Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline.Materials and Methods:N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5.Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = −0.38, 95% CI [−0.54 – −0.19], p < 0.001) and inferior-temporal lobe (r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02).Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.

The heritability of amyloid burden in older adults: the Older Australian Twins Study

ObjectiveTo determine the proportional genetic contribution to the variability of cerebral β-amyloid load in older adults using the classic twin design.MethodsParticipants (n=206) comprising 61 monozygotic (MZ) twin pairs (68 (55.74%) females; mean age (SD): 71.98 (6.43) years), and 42 dizygotic (DZ) twin pairs (56 (66.67%) females; mean age: 71.14 (5.15) years) were drawn from the Older Australian Twins Study. Participants underwent detailed clinical and neuropsychological evaluations, as well as MRI, diffusion tensor imaging (DTI) and amyloid PET scans. Fifty-eight participants (17 MZ pairs, 12 DZ pairs) had PET scans with 11Carbon-Pittsburgh Compound B, and 148 participants (44 MZ pairs, 30 DZ pairs) with 18Fluorine-NAV4694. Cortical amyloid burden was quantified using the centiloid scale globally, as well as the standardised uptake value ratio (SUVR) globally and in specific brain regions. Small vessel disease (SVD) was quantified using total white matter hyperintensity volume on MRI, and peak width of skeletonised mean diffusivity on DTI. Heritability (h2) and genetic correlations were measured with structural equation modelling under the best fit model, controlling for age, sex, tracer and scanner.ResultsThe heritability of global amyloid burden was moderate (0.41 using SUVR; 0.52 using the centiloid scale) and ranged from 0.20 to 0.54 across different brain regions. There were no significant genetic or environmental correlations between global amyloid burden and markers of SVD.ConclusionAmyloid deposition, the hallmark early feature of Alzheimer’s disease, is under moderate genetic influence, suggesting a major environmental contribution that may be amenable to intervention.

Association between Benton Visual Retention Test scores and PET imaging in elderly adults

Background: The Benton Visual Retention Test (BVRT) is a well-validated and reliable test for assessing visual memory and visuospatial function. However, the association between the BVRT score and imaging biomarker of Alzheimer’s disease (AD) remains unclear. Objective: This study examined whether the BVRT score is associated with brain amyloid burden and cortical glucose metabolism in elderly adults without dementia. Methods: A total of 69 elderly adults without dementia, including 45 subjects with amnestic mild cognitive impairment and 24 cognitively healthy adults, underwent the BVRT and 11C-Pittsburgh compound B (PiB) and 18F-fluorodeoxyglucose (FDG) positron emission tomography. The correct scores in the BVRT were used for analyses. A multiple linear regression analysis was conducted to investigate the relationship between BVRT scores and PiB or FDG uptake. Moreover, a voxel-wise linear regression analysis of the association between BVRT scores and PiB or FDG uptake was conducted using Statistical Parametric Mapping. Results: After adjusting for age, sex, education, and ApoE4 status, the BVRT scores were inversely correlated with the mean PiB uptake (β = −0.35, P = 0.003), whereas they were positively correlated with FDG uptake (β = 0.266, P = 0.038). Moreover, the BVRT scores were inversely correlated with amyloid burden in the right superior temporal and superior frontal gyri and the left parietal lobe, whereas they were positively correlated with cortical glucose metabolism in the right posterior cingulate and milled temporal gyri, left temporoparietal lobe, and right superior frontal gyrus. Conclusion: BVRT scores are correlated with brain amyloid burden and cortical glucose metabolism, mainly in regions commonly affected in AD.

Electrocardiogram Characteristics and Prognostic Value in Light-Chain Amyloidosis: A Comparison With Cardiac Magnetic Resonance Imaging

Background: An electrocardiogram (ECG) is a simple and cheap non-invasive tool that shows various abnormalities and has prognostic value for patients with light-chain amyloidosis (AL). The present study aimed to explore the association between ECG characteristics and cardiac magnetic resonance (CMR)-detected amyloid burden and to investigate the prognostic value of ECG in AL amyloidosis.Methods: We prospectively enrolled 99 patients with AL amyloidosis (56 male patients; median age, 58 y). Detailed clinical information, 12-lead ECG, and CMR data were collected. All patients were followed up longitudinally, and the endpoint was all-cause mortality. ECG characteristics were analyzed and correlated with the degree of late gadolinium enhancement (LGE) and extracellular volume (ECV) by T1 mapping on CMR. The prognostic value of ECG characteristics was analyzed using Kaplan–Meier survival analysis and multivariate Cox regression.Results: During a median follow-up period of 33 months, 69 of the 99 patients died. Fragmented Q wave-R wave-S wave (QRS), pathological Q waves, the Sokolow index, QRS duration, and voltages were significantly associated with the extent of LGE, native T1, and ECV by CMR (p < 0.05). Fragmented QRS and Sokolow index showed independent prognostic value in AL amyloidosis (p = 0.001; p = 0.026, respectively). Fragmented QRS remained independent after adjusting for clinical values (hazard ratio: 2.034; 95% confidence interval: 1.148–3.603; p = 0.015). However, no ECG characteristics were independent predictors for prognosis in AL amyloidosis when LGE and ECV were included in the multivariate analysis.Conclusion: ECG abnormalities showed significant association with CMR indicators of amyloid burden. Fragmented QRS has an independent prognostic value in AL amyloidosis and could be used as an alternative marker when CMR is not available.

Is Amyloid Burden Measured by 18F-Flutemetamol PET Associated with Progression in Clinical Alzheimer’s Disease?

Background: Patients with Alzheimer’s disease (AD) show heterogeneity in clinical progression rate, and we have limited tools to predict prognosis. Amyloid burden from 18F-Flutemetamol positron emission tomography (PET), as measured by standardized uptake value ratios (SUVR), might provide prognostic information. Objective: We investigate whether 18F-Flutemetamol PET composite or regional SUVRs are associated with trajectories of clinical progression. Methods: This observational longitudinal study included 94 patients with clinical AD. PET images were semi-quantified with normalization to pons. Group-based trajectory modeling was applied to identify trajectory groups according to change in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) over time. Multinomial logistic regression models assessed the association of SUVRs with trajectory group membership. Results: Three trajectory groups were identified. In the regression models, neither composite nor regional SUVRs were associated with trajectory group membership. Conclusion: There were no associations between CDR progression and 18F-Flutemetamol PET-derived composite SUVRs or regional SUVRs in clinical AD.