Association between Marital Status and Cognitive Impairment in a Multi-Ethnic Asian Population.

OBJECTIVE: This study aims to examine the potential factors associated with marital status and determine the association between marital status and cognitive impairment in a multi-ethnic Asian population. METHOD: This study included 2321 participants from Singapore Multi-Ethnic Cohort revisit study (aged 40-89). Participants were classified into married and unmarried group at baseline and follow-up according to self-reported marital status. Mini-Mental Status Examination (MMSE) was administered, and cognitive impairment was defined as a MMSE <26. We conducted both cross-sectional and longitudinal analyses to examine the association of marital status at one time point as well as marital transition with cognitive impairment. RESULTS: Of the 2321 participants, a total of 1914 (82.5%) were married. The factors associated with marital status included younger age, male sex, higher household income, higher education, and higher physical activity levels. Additionally, married participants also had higher alternative healthy eating index (AHEI-2010) scores, and a lower burden of hypertension and diabetes. Among those who were married, the median (Q1, Q3) MMSE score was 29 (28,30) while those who were unmarried was 29 (27, 30) (p <0.01). Participants who had never been married had the highest odds of cognitive impairment compared to their married counterparts (Model III: OR=1.48, 95% CI: 1.03, 2.14). Older age (p-interaction value=0.003) and Indian ethnicity (p-interaction value=0.028) further strengthened these associations. CONCLUSION: Marriage was associated with lower odds of cognitive impairment. Marriage provides social support, companionship, and engagement in mentally stimulating activities contributing to better cognitive health. By identifying risk factors such as marital status, interventions and support systems can be developed to promote healthy cognitive aging.

Incremental Value of Multidomain Risk Factors for Dementia Prediction: A Machine Learning Approach.

OBJECTIVE: The current evidence regarding how different predictor domains contributes to predicting incident dementia remains unclear. This study aims to assess the incremental value of five predictor domains when added to a simple dementia risk prediction model (DRPM) for predicting incident dementia in older adults. DESIGN: Population-based, prospective cohort study. SETTING: UK Biobank study. PARTICIPANTS: Individuals aged 60 or older without dementia. MEASUREMENTS: Fifty-five dementia-related predictors were gathered and categorized into clinical and medical history, questionnaire, cognition, polygenetic risk, and neuroimaging domains. Incident dementia (all-cause) and the subtypes, Alzheimer's disease (AD) and vascular dementia (VaD), were determined through hospital and death registries. Ensemble machine learning (ML) DRPMs were employed for prediction. The incremental values of risk predictors were assessed using the percent change in Area Under the Curve (∆AUC%) and the net reclassification index (NRI). RESULTS: The simple DRPM which included age, body mass index, sex, education, diabetes, hyperlipidaemia, hypertension, depression, smoking, and alcohol consumption yielded an AUC of 0.711 (± 0.008 SD). The five predictor domains exhibited varying levels of incremental value over the basic model when predicting all-cause dementia and the two subtypes. Neuroimaging markers provided the highest incremental value in predicting all-cause dementia (∆AUC% +9.6%) and AD (∆AUC% +16.5%) while clinical and medical history data performed the best at predicting VaD (∆AUC% +12.2%). Combining clinical and medical history, and questionnaire data synergistically enhanced ML DRPM performance. CONCLUSION: Combining predictors from different domains generally results in better predictive performance. Selecting predictors involves trade-offs, and while neuroimaging markers can significantly enhance predictive accuracy, they may pose challenges in terms of cost or accessibility.

Association of diet quality with hand grip strength weakness and asymmetry in a multi-ethnic Asian cohort.

Hand grip strength (HGS) is an important diagnostic tool for sarcopenia and a reliable predictor for age-related chronic diseases and mortality. Interventions in nutrition have been shown as a low-cost strategy to maintain muscular strength and mass. However, there are limited data on the effect of diet on HGS in Southeast Asian populations. This study aims to investigate the association of diet quality with HGS weakness and asymmetry in a multi-ethnic population in Singapore. This cross-sectional study used data from the Singapore Multi-Ethnic Cohort (n = 1547). Dietary data were collected using a validated semi-quantitative FFQ and summarised as the Dietary Quality Index - International (DQI-I). HGS was calculated as the maximum value of six measurements from both hands. HGS weakness and asymmetry were defined using well-recognised criteria. Multivariable linear regression and logistic regression were utilised for continuous and binary outcomes, respectively, adjusting for age, sex, ethnicity, physical activity and smoking status. It was found that the highest quartile of DQI-I was significantly associated with higher HGS (ß = 1·11; 95 % CI 0·41, 1·82; Pfor trend < 0·001) and lower odds of HGS asymmetry (OR = 0·71; 95 % CI 0·53, 0·94; Pfor trend = 0·035) and both HGS weakness and asymmetry (OR = 0·50; 95 % CI 0·32, 0·76; Pfor trend = 0·004). Among the different components of DQI-I, only dietary adequacy was significantly associated with higher HGS (Pfor trend < 0·001) and lower odds for both HGS weakness and asymmetry (Pfor trend = 0·006). Our findings support that DQI-I, an indicator of overall diet quality, can be used to provide dietary guidelines for prevention and management of muscle wasting, sarcopenia and frailty.

Association of a healthy ageing index with health-related outcomes in a multi-ethnic cohort from Singapore.

BACKGROUND: The global population is ageing rapidly and it is important to promote healthy ageing. The Healthy Ageing Index (HAI) is a comprehensive measure of health, but there is limited research on its association with other age-related outcomes. The management of an aging population necessitates considerations even among generally healthy adults, as age-related diseases often remain unaccounted for until later stages of life. This study explores the association of risk factors with HAI and its association with peripheral artery disease (PAD), muscle strength, health-related quality of life (HRQoL), and psychological distress in the Singapore Multi-Ethnic Cohort study. METHODS: This cross-sectional study involved 1909 participants (median (Q1, Q3) age: 53 (48, 60) years and 59.3% females) from Singapore Multi-Ethnic Cohort study. The risk factors of HAI included age, gender, ethnicity, education level, smoking, alcohol consumption, employment, BMI and past medical histories. PAD was assessed using ankle-brachial index (ABI), handgrip strength (HGS), HRQoL with the EQ-5D-5 L questionnaire and psychological distress via the Kessler Psychological Distress Scale (K10). HAI components were assessed using relevant marker tests. RESULTS: Older age, Malay and Indian ethnicities, unemployment, high BMI and histories of CHD, hypercholesterolaemia, tumours and TIA/stroke were associated with lower HAI scores indicative of poorer health. Higher HAI scores were associated with females and higher education levels. Lower HAI scores were significantly associated with low ABI, high K10 scores, mobility and anxiety/depression dimensions of EQ-5D-5 L. CONCLUSION: The most important factors associated with HAI were age, sex, ethnicity, education, unemployment, BMI and a history of health conditions. Lower HAI scores were significantly associated with PAD, lower HRQoL and psychological distress. Thus, the HAI demonstrates promise as an evaluation method for assessing PAD, overall muscle strength and HRQoL in a population-based setting.

Housing status is protective of neuropsychiatric symptoms among dementia-free multi-ethnic Asian elderly.

BACKGROUND: Housing has been associated with dementia risk and disability, but associations of housing with differential patterns of neuropsychiatric symptoms (NPS) among dementia-free older adults remain to be explored. The present study sought to explore the contribution of housing status on NPS and subsyndromes associated with cognitive dysfunction in community-dwelling dementia-free elderly in Singapore. METHODS: A total of 839 dementia-free elderly from the Epidemiology of Dementia in Singapore (EDIS) study aged ≥ 60 were enrolled in the current study. All participants underwent clinical, cognitive, and neuropsychiatric inventory (NPI) assessments. The housing status was divided into three categories according to housing type. Cognitive function was measured by a comprehensive neuropsychological battery. The NPS were assessed using 12-term NPI and were grouped into four clinical subsyndromes: psychosis, hyperactivity, affective, and apathy. Associations of housing with composite and domain-specific Z-scores, as well as NPI scores, were assessed using generalized linear models (GLM). Binary logistic regression models analysed the association of housing with the presence of NPS and significant NPS (NPI total scores ≥ 4). RESULTS: Better housing status (5-room executive apartments, condominium, or private housing) was associated with better NPS (OR = 0.49, 95%CI = 0.24 to 0.98, P < 0.05) and significant NPS profile (OR = 0.20, 95%CI = 0.08 to 0.46, P < 0.01), after controlling for demographics, risk factors, and cognitive performance. Compared with those living in 1-2 room apartments, older adults in better housing had lower total NPI scores (ß=-0.50, 95%CI=-0.95 to -0.04, P = 0.032) and lower psychosis scores (ß=-0.36, 95%CI=-0.66 to -0.05, P = 0.025), after controlling for socioeconomic status (SES) indexes. Subgroup analysis indicated a significant correlation between housing type and NPS in females, those of Malay ethnicity, the more educated, those with lower income, and those diagnosed with cognitive impairment, no dementia (CIND). CONCLUSIONS: Our study showed a protective effect of better housing arrangements on NPS, especially psychosis in a multi-ethnic Asian geriatric population without dementia. The protective effect of housing on NPS was independent of SES and might have other pathogenic mechanisms. Improving housing could be an effective way to prevent neuropsychiatric disturbance among the elderly.

CT-based volumetric measures obtained through deep learning: Association with biomarkers of neurodegeneration.

INTRODUCTION: Cranial computed tomography (CT) is an affordable and widely available imaging modality that is used to assess structural abnormalities, but not to quantify neurodegeneration. Previously we developed a deep-learning-based model that produced accurate and robust cranial CT tissue classification. MATERIALS AND METHODS: We analyzed 917 CT and 744 magnetic resonance (MR) scans from the Gothenburg H70 Birth Cohort, and 204 CT and 241 MR scans from participants of the Memory Clinic Cohort, Singapore. We tested associations between six CT-based volumetric measures (CTVMs) and existing clinical diagnoses, fluid and imaging biomarkers, and measures of cognition. RESULTS: CTVMs differentiated cognitively healthy individuals from dementia and prodromal dementia patients with high accuracy levels comparable to MR-based measures. CTVMs were significantly associated with measures of cognition and biochemical markers of neurodegeneration. DISCUSSION: These findings suggest the potential future use of CT-based volumetric measures as an informative first-line examination tool for neurodegenerative disease diagnostics after further validation. HIGHLIGHTS: Computed tomography (CT)-based volumetric measures can distinguish between patients with neurodegenerative disease and healthy controls, as well as between patients with prodromal dementia and controls. CT-based volumetric measures associate well with relevant cognitive, biochemical, and neuroimaging markers of neurodegenerative diseases. Model performance, in terms of brain tissue classification, was consistent across two cohorts of diverse nature. Intermodality agreement between our automated CT-based and established magnetic resonance (MR)-based image segmentations was stronger than the agreement between visual CT and MR imaging assessment.

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.

Pathology-based brain arterial disease phenotypes and their radiographic correlates.

INTRODUCTION: Brain arterial diseases, including atherosclerosis, vasculitis, and dissections, are major contributors to cerebrovascular morbidity and mortality worldwide. These diseases not only increase the risk of stroke but also play a significant role in neurodegeneration and dementia. Clear and unambiguous terminology and classification of brain arterial disease phenotypes is crucial for research and clinical practice. MATERIAL AND METHODS: This review aims to summarize and harmonize the terminology used for brain large and small arterial phenotypes based on pathology studies and relate them to imaging phenotypes used in medical research and clinical practice. CONCLUSIONS AND RESULTS: Arteriosclerosis refers to hardening of the arteries but does not specify the underlying etiology. Specific terms such as atherosclerosis, calcification, or non-atherosclerotic fibroplasia are preferred. Atherosclerosis is defined pathologically by an atheroma. Other brain arterial pathologies occur and should be distinguished from atherosclerosis given therapeutic implications. On brain imaging, intracranial arterial luminal stenosis is usually attributed to atherosclerosis in the presence of atherosclerotic risk factors but advanced high-resolution arterial wall imaging has the potential to more accurately identify the underlying pathology. Regarding small vessel disease, arteriosclerosis is ambiguous and arteriolosclerosis is often used to denote the involvement of arterioles rather than arteries. Lipohyalinosis is sometimes used synonymously with arteriolosclerosis, but less accurately describes this common small vessel thickening which uncommonly shows lipid. Specific measures of small vessel wall thickness, the relationship to the lumen as well as changes in the layer composition might convey objective, measurable data regarding the status of brain small vessels.

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.

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.

Associations of neuroimaging markers with depressive symptoms over time in middle-aged and elderly persons.

BACKGROUND: Cerebrovascular disease is regarded as a potential cause of late-life depression. Yet, evidence for associations of neuroimaging markers of vascular brain disease with depressive symptoms is inconclusive. We examined the associations of neuroimaging markers and depressive symptoms in a large population-based study of middle-aged and elderly persons over time. METHODS: A total of 4943 participants (mean age = 64.6 ± 11.1 years, 55.7% women) from the Rotterdam Study were included. At baseline, total brain volume, gray matter volume, white matter volume, white matter hyperintensities volume, cortical infarcts, lacunar infarcts, microbleeds, white matter fractional anisotropy, and mean diffusivity (MD) were measured with a brain MRI (1.5T). Depressive symptoms were assessed twice with the Center for Epidemiologic Studies Depression scale (median follow-up time: 5.5 years, IQR = 0.9). To assess temporal associations of neuroimaging markers and depressive symptoms, linear mixed models were used. RESULTS: A smaller total brain volume (ß = -0.107, 95% CI -0.192 to -0.022), larger white matter hyperintensities volume (ß = 0.047, 95% CI 0.010-0.084), presence of cortical infarcts (ß = 0.194, 95% CI 0.047-0.341), and higher MD levels (ß = 0.060, 95% CI 0.022-0.098) were cross-sectionally associated with more depressive symptoms. Longitudinal analyses showed that small total brain volume (ß = -0.091, 95% CI -0.167 to -0.015) and presence of cortical infarcts (ß = 0.168, 95% CI 0.022-0.314) were associated with increasing depressive symptoms over time. After stratification on age, effect sizes were more pronounced at older ages. CONCLUSIONS: Neuroimaging markers of white matter microstructural damage were associated with depressive symptoms longitudinally in this study of middle-aged and elderly persons. These associations were more pronounced at older ages, providing evidence for the role of white matter structure in late-life depressive symptomatology.

Association between nutrition and cognition in a multi-ethnic cohort from Singapore.

BACKGROUND: Nutrition, a modifiable risk factor, presents a low-cost prevention strategy to reduce the burden of cognitive impairment and dementia. However, studies examining the effects of dietary patterns on cognition are lacking in multi-ethnic Asian populations. We investigate the association between diet quality, measured with the Alternative Healthy Eating Index (AHEI)-2010, and cognitive impairment in middle-aged and older adults of different ethnicities (Chinese, Malay, Indian) in Singapore. METHODS: This cross-sectional study (n = 3138; mean age: 50.4 ± 9.8, 58.4% women) was based on data from the Singapore Multi-Ethnic Cohort. Dietary intake collected with a validated semi-quantitative Food Frequency Questionnaire was converted into AHEI-2010 scores. Cognition, assessed with the Mini-Mental State Examination (MMSE), was analysed as a continuous or binary outcome (cognitively impaired or not, using cut-offs of ≥ 24, 26 or 28 for no education, primary school education and secondary school education and above). Multivariable linear and logistic regression models were used to examine associations between AHEI-2010 and cognition, adjusting for covariates. RESULTS: A total of 988 (31.5%) participants had cognitive impairment. Higher AHEI-2010 scores were significantly associated with higher MMSE scores [ß = 0.44; 95% confidence interval (CI) 0.22-0.67 highest vs. lowest quartile; p-trend < 0.001] and lower odds of cognitive impairment [OR 0.69; 95% CI 0.54-0.88; p-trend = 0.01] after adjusting for all the covariates. No significant associations were observed for individual dietary components of the AHEI-2010 with MMSE or cognitive impairment. CONCLUSION: Healthier dietary patterns were associated with better cognitive function in middle-aged and older Singaporeans. These findings could inform better support to promote healthier dietary patterns in Asian populations.

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.

Epidemiologic Trends, Social Determinants, and Brain Health: The Role of Life Course Inequalities.

Brain health as expressed in our mental health and occurrence of specific disorders such as dementia and stroke is vitally important to quality of life, functional independence, and risk of institutionalization. Maintaining brain health is, therefore, a societal imperative, and public health challenge, from prevention of acquisition of brain disorders, through protection and risk reduction to supporting those with such disorders through effective societal and system approaches. To identify possible mechanisms that explain the differential effect of potentially modifiable risk factors, and factors that may mitigate risk, a life course approach is needed. This is key to understanding how poor health can accumulate from the earliest life stages. It also allows us to integrate and investigate key material, behavioral, and psychological factors that generate health inequalities within and across communities and societies. This review provides a narrative on how brain health is intimately linked to wider health determinants, thus importance for clinicians and societies alike. There is compelling evidence accumulated from research over decades that socioeconomic status, higher education, and healthy lifestyle extend life and compress major morbidities into later life. Brain health is part of this, but collective action has been limited, partly because of the separation of disciplines and focus on highly reductionist approaches in that clinicians and associated research have focused more on mitigation and early detection of specific diseases. However, clinicians could be part of the drive for better brain health for all society to support life courses that have more protection and less risk. There is evidence of change in such risks for conditions such as stroke and dementia across generations. The evidence points to the importance of starting with parental health and life course inequalities as a central focus.

Prediction of dementia using diffusion tensor MRI measures: the OPTIMAL collaboration.

OBJECTIVES: It has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but also in mild cognitive impairment. To determine whether DTI measures were associated with cognition cross-sectionally and predicted future dementia risk across the full range of SVD severity, we established the International OPtimising mulTImodal MRI markers for use as surrogate markers in trials of Vascular Cognitive Impairment due to cerebrAl small vesseL disease collaboration which included six cohorts. METHODS: Among the six cohorts, prospective data with dementia incidences were available for three cohorts. The associations between six different DTI measures and cognition or dementia conversion were tested. The additional contribution to prediction of other MRI markers of SVD was also determined. RESULTS: The DTI measure mean diffusivity (MD) median correlated with cognition in all cohorts, demonstrating the contribution of WM damage to cognition. Adding MD median significantly improved the model fit compared to the clinical risk model alone and further increased in all single-centre SVD cohorts when adding conventional MRI measures. Baseline MD median predicted dementia conversion. In a study with severe SVD (SCANS) change in MD median also predicted dementia conversion. The area under the curve was best when employing a multimodal MRI model using both DTI measures and other MRI measures. CONCLUSIONS: Our results support a central role for WM alterations in dementia pathogenesis in all cohorts. DTI measures such as MD median may be a useful clinical risk predictor. The contribution of other MRI markers varied according to disease severity.

Association of Arterial Spin Labeling Parameters With Cognitive Decline, Vascular Events, and Mortality in a Memory-Clinic Sample.

BACKGROUND: Cognitive decline in older adults has been attributed to reduced cerebral blood flow (CBF). Recently, the spatial coefficient of variation (sCoV) of ASL has been proposed as a proxy marker of cerebrovascular insufficiency. We investigated the association between baseline ASL parameters with cognitive decline, incident cerebrovascular disease, and risk of vascular events and mortality. DESIGN, SETTING, AND PARTICIPANTS: About 368 memory-clinic patients underwent three-annual neuropsychological assessments and brain MRI scans at baseline and follow-up. MRIs were graded for white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), cortical infarcts, and intracranial stenosis. Baseline gray (GM) and white matter (WM) CBF and GM-sCoV were obtained with ExploreASL from 2D-EPI pseudo-continuous ASL images. Cognitive assessment was done using a validated neuropsychological battery. Data on incident vascular events (heart disease, stroke, transient ischemic attack) and mortality were obtained. RESULTS: Higher baseline GM-sCoV was associated with decline in the memory domain over 3 years of follow-up. Furthermore, higher GM-sCoV was associated with a decline in the memory domain only in participants without dementia. Higher baseline GM-sCoV was associated with progression of WMH and incident CMBs. During a mean follow-up of 3 years, 29 (7.8%) participants developed vascular events and 18 (4.8%) died. Participants with higher baseline mean GM-sCoV were at increased risk of vascular events. CONCLUSIONS: Higher baseline GM-sCoV of ASL was associated with a decline in memory and risk of cerebrovascular disease and vascular events, suggesting that cerebrovascular insufficiency may contribute to accelerated cognitive decline and worse clinical outcomes in memory clinic participants.

Cerebrovascular disease in suspected non-Alzheimer's pathophysiology and cognitive decline over time.

BACKGROUND: The underlying cause of cognitive decline in individuals who are positive for biomarkers of neurodegeneration (N) but negative for biomarkers of amyloid-beta (A), designated as Suspected non-Alzheimer's pathophysiology (SNAP), remains unclear. We evaluate whether cerebrovascular disease (CeVD) is more prevalent in those with SNAP compared to A-N- and A+N+ individuals and whether CeVD is associated with cognitive decline over time in SNAP patients. METHODS: A total of 216 individuals from a prospective memory clinic cohort (mean [SD] age, 72.7 [7.3] years, 100 women [56.5%]) were included and were diagnosed as no cognitive impairment (NCI), cognitive impairment no dementia (CIND), Alzheimer's dementia (AD) or vascular dementia (VaD). All individuals underwent clinical evaluation and neuropsychological assessment annually for up to 5 years. Carbon 11-labeled Pittsburgh Compound B ([11 C]-PiB) or [18 F]-flutafuranol-positron emission spectrometry imaging was performed to ascertain amyloid-beta status. Magnetic resonance imaging was performed to assess neurodegeneration as measured by medial temporal atrophy ≥2, as well as significant CeVD (sCeVD) burden, defined by cortical infarct count ≥1, Fazekas score ≥2, lacune count ≥2 or cerebral microbleed count ≥2. RESULTS: Of the 216 individuals, 50 (23.1%) A-N+ were (SNAP), 93 (43.1%) A-N-, 36 (16.7%) A+N- and 37 (17.1%) A+N+. A+N+ individuals were significantly older, while A+N+ and SNAP individuals were more likely to have dementia. The SNAP group had a higher prevalence of sCeVD (90.0%) compared to A-N-. Moreover, SNAP individuals with sCeVD had significantly steeper decline in global cognition compared to A-N- over 5 years (p = 0.042). CONCLUSIONS: These findings suggest that CeVD is a contributing factor to cognitive decline in SNAP. Therefore, SNAP individuals should be carefully assessed and treated for CeVD.

The Associations Between Intracranial Stenosis, Brain Amyloid-beta, and Cognition in a Memory Clinic Sample.

BACKGROUND: Intracranial stenosis (ICS) and brain amyloid-beta (Aß) have been associated with cognition and dementia. We aimed to investigate the association between ICS and brain Aß and their independent and joint associations with cognition. METHODS: We conducted a cross-sectional study of 185 patients recruited from a memory clinic. ICS was measured on 3-dimensional time-of-flight magnetic resonance angiography and defined as stenosis ≥50%. Brain Aß was measured with [ 11 C] Pittsburgh compound B-positron emission tomography imaging. Cognition was assessed with a locally validated neuropsychological battery. RESULTS: A total of 17 (9.2%) patients had ICS, and the mean standardized uptake value ratio was 1.4 (±0.4 SD). ICS was not significantly associated with brain Aß deposition. ICS was significantly associated with worse global cognition (ß: -1.26, 95% CI: -2.25; -0.28, P =0.013), executive function (ß: -1.04, 95% CI: -1.86; -0.22, P =0.015) and visuospatial function (ß: -1.29, 95% CI: -2.30; -0.27, P =0.015). Moreover, in ICS patients without dementia (n=8), the presence of Aß was associated with worse performance on visuomotor speed. CONCLUSIONS: ICS was significantly associated with worse cognition and showed interaction with brain Aß such that patients with both pathologies performed worse on visuomotor speed specifically in those without dementia. Further studies may clarify if ICS and brain Aß deposition indeed have a synergistic association with cognition.

Clinical Relevance of Cortical Cerebral Microinfarcts on 1.5T Magnetic Resonance Imaging in the Late-Adult Population.

BACKGROUND AND PURPOSE: Cortical cerebral microinfarcts (CMIs) have been linked with dementia and impaired cognition in cross-sectional studies. However, the clinical relevance of CMIs in a large population-based setting is lacking. We examine the association of cortical CMIs detected on 1.5T magnetic resonance imaging with cardiovascular risk factors, cerebrovascular disease, and brain tissue volumes. We further explore the association between cortical CMIs with cognitive decline and risk of stroke, dementia, and mortality in the general population. METHODS: Two thousand one hundred fifty-six participants (age: 75.7±5.9 years, women: 55.6%) with clinical history and baseline magnetic resonance imaging (January 2009-December 2013) were included from the Rotterdam Study. Cortical CMIs were graded based on a previously validated method. Markers of cerebrovascular disease and brain tissue volumes were assessed on magnetic resonance imaging. Cognition was assessed using a detailed neuropsychological test at baseline and at 5 years of follow-up. Data on incident stroke, dementia, and mortality were included until January 2016. RESULTS: Two hundred twenty-seven individuals (10.5%) had ≥1 cortical CMIs. The major risk factors of cortical CMIs were male sex, current smoking, history of heart disease, and stroke. Furthermore, presence of cortical CMIs was associated with infarcts and smaller brain volume. Persons with cortical CMIs showed cognitive decline in Stroop tests (color-naming and interference subtasks; ß for color-naming, 0.18 [95% CI, 0.04-0.33], P interaction ≤0.001 and ß for interference subtask, 1.74, [95% CI, 0.66-2.82], P interaction ≤0.001). During a mean follow-up of 5.2 years, 73 (4.3%) individuals developed incident stroke, 95 (5.1%) incident dementia, and 399 (19.2%) died. People with cortical CMIs were at an increased risk of stroke (hazard ratio, 1.18 [95% CI, 1.09-1.28]) and mortality (hazard ratio, 1.09 [95% CI, 1.00-1.19]). CONCLUSIONS: Cortical CMIs are highly prevalent in a population-based setting and are associated with cardiovascular disease, cognitive decline, and increased risk of stroke and mortality. Future investigations will have to show whether cortical CMIs are a useful biomarker to intervene upon to reduce the burden of stroke.

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.