Current advances in digital cognitive assessment for preclinical Alzheimer\u27s disease

There is a pressing need to capture and track subtle cognitive change at the preclinical stage of Alzheimer\u27s disease (AD) rapidly, cost-effectively, and with high sensitivity. Concurrently, the landscape of digital cognitive assessment is rapidly evolving as technology advances, older adult tech-adoption increases, and external events (i.e., COVID-19) necessitate remote digital assessment. Here, we provide a snapshot review of the current state of digital cognitive assessment for preclinical AD including different device platforms/assessment approaches, levels of validation, and implementation challenges. We focus on articles, grants, and recent conference proceedings specifically querying the relationship between digital cognitive assessments and established biomarkers for preclinical AD (e.g., amyloid beta and tau) in clinically normal (CN) individuals. Several digital assessments were identified across platforms (e.g., digital pens, smartphones). Digital assessments varied by intended setting (e.g., remote vs. in-clinic), level of supervision (e.g., self vs. supervised), and device origin (personal vs. study-provided). At least 11 publications characterize digital cognitive assessment against AD biomarkers among CN. First available data demonstrate promising validity of this approach against both conventional assessment methods (moderate to large effect sizes) and relevant biomarkers (predominantly weak to moderate effect sizes). We discuss levels of validation and issues relating to usability, data quality, data protection, and attrition. While still in its infancy, digital cognitive assessment, especially when administered remotely, will undoubtedly play a major future role in screening for and tracking preclinical AD

Detecting Subtle Changes in Visuospatial Executive Function and Learning in the Amnestic Variant of Mild Cognitive Impairment

BACKGROUND AND PURPOSE: Amnestic mild cognitive impairment (aMCI) is a putative prodromal stage of Alzheimer's disease (AD) characterized by deficits in episodic verbal memory. Our goal in the present study was to determine whether executive dysfunction may also be detectable in individuals diagnosed with aMCI. METHODS: This study used a hidden maze learning test to characterize component processes of visuospatial executive function and learning in a sample of 62 individuals with aMCI compared with 94 healthy controls. RESULTS: Relative to controls, individuals with aMCI made more exploratory/learning errors (Cohen's d = .41). Comparison of learning curves revealed that the slope between the first two of five learning trials was four times as steep for controls than for individuals with aMCI (Cohen's d = .64). Individuals with aMCI also made a significantly greater number of rule-break/error monitoring errors across learning trials (Cohen's d = .21). CONCLUSIONS: These results suggest that performance on a task of complex visuospatial executive function is compromised in individuals with aMCI, and likely explained by reductions in initial strategy formulation during early visual learning and "on-line" maintenance of task rules

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Optimizing the preclinical Alzheimer's cognitive composite with semantic processing: The PACC5

Introduction: Amyloid-related decline in semantic memory was recently shown to be observable in the preclinical period of Alzheimer's disease. Cognitive composites designed to be sensitive to cognitive change in preclinical Alzheimer's disease (e.g., preclinical Alzheimer's cognitive composite [PACC]) and currently used in secondary prevention trials do not currently integrate measures of semantic processing. Our objective was to determine whether a standard semantic measure (i.e., category fluency [CAT] to animals, fruits, and vegetables) adds independent information above and beyond Aβ-related decline captured by the PACC. Methods: Clinically normal older adults from the Harvard Aging Brain Study were identified at baseline as Aβ+ (n = 70) or Aβ− (n = 209) using Pittsburgh compound B–positron emission tomography imaging and followed annually with neuropsychological testing for 3.87 ± 1.09 years. The relationships between PACC, CAT, and variations of the PACC including/excluding CAT were examined using linear mixed models controlling for age, sex, and education. We additionally examined decline on CAT by further grouping Aβ+ participants into preclinical stage 1 and stage 2 on the basis of neurodegeneration markers. Results: CAT explained unique variance in amyloid-related decline, with Aβ+'s continuing to decline relative to Aβ−'s in CAT even after controlling for overall PACC decline. In addition, removal of CAT from the PACC resulted in a longitudinal Aβ+/− effect size reduction of 20% at 3-year follow-up and 12% at 5-year follow-up. Finally, both stage 1 and stage 2 participants declined on CAT in comparison with stage 0, suggesting CAT declines early within the preclinical trajectory. Conclusion: Addition of CAT to the PACC provides unique information about early cognitive decline not currently captured by the episodic memory, executive function, and global cognition components and may therefore improve detection of early Aβ-related cognitive decline

Validation of a Remote and Fully Automated Story Recall Task to Assess for Early Cognitive Impairment in Older Adults: Longitudinal Case-Control Observational Study

BackgroundStory recall is a simple and sensitive cognitive test that is commonly used to measure changes in episodic memory function in early Alzheimer disease (AD). Recent advances in digital technology and natural language processing methods make this test a candidate for automated administration and scoring. Multiple parallel test stimuli are required for higher-frequency disease monitoring. ObjectiveThis study aims to develop and validate a remote and fully automated story recall task, suitable for longitudinal assessment, in a population of older adults with and without mild cognitive impairment (MCI) or mild AD. MethodsThe “Amyloid Prediction in Early Stage Alzheimer’s disease” (AMYPRED) studies recruited participants in the United Kingdom (AMYPRED-UK: NCT04828122) and the United States (AMYPRED-US: NCT04928976). Participants were asked to complete optional daily self-administered assessments remotely on their smart devices over 7 to 8 days. Assessments included immediate and delayed recall of 3 stories from the Automatic Story Recall Task (ASRT), a test with multiple parallel stimuli (18 short stories and 18 long stories) balanced for key linguistic and discourse metrics. Verbal responses were recorded and securely transferred from participants’ personal devices and automatically transcribed and scored using text similarity metrics between the source text and retelling to derive a generalized match score. Group differences in adherence and task performance were examined using logistic and linear mixed models, respectively. Correlational analysis examined parallel-forms reliability of ASRTs and convergent validity with cognitive tests (Logical Memory Test and Preclinical Alzheimer’s Cognitive Composite with semantic processing). Acceptability and usability data were obtained using a remotely administered questionnaire. ResultsOf the 200 participants recruited in the AMYPRED studies, 151 (75.5%)—78 cognitively unimpaired (CU) and 73 MCI or mild AD—engaged in optional remote assessments. Adherence to daily assessment was moderate and did not decline over time but was higher in CU participants (ASRTs were completed each day by 73/106, 68.9% participants with MCI or mild AD and 78/94, 83% CU participants). Participants reported favorable task usability: infrequent technical problems, easy use of the app, and a broad interest in the tasks. Task performance improved modestly across the week and was better for immediate recall. The generalized match scores were lower in participants with MCI or mild AD (Cohen d=1.54). Parallel-forms reliability of ASRT stories was moderate to strong for immediate recall (mean rho 0.73, range 0.56-0.88) and delayed recall (mean rho=0.73, range=0.54-0.86). The ASRTs showed moderate convergent validity with established cognitive tests. ConclusionsThe unsupervised, self-administered ASRT task is sensitive to cognitive impairments in MCI and mild AD. The task showed good usability, high parallel-forms reliability, and high convergent validity with established cognitive tests. Remote, low-cost, low-burden, and automatically scored speech assessments could support diagnostic screening, health care, and treatment monitoring

Unsupervised mobile app-based cognitive testing in a population-based study of older adults born 1944

Background: Mobile app-based tools have the potential to yield rapid, cost-effective, and sensitive measures for detecting dementia-related cognitive impairment in clinical and research settings. At the same time, there is a substantial need to validate these tools in real-life settings. The primary aim of this study was thus to evaluate the feasibility, validity, and reliability of mobile app-based tasks for assessing cognitive function in a population-based sample of older adults. Method: A total of 172 non-demented (Clinical Dementia Rating 0 and 0.5) older participants (aged 76–77) completed two mobile app-based memory tasks—the Mnemonic Discrimination Task for Objects and Scenes (MDT-OS) and the long-term (24 h) delayed Object-In-Room Recall Task (ORR-LDR). To determine the validity of the tasks for measuring relevant cognitive functions in this population, we assessed relationships with conventional cognitive tests. In addition, psychometric properties, including test-retest reliability, and the participants’ self-rated experience with mobile app-based cognitive tasks were assessed. Result: MDT-OS and ORR-LDR were weakly-to-moderately correlated with the Preclinical Alzheimer's Cognitive Composite (PACC5) (r = 0.3–0.44, p <.001) and with several other measures of episodic memory, processing speed, and executive function. Test-retest reliability was poor–to-moderate for one single session but improved to moderate–to-good when using the average of two sessions. We observed no significant floor or ceiling effects nor effects of education or gender on task performance. Contextual factors such as distractions and screen size did not significantly affect task performance. Most participants deemed the tasks interesting, but many rated them as highly challenging. While several participants reported distractions during tasks, most could concentrate well. However, there were difficulties in completing delayed recall tasks on time in this unsupervised and remote setting. Conclusion: Our study proves the feasibility of mobile app-based cognitive assessments in a community sample of older adults, demonstrating its validity in relation to conventional cognitive measures and its reliability for repeated measurements over time. To further strengthen study adherence, future studies should implement additional measures to improve task completion on time

Mean Exploratory Errors and Rule Break Errors (with Standard Errors) over five learning trials of the Groton Maze Learning Test in Healthy Controls versus aMCI groups.

<p>Mean Exploratory Errors and Rule Break Errors (with Standard Errors) over five learning trials of the Groton Maze Learning Test in Healthy Controls versus aMCI groups.</p

Demographic characteristics of healthy elderly and aMCI groups.

<p><i>Note</i>: aMCI = Mild cognitive impairment-amnestic subtype; SD = standard deviation.</p><p>*Groups differ, p<.05.</p