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

Associations of Stages of Objective Memory Impairment With Amyloid PET and Structural MRI

Background and objectivesThe goal of this work was to investigate the neuroimaging correlates of the Stages of Objective Memory Impairment (SOMI) system operationalized with the Free and Cued Selective Reminding Test (FCSRT), a widely used episodic memory measure.MethodsThe FCSRT begins with a study phase in which items (e.g., grapes) are identified in response to unique semantic cues (e.g., fruit) that are used in the test phase to prompt recall of items not retrieved by free recall. There are 3 test trials of the 16 items (maximum 48). Data from 4,484 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were used. All participants had amyloid PET imaging, and a subset of 1,262 β-amyloid (Aβ)-positive had structural MRIs. We compared the Aβ mean cortical standardized uptake value ratio (SUVR) and volumetric measures of hippocampus, parahippocampal gyrus, entorhinal cortex, and inferior temporal cortex between the 5 SOMI stages.ResultsParticipants had a mean age of 71.3 (SD 4.6) years; 40.6% were male; and 34.6% were APOE ε4 positive. Half had no memory impairment; the other half had retrieval deficits, storage limitations, or both. Analysis of covariance in the entire sample while controlling for age, sex, education, and APOE ε4 showed that individuals in higher SOMI stages had higher global amyloid SUVR (p < 0.001). Both SOMI-4 and -3 subgroups had higher amyloid SUVR than SOMI-0 and SOMI-1 subgroups. Individuals in higher SOMI stages had smaller hippocampal volume (p = 0.003), entorhinal cortex (p < 0.05), and inferior temporal lobes (p < 0.05), but there was no difference between parahippocampal gyrus volume of different SOMI stages. Pairwise comparison of SOMI subgroups showed that the SOMI-4, -3, and -2 subgroups had smaller hippocampal volume than the SOMI-0 and -1 subgroup. The SOMI-4 subgroup had significantly smaller entorhinal cortex and smaller inferior temporal lobe compared to all other groups.DiscussionPresence of Alzheimer disease pathology is closely related to memory impairment according to SOMI stages in the cognitively unimpaired sample of A4. Results from structural MRIs suggest that memory storage impairment (SOMI-3 and -4) is present when there is widespread medial temporal lobe atrophy.Trial registration informationClinicalTrials.gov identifier: NCT02008357.Classification of evidenceThis study provides Class I evidence that, in normal older individuals, higher stages of memory impairment assessed with FCSRT were associated with higher amyloid imaging burden and lower volume of hippocampus, entorhinal cortex, and inferior temporal lobes

Harmonizing healthcare and other resource measures for evaluating economic costs in substance use disorder research

Background Standardization and harmonization of healthcare resource utilization data can improve evaluations of the economic impact of treating people with substance use disorder (SUD), including reductions in use of expensive hospital and emergency department (ED) services, and can ensure consistency with current cost-effectiveness and cost-benefit analysis guidelines. Methods We examined self-reported healthcare and other resource utilization data collected at baseline from three National Institute on Drug Abuse (NIDA)-funded Seek, Test, Treat, and Retain intervention studies of individuals living with/at risk for HIV with SUD. Costs were calculated by multiplying mean healthcare resource utilization measures by monetary conversion factors reflecting cost per unit of care. We normalized baseline recall timeframes to past 30 days and evaluated for missing data. Results We identified measures that are feasible and appropriate for estimating healthcare sector costs including ED visits, inpatient hospital and residential facility stays, and outpatient encounters. We also identified two self-reported measures to inform societal costs (days experiencing SUD problems, participant spending on substances). Missingness was 8% or less for all study measures and was lower for single questions measuring utilization in a recall period. Conclusions We recommend including measures representing units of service with specific recall periods (e.g., 6 months vs. lifetime), and collecting healthcare resource utilization data using single-question measures to reduce missingness

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

Male breast cancer in BRCA1 and BRCA2 mutation carriers : pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Background: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 x 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 x 10(-12)). Conclusions: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.Peer reviewe

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