Harmonization of neuropsychological assessment for vascular cognitive disorders (VCD) is important for ensuring the highest standards for diagnostic and post-diagnostic care. A battery jointly proposed by the NINDS-CSN has received much support. Considering significant developments in the field, and an urgent need for consensus on remote and computerised assessment methods, an international expert group was commissioned to develop an updated harmonized battery and associated assessment guidelines for VCD using the Delphi process. A modified Delphi consensus method was used, involving an iterative, multi-staged series of structured surveys with feedback of anonymized responses from experts in the neuropsychological assessment of vascular cognitive disorders. Three rounds were planned, with the possibility of a fourth round, if required to reach consensus. Literature reviews on harmonized neuropsychological assessment were conducted by a team of researchers, which informed the first structured questionnaire. Consensus was sought on the cognitive domains and subdomains that should be assessed, on specific tests per domain, and for additional guidelines including on non-traditional assessment methods and cultural-linguistic considerations. Consensus was defined as agreement or disagreement on any statement of ≥ 75%, near consensus as 66 – 75%, and <66% as non-consensus. Statements that reached consensus were removed from subsequent rounds, as were most that had non-consensus, with some being reworded. A virtual meeting was held for experts to discuss contentious issues and advise on the process. Forty-four experts in neuropsychological assessment from a range of international regions consented to participate, and 31 completed the Round 1 survey. The final survey is being completed, then the assessment battery and additional guidelines will be finalized to be approved formally by all participants. The harmonized neuropsychological assessment standards could be adopted internationally and complement the NINDS-CSN battery, thereby further facilitating consistent neuropsychological assessment of VCD between clinicians and researchers.

The initiation of cognitive impairment is triggered by a myriad of pathological events occurring decades before clinical symptoms manifest. Perturbed glucose and fatty acid metabolism notably contribute to the development of cognitive impairment, progressing further into clinical dementia. These metabolic alterations are evident in plasma through changes in specific metabolites. Notably, these changes are characteristic features in the pathophysiology of depression, a significant risk factor for cognitive impairment. This project aims to establish a blood-based biomarker signature for early identification of cognitive changes in individuals with depression. Moreover, it aims to assist in diagnosing and understanding disease progression by quantifying plasma metabolite levels linked to fatty acid metabolism in samples obtained from participants in the Sydney Memory and Ageing Study. Plasma samples underwent analysis to quantify fatty acids and carnitines using chemical derivatization through UPLC-MRM/MS coupled with a 4000 QTRAP mass spectrometer which was equipped with an electrospray ion (ESI) source and operated in the multiple-reaction monitoring (MRM) mode with negative-ion (-) detection.10-μL aliquots of each of the resultant calibration solutions and each of the sample solutions were injected for analysis. ANCOVA, revealed significant changes in the levels of several biomarkers including glycolic acid (p-value: 0.033), C181 carnitine (p-value: 0.013), glutaric acid (p-value: 0.08) levels in groups with Mild Cognitive Impairment (MCI) and MCI with comorbid depression compared to healthy groups. ROC curve analysis demonstrated that glutaric acid effectively distinguished between MCI and non-MCI participants. The optimal threshold for classifying participants into MCI and non-MCI groups was determined using the Youden Index to dichotomize them based on high and low biomarker levels. Logistic regression analysis, adjusting for age, sex, APOE ε4 genotype, and comorbid depression, revealed a significant association between glutaric acid levels and cognitive impairment in the context of depression, with a p-value of <0.001 and an odds ratio of 2.49. Glutaric acid proved to be a reliable discriminator between participants with MCI and those without MCI. The aforementioned findings revealed a strong correlation between glutaric acid and cognitive impairment associated with depression which could be used as biomarker for early detection of cognitice impairment.

Compensation has been proposed as a mechanism to explain how individuals in very old age remain able to maintain normal cognitive functioning. Previous studies have provided evidence on the role of increasing functional connectivity as a compensatory mechanism for age-related white matter damage. However, we lack direct investigation into how these mechanisms contribute to the preservation of cognition in the very old population. We examined a cohort of near-centenarians and centenarians without dementia (aged 95-103 years, n=44). We constructed a structural disconnection matrix based on the disruption of white matter pathways caused by white matter hyperintensities (WMHs), aiming to explore the relationship between functional connections, cognitive preservation and white matter damage. Our results revealed that structural damage can reliably explain the variations of functional connections or cognitive maintenance. Notably, we found significant correlations between the weights in the functional connectivity model and the weights in the cognition model. We observed positive correlations between models for brain disconnections and cognitive function in near-centenarians and centenarians. The strongest effects were found between attention and somatomotor network (SMN) (r=0.397, p<0.001), memory and SMN (r=0.333 p<0.001), fluency and visual network (VIS) - control network (CN) (r=0.406, p<0.001), language and VIS (r=0.309, p<0.001), visuospatial ability and VIS-default mode network (DMN) (r=0.464, p<0.001), as well as global cognition and VIS-DMN (r=0.335, p<0.001). These findings suggest that enhancement of functional connectivity may serve as a compensatory mechanism, such that it mitigates the effects of white matter damage and contributes to preserved cognitive performance in very old age.

Situational factors can influence cognitive performance and should be considered for conducting cognitive assessments. The objective of this project was to develop a checklist for Cognitive Assessment Requirements (CARE) to identify these situational factors before conducting cognitive assessments and account for them. This study employed a four-round Delphi approach involving 22 experts to identify situational factors that can impact cognitive assessment results. The development of a robust and well-balanced checklist was guided by a consensus-driven approach, which considered metrics such as Interquartile Deviation (IQD) (> 1.00), Percentage of Positive Responses (PPR, above 60%), and mean importance ratings (< 3 on a 5-point Likert scale) to assess both degree of agreement and item importance. Consensus was reached, leading to a 14-item checklist to evaluate cognitive assessment requirements. These items were categorized into six groups: Acute Illness or Physical Discomfort, Medication Effects and Substance Use, Sleep Quality and Fatigue, Emotional State, Language factors, and Environmental factors. The CARE can be employed prior to cognitive assessments to identify situational factors of relevance to the individual client, thereby creating a more favorable environment for cognitive evaluation, and enhancing the reliability of the assessment findings. Furthermore, the CARE can help determine the level of confidence in the results by assessing whether the conditions are conducive to testing or if situational factors may undermine the validity of the evaluation.

The effects of the COVID-19 pandemic extend beyond the viral impact and include social and psychological effects of the ensuing lockdowns and restrictions. Australia’s lengthy lockdowns present an opportunity to study changes in the physical and mental wellbeing of older adults resulting from extended social isolation, a known risk factor for dementia, in the absence of high infection or mortality rates. Sydney Memory and Ageing Study, Sydney Centenarian Study, and CogSCAN study participants were mailed questionnaires about in-person and remote social contact and access to resources during the 2020 Sydney lockdown. Responses were linked to existing medical history and cognitive status data from 2018-2019. Respondents were classified based on self-reported poor outcomes (PO), defined as feeling worse because of the pandemic in three domains: overall health, emotional and psychological health, and physical activity. Cognitive impairment was defined as presence of DSM-V neurocognitive disorders as determined by clinical consensus, MMSE <27, or ACE-III <88. Factors associated with PO were explored. Of the 335 participants who responded to the COVID-19 questionnaire by January 2021, 75 (22.4%) met criteria for cognitive impairment. None of the respondents reported ever being symptomatic at the time of study. Only 19 (5.7%) personally knew someone who had COVID-19. Most (156, 46.7%) participants had no POs, 112 had one, and 67 had two or more. Cognitive status was not associated with POs. Compared to no POs, PO participants actively reduced in-person contact, overall social contact, had more difficulty accessing food and medical resources. Despite PO participants communicating more frequently with friends and family by phone, and reporting having changed their social support, they also had lower scores in questionnaires for life satisfaction and loneliness. Older adults who reported poorer outcomes during lockdown had greater reduced social contact. Despite efforts to adapt their social support networks through increased phone-based social interactions, they still reported worse life satisfaction and more loneliness. Difficulties in adapting to changing social circumstances and isolation may confer a greater susceptibility to loneliness. Further work is needed to understand the relationship between susceptibility to loneliness and future dementia risk.

Importance:Several sets of diagnostic criteria have been proposed for vascular cognitive impairment and dementia (VCID). The International Society for Vascular Behavioural and Cognitive Disorders (VasCog) working group published comprehensive operationalized criteria in 2014. Considering subsequent advances in the field, a revision was needed. Objective:To update the VasCog criteria to achieve consensus on diagnosis of VCID. Design, Setting, and Participants:VasCog criteria and other published diagnostic guidelines, aided by literature review of recent developments in VCID, were used as reference points for an online Delphi survey (minimum 3 rounds, ≥75% threshold for agreement), including operationalization of criteria and guidance on potential biomarkers. Seventy international experts from diverse international regions were invited to participate in 2023. Results:Three survey rounds included 49 to 54 participants that agreed on VasCog-2 diagnostic criteria for preclinical, mild, and major dementia levels of vascular cognitive impairment (under the overarching term VCID). Research guidelines, including the use of novel neuroimaging and fluid biomarkers, were also agreed on. The World Stroke Organization (WSO) endorsed the criteria, hence named VasCog-2-WSO. Conclusions and Relevance:The VasCog-2-WSO criteria update the VasCog criteria for the diagnosis of VCID, providing operationalization and additional guidance on potential neuroimaging and fluid biomarkers. VasCog-2-WSO should provide an international standard for VCID diagnosis, facilitating diagnostic consistency among clinicians and researchers.

Objectives This study investigated the cross-sectional associations between participants’ scores on five cognitive domains and global cognition and their scores on a multidimensional measure of self-perceptions of aging. This study also investigated whether 12-year change in the same cognitive domains and global cognition was associated with self-perceptions of aging. Design Cross-sectional and longitudinal secondary analyses of a cohort study. Participants Participants were 103 individuals (mean age at 12-year follow-up = 87.43 years; SD = 3.60; 60.2 % women) enrolled in the Sydney Memory and Aging Study (MAS) with 12-years of follow-up data. Measurements Cognitive domains assessed over 7 waves were attention processing speed, language, executive function, visuospatial abilities, and memory. Self-perceptions of aging were assessed only at wave 7 using the three subscales of the Laidlaw’ Attitudes to Aging Questionnaire: psychological growth, psychosocial loss, and (positive) physical change. Results After having adjusted for age, sex, marital status, occupation when working, depressive symptoms, and numbers of physical health conditions and for multiple comparisons there were no significant cross-sectional associations between cognitive abilities and global cognition and the subscales of the Attitudes to Aging Questionnaire. After having adjusted for baseline cognition, age, sex, marital status, occupation when working, depressive symptoms, and numbers of physical health conditions there were no significant longitudinal associations between change in cognitive abilities and in general cognition and the subscales of the Attitudes to Aging Questionnaire. Conclusions Cross-sectional and change scores on cognitive tasks and global cognition do not have an effect on Attitudes to Aging after having controlled for depressive symptoms.

IntroductionStudies investigating the associations between change in health indicators and multidimensional measures of self-perceptions of aging in very old age are scarce. This study investigated whether levels of and 12-year changes in objective and subjective indicators of cognitive, mental, and physical health explain variance in the self-perceptions of aging of very old individuals at follow-up.MethodsParticipants were 174 individuals enrolled in the Australian Memory and Aging Study (mean age = 87.41; SD = 3.67; 60% women). As health indicators, we used global cognition, the Memory Assessment Clinic Questionnaire, the Goldberg Anxiety Scale, the Geriatric Depression Scale, number of diagnosed health conditions, and self-rated health. Self-perceptions of aging were assessed with the Laidlaw Attitudes to Aging Questionnaire, which comprises three subscales capturing perceived psychological growth, psychosocial loss, and positive physical change. Simple and multivariable linear regression models were estimated.ResultsCross-sectionally, in multivariable linear regression models, more anxiety symptoms were associated with higher psychosocial loss (R2 = 6%) and higher self-rated health (R2 = 14%) was associated with higher perceived positive physical change. Cognition was not significantly associated with attitudes to aging subscales. Longitudinally, less increase in depressive symptoms was associated with less perceived psychosocial loss (R2 = 5%) and with greater perceived positive physical change (R2 = 11%).ConclusionSelf-perceptions of aging in different domains are cross-sectionally associated with different health indicators. However, among cognitive, mental, and physical health indicators, changes in depressive symptoms are the most correlated with perceived psychosocial loss in very old age.

Social cognition is crucial to optimal social functioning outcomes in older adults, with implications for overall health and wellbeing. Moreover, poor social cognition is a diagnostic criterion for neurocognitive disorders (NCDs). Prior work has studied the social cognitive subdomains (theory of mind (ToM), affective empathy, emotion recognition, and social behaviour) and found mild cognitive impairment and dementia to be associated with poorer performance in specific tasks and informant-reported changes respectively. These patterns in NCDs need to be distinguished from normal age-related changes, and more information is needed to ascertain what factors predict social cognitive decline in healthy ageing. 132 non-demented participants [mean MMSE 29.23 (SD 0.99)] aged 60 to 100 underwent comprehensive social cognitive assessments that varied based on modality of information (Figure 1), alongside neurocognitive assessments and affective questionnaires. Participants were divided based on decades to study age-related changes. Linear regression models identified significant predictors of social cognition performance amongst demographic, neuropsychological assessment scores, affective scores, and social networks. Age was associated with poorer performance in ToM tasks, specifically the Reading the Mind in the Eyes Test (RMET), Multifaceted Empathy Test (MET) Cognitive subscale, and The Awareness of Social Inference Test (TASIT) part 3, and emotion recognition tasks, specifically the FACES task and TASIT 1, for expressions of anger, disgust, and sadness (Table 1). In regression models (Table 2), age was a significant predictor of RMET and FACES performance. In MET cognitive and both TASITs, neuropsychological tasks, mainly executive function, were predictive. Poorer executive function predicted performance for identifying unspoken emotions (“Feel” subscore) in TASIT 3. MET Emotional and the self-rated Interpersonal Reactivity Index (IRI) Empathic Concern subscale was associated with less anxiety and more positive emotions at assessment. In ToM and emotion recognition, unimodal task performance was associated with age and some cognitive factors, and multimodal task performance was largely associated with executive function. Performance in affective empathy tasks was linked to affective measures. Poor performance in multimodal tasks likely reflects executive dysfunction in consolidating multiple streams of social information, while some declining performance in unimodal tasks may be normative to ageing.

Language and cultural factors are known to influence cognitive performance on neuropsychological measures used to assess cognitive impairment and dementia. A new measure, the Characterising Language Experience and Acculturation Questionnaire (CLEAr-Q) was developed to address the gap in access to a brief measure of these factors in the Australian context. The aim is to validate and further develop the CLEAr-Q as a tool to capture linguistic and acculturation variables to improve measurement of cognition in older adults from Culturally and Linguistically Diverse (CALD) backgrounds. The CLEAr-Q was initially created as a paper questionnaire and completed by all older adults from CALD backgrounds in the CogSCAN Study. Items were drawn from the literature and adapted based on feedback from the CogSCAN group. An online version for validation with a larger sample was then developed with consultation from a CALD community working group via an adapted participatory research framework. The anonymous survey is completed online in English and data collection will conclude in February 2024. Preliminary analysis (e.g., Pearson correlation) will be conducted to check for redundant items and to select linguistic and acculturation variables (Table 1) to be included in an exploratory factor analysis; this will establish the factor structure and develop a streamlined, psychometrically validated version of the CLEAr-Q . The CogSCAN sample included 75 participants aged 60-95 who reported speaking and/or reading a language other than English (LOTE). The validation sample to date consists of 244 participants aged 60-90 who reported speaking and/or reading a LOTE at a functional level, were born in over 50 overseas countries (Figure 1) and speak on average more than two languages (Table 2). Data analysis is in progress. Results will contribute to validating the CLEAr-Q and demonstrating its utility to characterise known diversity in CALD samples. Future directions include examining the relative importance of linguistic and acculturation variables from the CLEAr-Q in predicting cognitive performance, which is expected to improve diagnostic accuracy of current neuropsychological measures for assessment of cognitive impairment and dementia in older adults from CALD backgrounds.

OBJECTIVES:Emerging evidence suggests all-cause acute hospitalizations are associated with cognitive decline, rather than being associated only with specific inpatient contexts (surgery, critical care and delirium). This study clarifies this association in an Australian context. METHODS:This study is a secondary analysis of four biennial waves of prospective population-based neuropsychological measures from 1026 functionally independent Sydney Memory and Ageing Study participants aged 70-90 years at baseline, and contemporaneous probabilistically-linked hospitalization data. The outcome measures were global cognition baseline (intercept) and change (slope) and their associations with hospitalization episodes and cumulative length of stay (cLOS) variables in five consecutive 2-year time intervals. RESULTS:One thousand twenty-six individuals had a mean age of 78.8 years, a mean Mini-Mental State Examination score of 28.7, a mean of 3.3 hospitalizations and 18.9 days in hospital over 10 years. Mean global cognition z-score change/year was -0.133, adjusted for age, sex and education. Hospitalizations and cLOS in the final time interval were associated with a change in slope of -0.012 global cognition z-score/hospitalization/year (Standard Error [SE] = 0.005, p = 0.014) and -0.002 z-score/day-in-hospital/year (SE = 0.001, p < 0.001). Further investigation of these associations with time-lagged models showed that pooled recent hospitalizations were associated with accelerated cognitive decline of -0.036 change in cognition/year/episode-of-hospitalization (SE = 0.012, p = 0.004) and -0.008 change in cognition/year/day-in-hospital (SE = 0.002, p < 0.001) rather than non-recent hospitalizations (Wald test for difference between pooled recent and non-recent effects had p-values of 0.011 and < 0.001 for hospitalization episodes and days respectively). CONCLUSIONS:This study confirms and adds nuance to international findings that overnight hospitalization is associated with accelerated cognitive decline. This association was dose-dependent, had a recency effect and was independent of illness severity in the case of cLOS. These findings suggest that all-cause acute hospitalization may be a reversible risk factor for cognitive decline. This needs further clarification and the development of interventions to minimise the impact of acute illness hospitalization on cognitive trajectory. To this end, broadening the scope of acute care in the home and the prevention and treatment of neuroinflammation are priorities for further investigation.

OBJECTIVE:To examine whether later-life development of neuropsychiatric symptoms (NPS) or a modified diagnosis of mild behavioral impairment (MBI) are associated with future cognitive decline. DESIGN:Prospective Cohort Study SETTING: Community PARTICIPANTS: 823 individuals without dementia aged 70-90 years from the Sydney Memory and Ageing Study, followed over six years. MEASUREMENTS:Biennially, cognition was assessed through neuropsychological testing, and clinical diagnoses of mild cognitive impairment (MCI) and dementia were made by expert consensus. NPS was evaluated using the Bayer Activities of Daily Living scale and Neuropsychiatric Inventory (NPI). Based on published algorithms, modified diagnoses of MBI (MBI-Lite) were obtained. The relationship between behavior at baseline and neuropsychological test scores six years later was examined using linear regression. Cox regression was performed to evaluate associations between behavior and both incident dementia and incident categorical progression. Apolipoprotein E ε4 allele carrier status and cardiovascular disease risk were controlled for in all analysis. RESULTS:Higher total NPI scores were associated with worse global cognition scores at six years (β = -0.03, p = .007) and increased risk of incident dementia over six years (HR=1.06, p = .003). Presence of NPS of clinically significant severity and frequency was associated with worse global cognition scores for those with normal cognition (β = -0.44, p = .001), but not those with MCI at baseline (β = 0.22, p = .389). Diagnosis with MBI-Lite, was also associated with worse global cognition scores (β = -0.28, p = .028). CONCLUSIONS:Certain measures of NPS in cognitively normal older adults may herald future cognitive decline and be useful for early diagnosis and dementia research.

INTRODUCTION:Features of the neighborhood environment and ambient air pollution have been associated with onset and progression of neurocognitive disorders, but data from longitudinal population-based studies are limited. METHODS:One thousand thirty-six participants (78.3 ± 4.8 years) of the Sydney Memory and Ageing Study were followed for up to 13.7 years with biennial cognitive assessments. Neighborhood environmental features were assessed around the participants' homes. Associations between environmental features and transitions to cognitive states were estimated. RESULTS:Population density, street connectivity, access to commercial services, public transport, water bodies, and tree canopy were associated with a lower likelihood of worsening cognitive state. The opposite was observed for annual average concentrations of PM2.5. Access to parkland, blue spaces, and public transport were associated with a higher likelihood of reversal from mild cognitive impairment to normal cognition. DISCUSSION:Healthy neighborhood environments may delay cognitive decline and the onset of dementia in older individuals. HIGHLIGHTS:This is the first published study on neighborhood built and natural environmental correlates of transition to dementia. This study was conducted in socially advantaged areas with relatively low ambient air pollution. Walkable neighborhoods are associated with a lower likelihood of worsening cognitive state. Neighborhood tree canopy is consistently predictive of better cognitive outcomes. Access to public transport, and blue and green spaces is associated with higher probability of improved cognitive state.

Effective, scalable dementia prevention interventions are needed to address modifiable risk factors given global burden of dementia and challenges in developing disease-modifying treatments. A single-blind randomized controlled trial assessed an online multidomain lifestyle intervention to prevent cognitive decline over 3 years. Participants were dementia-free community-dwelling Australians aged 55–77 years with modifiable dementia risk factors. Eligible participants (n = 6,104, 64

There is a need to study dementia risk factors more equitably across high-income countries (HICs) and low- and middle-income countries (LMICs). Cohort Studies of Memory in an International Consortium (COSMIC) is doing this by bringing together cohort studies of cognitive ageing from around the world to study dementia risk factors in a truly international way. COSMIC researchers have investigated a wide range of dementia risk factors across the diverse member studies and shown that some factors have different levels of association with dementia in different regions and populations. These differences include some cardiovascular and lifestyle factors having stronger associations with cognitive decline and dementia among Asian people than among White people. Conversely, more social factors were associated with reduced chances of mild cognitive impairment or dementia among Asian people than among White people. Interventions to prevent or delay dementia will require tailoring to optimise the local effect. COSMIC is currently developing methods to reliably assess dementia from limited data in under-resourced regions, producing dementia risk models appropriate for LMICs, and increasing its attention to genetics, biomarkers, and environmental factors across diverse regions and populations. Further, COSMIC is helping to train new researchers in LMICs, and COSMIC members are among the first to be boarded on Dementias Platform Australia, a secure data exchange platform facilitating cohort study data access by researchers anywhere in the world. We invite cohort studies from LMICs or under-studied populations to join COSMIC and help make dementia research as globally representative and collaborative as possible.

INTRODUCTIONWhite matter hyperintensities (WMHs) are an important imaging marker for cerebral small vessel diseases, but their risk factors and cognitive associations have not been well documented in populations of different ethnicities and/or from different geographical regions.METHODSWe investigated how WMHs were associated with vascular risk factors and cognition in both Whites and Asians, using data from five population-based cohorts of non-demented older individuals from Australia, Singapore, South Korea, and Sweden (N = 1946). WMH volumes (whole brain, periventricular, and deep) were quantified with UBO Detector and harmonized using the ComBat model. We also harmonized various vascular risk factors and scores for global cognition and individual cognitive domains.RESULTSFactors associated with larger whole brain WMH volumes included diabetes, hypertension, stroke, current smoking, body mass index, higher alcohol intake, and insufficient physical activity. Hypertension and stroke had stronger associations with WMH volumes in Whites than in Asians. No associations between WMH volumes and cognitive performance were found after correction for multiple testing.CONCLUSIONThe current study highlights ethnic differences in the contributions of vascular risk factors to WMHs.

Cognitive, social, and physical activities, collectively linked to cognitive reserve, are associated with better late-life cognitive outcomes. To better understand the building of cognitive reserve, we investigated which of these activities, during which stages of life, had the strongest associations with late-life cognitive performance. From the Sydney Memory and Aging Study, 546 older Australians, who were community-dwelling and without a dementia diagnosis at recruitment (Mage 80.13 years, 52.2% female), were asked about their engagement in social, physical, and cognitive activities throughout young adulthood (YA), midlife (ML), and late-life (LL). Comprehensive neuropsychological testing administered biennially over 6 years measured baseline global cognition and cognitive decline. In our study, YA, but not ML nor LL, cognitive activity was significantly associated with late-life global cognition (β = 0.315, p < .001). A follow-up analysis pointed to the formal education component of the YA cognitive activity measure, rather than YA cognitive leisure activities, as a significant predictor of better late-life global cognition (β = 0.146, p = .003). YA social activity and LL cognitive activity were significantly associated with less cognitive decline (β = 0.023, p < .001, and β = 0.016, p = .022, respectively). Physical activity was not found to be associated with global cognition or cognitive decline. Overall, YA cognitive activity was associated with better late-life cognition, and YA social and LL cognitive activities were associated with less cognitive decline. Formal education emerges as the key contributor in the association between YA cognitive activity and late-life global cognition.

INTRODUCTION:The LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics. METHODS:We combined data from 21 prospective cohorts across six continents (N = 31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis. RESULTS:A one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed. DISCUSSION:Modifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups. HIGHLIGHTS:A two-step individual participant data meta-analysis was conducted. This was done at a global scale using data from 21 ethno-regionally diverse cohorts. The association between a modifiable dementia risk score and dementia was examined. The association was modified by geographical region and age at baseline. Yet, modifiable dementia risk and protective factors appear relevant in all investigated groups and regions.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

Importance:Poststroke cognitive impairment is common, but the cognitive trajectory following a first stroke, relative to prestroke cognitive function, remains unclear. Objective:To map the trajectory of cognitive function before any stroke and after stroke in global cognition and in 4 cognitive domains, as well as to compare the cognitive trajectory prestroke in stroke survivors with the trajectory of individuals without incident stroke over follow-up. Design, Setting, and Participants:The study used harmonized and pooled data from 14 population-based cohort studies included in the Cohort Studies of Memory in an International Consortium collaboration. These studies were conducted from 1993 to 2019 across 11 countries among community-dwelling older adults without a history of stroke or dementia. For this study, linear mixed-effects models were used to estimate trajectories of cognitive function poststroke relative to a stroke-free cognitive trajectory. The full model adjusted for demographic and vascular risk factors. Data were analyzed from July 2022 to March 2024. Exposure:Incident stroke. Main outcomes and measures:The primary outcome was global cognition, defined as the standardized average of 4 cognitive domains (language, memory, processing speed, and executive function). Cognitive domain scores were formed by selecting the most commonly administered test within each domain and standardizing the scores. Results:The study included 20 860 participants (12 261 [58.8%] female) with a mean (SD) age of 72.9 (8.0) years and follow-up of 7.51 (4.2) years. Incident stroke was associated with a substantial acute decline in global cognition (-0.25 SD; 95% CI, -0.33 to -0.17 SD), the Mini-Mental State Examination, and all cognitive domains (ranging from -0.17 SD to -0.22 SD), as well as accelerated decline in global cognition (-0.038 SD per year; 95% CI, -0.057 to -0.019 SD per year) and all domains except memory (ranging from -0.020 to -0.055 SD per year), relative to a stroke-free cognitive trajectory. There was no significant difference in prestroke slope in stroke survivors compared with the rate of decline in individuals without stroke in all cognitive measures. The mean rate of decline without a previous stroke was -0.049 SD per year (95% CI, -0.051 to -0.047 SD) in global cognition. Conclusions and relevance:In this cohort study using pooled data from 14 cohorts, incident stroke was associated with acute and accelerated long-term cognitive decline in older stroke survivors.