Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Prevalence, Trajectory, and Predictors of Poststroke Pain: Retrospective Analysis of Pooled Clinical Trial Data Set.

BACKGROUND: Poststroke pain remains underdiagnosed and inadequately managed. To inform the optimum time to initiate interventions, we examined prevalence, trajectory, and participant factors associated with poststroke pain. METHODS: Eligible studies from the VISTA (Virtual International Stroke Trials Archives) included an assessment of pain. Analyses of individual participant data examined demography, pain, mobility, independence, language, anxiety/depression, and vitality. Pain assessments were standardized to the European Quality of Life Scale (European Quality of Life 5 Dimensions 3 Level) pain domain, describing no, moderate, or extreme pain. We described pain prevalence, associations between participant characteristics, and pain using multivariable models. RESULTS: From 94 studies (n>48 000 individual participant data) in VISTA, 10 (n=10 002 individual participant data) included a pain assessment. Median age was 70.0 years (interquartile range [59.0-77.1]), 5560 (55.6%) were male, baseline stroke severity was National Institutes of Health Stroke Scale score 10 (interquartile range [7-15]). Reports of extreme pain ranged between 3% and 9.5% and were highest beyond 2 years poststroke (31/328 [9.5%]); pain trajectory varied by study. Poorer independence was significantly associated with presence of moderate or extreme pain (5 weeks-3 months odds ratio [OR], 1.5 [95% CI, 1.4-1.6]; 4-6 months OR, 1.7 [95% CI, 1.3-2.1]; >6 months OR, 1.5 [95% CI, 1.2-2.0]), and increased severity of pain (5 weeks-3 months: OR, 1.2 [95% CI, 1.1-1.2]; 4-6 months OR, 1.1 [95% CI, 1.1-1.2]; >6 months, OR, 1.2 [95% CI, 1.1-1.2]), after adjusting for covariates. Anxiety/depression and lower vitality were each associated with pain severity. CONCLUSIONS: Between 3% and 9.5% of participants reported extreme poststroke pain; the presence and severity of pain were independently associated with dependence at each time point. Future studies could determine whether and when interventions may reduce the prevalence and severity of poststroke pain.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

BACKGROUND: White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. METHODS: We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. RESULTS: In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. CONCLUSIONS: In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

Association between Baseline NIHSS Limb Motor Score and Functional Recovery after Stroke: Analysis Based on a Multicountry Dataset.

INTRODUCTION: Motor skills are the domains most often affected by stroke, but a comprehensive assessment of motor function is often impractical in the acute setting. It could be useful to have a brief simple tool allowing the stratification of patients at the time of inclusion in clinical studies. Hence, our primary objective was to evaluate whether the baseline NIH Stroke Scale limb motor score (b-NIHSS-LMS), obtained by summing the four motor items 5a to 6b of the NIHSS, is associated with functional recovery assessed by the modified Rankin Score (mRS). A secondary objective was to apply this new tool in the context of a clinical trial. METHODS: The analysed population considered for this research included subjects from a large published, double-blind, multicentre trial, randomised to receive either a combination of various herbal and non-herbal components (MLC601) or placebo, administered within 72 h after an acute ischaemic stroke of intermediate severity (defined by baseline NIH Stroke Scale [b-NIHSS] score of 8-14). Associations between b-NIHSS-LMS and favourable outcome, i.e., mRS 0-1 at month 3, were evaluated using logistic regression adjusted for baseline covariates and study treatment. RESULTS: The analysis included 533 subjects with an acute ischaemic stroke of intermediate severity assessed at month 3. Analyses showed that b-NIHSS-LMS was independently associated with a favourable outcome (OR 0.84; 95% confidence interval 0.76-0.92; p < 0.0003) at 3 months. Furthermore, in the clinical study considered, a selection of patients based upon a sufficient level of motor impairment at study entry (b-NIHSS-LMS ≥3) would result in the detection of a more pronounced and longer-lasting treatment effect. Indeed, ORs of treatment effect versus placebo in the selected subgroup (b-NIHSS-LMS ≥3) were statistically significant from months 3-24. DISCUSSION/CONCLUSIONS: As an independent association between b-NIHSS-LMS and functional recovery after an acute ischaemic stroke of intermediate severity was established in this study, we suggest that the b-NIHSS-LMS can be used as a stratification factor in large clinical trials to define a target population with poststroke motor impairments.

Strategic white matter hyperintensity locations for cognitive impairment: A multicenter lesion-symptom mapping study in 3525 memory clinic patients.

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment. HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.

Antiplatelets and Anticoagulants in Ischemic Stroke,Transient Ischaemic Attack: A Practice Survey Among Singapore Neurologists.

PURPOSE: Evidence-based stroke clinical practice guidelines provide guidance as how to best manage patients with cerebrovascular disease. Where there are grey zones, the clinician decides what she/he feels is the most appropriate in that circumstance. This study was performed to determine how adult neurologists in Singapore would use antiplatelets(AP) and anticoagulants(AC) for their ischemic stroke patients in various settings where the evidence is uncertain. METHODS: A standardised questionnaire was sent to adult neurologists in Singapore. The questions evaluated their preferred type and dose of AP, use of heparin prior to initiating warfarin, and their preferred treatments in 6 different clinical scenarios. RESULTS: A total of 31/33 neurologists responded (93.9%). For long term secondary prevention, 71.0% preferred aspirin only, 22.6% clopidogrel/ticlopidine only, 6.5% aspirin plus dipyridamole. Anticoagulation with warfarin was initiated with a heparin bolus by 45.2%. AC were preferred by 80.6% for stroke in evolution, 80.6% for presumed basilar artery thrombosis, 54.8% for crescendo TIAs. For patients awaiting CEA, 58.1% preferred AP, 32.3% AC. For patients on preferred AP developing another cerebrovascular event with no new underlying cause, 48.4% would change AP, 25.8% would add another AP. For patients on adequate AC for non-cardioembolism developing another cerebrovascular event, 54.8% would add anti-platelet, 19.4% would increase AC. CONCLUSIONS: The widespread use of aspirin for long-term secondary prevention is similar to other countries. The variation in the use of antithrombotic agents in other settings may reflect the lack of sufficient evidence to guide therapy in the various specific stroke patient management scenarios. KEY WORDS: neurologist, practice, antiplatelet, anticoagulant, stroke, cerebrovascular disease.

Blood-Based Cardiac Biomarkers and the Risk of Cognitive Decline, Cerebrovascular Disease, and Clinical Events.

Background and Purpose: Cardiac biomarkers, NT-proBNP (N-terminal probrain natriuretic peptide), hs-cTnT (high-sensitivity-cardiac troponin T), and GDF-15 (growth differentiation factor-15) have been proposed as important biomarkers of early vascular pathology. However, little is known of the longitudinal associations of these cardiac biomarkers with cerebrovascular disease and clinical events. We examine the association of blood-based cardiac biomarkers (NT-proBNP, hs-cTnT, and GDF-15) with cognitive decline, incident cerebrovascular disease, vascular events, and mortality. Methods: Four hundred thirty-four memory-clinic patients provided blood samples at baseline, underwent 3 annual neuropsychological assessments and brain magnetic resonance imaging scans at baseline and follow-up. NT-proBNP and hs-cTnT concentrations were measured by electrochemiluminescence immunoassay and GDF-15 by quantitative sandwich immunoassay. Baseline and follow-up magnetic resonance imagings were graded for white matter hyperintensities, lacunes, cerebral microbleeds, cortical infarcts, and intracranial stenosis. Data on incident vascular events and mortality were obtained. Results: Patients with higher levels of NT-proBNP, hs-cTnT, and GDF-15 showed greater decline in memory domain. Additionally, hs-cTnT was associated with decline in global cognition, executive function, and visuomotor speed. Higher levels of NT-proBNP were associated with incident cerebral microbleeds and hs-cTnT with incident cortical infarcts. During a mean follow-up of 3 years, 26 (5.9%) patients died and 35 (8.1%) developed vascular events. Patients with higher levels of NTpro-BNP and hs-cTnT were at increased risk of vascular events whereas those with higher levels of NT-proBNP and GDF-15 were at risk of mortality. Conclusions: Higher levels of blood-based cardiac biomarkers were associated with decline in memory and risk of vascular events and mortality. Moreover, NT-proBNP and hs-cTnT were associated with incident cerebral microbleeds and cortical infarcts. Thus, these biomarkers are potentially useful in identifying patients at risk of adverse vascular events and death.

Stroke Epidemiology in Oceania: A Review.

BACKGROUND AND PURPOSE: Oceania, comprising the regions Australasia, Melanesia, Micronesia, and Polynesia, is home to 42 million living in 8.5 million square kilometres of land. This paper comprises a review of the epidemiology of stroke in countries in this region. METHODS: Information on epidemiology of stroke in Oceania was sought from data from the Global Burden of Disease (GBD) study (incidence, mortality, incidence:mortality ratio [IMR], prevalence, disability-adjusted life-years [DALYs] lost due to stroke, and subtypes), World Health Organization (WHO) (vascular risk factors in the community), and PubMed (incidence, prevalence, and stroke subtypes). Data were analyzed by region to allow inter-country comparison within each region. RESULTS: In 2010, age- and sex-standardized stroke mortality rates were lowest in Australasia (29.85-31.67/100,000) and highest in Melanesia and Micronesia (56.04-187.56/100,000), with wide ranges especially in Melanesia. Incidence rates were lowest in Australasia (101.36-105.54/100,000), similarly high elsewhere. Standardized IMR (0.98-3.39) was the inverse of the mortality rates and mirrored the prevalence rates (202.91-522.29/100,000). DALY rates (398.22-3,781.78/100,0000) mirrored the mortality rates. Stroke risk factors show a variable pattern - hypertension is generally the most common medical risk factor among males (18.0-26.6%), while among females, diabetes mellitus is the most common in Micronesia and Polynesia (21.5-28.4%). Among the lifestyle factors, current smoking is the most common in Melanesia among males, while obesity is generally the most common factor among females. Ischaemic stroke comprises 70% of stroke subtypes. Trend data show significant falls in standardized mortality rates and DALYs in most regions and falls in incidence in almost all countries. There is significant economic impact, particularly due to young strokes; some ethnicities are at higher risk than others, for example, Maoris and Pacific Islanders. CONCLUSIONS: Stroke is a major healthcare problem in Oceania. Variations in stroke epidemiology are found between countries in Oceania. Data are lacking in some; more research into the burden of stroke in Oceania is needed. With the expected increase in life expectancy and vascular risk factors, the burden of stroke in Oceania will likely rise. Some of the disparities in stroke burden may be addressed by great investment in healthcare.

The Impact of Strategic White Matter Hyperintensity Lesion Location on Language.

OBJECTIVE: The impact of white matter hyperintensities (WMH) on language possibly depends on lesion location through disturbance of strategic white matter tracts. We examined the impact of WMH location on language in elderly Asians. DESIGN: Cross-sectional. SETTING: Population-based. PARTICIPANTS: Eight-hundred nineteen residents of Singapore, ages (≥65 years). MEASUREMENTS: Clinical, cognitive and 3T magnetic resonance imaging assessments were performed on all participants. Language was assessed using the Modified Boston Naming Test (MBNT) and Verbal Fluency (VF). Hypothesis-free region-of-interest-based (ROI) analyses based on major white matter tracts were used to determine the association between WMH location and language. Conditional dependencies between the regional WMH volumes and language were examined using Bayesian-network analysis. RESULTS: ROI-based analyses showed that WMH located within the anterior thalamic radiation (mean difference: -0.12, 95% confidence interval [CI]: -0.22; -0.02, p = 0.019) and uncinate fasciculus (mean difference: -0.09, 95% CI: -0.18; -0.01, p = 0.022) in the left hemisphere were significantly associated with worse VF but did not survive multiple testing. Conversely, WMH volume in the left cingulum of cingulate gyrus was significantly associated with MBNT performance (mean difference: -0.09, 95% CI: -0.17; -0.02, p = 0.016). Bayesian-network analyses confirmed the left cingulum of cingulate gyrus as a direct determinant of MBNT performance. CONCLUSION: Our findings identify the left cingulum of cingulate gyrus as a strategic white matter tract for MBNT, suggesting that language - is sensitive to subcortical ischemic damage. Future studies on the role of sporadic ischemic lesions and vascular cognitive impairment should not only focus on total WMH volume but should also take WMH lesion location into account when addressing language.

Asia Pacific Stroke Conference 2021.

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Stroke Care during the COVID-19 Pandemic: International Expert Panel Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.

Vision, vision-specific functioning and mobility, and their relationship with clinically assessed cognitive impairment.

BACKGROUND: The relationship between self-reported visual disability and cognitive impairment in older individuals is unclear. OBJECTIVE: To determine the relationship of vision-specific functioning (VSF), vision-specific mobility (VSM) and visual acuity (VA) with clinically assessed cognitive impairment in the Epidemiology of Dementia in Singapore study. DESIGN: Cross-sectional. SETTING: Population-based. SUBJECTS: Eight hundred and seventy-four adults aged ≥60 years at higher risk of possible cognitive impairment by the Abbreviated Mental Test and progressive forgetfulness question. METHODS: VSF and VSM were measured using Rasch-transformed continuous scores of two Impact of Vision Impairment questionnaire domains. Cognitive impairment was objectively determined using detailed neuropsychological testing and defined as no cognitive impairment (NCI), mild cognitive impairment-no dementia (CIND), moderate CIND only and moderate CIND or dementia. Associations were assessed using multinomial logistic regression models. RESULTS: Of the 874 participants (49.0% males, mean age (SD) 65.5 (7.0) years), 277, 281 and 316 had NCI, mild CIND and moderate CIND or dementia, respectively. Compared to NCI, the odds of moderate CIND, and moderate CIND or dementia increased for every SD worsening in VSF (OR: 1.44, 95% CI 1.14-1.82, and OR: 1.52, 95%CI 1.19-1.94, respectively) and VSM (OR: 1.42, 95%CI 1.11-1.81, and OR: 1.50, 95%CI 1.15-1.95). Similarly, the odds of mild CIND (OR: 1.62, 95%CI 1.19-2.22), moderate CIND (OR: 1.93, 95%CI 1.45-2.58), and moderate CIND or dementia (OR: 2.25, 95%CI 1.62-3.11) increased significantly with every SD worsening of VA. CONCLUSIONS: Our results emphasise the importance of interventions to prevent vision loss and improve quality of life to reduce likelihood of age-related cognitive decline.

Burden of informal care in stroke survivors and its determinants: a prospective observational study in an Asian setting.

BACKGROUND: Informal caregiving is an integral part of post-stroke recovery with strenuous caregiving demands often resulting in caregiving burden, threatening sustainability of caregiving and potentially impacting stroke survivor's outcomes. Our study aimed to examine and quantify objective and subjective informal care burden after stroke; and to explore the factors associated with informal care burden in Singapore. METHODS: Stroke patients and their informal caregivers were recruited from all five tertiary hospitals in Singapore from December 2010 to September 2013. Informal care comprised of assistance provided by informal caregivers with any of the activities of daily living. Informal care burden was measured by patients' likelihood of requiring informal care, hours of informal care required, and informal caregivers' Zarit's Burden Score. We examined informal care burden at 3-months and 12-months post-stroke. Generalized linear regressions were applied with control variables including patients' and informal caregivers' demographic characteristics, arrangement of informal care, and patients' health status including stroke severity (measured using National Institute of Health Stroke Scale), functional status (measured using Modified Rankin Scale), self-reported depression, and common comorbidities. RESULTS: Three hundred and five patients and 263 patients were examined at 3-months and 12-months. Around 35% were female and 60% were Chinese. Sixty three percent and 49% of the patients required informal care at 3-months and 12-months point, respectively. Among those who required informal care, average hours required per week were 64.3 h at 3-months and 76.6 h at 12-months point. Patients with higher functional dependency were more likely to require informal care at both time points, and required more hours of informal care at 3-months point. Female informal caregivers and those caring for patients with higher functional dependency reported higher Zarit's Burden. While informal caregivers who worked full-time reported higher burden, those caring for married stroke patients reported lower burden at 3-months point. Informal caregivers who co-cared with foreign domestic workers, i.e.: stay-in migrant female waged domestic workers, reported lower burden. CONCLUSIONS: Informal care burden remains high up to 12-months post-stroke. Factors such as functional dependency, stroke severity, informal caregiver gender and co-caring with foreign domestic workers were associated with informal care burden.

Longitudinal trajectory of Amyloid-related hippocampal subfield atrophy in nondemented elderly.

Hippocampal atrophy and abnormal ß-Amyloid (Aß) deposition are established markers of Alzheimer's disease (AD). Nonetheless, longitudinal trajectory of Aß-associated hippocampal subfield atrophy prior to dementia remains unclear. We hypothesized that elevated Aß correlated with longitudinal subfield atrophy selectively in no cognitive impairment (NCI), spreading to other subfields in mild cognitive impairment (MCI). We analyzed data from two independent longitudinal cohorts of nondemented elderly, including global PET-Aß in AD-vulnerable cortical regions and longitudinal subfield volumes quantified with a novel auto-segmentation method (FreeSurfer v.6.0). Moreover, we investigated associations of Aß-related progressive subfield atrophy with memory decline. Across both datasets, we found a converging pattern that higher Aß correlated with faster CA1 volume decline in NCI. This pattern spread to other hippocampal subfields in MCI group, correlating with memory decline. Our results for the first time suggest a longitudinal focal-to-widespread trajectory of Aß-associated hippocampal subfield atrophy over disease progression in nondemented elderly.

Frequency and Clinical Impact of Serious Adverse Events on Post-Stroke Recovery with NeuroAiD (MLC601) versus Placebo: The CHInese Medicine Neuroaid Efficacy on Stroke Recovery Study.

BACKGROUND: Most comparative clinical trials are designed to assess the treatment effect for efficacy endpoints, with less emphasis on the analysis of safety outcomes. However, an extensive analysis of safety data could demonstrate beneficial results in terms of effectiveness by reducing serious adverse events (SAEs), and their unfavourable clinical impact on the study population. We aimed to conduct an exploratory analysis of the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study safety database comparing the frequency of SAEs and their clinical impacts among subjects having received MLC601 or placebo during the first 3 months post-stroke. METHODS: Analyses were performed by using the safety database of the multicentre, randomised, double-blind, placebo-controlled CHIMES study of 3 months of NeuroAiD versus placebo in subjects with acute ischaemic stroke of intermediate severity in the preceding 72 h. SAEs as reported by investigators at any time-point during the 3-month study were analysed on their frequency and that of any of their outcomes (death, and life threatening, new and/or prolonged hospitalisation, disability, and medical importance, in surviving subjects), as well as their time to onset and resolution. RESULTS: Of the 1,099 subjects in the CHIMES study, 1,087 were included in the safety analysis (MLC601 = 542) and (placebo = 545); the 12 who did not receive study treatment were excluded. There was a total of 135 subjects with SAEs (MLC601 = 60, placebo = 75). At baseline, overall, subjects with SAEs were older and had lower MMSE score. In the MLC601 group, they had higher NIHSS score, and more frequently a history of ischaemic heart disease and hyperlipidaemia. The number of SAEs per subjects was statistically significantly lower in the MLC601 group than placebo one, especially for subjects with ≥2 SAEs (6.7 vs. 29.3%; p < 0.001). This benefit was seen throughout the study period and during the initial hospitalisation. The main clinical impact of SAEs was an increase in hospitalisation time, reduced in the MLC601 arm with the rate of subjects hospitalised for a prolonged period being significantly threefold lower in surviving subjects (1.1 vs. 3.7%; p < 0.01). CONCLUSIONS: This post hoc analysis of SAEs from the CHIMES study database shows that subjects receiving a 3-month course of MLC601 experienced fewer SAEs, with lower rates of harmful clinical impacts, especially in terms of hospitalisation duration. These findings could translate to a benefit in terms of reduction of both healthcare burden and additional medical costs.

Hearing handicap in Asian patients with dementia.

BACKGROUND: Hearing loss and hearing handicap may contribute to cognitive impairment and dementia. The purpose of this study was to analyze the association between hearing loss and hearing handicap with dementia in an Asian memory clinic parents. METHODS: This study includes the data obtained from patients with mild dementia who attended the National University hospital memory clinic and non-demented healthy subjects among spouses and caregivers who are non-genetically related to our patients. All participants underwent comprehensive physical, medical, neuropsychological and audiological assessments (i.e. pure tone audiometry - PTA). Disabling hearing loss was defined as a hearing loss of >40 dB in the better ear on PTA. Amsterdam Inventory for Auditory Disability and Handicap (AIADH) questionnaire was administered through the verbal interview to measure their hearing handicap score. Linear regression models were used to investigate the association between hearing loss and hearing handicap with dementia. Mean differences (ß) with 95% confidence intervals (CI) were calculated. RESULTS: 91 participants (65-90 years old) were recruited for this study; 39 of them were patients with dementia and 52 were non-demented healthy controls. 48.7% of the patients with dementia had disabling hearing loss, which is higher than the non-demented controls (25.0%) (p = 0.019). The significant association between hearing handicap (as measured by AIADH) and dementia was observed, which was independent of demographic factors and audiology related history and PTA average (ß = -6.40; 95% CI =0.11.99, -0.81, p = 0.025). There was no independent association between hearing loss and dementia (p > 0.05). CONCLUSION: A significant association between hearing handicap and dementia was found. The mechanism of this association requires further research and may involve higher order central processing disorder.

Mechanisms Linking White Matter Lesions, Tract Integrity, and Depression in Alzheimer Disease.

OBJECTIVE: Late-life depression involves the disconnection of white matter tracts that regulate mood. A pathogenic link between poor tract integrity and depressive symptoms is believed to be white matter lesions (WML), however the mechanisms linking tract integrity, WML, and depression remains unexplored. The authors sought to identify whether the association between reduced tract integrity and depressive symptoms is mediated by WML in patients with Alzheimer disease (AD), and whether individual characteristics moderate this effect. METHODS: This was a cross-sectional study in a tertiary memory clinic. A total of 91 patients with mild AD and 79 healthy elderly, comparable in depressive symptoms, white matter hyperintensities (WMH) volume, cardiovascular risk, age, and sex were chosen. Tract integrity was assessed using diffusion tensor imaging, WML were indexed as WMH, measured using fluid-attenuation inversion recovery imaging, and depressive symptoms were measured with the informant-based Geriatric Depression Scale. RESULTS: In patients with mild AD, reduced tract integrity in right hemispheric cortical-subcortical tracts and the genu of the corpus callosum was moderately associated with depressive symptoms. This association was fully mediated by WML. Moderation analysis indicated that old age strengthened the association between all tracts and depressive symptoms, as mediated by WML. In cognitively healthy elderly, neither tracts nor WML were related to depressive symptoms. CONCLUSION: Reduced tract integrity may be important but not sufficient for the manifestation of depressive symptoms in mild AD. Instead, WML may drive the pathogenic link between reduced tract integrity and depressive symptoms.

Stroke Factors Associated with Thrombolysis Use in Hospitals in Singapore and US: A Cross-Registry Comparative Study.

BACKGROUND AND OBJECTIVES: This paper aims to describe and compare the characteristics of 2 stroke populations in Singapore and in St. Louis, USA, and to document thrombolysis rates and contrast factors associated with its uptake in both populations. METHODS: The stroke populations described were from the Singapore Stroke Registry (SSR) in -Singapore and the Cognitive Rehabilitation Research Group Stroke Registry (CRRGSR) in St. Louis, MO, USA. The registries were compared in terms of demographics and stroke risk factor history. Logistic regression was used to determine factors associated with thrombolysis uptake. RESULTS: A total of 39,323 and 8,106 episodes were recorded in SSR and CRRGSR, respectively, from 2005 to 2012. Compared to CRRGSR, patients in SSR were older, male, and from the ethnic majority. Thrombolysis rates in SSR and CRRGSR were 2.5 and 8.2%, respectively, for the study period. History of ischemic heart disease or atrial fibrillation was associated with increased uptake in both populations, while history of stroke was associated with lower uptake. For SSR, younger age and males were associated with increased uptake, while having a history of smoking or diabetes was associated with decreased uptake. For CRRGSR, ethnic minority status was associated with decreased uptake. CONCLUSIONS: The comparison of stroke populations in Singapore and St Louis revealed distinct differences in clinicodemographics of the 2 groups. Thrombolysis uptake was driven by nonethnicity demographics in Singapore. Ethnicity was the only demographic driver of uptake in the CRRGSR population, highlighting the need to target ethnic minorities in increasing access to thrombolysis.