Fergus N. Doubal

Background and ObjectivesCross-sectional studies suggest that retinal microvascular abnormalities measured by optical coherence tomography angiography (OCTA) are associated with cerebral small vess...

Background and ObjectivesRecent small subcortical infarcts (RSSI) are common, but little is known about their tissue fates and relevance for clinical outcomes. We assessed predictors for long-term ...

BACKGROUND: The Fazekas score is widely used to grade white matter hyperintensities (WMHs) in cerebral small vessel disease, yet the equivalent volume of each grade is unclear. We quantified the correspondence between Fazekas scores and WMH volume, normalized ratios, and derived conversion equations across populations. METHODS: We analyzed 1220 participants from 4 mostly United Kingdom–based cohorts representing different cerebral small vessel disease severities: community-dwelling (LBC1936 [Lothian Birth Cohort 1936]), stroke (MSS2 [Mild Stroke Study 2] and MSS3 [Mild Stroke Study 3]), and a cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy-enriched cohort (INVESTIGATE [Imaging Neuro-Vascular, Endothelial and Structural Integrity in Preparation to Treat Small Vessel Diseases]). WMH burden was quantified as absolute WMH volume and as normalized ratios: WMH volume as a percentage of brain volume and WMH volume as a percentage of intracranial volume. Transition zones were defined as the overlap of WMH volume interquartile ranges between adjacent Fazekas scores. Linear, exponential (nonlinear least squares), and log-linear (ln WMH≈Fazekas score and zeros excluded) models were fitted; model fit was assessed using mean squared error, (pseudo-)R ² , and Vuong tests. Periventricular-versus-deep WMH patterns within each total Fazekas score were compared using the Kruskal-Wallis test. RESULTS: The pooled cohort had a mean age of 69.4±8.9 years; 700 of 1227 records (57.1%) were male. WMH burden increased monotonically with a Fazekas score in all cohorts. Adjacent-grade separation was strongest in LBC1936 (all P ≤0.002) but weaker at lower grades in MSS2, MSS3, and INVESTIGATE. The widest transition zones occurred between Fazekas grades of 3 to 4 and 4 to 5, whereas a clear WMH volume gap separated grades 5 and 6. Exponential models generally fit better than linear models, with lower mean squared error and supportive Vuong tests in most cohorts. Log-linear sensitivity analyses showed similar fitted trajectories after back-transformation. WMH burden did not differ consistently by periventricular-versus-deep distribution within Fazekas grades. CONCLUSIONS: WMH burden followed an exponential trajectory across Fazekas scores, with population-dependent progression. The resulting conversion equations enabled bidirectional translation between visual Fazekas score and quantitative WMH volume, facilitating cross-study comparison, large-scale epidemiology, and might facilitate clinical decision-making in cerebral small vessel disease.

Background: Lacunar stroke can cause cognitive decline and dependency. The LACI‐2 (Lacunar Intervention Trial‐2) trial showed that 12 months of treatment with isosorbide‐mononitrate (ISMN) or cilostazol improved these outcomes. We tested whether this effect was present at 6 months. Methods: LACI‐2 was a prospective randomized open‐label blinded‐end point 2×2‐factorial phase‐2b trial assessing feasibility, safety, and proof‐of‐concept of 1 year of ISMN (40–60 mg) or cilostazol (200 mg). Participants aged >30 years had clinical lacunar stroke, compatible neuroimaging, and capacity to consent. The primary clinical outcome was the composite of stroke, myocardial infarction, dependency (modified Rankin Scale score >2), cognitive impairment ( Diagnostic and Statistical Manual version 5, 7‐level >0) and death; key secondary outcomes included the composite components, mood and stroke impact scale. Global analysis of the stroke impact scale was analyzed using the Wei–Lachin test with result given as Mann–Whitney difference. Results: Baseline characteristics were balanced across 363 participants: median age 64 (56–72) years, 31% female, and median onset to randomization 79 (27–244) days. At 6 months, participants allocated to ISMN versus control had fewer composite events (adjusted odds ratio [OR], 0.74 [95% CI, 0.55–0.99]) and improved stroke impact (Mann–Whitney difference, −0.15 [95% CI −0.25 to −0.05]). Cilostazol versus control improved cognition ( Diagnostic and Statistical Manual version 5, 7‐level scale, adjusted common OR, 0.64 [95% CI, 0.41–0.99]). ISMN/cilostazol versus control improved cognition ( Diagnostic and Statistical Manual version 5, 7‐level adjusted common OR, 0.40 [95% CI, 0.21–0.78]), mood (Zung adjusted mean difference, −6.94 [95% CI, −12.25 to −1.64]) and global stroke impact (Mann–Whitney difference, −0.23 [95% CI, −0.37 to −0.09]). Conclusions: A reduction in the composite outcome, cognitive impairment, dependency, and stroke impact was seen within 6 months of starting ISMN or cilostazol. Registration: URL: www.isrctn.com ; Unique Identifier: ISRCTN14911850.

Introduction: Stroke is often followed by vascular cognitive impairment and vascular dementia, the most feared complications of stroke. However, understanding of post-stroke cognitive impairment remains limited. Methods: Rates, Risks and Routes to Reduce Vascular Dementia (R4VaD) is an observational cohort study of post-stroke cognition. Patients with haemorrhagic or ischaemic stroke, or transient ischaemic attack, were recruited within six weeks of stroke from hospitals across the UK. Consent was obtained from patients with capacity or from relatives/friends in those without capacity. The primary outcome is dementia rate and its severity at two years assessed using a 7-level ordinal cognition outcome. Final dementia rate will be compared in those with mild stroke/TIA (worst NIHSS <=7) versus severe stroke (NIHSS >7). Secondary outcomes will include cognitive impairment, function, mood and quality of life, and predictors of cognitive impairment at one and two years. Data are shown as number (%), median [interquartile range, IQR] or mean (standard deviation, SD). Results: We recruited 2441 patients from 50 hospitals. Of these, 2432 (99.6%) had a qualifying event of stroke or TIA. The mean age was 68.2 years (SD 13.5), females 979 (40.3%), ethnic minority 170 (7.0%), NIHSS <=7 1962 (80.7%), onset to recruitment 5 days [IQR 3-13] and diagnosis ICH 192 (7.9%), ischaemic stroke 2097 (86.2%), TIA 143 (5.9%). The distribution of cognition at baseline (within 6 weeks of onset) was: normal 1300 (53.5%), minor neurocognitive disorder-single domain 351 (14.4%), minor neurocognitive disorder-multi domain 263 (10.8%), major neurocognitive disorder-mild 387 (15.9%), major neurocognitive disorder-moderate 108 (4.4%) and major neurocognitive disorder-severe 23 (0.1%). Participants with more severe stroke were recruited later (8 [IQR 3-17] vs 5 [2-11] days, p<0.001), less likely to have capacity (86.3% vs 96.8%, p<0.001) and more likely to have had an intracerebral haemorrhage (12.0% vs 6.8%, p<0.001). Conclusion: We provide baseline data with the statistical analysis plan in the appendix. The data highlight the substantial under-appreciated cognitive burden of stroke, even in the first few days and weeks after onset.

BACKGROUND: Stenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small-vessel disease (cSVD) remain contentious. We investigated the associations of large-artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes. METHODS: We prospectively recruited patients with lacunar or mild nonlacunar stroke, with demographic, stroke-related, cognitive, functional, and magnetic resonance imaging (index and incident infarcts, cSVD markers) assessments at baseline and 1 year. LAS was defined as ≥50% intracranial or cervical artery stenosis; basilar artery dolichoectasia was defined by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated from multivariable logistic, linear, and proportional odds regression models adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large-artery pathology and cSVD. RESULTS: Among 229 patients (mean age, 65.9±11.1 years; 131 [57.2%] lacunar stroke), LAS and basilar artery dolichoectasia were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio, 0.49 [95% CI, 0.23–0.99]) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, basilar artery dolichoectasia was strongly associated with lacunar stroke (odds ratio, 4.67 [95% CI, 1.87–13.14]), higher cSVD scores (ordinal analysis; odds ratio, 2.57 [95% CI, 1.28–5.25]), incident infarcts (75% subcortical; odds ratio, 2.29 [95% CI, 1.01–5.14]), and greater progression of white matter hyperintensities over 1 year (β, 0.15 [95% CI, 0.01–0.29] per log ₁₀ -transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings. CONCLUSIONS: cSVD, including lacunar stroke, was unrelated to LAS but strongly associated with dolichoectasia and wider arteries. These findings support a nonatheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted.

Background Outcome after stroke varies according to stroke subtype by location, but healthcare systems data studies do not include subtyping information. We linked natural language processing (NLP) of brain imaging reports to routinely collected data to estimate risk of death and other outcomes after stroke subtypes in a nationwide dataset. Methods We applied a previously validated NLP algorithm to all CT and MRI head scan reports in Scotland between 2010 and 2018. We linked the reports to hospital readmissions, prescriptions and death data to identify and characterize people with stroke, and to categorize into deep and cortical ischemic stroke, deep and lobar intracerebral hemorrhage (ICH), subarachnoid hemorrhage, and subdural hemorrhage. We used a matched cohort design, and age- and sex-matched four controls per case who never had a stroke. By subtype, we estimated rehospitalization with stroke, myocardial infarction (MI), cancer, dementia, epilepsy and death, accounting for confounders and competing risk of death. Results From 785,331 people with a head scan, we identified 64,219 with clinical stroke phenotypes (mean age 73.4yrs, 49.5% male), and subtyped 12,616 with deep ischaemic stroke; 14,103 with cortical ischaemic stroke; 1,814 with deep ICH; and 1,456 with lobar ICH. There was higher absolute rate of 1-year hospital readmission for lobar compared with deep ICH (4.9% [95%CI 3.9% - 6.1%] vs 3.4% [2.6% - 4.3%]), higher risk of dementia beyond 6 months after lobar ICH compared to controls than for other stroke subtypes (aHR 3.5 [2.3-5.3]); and higher risk of MI within 6 months of cortical ischemic stroke than for other stroke subtypes (aHR 4.6 [3.4-6.3]). Conclusions NLP of free-text reports linked to coded data successfully subtyped stroke at scale, and we estimated risk of clinically relevant outcomes. Future work should use free text to enable large-scale audit and epidemiology of people with stroke.

Background: Novel risk factors for stroke, such as occupation, are increasingly under exploration. We investigate if specific occupational exposures and settings increase the risk of developing small‐vessel disease (SVD), including SVD‐related strokes. Methods: We performed a systematic review on stroke–occupation associations and then analyzed data from patients presenting to Lothian stroke services with mild ischemic stroke (modified Rankin Scale score ≤2). We performed magnetic resonance imaging and inquired about occupational status. We assessed relationships between high‐risk occupations (per Control to Substances Hazardous to Health guidelines) and standard occupational classifications (per Standard Occupational Classifications criteria) against white matter hyperintensity volumes, SVD score, and stroke subtype. Results: Our systematic review identified 37 papers assessing occupations/broad occupational classifications (n=13), psychosocial work‐related factors (n=11), and occupational exposure to hazardous substances (n=13). We then analyzed data from 414 participants and found, after adjustment for age, hypercholesterolemia, socioeconomic status, years of education, hypertension, diabetes, and smoking history, that high‐risk occupations were associated with higher SVD scores (odds ratio, 1.64 [95% CI, 1.07–2.54]; n=357; P =0.02) but not for lacunar stroke subtype (odds ratio, 1.03 [95% CI, 0.64–1.67]; n=358; P =0.90) or white matter hyperintensity volume (% intracranial volume) (β=−0.003 [95% CI, −0.015 to 0.008]; n=357; P =0.60). Examples of high‐risk occupations include drivers, engineers, and skilled trade workers. No associations were found for standard occupational classifications. Conclusions: This systematic review shows limited data on stroke–occupation associations. Our analysis showed that high‐risk occupations are associated with higher SVD scores but not stroke subtype. Registration: URL: www.crd.york.ac.uk/PROSPERO ; Unique Identifier: 42024466671.

Background: Stenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small vessel disease (cSVD) remain contentious. We investigated associations of large artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes. Methods: We prospectively recruited patients with lacunar or mild non-lacunar stroke, with demographic, stroke-related, cognitive, functional, and MRI (index and incident infarcts, cSVD markers) assessments at baseline and one year. LAS was defined as ≥50% intracranial or cervical artery stenosis; basilar artery dolichoectasia (BADE) by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated using multivariable regression adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large artery pathology and cSVD. Results: Among 229 patients (mean age 65.9±11.1 years; 131 [57.2%] lacunar stroke), LAS and BADE were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio [OR], 0.49; 95%CI, 0.23-0.99) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, BADE was strongly associated with lacunar stroke (OR, 4.67; 95%CI, 1.87-13.14), higher cSVD scores (ordinal analysis; OR, 2.57; 95%CI, 1.28-5.25), incident infarcts (75% subcortical; OR, 2.29; 95%CI, 1.01-5.14), and greater progression of white matter hyperintensities over one year (β, 0.15; 95%CI, 0.01-0.29; per log ₁₀ -transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings. Conclusions: cSVD, including lacunar stroke, was unrelated to LAS, but strongly associated with dolichoectasia and wider arteries. These findings support a non-atheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted. Clinical Perspective: What Is New?: ● Large artery stenosis was unlikely to represent a causal mechanism for lacunar stroke and showed no association with cerebral small vessel disease (cSVD) imaging markers. ● Dolichoectasia and intracranial arterial widening emerged as vascular phenotypes strongly associated with cSVD, including its progression and lacunar stroke subtype. What Are the Clinical Implications?: ● Distinct large artery phenotypes have divergent etiopathological implications for cSVD. Our findings support a non-atheromatous, intrinsic microvascular pathology as the principal mechanism of lacunar stroke and cSVD. ● Mechanism-based therapeutic strategies for lacunar stroke and cSVD, moving beyond conventional approaches focused on atherosclerosis or cardioembolism, are warranted.