Feasibility of Digital Memory Assessments in an Unsupervised and Remote Study Setting

Sensitive and frequent digital remote memory assessments via mobile devices hold the promise to facilitate the detection of cognitive impairment and decline. However, in order to be successful at scale, cognitive tests need to be applicable in unsupervised settings and confounding factors need to be understood. This study explored the feasibility of completely unsupervised digital cognitive assessments using three novel memory tasks in a Citizen Science project across Germany. To that end, the study aimed to identify factors associated with stronger participant retention, to examine test-retest reliability and the extent of practice effects, as well as to investigate the influence of uncontrolled settings such as time of day, delay between sessions or screen size on memory performance. A total of 1,407 adults (aged 18-89) participated in the study for up to 12 weeks, completing weekly memory tasks in addition to short questionnaires regarding sleep duration, subjective cognitive complaints as well as cold symptoms. Participation across memory tasks was pseudorandomized such that individuals were assigned to one of three memory paradigms resulting in three otherwise identical sub-studies. One hundred thirty-eight participants contributed to two of the three paradigms. Critically, for each memory task 12 independent parallel test sets were used to minimize effects of repeated testing. First, we observed a mean participant retention time of 44 days, or 4 active test sessions, and 77.5% compliance to the study protocol in an unsupervised setting with no contact between participants and study personnel, payment or feedback. We identified subject-level factors that contributed to higher retention times. Second, we found minor practice effects associated with repeated cognitive testing, and reveal evidence for acceptable-to-good retest reliability of mobile testing. Third, we show that memory performance assessed through repeated digital assessments was strongly associated with age in all paradigms, and individuals with subjectively reported cognitive decline presented lower mnemonic discrimination accuracy compared to non-complaining participants. Finally, we identified design-related factors that need to be incorporated in future studies such as the time delay between test sessions. Our results demonstrate the feasibility of fully unsupervised digital remote memory assessments and identify critical factors to account for in future studies

Novelty-Related fMRI Responses of Precuneus and Medial Temporal Regions in Individuals at Risk for Alzheimer Disease

BACKGROUND AND OBJECTIVES: We assessed whether novelty-related fMRI activity in medial temporal lobe regions and the precuneus follows an inverted U-shaped pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with a higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy. METHODS: We studied 499 participants aged 60-88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of β-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel > highly familiar scenes) in entorhinal cortex, hippocampus, and precuneus as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, sex, study site, and education. RESULTS: In the precuneus, we observed an inverted U-shaped pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared with HC, but not in patients with AD who showed relatively lower activity than MCI. This nonlinear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to the precuneus, hippocampal activity was reduced in AD dementia compared with all other groups and related to AD biomarkers. DISCUSSION: Novelty-related activity in the precuneus follows a nonlinear pattern across the clinical spectrum of increased AD risk. Although the underlying mechanism remains unclear, increased precuneus activity might represent an early signature of memory impairment. Our results highlight the nonlinearity of activity alterations that should be considered in clinical trials using functional outcome measures or targeting hyperactivity

The concept of regularization: resolving the problem of surface dyslexia in semantic variant primary progressive aphasia across different languages

Surface dyslexia, a diagnostic feature of the semantic variant of primary progressive aphasia (svPPA), is difficult to observe in many languages. It can be conceptualized as one manifestation of a more general "regularization" effect-that is, with semantic impairment, patients fail to recognize exceptions and revert to default rules. Objective: We predicted that, analogous to surface dyslexia in English, German patients with svPPA would regularize irregular verbs, especially those of lower frequency and in the less frequently used preterite tense. Method: Regularization was investigated in German through past-tense verb inflectional morphology in N = 10 svPPA, N = 5 PPA related to Alzheimer pathology (Aβ+PPA), N = 5 patients with nonfluent variant PPA (nfvPPA), N = 12 typical (amnestic presentation) Alzheimer's disease (AD), and N = 32 healthy controls. The task involved perfect- and preterite-tense inflection of regular and irregular verbs of high and low frequency. Results: Errors in svPPA particularly involved regularization (e.g., I swim → I swimmed, I have swimmed), whereas Aβ+PPA made a wide range of other errors (e.g., verb agreement or tense errors). Regularization was rare in AD and controls, whereas the expected frequency effects (low worse than high) were found in svPPA. nfvPPA had profound difficulties in inflecting verbs in general. Conclusion: The study illustrates how tests tailored to a specific language can reveal the regularization effect of svPPA. For more universal diagnostic recommendations, future revisions for svPPA should consider substituting the criterion of surface dyslexia for that of a general criterion of regularization of language rules, the former being an example of the latter

The atrophy pattern in Alzheimer-related PPA is more widespread than that of the frontotemporal lobar degeneration associated variants

Objective: The three recognized variants of primary progressive aphasia (PPA) are associated with different loci of degeneration—left posterior perisylvian in logopenic variant (lvPPA), left frontal operculum in non-fluent variant (nfvPPA), and left rostroventral-temporal in semantic variant (svPPA). Meanwhile, it has become apparent that patients with lvPPA, in which Alzheimer pathology is the norm, frequently have more extensive language deficits—namely semantic and grammatical problems—than is captured in the strict diagnostic recommendations for this variant. We hypothesized that this may be because the degeneration in AD-related PPA typically extends beyond the left posterior perisylvian region. Methods: Magnetic resonance images from 25 PPA patients (9AD-related PPA, 10 svPPA, 6 nfvPPA) and a healthy control cohort were used to calculate cortical thickness in three regions of interest (ROIs). The three ROIs being the left-hemispheric loci of maximal reported degeneration for each of the three variants of PPA. Results: Consistent with past studies, the most severe cortical thinning was in the posterior perisylvian ROI in AD-related PPA; the ventral temporal ROI in svPPA; and the frontal opercular ROI in nfvPPA. Significant cortical thinning in AD-related PPA, however, was evident in all three ROIs. In contrast, thinning in svPPA and nfvPPA was largely restricted to their known peak loci of degeneration. Conclusions: Although cortical degeneration in AD-related PPA is maximal in the left posterior perisylvian region, it extends more diffusely throughout the left hemisphere language network offering a plausible explanation for why the linguistic profile of lvPPA so often includes additional semantic and grammatic deficits