BACKGROUND:Despite remarkable advances in stroke management, there is a continued lack of evidence to guide care for the 1 in 3 stroke patients living with disability or dementia (PLWD). To help inform best practices, this study sought to understand how physicians approach the complex issue of determining goals of care for PLWD and what challenges they encounter. METHODS:In a mixed-methods investigation, we invited physicians involved in stroke care to participate in semistructured interviews and an online survey, enquiring into perspectives on stroke management in PLWD. Interviews were analyzed using an interpretive grounded theory approach. Qualitative findings were triangulated with results from a descriptive analysis of survey items. RESULTS:Of 82 approached physicians, 30 participated in interviews (43% from North America, 77% with ≥10 years of experience; 60% neurologists); of 200 consenting to the survey, 132 completed it (37% from North America, 51% with ≥10 years of experience, 56% neurologists). For both prestroke disability and dementia, survey respondents most frequently indicated severity of the prior condition (87% [95% CI, 80%-91%] and 89% [95% CI, 82%-93%]) and quality of life (88% [95% CI, 82%-93%] and 87% [95% CI, 80%-91%]) as either very or extremely important in decision-making. However, interviewed physicians emphasized uncertainty in evaluating these factors and forming perceptions of patient prognosis and treatment appropriateness. This was attributed to limited reliable information regarding patients' prior well-being and wishes, and paucity of PLWD-specific evidence to guide stroke management. While these ambiguous circumstances appeared to warrant a highly individualized approach to care, physicians also recognized the consequent high risk of biases affecting equity. CONCLUSIONS:Physicians encounter profound, multifaceted uncertainty in determining goals of care for PLWD, which may contribute to adverse variability in stroke management. This uncertainty may be eased by routinely documenting patients' baseline well-being and advance healthcare directives in clinical practice and promoting inclusion of PLWD in stroke research, in both contexts, considering patient and family perspectives on quality of life and favorable outcomes.

Cerebral small vessel disease (CSVD) is the most common cause of vascular cognitive impairment, but its relationship to cognition across the neurocognitive spectrum is not fully understood. CSVD burden can be inferred from several magnetic resonance imaging (MRI) markers, which can be combined to generate a CSVD score. We investigated the association between CSVD score with various cognitive measures. Baseline data from 972 participants [Table 1] from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study were analyzed [11.9% cognitively unimpaired [CU], 14.7% subjective cognitive decline [SCD], 36.4% mild cognitive impairment [MCI], 36.9% dementia). Brain MRI scans were visually rated for Standards for Reporting Vascular Changes on Neuroimaging (STRIVE)-based evidence of vascular brain injury (lacunes, microbleeds, white matter hyperintensities [WMH], cortical superficial siderosis [cSS], enlarged perivascular spaces [EPVS]). Three CSVD scores corresponding to global, cerebral amyloid angiopathy (CAA-CSVD)-specific, and hypertensive arteriopathy (HTNA-CSVD)-specific CSVD burden were generated [Table 2]. Cognitive measures included the Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating sum of boxes (CDR-SB), and a composite neuropsychological battery test z-score. We modelled CSVD score (exposure) associations with five outcomes: Hachinski ischemic score (negative binomial regression), MoCA total score (linear regression), CDR-SB (median quantile regression), and neuropsychological battery composite z-score (linear regression), cognitive diagnosis (ordinal logistic regression). Covariates included age, sex, and education. Global, CAA- and HTNA-CSVD scores were all associated with greater Hachinski ischemic score, poorer MoCA score, higher CDR-SB, and poorer composite neuropsychological battery test z-score [Table 3]. Both global CSVD score (adjusted odds ratio [aOR]=1.14, 95%CI: [1.02, 1.26], p  = .02) and HTNA-CSVD score (aOR=1.18, 95%CI: [1.04, 1.35], p  = .01) were associated with higher odds of a more severe cognitive diagnosis compared to a less severe cognitive diagnosis (e.g., dementia vs MCI/SCD/CU), but not CAA-CSVD score (aOR=1.09, 95%CI: [0.97, 1.24], p  = .15). Older adults with greater CSVD burden, as evidenced by multiple MRI markers, exhibit poorer cognition and functional performance across the neurocognitive continuum. Notably, these associations were observed not only for global CSVD but also for both CAA- and HTNA-specific CSVD scores, suggesting the importance of evaluating these specific pathologies when assessing cerebrovascular contributions to cognitive decline.

BACKGROUND:Rural residents have been experiencing higher stroke mortality than urban residents, and the gap has widened. Disparity in postacute care after stroke may increase the rural-urban gaps of mortality and disability. We aimed to examine whether rural patients with stroke receive the same postacute care and achieve comparable outcomes to urban patients. METHODS:We conducted a cohort study of Medicare beneficiaries aged ≥65 years treated in the Get With The Guidelines-Stroke participating hospitals for acute ischemic stroke during 2017 to 2022. We used restricted mean home-time to compare 1-year home-time among patients discharged from rural versus urban hospitals and the Cox proportional hazards model for all-cause mortality and readmission, adjusting for patient and hospital characteristics. RESULTS:The analysis included 29 734 patients treated in rural hospitals and 478 122 in urban hospitals, with a mean age of 79 years, and 55.5% were women. Compared with patients in urban hospitals, patients in rural hospitals were less commonly discharged to inpatient rehabilitation facilities (20.1% versus 25.1%; adjusted odds ratio, 0.76 [95% CI, 0.69-0.84]) and more frequently to skilled nursing facilities (24.5% versus 20.9%; adjusted odds ratio, 1.21 [95% CI, 1.11-1.32]). Compared with urban patients, rural patients had 1.8 fewer days of home-time (95% CI, -3.2 to -0.3) overall; rural patients discharged to skilled nursing facilities had 5.7 fewer days of home-time (95% CI, -9.0 to -2.3), and those discharged home had 2.2 fewer days of home-time (95% CI, -3.7 to -0.7). Rural patients overall had comparable all-cause mortality with urban patients (adjusted hazard ratio, 1.01 [95% CI, 0.98-1.05]) and lower all-cause readmission (adjusted hazard ratio, 0.92 [95% CI, 0.90-0.95]). However, rural patients who were discharged home had higher all-cause mortality than urban patients (adjusted hazard ratio, 1.11 [95% CI, 1.05-1.17]). CONCLUSIONS:Compared with urban patients, rural patients with stroke had less inpatient rehabilitation facility and more skilled nursing facility utilization, less home-time, but similar mortality. Further efforts are needed to ensure equitable postacute care in rural areas.

Background/Objectives: Longer lifetime exposure to endogenous estradiol (LEE2) has been associated with lower risk of age-related cognitive decline and dementia. Complementary to cognitive decline, behavioral and functional decline are also predictive of dementia risk; however, the association between LEE2 and these domains is underexplored. We investigated whether LEE2 is correlated with later-life changes in behavior and function. Methods: Baseline data from 1156 females enrolled in the CAN-PROTECT study were analyzed. LEE2 was estimated based on the length of the reproductive period (menopause age-menarche age) plus years pregnant and scaled in 5-year increments. Objective cognition was measured using the CAN-PROTECT neuropsychological battery, while subjective cognition, behavior, and function were measured using the Revised Everyday Cognition (ECog-II) scale, Mild Behavioral Impairment Checklist (MBI-C), and Standard Assessment of Global Everyday Activities (SAGEA) scale, respectively. Linear regressions modeled the association between LEE2 and neuropsychological performance. Three separate negative binomial regression models examined the association between LEE2 and ECog-II, MBI-C, and SAGEA total scores. All models adjusted for menopause hormone therapy, menopause type, age at first childbirth, body mass index, age, education, and ethnocultural background. Results: Each five-year increase in LEE2 was associated with a lower MBI-C score (count ratio [CR] = 0.89, 95% CI [0.82, 0.97]) and lower SAGEA score (CR = 0.91, 95% CI [0.84, 0.98]). LEE2 was not significantly associated with any objective or subjective cognitive measures. Conclusions: Longer LEE2 may associate with lower severity of later-life behavioral and functional symptoms in older women.

BACKGROUND:Cerebral small vessel disease (SVD) is a major cause of ischemic stroke, intracerebral hemorrhage, and dementia. Despite its importance, there are few studies of its prevalence and how cerebral SVD varies across the world, different age ranges, sexes, and magnetic resonance imaging (MRI) parameters. SVD can be estimated using MRI neuroimaging markers, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and perivascular spaces (PVS). AIMS:This study aimed to document the global prevalence of SVD based on population-based or large community-based MRI studies and to determine how SVD prevalence varies by region, mean age, and sex. With SVD neuroimaging markers being the standard to assess SVD prevalence, we aimed to investigate how different MRI acquisition parameters may influence its prevalence. SUMMARY OF REVIEW:In this systematic review and meta-analysis, articles were searched from the Ovid MEDLINE and EMBASE databases between 1 January 2000 and 31 March 2024, without language restrictions. Title and abstract screening, full-text review, and data extraction were performed by at least two independent reviewers. The prevalence of SVD, subject demographic information, and MRI acquisition parameters were extracted. The Risk of Bias for Non-randomized Studies tool was used. The protocol was registered on PROSPERO (CRD42022311133). Of 14,582 studies identified, 246 studies spanning 40 countries were included in the systematic review. In the meta-analysis, 85 studies (88 cohorts) from 17 regions (n = 1,562,765) were included. The quality of studies was high (mean score 7.67 out of 8, ranging between 5 and 8). The pooled prevalence of moderate-to-severe WMH was 18.9%, and the pooled mean of WMH volume was 4.4 mL. Pooled prevalences of lacunes, cerebral microbleeds (CMBs), and moderate-to-severe perivascular spaces (PVS) were 11.2%, 10.3%, and 22.6%, respectively. A lower lacune prevalence (7.3% vs 13.3%; adjusted OR (aOR) [95% confidence interval (CI)]: 0.45 [0.30-0.68]) but higher PVS prevalence (30.9% vs 19.6%; aOR [95% CI]: 12.15 [2.12-69.46]) was found in Europe compared with Asia. A higher mean age of the studies was associated with a higher prevalence of most SVD markers, except for PVS. There was an overall trend of more lacunes and CMBs in males. MRI field strength, sequence used, and slice thickness could potentially influence the reported SVD prevalence, especially for WMH volume and CMB count. There was high heterogeneity in the studies (>95%) that was not resolved by performing analyses stratified by Global Burden of Disease (GBD) regions, age groups, study design, or MRI parameters. CONCLUSION:This systematic review and meta-analysis based on large MRI studies demonstrated that SVD is a common health problem affecting about one-fifth of the adult population. SVD prevalence differs in regions separated by geographical regions. SVD prevalence is higher with increasing age. There is an overall trend of more lacunes and CMBs in males. WMH volume and CMB are SVD markers prone to the variability of MRI acquisition parameters, and a harmonised SVD scanning protocol should be used. More studies from middle- and low-income regions would benefit the estimation of a truly global prevalence of SVD.

INTRODUCTION:Glomerular hyperfiltration has previously been associated with cardiovascular events and mortality but has scarcely been investigated in patients with stroke. PATIENTS AND METHODS:We used pooled data from an individual patient data meta-analysis of prospective, cohort studies of stroke or TIA populations. For this analysis, we included participants from study sites that collected estimated glomerular filtration rate (eGFR) at stroke presentation. Using Cox proportional hazards regression, we investigated the risk of death, any stroke and vascular death according to glomerular hyperfiltration, defined as having an eGFR greater than the age- and sex-adjusted 95th percentile. We also investigated these outcomes according to eGFR as a continuous variable, modelled using fractional polynomials. RESULTS:A total of 11,175 patients (mean age 70.7 years, 42% female) were included in the analysis, 554 (4.9%) with hyperfiltration. Compared to the normofiltration group (absence of hyperfiltration and eGFR ≥ 60 mL/min/1.73 m2), the hyperfiltration group had a higher rate of all-cause death, 147 per 1000 person-years (95% CI, 119-180) vs 61 (95% CI, 57-66). Compared to normofiltration, hyperfiltration was independently associated with the risk of death from any cause (adjusted hazard ratio [HR] 1.76; 95% CI, 1.46-2.11; P < .001) and the risk of vascular death (adjusted HR 1.68; 95% CI, 1.29-2.17; P < .001). There were non-linear associations of eGFR with risk of death and vascular death, with increasing risk at both low and high eGFR (Pnon-linearity < .001 for both). DISCUSSION AND CONCLUSION:Glomerular hyperfiltration was associated with a 76% increased risk of death and a 68% increased risk of vascular death in multivariable models adjusted for age, sex and comorbidities. Glomerular hyperfiltration may be associated with adverse health outcomes, specifically in patients with ischaemic stroke. Further research is needed to confirm these findings.

Background Loss of independence in activities of daily living (ADL) is a diagnostic criterion for dementia, including Alzheimer disease (AD). However, subtle but persistent functional impairment (FI) may emerge in pre-dementia stages without compromising independence, and signal early neurodegeneration. Plasma p-tau217, its ratio to amyloid-β42 (ptau217/Aβ42), and neurofilament light (NfL) are sensitive biomarkers of AD pathology and neuroaxonal injury; yet their relationship with FI in dementia-free older adults remains unclear. We examined these associations to evaluate persistent FI as an early clinical marker of AD-related neurodegeneration. Methods Dementia-free participants were drawn from the Alzheimer's Disease Neuroimaging Initiative. Three Functional Activities Questionnaire items–“preparing a hot beverage”, “preparing a balanced meal”, and “shopping”–were identified by factor analysis as reflecting function more than cognition. Persistent-FI was operationalized as FI present at >two-thirds of pre-dementia visits. Comparator groups included Transient-FI and No-FI. Plasma p-tau217, Aβ42, and NfL were measured using Fujirebio and Simoa assays. Linear regressions modeled cross-sectional associations between FI status and biomarker levels, adjusting for demographics, APOE-ε4 status, cognitive performance, and neuropsychiatric burden. Results Among 796 dementia-free individuals (age=73.6; 40.4% female; 34.3% mild cognitive impairment), Persistent FI was associated with higher plasma p-tau217 (exp(β)=1.35; 95%CI: 1.11-1.64; p=0.003), ptau217/Aβ42 (exp(β)=1.32; 95%CI: 1.06-1.64; p=0.012), and NfL (exp(β)=1.18; 95%CI: 1.06-1.32; p=0.003), relative to no FI. Transient FI showed no biomarker associations. Conclusions Persistent mild FI may represent an early functional manifestation of AD-related pathology. Longitudinal assessment of mild FI may offer a low-cost, scalable, and clinically intuitive approach for identifying biomarker-positive at-risk individuals.

Importance:Tenecteplase is an alternative to alteplase for intravenous thrombolysis in acute ischemic stroke given its simplified administration and comparable safety and efficacy. However, its impact on workflow metrics that may affect clinical outcomes, such as door-to-needle and door-in-door-out times, has not been well-characterized. Objective:To compare door-to-needle and door-in-door-out times between tenecteplase-treated and alteplase-treated patients with acute ischemic stroke in US hospitals. Design, Setting, and Participants:This cohort study used data from the American Heart Association's Get With The Guidelines-Stroke registry between July 1, 2020, and June 30, 2022. The analysis included adult patients with ischemic stroke who received intravenous thrombolysis. Data analysis was conducted from August to November 2023. Exposure:Tenecteplase or alteplase treatment in a consecutive series of patients with ischemic stroke. Main Outcomes and Measures:Primary outcomes were door-to-needle time among patients who arrived directly to the reporting hospital and door-in-door-out time among those transferred after thrombolytic administration. Secondary outcomes were door-to-puncture and other endovascular workflow metrics among patients treated with thrombectomy after thrombolysis. Generalized linear mixed models were used to assess the association between thrombolytic treatment and workflow time intervals outcomes. Results:Of 133 228 thrombolysis-treated patients (mean [SD] age, 68.3 [14.8] years; 64 173 female [48.2%]; median [IQR] National Institutes of Health Stroke Scale score, 7 [3-14]), 13 988 (10.5%) received tenecteplase, and 119 240 (89.5%) received alteplase. The mean (SD) door-to-needle time was significantly shorter with tenecteplase vs alteplase (47.0 [26.8] vs 52.7 [28.0] minutes; adjusted mean difference, -3.13 minutes; 95% CI, -3.84 to -2.42 minutes). Door-to-needle time 30 minutes or less occurred more frequently with tenecteplase than with alteplase (2955 of 9893 patients [29.9%] vs 14 781 of 72 539 patients [20.4%]; adjusted odds ratio [aOR], 1.34; 95% CI, 1.25 to 1.44), as did door-to-needle time 45 minutes or less (5766 of 9893 patients [58.3%] vs 35 238 of 72 539 patients [48.6%]; aOR, 1.24; 95% CI, 1.17 to 1.32) and 60 minutes or less (7670 of 9893 patients [77.5%] vs 51 282 of 72 539 patients [70.7%]; aOR, 1.25; 95% CI, 1.17 to 1.33). Among transferred patients likely eligible for mechanical thrombectomy, mean (SD) door-in-door-out times were shorter for tenecteplase vs alteplase (108.3 [31.6] vs 114.1 [32.0] minutes; adjusted mean difference, -5.94 minutes; 95% CI, -9.10 to -2.77 minutes). Among patients receiving thrombectomy, shorter times were observed in the tenecteplase group for door-to-arterial puncture, door-to-device deployment, and door-to-reperfusion. Hospitals that transitioned to tenecteplase during the study period had faster door-to-needle time times after vs before the switch (mean [SD], 51.1 [12.1] vs 52.7 [10.8] minutes; adjusted mean difference, -1.52 minutes; 95% CI, -2.88 to -0.15 minutes). Conclusions and Relevance:In this analysis of a large nationwide registry, tenecteplase was associated with faster door-to-needle and door-in-door-out times than alteplase. These workflow advantages provide support for broader use of tenecteplase for stroke thrombolysis.

BACKGROUND:Alzheimer's disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one-third of the population-attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50-70%). The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy), and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischemic stroke and intracerebral hemorrhage also contributes. AIMS AND METHODS:In this World Stroke Organization (WSO) scientific statement, we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive. RESULTS:We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalog transcriptomic and proteomic studies that have revealed novel candidate molecules (COL4A1/4A2, HTRA1, TRIM47, FOXF2) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease and potential biochemical markers (vascular endothelial growth factor-A, placental growth factor, interleukin-6, matrix metalloproteinase-9, cathepsin-B). We highlight the potential for vascular interventions to treat not only vascular dementia but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signaling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3 fatty acids, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia. CONCLUSION:The vascular contribution to dementia is i) substantial, ii) increasingly understood at molecular and mechanistic levels, iii) a source of potential treatment opportunities.Data Access Statement:no original data are presented in this document.

Enlarged perivascular spaces (EPVS) and mild behavioral impairment (MBI) are associated with greater dementia risk. We investigated cross-sectional associations between EPVS burden and MBI presence and symptom severity. Participants were dementia-free older adults in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. EPVS were assessed using a validated visual rating scale applied to T2-weighted magnetic resonance imaging. MBI was measured using the informant-reported MBI Checklist (MBI-C) with a cut-point of ≥6 for MBI presence. Multivariable logistic and zero-inflated negative binomial regressions modelled EPVS associations with MBI presence and symptom severity, respectively, adjusting for age, education, and Montreal Cognitive Assessment score, with and EPVS*sex interaction term. Among 363 participants (52.9% female), every 1-point rise in total EPVS score was associated with 1.29-fold greater odds of having MBI (95%CI:1.07–1.54, p  = 0.007). When examining regional EPVS burden, those with higher centrum semiovale scores had greater odds of MBI (aOR=1.48, 95%CI:1.09–12.02, p  = 0.01), but this association was not significant for the basal ganglia (aOR=1.39, 95%CI:0.97–1.99, p  = 0.07) or midbrain (aOR=1.48, 95%CI:0.80–2.76, p  = 0.21). Total and regional EPVS scores were not associated with MBI symptom severity. None of the associations were moderated by sex. Older adults with greater global and centrum semiovale EPVS burden are more likely to have MBI. These findings suggest that early microvascular pathology may contribute to later-life emergent and persistent behavioural symptoms, although longitudinal data are required, along with other indicators of vascular pathology.

BACKGROUND:Air pollution is a risk factor for dementia, but its role in early cognitive dysfunction is not clear. We aimed to investigate the association of air pollution with cognitive function, and the role of cardiovascular risk factors and greenspace in this association. METHODS:The CAHHM (Canadian Alliance for Healthy Hearts and Minds Cohort Study) is a cohort of Canadian adults recruited between 2014 and 2018, for whom averages of exposures to NO2 and fine particulate matter were estimated for 5 years before recruitment. Outcomes included the Montréal Cognitive Assessment and Digit Symbol Substitution Test for cognitive function, and magnetic resonance imaging-measured covert vascular brain injury. Generalized linear mixed models assessed pollutant associations with outcomes in this cross-sectional analysis. RESULTS:A total of 6878 adults participated in the study, with a mean age of 57.6 years (SD=8.8), and 55.6% were women. Mean (SD; range) 5-year pollutant concentrations preceding enrollment for fine particulate matter were 6.9 μg/m3 (2.0 [1.8-11.2]), and for NO2 were 12.9 parts per billion (5.9 [0.9-33.9]). In adjusted models, a 5 μg/m3 higher fine particulate matter concentration was associated with 0.44 points lower Montréal Cognitive Assessment (95% CI, -0.62 to -0.25) and 1.31 points lower Digit Symbol Substitution Test (95% CI, -2.41 to -0.22) scores. A 5 parts per billion higher NO2 concentration was associated with 0.12 points lower Montréal Cognitive Assessment (95% CI, -0.17 to -0.07) and 0.38 points lower Digit Symbol Substitution Test (95% CI, -0.70 to -0.05) scores. A 5 parts per billion higher NO2 concentration was associated with higher odds of covert vascular brain injury (adjusted odds ratio, 1.08 [95% CI, 1.00-1.17]). Cardiovascular risk factors and greenspace did not change these associations. CONCLUSIONS:Fine particulate matter and NO2 were associated with lower cognitive function scores in middle-aged adults living in Canada, independent of cardiovascular risk factors. Our results warrant longitudinal follow-up to study the impact of air pollution on cognitive decline.

Mild Behavioural Impairment (MBI) is defined by later-life onset of persistent behavioural changes and is recognized as a risk marker for cognitive decline and dementia. Apathy, a core MBI domain characterized by diminished interest, initiative, and emotional reactivity, can emerge before dementia and is hypothesized to be associated with structural brain changes. While previous studies have explored Alzheimer disease (AD)-related neuroanatomical substrates of apathy in the dementia clinical stage, few have investigated these associations in cognitively normal (CN) or mild cognitive impairment (MCI) individuals with persistent apathy consistent with MBI. Thus, this study explores structural brain differences between individuals with MBI-apathy and those without neuropsychiatric symptoms (no-NPS). Participants (n = 446; mean age = 69.6 years; 79.8% CN; 62.8% female) were drawn from the National Alzheimer's Coordinating Center and categorized into MBI-apathy (n = 59) and no-NPS (n = 387) groups. Linear regressions were used to model associations between NPS group and regional brain measures, with adjustments for age, sex, years of education, apolipoprotein E4 carrier status, intracranial volume, and Mini-Mental State Examination score, with false discovery rate (FDR) correction for multiple comparisons. Primary outcomes included two predefined AD meta-regions-of-interest (ROIs): 1) thickness: a composite measure of mean cortical thickness across the entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, inferior parietal lobule, fusiform gyrus, and precuneus; and 2) volume: a composite measure of mean cortical and subcortical grey matter volume across the hippocampus, entorhinal cortex, amygdala, middle temporal gyrus, inferior parietal lobule, and precuneus. Primary outcomes also included cortical thickness and grey matter volume among individual ROIs including the ventral striatum (VS), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC), and dorsolateral prefrontal cortex (dlPFC). MBI-apathy status was associated with significantly lower AD-meta-ROI cortical thickness (Z-score difference [95% CI]; FDR-corrected p-value, -0.43 [-0.73 - [-0.12]]; 0.025) and lower AD meta-ROI grey matter volume (-0.50 [-0.71 - [-0.30]]; <0.001). MBI-apathy was also associated with significantly lower dlPFC thickness (-0.40, [-0.70 - [-0.09]]; 0.02) and volume (-0.28 [-0.50 - [-0.06]]; 0.026) and lower OFC volume (-0.32, [-0.57 - [-0.07]]; 0.026) compared to the no-NPS group. Within a non-dementia sample, MBI-apathy was more strongly associated with established AD-vulnerable regions than with regions that have been traditionally implicated in apathy in dementia. Results suggests that during CN and MCI stages, MBI-apathy may reflect early AD-related neurodegeneration, with conventional apathy-related structural changes becoming more prominent as disease progresses.

INTRODUCTION:Quality of life (QoL) captures objective life conditions, subjective wellbeing, and personal aspirations. Interest is growing in ability-based, patient-centered instruments, not confounded by health outcomes. The Quality of Life and Function Five Domain Scale (QFS-5) uses a multi-dimensional approach to measure QoL emphasizing abilities and life engagement. We describe the development and validation of the QFS-5 in a large sample of community-dwelling older adults. METHODS:The validation sample comprised 1610 participants aged ≥ 50 from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behavior, Function, and Caregiving in Aging (CAN-PROTECT). Internal consistency was assessed using Cronbach's alpha and item-total correlations. Confirmatory factor analysis (CFA) evaluated domain structure. Criterion validity was tested through Pearson's correlation with the EuroQol-5D (EQ-5D). Convergent and discriminant validity were evaluated from associations with cognitive, mental health, and functional measures. Floor and ceiling effects were investigated. RESULTS:The QFS-5 demonstrated excellent internal consistency (α = 0.92); CFA supported the proposed domain structure with strong item loadings. Criterion validity was confirmed with correlation of -0.61 against the EQ-5D; higher symptom burden on related scales were associated with lower QFS-5 scores. Floor effects were minimal, while modest ceiling effects were observed in some domains. No significant floor or ceiling effects were found in participants with frailty. CONCLUSION:Validity and reliability are established for this ability-based QoL scale, within a sample of mostly cognitively unimpaired, community-dwelling older adults. The QFS-5 aligns with EQ-5D, demonstrating potential clinical and research utility to measure relevant patient-reported QoL outcomes.

Background and Objectives The cost and complexity of phase 2 randomized-controlled trials (RCTs) hinder further development of promising treatment candidates for Alzheimer disease (AD). The Simon Two-Stage futility trial design, originally developed for oncology, offers a streamlined approach to evaluate potential disease-modifying therapies by comparing single-arm outcomes with historical controls, but is predicated on identifying outcome measures that reliably worsen with the natural history of the disease, with minimal risk of improvement. We sought to determine the feasibility of such futility trials in AD-associated dementia and mild cognitive impairment (MCI) using a large prospective cohort.Methods We analyzed longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive decline was assessed using AD Assessment Scale-Cognitive Subscale (ADAS-Cog 11 and ADAS-Cog 13), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Mini-Mental State Examination (MMSE) at 6, 12, and 24 months using different thresholds for worsening vs improvement. Binary logistic regression models examined baseline factors associated with cognitive worsening using different thresholds of worsening for each outcome of interest to assess what additional selection criteria may be needed for futility trials in AD-associated dementia vs MCI. Sample size estimates were derived based on expected rates of decline.Results Among 2,665 participants (mean age 73.4 years [SD: 7.5], 1,260 [47.3%] female, 424 with AD-associated dementia), the CDR-SB exhibited the largest percentage of decline in AD-associated dementia and MCI, with 60.6% of patients with AD-associated dementia showing worsening when using a threshold of >= 1.0 points at 12 months vs 6.2% showing improvement. ADAS-Cog 11 and 13 showed similar decline patterns; for example, 41.7% with AD-associated dementia worsened by >= 5 points at 12 months on ADAS-Cog 13, whereas 5.8% improved. MMSE exhibited lower sensitivity; 25.8% with AD-associated dementia worsened by >= 5 points at 12 months, whereas 2.9% improved. Shorter trials (6-12 months) with 35-62 participants seemed feasible in AD-associated dementia, whereas MCI trials seemed to require 24 months and specific entry criteria based on age, apolipoprotein E epsilon 4 status, and baseline CDR-SB performance.Discussion Futility trials seem feasible in AD-associated dementia, offering a faster, cost-effective alternative to traditional phase 2 RCTs. CDR-SB seems to be the optimal primary outcome. Further validation in clinical trial data sets is warranted.

BackgroundFamily and friend care partners play a vital role in supporting individuals with neurocognitive disorders, such as Alzheimer's disease dementia. Care partners are often uncompensated and face multifaceted challenges that contribute to stress. The Care Partner Stress Scale (CPSS) was developed to assess caregiver stress across seven domains: cognition, behavior, function; unmet needs and emotional impact; work and financial strain; family and interpersonal conflict; and situational perception.ObjectiveTo evaluate psychometric properties of the CPSS in care partners of individuals with neurocognitive or neurodegenerative diseases of aging.MethodsThe CPSS was completed by 168 (83.93% female, age = 61.98 years) care partners in the CAN-PROTECT online cohort. Participants completed measures of depression, anxiety, quality of life, function, loneliness, and life satisfaction and engagement. We assessed internal consistency, item-total correlations, convergent and discriminant validity, and floor/ceiling effects.ResultsThe CPSS demonstrated excellent internal consistency (α = 0.95, 95% CI: 0.94-0.96), with item-total correlations >0.23. Higher CPSS scores were associated with greater depression (b = 2.38, 95%CI [0.72, 4.03], p = 0.005), anxiety (b = 4.47, 95%CI [2.44, 6.50], p < 0.001), and anxious distress (b = 6.37, 95%CI [3.54, 9.21], p < 0.001), as well as lower life satisfaction (b = -3.42, 95%CI [-5.61, -1.23], p = 0.002), poorer social relationships (b = -2.31, 95%CI [-4.54, -0.09] p = 0.042), greater loneliness (b = 5.26, 95%CI [1.33, 9.19], p = 0.009), and poorer life engagement (b = 2.89, 95%CI [1.23, 4.65], p = 0.001). CPSS scores were not associated with self-care (b = -1.06, 95%CI [-5.03, 2.92], p = 0.600). Floor effects were minimal (0.60%), with no ceiling effects.ConclusionsFindings provide initial support for multidimensional assessment of care partner stress in neurocognitive disorders.

BACKGROUND AND OBJECTIVES:Enlarged perivascular spaces (EPVSs) in the basal ganglia (BG-EPVS) are an important marker of cerebral small vessel disease (cSVD), and EPVS in the centrum semiovale (CSO-EPVS) are part of the diagnostic criteria for cerebral amyloid angiopathy. We aimed to investigate associations of EPVS with reduced estimated glomerular filtration rate (eGFR) and glomerular hyperfiltration (higher than normal eGFR), which have scarcely been studied previously. METHODS:In this cross-sectional study, we used pooled individual patient data from the Microbleeds International Collaborative Network which includes patients with ischemic stroke or transient ischemic attack. We investigated associations of impaired kidney function, defined as an eGFR of 30-60 or <30 mL/minute/1.73 m2, and glomerular hyperfiltration, defined as eGFR above the age-adjusted and sex-adjusted 95th centile, with BG-EPVS and CSO-EPVS severity. EPVS were rated according to a validated 5-point ordinal scale, and combined cSVD burden was rated using a validated 5-point ordinal scale with 1 point assigned for the presence of each of the following: severe white matter hyperintensities, ≥1 cerebral microbleed, ≥1 lacune, and BG-EPVS ≥11. Normal glomerular filtration was defined as eGFR ≥60 without hyperfiltration. We used multivariable ordinal logistic regression models to estimate risk of increased EPVS and cSVD burden severity adjusted for age, sex, and comorbidities. RESULTS:Seven thousand two hundred fifty-four patients (mean age 71 ± 13 years, 43% female) were included in the analysis, 357 with glomerular hyperfiltration, 1,692 with eGFR 30-60, and 256 with eGFR <30. Compared with normal glomerular filtration, hyperfiltration was independently associated with BG-EPVS (adjusted odds ratio [aOR] 1.38, 95% CI 1.11-1.70, p < 0.001) and CSO-EPVS (aOR 1.34, 95% CI 1.08-1.64, p = 0.011). Associations of eGFR 30-60 and eGFR <30 with EPVS were not statistically significant. Compared with normal glomerular filtration, eGFR <30 (aOR 1.27, 95% CI 1.03-1.57) was independently associated with increased cSVD burden, but eGFR 30-60 (aOR 1.06, 95% CI 0.95-1.20) and hyperfiltration (aOR 1.15, 95% CI 0.98-1.34) were not. DISCUSSION:Glomerular hyperfiltration was independently associated with EPVS severity, in both the basal ganglia and centrum semiovale. eGFR <30 was independently associated with total cSVD burden. A key limitation was a lack of repeated eGFR measurements.

Introduction: Prior studies evaluating the relationship between antiplatelet therapy (APT) and outcomes after spontaneous intracerebral hemorrhage (ICH) have grouped all antiplatelet agents together, and it is therefore unclear if specific antiplatelet agents or particular combinations of antiplatelet medications have differential effects on ICH outcomes. Methods: We performed a retrospective cohort study of patients with ICH from 2011-2021 in the Get With The Guidelines-Stroke registry. The exposure was the type of APT defined as either monothrerapy (aspirin, clopidogrel, prasugrel, ticagrelor used alone), dual APT combinations involving these 4 medications, or no APT. The outcomes were in-hospital mortality, and unfavorable discharge disposition defined as a composite of in-hospital mortality or hospice discharge. We used multiple logistic regression to study the relationship between incremental APT combinations and outcomes, after adjustment for demographics, vascular comorbidities, ICH severity (NIHSS Stroke Scale, external ventricular drain use), hospital characteristics (teaching status, urban location, annual case volume), and withdrawal of care. Results: Among 426,481 patients with ICH, 109,512 were on APT monotherapy, 17,009 were on dual APT, while 300,558 did not receive any APT prior to the ICH. In the multivariate logistic regression analyses, aspirin monotherapy was not associated with higher mortality compared with no APT, but clopidogrel, prasugrel, and ticagrelor monotherapies, and all dual APT combinations, were associated with higher odds of in-hospital mortality (Figure 1). Aspirin monotherapy was associated with lower odds of unfavorable discharge disposition compared with no APT, but there was a trend suggesting higher odds of unfavorable discharge disposition with other APT monotherapies and dual APT combinations (Figure 2). Conclusions: In a large, diverse US cohort of ICH patients, increasing potency of antiplatelet therapy at the time of ICH was associated with higher mortality and a trend toward poor discharge disposition. Better knowledge of these relationships will be crucial in the management of antiplatelet associated ICH.