Participant and study partner prediction and identification of cognitive impairment in preclinical Alzheimer’s disease: study partner vs. participant accuracy

Ryan et al. Alzheimer's Research & Therapy https://doi.org/10.1186/s13195-019-0539-3 (2019) 11:85 RESEARCH Open Access Participant and study partner prediction and identification of cognitive impairment in preclinical Alzheimer’s disease: study partner vs. participant accuracy Mary M. Ryan1*, Joshua D. Grill2,3,4,5*† , Daniel L. Gillen1,2*† and for the Alzheimer’s Disease Neuroimaging Initiative Abstract Background: Preclinical Alzheimer’s disease (AD) clinical trials require participants to enroll with a study partner, a person who can attend visits and report changes in the participant’s cognitive ability. Whether study partners, compared to participants themselves, provide added information about participant cognition in preclinical AD trials is an open question. We tested the hypothesis that study partners provide meaningful information related to participant cognition cross-sectionally and longitudinally, and assessed whether amyloid status modified observed effects. Methods: We assessed participant and study partner Everyday Cognition (ECog) scores and participant Alzheimer’s Disease Assessment Scale 13-item cognitive subscale (ADAS13) data from 335 cognitively normal participant-partner dyads in the AD Neuroimaging Initiative. We used random forest and linear mixed effects (LME) models to predict ADAS13 scores as a function of participant and/or study partner ECog scores over time. LME models were adjusted for potential confounding factors, including APOE4 status, amyloid status, baseline age, years of education, and sex. Random forest models were split into the above factors, as well as race/ethnicity and other available neuropsychological battery test scores. Results: In random forest models predicting ADAS13 12 months from baseline, we observed no difference in the estimated mean variable importance (eMVI) associated with baseline study partner ECog compared to the baseline participant ECog (eMVI = 0.15, 95%CB 0.13, 0.16 for partner; eMVI = 0.15, 95%CB 0.14, 0.16 for participant). In models predicting ADAS13 48 months after baseline, the eMVI associated with baseline study partner ECog was slightly lower than that associated with baseline participant ECog (eMVI = 0.21, 95%CB 0.20, 0.22 for partner; eMVI = 0.24, 95%CB 0.22, 0.25 for participant). In cross-sectional models, study partner eMVI was twice as large as participant eMVI at 12 months (eMVI = 0.20, 95%CB 0.19, 0.21 for partner; eMVI = 0.09, 95%CB 0.09, 0.10 for participant) and three times as large at 48 months (eMVI = 0.38, 95%CB 0.36, 0.39 for partner; eMVI = 0.13, 95%CB 0.12, 0.14 for participant). We did not observe qualitative differences by amyloid status. Conclusions: While baseline participant reports reasonably predict subsequent cognitive change, informants perform better at cross-sectionally recognizing cognitive status as observation time grows. The study partner requirement may be essential to ensure trial data integrity, especially in longer trials. Keywords: Alzheimer’s disease, Study partner, preclinical, ADNI * Correspondence: ; ; † Joshua D. Grill and Daniel L. Gillen are co-senior authors. 1 Department of Statistics, University of California, Irvine, Irvine, CA 92697, USA 2 Institute for Memory Impairments and Neurological Disorders, University of California, Irvine 92697, CA, USA Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ryan et al. Alzheimer's Research & Therapy (2019) 11:85 Introduction Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in dementia—cognitive and functional impairment that interrupts independence in daily life. US Food and Drug Administration (FDA) approval for new AD treatments historically requires demonstration of both functional and cognitive benefit in AD dementia clinical trials. Demonstration of functional benefit, along with logistical needs related to study compliance and ethical needs related to informed consent, requires that AD dementia trial participants enroll with a study partner [1, 2]. In an effort to intervene earlier in the disease process, before neurodegeneration reaches severe stages, researchers have begun performing clinical trials that enroll patients whose disease does not meet the criteria for dementia. This includes trials of patients with mild cognitive impairment (MCI), a construct defined by objective cognitive impairment without functional loss or impaired activities of daily living. MCI patients with biomarker evidence of AD, such as elevated brain levels of amyloid-β42, which can be observed through the use of neuroimaging and cerebrospinal fluid (CSF) protein analysis [3], meet the criteria for MCI due to AD or prodromal AD [4, 5]. To intervene even earlier in disease, preclinical AD trials enroll patients with no cognitive impairment but biomarker evidence of AD [6]. Participants in preclinical and prodromal AD trials are expected to be able to provide informed consent and to comply with study requirements. Yet, the need for informants who report participant cognitive and functional performance in these trials is less understood. Study partners may perform better at predicting future AD dementia than do patients with MCI [7, 8], while other studies show that patients with MCI are fairly accurate at assessing their current cognitive state [9]. Preliminary studies indicate that self-reports from cognitively normal participants may better predict future outcomes than do study partners [10, 11]. Whether these relationships are altered in the presence of AD biomarkers remains an area in need of study. Initial preclinical AD trials require participants to enroll with study partners [12]. An open question remains, though, whether participants themselves or their partners provide more meaningful information on trial outcomes. In this study, we sought to determine if study partners provide additional information, in relation to preclinical AD study participants, in predicting future cognitive decline or assessing current cognitive performance, and assessed whether amyloid status modified observed effects. We hypothesized that study partners would provide more meaningful information than participants over time, but that this effect would be observed only in participants with elevated brain amyloid. Page 2 of 8 Methods Data collection We used data from the AD Neuroimagin (...truncated)