholding of its response, applied to brain magnetic resonance images (MRI) from patients with sporadic small vessel disease acquired at 3 T. RESULTS: The method is robust against inter-observer differences in threshold selection, but separate thresholds for each region of interest (i.e., basal ganglia, centrum semiovale, and midbrain) are required. Noise needs to be assessed prior to selecting these thresholds, as effect of noise and imaging artefacts can be mitigated with a careful optimisation of these thresholds. PVS segmentation from T1-weighted images alone, misses small PVS, therefore, underestimates PVS count, may overestimate individual PVS volume especially in the basal ganglia, and is susceptible to the inclusion of calcified vessels and mineral deposits. Visual analyses indicated the incomplete and fragmented detection of long and thin PVS as the primary cause of errors, with the Frangi filter coping better than the Jerman filter. COMPARISON WITH EXISTING METHODS: Limits of validity to a SOTA PVS segmentation method applied to 3 T MRI with confounding pathology are given. CONCLUSIONS: Evidence presented reinforces the STRIVE-2 recommendation of using T2-weighted images for PVS assessment wherever possible. The Frangi filter is recommended for PVS segmentation from MRI, offering robust output against variations in threshold selection and pathology presentation.

Magnetic Resonance Imaging Tissue Signatures Associated With White Matter Changes Due to Sporadic Cerebral Small Vessel Disease Indicate That White Matter Hyperintensities Can Regress.

BACKGROUND: White matter hyperintensities (WMHs) might regress and progress contemporaneously, but we know little about underlying mechanisms. We examined WMH change and underlying quantitative magnetic resonance imaging tissue measures over 1 year in patients with minor ischemic stroke with sporadic cerebral small vessel disease. METHODS AND RESULTS: We defined areas of stable normal-appearing white matter, stable WMHs, progressing and regressing WMHs based on baseline and 1-year brain magnetic resonance imaging. In these areas we assessed tissue characteristics with quantitative T1, fractional anisotropy (FA), mean diffusivity (MD), and neurite orientation dispersion and density imaging (baseline only). We compared tissue signatures cross-sectionally between areas, and longitudinally within each area. WMH change masks were available for N=197. Participants' mean age was 65.61 years (SD, 11.10), 59% had a lacunar infarct, and 68% were men. FA and MD were available for N=195, quantitative T1 for N=182, and neurite orientation dispersion and density imaging for N=174. Cross-sectionally, all 4 tissue classes differed for FA, MD, T1, and Neurite Density Index. Longitudinally, in regressing WMHs, FA increased with little change in MD and T1 (difference estimate, 0.011 [95% CI, 0.006-0.017]; -0.002 [95% CI, -0.008 to 0.003] and -0.003 [95% CI, -0.009 to 0.004]); in progressing and stable WMHs, FA decreased (-0.022 [95% CI, -0.027 to -0.017] and -0.009 [95% CI, -0.011 to -0.006]), whereas MD and T1 increased (progressing WMHs, 0.057 [95% CI, 0.050-0.063], 0.058 [95% CI, 0.050 -0.066]; stable WMHs, 0.054 [95% CI, 0.045-0.063], 0.049 [95% CI, 0.039-0.058]); and in stable normal-appearing white matter, MD increased (0.004 [95% CI, 0.003-0.005]), whereas FA and T1 slightly decreased and increased (-0.002 [95% CI, -0.004 to -0.000] and 0.005 [95% CI, 0.001-0.009]). CONCLUSIONS: Quantitative magnetic resonance imaging shows that WMHs that regress have less abnormal microstructure at baseline than stable WMHs and follow trajectories indicating tissue improvement compared with stable and progressing WMHs.

Impact of long-term white matter hyperintensity changes on mobility and dexterity.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, are related to worse clinical outcomes after stroke. We assessed the impact of white matter hyperintensity changes over 1 year after minor stroke on change in mobility and dexterity, including differences between the dominant and non-dominant hands and objective in-person assessment versus patient-reported experience. We recruited participants with lacunar or minor cortical ischaemic stroke, performed medical and cognitive assessments and brain MRI at presentation and at 1 year. At both time points, we used the timed-up and go test and the 9-hole peg test to assess mobility and dexterity. At 1 year, participants completed the Stroke Impact Scale. We ran two linear mixed models to assess change in timed-up and go and 9-hole peg test, adjusted for age, sex, stroke severity (National Institutes of Health Stroke Scale), dependency (modified Rankin Score), vascular risk factor score, white matter hyperintensity volume (as % intracranial volume) and additionally for 9-hole peg test: Montreal cognitive assessment, hand (dominant/non-dominant), National Adult Reading Test (premorbid IQ), index lesion side. We performed ordinal logistic regression, corrected for age and sex, to assess relations between timed-up and go and Stroke Impact Scale mobility, and 9-hole peg test and Stroke Impact Scale hand function. We included 229 participants, mean age 65.9 (standard deviation = 11.13); 66% male. 215/229 attended 1-year follow-up. Over 1 year, timed-up and go time increased with aging (standardized ß [standardized 95% Confidence Interval]: 0.124[0.011, 0.238]), increasing National Institutes of Health Stroke Scale (0.106[0.032, 0.180]), increasing modified Rankin Score (0.152[0.073, 0.231]) and increasing white matter hyperintensity volume (0.176[0.061, 0.291]). Men were faster than women (-0.306[0.011, 0.238]). Over 1 year, slower 9-hole peg test was related to use of non-dominant hand (0.290[0.155, 0.424]), aging (0.102[0.012, 0.192]), male sex (0.182[0.008, 0.356]), increasing National Institutes of Health Stroke Scale (0.160 [0.094, 0.226]), increasing modified Rankin Score (0.100[0.032, 0.169]), decreasing Montreal cognitive assessment score (-0.090[-0.167, -0.014]) and increasing white matter hyperintensity volume (0.104[0.015, 0.193]). One year post-stroke, Stroke Impact Scale mobility worsened per second increase on timed-up and go, odds ratio 0.67 [95% confidence interval 0.60, 0.75]. Stroke Impact Scale hand function worsened per second increase on the 9-hole peg test for the dominant hand (odds ratio 0.79 [0.71, 0.86]) and for the non-dominant hand (odds ratio 0.88 [0.83, 0.93]). Decline in mobility and dexterity is associated with white matter hyperintensity volume increase, independently of stroke severity. Mobility and dexterity declined more gradually for stable and regressing white matter hyperintensity volume. Dominant and non-dominant hands might be affected differently. In-person measures of dexterity and mobility are associated with self-reported experience 1-year post-stroke.

Incident Infarcts in Patients With Stroke and Cerebral Small Vessel Disease: Frequency and Relation to Clinical Outcomes.

BACKGROUND AND OBJECTIVES: Factors associated with cerebral small vessel disease (SVD) progression, including incident infarcts, are unclear. We aimed to determine the frequency of incident infarcts over 1 year after minor stroke and their relation to baseline SVD burden, vascular risks, and recurrent stroke and cognitive outcomes. METHODS: We recruited patients with lacunar or nondisabling cortical stroke. After diagnostic imaging, we repeated structural MRI at 3-6 monthly intervals for 12 months, visually assessing incident infarcts on diffusion-weighted imaging or FLAIR. We used logistic regression to determine associations of baseline vascular risks, SVD score, and index stroke subtype with subsequent incident infarcts. We assessed cognitive and functional outcomes at 1 year using Montreal Cognitive Assessment (MoCA) and modified Rankin scale (mRS), adjusting for baseline age, mRS, MoCA, premorbid intelligence, and SVD score. RESULTS: We recruited 229 participants, mean age 65.9 (SD 11.1). Over half of all participants, 131 of 229 (57.2%) had had an index lacunar stroke. From baseline to 1-year MRI, we detected 117 incident infarcts in n = 57/229 (24.8%) participants. Incident infarcts were mainly of the small subcortical (86/117 [73.5%] in n = 38/57 [66.7%]) vs cortical infarct subtype (n = 19/57 [33.3%]). N = 39/57 participants had incident infarcts at 1 visit; 18 of 57 at 2 or more visits; and 19 of 57 participants had multiple infarcts at a single visit. Only 7 of 117 incident infarcts corresponded temporally to clinical stroke syndromes. The baseline SVD score was the strongest predictor of incident infarcts (adjusted odds ratio [OR] 1.87, 95% CI 1.39-2.58), while mean arterial pressure was not associated. All participants with incident infarcts were prescribed an antiplatelet or anticoagulant. Lower 1-year MoCA was associated with lower baseline MoCA (ß 0.47, 95% CI 0.33-0.61), lower premorbid intelligence, and older age. Higher 1-year mRS was associated with higher baseline mRS only (OR 5.57 [3.52-9.10]). Neither outcome was associated with incident infarcts. DISCUSSION: In the year after stroke in a population enriched for lacunar stroke, incident infarcts occurred in one-quarter and were associated with worse baseline SVD. Most incident infarcts detected on imaging did not correspond to clinical stroke/transient ischemic attack. Worse 1-year cognition and function were not associated with incident infarcts.

Paranasal sinuses opacification on magnetic resonance imaging in relation to brain health in sporadic small vessel disease - Systematic review and pilot analysis.

BACKGROUND: The paranasal sinus mucosal thickening, visible in magnetic resonance imaging (MRI), maybe a source of inflammation in microvessels, but its relationship with small vessel disease (SVD) is unclear. We reviewed the literature and analysed a sample of patients with sporadic SVD to identify any association between paranasal sinus opacification severity and SVD neuroimaging markers. METHODS: We systematically reviewed MEDLINE and EMBASE databases up to April 2020 for studies on paranasal sinus mucosal changes in patients with SVD, cerebrovascular disease (CVD), and age-related neurodegenerative diseases. We analysed clinical and MRI data from 100 participants in a prospective study, the Mild Stroke Study 3 (ISRCTN 12113543) at 1-3, 6 and 12 months following a minor stroke to test key outcomes from the literature review. We used multivariate linear regression to explore associations between modified Lund-Mackay (LM) scores and brain, white matter hyperintensities (WMH), enlarged perivascular spaces (PVS) volumes at each time point, adjusted for baseline age, sex, diabetes, hypercholesterolaemia, hypertension and smoking. RESULTS: The literature review, after screening 3652 publications, yielded 11 primary studies, for qualitative synthesis with contradictory results, as positive associations/higher risk from 5/7 CVD studies were contradicted by the two studies with largest samples, and data from dementia studies was equally split in their outcome. From the pilot sample of patients analysed (female N = 33, mean age 67.42 (9.70) years), total LM scores had a borderline negative association with PVS in the centrum semiovale at baseline and 6 months (B = -0.25, SE = 0.14, p = 0.06) but were not associated with average brain tissue, WMH or normal-appearing white matter volumes. CONCLUSION: The inconclusive results from the literature review and empirical study justify larger studies between PVS volume and paranasal sinuses opacification in patients with sporadic SVD.

Associations of Peak-Width Skeletonized Mean Diffusivity and Post-Stroke Cognition.

Post-stroke cognitive impairment is common and can have major impact on life after stroke. Peak-width of Skeletonized Mean Diffusivity (PSMD) is a diffusion imaging marker of white matter microstructure and is also associated with cognition. Here, we examined associations between PSMD and post-stroke global cognition in an ongoing study of mild ischemic stroke patients. We studied cross-sectional associations between PSMD and cognition at both 3-months (N = 229) and 1-year (N = 173) post-stroke, adjusted for premorbid IQ, sex, age, stroke severity and disability, as well as the association between baseline PSMD and 1-year cognition. At baseline, (mean age = 65.9 years (SD = 11.1); 34% female), lower Montreal Cognitive Assessment (MoCA) scores were associated with older age, lower premorbid IQ and higher stroke severity, but not with PSMD (ßstandardized = −0.116, 95% CI −0.241, 0.009; p = 0.069). At 1-year, premorbid IQ, older age, higher stroke severity and higher PSMD (ßstandardized = −0.301, 95% CI −0.434, −0.168; p < 0.001) were associated with lower MoCA. Higher baseline PSMD was associated with lower 1-year MoCA (ßstandardized = −0.182, 95% CI −0.308, −0.056; p = 0.005). PSMD becomes more associated with global cognition at 1-year post-stroke, possibly once acute effects have settled. Additionally, PSMD in the subacute phase after a mild stroke could help predict long-term cognitive impairment.

Relationship between inferior frontal sulcal hyperintensities on brain MRI, ageing and cerebral small vessel disease.

Raised signal in cerebrospinal fluid (CSF) on fluid-attenuated inversion recovery (FLAIR) may indicate raised CSF protein or debris and is seen in inferior frontal sulci on routine MRI. To explore its clinical relevance, we assessed the association of inferior frontal sulcal hyperintensities (IFSH) on FLAIR with demographics, risk factors, and small vessel disease markers in three cohorts (healthy volunteers, n=44; mild stroke patients, n=105; older community-dwelling participants from Lothian birth cohort 1936, n=101). We collected detailed clinical data, scanned all subjects on the same 3T MRI scanner and 3-dimensional FLAIR sequence and developed a scale to rate IFSH. In adjusted analyses, the IFSH score increased with age (per 10-year increase; OR 1.69; 95% CI, 1.42-2.02), and perivascular spaces score in centrum semiovale in stroke patients (OR 1.73; 95% CI, 1.13-2.69). Since glymphatic CSF clearance declines with age and drains partially via the cribriform plate to the nasal lymphatics, IFSH on 3T MRI may be a non-invasive biomarker of altered CSF clearance and justifies further research in larger, more diverse samples.

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3.

BACKGROUND: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood-brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease.Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood-brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543. SUMMARY: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy.