The relationship of history of psychiatric and substance use disorders on risk of dementia among racial and ethnic groups in the United States.

Introduction: Dementia is characterized by significant declines in cognitive, physical, social, and behavioral functioning, and includes multiple subtypes that differ in etiology. There is limited evidence of the influence of psychiatric and substance use history on the risk of dementia subtypes among older underrepresented racial/ethnic minorities in the United States. Our study explored the role of psychiatric and substance use history on the risk of etiology-specific dementias: Alzheimer's disease (AD) and vascular dementia (VaD), in the context of a racially and ethnically diverse sample based on national data. Methods: We conducted secondary data analyses based on the National Alzheimer's Coordinating Center Uniform Data Set (N = 17,592) which is comprised a large, racially, and ethnically diverse cohort of adult research participants in the network of US Alzheimer Disease Research Centers (ADRCs). From 2005 to 2019, participants were assessed for history of five psychiatric and substance use disorders (depression, traumatic brain injury, other psychiatric disorders, alcohol use, and other substance use). Cox proportional hazard models were used to examine the influence of psychiatric and substance use history on the risk of AD and VaD subtypes, and the interactions between psychiatric and substance use history and race/ethnicity with adjustment for demographic and health-related factors. Results: In addition to other substance use, having any one type of psychiatric and substance use history increased the risk of developing AD by 22-51% and VaD by 22-53%. The risk of other psychiatric disorders on AD and VaD risk varied by race/ethnicity. For non-Hispanic White people, history of other psychiatric disorders increased AD risk by 27%, and VaD risk by 116%. For African Americans, AD risk increased by 28% and VaD risk increased by 108% when other psychiatric disorder history was present. Conclusion: The findings indicate that having psychiatric and substance use history increases the risk of developing AD and VaD in later life. Preventing the onset and recurrence of such disorders may prevent or delay the onset of AD and VaD dementia subtypes. Prevention efforts should pay particular attention to non-Hispanic White and African American older adults who have history of other psychiatric disorders.Future research should address diagnostic shortcomings in the measurement of such disorders in ADRCs, especially with regard to diverse racial and ethnic groups.

Reliability of the NACC Telephone-administered Neuropsychological Battery (T-cog) and Montreal Cognitive Assessment for participants in the USC ADRC.

Introduction: Restrictions during the COVID-19 pandemic necessitated remote administration of neuropsychological testing. We assessed the test-retest reliability for a telephone-administered cognitive battery, recommended for use in the National Institute on Aging Alzheimer's Disease Research Center (ADRC). Methods: 64 participants in the University of Southern California ADRC clinical core underwent repeat telephone evaluation using the T-cog Neuropsychological Battery. Reliability was measured by intraclass correlation coefficient (ICC) for continuous variables and weighted Kappa coefficient for categorical variables. Mean scores for Montreal Cognitive Assessment (MoCA) total and Craft Story 21 Immediate and Delayed Recall were compared using paired t tests. Results: Mean age was 74.8 (8.3 standard deviation); 73.4% were female. ICCs ranged from 0.52 to 0.84, indicating moderate test-retest reliability except for number span backward, which showed poor reliability. Weighted Kappa for MoCA items ranged from -0.016 to 0.734; however, relatively good observed agreement was seen across all items (70.3% to 98.4%). Although MoCA total scores did not significantly change, Craft Story 21 Immediate and Delayed Recall mean scores increased between first and second administrations (P < 0.0001). Discussion: Test-retest reliability for the T-cog Neuropsychological Battery is adequate. The variation seen in testing is similar to results seen from face-to-face testing, with Craft Story 21 recall showing modest and expected practice effects. Highlights: Moderate test-retest reliability is seen in most measures of the National Alzheimer's Coordinating Center Neuropsychological Test Battery and the Montreal Cognitive Assessment (MoCA).Intraclass correlation coefficients ranged from 0.52 to 0.84, except for number Span backward.Weighted Kappa for MoCA items varied, but good observed agreement was seen.MoCA total mean score did not change significantly between administrations.Craft Story 21 Immediate and Delayed Recall means increased on repeat testing (P < 0.0001).

The need to show minimum clinically important differences in Alzheimer's disease trials.

Deciding on the smallest change in an outcome that constitutes a clinically meaningful treatment effect (ie, the minimum clinically important difference [MCID]) is fundamental to interpreting clinical trial outcomes, making clinical decisions, and designing studies with sufficient statistical power to detect any such effect. There is no consensus on MCIDs for outcomes in Alzheimer's disease trials, but the US Food and Drug Administration's consideration of aducanumab clinical trials data has exposed the uncertainty of the clinical meaning of statistically significant but small improvements. Although MCIDs for outcomes, including Clinical Dementia Rating-Sum of Boxes and Mini-Mental State Examination in Alzheimer's disease have been reported, the Food and Drug Administration's guidelines, drafted in 1989 to facilitate regulatory approval of substantially effective antidementia drugs, do not specify quantified minimum differences. Although it is important that regulatory requirements encourage drug development and approval, without MCIDs, sponsors are motivated to power trials to detect statistical significance for only small and potentially inconsequential effects on clinical outcomes. MCIDs benefit patients, family members, caregivers, and health-care systems and should be incorporated into clinical trials and drug development guidance for Alzheimer's disease.

A randomized clinical trial to evaluate home-based assessment of people over 75 years old.

INTRODUCTION: There is an unmet need for effective methods for conducting dementia prevention trials. METHODS: Home-based assessment study compared feasibility and efficiency, ability to capture change over time using in-home instruments, and ability to predict cognitive conversion using predefined triggers in a randomized clinical trial in (1) mail-in questionnaire/live telephone interviews, (2) automated telephone/interactive voice recognition, and (3) internet-based computer Kiosk technologies. Primary endpoint was defined as cognitive conversion. RESULTS: Analysis followed a modified intent-to-treat principle. Dropout rates were low and similar across technologies but participants in Kiosk were more likely to dropout earlier. Staff resources needed were higher in Kiosk. In-home instruments distinguished conversion and stable groups. Cognitively stable group showed improvement in cognitive measures. Triggering was associated with higher likelihood of conversion but statistically significant only in mail-in questionnaire/live telephone interviews. DISCUSSION: Relatively low efficiency of internet-based assessment compared with testing by live-assessors has implications for internet-based recruitment and assessment efforts currently proposed for diverse populations.

Evaluation of Medicare Claims Data as a Tool to Identify Dementia.

BACKGROUND: Medicare claims record linkage has been used to identify diagnosed dementia cases in order to estimate dementia prevalence and cost of care. Claims records in the 1990 s and early 2000 s have been found to provide 85% - ∼90% sensitivity and specificity. OBJECTIVE: Considering that dementia awareness has improved over time, we sought to examine sensitivity and specificity of more recent Medicare claims records against a standard criterion, clinical diagnosis of dementia. METHODS: For a sample of patients evaluated at the University of Southern California Alzheimer Disease Research Center (ADRC), we performed database linkage with Medicare claims files for a six-year period, 2007-2012. We used clinical diagnosis at the ADRC as the criterion diagnosis in order to calculate sensitivity and specificity. RESULTS: Medicare claims correctly identified 85% of dementia patients and 77% of individuals with normal cognition. About half of patients clinically diagnosed with mild cognitive impairment had dementia diagnoses in Medicare claims. Misclassified dementia patients (i.e., missed diagnosis by Medicare claims) had more favorable Mini-Mental State Examination and Clinical Dementia Rating scores and were less likely to present behavioral symptoms than correctly-classified dementia patients. CONCLUSIONS: Database linkage to Medicare claims records is an efficient and reasonably accurate tool to identify dementia cases in a population-based cohort. However, possibilities of obtaining biased results due to misclassification of dementia status need to be carefully considered to use Medicare claims diagnosis for etiologic research studies. Additional confirmation of dementia diagnosis may also be considered. A larger study is warranted to confirm our findings.

Practice effects due to serial cognitive assessment: Implications for preclinical Alzheimer's disease randomized controlled trials.

INTRODUCTION: Practice effects are characteristic of nearly all standard cognitive tasks when repeated during serial assessments and are frequently important confounders in clinical trials. METHODS: We summarize evidence that gains in neuropsychological test performance scores associated with practice effects occur as artifactual changes associated with serial testing within clinical trials. We identify and emphasize such gains in older, non-cognitively impaired individuals and estimate an effect size of 0.25 for composite cognitive measures in older populations assessed three times in a 6- to 12-month period. RESULTS: We identified three complementary approaches that can be used to attenuate practice effects: (1) massed practice in a prebaseline period to reduce task familiarity effects; (2) tests designed to reduce practice-related gains so that item-specific driven improvements are minimized by using tasks that minimize strategy and/or maximize interitem interference; and (3) well-matched alternate forms. DISCUSSION: We have drawn attention to and increased awareness of practice effect-related gains that could result in type 1 or type 2 errors in trials. Successfully managing practice effects will eliminate a large source of error and reduce the likelihood of misinterpretation of clinical trials outcomes.

Is sertraline treatment or depression remission in depressed Alzheimer patients associated with improved caregiver well being? Depression in Alzheimer's Disease Study 2.

OBJECTIVE: We wanted to assess if sertraline treatment (versus placebo) or remission of depression at 12 weeks (versus nonremission) in Alzheimer patients is associated with improved caregiver well being. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of sertraline for the treatment of depression in individuals with Alzheimer disease in five clinical research sites across the United States. Participants were caregivers of patients enrolled in the Depression in Alzheimer's Disease Study 2 (N = 131). All caregivers received standardized psychosocial support throughout the study. Caregiver outcome measures included depression (Beck Depression Inventory), distress (Neuropsychiatric Inventory), burden (Zarit Burden Interview), and quality of life (Medical Outcomes Study Short Form Health Survey). RESULTS: Fifty-nine percent of caregivers were spouses, 63.4% were women, and 64.1% were white. Caregivers of patients in both treatment groups had significant reductions in distress scores over the 24-week study period, but there was not a greater benefit for caregivers of patients taking sertraline. However, caregivers of patients whose depression was in remission at week 12 had greater declines in distress scores over the 24 weeks than caregivers of patients whose depression did not remit by week 12. CONCLUSION: Patient treatment with sertraline was not associated with significantly greater reductions in caregiver distress than placebo treatment. Distress but not level of depression or burden lessened for all caregivers regardless of remission status and even more so for those who cared for patients whose depression remitted. Results imply an interrelationship between caregiver distress and patient psychiatric outcomes.

Caregiver burden, health utilities, and institutional service use in Alzheimer's disease.

OBJECTIVE: This study examined the moderating effect of caregiver burden on the relationship between the health status of Alzheimer's disease (AD) patients and their use of institutional services (i.e., hospitalization, nursing home, and residential care). METHODS: Data were obtained at baseline and at 3, 6, and 9 months following study entry on 421 community-dwelling patients with AD in the Clinical Antipsychotic Trials of Intervention Effectiveness for AD. The outcome variable includes use of any institutional services. Logistic regression was employed to estimate the interaction between Health Utility Index Mark III score (a general health status measure) and four concurrent caregiver burden measures at outcome. Marginal effects were calculated and plotted using random effects models for observations at multiple time points per individual. Average effects were calculated across all observations using models without random effects. RESULTS: Random effects results suggest that caregiver burden weakens the inverse relationship between health utilities and institutional service use, leading to greater likelihood of institutional use than would be expected at a given level of health. This is indicated by positive and significant signs on the Health Utility Index Mark III*caregiver burden interaction when burden is measured using the Caregiver Distress Scale, Beck Depression Inventory, and Caregiver Assessment Survey (all p < 0.05). It is reinforced by positive and significant average effects deriving from Caregiver Distress and Beck Depression Inventory models without random effects (both p < 0.10). Results derived from the Burden Interview Scale, although positive, were non-significant and weak by comparison. CONCLUSION: Caregiver support interventions should be offered to individuals caring for less-advanced AD patients. Otherwise, healthy patients may be at increased risk for institutionalization when caregivers experience high levels of burden.

Effect of second-generation antipsychotics on caregiver burden in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) imposes a severe burden upon patients and their caregivers. Severity of psychiatric symptoms and behavioral disturbances is an important determinant of caregivers' experience of burden. These symptoms may be improved with atypical antipsychotic treatment. OBJECTIVE: Data from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) trial were used to evaluate the effect of atypical antipsychotics versus placebo on the experiences of caregivers of outpatients with AD. METHOD: We compared the effect of atypical antipsychotic drugs (olanzapine, risperidone, or quetiapine-considered together as a group) versus placebo on the experiences of caregivers of AD outpatients (diagnosed according to DSM-IV-TR). We also evaluated whether improvement in patients' psychiatric and behavioral symptoms mediated the relationship between drug treatment and caregiver burden. The CATIE-AD trial, conducted from April 2001 through November 2004, included outpatients (mean age = 77.9 years [SD = 7.5 years]) in usual care settings and assessed treatment effectiveness over a 9-month period at 42 US sites. In a set of secondary analyses, data from CATIE-AD participants who had at least 1 postbaseline outcome assessment and data from their caregivers were examined in an intention-to-treat (ITT) analysis (N = 361). A phase 1-only analysis was conducted including only observations while patients were receiving the initially randomized drug (N = 153). The Burden Interview, the Beck Depression Inventory, and the Neuropsychiatric Inventory (NPI) Caregiver Distress Scale were used to evaluate caregiver burden. RESULTS: In both ITT and phase 1-only analyses, caregivers of patients treated with second-generation antipsychotics scored significantly lower than caregivers of patients receiving placebo on both the Burden Interview (P = .0090) and the NPI Caregiver Distress Scale (P = .0209). These differences appeared to have been mediated by lower levels of agitation, hostility, and psychotic distortions. CONCLUSION: In AD patients with symptoms of psychosis, agitation, or aggressive behavior, medications can have a small but significant impact on caregiver burden.

Anti-aß therapeutics in Alzheimer's disease: the need for a paradigm shift.

Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid ß-peptide (Aß) production, aggregation, or accumulation. Translational models suggest that anti-Aß therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti-Aß therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective. The lack of alignment between human clinical studies and preclinical studies, together with predictions about optimal trial design based on our understanding of the initiating role of Aß aggregates in AD, has created a treatment versus prevention dilemma. In this perspective, we discuss why it is imperative to resolve this dilemma and suggest ways for moving forward in the hopes of enhancing the development of truly effective AD therapeutics.

Adding delayed recall to the Alzheimer Disease Assessment Scale is useful in studies of mild cognitive impairment but not Alzheimer disease.

OBJECTIVE: To determine if the addition of delayed recall (DR) assessment adds sensitivity to the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog) in clinical trials in mild cognitive impairment (MCI) and Alzheimer Disease (AD). BACKGROUND: Memory, particularly DR, is the most sensitive test for early detection of AD and MCI. However, it is not clear that assessment of DR adds benefit for measuring change over time after a diagnosis is made or in clinical trials. The ADAS-cog is the most commonly used tool to assess treatment efficacy in AD clinical trials. In an attempt to improve sensitivity to change, assessment of DR after the 3-trial, 10-word list was added to the standard 11-item ADAS-cog. We examined the added value of the DR in participants with MCI and AD followed for at least 1 year. DESIGN/METHODS: Data from 111 subjects with AD and 259 subjects with MCI who were randomly assigned to the placebo arm of 2 clinical trials were included. Participants with AD had Mini-Mental State Examination scores of 13 to 27 and those with MCI had 24 to 30. We calculated the ADAS-cog11 score based on the original 11 items (range: best to worse, 0 to 70), the DR item score (range: 0 to 10 words not recalled), and the ADAS-cog12 (range: 0 to 80). We assessed the rate of missing items for DR over time, the change scores, the association between scores and baseline performance, and used longitudinal mixed effects regression models to examine the rate of change. RESULTS: At baseline AD subjects were near floor on DR (8.93 ± 1.6 SD) and showed little change over 1 year (0.12 ± 1.34); the MCI subjects baseline DR was 6.2 ± 2.2 with 1-year change of 0.20±1.7. We compared standardized change (change/SD) for ADAS-cog11, and 12 in MCI and found a 10% improvement with ADAS-cog12; there was no improvement in the AD group. In a subset of MCI and AD cases with matching Mini-Mental State Examination (23 to 27), the ADAS-cog12 provided an 18% improvement in standardized change in MCI subjects, with no benefit in the AD cohort, primarily owing to increased variance. CONCLUSIONS/RELEVANCE: The addition of DR to the ADAS-cog score increased the ability to detect change in subjects with MCI over 1 year compared with the ADAS-cog11 but increased the variance in subjects with AD, even in those with mild impairment These findings speak to the need to tailor outcome measures to the specific study population and diagnosis for maximal efficiency and economy when conducting clinical trials.

Caregiver burden in Alzheimer disease: cross-sectional and longitudinal patient correlates.

OBJECTIVES: Alzheimer disease (AD) imposes a severe burden on patients and their caregivers. Although there is substantial evidence of the adverse impact of burden, considerably less is known about its specific correlates and potential causes. DESIGN: The authors use data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)-AD study to examine the relationship of burden and depression among AD caregivers to patient and caregiver sociodemographic characteristics, patients' cognitive status, psychiatric and behavioral symptoms, functional abilities, quality of life, and intensity of care provided by caregivers. SETTING: CATIE-AD included outpatients in usual care settings and assessed treatment outcomes during 9 months. PARTICIPANTS: Data were examined from 421 ambulatory outpatients with a diagnosis of dementia of the Alzheimer type or probable AD with agitation or psychosis. MEASURES: The Burden Interview, the Beck Depression Inventory, and the Caregiver Distress Scale were used to evaluate caregiver burden. RESULTS: More severe psychiatric and behavioral problems and decreased patient quality of life, as well as lower functional capability were significantly associated with higher levels of burden and depression among caregivers at baseline. Six-month changes showed that decreased symptoms and improved quality of life were associated with decreased burden and accounted for most of the explained variance in change in burden measures. CONCLUSION: Severity of psychiatric symptoms, behavioral disturbances, and patients' quality of life are the main correlates of caregivers' experience burden. Psychosocial and pharmacologic interventions targeting these two aspects of the disorder are likely to not only alleviate patient suffering but also promote caregiver well-being.

Caregiver burden, health utilities, and institutional service costs among community-dwelling patients with Alzheimer disease.

This study examined the moderating effect of caregiver burden on the relationship between patients' health status and institutional costs in Alzheimer disease (AD). Data were obtained on whether 421 community-dwelling patients with AD in the CATIE-AD trial received institutional services in the month preceding baseline and at 3-month, 6-month, and 9-month follow-up. All participants had a caregiver who lived with or visited them regularly. Outcome variables include hospital, nursing home, residential, and combined institutional costs. Mixed models were employed to estimate the interaction of Health Utility Index (HUI)-III scores (a health status measure) and 5 measures of caregiver burden. Wherever significant, results indicate that greater caregiver burden weakens the inverse relationship between health utilities and institutional costs, leading to greater costs than would be expected at a given level of health. Altogether 45.0% of the models (9/20) showed this effect (positive coefficient on the burden-HUI interaction term). Interventions to support caregivers should be based on caregiver burden, regardless of care recipient health status, for even seemingly manageable patients may be at heightened risk for institutionalization if caregivers experience sufficiently high levels of burden.

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

Assessing the relationship between health utilities, quality of life, and health services use in Alzheimer's disease.

OBJECTIVES: To examine the relationship between use of multiple health services and health utilities, quality of life and other factors in Alzheimer's disease (AD). DESIGN: Data were obtained via caregiver proxy at baseline and 3- 6- and 9-months post-random assignment among 421 community-dwelling AD patients participating in the CATIE-AD trial of anti-psychotic medications. Service use includes both institutional and outpatient services. Correlates include the AD-Related Quality of Life Scale (ADRQoL), Health Utilities Index (HUI)-III, Neuropsychiatric Inventory, Mini Mental Status Examination, and AD-Cooperative Study Activities of Daily Living Scale. Chi squared tests, t-tests and logistic regression (using general estimating equations) were used to examine the correlates of service use. RESULTS: Three quarters (74.2%) used at least one service each month. Average monthly utilization rates for specific service types were: 4.5%, inpatient hospital; 5.6%, nursing home; 3.9%, residential care; 44.0%, AD-related outpatient; 9.4%, mental health outpatient; and 45.5%, medical-surgical outpatient. The likelihood of using any service was higher among older patients [Odds Ratio (OR) = 1.03] and non-Hispanic Whites (OR = 1.61). Each 0.10 increment on the Health Utilities Index (HUI)-III was associated with a 7.0% decrease in the odds of using one or more service (OR = 0.93). The odds of using outpatient and institutional services were 6.0% and 10.0% lower, respectively, for each 0.10 increment on the HUI-III (OR = 0.94, OR = 0.90). The AD-Related Quality of Life Scale proved significantly related to outpatient medical-surgical services only (OR = 1.01). CONCLUSION: Findings suggest that the HUI-III could be combined with other known correlates of service use to inform population planning associated with AD.

Psychometric comparison of computerized and standard administration of the neurocognitive assessment instruments selected by the CATIE and MATRICS consortia among patients with schizophrenia.

UNLABELLED: Neurocognitive assessment is an essential component for clinical trials of candidate "cognitive-enhancing" treatments for schizophrenia. However, manual administration of large, paper-based, neurocognitive batteries is often inefficient, error-prone, and inconsistent across multiple sites. Existing computerized testing systems are also limited both in the assessment instruments available and in the range of impairments that can be accommodated with the subject sitting alone at a single display. Therefore, a dual-display computerized testing system was developed, with funding from the National Institute of Mental Health (NIMH), that integrates (rather than replaces) the examiner for computerized administration of standard neurocognitive assessment batteries. PURPOSE: To compare standard administration versions (SAVs) of tests selected by the NIMH-sponsored CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) and MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) consortia, with structurally- and functionally-equivalent, computerized administration versions (CAVs). METHOD: 116 outpatients with schizophrenia received both the SAVs and CAVs within one week and again, approximately 30 days later. RESULTS: Intraclass Correlation Coefficient (ICC) comparisons between SAVs and CAVs yielded highly significant measures of absolute agreement for all tests, ranging 0.61-0.95. ICCs for test-retest reliability, ranging 0.56-0.94 for SAVs and 0.59-0.98 for CAVs, were also highly significant for both batteries, though significantly higher for CAVs overall. CONCLUSIONS: The CAVs of the neurocognitive assessment instruments selected by the CATIE and MATRICS consortia are substantially equivalent to antecedent SAVs. Importantly, the increased reliability afforded by computerization highlight the potential for increasing power, thereby decreasing sample size requirements, for clinical evaluations of putative "cognitive-enhancing" treatments.