Modelling the Distribution of Cognitive Outcomes for Early-Stage Neurocognitive Disorders: A Model Comparison Approach.

Background: Cognitive assessments for patients with neurocognitive disorders are mostly measured by the Montreal Cognitive Assessment (MoCA) and Visual Cognitive Assessment Test (VCAT) as screening tools. These cognitive scores are usually left-skewed and the results of the association analysis might not be robust. This study aims to study the distribution of the cognitive outcomes and to discuss potential solutions. Materials and Methods: In this retrospective cohort study of individuals with subjective cognitive decline or mild cognitive impairment, the inverse-transformed cognitive outcomes are modelled using different statistical distributions. The robustness of the proposed models are checked under different scenarios: with intercept-only, models with covariates, and with and without bootstrapping. Results: The main results were based on the VCAT score and validated via the MoCA score. The findings suggested that the inverse transformation method improved the modelling the cognitive scores compared to the conventional methods using the original cognitive scores. The association of the baseline characteristics (age, gender, and years of education) and the cognitive outcomes were reported as estimates and 95% confidence intervals. Bootstrap methods improved the estimate precision and the bootstrapped standard errors of the estimates were more robust. Cognitive outcomes were widely analysed using linear regression models with the default normal distribution as a conventional method. We compared the results of our suggested models with the normal distribution under various scenarios. Goodness-of-fit measurements were compared between the proposed models and conventional methods. Conclusions: The findings support the use of the inverse transformation method to model the cognitive outcomes instead of the original cognitive scores for early-stage neurocognitive disorders where the cognitive outcomes are left-skewed.

Mild Behavioral Impairment and Cerebrovascular Profiles Are Associated with Early Cognitive Impairment in a Community-Based Southeast Asian Cohort.

Background: Mild behavioral impairment (MBI) is one of the earliest observable changes when a person experiences cognitive decline and could be an early manifestation of underlying Alzheimer's disease neuropathology. Limited attention has been given to investigating the clinical applicability of behavioral biomarkers for detection of prodromal dementia. Objective: This study compared the prevalence of self-reported MBI and vascular risk factors in Southeast Asian adults to identify early indicators of cognitive impairment and dementia. Methods: This cohort study utilized baseline data from the Biomarkers and Cognition Study, Singapore (BIOCIS). 607 participants were recruited and classified into three groups: cognitively normal (CN), subjective cognitive decline (SCD), and mild cognitive impairment (MCI). Group comparisons of cognitive-behavioral, neuroimaging, and blood biomarkers data were applied using univariate analyses. Multivariate logistic regression analyses were conducted to investigate the association between cerebrovascular disease, vascular profiles, and cognitive impairment. Results: SCD had significantly higher depression scores and poorer quality of life (QOL) compared to CN. MCI had significantly higher depression scores; total MBI symptoms, MBI-interest, MBI-mood, and MBI-beliefs; poorer sleep quality; and poorer QOL compared to CN. Higher Staals scores, glucose levels, and systolic blood pressure were significantly associated with MCI classification. Fasting glucose levels were significantly correlated with depression, anxiety, MBI-social, and poorer sleep quality. Conclusions: The results reflect current research that behavioral changes are among the first symptoms noticeable to the person themselves as they begin to experience cognitive decline. Self-reported questionnaires may aid in early diagnoses of prodromal dementia. Behavioral changes and diabetes could be potential targets for preventative healthcare for dementia.

The role of perfusion, grey matter volume and behavioural phenotypes in the data-driven classification of cognitive syndromes.

BACKGROUND: The use of structural and perfusion brain imaging in combination with behavioural information in the prediction of cognitive syndromes using a data-driven approach remains to be explored. Here, we thus examined the contribution of brain structural and perfusion imaging and behavioural features to the existing classification of cognitive syndromes using a data-driven approach. METHODS: Study participants belonged to the community-based Biomarker and Cognition Cohort Study in Singapore who underwent neuropsychological assessments, structural-functional MRI and blood biomarkers. Participants had a diagnosis of cognitively normal (CN), subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and dementia. Cross-sectional structural and cerebral perfusion imaging, behavioural scale data including mild behaviour impairment checklist, Pittsburgh Sleep Quality Index and Depression, Anxiety and Stress scale data were obtained. RESULTS: Three hundred seventy-three participants (mean age 60.7 years; 56% female sex) with complete data were included. Principal component analyses demonstrated that no single modality was informative for the classification of cognitive syndromes. However, multivariate glmnet analyses revealed a specific combination of frontal perfusion and temporo-frontal grey matter volume were key protective factors while the severity of mild behaviour impairment interest sub-domain and poor sleep quality were key at-risk factors contributing to the classification of CN, SCI, MCI and dementia (p < 0.0001). Moreover, the glmnet model showed best classification accuracy in differentiating between CN and MCI cognitive syndromes (AUC = 0.704; sensitivity = 0.698; specificity = 0.637). CONCLUSIONS: Brain structure, perfusion and behavioural features are important in the classification of cognitive syndromes and should be incorporated by clinicians and researchers. These findings illustrate the value of using multimodal data when examining syndrome severity and provide new insights into how cerebral perfusion and behavioural impairment influence classification of cognitive syndromes.

APOE4 carrier status determines association between white matter disease and grey matter atrophy in early-stage dementia.

BACKGROUND: White matter hyperintensities, a neuroimaging marker of small-vessel cerebrovascular disease and apolipoprotein ε4 (APOE4) allele, are important dementia risk factors. However, APOE4 as a key effect modifier in the relationship between white matter hyperintensities and grey matter volume needs further exploration. METHODS: One hundred ninety-two early-stage dementia (including mild cognitive impairment and mild dementia) and 259 cognitively unimpaired participants from a neurocognitive research cohort with neuroimaging data, APOE genotyping, and neuropsychological assessments were studied. We investigated independent and interactive effects of white matter hyperintensities and APOE4 on whole-brain voxel-wise grey matter volume using voxel-based morphometry (uncorrected p < 0.001; minimum cluster size = 100 voxels). We further assessed interactive effects between APOE4 and white matter hyperintensities on global cognition, memory, and executive function in early-stage dementia and cognitively unimpaired participants. RESULTS: Independent of APOE4 status, higher white matter hyperintensity load was associated with greater grey matter atrophy across frontal, parietal, temporal, and occipital lobes in cognitively unimpaired and early-stage dementia subjects. However, interaction analyses and independent sample analyses revealed that APOE4 non-carriers demonstrated greater white matter hyperintensity-associated grey matter atrophy compared to APOE4 carriers in both cognitively unimpaired and early-stage dementia groups. Additional confirmatory analyses among APOE4 non-carriers demonstrated that white matter hyperintensities resulted in widespread grey matter loss. Analyses of cognitive function demonstrated that higher white matter hyperintensity load was associated with worse global (Mini-Mental State Examination, Montreal Cognitive Assessment) and executive function (Color Trails 2) in APOE4 non-carriers compared to APOE4 carriers in early-stage dementia but not cognitively unimpaired participants. CONCLUSIONS: The association between white matter hyperintensities and grey matter loss is more pronounced in APOE4 non-carriers than APOE4 carriers in the cognitively unimpaired and early-stage dementia stages. Furthermore, white matter hyperintensity presence results in poorer executive function in APOE4 non-carriers compared to APOE4 carriers. This finding may have significant impact on the design of clinical trials with disease modifying therapies.

Usefulness of the Visual Cognitive Assessment Test in Detecting Mild Cognitive Impairment in the Community.

BACKGROUND: A delay in the detection of mild cognitive impairment (MCI) in the community delays the opportunity for early intervention. Accurate tools to detect MCI in the community are lacking. The Visual Cognitive Assessment Test (VCAT) is a visual based cognitive test useful for multilingual populations without the need for translation. OBJECTIVE: Here, we evaluate the usefulness of VCAT in detecting MCI in a community population in Singapore. METHODS: We recruited 301 participants from the community who completed a detailed neuropsychological assessment and 170 of them completed a 3T magnetic resonance imaging (MRI) brain scan. We performed a receiver operating characteristics analysis to test the diagnostic performance of VCAT compared to Montreal Cognitive Assessment (MoCA) in distinguishing MCI from cognitively normal (CN) by measuring area under the curve (AUC). To test for the association of VCAT with structural MRI, we performed a Pearson's correlation analysis for VCAT and MRI variables. RESULTS: We recruited 39 CN and 262 MCI participants from Dementia Research Centre (Singapore). Mean age of the cohort was 63.64, SD = 9.38, mean education years was 13.59, SD = 3.70 and majority were women (55.8%). VCAT was effective in detecting MCI from CN with an AUC of 0.794 (95% CI 0.723-0.865) which was slightly higher than MoCA 0.699 (95% CI 0.621-0.777). Among subjects with MCI, VCAT was associated with medial temporal lobe atrophy (ρ = -0.265, p = 0.001). CONCLUSIONS: The VCAT is useful in detecting MCI in the community in Singapore and may be an effective measure of neurodegeneration.

Amyloid-Tau-Neurodegeneration Profiles and Longitudinal Cognition in Sporadic Young-Onset Dementia.

We examined amyloid-tau-neurodegeneration biomarker effects on cognition in a Southeast-Asian cohort of 84 sporadic young-onset dementia (YOD; age-at-onset <65 years) patients. They were stratified into A+N+, A- N+, and A- N- profiles via cerebrospinal fluid amyloid-ß1-42 (A), phosphorylated-tau (T), MRI medial temporal atrophy (neurodegeneration- N), and confluent white matter hyperintensities cerebrovascular disease (CVD). A, T, and CVD effects on longitudinal Mini-Mental State Examination (MMSE) were evaluated. A+N+ patients demonstrated steeper MMSE decline than A- N+ (ß = 1.53; p = 0.036; CI 0.15:2.92) and A- N- (ß = 4.68; p = 0.001; CI 1.98:7.38) over a mean follow-up of 1.24 years. Within A- N+, T- CVD+ patients showed greater MMSE decline compared to T+CVD- patients (ß = - 2.37; p = 0.030; CI - 4.41:- 0.39). A+ results in significant cognitive decline, while CVD influences longitudinal cognition in the A- sub-group.

Safety and Usefulness of Lumbar Puncture for the Diagnosis and Management of Young-Onset Cognitive Disorders.

BACKGROUND: Young-onset cognitive disorders (YOCD) often manifests with complex and atypical presentations due to underlying heterogenous pathologies. Therefore, a biomarker-based evaluation will allow for timely diagnosis and definitive management. OBJECTIVE: Here, we evaluated the safety and usefulness of cerebrospinal fluid (CSF) sampling through lumbar puncture (LP) in YOCD patients in a tertiary clinical setting. METHODS: Patients with mild cognitive impairment (MCI) and mild dementia with age of onset between 45-64 years were evaluated. Patients underwent magnetic resonance imaging and their medial temporal lobe atrophy (MTA) was rated. LP side-effects and the impact of the CSF findings on diagnosis and management were analyzed. RESULTS: 142 patients (53 (37.32%) MCI, 51 (35.92%) dementia of the Alzheimer's disease [DAT] type, and 38 (26.76%) non-AD type dementia) who underwent LP between 2015 to 2021 were analyzed. Using post-LP results and MTA ratings, 74 (52.11%) patients met the AT(N) criteria for AD. 56 (39.44%) patients (28 out of 53 (50.0%) MCI, 12 out of 51 (21.43%) DAT, and 16 out of 38 (28.57%) non-AD dementia) had a change in diagnosis following LP. 13 (9.15%) patients developed side-effects post-LP (11 (84.62%) patients had headache, 1 (7.69%) patient had backache, and 1 (7.69%) patient had headache and backache). 32 (22.54%) patients had a change in management post-LP, 24 (75.0%) had medication changes, 10 (31.30%) had referrals to other specialists, and 3 (9.40%) was referred for clinical trial with disease modifying interventions. CONCLUSION: LP is well-tolerated in YOCD and can bring about relevant clinical decisions with regards to the diagnosis and management of this complex clinical condition.

The Association Between Diabetes Mellitus and Mild Behavioral Impairment Among Mild Cognitive Impairment: Findings from Singapore.

BACKGROUND: Mild behavioral impairment (MBI) describes persistent behavioral changes in later life as an at-risk state for dementia. While cardiovascular risk factors (CVRFs) are linked to dementia, it is uncertain how CVRFs are associated with MBI. OBJECTIVE: To determine the prevalence of MBI and its association with CVRFs among cognitively normal (CN) and mild cognitive impairment (MCI) individuals in Singapore. METHODS: 172 individuals (79 CN and 93 MCI) completed the MBI-checklist (MBI-C). The prevalence of MBI and MBI-C sub-domain characteristics among CN and MCI were examined. Regression models evaluated the relationships between MBI-C sub-domain scores with CVRFs. RESULTS: The prevalence of MBI and mean MBI-C total score were significantly higher among MCI than CN (34.4%versus 20.3%, p = 0.022 and 7.01 versus 4.12, p = 0.04). The highest and lowest-rated sub-domains among CN and MCI were impulse dyscontrol and abnormal thoughts and perception respectively. Within the MCI cohort, a higher proportion of individuals with diabetes mellitus (DM) had MBI compared to individuals without DM (28.1%versus 10.4%, p = 0.025). The interaction of DM and MCI cohort resulted in significantly higher mean MBI-C total, decreased motivation, emotional dysregulation, impulse dyscontrol, and abnormal thoughts and perception sub-domain scores. CONCLUSION: The prevalence of MBI is higher among a Singapore cohort compared to Caucasian cohorts. The associations of DM with both the presence and severity of MBI among MCI suggest that DM may be a risk factor for MBI. The optimization of DM may be a potential therapeutic approach to improve clinical outcomes among MCI with MBI.

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.

Randomized Controlled Trials of Psychoeducation Modalities in the Management of Bipolar Disorder: A Systematic Review.

OBJECTIVE: This review sought to summarize the extant literature on the efficacy of 4 modalities of psychoeducation (individual, group, family, internet- based) in the management of patients with bipolar disorder. DATA SOURCES: We searched the digital databases (Science Direct, Scopus, PubMed/MEDLINE) for relevant randomized controlled trials (RCTs) pertaining to psychoeducation in bipolar disorder from inception to February 2017. Keywords and combinations used included psychoeducation, bipolar disorder, individual, family, group, and internet. Reference lists of review articles were also used for retrieval of relevant articles. STUDY SELECTION: We retrieved 48 studies and ultimately reviewed 40 RCTs meeting inclusion criteria. Studies were included if they were in English, were RCTs of different psychoeducation modalities managing patients with bipolar disorder, and used standardized assessment of outcomes of psychoeducation. DATA EXTRACTION: We examined each of the selected publications for relevant data. RESULTS: The majority of psychoeducation RCTs (28 of 40 studies, 70.0%) focused on group and family psychoeducation, with positive benefits reported in clinical outcomes, treatment, and functioning measures. Group psychoeducation was associated with reduced illness recurrences, decreased number and duration of hospitalizations, increased time to illness relapse, better treatment adherence, higher therapeutic lithium levels, and reduced stigma. Family psychoeducation was associated with reductions in illness recurrence, hospitalization rates, and better illness trajectory as well as increased caregiver knowledge, skills, support, and sense of well-being and reduced caregiver burden. There are fewer RCTs on individual and internet-based psychoeducation, with findings being inconsistent or negative. CONCLUSIONS: Future studies may include direct comparisons of different psychoeducation modalities to elucidate specific benefits of unique psychoeducation interventions at different phases of bipolar disorder.