Naturalistic assessment of reaction time variability in older adults at risk for Alzheimer's disease.

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.

Comparing Tau PET Visual Interpretation with Tau PET Quantification, Cerebrospinal Fluid Biomarkers, and Longitudinal Clinical Assessment.

BACKGROUND: 18F-flortaucipir PET received FDA approval to visualize aggregated neurofibrillary tangles (NFTs) in brains of adult patients with cognitive impairment being evaluated for Alzheimer's disease (AD). However, manufacturer's guidelines for visual interpretation of 18F-flortaucipir PET differ from how 18F-flortaucipir PET has been measured in research settings using standardized uptake value ratios (SUVRs). How visual interpretation relates to 18F-flortaucipir PET SUVR, cerebrospinal fluid (CSF) biomarkers, or longitudinal clinical assessment is not well understood. OBJECTIVE: We compare various diagnostic methods in participants enrolled in longitudinal observational studies of aging and memory (n = 189, 23 were cognitively impaired). METHODS: Participants had tau PET, Aß PET, MRI, and clinical and cognitive evaluation within 18 months (n = 189); the majority (n = 144) also underwent lumbar puncture. Two radiologists followed manufacturer's guidelines for 18F-flortaucipir PET visual interpretation. RESULTS: Visual interpretation had high agreement with SUVR (98.4%)and moderate agreement with CSF p-tau181 (86.1%). Two participants demonstrated 18F-flortaucipir uptake from meningiomas. Visual interpretation could not predict follow-up clinical assessment in 9.52% of cases. CONCLUSION: Visual interpretation was highly consistent with SUVR (discordant participants had hemorrhagic infarcts or occipital-predominant AD NFT deposition) and moderately consistent with CSF p-tau181 (discordant participants had AD pathophysiology not detectable on tau PET). However, close association between AD NFT deposition and clinical onset in group-level studies does not necessarily hold at the individual level, with discrepancies arising from atypical AD, vascular dementia, or frontotemporal dementia. A better understanding of relationships across imaging, CSF biomarkers, and clinical assessment is needed to provide appropriate diagnoses for these individuals.

Increased cognitive effort costs in healthy aging and preclinical Alzheimer's disease.

Life-long engagement in cognitively demanding activities may mitigate against declines in cognitive ability observed in healthy or pathological aging. However, the "mental costs" associated with completing cognitive tasks also increase with age and may be partly attributed to increases in preclinical levels of Alzheimer's disease (AD) pathology, specifically amyloid. We test whether cognitive effort costs increase in a domain-general manner among older adults, and further, whether such age-related increases in cognitive effort costs are associated with working memory (WM) capacity or amyloid burden, a signature pathology of AD. In two experiments, we administered a behavioral measure of cognitive effort costs (cognitive effort discounting) to a sample of older adults recruited from online sources (Experiment 1) or from ongoing longitudinal studies of aging and dementia (Experiment 2). Experiment 1 compared age-related differences in cognitive effort costs across two domains, WM and speech comprehension. Experiment 2 compared cognitive effort costs between a group of participants who were rated positive for amyloid relative to those with no evidence of amyloid. Results showed age-related increases in cognitive effort costs were evident in both domains. Cost estimates were highly correlated between the WM and speech comprehension tasks but did not correlate with WM capacity. In addition, older adults who were amyloid positive had higher cognitive effort costs than those who were amyloid negative. Cognitive effort costs may index a domain-general trait that consistently increases in aging. Differences in cognitive effort costs associated with amyloid burden suggest a potential neurobiological mechanism for age-related differences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Differences in Driving Outcomes Among Cognitively Normal African American and Caucasian Older Adults.

OBJECTIVE: To examine the effect of race in driving performance and behavior prospectively among cognitively normal older adults. METHODS: Cognitively normal participants (Clinical Dementia Rating 0), ≥ 65 years of age (n = 177) were selected from prospective, longitudinal studies at the Knight Alzheimer Disease Research Center at Washington University. Self-reported driving behavior (Driving Habits Questionnaire) and driving performance (road test) were annually assessed. Daily driving behavior data were collected using the Driving Real World In-Vehicle Evaluation System (DRIVES). Baseline differences between African Americans and Caucasians were tested using t tests and general linear models. Amyloid imaging and cerebrospinal fluid Alzheimer disease (AD) biomarkers were compared across groups. Linear mixed models examined change in daily driving behavior over time. Survival analyses tested time to a marginal or fail rating on the road test. RESULTS: There were no differences between African Americans (n = 34) and Caucasians (n = 143) in age, sex, education, or vascular risk factors. Baseline self-reported driving behavior and road test performance were largely similar for both races. Longitudinal analyses using the DRIVES data aggregated monthly showed that African Americans had a greater reduction in number of trips made per month, miles driven per month, and trips with aggressive behavior compared to Caucasians. These effects remained after controlling for AD biomarkers, age, education, and sex. CONCLUSIONS: In this sample of cognitively normal older adults, African Americans had a greater reduction of daily driving behavior compared to Caucasians. Observed racial differences may reflect differences in environmental/social factors, changes in cognition, and/or physical functioning.

A 2.5-Year Longitudinal Assessment of Naturalistic Driving in Preclinical Alzheimer's Disease.

BACKGROUND: Emerging evidence shows that cognitively normal older adults with preclinical Alzheimer's disease (AD) make more errors and are more likely to receive a marginal/fail rating on a standardized road test compared to older adults without preclinical AD, but the extent to which preclinical AD impacts everyday driving behavior is unknown. OBJECTIVE: To examine self-reported and naturalistic longitudinal driving behavior among persons with and without preclinical AD. METHOD: We prospectively followed cognitively normal drivers (aged 65 + years) with (n = 10) and without preclinical AD (n = 10) for 2.5 years. Preclinical AD was assessed using amyloid positron emission tomography (PET) with Pittsburgh Compound B. The Driving Habits Questionnaire assessed self-reported driving outcomes. Naturalistic driving was captured using a commercial GPS data logger plugged into the on-board diagnostics II port of each participant's vehicle. Data were sampled every 30 seconds and all instances of speeding, hard braking, and sudden acceleration were recorded. RESULTS: Preclinical AD participants went to fewer places/unique destinations, traveled fewer days, and took fewer trips than participants without preclinical AD. The preclinical AD group reported a smaller driving space, greater dependence on other drivers, and more difficulty driving due to vision difficulties. Persons with preclinical AD had fewer trips with any aggression and showed a greater decline across the 2.5-year follow-up period in the number of days driving per month and the number of trips between 1-5 miles. CONCLUSION: Changes in driving occur even during the preclinical stage of AD.

Assessment of Racial Disparities in Biomarkers for Alzheimer Disease.

Importance: Racial differences in molecular biomarkers for Alzheimer disease may suggest race-dependent biological mechanisms. Objective: To ascertain whether there are racial disparities in molecular biomarkers for Alzheimer disease. Design, Setting, and Participants: A total of 1255 participants (173 African Americans) were enrolled from January 1, 2004, through December 31, 2015, in longitudinal studies at the Knight Alzheimer Disease Research Center at Washington University and completed a magnetic resonance imaging study of the brain and/or positron emission tomography of the brain with Pittsburgh compound B (radioligand for aggregated amyloid-ß) and/or cerebrospinal fluid (CSF) assays for the concentrations of amyloid-ß42, total tau, and phosphorylated tau181. Independent cross-sectional analyses were conducted from April 22, 2016, to August 27, 2018, for each biomarker modality with an analysis of variance or analysis of covariance including age, sex, educational level, race, apolipoprotein E (APOE) ε4 allele status, and clinical status (normal cognition or dementia). All biomarker assessments were conducted without knowledge of the clinical status of the participants. Main Outcomes and Measures: The primary outcomes were hippocampal volumes adjusted for differences in intracranial volumes, global cerebral amyloid burden as transformed into standardized uptake value ratios (partial volume corrected), and CSF concentrations of amyloid-ß42, total tau, and phosphorylated tau181. Results: Of the 1255 participants (707 women and 548 men; mean [SD] age, 70.8 [9.9] years), 116 of 173 African American participants (67.1%) and 724 of 1082 non-Hispanic white participants (66.9%) had normal cognition. There were no racial differences in the frequency of cerebral ischemic lesions noted on results of brain magnetic resonance imaging, mean cortical standardized uptake value ratios for Pittsburgh compound B, or for amyloid-ß42 concentrations in CSF. However, in individuals with a reported family history of dementia, mean (SE) total hippocampal volumes were lower for African American participants than for white participants (6418.26 [138.97] vs 6990.50 [44.10] mm3). Mean (SE) CSF concentrations of total tau were lower in African American participants than in white participants (293.65 [34.61] vs 443.28 [18.20] pg/mL; P < .001), as were mean (SE) concentrations of phosphorylated tau181 (53.18 [4.91] vs 70.73 [2.46] pg/mL; P < .001). There was a significant race by APOE ε4 interaction for both CSF total tau and phosphorylated tau181 such that only APOE ε4-positive participants showed the racial differences. Conclusions and Relevance: The results of this study suggest that analyses of molecular biomarkers of Alzheimer disease should adjust for race. The lower CSF concentrations of total tau and phosphorylated tau181 in African American individuals appear to reflect a significant race by APOE ε4 interaction, suggesting a differential effect of this Alzheimer risk variant in African American individuals compared with white individuals.