Objectives

Physical activity may reduce the risk of cognitive decline in the elderly, but its effects among the oldest-old (i.e., those aged 85 years and older) are not well known. Our study assessed the association between very late-life physical activity and 5-year risk of mild cognitive impairment (MCI) or dementia and neuropsychological test performance among oldest-old women.

Methods

This prospective study was conducted at three sites. Participants included 1,249 women (mean [standard deviation] age: 83.3 [2.8] years). Baseline physical activity was measured by self-reported blocks walked per week and analyzed according to tertile. Five years later, surviving participants who were 85 years and older (oldest-old) completed neuropsychological testing and underwent adjudication of clinical cognitive status (normal, MCI, or dementia). All analyses were adjusted for baseline age, education, cognition, depression, body mass index, hypertension, smoking, and coronary artery disease.

Results

Compared with women in the lowest tertile, women in the highest tertile were less likely to develop dementia (13.0% versus 23.2%; multivariate adjusted odds ratio: 0.54 [95% confidence interval: 0.36-0.82]). However, risk of MCI was not associated with physical activity. Physical activity was also associated with higher performance 5 years later on tests of global cognition, category fluency, and executive function but not phonemic fluency, memory, or attention.

Conclusions

Higher level of very late-life physical activity was associated with a lower risk of subsequent dementia in oldest-old women. These findings support future studies for late-life physical activity interventions for the prevention of dementia among oldest-old women.

Introduction

Little is known about factors affecting motivation and satisfaction of participants in dementia prevention trials.

Methods

A Research Satisfaction Survey was administered to 422 nondemented older adults who participated in the Home-Based Assessment trial.

Results

Overall satisfaction was high, with means of all individual items near to above a value of 3 on a scale from 1 (worst) to 4 (best). Greater satisfaction was associated with staff-administered interviews versus automated technologies. The most liked aspects of research participation were volunteerism, opportunity to challenge and improve mental function, and positive interactions with staff. The least liked aspect was repetitiveness of the assessments. Participants requested more contact with staff and other older adults and more feedback on performance.

Discussion

Older adults' participation in research was primarily motivated by altruism. Methodologies that facilitate human contact, encourage feedback and novelty of tasks should be incorporated into future trial design.

OBJECTIVES: To identify research and practice gaps to establish future research priorities to advance the detection of cognitive impairment and dementia in the emergency department (ED). DESIGN: Literature review and consensus-based rankings by a transdisciplinary, stakeholder task force of experts, persons living with dementia, and care partners. SETTING AND PARTICIPANTS: Scoping reviews focused on adult ED patients. METHODS: Two systematic scoping reviews of 7 medical research databases focusing on best tools and approaches for detecting cognitive impairment and dementia in the ED in terms of (1) most accurate and (2) most pragmatic to implement. The results were screened, reviewed, and abstracted for relevant information and presented at the stakeholder consensus conference for discussion and ranked prioritization. RESULTS: We identified a total of 1464 publications and included 45 to review for accurate tools and approaches for detecting cognitive impairment and dementia. Twenty-seven different assessments and instruments have been studied in the ED setting to evaluate cognitive impairment and dementia, with many focusing on sensitivity and specificity of instruments to screen for cognitive impairment. For pragmatic tools, we identified a total of 2166 publications and included 66 in the review. Most extensively studied tools included the Ottawa 3DY and Six-Item Screener (SIS). The SIS was the shortest to administer (1 minute). Instruments with the highest negative predictive value were the SIS (vs MMSE) and the 4 As Test (vs expert diagnosis). The GEAR 2.0 Advancing Dementia Care Consensus conference ranked research priorities that included the need for more approaches to recognize more effectively and efficiently persons who may be at risk for cognitive impairment and dementia, while balancing the importance of equitable screening, purpose, and consequences of differentiating various forms of cognitive impairment. CONCLUSIONS AND IMPLICATIONS: The scoping review and consensus process identified gaps in clinical care that should be prioritized for research efforts to detect cognitive impairment and dementia in the ED setting. These gaps will be addressed as future GEAR 2.0 research funding priorities.

Introduction

Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD).

Methods

We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months).

Results

Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation.

Discussion

We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic studies of antiamyloid drugs.

Background

The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made.

Methods

We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined.

Results

Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned.

Discussion

These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials' validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.

Context

Several reports from small clinical trials have suggested that estrogen replacement therapy may be useful for the treatment of Alzheimer disease (AD) in women.

Objective

To determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate AD.

Design

The Alzheimer's Disease Cooperative Study, a randomized, double-blind, placebo-controlled clinical trial conducted between October 1995 and January 1999.

Setting

Thirty-two study sites in the United States.

Participants

A total of 120 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 28 who had had a hysterectomy.

Interventions

Participants were randomized to estrogen, 0.625 mg/d (n = 42), or 1.25 mg/d (n = 39), or to identically appearing placebo (n = 39). One subject withdrew after randomization but before receiving medication; 97 subjects completed the trial.

Main outcome measures

The primary outcome measure was change on the Clinical Global Impression of Change (CGIC) 7-point scale, analyzed by intent to treat; secondary outcome measures included other global measures as well as measures of mood, specific cognitive domains (memory, attention, and language), motor function, and activities of daily living; compared by the combined estrogen groups vs the placebo group at 2, 6, 12, and 15 months of follow-up.

Results

The CGIC score for estrogen vs placebo was 5.1 vs 5.0 (P = .43); 80% of participants taking estrogen vs 74% of participants taking placebo worsened (P = .48). Secondary outcome measures also showed no significant differences, with the exception of the Clinical Dementia Rating Scale, which suggested worsening among patients taking estrogen (mean posttreatment change in score for estrogen, 0.5 vs 0.2 for placebo; P = .01).

Conclusions

Estrogen replacement therapy for 1 year did not slow disease progression nor did it improve global, cognitive, or functional outcomes in women with mild to moderate AD. The study does not support the role of estrogen for the treatment of this disease. The potential role of estrogen in the prevention of AD, however, requires further research.

Background

Psychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice.

Objective

To establish research criteria for the diagnosis of psychosis in AD.

Methods

The International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria.

Results

Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers.

Conclusion

We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

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.

Psychosis is common among individuals with neurocognitive disorders, is difficult to manage, and causes considerable burden and stress to patients and caregivers. Developing effective treatments is a substantial unmet medical need but research has been slowed by the need for updated consensus diagnostic criteria. To address this need, the International Psychogeriatrics Association initiated a process to develop criteria for clinical use, research, and treatment development efforts. The process included clinical, regulatory, and industry stakeholders as well as input from a global network of experts in geriatric psychiatry responding to two surveys (N = 336). Results from the consensus process confirmed that clinicians wanted elaboration of aspects of the definition proposed by Jeste and Finkel in 2000 to ensure that the criteria are applied appropriately. Based on discussions, the survey, and emerging research, criteria were revised to apply to psychosis occurring with all major and mild neurocognitive disorders. Other important changes include providing examples of hallucinations and delusions and clarifying time course, impact, and exclusionary criteria. This definition of psychosis in major and mild neurocognitive disorders can be used to advance many types of research including development of much needed pharmacologic and nonpharmacologic interventions for psychosis in patients with neurocognitive disorders.