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Cerebrovascular disease is the second most common cause of cognitive disorders, usually referred to as vascular contributions to cognitive impairment and dementia (VCID) and makes some contribution to about 70 % of all dementias. Despite its importance, research into VCID has lagged as compared to cognitive impairment due to Alzheimer's disease. There is an increasing appreciation that closing this gap requires large national and international collaborations. This paper highlights 24 notable large-scale national and international efforts to advance research into VCID (MarkVCID, DiverseVCID, DISCOVERY, COMPASS-ND, HBC, RHU SHIVA, UK DRI Vascular Theme, STROKOG, Meta VCI Map, ISGC, ENIGMA-Stroke Recovery, CHARGE, SVDs@target, BRIDGET, CADASIL Consortium, CADREA, AusCADASIL, DPUK, DPAU, STRIVE, HARNESS, FINESSE, VICCCS, VCD-CRE Delphi). These collaborations aim to investigate the effects on cognition from cerebrovascular disease or impaired cerebral blood flow, the mechanisms of action, means of prevention and avenues for treatment. Consensus groups have been developed to harmonise global approaches to VCID, standardise terminology and inform management and treatment, and data sharing is becoming the norm. VCID research is increasingly a global collaborative enterprise which bodes well for rapid advances in this field.

Introduction In population-based research, disease ascertainment algorithms can be as accurate as, and less costly than, performing supplementary clinical examinations on selected participants to confirm a diagnosis of a neurocognitive disorder (NCD), but they require cohort-specific validation. To optimise the use of the Canadian Longitudinal Study on Aging (CLSA) to understand the epidemiology and burden of NCDs, the CLSA Memory Study will validate an NCD ascertainment algorithm to identify CLSA participants with these disorders using routinely acquired study data.Methods and analysis Up to 600 CLSA participants with equal numbers of those likely to have no NCD, mild NCD or major NCD based on prior self-reported physician diagnosis of a memory problem or dementia, medication consumption (ie, cholinesterase inhibitors, memantine) and/or self-reported function will be recruited during the follow-up 3 CLSA evaluations (started August 2021). Participants will undergo an assessment by a study clinician who will also review an informant interview and make a preliminary determination of the presence or absence of an NCD. The clinical assessment and available CLSA data will be reviewed by a Central Review Panel who will make a final categorisation of participants as having (1) no NCD, (2) mild NCD or, (3) major NCD (according to fifth version of the Diagnostic and Statistical Manual of Mental Disorders criteria). These will be used as our gold standard diagnosis to determine if the NCD ascertainment algorithm accurately identifies CLSA participants with an NCD. Weighted Kappa statistics will be the primary measure of agreement. Sensitivity, specificity, the C-statistic and the phi coefficient will also be estimated.Ethics and dissemination Ethics approval has been received from the institutional research ethics boards for each CLSA Data Collection Site (Université de Sherbrooke, Hamilton Integrated Research Ethics Board, Dalhousie University, Nova Scotia Health Research Ethics Board, University of Manitoba, McGill University, McGill University Health Centre Research Institute, Memorial University of Newfoundland, University of Victoria, Élisabeth Bruyère Research Institute of Ottawa, University of British Columbia, Island Health (Formerly the Vancouver Island Health Authority, Simon Fraser University, Calgary Conjoint Health Research Ethics Board).The results of this work will be disseminated to public health professionals, researchers, health professionals, administrators and policy-makers through journal publications, conference presentations, publicly available reports and presentations to stakeholder groups.

Introduction To date, there is no broadly accepted dementia risk score for use in individuals with mild cognitive impairment (MCI), partly because there are few large datasets available for model development. When evidence is limited, the knowledge and experience of experts becomes more crucial for risk stratification and providing MCI patients with prognosis. Structured expert elicitation (SEE) includes formal methods to quantify experts’ beliefs and help experts to express their beliefs in a quantitative form, reducing biases in the process. This study proposes to (1) assess experts’ beliefs about important predictors for 3-year dementia risk in persons with MCI through SEE methodology and (2) to integrate expert knowledge and patient data to derive dementia risk scores in persons with MCI using a Bayesian approach.Methods and analysis This study will use a combination of SEE methodology, prospectively collected clinical data, and statistical modelling to derive a dementia risk score in persons with MCI . Clinical expert knowledge will be quantified using SEE methodology that involves the selection and training of the experts, administration of questionnaire for eliciting expert knowledge, discussion meetings and results aggregation. Patient data from the Prospective Registry for Persons with Memory Symptoms of the Cognitive Neurosciences Clinic at the University of Calgary; the Alzheimer’s Disease Neuroimaging Initiative; and the National Alzheimer’s Coordinating Center’s Uniform Data Set will be used for model training and validation. Bayesian Cox models will be used to incorporate patient data and elicited data to predict 3-year dementia risk.Discussion This study will develop a robust dementia risk score that incorporates clinician expert knowledge with patient data for accurate risk stratification, prognosis and management of dementia.

Actively engaging people with lived experience (PWLE) in stroke-related clinical practice guideline development has not been effectively implemented. This pilot project evaluated the feasibility, perceived value, and effectiveness of the Community Consultation and Review Panel (CCRP), a new model to engage PWLE in the writing and review of Canadian Stroke Best Practice Recommendations. Responses to a standardized evaluation tool indicated that participants perceived the CCRP as valued, impactful, effective, and beneficial to stroke care. This project successfully demonstrated that values, experiences, and recommendations of PWLE can be effectively incorporated into guideline content and is applicable to all guideline development processes.

Background and purposePatients with transient ischemic attack (TIA) show evidence of cognitive impairment but the reason is not clear. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. We report WM changes using DTI and the relationship with neuropsychological performance in a cohort of transient ischemic attack (TIA) and non-TIA subjects.MethodsNinety-five TIA subjects and 51 non-TIA subjects were assessed using DTI and neuropsychological batteries. Fractional anisotropy (FA) and mean diffusivity (MD) maps were generated and measurements were collected from WM tracts. Adjusted mixed effects regression modelled the relationship between groups and DTI metrics.ResultsTransient ischemic attack subjects had a mean age of 67.9 ± 9.4 years, and non-TIA subjects had a mean age 64.9 ± 9.9 years. The TIA group exhibited higher MD values in the fornix (0.36 units, P < 0.001) and lower FA in the superior longitudinal fasciculus (SLF) (-0.29 units, P = 0.001), genu (-0.22 units, P = 0.016), and uncinate fasciculus (UF) (-0.26 units, P = 0.004). Compared to non-TIA subjects, subjects with TIA scored lower on the Addenbrooke's Cognitive Assessment-Revised (median score 95 vs 91, P = 0.01) but showed no differences in scores on the Montreal Cognitive Assessment (median 27 vs 26) or the Mini-Mental State Examination (median 30). TIA subjects had lower scores in memory (median 44 vs 52, P < 0.01) and processing speed (median 45 vs 62, P < 0.01) but not executive function, when compared to non-TIA subjects. Lower FA and higher MD in the fornix, SLF, and UF were associated with poorer performance on tests of visual memory and executive function but not verbal memory. Lower FA in the UF and fornix were related to higher timed scores on the TMT-B (P < 0.01), and higher SLF MD was related to higher scores on TMT-B (P < 0.01), confirming worse executive performance in the TIA group.ConclusionsDTI scans may be useful for detecting microstructural disease in TIA subjects before cognitive symptoms develop. DTI parameters, white matter hyperintensities, and vascular risk factors underly some of the altered neuropsychological measures in TIA subjects.

Hypertension is the strongest modifiable risk factor for subcortical ischemic changes and is also a risk factor for Alzheimer's dementia. We used neuroimaging to investigate the pathological basis of early cognitive symptoms in patients with hypertension.In this cross-sectional cohort study 67 patients age >60 years with hypertension and Clinical Dementia Rating scale score of 0.5 without dementia, and without history of symptomatic stroke, underwent MRI for measurement of subcortical vascular changes and positron emission tomography (PET) scan with Pittsburgh Compound B (PiB-PET) to detect beta-amyloid deposition. These imaging measures were related to neuropsychological tests of memory, executive function and processing speed.Mean age was 75.0 (standard deviation, SD, 7.3). Mean neuropsychological Z scores were: episodic memory -0.63 (SD 1.23), executive function -0.40 (SD 1.10), processing speed -0.24 (SD 0.88); 22 of the 67 subjects met criteria for mild cognitive impairment (MCI) and the remaining 45 subjects had subjective cognitive concerns only. In multivariable models adjusting for age and years of education, each 0.1 unit increase in mean cortical PiB-PET binding was associated with 0.14 lower mean Z score for episodic memory (95% CI -0.28 to -0.01). This means that for every 0.1 unit increase in mean cortical PiB-PET, episodic memory was 0.14 standard deviations lower. White matter hyperintensity volume, silent brain infarcts and microbleeds were not associated with neuropsychological test scores.Episodic memory was prominently affected in hypertensive participants with MCI or subjective cognitive concerns, and was associated with PiB-PET binding. This suggests a prominent role for Alzheimer pathology in cognitive impairment even in hypertensive participants at elevated risk for vascular cognitive impairment.

The primary purpose of this Brain in Motion (BIM) sub-study was to determine the 6-month stability of resting blood flow velocity and cerebrovascular responsiveness to a euoxic hypercapnic challenge in a group of physically inactive community dwelling men and men aged ≥55 yrs (range 55-92 yrs). At baseline and 6 months later 88 women (65±6 yr) and 78 men (67±7 yr) completed a hypercapnic challenge (step changes from resting end-tidal PCO2 ((PETCO2) to +1, +5 and +8 mmHg above rest) while cerebral blood flow velocity was assessed using transcranial Doppler ultrasound. Peak velocity of the middle cerebral artery (MCAv) was increased (p0.05) when MCAv was normalized to PETCO2. During hypercapnia, MCAv tended to be increased at follow-up, but this finding was absent when MCAv/PETCO2 was compared across time. Cerebrovascular reactivity (i.e., ΔMCAv/ΔPETCO2) was similar (p>0.05) between testing occasions regardless of the approach taken (i.e., considering only the lower step [from +1 to +5 mmHg]; the upper step [+5 to +8 mmHg]; or the complete test taken together). In conclusion, this study has shown that cerebral blood flow and cerebrovascular responsiveness to acute euoxic hypercapnia are stable in older, healthy adults over a 6-month period. Modest changes in MCAv over time must be viewed in the context of underlying differences in PETCO2, an important finding with implications for future studies considering cerebral blood flow velocity.

Advances in genetic technology have revealed that variation in the same gene can cause both rare familial and common sporadic forms of the same disease. Cerebral amyloid angiopathy (CAA), a common cause of symptomatic intracerebral hemorrhage (ICH) in the elderly, can also occur in families in an autosomal dominant pattern. The majority of affected families harbor mutations in the Beta amyloid Peptide (Aβ) coding region of the gene for amyloid precursor protein (APP) or have duplications of chromosomal segments containing APP.A total of 58 subjects with a diagnosis of probable or definite CAA according to validated criteria were included in the present study. We sequenced the Aβ coding region of APP in 58 individuals and performed multiplex ligation-dependent probe amplification to determine APP gene dosage in 60. No patient harbored a known or novel APP mutation or gene duplication. The frequency of mutations investigated in the present study is estimated to range from 0% to 8% in individuals with probable CAA in the general population, based on the ascertained sample size.We found no evidence that variants at loci associated with familial CAA play a role in sporadic CAA. Based on our findings, these rare highly-penetrant mutations are unlikely to be seen in sporadic CAA patients. Therefore, our results do not support systematic genetic screening of CAA patients who lack a strong family history of hemorrhage or dementia.

Background Long-term outcomes for Medicare beneficiaries hospitalised with transient ischaemic attack (TIA) and role of ABCD2 score in identifying high-risk individuals are not studied.Methods We identified 40 825 Medicare beneficiaries hospitalised from 2011 to 2014 for a TIA to a Get With The Guidelines (GWTG)-Stroke hospital and classified them using ABCD2 score. Proportional hazards models were used to assess 1-year event rates of mortality and rehospitalisation (all-cause, ischaemic stroke, haemorrhagic stroke, myocardial infarction, and gastrointestinal and intracranial haemorrhage) for high-risk versus low-risk groups adjusted for patient and hospital characteristics.Results Of the 40 825 patients, 35 118 (86%) were high risk (ABCD2 ≥4) and 5707 (14%) were low risk (ABCD2=0–3). Overall rate of mortality during 1-year follow-up after hospital discharge for the index TIA was 11.7%, 44.3% were rehospitalised for any reason and 3.6% were readmitted due to stroke. Patients with ABCD2 score ≥4 had higher mortality at 1 year than not (adjusted HR 1.18, 95% CI 1.07 to 1.30). Adjusted risks for ischaemic stroke, all-cause readmission and mortality/all-cause readmission at 1 year were also significantly higher for patients with ABCD2 score ≥4 vs 0–3. In contrast, haemorrhagic stroke, myocardial infarction, gastrointestinal bleeding and intracranial haemorrhage risk were not significantly different by ABCD2 score.Conclusions This study validates the use of ABCD2 score for long-term risk assessment after TIA in patients aged 65 years and older. Attentive efforts for community-based follow-up care after TIA are needed for ongoing prevention in Medicare beneficiaries who were hospitalised for TIA.

Hyperacute, spontaneous, and severe parenchymal postischemic hemorrhage is considered rare but might be frequently misdiagnosed as primary intracerebral hemorrhage. The authors report 2 patients with catastrophic postischemic hemorrhage unrelated to anticoagulation, thrombolytics, or coagulopathy. Patient 1 was a 73-year-old woman with left posterior frontal lobe infarction, followed at 5.5 hours by massive postischemic hemorrhage leading to death. Patient 2 was a 52-year-old man with recent brain irradiation who developed left middle cerebral artery occlusion and basal ganglia infarction. Initial gradient-echo magnetic resonance imaging (MRI) showed petechial hemorrhage within areas of infarction and widespread old microbleeds. He developed massive postischemic hemorrhage at 12 hours, leading to death. The authors conclude that early brain imaging is essential to distinguish postischemic from primary brain hemorrhage. In patients with ischemic stroke, MRI findings such as hyperacute petechial hemorrhage or chronic cerebral microbleeds might predict subsequent parenchymal hemorrhage and thus have implications for tissue plasminogen activator use. [ABSTRACT FROM AUTHOR]

IntroductionWhite matter hyperintensities (WMHs) are frequently observed on magnetic resonance (MR) images in older adults, commonly appearing as areas of high signal intensity on fluid-attenuated inversion recovery (FLAIR) MR scans. Elevated WMH volumes are associated with a greater risk of dementia and stroke, even after accounting for vascular risk factors. Manual segmentation, while considered the ground truth, is both labor-intensive and time-consuming, limiting the generation of annotated WMH datasets. Un-annotated data are relatively available; however, the requirement of annotated data poses a challenge for developing supervised machine learning models.MethodsTo address this challenge, we implemented a multi-stage semi-supervised learning (M3SL) approach that first uses un-annotated data segmented by traditional processing methods (“bronze” and “silver” quality data) and then uses a smaller number of “gold”-standard annotations for model refinement. The M3SL approach enabled fine-tuning of the model weights with the gold-standard annotations. This approach was integrated into the training of a U-Net model for WMH segmentation. We used data from three scanner vendors (over more than five scanners) and from both cognitively normal (CN) adult and patients cohorts [with mild cognitive impairment and Alzheimer's disease (AD)].ResultsAn analysis of WMH segmentation performance across both scanner and clinical stage (CN, MCI, AD) factors was conducted. We compared our results to both conventional and transfer-learning deep learning methods and observed better generalization with M3SL across different datasets. We evaluated several metrics (F-measure, IoU, and Hausdorff distance) and found significant improvements with our method compared to conventional (p < 0.001) and transfer-learning (p < 0.001).DiscussionThese findings suggest that automated, non-machine learning, tools have a role in a multi-stage learning framework and can reduce the impact of limited annotated data and, thus, enhance model performance.

Abstract Decline in cognitive function is the most feared aspect of ageing. Poorer midlife cognitive function is associated with increased dementia and stroke risk. The mechanisms underlying variation in cognitive function are uncertain. Here, we assessed associations between 1160 proteins’ plasma levels and two measures of cognitive function, the digit symbol substitution test (DSST) and the Montreal Cognitive Assessment in 1198 PURE-MIND participants. We identified five DSST performance-associated proteins (NCAN, BCAN, CA14, MOG, CDCP1), with NCAN and CDCP1 showing replicated association in an independent cohort, GS (N = 1053). MRI-assessed structural brain phenotypes partially mediated (8–19%) associations between NCAN, BCAN, and MOG, and DSST performance. Mendelian randomisation analyses suggested higher CA14 levels might cause larger hippocampal volume and increased stroke risk, whilst higher CDCP1 levels might increase intracranial aneurysm risk. Our findings highlight candidates for further study and the potential for drug repurposing to reduce the risk of stroke and cognitive decline.

Background: : Preventing or reducing the risk of cognitive decline and dementia is of great public health interest. Longitudinal data from diverse samples are needed to properly inform clinicians, researchers, and policy makers. CAN-PROTECT is a recently launched online observational cohort study that assesses factors contributing to both risk for incident cognitive decline and dementia and resilience against brain aging, in participants across the lifespan. Methods: : Measures of cognition, behaviour, and quality of life administered to both participants and study partners were compared using partial Spearman correlations adjusted for participant and study partner age, sex, and education. In participants, relationships between cognition, behaviour, function, and quality of life were examined using adjusted multivariable linear and negative binomial regression models. Results: : In the first three-month window, 2150 participants spanning all Canadian provinces enrolled; 637 nominated study partners had already completed assessments. Engagement with the study was excellent, with many optional assessments completed. Initial analyses demonstrated relationships between cognition, behaviour, function, and quality of life. Discussion: : These preliminary results speak to the utility and feasibility of CAN-PROTECT to obtain data relevant to brain health, highlighting the public interest in participating in studies on cognition. The online portal facilitated participation of a geographically diverse sample. This group is ideal to study brain aging, dementia prevention, and early detection of neurodegenerative disease. Longitudinal data will provide additional insights. Several features of CAN-PROTECT are important to consider in terms of assessing risk and resilience in Canadians, and for further development and recruitment of a research-ready cohort.

Background Magnetic resonance imaging infarct topography may assist with determining stroke etiology. The influence of diffusion‐weighted imaging (DWI)‐positive lesions on etiology determination in patients with transient ischemic attack or minor stroke is not well studied. Methods and Results We prospectively enrolled patients between 2010 and 2017 in 2 studies; participants with a final diagnosis of probable or definite transient ischemic attack or stroke were pooled for analysis. The primary outcome was the adjudicated ischemic etiology. We compared proportion of each etiology (cardioembolic, large‐vessel, small‐vessel disease, other) in patients who had DWI positivity compared with DWI negativity. We used logistic regression to determine the adjusted odds ratio (OR) for each etiology compared with undetermined by DWI positivity. The final analysis included 1498 patients: 832 (55.5%) were DWI‐positive. DWI‐positive patients were more likely to be diagnosed with small‐vessel disease (19.1% versus 5.3%) and less likely with undetermined etiology (36.9% versus 53.0%; P

Abstract Although a decrease in stroke admissions during the SARS-CoV-2 pandemic has been observed, detailed analyses of the evolution of stroke metrics during the pandemic are lacking. We analyzed changes in stroke presentation, in-hospital systems-of-care, and treatment time metrics at two representative Comprehensive Stroke Centers (CSCs) during the first year of Coronavirus disease 2019 pandemic. From January 2018 to May 2021, data from stroke presentations to two CSCs were obtained. The study duration was split into: period 0 (prepandemic), period 1 (Wave 1), period 2 (Lull), and period 3 (Wave 2). Acute stroke therapies rates and workflow times were compared among pandemic and prepandemic periods. Analyses were adjusted for age, sex, comorbidities, and pre-morbid care needs. There was a significant decrease in monthly hospital presentations of stroke during Wave 1. Both centers reported declines in reperfusion therapies during Wave 1, slowly catching up but never to pre pandemic numbers, and dropping again in Wave 2. Both CSCs experienced in-hospital workflow delays during Waves 1 and 2, and even during the Lull period. Our results highlight the need for proactive strategies to reduce barriers to workflow and hospital avoidance for stroke patients during crisis periods.

Abstract Background Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally. Methods Data were from two independent referral-based cohorts, ADNI (mean[SD] follow-up 3.14[1.07] years) and MEMENTO (4.25[1.40] years), collected 2003–2021. Exposure was based on three-group stratification: 1) NPS meeting MBI criteria; 2) conventionally measured NPS (NPSnotMBI); and 3) noNPS. Cohorts were analyzed separately for: 1) cross-sectional associations between NPS status and ATN biomarkers (linear regressions); 2) 4-year longitudinal repeated-measures associations of MBI and NPSnotMBI with ATN biomarkers (hierarchical linear mixed-effects models-LMEs); and 3) rates of incident dementia (Cox proportional hazards regressions). Results Of 510 MCI participants, 352 were from ADNI (43.5% females; mean [SD] age, 71.68 [7.40] years), and 158 from MEMENTO (46.2% females; 68.98 [8.18] years). In ADNI, MBI was associated with lower Aβ42 (standardized β [95%CI], -5.52% [-10.48-(-0.29)%]; p = 0.039), and Aβ42/40 (p = 0.01); higher p-tau (9.67% [3.96–15.70%]; p = 0.001), t-tau (7.71% [2.70–12.97%]; p = 0.002), p-tau/Aβ42 (p

Introduction: Cerebral small vessel disease (SVD) is a common co-pathology in elderly and individuals with dementia. Neuroimaging markers of SVD include white matter hyperintensities (WMH) and MRI-visible perivascular spaces (PVS). However, the mechanisms underlying changes in these markers over time, whether ischemic or beta-amyloid (Aβ)-related, remain elusive. Here, we evaluated the effects of microstructural injury in the normal-appearing white matter and Aβ in the cerebral cortex on the progression of WMH and PVS over three years. Methods: Data was obtained from two independent cohorts: (i) TRIAD, comprising cognitively normal, MCI, and AD dementia participants (baseline: N=199, follow-up year 1 and 2: N=102 and 62); and (ii) MITNEC-C6, comprising “real-world” patients with mixed dementia and moderate-to- severe WMH burden (baseline: N=52, 2 years follow-up: N=25). We quantified global WMH and PVS volumes from FLAIR and T1w MRI. At baseline, we examined associations between these volumes and diffusion MRI-derived free water. Longitudinally, we employed linear [mixed-effect] models to investigate the relation of WMH or PVS volume changes over time with baseline free water, using cortical Aβ-PET, age, sex, and APOE-ε4 as covariates. Results: In TRIAD and MITNEC-C6 respectively, mean ages were 72±6 and 77±8 y, 60% and 42% were female, and 41% and 48% were Aβ-positive. At baseline, higher free water in normal- appearing white matter was associated with higher WMH volume (β_TRIAD=+0.34±0.06, P_TRIAD

Background Secondary prevention of ischemic stroke (IS) requires adequate diagnostic evaluation to identify the likely etiologic subtype. We describe hospital‐level variability in diagnostic testing and IS subtyping in a large nationwide registry. Methods and Results We used the GWTG‐Stroke (Get With The Guidelines–Stroke) registry to identify patients hospitalized with a diagnosis of acute IS at 1906 hospitals between January 1, 2016, and September 30, 2017. We compared the documentation rates and presence of risk factors, diagnostic testing, achievement/quality measures, and outcomes between patients with and without reported IS subtype. Recording of diagnostic evaluation was optional in all IS subtypes except cryptogenic, where it was required. Of 607 563 patients with IS, etiologic IS subtype was documented in 57.4% and missing in 42.6%. Both the rate of missing stroke pathogenesis and the proportion of cryptogenic strokes were highly variable across hospitals. Patients missing stroke pathogenesis less frequently had documentation of risk factors, evidence‐based interventions, or discharge to home. The reported rates of major diagnostic testing, including echocardiography, carotid and intracranial vascular imaging, and short‐term cardiac monitoring were 40% of patients. Long‐term cardiac rhythm monitoring was rarely reported, even in cryptogenic stroke. Conclusions Reporting of IS etiologic subtype and supporting diagnostic testing was low overall, with high rates of missing optional data. Improvement in the capture of these data elements is needed to identify opportunities for quality improvement in the diagnostic evaluation and secondary prevention of stroke.

Background This study explored the risk factors, neuroimaging features, and prognostic implications of nonhypertensive white matter hyperintensity (WMH) in patients with acute ischemic stroke and transient ischemic attack. Methods and Results We included 2283 patients with hypertension and 1003 without from a pool of 10 602. Associations of moderate‐to‐severe WMH with known risk factors, functional outcome, and a composite of recurrent stroke, myocardial infarction, and all‐cause mortality were evaluated. A subset of 351 patients without hypertension and age‐ and sex‐matched pairs with hypertension and moderate‐to‐severe WMH was created for a detailed topographic examination of WMH, lacunes, and microbleeds. Approximately 35% of patients without hypertension and 65% of patients with hypertensive stroke exhibited moderate‐to‐severe WMH. WMH was associated with age, female sex, and previous stroke, irrespective of hypertension. In patients without hypertension, WMH was associated with initial systolic blood pressure and was more common in the anterior temporal region. In patients with hypertension, WMH was associated with small vessel occlusion as a stroke mechanism and was more frequent in the periventricular region near the posterior horn of the lateral ventricle. The higher prevalence of occipital microbleeds in patients without hypertension and deep subcortical lacunes in patients with hypertension were also observed. Associations of moderate‐to‐severe WMH with 3‐month functional outcome and 1‐year cumulative incidence of the composite outcome were significant (both P

BackgroundStroke, even when minor, increases the risk of dementia. We aimed to determine whether patients with transient ischaemic attack (TIA) exhibit higher rates of cerebral and regional atrophy 1-year after first stroke symptoms and evaluate the relationship with small vessel disease and cognitive performance.MethodsTIA patients and controls without cognitive symptoms underwent high-resolution T1-weighted MRI and cognitive testing at baseline and 1-year. Percent brain volume change (PBVC) was measured, and the location of regional atrophy and small vessel disease (CSVD) burden was evaluated. Neuropsychological testing assessed memory, processing speed, and executive function.ResultsA total of 76 TIA patients and 53 controls of mean age 67 (SD = 8) and 68 years (SD = 8) were recruited. TIA patients demonstrated greater improvement of visual memory and executive function at 1-year. TIA patients had greater median PBVC/year compared to controls (−0.79% [(−1.22)-(−0.38)] vs. -0.41% [(−0.62)-0.19]; p

Abstract INTRODUCTION Hearing loss (HL) and mild behavioral impairment (MBI) are non‐cognitive markers of dementia. This study investigated the relationship between hearing and MBI and explored the influence of hearing aid use on the treatment of hearing loss, both cross‐sectionally and longitudinally. METHODS Data were analyzed from National Alzheimer's Coordinating Center participants, age ≥50, dementia‐free at baseline, collected between 2005 and 2022. Three self‐report questions were used to generate a three‐level categorical hearing variable: No‐HL, Untreated‐HL, and Treated‐HL. MBI status was derived from the informant‐rated Neuropsychiatric Inventory Questionnaire (NPI‐Q) using a published algorithm. At baseline (n = 7080), logistic regression was used to examine the association between hearing status (predictor) and the presence of global and domain‐specific MBI (outcome), adjusting for age, sex, cognitive diagnosis, and apolipoprotein E4 (APOE4). Cox proportional hazard models with time‐dependent covariates were used to examine the effect of (1) hearing status as exposure on the rate of incident MBI (n = 5889); and (2) MBI as exposure on the rate of incident HL in those with no HL at baseline (n = 6252). RESULTS Cross‐sectionally, participants with Untreated‐HL were more likely to exhibit global MBI (adjusted odds ratio (aOR) = 1.66, 95% CI: 1.24–2.21) and individual MBI domains of social inappropriateness (aOR = 1.95, 95% CI: 1.06–3.39), affective dysregulation (aOR = 1.71, 95% CI: 1.21–2.38), and impulse dyscontrol (aOR = 1.71, 95% CI: 1.21–2.38), compared to those with No‐HL. Participants with Treated‐HL (i.e., hearing aid use) did not differ from No‐HL for odds of global or most MBI domains, except for impulse dyscontrol (aOR = 1.38, 95% CI: 1.05–1.81). Longitudinally, we found relationships between Treated‐HL and incident MBI (adjusted hazard ratio (aHR) = 1.29, 95% CI: 1.01–1.63) and between MBI and incident Untreated‐HL (aHR = 1.51, 95% CI: 1.19–1.94). DISCUSSION Our cross‐sectional results support that hearing aid use is associated with lower odds of concurrent global MBI in dementia‐free participants. Longitudinally, relationships were found between MBI and HL. The severity of HL was not assessed, however, and may require further exploration. Highlights Hearing Loss (HL) and mild behavioral impairment (MBI) are markers of dementia Cross‐sectionally: Untreated‐HL was associated with global MBI burden, but HL treated with hearing aids was not We found associations between MBI and incident Untreated‐HL

Abstract INTRODUCTION We compared three operational case definitions of mild behavioral impairment (MBI) in the context of MBI prevalence estimates and dementia risk modeling. METHODS Participants were dementia‐free older adults (n = 13701) from the National Alzheimer's Coordinating Center. Operational case definitions of MBI were generated based on neuropsychiatric symptoms at one (OV), two‐consecutive (TCV), or more than two‐thirds (TTV) of dementia‐free study visits. Definitions were compared in prevalence and in Cox regressions using MBI to predict incident dementia. RESULTS OV MBI was the most prevalent (54.4%), followed by TCV (32.3%) and TTV (26.7%) MBI. However, OV MBI had the lowest rate of incident dementia (hazard ratio [HR] = 2.54, 95% confidence interval [CI]: 2.33–2.78) and generated poorer model metrics than TCV MBI (HR = 4.06, 95% CI: 3.74–4.40) and TTV MBI (HR = 5.77, 95% CI: 5.32–6.26). DISCUSSION Case ascertainment with longer timeframe MBI operational case definitions may more accurately define groups at risk of dementia in datasets lacking tools designed to detect MBI. Highlights Mild behavioral impairment (MBI) can identify older adults at risk of dementia. Neuropsychiatric symptom (NPS) assessment tools can be proxy measures for MBI. Hazard for dementia was highest for MBI defined by NPS presence at more than two‐thirds of visits.

Abstract Background Cox proportional hazards regression models and machine learning models are widely used for predicting the risk of dementia. Existing comparisons of these models have mostly been based on empirical datasets and have yielded mixed results. This study examines the accuracy of various machine learning and of the Cox regression models for predicting time-to-event outcomes using Monte Carlo simulation in people with mild cognitive impairment (MCI). Methods The predictive accuracy of nine time-to-event regression and machine learning models were investigated. These models include Cox regression, penalized Cox regression (with Ridge, LASSO, and elastic net penalties), survival trees, random survival forests, survival support vector machines, artificial neural networks, and extreme gradient boosting. Simulation data were generated using study design and data characteristics of a clinical registry and a large community-based registry of patients with MCI. The predictive performance of these models was evaluated based on three-fold cross-validation via Harrell’s concordance index (c-index), integrated calibration index (ICI), and integrated brier score (IBS). Results Cox regression and machine learning model had comparable predictive accuracy across three different performance metrics and data-analytic conditions. The estimated c-index values for Cox regression, random survival forests, and extreme gradient boosting were 0.70, 0.69 and 0.70, respectively, when the data were generated from a Cox regression model in a large sample-size conditions. In contrast, the estimated c-index values for these models were 0.64, 0.64, and 0.65 when the data were generated from a random survival forest in a large sample size conditions. Both Cox regression and random survival forest had the lowest ICI values (0.12 for a large sample size and 0.18 for a small sample size) among all the investigated models regardless of sample size and data generating model. Conclusion Cox regression models have comparable, and sometimes better predictive performance, than more complex machine learning models. We recommend that the choice among these models should be guided by important considerations for research hypotheses, model interpretability, and type of data.

Background It remains unclear if white matter hyperintensity (WMH) on magnetic resonance imaging adds relevant cerebrovascular prognostic information beyond vascular risk factors and demographics alone. Methods and Results We performed a post hoc analysis of hypertensive individuals in SPRINT‐MIND (Systolic Blood Pressure Intervention Trial–Memory and Cognition in Decreased Hypertension). The primary outcome was incident stroke or cognitive impairment (mild cognitive impairment or dementia). We fit logistic regression models with the predictors of Atherosclerotic Cardiovascular Disease Risk Score, age, sex, race, education, current cigarette smoking, and the SPRINT‐MIND randomization arm. WMH was subsequently included in the model to determine if it improved area under the receiver operating curve using the DeLong test. We used a structural equation model to determine the indirect effect on the primary outcome mediated through WMH. We included 727 individuals (mean age at baseline 67.7±8.4 years, 61.1% were men, 62.6% were non‐Hispanic White, and mean years of follow‐up was 3.6±0.9). Of the 727 individuals, 67 (9.2%) developed incident stroke or cognitive decline. The area under the receiver operating curve of the baseline model (without WMH) was 0.75 (95% CI, 0.70–0.81), and after the addition of WMH it increased to 0.81 (95% CI, 0.76–0.86) (P=0.004 for difference). The mediation analysis showed that 26.3% of the vascular risk's effect on the primary outcome is indirectly mediated through WMH. Conclusions In adult hypertensive individuals, we found that the addition of WMH to models predicting incident stroke or cognitive impairment improved the prognostic ability above vascular risk and demographics alone to a level consistent with excellent prediction. Registration Information REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

IntroductionCerebral amyloid angiopathy (CAA) is a small vessel disease that causes covert and symptomatic brain hemorrhaging. We hypothesized that persons with CAA would have increased brain iron content detectable by quantitative susceptibility mapping (QSM) on magnetic resonance imaging (MRI), and that higher iron content would be associated with worse cognition.MethodsParticipants with CAA (n = 21), mild Alzheimer’s disease with dementia (AD-dementia; n = 14), and normal controls (NC; n = 83) underwent 3T MRI. Post-processing QSM techniques were applied to obtain susceptibility values for regions of the frontal and occipital lobe, thalamus, caudate, putamen, pallidum, and hippocampus. Linear regression was used to examine differences between groups, and associations with global cognition, controlling for multiple comparisons using the false discovery rate method.ResultsNo differences were found between regions of interest in CAA compared to NC. In AD, the calcarine sulcus had greater iron than NC (β = 0.99 [95% CI: 0.44, 1.53], q < 0.01). However, calcarine sulcus iron content was not associated with global cognition, measured by the Montreal Cognitive Assessment (p > 0.05 for all participants, NC, CAA, and AD).DiscussionAfter correcting for multiple comparisons, brain iron content, measured via QSM, was not elevated in CAA compared to NC in this exploratory study.

BackgroundPrevious reports have suggested that patients with cerebral amyloid angiopathy (CAA) may harbor smaller white matter, basal ganglia, and cerebellar volumes compared to age-matched healthy controls (HC) or patients with Alzheimer’s disease (AD). We investigated whether CAA is associated with subcortical atrophy.MethodsThe study was based on the multi-site Functional Assessment of Vascular Reactivity cohort and included 78 probable CAA (diagnosed according to the Boston criteria v2.0), 33 AD, and 70 HC. Cerebral and cerebellar volumes were extracted from brain 3D T1-weighted MRI using FreeSurfer (v6.0). Subcortical volumes, including total white matter, thalamus, basal ganglia, and cerebellum were reported as proportion (%) of estimated total intracranial volume. White matter integrity was quantified by the peak width of skeletonized mean diffusivity.ResultsParticipants in the CAA group were older (74.0 ± 7.0, female 44%) than the AD (69.7 ± 7.5, female 42%) and HC (68.8 ± 7.8, female 69%) groups. CAA participants had the highest white matter hyperintensity volume and worse white matter integrity of the three groups. After adjusting for age, sex, and study site, CAA participants had smaller putamen volumes (mean differences, −0.024% of intracranial volume; 95% confidence intervals, −0.041% to −0.006%; p = 0.005) than the HCs but not AD participants (−0.003%; −0.024 to 0.018%; p = 0.94). Other subcortical volumes including subcortical white matter, thalamus, caudate, globus pallidus, cerebellar cortex or cerebellar white matter were comparable between all three groups.ConclusionIn contrast to prior studies, we did not find substantial atrophy of subcortical volumes in CAA compared to AD or HCs, except for the putamen. Differences between studies may reflect heterogeneity in CAA presenting syndromes or severity.

BackgroundParkinson’s disease (PD) and dementia with Lewy bodies (DLB) are part of a spectrum of Lewy body disorders, who exhibit a range of cognitive and gait impairments. Cognitive-motor interactions can be examined by performing a cognitive task while walking and quantified by a dual task cost (DTC). White matter hyperintensities (WMH) on magnetic resonance imaging have also been associated with both gait and cognition. Our goal was to examine the relationship between DTC and WMH in the Lewy body spectrum, hypothesizing DTC would be associated with increased WMH volume.MethodsSeventy-eight participants with PD, PD with mild cognitive impairment (PD-MCI), PD with dementia or DLB (PDD/DLB), and 20 cognitively unimpaired participants were examined in a multi-site study. Gait was measured on an electronic walkway during usual gait, counting backward, animal fluency, and subtracting sevens. WMH were quantified from magnetic resonance imaging using an automated pipeline and visual rating. A median split based on DTC was performed. Models included age as well as measures of global cognition and cardiovascular risk.ResultsCompared to cognitively unimpaired participants, usual gait speed was lower and DTC was higher in PD-MCI and PDD/DLB. Low DTC participants had higher usual gait speed. WMH burden was greater in high counting DTC participants. Frontal WMH burden remained significant after adjusting for age, cardiovascular risk and global cognition.ConclusionIncreased DTC was associated with higher frontal WMH burden in Lewy body disorders after adjusting for age, cardiovascular risk, and global cognition. Higher DTC was associated with age.

Abstract Background Despite the growing utility of cardiovascular magnetic resonance (CMR) for cardiac morphology and function, sex and age-specific normal reference values derived from large, multi-ethnic data sets are lacking. Furthermore, most available studies use a simplified tracing methodology. Using a large cohort of participants without history of cardiovascular disease (CVD) or risk factors from the Canadian Alliance for Healthy Heart and Minds, we sought to establish a robust set of reference values for ventricular and atrial parameters using an anatomically correct contouring method, and to determine the influence of age and sex on ventricular parameters. Methods and results Participants (n = 3206, 65% females; age 55.2 ± 8.4 years for females and 55.1 ± 8.8 years for men) underwent CMR using standard methods for quantitative measurements of cardiac parameters. Normal ventricular and atrial reference values are provided: (1) for males and females, (2) stratified by four age categories, and (3) for different races/ethnicities. Values are reported as absolute, indexed to body surface area, or height. Ventricular volumes and mass were significantly larger for males than females (p

Background The relationship between duration of transient neurological events and presence of diffusion‐weighted lesions by symptom type is unclear. Methods and Results This was a substudy of SpecTRA (Spectrometry for Transient Ischemic Attack Rapid Assessment), a multicenter prospective cohort of patients with minor ischemic cerebrovascular events or stroke mimics at academic emergency departments in Canada. For this study we included patients with resolved symptoms and determined the presence of diffusion‐weighted imaging (DWI) lesion on magnetic resonance imaging within 7 days. Using logistic regression, we evaluated the association between symptom duration and DWI lesion, assessing for interaction with symptom type (focal only versus nonfocal/mixed), and adjusting for age, sex, education, comorbidities, and systolic blood pressure. Of 658 patients included, a DWI lesion was present in 232 (35.1%). There was a significant interaction between symptom duration and symptom type. For those with focal‐only symptoms, there was a continuous increase in DWI probability up to 24 hours in duration (ranging from ≈40% to 80% probability). In stratified analyses, the increase in probability of DWI lesion with increased duration of focal symptoms was seen in women but not men. For those with nonfocal or mixed symptoms, predicted probability of DWI lesion was ≈35% and was greater in men, but did not increase with longer duration. Conclusions Increased duration of neurological deficits is associated with greater probability of DWI lesion in those with focal symptoms only. For individuals with nonfocal or mixed symptoms, about one‐third had DWI lesions, but the probability did not increase with duration. These results may be important to improve risk stratification of transient neurological events.

Introduction: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as “unusual”, but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. Methods: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. Results: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. Discussion: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.

Introduction: Transient ischaemic attack (TIA) is associated with increased risk of cognitive decline and dementia as early as one-year post-event. Regional brain atrophy measurements may predict future cognitive decline. Aims: 1) To determine whether Medial Temporal Atrophy (MTA) scores and interseptal distance (ISD) measurements are greater in patients with TIA compared to controls; and 2) To determine whether MTA and ISD predicts cognitive change one year after TIA. Methods: Baseline demographic, vascular risk factors, structural imaging and cognitive tests scores were compared between 103 Patients with TIA and 103 age-and-sex-matched controls from the Predementia Neuroimaging of Transient Ischaemic Attack (PREVENT) Study. MTA was assessed using the Schelten's Scale, and ISD was calculated as the distance between the septal nucleus of each hemisphere. Multiple linear regression models were used to evaluate how MTA and ISD related to cognitive change after adjusting for covariates. Results: Patients with TIA had larger ISD measurements (1.4 mm [SD=1.2] vs. 0.9 mm [SD=1.0]); p

Background and Aims: Patients with transient ischemic attack (TIA) have a substantially increased risk of early dementia. In this exploratory study, we aim to determine whether patients with TIA have 1) measurable regional cerebral hypoperfusion unrelated to the location of ischemia, and 2) determine the relationship of regional cerebral blood flow (rCBF) with their cognitive profiles. Methods: Patients with TIA (N = 49) and seventy-nine (N = 79) age and sex matched controls underwent formal neuropsychological testing and MRI. Quantitative arterial spin labelling rCBF maps (mL/min/100 g) were registered to the corresponding high resolution T1-weighted image. Linear regression was used to determine the association between demographic, clinical and cognitive variables and rCBF. Results: Patients with TIA had significantly (p

Abstract Background Mild behavioral impairment (MBI) is a syndrome that uses later‐life emergent and persistent neuropsychiatric symptoms (NPS) to identify a group at high risk for incident dementia. MBI is associated with neurodegenerative disease markers in advance of syndromic dementia. Functional connectivity (FC) correlates of MBI are understudied and could provide further insights into mechanisms early in the disease course. We used resting‐state functional magnetic resonance imaging (rs‐fMRI) to test the hypothesis that FC within the default mode network (DMN) and salience network (SN) of persons with MBI (MBI+) is reduced, relative to those without (MBI–). Methods From two harmonized dementia‐free cohort studies, using a score of ≥6 on the MBI Checklist to define MBI status, 32 MBI+ and 63 MBI– individuals were identified (mean age: 71.7 years; 54.7% female). Seed‐based connectivity analysis was implemented in each MBI group using the CONN fMRI toolbox (v20.b), with the posterior cingulate cortex (PCC) as the seed region within the DMN and anterior cingulate cortex (ACC) as the seed within the SN. The average time series from the PCC and ACC were used to determine FC with other regions within the DMN (medial prefrontal cortex, lateral inferior parietal cortex) and SN (anterior insula, supramarginal gyrus, rostral prefrontal cortex), respectively. Age, sex, years of education, and Montreal Cognitive Assessment scores were included as model covariates. The false discovery rate approach was used to correct for multiple comparisons, with a p‐value of .05 considered significant. Results For the DMN, MBI+ individuals exhibited reduced FC between the PCC and the medial prefrontal cortex, compared to MBI–. For the SN, MBI+ individuals exhibited reduced FC between the ACC and left anterior insula. Conclusion MBI in dementia‐free older adults is associated with reduced FC in networks known to be disrupted in dementia. Our results complement the evidence linking MBI with Alzheimer's disease biomarkers. Highlights Resting‐state functional magnetic resonance imaging was completed in 95 dementia‐free persons from FAVR and COMPASS‐ND studies. Participants were stratified by informant‐rated Mild Behavioral Impairment Checklist (MBI‐C) score, ≥6 for MBI+. MBI+ participants showed reduced functional connectivity (FC) within the default mode network and salience network. These FC changes are consistent with those seen in early‐stage Alzheimer's disease. MBI may help identify persons with early‐stage neurodegenerative disease.

Abstract Introduction Despite the association of vitamin D deficiency with incident dementia, the role of supplementation is unclear. We prospectively explored associations between vitamin D supplementation and incident dementia in 12,388 dementia‐free persons from the National Alzheimer's Coordinating Center. Methods Baseline exposure to vitamin D was considered D+; no exposure prior to dementia onset was considered D−. Kaplan–Meier curves compared dementia‐free survival between groups. Cox models assessed dementia incidence rates across groups, adjusted for age, sex, education, race, cognitive diagnosis, depression, and apolipoprotein E (APOE) ε4. Sensitivity analyses examined incidence rates for each vitamin D formulation. Potential interactions between exposure and model covariates were explored. Results Across all formulations, vitamin D exposure was associated with significantly longer dementia‐free survival and lower dementia incidence rate than no exposure (hazard ratio = 0.60, 95% confidence interval: 0.55–0.65). The effect of vitamin D on incidence rate differed significantly across the strata of sex, cognitive status, and APOE ε4 status. Discussion Vitamin D may be a potential agent for dementia prevention. Highlights In a prospective cohort study, we assessed effects of Vitamin D on dementia incidence in 12,388 participants from the National Alzheimer's Coordinating Center dataset. Vitamin D exposure was associated with 40% lower dementia incidence versus no exposure. Vitamin D effects were significantly greater in females versus males and in normal cognition versus mild cognitive impairment. Vitamin D effects were significantly greater in apolipoprotein E ε4 non‐carriers versus carriers. Vitamin D has potential for dementia prevention, especially in the high‐risk strata.

Abstract Background In the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort, participants underwent magnetic resonance imaging (MRI) of the brain, heart, and abdomen, that generated incidental findings (IFs). The approach to managing these unexpected results remain a complex issue. Our objectives were to describe the CAHHM policy for the management of IFs, to understand the impact of disclosing IFs to healthy research participants, and to reflect on the ethical obligations of researchers in future MRI studies. Methods Between 2013 and 2019, 8252 participants (mean age 58 ± 9 years, 54% women) were recruited with a follow-up questionnaire administered to 909 participants (40% response rate) at 1-year. The CAHHM policy followed a restricted approach, whereby routine feedback on IFs was not provided. Only IFs of severe structural abnormalities were reported. Results Severe structural abnormalities occurred in 8.3% (95% confidence interval 7.7–8.9%) of participants, with the highest proportions found in the brain (4.2%) and abdomen (3.1%). The majority of participants (97%) informed of an IF reported no change in quality of life, with 3% of participants reporting that the knowledge of an IF negatively impacted their quality of life. Furthermore, 50% reported increased stress in learning about an IF, and in 95%, the discovery of an IF did not adversely impact his/her life insurance policy. Most participants (90%) would enrol in the study again and perceived the MRI scan to be beneficial, regardless of whether they were informed of IFs. While the implications of a restricted approach to IF management was perceived to be mostly positive, a degree of diagnostic misconception was present amongst participants, indicating the importance of a more thorough consent process to support participant autonomy. Conclusion The management of IFs from research MRI scans remain a challenging issue, as participants may experience stress and a reduced quality of life when IFs are disclosed. The restricted approach to IF management in CAHHM demonstrated a fair fulfillment of the overarching ethical principles of respect for autonomy, concern for wellbeing, and justice. The approach outlined in the CAHHM policy may serve as a framework for future research studies. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT02220582 .

Background Gait is a complex task requiring coordinated efforts of multiple brain networks. To date, there is little evidence on whether gait is altered in cerebral amyloid angiopathy (CAA). We aimed to identify impairments in gait performance and associations between gait impairment and neuroimaging markers of CAA, cognition, and falls. Methods and Results Gait was assessed using the Zeno Walkway during preferred pace and dual task walks, and grouped into gait domains (Rhythm, Pace, Postural Control, and Variability). Participants underwent neuropsychological testing and neuroimaging. Falls and fear of falling were assessed through self‐report questionnaires. Gait domain scores were standardized and analyzed using linear regression adjusting for age, sex, height, and other covariates. Participants were patients with CAA (n=29), Alzheimer disease with mild dementia (n=16), mild cognitive impairment (n=24), and normal elderly controls (n=47). CAA and Alzheimer disease had similarly impaired Rhythm, Pace, and Variability, and higher dual task cost than normal controls or mild cognitive impairment. Higher Pace score was associated with better global cognition, processing speed, and memory. Gait measures were not correlated with microbleed count or white matter hyperintensity volume. Number of falls was not associated with gait domain scores, but participants with low fear of falling had higher Pace (odds ratio [OR], 2.61 [95% CI, 1.59–4.29]) and lower Variability (OR, 1.64 [95% CI, 1.10–2.44]). Conclusions CAA is associated with slower walking, abnormal rhythm, and greater gait variability than in healthy controls. Future research is needed to identify the mechanisms underlying gait impairments in CAA, and whether they predict future falls.

Abstract Background The economic burden of stroke on the healthcare system has been previously described, but sex differences in healthcare costs have not been well characterized. We described the direct person-level healthcare cost in men and women as well as the various health settings in which costs were incurred following stroke. Methods In this population-based cohort study of patients admitted to hospital with stroke between 2008 and 2017 in Ontario, Canada, we used linked administrative data to calculate direct person-level costs in Canadian dollars in the one-year following stroke. We used a generalized linear model with a gamma distribution and a log link function to compare costs in women and men with and without adjustment for baseline clinical differences. We also assessed for an interaction between age and sex using restricted cubic splines to model the association of age with costs. Results We identified 101,252 patients (49% were women, median age [Q1-Q3] was 76 years [65–84]). Unadjusted costs following stroke were higher in women compared to men (mean ± standard deviation cost was $54,012 ± 54,766 for women versus $52,829 ± 59,955 for men, and median cost was $36,703 [$16,496–$72,227] for women versus $32,903 [$15,485–$66,007] for men). However, after adjustment, women had 3% lower costs compared to men (relative cost ratio and 95% confidence interval 0.97 [0.96,0.98]). The lower cost in women compared to men was most prominent among people aged over 85 years (p for interaction = 0.03). Women incurred lower costs than men in outpatient care and rehabilitation, but higher costs in complex continuing care, long-term care, and home care. Conclusions Patterns of resource utilization and direct medical costs were different between men and women after stroke. Our findings inform public payers of the drivers of costs following stroke and suggest the need for sex-based cost-effectiveness evaluation of stroke interventions with consideration of costs in all care settings.

Background Health state utility values are commonly used to provide summary measures of health‐related quality of life in studies of stroke. Contemporaneous summaries are needed as a benchmark to contextualize future observational studies and inform the effectiveness of interventions aimed at improving post‐stroke quality of life. Methods and Results We conducted a systematic search of the literature using Medline, EMBASE, and Web of Science from January 1995 until October 2020 using search terms for stroke, health‐related quality of life, and indirect health utility metrics. We calculated pooled estimates of health utility values for EQ‐5D‐3L, EQ‐5D‐5L, AQoL, HUI2, HUI3, 15D, and SF‐6D using random effects models. For the EQ‐5D‐3L we conducted stratified meta‐analyses and meta‐regression by key subgroups. We screened 14 251 abstracts and 111 studies met our inclusion criteria (sample size range 11 to 12 447). EQ‐5D‐3L was reported in 78% of studies (study n=87; patient n=56 976). The pooled estimate for EQ‐5D‐3L at ≥3 months following stroke was 0.65 (95% CI, 0.63–0.67), which was ≈20% below population norms. There was high heterogeneity (I2>90%) between studies, and estimates differed by study size, case definition of stroke, and country of study. Women, older individuals, those with hemorrhagic stroke, and patients prior to discharge had lower pooled EQ‐5D‐3L estimates. Conclusions Pooled estimates of health utility for stroke survivors were substantially below population averages. We provide reference values for health utility in stroke to support future clinical and economic studies and identify subgroups with lower healthy utility. Registration URL: https://www.crd.york.ac.uk/prospero/. Unique Identifier: CRD42020215942.