A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

The PRC2.1 Subcomplex Opposes G1 Progression through Regulation of CCND1 and CCND2.

Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenomics approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued growth inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in promoting G1 progression.

Assessing the validity of a self-reported clinical diagnosis of schizophrenia.

Background: Diagnoses in psychiatric research can be derived from various sources. This study assesses the validity of a self-reported clinical diagnosis of schizophrenia. Methods: The study included 3,029 clinically ascertained participants with schizophrenia or psychotic disorders diagnosed by self-report and/or research interview and 1,453 UK Biobank participants with self-report and/or medical record diagnosis of schizophrenia or schizoaffective disorder depressed-type (SA-D). We assessed positive predictive values (PPV) of self-reported clinical diagnoses against research interview and medical record diagnoses. We compared polygenic risk scores (PRS) and phenotypes across diagnostic groups, and compared the variance explained by schizophrenia PRS to samples in the Psychiatric Genomics Consortium (PGC). Results: In the clinically ascertained sample, the PPV of self-reported schizophrenia to a research diagnosis of schizophrenia was 0.70, which increased to 0.81 when benchmarked against schizophrenia or SA-D. In UK Biobank, the PPV of self-reported schizophrenia to a medical record diagnosis was 0.74. Compared to self-report participants, those with a research diagnosis were younger and more likely to have a high school qualification (clinically ascertained sample) and those with a medical record diagnosis were less likely to be employed or have a high school qualification (UK Biobank). Schizophrenia PRS did not differ between participants that had a diagnosis from self-report, research diagnosis or medical record diagnosis. Polygenic liability r2, for all diagnosis definitions, fell within the distribution of PGC schizophrenia cohorts. Conclusions: Self-report measures of schizophrenia are justified in research to maximise sample size and representativeness, although within sample validation of diagnoses is recommended.

Cardiff Online Cognitive Assessment in a National Sample: Cross-Sectional Web-Based Study.

BACKGROUND: Psychiatric disorders are associated with cognitive impairment. We have developed a web-based, 9-task cognitive battery to measure the core domains affected in people with psychiatric disorders. To date, this assessment has been used to collect data on a clinical sample of participants with psychiatric disorders. OBJECTIVE: The aims of this study were (1) to establish a briefer version of the battery (called the Cardiff Online Cognitive Assessment [CONCA]) that can give a valid measure of cognitive ability ("g") and (2) to collect normative data and demonstrate CONCA's application in a health population sample. METHODS: Based on 6 criteria and data from our previous study, we selected 5 out of the original 9 tasks to include in CONCA. These included 3 core tasks that were sufficient to derive a measure of "g" and 2 optional tasks. Participants from a web-based national cohort study (HealthWise Wales) were invited to complete CONCA. Completion rates, sample characteristics, performance distributions, and associations between cognitive performance and demographic characteristics and mental health measures were examined. RESULTS: A total of 3679 participants completed at least one CONCA task, of which 3135 completed all 3 core CONCA tasks. Performance on CONCA was associated with age (B=-0.05, SE 0.002; P<.001), device (tablet computer: B=-0.26, SE 0.05; P<.001; smartphone: B=-0.46, SE 0.05; P<.001), education (degree: B=1.68, SE 0.14; P<.001), depression symptoms (B=-0.04, SE 0.01; P<.001), and anxiety symptoms (B=-0.04, SE 0.01; P<.001). CONCLUSIONS: CONCA provides a valid measure of "g," which can be derived using as few as 3 tasks that take no more than 15 minutes. Performance on CONCA showed associations with demographic characteristics in the expected direction and was associated with current depression and anxiety symptoms. The effect of device on cognitive performance is an important consideration for research using web-based assessments.

Functional characterization of Alzheimer's disease genetic variants in microglia.

Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.

Combinatorial transcription factor binding encodes cis-regulatory wiring of forebrain GABAergic neurogenesis.

Transcription factors (TFs) bind combinatorially to genomic cis-regulatory elements (cREs), orchestrating transcription programs. While studies of chromatin state and chromosomal interactions have revealed dynamic neurodevelopmental cRE landscapes, parallel understanding of the underlying TF binding lags. To elucidate the combinatorial TF-cRE interactions driving mouse basal ganglia development, we integrated ChIP-seq for twelve TFs, H3K4me3-associated enhancer-promoter interactions, chromatin and transcriptional state, and transgenic enhancer assays. We identified TF-cREs modules with distinct chromatin features and enhancer activity that have complementary roles driving GABAergic neurogenesis and suppressing other developmental fates. While the majority of distal cREs were bound by one or two TFs, a small proportion were extensively bound, and these enhancers also exhibited exceptional evolutionary conservation, motif density, and complex chromosomal interactions. Our results provide new insights into how modules of combinatorial TF-cRE interactions activate and repress developmental expression programs and demonstrate the value of TF binding data in modeling gene regulatory wiring.

Sociodemographic, mental health, and physical health factors associated with participation within re-contactable mental health cohorts: an investigation of the GLAD Study.

BACKGROUND: The Genetic Links to Anxiety and Depression (GLAD) Study is a large cohort of individuals with lifetime anxiety and/or depression, designed to facilitate re-contact of participants for mental health research. At the start of the pandemic, participants from three cohorts, including the GLAD Study, were invited to join the COVID-19 Psychiatry and Neurological Genetics (COPING) study to monitor mental and neurological health. However, previous research suggests that participation in longitudinal studies follows a systematic, rather than random, process, which can ultimately bias results. Therefore, this study assessed participation biases following the re-contact of GLAD Study participants. METHODS: In April 2020, all current GLAD Study participants (N = 36,770) were invited to the COPING study. Using logistic regression, we investigated whether sociodemographic, mental, and physical health characteristics were associated with participation in the COPING baseline survey (aim one). Subsequently, we used a zero-inflated negative binomial regression to examine whether these factors were also related to participation in the COPING follow-up surveys (aim two). RESULTS: For aim one, older age, female gender identity, non-binary or self-defined gender identities, having one or more physical health disorders, and providing a saliva kit for the GLAD Study were associated with an increased odds of completing the COPING baseline survey. In contrast, lower educational attainment, Asian or Asian British ethnic identity, Black or Black British ethnic identity, higher alcohol consumption at the GLAD sign-up survey, and current or ex-smoking were associated with a reduced odds. For aim two, older age, female gender, and saliva kit provision were associated with greater COPING follow-up survey completion. Lower educational attainment, higher alcohol consumption at the GLAD Study sign-up, ex-smoking, and self-reported attention deficit hyperactivity disorder had negative relationships. CONCLUSIONS: Participation biases surrounding sociodemographic and physical health characteristics were particularly evident when re-contacting the GLAD Study volunteers. Factors associated with participation may vary depending on study design. Researchers should examine the barriers and mechanisms underlying participation bias in order to combat these issues and address recruitment biases in future studies.

DRAGON-Data: a platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts.

BACKGROUND: Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood. AIMS: Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research. METHOD: As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant. RESULTS: We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation. CONCLUSIONS: DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.

Are profiles of social, cultural, and economic capital related to living well with dementia? Longitudinal findings from the IDEAL programme.

RATIONALE: Research exploring social, cultural, and economic capital among people with dementia is scarce. OBJECTIVE: We describe levels of social, cultural, and economic capital in people with dementia at baseline and levels of social and cultural capital 12 and 24 months later. We identify groups of people with dementia having different combinations of capital and explore whether the identified groups differ in personal characteristics at baseline and in quality of life (QoL), satisfaction with life (SwL), and well-being over time. METHOD: Baseline, 12-months, and 24-months data from 1537 people with dementia (age, mean = 76.4 years; SD = 8.5; Alzheimer's Disease = 55.4%) enrolled in the IDEAL cohort were analyzed. Social (interactions with friends, civic participation, social participation, neighborhood trust, social network), cultural (education, cultural participation) and economic (annual income) capital, QoL, SwL, well-being, and personal characteristics were assessed. RESULTS: Compared to people their age, people with dementia reported slightly lower frequency of interactions with friends, social networks and social support, civic and cultural participation, education, and annual income. However, social engagement, cultural participation, and annual income are low among British older adults. Latent profile analysis identified four groups that, based on their levels of social, cultural, and economic capital were named socially and economically privileged (18.0% of participants); financially secure (21.0% of participants); low capital (36.9% of participants); and very low capital (24.1% of participants). Latent growth curve models showed that over time QoL, SwL, and well-being remained largely stable for all groups. Compared to the low capital group, the socially and economically privileged and financially secure groups had higher QoL and well-being whereas the group with very low capital had poorer QoL, SwL, and well-being. CONCLUSIONS: New policies and efforts from the government, philanthropic foundations, the voluntary and primary care sectors are needed to address social, cultural, and economic disadvantage among people with dementia.

Factors associated with anxiety disorder comorbidity.

BACKGROUND: Anxiety and depressive disorders often co-occur and the order of their emergence may be associated with different clinical outcomes. However, minimal research has been conducted on anxiety-anxiety comorbidity. This study examined factors associated with anxiety comorbidity and anxiety-MDD temporal sequence. METHODS: Online, self-report data were collected from the UK-based GLAD and COPING NBR cohorts (N = 38,775). Logistic regression analyses compared differences in sociodemographic, trauma, and clinical factors between single anxiety, anxiety-anxiety comorbidity, anxiety-MDD (major depressive disorder) comorbidity, and MDD-only. Additionally, anxiety-first and MDD-first anxiety-MDD were compared. Differences in familial risk were assessed in those participants with self-reported family history or genotype data. RESULTS: Anxiety-anxiety and anxiety-MDD had higher rates of self-reported anxiety or depressive disorder diagnoses, younger age of onset, and higher recurrence than single anxiety. Anxiety-MDD displayed greater clinical severity/complexity than MDD only. Anxiety-anxiety had more severe current anxiety symptoms, less severe current depressive symptoms, and reduced likelihood of self-reporting an anxiety/depressive disorder diagnosis than anxiety-MDD. Anxiety-first anxiety-MDD had a younger age of onset, more severe anxiety symptoms, and less likelihood of self-reporting a diagnosis than MDD-first. Minimal differences in familial risk were found. LIMITATIONS: Self-report, retrospective measures may introduce recall bias. The familial risk analyses were likely underpowered. CONCLUSIONS: Anxiety-anxiety comorbidity displayed a similarly severe and complex profile of symptoms as anxiety-MDD but distinct features. For anxiety-MDD, first-onset anxiety had an earlier age of onset and greater severity than MDD-first. Anxiety disorders and comorbidity warrant further investigation and attention in research and practice.

Profiles of social, cultural, and economic capital as longitudinal predictors of stress, positive experiences of caring, and depression among spousal carers of people with dementia.

OBJECTIVE: We explored (1) social, cultural, and economic capital in spousal carers of people with dementia; (2) profiles of carers with different levels of capital; (3) whether the identified profiles differ in levels of stress and positive experiences of caring, and likelihood of depression over time. METHODS: Baseline (2014-2016), 12-month, and 24-month follow-up data were analyzed for 984 coresident spousal carers of people with dementia. We assessed social, cultural, and economic capital, stress, positive experiences of caring, depression. RESULTS: On average, carers reported infrequent social and cultural participation. Most carers were not socially isolated, trusted their neighbours, had education at least to age 16, and had an income aligned with the 2014 UK average. We identified four groups of carers with different levels of capital. Although on average stress was low, depression was infrequent, and positive experiences of caring were moderately frequent, the group of carers with lowest capital was the least stressed and reported the most positive experiences of caring over time. Compared to the two groups with better capital, those with poorer capital were more likely to be depressed over time. CONCLUSION: Social, cultural, and economic resources may decrease likelihood of depression, but not stress, in carers of people with dementia.

Patient characteristics associated with retrospectively self-reported treatment outcomes following psychological therapy for anxiety or depressive disorders - a cohort of GLAD study participants.

BACKGROUND: Progress towards stratified care for anxiety and depression will require the identification of new predictors. We collected data on retrospectively self-reported therapeutic outcomes in adults who received psychological therapy in the UK in the past ten years. We aimed to replicate factors associated with traditional treatment outcome measures from the literature. METHODS: Participants were from the Genetic Links to Anxiety and Depression (GLAD) Study, a UK-based volunteer cohort study. We investigated associations between retrospectively self-reported outcomes following therapy, on a five-point scale (global rating of change; GRC) and a range of sociodemographic, clinical and therapy-related factors, using ordinal logistic regression models (n = 2890). RESULTS: Four factors were associated with therapy outcomes (adjusted odds ratios, OR). One sociodemographic factor, having university-level education, was associated with favourable outcomes (OR = 1.37, 95%CI: 1.18, 1.59). Two clinical factors, greater number of reported episodes of illness (OR = 0.95, 95%CI: 0.92, 0.97) and higher levels of personality disorder symptoms (OR = 0.89, 95%CI: 0.87, 0.91), were associated with less favourable outcomes. Finally, reported regular use of additional therapeutic activities was associated with favourable outcomes (OR = 1.39, 95%CI: 1.19, 1.63). There were no statistically significant differences between fully adjusted multivariable and unadjusted univariable odds ratios. CONCLUSION: Therapy outcome data can be collected quickly and inexpensively using retrospectively self-reported measures in large observational cohorts. Retrospectively self-reported therapy outcomes were associated with four factors previously reported in the literature. Similar data collected in larger observational cohorts may enable detection of novel associations with therapy outcomes, to generate new hypotheses, which can be followed up in prospective studies.

High-throughput CRISPRi and CRISPRa technologies in 3D genome regulation for neuropsychiatric diseases.

Advances in genomics have led to the identification of many risk loci with hundreds of genes and thousands of DNA variants associated with neuropsychiatric disorders. A significant barrier to understanding the genetic underpinnings of complex diseases is the lack of functional characterization of risk genes and variants in biological systems relevant to human health and connecting disease-associated variants to pathological phenotypes. Characterizing gene and DNA variant functions requires genetic perturbations followed by molecular and cellular assays of neurobiological phenotypes. However, generating null or mutant alleles is low throughput, making it impossible to characterize disease-associated variants in large quantities efficiently. CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens can be leveraged to dissect the biological consequences of the tested genes and variants in their native context. Nevertheless, testing non-coding variants associated with complex diseases remains non-trivial. In this review, we first discuss the current challenges of interpreting the function of the non-coding genome and approaches to prioritizing disease-associated variants in the context of the 3D epigenome. Second, we provide a brief overview of high-throughput CRISPRi and CRISPRa screening strategies applicable for characterizing non-coding sequences in appropriate biological systems. Lastly, we discuss the promising prospects of using CRISPR-based technologies to dissect DNA sequences associated with neuropsychiatric diseases.

"Living Well" Trajectories Among Family Caregivers of People With Mild-to-Moderate Dementia in the IDEAL Cohort.

OBJECTIVES: Understanding whether and how caregivers' capability to "live well" changes over time, and the factors associated with change, could help target effective caregiver support. METHODS: We analyzed 3 time points (12 months apart) of Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort data from coresident spouse caregivers of community-dwelling individuals who had mild-to-moderate dementia at baseline, using latent growth and growth mixture models. Capability to "live well" was derived from measures of quality of life, well-being, and satisfaction with life. RESULTS: Data from 995 spouse caregivers at Time 1, 780 at Time 2, and 601 at Time 3 were included. The mean "living well" score decreased slightly over time. We identified 3 classes of caregivers: one with higher baseline scores declining slightly over time (Stable; 66.8%), one with low baseline scores remaining stable (Lower Stable; 26.0%), and one with higher baseline scores showing marked decline (Declining; 7.2%). Scores on baseline measures differentiated the Lower Stable, but not the Declining, from the Stable class. Longitudinally, the Declining class was associated with care recipient cognitive decline and increasing hours providing care, as well as caregiver stress and depression. Findings were similar when caregivers with other kin relationships were included. DISCUSSION: The findings indicate the importance of prompt identification of, and support for, caregivers at risk of the declining capability to "live well" and may assist in identifying those caregivers who could benefit most from targeted support.

Schizophrenia Polygenic Risk and Experiences of Childhood Adversity: A Systematic Review and Meta-analysis.

BACKGROUND AND HYPOTHESIS: Schizophrenia has been robustly associated with multiple genetic and environmental risk factors. Childhood adversity is one of the most widely replicated environmental risk factors for schizophrenia, but it is unclear if schizophrenia genetic risk alleles contribute to this association. STUDY DESIGN: In this systematic review and meta-analysis, we assessed the evidence for gene-environment correlation (genes influence likelihood of environmental exposure) between schizophrenia polygenic risk score (PRS) and reported childhood adversity. We also assessed the evidence for a gene-environment interaction (genes influence sensitivity to environmental exposure) in relation to the outcome of schizophrenia and/or psychosis. This study was registered on PROSPERO (CRD42020182812). Following PRISMA guidelines, a search for relevant literature was conducted using Cochrane, MEDLINE, PsycINFO, Web of Science, and Scopus databases until February 2022. All studies that examined the association between schizophrenia PRS and childhood adversity were included. STUDY RESULTS: Seventeen of 650 identified studies met the inclusion criteria and were assessed against the Newcastle-Ottawa Scale for quality. The meta-analysis found evidence for gene-environment correlation between schizophrenia PRS and childhood adversity (r = .02; 95% CI = 0.01, 0.03; P = .001), but the effect was small and therefore likely to explain only a small proportion of the association between childhood adversity and psychosis. The 4 studies that investigated a gene-environment interaction between schizophrenia PRS and childhood adversity in increasing risk of psychosis reported inconsistent results. CONCLUSIONS: These findings suggest that a gene-environment correlation could explain a small proportion of the relationship between reported childhood adversity and psychosis.

Characteristics of people living with undiagnosed dementia: findings from the CFAS Wales study.

BACKGROUND: Many people living with dementia remain undiagnosed, with diagnosis usually occurring long after signs and symptoms are present. A timely diagnosis is important for the wellbeing of the person living with dementia and the family, allowing them to plan and have access to support services sooner. The aim of this study was to identify demographic characteristics and neuropsychiatric symptoms associated with being undiagnosed, which may help clinicians be more aware of signs that could be indicative of early-stage or undetected dementia. METHODS: This cross-sectional study uses data from waves 1 and 2 (two years apart) of the Cognitive Function and Ageing Studies Wales (CFAS Wales). CFAS Wales participants were included who had a study assessment of dementia, as determined by the Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT) algorithm and by expert assessment, and who had had their primary care records checked for a clinical diagnosis of dementia. We identified 19 people with a diagnosis of dementia and 105 people living with undiagnosed dementia, and explored demographic characteristics and the presence or absence of a range of neuropsychiatric symptoms in the undiagnosed population using logistic regression. RESULTS: Findings suggest that people living with dementia who have better cognition, have more years of education, or live in more deprived areas are less likely to have a diagnosis. In terms of neuropsychiatric symptoms, depression and sleep problems were associated with being undiagnosed. Apathy was common across all people living with dementia, but those with a diagnosis were more likely to have severe apathy. CONCLUSIONS: This study has clinical practice implications as the findings may help clinicians be more aware of characteristics and symptoms of people who are undiagnosed or who are at greater risk of remaining undiagnosed, enabling them to be more vigilant in picking up signs of dementia at an earlier stage.

Web-Based Cognitive Testing in Psychiatric Research: Validation and Usability Study.

BACKGROUND: Cognitive impairments are features of many psychiatric disorders and affect functioning. A barrier to cognitive research on psychiatric disorders is the lack of large cross-disorder data sets. However, the collection of cognitive data can be logistically challenging and expensive. Web-based collection may be an alternative; however, little is known about who does and does not complete web-based cognitive assessments for psychiatric research. OBJECTIVE: The aims of this study are to develop a web-based cognitive battery for use in psychiatric research, validate the battery against the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, and compare the characteristics of the participants who chose to take part with those of the individuals who did not participate. METHODS: Tasks were developed by The Many Brains Project and selected to measure the domains specified by the MATRICS initiative. We undertook a cross-validation study of 65 participants with schizophrenia, bipolar disorder, depression, or no history of psychiatric disorders to compare the web-based tasks with the MATRICS Consensus Cognitive Battery. Following validation, we invited participants from 2 large ongoing genetic studies, which recruited participants with psychiatric disorders to complete the battery and evaluated the demographic and clinical characteristics of those who took part. RESULTS: Correlations between web-based and MATRICS tasks ranged between 0.26 and 0.73. Of the 961 participants, 887 (92.3%) completed at least one web-based task, and 644 (67%) completed all tasks, indicating adequate completion rates. Predictors of web-based participation included being female (odds ratio [OR] 1.3, 95% CI 1.07-1.58), ethnicity other than White European (OR 0.66, 95% CI 0.46-0.96), higher levels of education (OR 1.19, 95% CI 1.11-1.29), diagnosis of an eating disorder (OR 2.17, 95% CI 1.17-4) or depression and anxiety (OR 5.12, 95% CI 3.38-7.83), and absence of a diagnosis of schizophrenia (OR 0.59, 95% CI 0.35-0.94). Lower performance on the battery was associated with poorer functioning (B=-1.76, SE 0.26; P<.001). CONCLUSIONS: Our findings offer valuable insights into the advantages and disadvantages of testing cognitive function remotely for mental health research.

Longitudinal Trajectories of Quality of Life Among People With Mild-to-Moderate Dementia: A Latent Growth Model Approach With IDEAL Cohort Study Data.

OBJECTIVES: We aimed to examine change over time in self-rated quality of life (QoL) in people with mild-to-moderate dementia and identify subgroups with distinct QoL trajectories. METHODS: We used data from people with mild-to-moderate dementia followed up at 12 and 24 months in the Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort study (baseline n = 1,537). A latent growth model approach examined mean change over time in QoL, assessed with the QoL-AD scale, and investigated associations of baseline demographic, cognitive, and psychological covariates with the intercept and slope of QoL. We employed growth mixture modeling to identify multiple growth trajectories. RESULTS: Overall mean QoL scores were stable and no associations with change over time were observed. Four classes of QoL trajectories were identified: 2 with higher baseline QoL scores, labeled Stable (74.9%) and Declining (7.6%), and 2 with lower baseline QoL scores, labeled Stable Lower (13.7%) and Improving (3.8%). The Declining class had higher baseline levels of depression and loneliness, and lower levels of self-esteem and optimism, than the Stable class. The Stable Lower class was characterized by disadvantage related to social structure, poor physical health, functional disability, and low psychological well-being. The Improving class was similar to the Stable Lower class but had lower cognitive test scores. DISCUSSION: Understanding individual trajectories can contribute to personalized care planning. Efforts to prevent decline in perceived QoL should primarily target psychological well-being. Efforts to improve QoL for those with poorer QoL should additionally address functional impairment, isolation, and disadvantage related to social structure.

The Use and Costs of Paid and Unpaid Care for People with Dementia: Longitudinal Findings from the IDEAL Cohort.

BACKGROUND: The drivers of costs of care for people with dementia are not well understood and little is known on the costs of care for those with rarer dementias. OBJECTIVE: To characterize use and costs of paid and unpaid care over time in a cohort of people with dementia living in Britain. To explore the relationship between cohort members' demographic and clinical characteristics and service costs. METHODS: We calculated costs of health and social services, unpaid care, and out-of-pocket expenditure for people with mild-to-moderate dementia participating in three waves of the IDEAL cohort (2014-2018). Latent growth curve modelling investigated associations between participants' baseline sociodemographic and diagnostic characteristics and mean weekly service costs. RESULTS: Data were available on use of paid and unpaid care by 1,537 community-dwelling participants with dementia at Wave 1, 1,199 at Wave 2, and 910 at Wave 3. In models of paid service costs, being female was associated with lower baseline costs and living alone was associated with higher baseline costs. Dementia subtype and caregiver status were associated with variations in baseline costs and the rate of change in costs, which was additionally influenced by age. CONCLUSION: Lewy body and Parkinson's disease dementias were associated with higher service costs at the outset, and Lewy body and frontotemporal dementias with more steeply increasing costs overall, than Alzheimer's disease. Planners of dementia services should consider the needs of people with these relatively rare dementia subtypes as they may require more resources than people with more prevalent subtypes.