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.

Comorbid amyloid with cerebrovascular disease in domain-specific cognitive and neuropsychiatric disturbances: a cross-sectional memory clinic study.

Dementia is a multifactorial disorder that is likely influenced by both Alzheimer's disease (AD) and vascular pathologies. We evaluated domain-specific cognitive and neuropsychiatric dysfunction using a two-neuroimaging biomarker construct (beta-amyloid [Aß] and cerebrovascular disease [CeVD]). We analyzed data from 216 memory clinic participants (mean age = 75.9 ± 6.9; 56.5% female) with neuropsychological and neuropsychiatric assessments, 3T-MRI, and Aß-PET imaging. Structural equation modeling showed that the largest Aß (A+) effect was on memory (B = -1.50) and apathy (B = 0.26), whereas CeVD effects were largest on language (B = -1.62) and hyperactivity (B = 0.32). Group comparisons showed that the A+C+ group had greater memory impairment (B = -1.55), hyperactivity (B = 0.79), and apathy (B = 0.74) compared to A-C+; and greater language impairment (B = -1.26) compared to A+C-. These potentially additive effects of Aß and CeVD burden underline the importance of early detection and treatment of Aß alongside optimal control of vascular risk factors as a potential strategy in preventing cognitive and neurobehavioral impairment.

Associations of Blood Cardiovascular Biomarkers With Brain Free Water and Its Relationship to Cognitive Decline: A Diffusion-MRI Study.

BACKGROUND AND OBJECTIVES: There is an increasing awareness of the "Heart-Brain Connection," whereby cardiovascular function is connected with cognition. Diffusion-MRI studies reported higher brain free water (FW) was associated with cerebrovascular disease (CeVD) and cognitive impairment. In this study, we investigated whether higher brain FW was related to blood cardiovascular biomarkers and whether FW mediated the associations between blood biomarkers and cognition. METHODS: Participants recruited from 2 Singapore memory clinics between 2010 and 2015 underwent collection of blood samples and neuroimaging at baseline and longitudinal neuropsychological assessments up to 5 years. We examined the associations of blood cardiovascular biomarkers (high-sensitivity cardiac troponin-T [hs-cTnT], N-terminal pro-hormone B-type natriuretic peptide [NT-proBNP], and growth/differentiation factor 15 [GDF-15]) with brain white matter (WM) and cortical gray matter (GM) FW derived from diffusion MRI using whole brain voxel-wise general linear regression. We then assessed the relationships among baseline blood biomarkers, brain FW, and cognitive decline using path models. RESULTS: A total of 308 older adults (76 with no cognitive impairment, 134 with cognitive impairment no dementia, and 98 with Alzheimer disease dementia and vascular dementia; mean [SD] age: 72.1 [8.3]) were included. We found that blood cardiovascular biomarkers were associated with higher FW in widespread WM regions and in specific GM networks including the default mode, executive control, and somatomotor networks at baseline (p < 0.01, family-wise error corrected). Baseline FW in widespread WM and network-specific GM fully mediated the associations of blood biomarkers with longitudinal cognitive decline over 5 years. Specifically, in GM, higher FW in the default mode network mediated the relationship with memory decline (hs-cTnT: ß = -0.115, SE = 0.034, p = 0.001; NT-proBNP: ß = -0.154, SE = 0.046, p = 0.001; GDF-15: ß = -0.073, SE = 0.027, p = 0.006); by contrast, higher FW in the executive control network was responsible for executive function decline (hs-cTnT: ß = -0.126, SE = 0.039, p = 0.001; NT-proBNP: ß = -0.110, SE = 0.038, p = 0.004; GDF-15: ß = -0.117, SE = 0.035, p = 0.001). Similar full mediation effects of brain FW were also identified for baseline cognition. DISCUSSION: Results suggested a role of brain FW in linking cardiovascular dysfunction to cognitive decline. These findings provide new evidence for brain-heart interactions, paving the way for prediction and monitoring of domain-specific cognitive trajectory.

Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics.

Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between plasma ET status and cognition in a cohort of 470 elderly subjects attending memory clinics in Singapore. All participants underwent baseline plasma ET measurements as well as neuroimaging for CeVD and brain atrophy. Neuropsychological tests of cognition and function were assessed at baseline and follow-up visits for up to five years. Lower plasma ET levels were associated with poorer baseline cognitive performance and faster rates of decline in function as well as in multiple cognitive domains including memory, executive function, attention, visuomotor speed, and language. In subgroup analyses, the longitudinal associations were found only in non-demented individuals. Mediation analyses showed that the effects of ET on cognition seemed to be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities, and brain atrophy. Our findings support further assessment of plasma ET as a prognostic biomarker for accelerated cognitive and functional decline in pre-dementia and suggest possible therapeutic and preventative measures.

Deep-learning retinal vessel calibre measurements and risk of cognitive decline and dementia.

Previous studies have explored the associations of retinal vessel calibre, measured from retinal photographs or fundus images using semi-automated computer programs, with cognitive impairment and dementia, supporting the concept that retinal blood vessels reflect microvascular changes in the brain. Recently, artificial intelligence deep-learning algorithms have been developed for the fully automated assessment of retinal vessel calibres. Therefore, we aimed to determine whether deep-learning-based retinal vessel calibre measurements are predictive of risk of cognitive decline and dementia. We conducted a prospective study recruiting participants from memory clinics at the National University Hospital and St. Luke's Hospital in Singapore; all participants had comprehensive clinical and neuropsychological examinations at baseline and annually for up to 5 years. Fully automated measurements of retinal arteriolar and venular calibres from retinal fundus images were estimated using a deep-learning system. Cox regression models were then used to assess the relationship between baseline retinal vessel calibre and the risk of cognitive decline and developing dementia, adjusting for age, gender, ethnicity, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes, and smoking. A total of 491 participants were included in this study, of whom 254 developed cognitive decline over 5 years. In multivariable models, narrower retinal arteriolar calibre (hazard ratio per standard deviation decrease = 1.258, P = 0.008) and wider retinal venular calibre (hazard ratio per standard deviation increase = 1.204, P = 0.037) were associated with increased risk of cognitive decline. Among participants with cognitive impairment but no dementia at baseline (n = 212), 44 progressed to have incident dementia; narrower retinal arteriolar calibre was also associated with incident dementia (hazard ratio per standard deviation decrease = 1.624, P = 0.021). In summary, deep-learning-based measurement of retinal vessel calibre was associated with risk of cognitive decline and dementia.

The discriminant validity of single-question assessments of subjective cognitive complaints in an Asian older adult population.

Objective: To compare the discriminant validity of three different single-question assessments of subjective cognitive complaints (SCC) for dementia in a community-based older adult population in Singapore. Methods: Eligible older adults aged ≥60 were recruited into phase I for identifying those who require further assessment using the Abbreviated Mental Test (AMT) and progressive forgetfulness question (PFQ). Participants who failed either tests entered phase II and were administered various single-question assessments of SCC, such as the 8th question on the patient Ascertain Dementia 8 (AD8-8pt), informant AD8 (AD8-8info), and the 10th item on the Geriatric Depression Scale (GDS-10), followed by the Montreal Cognitive Assessment (MoCA) and a formal neuropsychological battery to identify the participant's cognitive status by a research diagnosis and DSM-IV criteria. Differences in characteristics among diagnostic groups were compared. All discriminatory indices (sensitivity, specificity, positive, and negative predictive values, overall accuracy) for these single-question assessments and their combinations with the MoCA were calculated and reported to confirm their discriminant validity in identifying the existence of subjective complaints and objective impairment. Results: A total of 3,780 participants were assessed at phase I, of which 957 entered and completed phase II. Of whom, 911 were dementia-free and 46 had dementia. The MoCA (13/14) displayed good sensitivity (95.6%), specificity (81.5%), and overall accuracy (82.1%) for dementia detection. The GDS-10 and AD8-8pt showed poor discriminant validity, while the AD8-8info had the highest specificity (83.2%) and the greatest overall accuracy (82.5%) for dementia. Compensatory combination of the AD8-8info with MoCA, the sensitivity and positive predictive values were optimized (100%), while the conjunctive combination of two tools achieved excellent specificity (96.3%) and overall accuracy (94.8%) in discriminating dementia patients. Conclusion and implications: Combining a reliable single-question SCC assessment with an objective tool can efficiently discriminate dementia patients from healthy older adults in the community.

Prevalence, Clinical Correlates, Cognitive Trajectories, and Dementia Risk Associated With Mild Behavioral Impairment in Asians.

Objective: Mild behavioral impairment (MBI) is characterized as later-life-emergent and persistent neuropsychiatric symptoms (NPS). The symptom persistence criterion of MBI has shown to increase the signal-to-noise ratio of the syndrome, decreasing the likelihood of false-positive NPS. However, the long-term cognitive and prognostic impact of MBI remains to be evaluated against the traditional framework of NPS, especially in Asian cohorts. This study investigated the epidemiologic characteristics of MBI in a prospective clinical cohort of Singaporean elderly.Methods: A total of 304 dementia-free individuals (mean [SD] age = 72.2 [8.0] years, 51.6% female) were recruited between August 2010 and October 2019. All participants underwent annual neuropsychological, neuropsychiatric, and clinical assessments for 4 consecutive years and were diagnosed as having no cognitive impairment (NCI) or cognitive impairment-no dementia (CIND). MBI was ascertained using both baseline and year-1 Neuropsychiatric Inventory assessments. Cognitive Z-scores and Clinical Dementia Rating Sum-of-Boxes (CDR-SoB) scores were calculated.Results: The prevalence of MBI was 14.5% (7.1% of NCI, 12.9% of CIND-mild, and 24.7% of CIND-moderate patients). MBI patients showed poorer cognitive function at baseline (F1,295 = 8.13 [SE = 0.47], P = .005), primarily in memory and executive function domains. MBI was associated with accelerated decline in global cognition (ß = -0.15; 95% CI, -0.23 to -0.07) along with faster increase in CDR-SoB (ß = 0.92; 95% CI, 0.62 to 1.21) as compared to individuals without symptoms or transient NPS. A total of 38.6% of MBI patients developed dementia as compared to 12.3% of non-MBI elderly (χ2 = 19.29, P < .001). MBI increased risk of incident dementia by 2.56-fold as compared to no symptoms or transient NPS, regardless of cognitive impairment.Conclusions: MBI is a neurobehavioral risk factor for dementia, representing a potential target for dementia risk modeling, preventive intervention, and disease management.

Interactions of comorbid neuropsychiatric subsyndromes with neurodegenerative and cerebrovascular pathologies on cognition.

Comorbid neuropsychiatric symptoms are commonly found in individuals with dementia and is likely influenced by a combination of neurodegenerative and cerebrovascular pathophysiology. We evaluated the associations of a validated composite MRI-based quantitative measure of both neurodegeneration (hippocampus volume and cortical thickness of AD-specific regions) and cerebrovascular disease (CeVD; white matter hyperintensities and infarcts) with neuropsychiatric subsyndromes, and their interactions on cognition in a community-based sample across the disease spectrum (N = 773). Lower composite MRI scores corresponding to greater comorbid neurodegeneration and CeVD burden were associated with hyperactivity (OR = 1.48) and apathy (OR = 1.90) subsyndromes. Lower MRI scores with concomitant hyperactivity was associated with greater cognitive impairment, especially in patients who were at least moderately impaired, while the interaction with apathy was not dependent on disease stage. These MRI scores interaction models resulted in a better fit than models consisting of neurodegeneration or CeVD alone. Integrating multiple biomarkers with specific, disease stage-dependent neuropsychiatric subsyndromes may provide a more holistic risk profile to facilitate the identification of individuals at the highest risk of disease progression.

Neuropsychiatric Correlates of Small Vessel Disease Progression in Incident Cognitive Decline: Independent and Interactive Effects.

BACKGROUND: Cerebral small vessel disease (SVD) and neuropsychiatric symptoms (NPS) independently increase the risk of cognitive decline. While their co-existence has been reported in the preclinical stage of dementia, longitudinal data establishing the prognosis of their associations, especially in an Asian context remains limited. OBJECTIVE: This study investigated the role of SVD and NPS progressions on cognitive outcomes over 2 years in a dementia-free elderly cohort. METHODS: 170 dementia-free elderly with baseline and 2-year neuropsychological assessments and MRI scans were included in this study. White matter hyperintensities (WMH), lacunes, and microbleeds (CMBs) were graded as markers of SVD. The Neuropsychiatric Inventory (NPI) was used to measure NPS. Generalized estimating equations modelling evaluated the relationship between NPI change and SVD progression. Logistic regression evaluated the risk of incident cognitive decline with both SVD and NPS. All models were adjusted for demographics, baseline cerebrovascular diease, and medial temporal lobe atrophy. RESULTS: Higher NPI scores were associated with higher SVD burden at baseline. Subjects with WMH progression had greater increase in total NPI (ß[SE] = 0.46[0.19], p = 0.016), driven by hyperactivity subsyndrome (ß[SE] = 0.88[0.34], p = 0.007). Subjects with incident CMBs had greater increase in psychosis subsyndrome (ß[SE] = 0.89[0.30], p < 0.001). Subjects with progressions in both SVD and NPS were more likely to develop cognitive decline over 2 years (OR[95% CI] = 4.17[1.06-16.40], p < 0.05). CONCLUSION: Our findings support worsening of NPS as a clinical indicator of SVD progression and are associated with cognitive decline over 2 years. Early detection of NPS and targeted interventions on SVD burden may improve NPS outcomes.

The Informant AD8 Can Discriminate Patients with Dementia From Healthy Control Participants in an Asian Older Cohort.

OBJECTIVES: The informant-AD8 (i-AD8) was found to be reliable in detecting cognitive impairment and dementia in tertiary and primary health care settings. We evaluated the discriminability of the i-AD8, as compared to other brief cognitive measures, and its combination with the 5-minute Montreal Cognitive Assessment (MoCA) and Mini-Cog in detecting very mild dementia in an Asian older cohort. DESIGN: The Epidemiology of Dementia in Singapore (EDIS) study recruited participants from a population-based eye disease study who were of Chinese, Malay, and Indian ethnicities. SETTING AND PARTICIPANTS: Participants aged ≥60 years were clinically assessed and diagnosed using the Clinical Dementia Rating (CDR) scale. Of the 761 participants recruited, 526 (69.1%) had no dementia (CDR = 0), 193 (25.4%) had very mild dementia (CDR = 0.5), and 42 (5.5%) had dementia (CDR ≥ 1). MEASURES: Participants were administered the Mini-Mental State Examination, MoCA, Mini-Cog, and a local neuropsychological battery. Their informants were interviewed using the i-AD8. Receiver operating characteristic analyses were conducted to establish the optimal cut-off points, and all discriminatory indices were calculated. RESULTS: The i-AD8 was good and equivalent to other cognitive tools in detecting dementia [area under the curve (AUC) = 0.89, sensitivity = 0.76, and specificity = 0.94] but only fair in detecting very mild dementia (AUC = 0.69, sensitivity = 0.62, and specificity = 0.73). Combination of the i-AD8 with 5-minute MoCA or Mini-Cog in compensatory or in conjunction showed minimal improvement to the clinical utility for dementia or very mild dementia. All scales yielded a high rate of false positives (positive predictive value < 0.70). CONCLUSIONS AND IMPLICATIONS: The i-AD8 has good discriminatory power in detecting dementia (CDR ≥ 1) and is brief enough to be applied as an effective screening tool in the community. However, the i-AD8 and other cognitive tools lacked classification accuracy in detecting very mild dementia (CDR = 0.5).

Caregiver-Reported Sleep Disturbances Are Associated With Behavioral and Psychological Symptoms in an Asian Elderly Cohort With Cognitive Impairment-No Dementia.

OBJECTIVE: Sleep disturbances were found to be associated with more behavioral and psychological symptoms (BPS) in early patients with Alzheimer's disease (AD). However, data on preclinical stages of dementia are lacking. Hence, the present study sought to investigate the association between sleep disturbances and BPS in dementia-free elderly with varying severity of cognitive impairment in an Asian sample. METHODS: Community-living elderly were recruited and administered a comprehensive cognitive battery (vascular dementia battery [VDB]) and the Neuropsychiatric Inventory to assess symptoms of sleep disturbances and BPS. Severity of cognitive impairment was diagnosed and classified as no cognitive impairment (NCI), cognitive impairment-no dementia (CIND) -mild (1-2 impaired domains on the VDB), and CIND-moderate (≥3 impaired domains on the VDB). Analysis of variance was conducted to assess the associations between the presence of sleep disturbances and BPS scores in each diagnostic group. Logistic regression was used to examine whether the coexistence of sleep disturbances and other BPS was associated with CIND-moderate, which is known to carry a higher risk of progression to AD. RESULTS: Among 839 elderly, 79 (9.4%) reported sleep disturbances. Participants with sleep disturbances had higher total BPS burden than those without among CIND participants but not in NCIs. Furthermore, CIND-moderate participants with sleep disturbances had more delusions, hallucinations, anxiety, depression, irritability, aberrant motor behavior, and appetite change ( P < .05). The presence of both sleep disturbances and other BPS was associated with CIND-moderate (odds ratio: 2.5, 95% confidence interval: 1.1-5.5). CONCLUSIONS: Sleep disturbances are associated with higher total BPS burden and specific BPS among elderly patients with cognitive impairment, particularly those with CIND moderate, which carries higher risk of developing dementia.