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Naturalistic assessment of reaction time variability in older adults at risk for Alzheimer’s disease
- Matthew S. Welhaf, Hannah Wilks, Andrew J. Aschenbrenner, David A. Balota, Suzanne E. Schindler, Tammie L.S. Benzinger, Brian A. Gordon, Carlos Cruchaga, Chengjie Xiong, John C. Morris, Jason Hassenstab
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- Journal:
- Journal of the International Neuropsychological Society , First View
- Published online by Cambridge University Press:
- 29 January 2024, pp. 1-11
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Objective:
Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer’s disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD.
Method:Three hundred and seventy older adults (aged 75.8 +/− 5.8 years) completed a week of remote daily testing on the Ambulatory Research in Cognition (ARC) smartphone platform and also completed clinical, genetic, and conventional in-clinic cognitive assessments. RT variability was assessed in a brief (20-40 seconds) processing speed task using two different measures of variability, the Coefficient of Variation (CoV) and the Root Mean Squared Successive Difference (RMSSD) of RTs on correct trials.
Results:Symptomatic participants showed greater variability compared to cognitively normal participants. When restricted to cognitively normal participants, APOE ε4 carriers exhibited greater variability than noncarriers. Both CoV and RMSSD showed significant, and similar, correlations with several in-clinic cognitive composites. Finally, both RT variability measures significantly mediated the relationship between APOE ε4 status and several in-clinic cognition composites.
Conclusions:Attentional fluctuations over 20–40 seconds assessed in daily life, are sensitive to clinical status and genetic risk for AD. RT variability appears to be an important predictor of cognitive deficits during the preclinical disease stage.
1 What Can we Learn from High Frequency Smartphone-Based Cognitive Assessments?
- Jason Hassenstab
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 205-206
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Objective:
Smartphone-based cognitive assessments can provide unique information about cognition that is difficult or impossible with traditional cognitive assessments. Using high-frequency measurement “burst” designs, we have shown that older adults are capable and willing to participate in smartphone-based research, that this method dramatically improves between-subject reliability compared to traditional methods and demonstrates extraordinary test-retest reliabilities, and that high-frequency measurement can reveal time of day effects that are increased in those with elevated Alzheimer’s disease biomarkers. In this symposium session, we will provide an overview of our current work in older adults at risk for AD and highlight new analyses on the interaction between day to day variability in sleep and cognition. We will also cover our approach for measuring smartphone latencies, a critical aspect of bring-your-own-device (BYOD) studies.
Participants and Methods:The Ambulatory Research in Cognition (ARC) smartphone application for iOS and Android administers custom-designed tests of associate memory, processing speed, and spatial working memory. ARC uses a measurement burst design in which very brief (typically 60s or less) tests are completed at random times several times per day for up to one week. Measurement burst designs rely on principles from ecological momentary assessment, and can be described with a simple formula: 1. Test often and everywhere, 2. Keep assessments brief, and 3. Combine the data across sessions to increase reliability. At the Knight Alzheimer’s Disease Research Center at Washington University in St Louis, we have enrolled over 400 participants (ages 60-99 years) at risk for AD in ARC studies. These participants are comprehensively assessed with traditional cognitive tests, clinical examinations, neuroimaging, and fluid biomarkers. ARC also assesses sleep with the Pittsburgh Sleep Quality Index that captures essential sleep parameters, which are assessed daily during each 7-day measurement burst. Analyses of sleep and cognition focused on parameters including total sleep time, number of awakenings, sleep quality ratings, and an extremes analysis comparing cognition after nights with more sleep and after nights with less sleep.
Results:Overall, participants reporting less total sleep time and more awakenings had lower memory and processing speed scores. This remained significant after modeling covariates including age, self-reported gender, education, and APOE ε4 status. Compared to nights with the most sleep, memory was worse after the nights with the poorest sleep.
Conclusions:When considering AD biomarkers in these analyses, participants with elevated AD biomarkers, including neurofilament light chain (NfL) and phosphorylated-tau181 (p-tau181), demonstrated more impacts of poor sleep on cogntion, such that the nights with the least sleep tended to impact cognition more than in those with normal biomarker levels, suggesting an important role for sleep in maintaining cognition in preclinical and early symptomatic AD. Interestingly, self-reported sleep quality was not associated with ARC cognitive tests, consistent with studies emphasizing the need for more quantitative assessments of sleep quality. In addition to these sleep data, we will review publications using the ARC platform, including a recently accepted manuscript in JINS (Nicosia et al., 2022).
6 Examining Interactions Between Longitudinal, Intraindividual Fluctuations in Cognition and Alzheimer’s Disease Biomarkers to Predict Eventual Disease Progression
- Hannah M Wilks, Carlos Cruchaga, Anne Fagan, Suzanne Schindler, John C Morris, Jason Hassenstab
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 410-411
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The purpose of the present study was to study the clinical significance of fluctuations in cognitive impairment status in longitudinal studies of normal aging and dementia. Several prior studies have shown fluctuations in cognition in longitudinal studies is associated with greater risk of conversion to dementia. The present study defines “reverters” as participants who revert between cognitive normality and abnormality according to the Clinical Dementia Rating (CDRTM). A defining feature of the CDR at the Knight Alzheimer’s Disease Research Center (Knight ADRC) at Washington University in St. Louis is that the CDR is calculated by clinicians blinded to cognitive data and any prior assessments so that conclusions are drawn free of circularity and examiner bias. We hypothesized reverters, when compared to cognitively normal participants who remain unimpaired, would have worse cognition, abnormal biomarkers, and would eventually progress to a stable diagnosis of cognitive impairment.
Participants and Methods:From ongoing studies of aging and dementia at the Knight ADRC, we selected cognitively normal participants with at least three follow-up visits. Participants fell into three categories: stable cognitively normal (“stable CN”), converters to stable dementia (“converters”), and reverters. Cognitive scores at each visit were z-scored for comparison between groups. A subset of participants had fluid biomarker data available including cerebrospinal fluid (CSF) amyloid and phosphorylated-tau species, and plasma neurofilament light chain (NfL). Mixed effect models evaluated group relationships between biomarker status, APOE £4 status, and CDR progression.
Results:930 participants were included in the study with an average of 5 years of follow-up (Table 1). 661 participants remained cognitively normal throughout their participation while 142 progressed to stable dementia and 127 participants had at least one instance of reversion. Compared to stable CN, reverters had more abnormal biomarkers at baseline, were more likely to carry an APOE £4 allele, and had better cognitive performance at baseline (Table 2, Figure 1). Compared to converters, reverters had less abnormal biomarkers at baseline, were less likely to carry an APOE £4 allele, and had overall better cognitive performance at baseline. In longitudinal analyses, cognitive trajectories of reverters exhibited a larger magnitude of decline compared to stable CNs but the magnitude of decline was not as steep as converters.
Conclusions:Our results confirm prior studies that showed reversion in cognitive status, when compared to stable cognitive normality, is associated with worse overall genetic, biomarker and cognitive outcomes. Longitudinal analyses demonstrated reverters show significantly more decline than stable participants and a higher likelihood of eventual conversion to a stable dementia diagnosis. Reverters’ cognitive trajectories appear to occupy a transitional phase in disease progression between that of cognitive stability and more rapid and consistent progression to stable dementia. Identifying participants in the preclinical phase of AD who are most likely to convert to symptomatic AD is critical for secondary prevention clinical trials. Our results suggest that examining intraindividual variability in cognitive impairment using unbiased, longitudinal CDR scores may be a good indicator of preclinical AD and predict eventual conversion to symptomatic AD.
65 Mayo Test Drive raw composite criterion validity: a brief remote self-administered digital cognitive composite shows similar ability to differentiate PET-defined biomarker groups as a global composite from a person-administered neuropsychological battery in cognitively unimpaired individuals on the Alzheimer’s continuum
- Nikki H. Stricker, Aimee J. Karstens, Teresa J. Christianson, John L. Stricker, Winnie Z. Fan, Sabrina M. Albertson, Ryan D. Frank, Mary M. Machulda, Walter K. Kremers, Jason Hassenstab, Julie A. Fields, Jonathan Graff-Radford, Clifford R. Jack, Jr., David S. Knopman, Michelle M. Mielke, Ronald C. Petersen
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 371-372
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Objective:
Mayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web-based multi-device (smartphone, tablet, personal computer) platform optimized for remote self-administered cognitive assessment that includes a computer-adaptive word list memory test (Stricker Learning Span; SLS; Stricker et al., 2022; Stricker et al., in press) and a measure of processing speed (Symbols Test: Wilks et al., 2021). Study aims were to determine criterion validity of MTD by comparing the ability of the MTD raw composite and in-person administered cognitive measures to differentiate biomarkerdefined groups in cognitively unimpaired (CU) individuals on the Alzheimer’s continuum.
Participants and Methods:Mayo Clinic Study of Aging CU participants (N=319; mean age=71, SD=11, range=37-94; mean education=16, SD=2, range=6-20; 47% female) completed a brief remote cognitive assessment (∼0.5 months from in-person visit). Brain amyloid and brain tau PET scans were available within 3 years. Overlapping groups were formed for 1) those on the Alzheimer’s disease (AD) continuum (A+, n=110) or not (A-, n=209), and for 2) those with biological AD (A+T+, n=43) or with no evidence of AD pathology (A-T-, n=181). Primary outcome variables were MTD raw composite (SLS sum of trials + an accuracy-weighted Symbols response time measure), Global-z (average of 9 in-person neuropsychological measures) and an in-person screening measure (Kokmen Short Test of Mental Status, STMS; which is like the MMSE). Linear model ANOVAs were used to investigate biomarker subgroup differences and Hedge’s G effect sizes were derived, with and without adjusting for demographic variables (age, education, sex).
Results:Remotely administered MTD raw composite showed comparable to slightly larger effect sizes compared to Global-z. Unadjusted effect sizes for MTD raw composite for differentiating A+ vs. A- and A+T+ vs. A-T- groups, respectively, were -0.57 and -0.84 and effect sizes for Global-z were -0.54 and -0.73 (all p’s<.05). Because biomarker positive groups were significantly older than biomarker negative groups, group differences were attenuated after adjusting for demographic variables, but MTD raw composite remained significant for A+T+ vs A-T- (adjusted effect size -0.35, p=.007); Global-z did not reach significance for A+T+ vs A-T- (adjusted effect size -0.19, p=.08). Neither composite reached significance for adjusted analyses for the A+ vs A- comparison (MTD raw composite adjusted effect size= -.22, p=.06; Global-z adjusted effect size= -.08, p=.47). Results were the same for an alternative MTD composite using traditional z-score averaging methods, but the raw score method is preferred for comparability to other screening measures. The STMS screening measure did not differentiate biomarker groups in any analyses (unadjusted and adjusted p’s>.05; d’s -0.23 to 0.05).
Conclusions:Remotely administered MTD raw composite shows at least similar ability to separate biomarker-defined groups in CU individuals as a Global-z for person-administered measures within a neuropsychological battery, providing evidence of criterion validity. Both the MTD raw composite and Global-z showed greater ability to separate biomarker positive from negative CU groups compared to a typical screening measure (STMS) that was unable to differentiate these groups. MTD may be useful as a screening measure to aid early detection of Alzheimer’s pathological changes.
Unsupervised high-frequency smartphone-based cognitive assessments are reliable, valid, and feasible in older adults at risk for Alzheimer’s disease
- Jessica Nicosia, Andrew J. Aschenbrenner, David A. Balota, Martin J. Sliwinski, Marisol Tahan, Sarah Adams, Sarah S. Stout, Hannah Wilks, Brian A. Gordon, Tammie L. S. Benzinger, Anne M. Fagan, Chengjie Xiong, Randall J. Bateman, John C. Morris, Jason Hassenstab
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue 5 / June 2023
- Published online by Cambridge University Press:
- 05 September 2022, pp. 459-471
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Objective:
Smartphones have the potential for capturing subtle changes in cognition that characterize preclinical Alzheimer’s disease (AD) in older adults. The Ambulatory Research in Cognition (ARC) smartphone application is based on principles from ecological momentary assessment (EMA) and administers brief tests of associative memory, processing speed, and working memory up to 4 times per day over 7 consecutive days. ARC was designed to be administered unsupervised using participants’ personal devices in their everyday environments.
Methods:We evaluated the reliability and validity of ARC in a sample of 268 cognitively normal older adults (ages 65–97 years) and 22 individuals with very mild dementia (ages 61–88 years). Participants completed at least one 7-day cycle of ARC testing and conventional cognitive assessments; most also completed cerebrospinal fluid, amyloid and tau positron emission tomography, and structural magnetic resonance imaging studies.
Results:First, ARC tasks were reliable as between-person reliability across the 7-day cycle and test-retest reliabilities at 6-month and 1-year follow-ups all exceeded 0.85. Second, ARC demonstrated construct validity as evidenced by correlations with conventional cognitive measures (r = 0.53 between composite scores). Third, ARC measures correlated with AD biomarker burden at baseline to a similar degree as conventional cognitive measures. Finally, the intensive 7-day cycle indicated that ARC was feasible (86.50% approached chose to enroll), well tolerated (80.42% adherence, 4.83% dropout), and was rated favorably by older adult participants.
Conclusions:Overall, the results suggest that ARC is reliable and valid and represents a feasible tool for assessing cognitive changes associated with the earliest stages of AD.