Shortening the Alzheimer's disease assessment scale cognitive subscale.

BACKGROUND: A short yet reliable cognitive measure is needed that separates treatment and placebo for treatment trials for Alzheimer's disease. Hence, we aimed to shorten the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and test its use as an efficacy measure. METHODS: Secondary data analysis of participant-level data from five pivotal clinical trials of donepezil compared with placebo for Alzheimer's disease (N = 2,198). Across all five trials, cognition was appraised using the original 11-item ADAS-Cog. Statistical analysis consisted of sample characterization, item response theory (IRT) to identify an ADAS-Cog short version, and mixed models for repeated-measures analysis to examine the effect sizes of ADAS-Cog change on the original and short versions in the placebo versus donepezil groups. RESULTS: Based on IRT, a short ADAS-Cog was developed with seven items and two response options. The original and short ADAS-Cog correlated at baseline and at weeks 12 and 24 at 0.7. Effect sizes based on mixed modeling showed that the short and original ADAS-Cog separated placebo and donepezil comparably (ADAS-Cog original ES = 0.33, 95% CI = 0.29, 0.40, ADAS-Cog short ES = 0.25, 95% CI =0.23, 0.34). CONCLUSIONS: IRT identified a short ADAS-cog version that separated donepezil and placebo, suggesting its clinical potential for assessment and treatment monitoring.

Adult Attention-Deficit/Hyperactivity Disorder and the Risk of Dementia.

Importance: Evidence that adult attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk of dementia is scarce and inconsistent, and potential sources of bias are untested. Objective: To examine the association between adult ADHD and the risk of dementia. Design, Setting, and Participants: This prospective national cohort study consisted of 109 218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020. Participants were aged 51 to 70 years in 2003. Statistical analysis was conducted from December 2022 to August 2023. Exposure: Adult ADHD was a time-varying covariate, classified as present from the age of the first diagnosis (using the International Classification of Diseases, Ninth Revision, and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision); otherwise, absent. Main Outcome and Measures: Cox regression models were fitted to quantify the association between adult ADHD and the risk of incident dementia with hazard ratios (HRs) and their 95% CIs unadjusted and in the primary analysis, using inverse probability weights, adjusted for 18 sources of potential confounding. In 14 complementary analyses, subgroup and sensitivity analyses were implemented. Results: At the beginning of the follow-up, the sample of 109 218 participants had a mean (SD) age of 57.7 (5.5) years, 56 474 participants (51.7%) were female, and 52 744 (48.3%) were male. During follow-up, 730 participants (0.7%) received a diagnosis of adult ADHD, and 7726 (7.1%) received a diagnosis of dementia. Dementia occurred among 96 of 730 participants (13.2%) with adult ADHD and 7630 of 108 488 participants (7.0%) without adult ADHD. In the primary analysis, compared with the absence of adult ADHD, the presence of adult ADHD was statistically significantly (P < .001) associated with an increased dementia risk (unadjusted HR, 3.62 [95% CI, 2.92-4.49; P < .001]; adjusted HR, 2.77 [95% CI, 2.11-3.63; P < .001]). Twelve of the 14 complementary analyses did not attenuate the conclusions based on the results of the primary analysis. There was, however, no clear increase in the risk of dementia associated with adult ADHD among those who received psychostimulant medication, and evidence of reverse causation was mild. Conclusions and Relevance: In this cohort study of individuals born between 1933 and 1952 and followed up in old age, adult ADHD was associated with an increased risk of dementia. Policy makers, caregivers, patients, and clinicians may wish to monitor reliably for ADHD in old age.

Is cognition integral to psychopathology? A population-based cohort study.

BACKGROUND: Lower cognitive functioning has been documented across psychiatric disorders and hypothesized to be a core deficit of mental disorders. Situating psychopathology and cognition as part of a unitary construct is therefore important to understanding the etiology of psychiatric disorders. The current study aims to test competing structural models of psychopathology and cognition in a large national cohort of adolescents. METHODS: The analytic sample consisted of 1189 participants aged 16-17 years, screened by the Israeli Draft Board. Psychopathology was assessed using a modified version of the Brief Symptom Inventory, and cognition was assessed based on four standardized test scores ((1) mathematical reasoning, concentration, and concept manipulation; (2) visual-spatial problem-solving skills and nonverbal abstract reasoning; (3) verbal understanding; (4) categorization and verbal abstraction). Confirmatory factor analysis was implemented to compare competing structural models of psychopathology with and without cognition. Sensitivity analyses examined the models in different subpopulations. RESULTS: Confirmatory factor analysis indicated a better model fit of psychopathological symptoms without cognition (RMSEA = 0.037; TLI = 0.991; CFI = 0.992) than with cognition (RMSEA = 0.04-0.042; TLI = 0.987-0.988; CFI = 0.988-0.989). Sensitivity analyses supported the robustness of these results with a single exception. Among participants with low cognitive abilities (N = 139), models that integrated psychopathological symptoms with cognition had a better fit compared to models of psychopathology without cognition. CONCLUSIONS: The current study suggests that cognition and psychopathology are, generally, independent constructs. However, within low cognitive abilities, cognition was integral to the structure of psychopathology. Our results point toward an increased vulnerability to psychopathology in individuals with low cognitive abilities and may provide valuable information for clinicians.

Opioid Exposure and the Risk of Dementia: A National Cohort Study.

OBJECTIVES: To examine the association between prescription opioid use and the risk of dementia in old-age, since existing studies of the association are few, and the evidence is inconsistent. DESIGN: Prospective national cohort study (N = 91,307, aged 60 years and over), without a dementia diagnosis for ten years, followed-up for incident dementia from January 2013 to October 2017. MEASUREMENTS: Opioid exposure was based on opioid purchases classified from Anatomical Therapeutic Chemical Classification system codes (N02A), and classified as exposed if the purchase period covered at least 60 days within a 120-day interval; otherwise, unexposed. SETTING: Healthcare maintenance organization in Israel. RESULTS: During follow-up, 2,849 (3.1%) persons were opioid exposed (mean age 73.94 ± 6.71 years), and 5,298 (5.8 %) persons developed dementia (mean age 78.07 ± 6.54 years). Cox regression models were fitted to quantify the risk of incident dementia with Hazard Ratios (HR) and their associated 95% Confidence Intervals (CI). The opioid exposed group aged 75+ to 80 years were at an increased risk of incident dementia (Adjusted HR = 1.39, 95% CI = 1.01, 1.92, Z-statistic = 2.02, p <0.05) compared to the unexposed. The point-precision estimates were generally similar to the primary analysis across fourteen sensitivity analyses. CONCLUSION: Policymakers, caregivers, patients, and clinicians may wish to consider that opioid exposure aged 75-80 is linked with an increased dementia risk to balance the potential benefits and adverse side effects of opioid use in old age.

Serum folate deficiency and the risks of dementia and all-cause mortality: a national study of old age.

BACKGROUND: The association between serum folate deficiency and the risk of dementia in old age is unclear, perhaps owing to small sample sizes, the competing risk of mortality or reverse causation. OBJECTIVE: To examine the associations between serum folate deficiency and the risks of incident dementia and all-cause mortality in a large national sample of older adults. METHODS: A prospective cohort aged 60-75 years (n=27 188) without pre-existing dementia for at least 10 years, was tested for serum concentrations of folate and followed up for dementia or all-cause mortality. Serum folate deficiency was classified as present (<4.4 ng/mL), otherwise absent. HRs and 95% CIs from competing risks Cox models were fitted to quantify the associations between serum folate deficiency and the risks of dementia and all-cause mortality. To examine reverse causation, the analysis was stratified by duration of follow-up. FINDINGS: The presence compared with the absence of serum folate deficiency was associated with higher risks of dementia (HR=1.68; 95% CI 1.32 to 2.13; p<0.001) and all-cause mortality (HR=2.98; 95% CI 2.52 to 3.52; p<0.001). Evidence for reverse causation were moderate for dementia and mild for all-cause mortality. CONCLUSIONS: Serum concentrations of folate may function as a biomarker used to identify those at risk of dementia and mortality; however, reverse causation is likely. Further research is needed to examine the role of serum folate deficiency in dementia aetiology. CLINICAL IMPLICATIONS: Serum folate deficiency in older adults requires monitoring and treatment for preventative measures and/or as part of implemented therapeutic strategies.

Gender differences in quality of life and the course of schizophrenia: national study.

BACKGROUND: Evidence from various sources suggests that females with schizophrenia tend to report lower quality of life than males with schizophrenia despite having a less severe course of the disorder. However, studies have not examined this directly. AIMS: To examine gender differences in the association between quality of life and the risk of subsequent psychiatric hospital admissions in a national sample with schizophrenia. METHOD: The sample consisted of 989 (60.90%) males and 635 (39.10%) females with an ICD-10 diagnosis of schizophrenia. Quality of life was assessed and scored using the Manchester Short Assessment of Quality of Life. The course of schizophrenia was assessed from the number of psychiatric hospital admissions. Participants completed the quality of life assessment and were then followed up for 18-months for subsequent psychiatric admissions. Hazard ratios (HR) from Cox proportional hazards regression models were estimated unadjusted and adjusted for covariates (age at schizophrenia onset and birth year). Analyses were computed for males and females separately, as well as for the entire cohort. RESULTS: A subsample of 93 males and 55 females was admitted to a psychiatric hospital during follow-up. Higher quality of life scores were significantly (P < 0.05) associated with a reduced risk of subsequent admissions among males (unadjusted: HR = 0.96, 95% CI 0.93-0.99; adjusted HR = 0.96, 95% CI 0.93-0.99) but not among females (unadjusted: HR = 0.97, 95% CI 0.93-1.02; adjusted HR = 0.97, 95% CI 0.93-1.02). CONCLUSIONS: Quality of life in schizophrenia is a gender-specific construct and should be considered as such in clinical practice and future research.

Cognitive impairment networks in Alzheimer's disease: Analysis of three double-blind randomized, placebo-controlled, clinical trials of donepezil.

Psychometric network analysis is an alternative theoretically-driven analytic approach that has the potential to conceptualize cognitive impairment in Alzheimer's disease differently than was previously assumed and consequently detect unknown treatment effects. Based on individual participant data, extracted from three double-blind, randomized placebo-controlled clinical trials, psychometric networks were computed on observed Alzheimer's Disease Assessment Scale Cognitive Subscale scores at baseline (N=1,554) and on predicted change scores at 24 weeks of follow-up for participants who received donepezil (N=797) or placebo (N=484). A novel conceptualization of cognitive impairment in Alzheimer's disease was displayed through the baseline network, that had 90% (n=27) positive statistically significant (p<0.05) associations, and a most central aspect of ideational praxis. Following 24 weeks, treatment effects emerged via the differences between the change score networks. The donepezil network had more statistically significant (p<0.05) positive associations and a higher global strength (n=15; S=1.22; p=0.03), than the placebo network (n=8; S=0.57). This suggests that for those who were treated with donepezil compared with placebo, cognition is a more unified construct. The main aspects of change in cognitive impairment were comprehension of spoken language for the donepezil network and spoken language ability for the placebo network. Comprehension of spoken language apears to be most sensitive to psychopharmaceutical interventions and should therefore be closely monitored. Overall, our psychometric network analysis presents a new conceptualization of cognitive impairment in Alzheimer's disease, points to previously unknown treatment effects and highlights well-defined aspects of cognitive impairment  that may translate into future treatment targets.

Capturing adolescents in need of psychiatric care with psychopathological symptoms: A population-based cohort study.

BACKGROUND: The current study aims to overcome past methodological limitations and capture adolescents in need of psychiatric care with psychopathological symptoms in a cohort with unrestricted access to mental health professionals. METHODS: The study source population consisted of a random sample of adolescents aged 16-17 years (N=1,369) assessed by the Israeli Draft Board. An adapted version of the Brief Symptom Inventory was used to identify clinically relevant psychopathological symptoms with scores categorized as severe if they were in the top 10th percentile of symptoms, otherwise not severe. An independent interview with a subsequent referral to a mental health professional was used to categorize adolescents in need of psychiatric care. To examine the association between severe psychopathological symptoms and the need for psychiatric care, logistic regression models were fitted unadjusted and adjusted for age, sex, and intellectual assessment scores. Adjusted classification measures were estimated to examine the utility of severe psychopathological symptoms for clinical prediction of need for psychiatric care. RESULTS: Information on 1,283 adolescents was available in the final analytic sample. Logistic regression modeling showed a statistically significant (p<0.001) association between self-reported severe psychopathological symptoms and the need for psychiatric care (OR adjusted: 4.38; 95% CI: 3.55-5.40). Severe psychopathological symptoms had a classification accuracy of 83% (CI: 81%-85%). CONCLUSIONS: Severe psychopathological symptoms, although accounting for a fair proportion of treatment seeking, would perhaps be better useful for classification purposes alongside other variables rather than in isolation.

Risk of dementia and death in very-late-onset schizophrenia-like psychosis: A national cohort study.

Knowledge is limited regarding the risks of death and dementia in very-late onset schizophrenia-like psychosis (VLOS). This study aims to scrutinize the associations between VLOS with the risks of death and dementia. Based on a prospective Israeli cohort study with national coverage, 94,120 persons without dementia or schizophrenia diagnoses aged 60 to 90 in 2012 were followed-up for the risks of dementia or death from 2013 to 2017. VLOS was classified as present from the age of the first ICD-9 diagnosis during follow-up, otherwise as absent. Hazard ratios (HR) with confidence intervals (95% CI) were computed with survival models to quantify the associations between VLOS and the risks of death and dementia, without and with adjustment for confounding. Nine sensitivity analyses were computed to examine the robustness of the results. The group with VLOS, compared to the group without, had higher death (n = 61, 18.5% vs. n = 7028, 7.5%, respectively) and dementia (n = 64, 19.5% vs. n = 5962, 6.4%, respectively) rates. In the primary analysis, the group with VLOS compared to the group without had increased risks of death (unadjusted HR = 3.10, 95% CI = 2.36, 4.06, P < .001; adjusted HR = 2.89, 95% CI = 2.15, 3.89; P < .001) and dementia (unadjusted HR = 3.81, 95% CI = 2.90, 4.99, P < .001; adjusted HR = 2.67, 95% CI = 1.82, 3.91; P < .001). The results remained statistically significant (P < .05) in all sensitivity analyses, including among persons without antipsychotic medication. The results may support notions of increased dementia risk and accelerated aging in VLOS, or that VLOS is a prodromal state of dementia.

Network analysis of the structure and change in the mini-mental state examination: a nationally representative sample.

PURPOSE: The structure of the mini-mental state examination (MMSE) is inconsistent across factor analytic studies, and yet to be examined based on network analysis. The current study aims to identify the (I) cross-sectional network structure and (II) longitudinal network changes of the MMSE. METHODS: The MMSE was administered to a nationally representative sample of older adults (age 50 and over) in Ireland twice over 4 years (2012-2013: N = 7207; 2016: N = 5715). Psychometric network analysis was computed at each time point to identify structure, strength and magnitude of the network associations. Item clustering was examined, and modularity scores were computed to measure the overall strength of clustering. Centrality indices were used to identify the main aspects of the MMSE. Longitudinal differences between the networks were examined. RESULTS: Cross-sectionally, the MMSE network structure clustered into a single community (modularity score = 0) with orientation items identified as most central. Longitudinally, the MMSE was time invariant regarding structure, centrality and magnitude of the positive associations between the items. The average magnitude of the negative associations increased over time[(t(65.15) = 3.78, p < 0.001; time 1: M = - 0.59, SD = 0.58 time 2: M = - 1.65, SD = 1.97] as did their percentage. CONCLUSION: Network analysis of the MMSE showed that the measure consisted of a single entity of cognitive functioning irrespective of time. Orientation items were repeatedly identified as most central. Longitudinal changes of the network were evident in increased negative associations between selected cognitive components after 4 years of follow-up. These changes may be explained by neuro-cognitive compensation processes.

Exposure to Antidepressant Medication and the Risk of Incident Dementia.

OBJECTIVE: To test competing hypotheses that monotherapeutic antidepressant exposure is associated with an increased versus a decreased risk of dementia. METHODS: A prospective national matched cohort study from Israel (N = 71,515) without dementia (2002-2012) aged 60 and over were followed up for incident dementia from May 2013 to October 2017. Exposure to antidepressant monotherapy was classified with Anatomical Therapeutic Chemical Codes (N06A) from January 1, 2013 to December 31, 2016. The association between antidepressant monotherapy and the risk of incident dementia was quantified with hazard ratios (HR) and their 95% confidence intervals (CI) obtained from Cox regression models unadjusted and adjusted for 42 covariates. The robustness of the results was tested with 24 sensitivity analyses: 19 analyses restricted to subsamples with plausible differential dementia risks (e.g., anxiety and depression), and 5 analyses across and within antidepressant drug classes. RESULTS: In the primary analysis, the risk of incident dementia for the group exposed to antidepressant monotherapy compared to the group unexposed to antidepressants was estimated with an unadjusted HR = 4.09 (df = 1, 95% Wald CI = 3.64, 4.60) and an adjusted HR = 3.43 (df = 1, 95% Wald CI = 3.04, 3.88). Across the 24 sensitivity analyses the estimated adjusted HR values ranged from 1.99 to 5.47. CONCLUSION: In this study, monotherapeutic antidepressant exposure in old age was associated with increased incident dementia. Clinicians, caregivers, and patients may wish to consider this potentially negative consequence of antidepressant exposure and aim to balance the costs and benefits of treatment.

Age of onset and quality of life among males and females with schizophrenia: A national study.

BACKGROUND: Age of onset is considered central to understanding the course of schizophrenia, yet little is known regarding its association with quality of life in general, and specifically among males and females. AIMS: To examine the association between the age of schizophrenia onset and quality of life, in general, and among males and females, using data from a national sample and competing statistical models. METHODS: Participants with a diagnosis of schizophrenia (N = 1624) completed the Manchester Short Assessment of Quality of Life (MSA-QoL) and were rated on a parallel measure by their professional caregivers (N = 578). Multiple regression analysis models were computed for self-appraised quality of life, and mixed models with random intercepts were used for caregivers. Six competing models were tested for parsimony for each rating source. Three models without adjustment and three models adjusted for confounding variables. Sensitivity analyses were conducted for males and females separately. RESULTS: Age of onset was statistically significantly (P < .05) negatively associated with self-appraised and caregiver-appraised quality of life on aggregate and among females. Among males, a significant (P < .01) quadratic effect of onset age on self-appraised quality of life demonstrated a negative association up to onset age of 36.67 years, after which the association was positive. CONCLUSIONS: An earlier age of onset is associated with a better quality of life in schizophrenia which is tentatively explained by social decline. Specific trends in psychiatric symptom severity may account for this association among females while social advantages may account for the particular results found among males.

Quality of life disparities between persons with schizophrenia and their professional caregivers: Network analysis in a National Cohort.

BACKGROUND: Disparities between mental health patients and their professional caregivers in quality of life appraisals have been identified, however, the structure that such disparities assume is unknown. AIMS: To examine the network structure of quality of life appraisals and disparities using network analysis. METHODS: Participants were 1639 persons with schizophrenia using psychiatric rehabilitation services and their primary professional caregivers (N=582). Quality of life for persons with schizophrenia was measured based on an abbreviated version of the Manchester Short Assessment of Quality of Life. Appraisals were made self-reported and by professional caregivers. Disparities scores between the aforementioned were computed. Network analysis was performed on all quality of life appraisals. Sensitivity analyses were conducted. RESULTS: The self-appraised network significantly (p<0.05) differed by network strength compared to the caregiver-appraised network. Self-appraised network communities (clusters of quality of life items) were health conditions and socioeconomic system, whereas caregiver-appraised network communities were social activities, and combined socioeconomic and health conditions. Strength centrality was highest for self-appraised social status and for caregiver-appraised residential status (Z=1.63, Z=1.12, respectively). The disparity scores network clustered into two communities: social relations and combined financial and health conditions. The most central appraisal disparities were in social status. CONCLUSIONS: Quality of life differed when self-appraised by persons with schizophrenia compared to when appraised by their professional caregivers, yet the salient role of social relations was shared. The latter may be an initial focus of discussion by persons with schizophrenia and their caregivers.