Prediction of disorientation by accelerometric and gait features in young and older adults navigating in a virtually enriched environment

OBJECTIVE: To determine whether gait and accelerometric features can predict disorientation events in young and older adults. METHODS: Cognitively healthy younger (18–40 years, n = 25) and older (60–85 years, n = 28) participants navigated on a treadmill through a virtual representation of the city of Rostock featured within the Gait Real-Time Analysis Interactive Lab (GRAIL) system. We conducted Bayesian Poisson regression to determine the association of navigation performance with domain-specific cognitive functions. We determined associations of gait and accelerometric features with disorientation events in real-time data using Bayesian generalized mixed effect models. The accuracy of gait and accelerometric features to predict disorientation events was determined using cross-validated support vector machines (SVM) and Hidden Markov models (HMM). RESULTS: Bayesian analysis revealed strong evidence for the effect of gait and accelerometric features on disorientation. The evidence supported a relationship between executive functions but not visuospatial abilities and perspective taking with navigation performance. Despite these effects, the cross-validated percentage of correctly assigned instances of disorientation was only 72% in the SVM and 63% in the HMM analysis using gait and accelerometric features as predictors. CONCLUSION: Disorientation is reflected in spatiotemporal gait features and the accelerometric signal as a potentially more easily accessible surrogate for gait features. At the same time, such measurements probably need to be enriched with other parameters to be sufficiently accurate for individual prediction of disorientation events

LATE: Nicht jede Demenz ist Alzheimer – Diskussion einer neuen Krankheitsentität am Fallbeispiel

Limbic-predominant age-related TDP-43 (Transactivation response(TAR)-DNA-binding protein 43 kDa) encephalopathy (LATE) has recently been characterized as a distinct neuropathological entity within the spectrum of dementia. Neuropathological alterations in the sense of LATE were already previously described as a comorbidity to Alzheimer's disease (AD) and it has been diagnosed independently from AD pathology in autopsy studies since 2008. The framework of LATE would account for the pathogenetic impact of limbic TDP-43 proteinopathy as a driver of amnestic dementia, either together with comorbid typical AD changes or as a distinct feature. The LATE possibly explains divergent clinical observations and biomarker results in patients suffering from severe amnestic impairment without biomarker evidence of AD-related amyloid and tau alterations. Whether LATE represents a distinct neuropathological entity or is part of the spectrum of neurodegenerative diseases associated with TDP-43 is currently a matter of debate. Further studies on the role of TDP-43 in the development of amnestic dementia are urgently needed. Thus, the enrichment of an amnestic phenotype in amyloid-centered therapeutic drug studies bears the risk of higher rates of patients with TDP-43 comorbidity, which could hinder the proof of efficacy in such trials. This article presents the current state of the discussion on LATE and illustrates the concept and the clinical considerations with a case study

Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer’s disease: results from the DELCODE study

Abstract Background Neuroinflammation constitutes a pathological hallmark of Alzheimer’s disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD. Methods Data of 74 healthy controls (HC), 99 subjective cognitive decline (SCD), 75 mild cognitive impairment (MCI), 23 AD relatives, and 38 AD subjects were obtained from the DELCODE cohort. A panel of 20 serum biomarkers was determined using immunoassays. Analyses were adjusted for age, sex, APOE status, and body mass index and included correlations between serum and CSF marker levels and AD biomarker levels. Group-wise comparisons were based on screening diagnosis and routine AD biomarker-based schematics. Structural imaging data were combined into composite scores representing Braak stage regions and related to serum biomarker levels. The Preclinical Alzheimer’s Cognitive Composite (PACC5) score was used to test for associations between the biomarkers and cognitive performance. Results Each experimental marker displayed an individual profile of interrelations to AD biomarkers, imaging, or cognition features. Serum-soluble AXL (sAXL), IL-6, and YKL-40 showed the most striking associations. Soluble AXL was significantly elevated in AD subjects with pathological CSF beta-amyloid/tau profile and negatively related to structural imaging and cognitive function. Serum IL-6 was negatively correlated to structural measures of Braak regions, without associations to corresponding IL-6 CSF levels or other AD features. Serum YKL-40 correlated most consistently to CSF AD biomarker profiles and showed the strongest negative relations to structure, but none to cognitive outcomes. Conclusions Serum sAXL, IL-6, and YKL-40 relate to different AD features, including the degree of neuropathology and cognitive functioning. This may suggest that peripheral blood signatures correspond to specific stages of the disease. As serum markers did not reflect the corresponding CSF protein levels, our data highlight the need to interpret serum inflammatory markers depending on the respective protein’s specific biology and cellular origin. These marker-specific differences will have to be considered to further define and interpret blood-based inflammatory profiles for AD research

Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve

Introduction: Several lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them. Methods: We systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE). Results: Regarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM. Discussion: Our results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology

Data_Sheet_1_Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve.pdf

IntroductionSeveral lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them.MethodsWe systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE).ResultsRegarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM.DiscussionOur results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology.</p