Dementia in Southeast Asia: influence of onset-type, education, and cerebrovascular disease.

BACKGROUND: Southeast Asia represents 10% of the global population, yet little is known about regional clinical characteristics of dementia and risk factors for dementia progression. This study aims to describe the clinico-demographic profiles of dementia in Southeast Asia and investigate the association of onset-type, education, and cerebrovascular disease (CVD) on dementia progression in a real-world clinic setting. METHODS: In this longitudinal study, participants were consecutive series of 1606 patients with dementia from 2010 to 2019 from a tertiary memory clinic from Singapore. The frequency of dementia subtypes stratified into young-onset (YOD; <65 years age-at-onset) and late-onset dementia (LOD; ≥65 years age-at-onset) was studied. Association of onset-type (YOD or LOD), years of lifespan education, and CVD on the trajectory of cognition was evaluated using linear mixed models. The time to significant cognitive decline was investigated using Kaplan-Meier analysis. RESULTS: Dementia of the Alzheimer's type (DAT) was the most common diagnosis (59.8%), followed by vascular dementia (14.9%) and frontotemporal dementia (11.1%). YOD patients accounted for 28.5% of all dementia patients. Patients with higher lifespan education had a steeper decline in global cognition (p<0.001), with this finding being more pronounced in YOD (p=0.0006). Older patients with a moderate-to-severe burden of CVD demonstrated a trend for a faster decline in global cognition compared to those with a mild burden. CONCLUSIONS: There is a high frequency of YOD with DAT being most common in our Southeast Asian memory clinic cohort. YOD patients with higher lifespan education and LOD patients with moderate-to-severe CVD experience a steep decline in cognition.

Cerebral Small Vessel Disease Influences Hippocampal Subfield Atrophy in Mild Cognitive Impairment.

To investigate patterns of hippocampal subfield atrophy among patients with amnestic mild cognitive impairment, stratified by severity of small vessel disease (SVD) and corresponding associations with cognitive domains. One hundred seventy-six MCI subjects (mean age = 65.56 years, SD = 8.77) underwent neuropsychological assessments and magnetic resonance imaging. SVD was rated 0 (no SVD), 1 (mild SVD) and 2 (moderate to severe SVD) based on load of white matter hyperintensities (WMH) and lacunes. Demographics, cerebrovascular risk factors, grey and white matter volumes and hippocampal subfield atrophies were compared across SVD severity through ANCOVA analyses. Subjects were categorized into positive or negative SVD-hippocampal subfield atrophy (HSA) and influence of positive SVD-HSA on episodic memory and frontal executive function was evaluated through ANCOVA analyses. All analyses corrected for covariates and bias-corrected bootstrap estimation with 1000 resamples was applied with Bonferroni correction. Hippocampal subfield atrophy worsened with increasing SVD severity. Positive SVD-HSA was characterised by significant atrophy in the subiculum, CA1, CA4, molecular layer and dentate gyrus. Greater atrophy was seen with moderate to severe SVD compared to mild SVD in these subfields. Atrophy in the five subfields of SVD-HSA was significantly associated with poor episodic memory and frontal executive function. Presence and burden of SVD influences the pattern and severity of hippocampal subfield atrophy. SVD-related hippocampal subfield atrophy is associated with poorer episodic memory and frontal executive function in mild cognitive impairment.

Frontotemporal dementia and COVID-19: Hypothesis generation and roadmap for future research.

The COVID-19 pandemic has caused tremendous suffering for patients with dementia and their caregivers. We conducted a survey to study the impact of the pandemic on patients with mild frontotemporal dementia (FTD). Our preliminary findings demonstrate that patients with FTD have significant worsening in behavior and social cognition, as well as suffer greater negative consequences from disruption to health-care services compared to patients with AD. The reduced ability to cope with sudden changes to social environments places patients with FTD at increased vulnerability to COVID-19 infection as well as to poorer clinical and social outcomes. Caregivers of FTD patients also demonstrate high burden during crisis situations. A proportion of patients with FTD benefitted from use of web-based interactive platforms. In this article, we outline the priority areas for research as well as a roadmap for future collaborative research to ensure greatest benefit for patients with FTD and their caregivers.

Construct validity of the Visual Cognitive Assessment Test (VCAT)-a cross-cultural language-neutral cognitive screening tool.

BACKGROUND: The Visual Cognitive Assessment Test (VCAT) is a language-neutral cognitive screening tool designed for use in culturally diverse populations without the need for translations or adaptations. While it has been established to be language-neutral, the VCAT's construct validity has not been investigated. METHODS: 471 participants were recruited, comprising 233 healthy comparisons, 117 mild cognitive impairment (MCI), and 121 mild Alzheimer's disease (AD) patients. VCAT and domain-specific neuropsychological tests were administered in the same sitting. Construct validity was assessed by analyzing domain-specific associations between the VCAT and well-established cognitive assessments. Reliability (internal consistency) was measured by Cronbach's alpha. Diagnostic ability (area under the curve) and recommended cutoffs were determined by receiver operating characteristic (ROC) analysis. RESULTS: The VCAT and its subdomains demonstrated good construct validity in terms of both convergent and divergent validity and good internal consistency (α = .74). ROC analysis found that the VCAT was on par with the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at distinguishing between healthy comparisons, MCI, and mild AD. Consistent with previous studies, VCAT scores were not affected by language of administration or ethnicity in our cohort. Findings suggest the following cutoffs: Dementia 0-19, MCI 20-24, Normal 25-30. CONCLUSION: This study established the construct validity of the VCAT, which is vital to ensure its subdomains effectively measure the cognitive processes they were designed to. The VCAT is capable of detecting early cognitive impairments and allows for meaningful cross-cultural comparisons, especially useful for international collaborations and clinical trials, and for clinical use in diverse multiethnic populations.

Medial Temporal Atrophy in Amyloid-Negative Amnestic Type Dementia Is Associated with High Cerebral White Matter Hyperintensity.

BACKGROUND: Non-amyloid mechanisms behind neurodegeneration and cognition impairment are unclear. Cerebrovascular disease (CVD) may play an important role in suspected non-Alzheimer's pathophysiology (SNAP), especially in Asia. OBJECTIVE: To examine the association between CVD and medial temporal lobe atrophy (MTA) in amyloid-ß negative patients with mild amnestic type dementia. METHODS: Thirty-six mild dementia patients with complete neuropsychological, cerebrospinal fluid (CSF) biomarker, and neuroimaging information were included. Only patients with clinically significant MTA were recruited. Patients were categorized based on their CSF Aß levels. Neuroimaging and neuropsychological variables were analyzed. RESULTS: Despite comparable MTA between Aß positive and negative patients, Aß-negative patients had significantly greater white matter hyperintensities (WMH; Total Fazekas Rating) than their Aß-positive counterparts (6.42 versus 4.19, p = 0.03). A larger proportion of Aß-negative patients also had severe and confluent WMH. Regression analyses controlling for baseline characteristics yielded consistent results. CONCLUSION: Our findings demonstrate that MTA is associated with greater CVD burden among Aß-negative patients with amnestic type dementia. CVD may be an important mechanism behind hippocampal atrophy. This has implications on clinical management strategies, where measures to reduce CVD may slow neurodegeneration and disease progression.

Cerebrovascular Disease Is a Risk for Getting Lost Behavior in Prodromal Dementia.

Cerebrovascular disease (CVD) contributes to spatial navigation deficits; however, the everyday outcomes of this association remain unexplored. We investigated whether CVD was a risk for getting lost behavior (GLB) in elderly with mild cognitive impairment (MCI) and mild Alzheimer disease (AD). Getting lost behavior was assessed using a semistructured clinical interview and was associated with white matter lesions (WMLs) in patients with MCI. Specifically, right occipital WMLs increased the odds of GLB by 12 times (P = .03) and right temporal WMLs increased the odds of GLB by 4 times (P = .01), regardless of age, gender, global cognitive impairment, and occipital or medial temporal gray matter atrophy. Hypertension increased the risk of GLB in MCI by contributing to the burden of WMLs. White matter lesions were not associated with GLB in mild AD. Our findings suggest that interventions aimed at reducing GLB in prodromal dementia may involve preventing WMLs by optimizing hypertension control.

Serial position effects differ between Alzheimer's and vascular features in mild cognitive impairment.

Individuals with mild cognitive impairment (MCI) exhibit varying serial position effect (SPE) performances. The relationship between SPE performance in word list recall and clinical, genetic, and neuroimaging features of MCI requires elucidation. 119 MCI and 68 cognitively normal (CN) participants underwent cognitive assessment, apolipoprotein E (ApoE) genotyping, and volumetric MRI brain scans processed via voxel-based morphometry. A 10-word recall task was used to assess SPE performance in relation to recency and primacy recall. MCI participants were classified as having Good SPE performance (high primacy and recency, Good SPE) or Poor SPE performance (low primacy only, LP-SPE; low recency only, LR-SPE; or both low, Low SPE). Poor SPE participants had reduced grey matter (GM) volumes and increased white matter hyperintensities (WMH) volumes. Participants with LP-SPE demonstrated reduced hippocampal GM volumes and were more likely to be ApoE ε4 carriers. LR-SPE was associated with higher WMH volumes. Presence of both greater WMH volumes and ApoE ε4 resulted in Low SPE. LP-SPE MCI participants had features typical of Alzheimer's disease. LR-SPE MCI was associated with increased WMH volumes, likely representing vascular pathology. SPE profiles are associated with distinct clinical patterns of MCI pathophysiology and could have potential as a clinical marker.

The influence of language and culture on cognitive assessment tools in the diagnosis of early cognitive impairment and dementia.

INTRODUCTION: Cognitive assessment tools measure cognitive impairment and complement biomarkers to link cognitive symptoms with pathophysiological processes underlying dementia. However, language and cultural differences in multilingual populations can influence the interpretation of cognitive assessment tools when applied in cross-cultural and multinational studies. Areas covered: This article examines the influence of culture and language on the interpretation of the Mini-Mental State Examination, Montreal Cognitive Assessment, and Alzheimer's Disease Assessment Scale-cognitive subscale, which are more commonly used worldwide. It discusses how this impacted multinational studies. Lastly, it presents language-neutral tools such as the Visual Cognitive Assessment Test, which do not require translation when applied in multilingual populations. Expert commentary: Linguistic and cultural variation within tools due to translation and differences in administration introduce method bias and differential item functioning, which influence the interpretation of cognitive scores in multinational studies. The ultimate goal is to have a tool that accurately measures cognitive impairment, yet with minimal influence from linguistic, cultural, educational, and demographic differences, through concerted international efforts to harmonize the development and validation of tools. While recently developed visual-based language-neutral tools show promise in the early detection of cognitive impairment, further validation will be required for these tools to be applied internationally.

A novel language-neutral Visual Cognitive Assessment Test (VCAT): validation in four Southeast Asian countries.

BACKGROUND: Cognitive screeners are imperative for early diagnosis of dementia. The Visual Cognitive Assessment Test (VCAT) is a language-neutral, visual-based test which has proven useful for a multilingual population in a single-center study. However, its performance utility is unknown in a wider and more diverse Southeast Asian cohort. METHODS: We recruited 164 healthy controls (HC) and 120 cognitively impaired (CI) subjects- 47 mild cognitive impairment (MCI) and 73 mild Alzheimer's disease (AD) dementia participants, from four countries between January 2015 and August 2016 to determine the usefulness of a single version of the VCAT, without translation or adaptation, in a multinational, multilingual population. The VCAT was administered along with established cognitive evaluation. RESULTS: The VCAT, without local translation or adaptation, was effective in discriminating between HC and CI subjects (MCI and mild AD dementia). Mean (SD) VCAT scores for HC and CI subjects were 22.48 (3.50) and 14.17 (5.05) respectively. Areas under the curve for Montreal Cognitive Assessment (0.916, 95% CI 0.884-0.948) and the VCAT (0.905, 95% CI 0.870-0.940) in discriminating between HCs and CIs were comparable. The multiple languages used to administer VCAT in four countries did not significantly influence test scores. CONCLUSIONS: The VCAT without the need for language translation or cultural adaptation showed satisfactory discriminative ability and was effective in a multinational, multilingual Southeast Asian population.

High Caregiver Burden in Young Onset Dementia: What Factors Need Attention?

BACKGROUND: There is an increase in prevalence of young onset dementia (YOD). The specific problems among YOD patients and levels of caregiver burden (CB) in this group warrants further evaluation. OBJECTIVE: To evaluate and compare level of CB in YOD and late onset dementia (LOD). Also, we sought to understand the specific factors, such as neuropsychiatric symptoms, that may affect the levels of caregiver burden in the YOD group. METHODS: Patient-caregiver dyads with YOD and LOD were recruited from a tertiary neurology center. Levels of CB between YOD and LOD were compared among 183 patient-caregiver dyads. CB was quantified using the Zarit Burden Inventory (ZBI). Neuropsychological evaluations as well as the Neuropsychiatric Inventory were performed. Factors that influenced level of CB in YOD group was investigated with regression analyses. RESULTS: There were 57 YOD and 126 LOD dyads. Caregivers of YOD subjects reported significantly higher levels of burden compared to caregivers of LOD subjects (ZBI: 17.3 versus 13.94; p = 0.015). 52.6% of YOD caregivers reported a high caregiver burden. When compared to caregivers of LOD, the odds of a caregiver of YOD reporting high caregiver burden was 2.34 (95% CI: 1.22-4.49: p = 0.010). YOD dyads with a high caregiver burden had significantly higher neuropsychiatric inventory scores. Risk factors for high caregiver burden in YOD included family history of dementia and behavioral symptoms including disinhibited behavior, delusions, and apathy. CONCLUSION: Targeted support for caregivers of patients with YOD is needed to address the higher CB in this group.

Getting Lost Behavior in Patients with Mild Alzheimer's Disease: A Cognitive and Anatomical Model.

BACKGROUND: Getting lost behavior (GLB) in the elderly is believed to involve poor top-down modulation of visuospatial processing, by impaired executive functions. However, since healthy elderly and elderly with Alzheimer's disease (AD) experience a different pattern of cognitive decline, it remains unclear whether this hypothesis can explain GLB in dementia. OBJECTIVE: We sought to identify whether poor executive functions and working memory modulate the relationship between visuospatial processing and prevalence of GLB in healthy elderly and patients with AD. Complementary to this, we explored whether brain regions critical for executive functions modulate the relationship between GLB and brain regions critical for visuospatial processing. METHOD: Ninety-two participants with mild AD and 46 healthy age-matched controls underwent neuropsychological assessment and a structural MRI. GLB was assessed using a semistructured clinical interview. Path analysis was used to explore interactions between visuospatial deficits, executive dysfunction/working memory, and prevalence of GLB, in AD and controls independently. RESULTS: For both healthy controls and patients with mild AD, visuospatial processing deficits were associated with GLB only in the presence of poor working memory. Anatomically, GLB was associated with medial temporal atrophy in patients with mild AD, which was not strengthened by low frontal gray matter (GM) volume as predicted. Instead, medial temporal atrophy was more strongly related to GLB in patients with high frontal GM volumes. For controls, GLB was not associated with occipital, parietal, medial temporal, or frontal GM volume. CONCLUSION: Cognitively, a top-down modulation deficit may drive GLB in both healthy elderly and patients with mild AD. This modulation effect may be localized in the medial temporal lobe for patients with mild AD. Thus, anatomical substrates of GLB in mild AD may not follow the typical top-down modulation mechanisms often reported in the healthy aging population. Implications advance therapeutic practices by highlighting the need to target both working memory and visuospatial deficits simultaneously, and that anatomical substrates of GLB may be disease specific.

Atrial Fibrillation is Independently Associated with Cognitive Impairment after Ischemic Stroke.

BACKGROUND: While atrial fibrillation (AF) is an important risk factor for ischemic strokes and mild cognitive impairment (MCI) in Alzheimer's disease, the association between AF and post-stroke cognitive impairment (PSCI), and the factors mediating this association, is unclear. OBJECTIVE: To investigate the role of AF in PSCI, especially in relation to other markers of cerebrovascular disease. METHODS: 445 subjects with mild ischemic stroke without pre-stroke cognitive decline were assessed 3-6 months post-stroke for cognitive deficits. MRIs were reviewed by trained raters for acute infarct characteristics, global cortical atrophy, white matter hyperintensities, cerebral microbleeds, and intracranial stenosis. Logistic regression analysis was used to identify factors independently associated with PSCI. Subjects were also categorized according to paroxysmal (pAF) or persistent/chronic AF (p/cAF), and presence or absence of AF or large cortical infarcts (LCI) to study cognitive trends. RESULTS: 80 (18.0%) subjects had AF. 76.3% of AF subjects and 42.7% of subjects without AF had PSCI. The odds ratio (OR) of AF in developing PSCI was 2.31 (95% CI: 1.12-4.75; p = 0.035), after correcting for other risk factors. pAF subjects and AF subjects with LCIs had higher ORs for PSCI. AF subjects performed worse in neuropsychological tasks associated with global cognition, episodic memory, and executive function. CONCLUSION: AF is a significant risk factor for PSCI, even after correcting for AF-related infarcts. Other mechanisms, such as hypoperfusion, microhemorrhages, and neuroinflammation, may be at play. All stroke patients with AF, regardless of the type of infarction, should be closely monitored for PSCI.

Depressive symptoms influence global cognitive impairment indirectly by reducing memory and executive function in patients with mild cognitive impairment.

BACKGROUND: Depressive symptoms negatively influence global cognition in the elderly; however, the mechanism of this effect remains unclear. OBJECTIVE: To investigate whether depressive symptoms influence global cognitive function in patients with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) by impeding specific neuropsychological abilities and under what conditions this effect might occur. METHOD: A sample of 259 participants (104 cognitively normal elderly controls, 66 patients with MCI and 89 patients with mild AD) underwent a comprehensive neuropsychological assessment. Global cognitive impairment was indexed by the composite of Mini-Mental State Examination and Montreal Cognitive Assessment scores and severity of depressive symptoms was measured with the Geriatric Depression Scale (GDS). RESULTS: Among patients with MCI, greater severity of depressive symptoms was associated with greater global cognitive impairment, with a moderate effect size. A mediation analysis revealed that patients with MCI experiencing depressive symptoms may exhibit global cognitive impairment because their depressive symptoms were reducing their capacity for working memory, episodic memory and non-speed-based executive functions. A moderation analysis indicated that this effect was consistent across age, gender, years of education and APOE-e4 status for working memory and episodic memory, and was observed in patients with MCI older than 65 years for executive functions. In cognitively normal elderly adults and patients with AD, depressive symptoms were not associated with global cognitive impairment. CONCLUSIONS: Depressive symptoms influence global cognitive function in patients with MCI indirectly by reducing mental space, mental flexibility and their capacity for consolidating and retrieving memories. These findings may guide clinicians to better diagnose and manage cognitive impairment in the context of concomitant depressive symptoms.