Dataset Information

The Computerized Cognitive Composite (C3) in an Alzheimer's Disease Secondary Prevention Trial.

ABSTRACT:

Background

Computerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.

Objective

To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).

Design

Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD).

Setting

Multi-center international study.

Participants

Clinically normal (CN) older adults (65-85; n=4486).

Measurements

Participants underwent florbetapir-Positron Emission Tomography for A?+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer's Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to A?+/- groups (n=1323/3163) and PACC.

Results

C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). A?+ performed worse on C3 compared with A?- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants.

Conclusions

These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.

SUBMITTER: Papp KV

PROVIDER: S-EPMC7755110 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

The Computerized Cognitive Composite (C3) in an Alzheimer's Disease Secondary Prevention Trial.

Papp K V KV Rentz D M DM Maruff P P Sun C-K CK Raman R R Donohue M C MC Schembri A A Stark C C Yassa M A MA Wessels A M AM Yaari R R Holdridge K C KC Aisen P S PS Sperling R A RA

The journal of prevention of Alzheimer's disease 20210101 1

<h4>Background</h4>Computerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.<h4>Objective</h4>To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).<h4>Design</h4>Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD).<h4>Setting</h4>Multi-center internatio ...[more]

PMID: 33336226

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Project description:BACKGROUND:There is growing interest in identifying sensitive composite cognitive tests to serve as primary endpoints in preclinical Alzheimer's disease (AD) treatment trials. We reported previously a composite cognitive test score sensitive to tracking preclinical AD decline up to 5?years prior to clinical diagnosis. Here we expand upon and refine this work, empirically deriving a composite cognitive test score sensitive to tracking preclinical AD decline up to 11?years prior to diagnosis and suitable for use as a primary endpoint in a preclinical AD trial. METHODS:This study used a longitudinal approach to maximize sensitivity to tracking progressive cognitive decline in people who progressed to the clinical stages of AD (n =?868) compared to those who remained cognitively unimpaired during the same time period (n =?989), thereby correcting for normal aging and practice effects. Specifically, we developed the Alzheimer's Prevention Initiative Preclinical Composite Cognitive test (APCC) to measure very early longitudinal cognitive decline in older adults with preclinical AD. Data from three cohorts from Rush University were analyzed using a partial least squares (PLS) regression model to identify optimal composites within different time periods prior to diagnosis, up to 11?years prior to diagnosis. The mean-to-standard deviation ratio (MSDRs) is an indicator of sensitivity to change and was used to inform the final calculation of the composite score. RESULTS:The optimal composite, the APCC, is calculated: 0.26*Symbol Digit Modalities +?2.24*MMSE Orientation to Time?+?2.14*MMSE Orientation to Place +?0.53*Logical Memory Delayed Recall +?1.36* Word List-Delayed Recall +?0.68*Judgment of Line Orientation +?1.39*Raven's Progressive Matrices Matrices (subset of 9 items from A and B). The MSDR of the APCC in a population of preclinical AD individuals who eventually progress to cognitive impairment, compared to those who remained cognitively unimpaired during the same time period, was -?1.10 over 1 year. CONCLUSIONS:The APCC is an empirically derived composite cognitive test score with high face validity that is sensitive to preclinical AD decline up to 11?years prior to diagnosis of the clinical stages of AD. The components of the APCC are supported by theoretical understanding of cognitive decline that occurs during preclinical AD. The APCC was used as a primary outcome in the API Generation Program trials.

Project description:Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline. Materials and Methods: N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5. Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21-0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59-0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = -0.20, 95% CI [-0.38 - -0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = -0.38, 95% CI [-0.54 - -0.19], p < 0.001) and inferior-temporal lobe (r = -0.23, 95% CI [-0.41 - -0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84-0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02). Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.

Project description:BackgroundIn Alzheimer's disease (AD), pathological changes may arise up to 20 years before the onset of dementia. This pre-dementia window provides a unique opportunity for secondary prevention. However, exposing non-demented subjects to putative therapies requires reliable biomarkers for subject selection, stratification, and monitoring of treatment. Neuroimaging allows the detection of early pathological changes, and longitudinal imaging can assess the effect of interventions on markers of molecular pathology and rates of neurodegeneration. This is of particular importance in pre-dementia AD trials, where clinical outcomes have a limited ability to detect treatment effects within the typical time frame of a clinical trial. We review available evidence for the use of neuroimaging in clinical trials in pre-dementia AD. We appraise currently available imaging markers for subject selection, stratification, outcome measures, and safety in the context of such populations.Main bodyAmyloid positron emission tomography (PET) is a validated in-vivo marker of fibrillar amyloid plaques. It is appropriate for inclusion in trials targeting the amyloid pathway, as well as to monitor treatment target engagement. Amyloid PET, however, has limited ability to stage the disease and does not perform well as a prognostic marker within the time frame of a pre-dementia AD trial. Structural magnetic resonance imaging (MRI), providing markers of neurodegeneration, can improve the identification of subjects at risk of imminent decline and hence play a role in subject inclusion. Atrophy rates (either hippocampal or whole brain), which can be reliably derived from structural MRI, are useful in tracking disease progression and have the potential to serve as outcome measures. MRI can also be used to assess comorbid vascular pathology and define homogeneous groups for inclusion or for subject stratification. Finally, MRI also plays an important role in trial safety monitoring, particularly the identification of amyloid-related imaging abnormalities (ARIA). Tau PET to measure neurofibrillary tangle burden is currently under development. Evidence to support the use of advanced MRI markers such as resting-state functional MRI, arterial spin labelling, and diffusion tensor imaging in pre-dementia AD is preliminary and requires further validation.ConclusionWe propose a strategy for longitudinal imaging to track early signs of AD including quantitative amyloid PET and yearly multiparametric MRI.

Dataset Information

The Computerized Cognitive Composite (C3) in an Alzheimer's Disease Secondary Prevention Trial.

Background

Objective

Design

Setting

Participants

Measurements

Results

Conclusions

Publications

The Computerized Cognitive Composite (C3) in an Alzheimer's Disease Secondary Prevention Trial.

Similar Datasets

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