Longitudinal cognitive decline characterizes the profile of non-PD-manifest GBA1 mutation carriers.

With disease-modifying treatment for Parkinson's disease (PD) associated with variants in the glucocerebrosidase gene (GBA1) under way, the challenge to design clinical trials with non-PD-manifest GBA mutation carriers (GBA1NMC) comes within close reach. To delineate trajectories of motor and non-motor markers as well as serum neurofilament light (sNfL) levels and to evaluate clinical endpoints as outcomes for clinical trials in GBA1NMC, longitudinal data of 56 GBA1NMC carriers and 112 age- and sex-matched GBA1 wildtype participants (GBA1wildtype) with up to 9 years of follow-up was analyzed using linear mixed-effects models (LMEM) and Kaplan-Meier survival analysis of clinical endpoints for motor and cognitive function. GBA1NMC showed worse performance in Pegboard, 20 m fast walking, global cognition as well as in executive and memory function at baseline. Longitudinally, LMEM revealed a higher annual increase of the MDS-UPDRS III bradykinesia subscore in GBA1NMC compared to GBA1wildtype, but comparable trajectories of all other motor and non-motor markers as well as sNfL. Kaplan-Meier survival analysis showed a significantly earlier progression to clinical endpoints of cognitive decline in GBA1NMC. Incidence of PD was significantly higher in GBA1NMC. In conclusion, our study extends data on GBA1NMC indicating early cognitive decline as a potentially characteristic feature. Comprehensive longitudinal assessments of cognitive function are crucial to delineate the evolution of early changes in GBA1NMC enabling a more accurate stratification and allow for a more precise definition of trial design and sample size.

[Patient and public involvement at the German Center for Mental Health: achievements and challenges]. / Patient and Public Involvement am Deutschen Zentrum für Psychische Gesundheit: Erreichtes und Herausforderungen.

BACKGROUND: Patient and public involvement (PPI) describes the participation of patients and relatives, i.e., experts by experience (EE), in the research process. The PPI has not been widely adopted in the fields of medicine and clinical psychology in Germany and there is a notable absence of institutional support. The German Center for Mental Health (DZPG), which has been under construction since May 2023, aims to achieve nationwide and cross-center implementation of PPI, constituting one of its primary objectives. Participation of EE is to be implemented in the DZPG at all levels of decision-making. OBJECTIVES: The article describes the origins, development and challenges associated with the implementation of participation structures and projects in the DZPG. The central political PPI committee in the DZPG, the Trilogue Center Council (TZR), developed a comprehensive PPI strategy for the DZPG in almost 3 years of work, before the beginning of the financial support of the DZPG. Among various measures, the strategy entails establishing a far-reaching representation for EE in all decision-making bodies of the DZPG, to involve EE as reviewers in evaluating research proposals, to integrate participatory elements into all studies of the DZGG and to foster user-initiated research endeavors. The implementation of the strategy is ensured by a cross-center PPI infrastructure, the Center for PPI, and scientific PPI consultants. The Center for PPI's tasks include supporting the voice of the EE and developing instruments and guidelines for participatory research, bringing together EE and researchers for joint DZPG projects as well as the documentation and quality assurance for participatory research. One of the particular challenges for the successful implementation of the PPI strategy is the limited experience with PPI in Germany in the field of mental health research and the widespread lack of structural implementation. Currently developed solution strategies include training for researchers and EE to communicate the benefits and pathways in the realization of PPI and thus enable shared decision-making and research. In addition, extensive access to knowledge and resources for EE will be created and uniform remuneration regulations for EE will be developed. CONCLUSION: A PPI strategy at the DZPG has been successfully developed and is currently being implemented by the cross-center infrastructure Center for PPI.

Walking parameters of older adults from a lower back inertial measurement unit, a 6-year longitudinal observational study.

Gait changes during aging and differs between sexes. Inertial measurement units (IMUs) enable accurate quantitative evaluations of gait in ambulatory environments and in large populations. This study aims to provide IMU-based gait parameters' values derived from a large longitudinal cohort study in older adults. We measured gait parameters, such as velocity, step length, time, variability, and asymmetry, from straight, self-paced 20-m walks in older adults (four visits: 715/1102/1017/957 participants) every second year over 6 years using an IMU at the lower back. Moreover, we calculated the associations of gait parameters with sex and age. Women showed lower gait speed, step length, step time, stride time, swing time, and stance time, compared to men. Longitudinal analyses suggest that these parameters are at least partly deteriorating within the assessment period of 2 years, especially in men and at an older age. Variability and asymmetry parameters show a less clear sex- and age-associated pattern. Altogether, our large longitudinal dataset provides the first sex-specific information on which parameters are particularly promising for the detection of age-related gait changes that can be extracted from an IMU on the lower back. This information may be helpful for future observational and treatment studies investigating sex and age-related effects on gait, as well as for studies investigating age-related diseases.

Autonomic Symptoms in Older Adults Are Common and Associated With Health-Related Quality of Life.

Background: Autonomic symptoms are common in older adults, and a large body of literature focusing on age-related diseases shows that autonomic symptoms in these diseases constrain Health-Related Quality of Life (HRQoL). To our best knowledge, the association between autonomic symptoms in older adults, independent of specific diseases, and HRQoL has not yet been assessed. Aim: To assess the frequency and the effect of autonomic symptoms in general, as well as orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor symptoms, on HRQoL in older adults. Methods: Cross-sectional data of the fourth visit of the Tübinger evaluation of Risk factors for Early detection of Neurodegeneration (TREND) study were included. Autonomic symptoms, as assessed with the Composite Autonomic Symptom Score 31 (COMPASS 31), were quantified and compared with HRQoL, as assessed with the EuroQol five-level version (EQ-5D-5L). Statistical analyses included Spearman's rank correlation and multiple linear regression analysis. Results: The analysis included 928 participants with a median of 68 years; 47% were women. Of those, 85% reported at least one autonomic symptom. Gastrointestinal and secretomotor symptoms were most common. The COMPASS 31 total score and all subdomains were significantly associated with reduced HRQoL. Among the subdomains, the strongest correlations with HRQoL were found for gastrointestinal and bladder symptoms. Overall, autonomic symptoms alone explained 20% of the variance of HRQoL; when depressive mood was added, the model explained 32%. Conclusion: Autonomic symptoms are associated with HRQoL and depressive symptoms in older adults.

The effect of age and gender on anti-saccade performance: Results from a large cohort of healthy aging individuals.

By 2050, the global population of people aged 65 years or older will triple. While this is accompanied with an increasing burden of age-associated diseases, it also emphasizes the need to understand the effects of healthy aging on cognitive processes. One such effect is a general slowing of processing speed, which is well documented in many domains. The execution of anti-saccades depends on a well-established brain-wide network ranging from various cortical areas and basal ganglia through the superior colliculus down to the brainstem saccade generators. To clarify the consequences of healthy aging as well as gender on the execution of reflexive and voluntary saccades, we measured a large sample of healthy, non-demented individuals (n = 731, aged 51-84 years) in the anti-saccade task. Age affected various aspects of saccade performance: The number of valid trials decreased with age. Error rate, saccadic reaction times (SRTs), and variability in saccade accuracy increased with age, whereas anti-saccade costs, accuracy, and peak velocity of anti-saccades and direction errors were not affected by age. Gender affected SRTs independent of age and saccade type with male participants having overall shorter SRTs. Our rigid and solid statistical testing using linear mixed-effect models provide evidence for a uniform slowing of processing speed independent of the actually performed eye movement. Our data do not support the assumption of a specific deterioration of frontal lobe functions with aging.

Intraindividual Neurofilament Dynamics in Serum Mark the Conversion to Sporadic Parkinson's Disease.

BACKGROUND AND OBJECTIVES: With disease-modifying treatment strategies on the horizon, stratification of individual patients at the earliest stages of Parkinson's disease (PD) is key-ideally already at clinical disease onset. Blood levels of neurofilament light chain (NfL) provide an easily accessible fluid biomarker that might allow capturing the conversion from prodromal to manifest PD. METHODS: We assessed longitudinal serum NfL levels in subjects converting from prodromal to manifest sporadic PD (converters), at-risk subjects, and matched controls (72 participants with ≈4 visits), using single-molecule array (Simoa) technique. RESULTS: While NfL levels were not increased at the prodromal stage, subjects converting to the manifest motor stage showed a significant intraindividual acceleration of the age-dependent increase of NfL levels. CONCLUSIONS: The temporal dynamics of intraindividual NfL blood levels might mark the conversion to clinically manifest PD, providing a potential stratification biomarker for individual disease onset in the advent of precision medicine for PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Cholinergic Pathway SNPs and Postural Control in 477 Older Adults.

Objective: To determine whether single nucleotide polymorphisms (SNPs) of the cholinergic system and quantitative parameters of postural control are associated in healthy older adults. This is a cross-sectional analysis from the TREND study. Methods: All participants performed a static postural control task for 30 s on a foam pad in semitandem stance and eyes closed. We analyzed mean power frequency (MPF), area, acceleration, jerk, and velocity from a mobile sensor worn at the lower back using a validated algorithm. Genotypes of four SNPs in genes involved in the cholinergic system (SLC5A7, CHAT, BCHE, CHRNA4) were extracted from the NeuroX chip. All participants present a normal neurological examination and a Minimental state examination score >24. Results: Four hundred and seventy seven participants were included. Mean age was 69 years, 41% were female. One SNP of the cholinergic pathway was significantly associated with a quantitative postural control parameter. The minor allele of rs6542746 in SLC5A7 was associated with lower MPF (4.04 vs. 4.22 Hz; p = 3.91 × 10-4). Moreover, the following associations showed trends toward significance: minor allele of rs6542746 in SLC5A7 with higher anteroposterior acceleration (318 vs. 287 mG; p = 0.005), and minor allele of rs3810950 in CHAT with higher mediolateral acceleration [1.77 vs. 1.65 log(mG); p = 0.03] and velocity [1.83 vs. 1.74 log(mm/s); p = 0.019]. Intraindividual occurrence of rs6542746 and rs3810950 minor alleles was dose-dependently related with lower MPF (p = 0.004). Conclusion: This observational study suggests an influence of SNPs of the cholinergic pathway on postural control in older adults.

Effect of physical activity on cognitive flexibility, depression and RBD in healthy elderly.

OBJECTIVE: The prevalence of Alzheimer's disease and Parkinson's disease increases with the raising number of elderly, which will be a challenging situation for the healthcare systems and society in the future. There is evidence that there are modifiable risk-factors e.g. physical activity for these diseases. Here, we study the interaction between sports inactivity with prodromal markers for neurodegeneration. PATIENTS AND METHODS: We investigated 667 neurologically healthy individuals cross-sectional and a subgroup longitudinal over six years. Participants were stratified by their weekly sports activity. Prodromal markers (depression and REM sleep behaviour disorder (RBD)) as well as single and dual-tasking parameters and cognitive parameters were compared between the groups. RESULTS: At baseline, sports activity was associated with lower BDI scores, lower occurrence of depressive syndrome and RBD, compared to sports inactivity. Further, active participants were faster in cognitive tasks associated with working memory and attention (Trail Making test part-A; TMT-B, ΔTMT-B-A) and better in gait and cognition parameters (single tasks and dual tasks) but not with overall cognition as measured with the MMSE. The association between physical inactivity and depression as well as TMT was present after six years. CONCLUSION: We found that sports activity has a positive effect on cognitive flexibility, depressive symptoms and sleep which are all signs for a possible ongoing neurodegenerative process. Therefore, our results strengthen the potential role of sports activity as a positive disease modifier.

Prospective longitudinal course of cognition in older subjects with mild parkinsonian signs.

BACKGROUND: Mild parkinsonian signs (MPS) are common in older people and are associated with an increased risk of different neurodegenerative diseases. This study prospectively evaluates the longitudinal course of cognitive performance in older individuals with MPS. METHODS: From the TREND study, 480 individuals neurologically healthy at baseline, aged between 50 and 80 years, with complete follow-up data for three assessments within a mean of 43.8 months, were included in this analysis. Participants underwent a detailed cognitive test battery, evaluation of prodromal markers for neurodegenerative diseases and history of vascular diseases at each study visit. In addition, plasma levels of amyloid-beta (Aß)1-40 and Aß1-42 were evaluated longitudinally. RESULTS: In 52 (11 %) of the 480 participants, MPS could be detected at baseline. These individuals had cognitive deficits significantly more often compared with controls at each time point and their cognitive performance showed a steeper decline during follow-up. In addition, their levels of plasma Aß1-42 were significantly lower than those of controls, and declined more rapidly over time. CONCLUSIONS: This longitudinal study shows that MPS are associated with cognitive decline and decrease in plasma Aß1-42, possibly indicating an ongoing neurodegenerative process.

Methods in Neuroepidemiology Characterization of European Longitudinal Cohort Studies in Parkinson's Disease--Report of the JPND Working Group BioLoC-PD.

BACKGROUND: Enormous effort is being put into the identification and characterization of symptoms that may be used as predictive and progression markers in Parkinson's disease (PD). An impressive number of PD patients and individuals at risk for or in the prodromal stage of PD are currently followed in longitudinal studies; however, there does not exist an overview on the kind of markers evaluated and the assessments used. METHODS: Information on the design, sample size, evaluated markers and assessments of 21 studies of the Joint Programme - Neurodegenerative Disease Research BioLoC-PD working group were collected by questionnaire. The studies were classified into at risk/prodromal or clinical PD cohorts. The assessments were grouped into quantitative assessments, investigator-rated assessments, investigator interviews, patient-rated questionnaires and caregiver-rated questionnaires. RESULTS: Compilation of these data revealed an interesting consensus on evaluated markers, but there was an enormous variability of assessments. Furthermore, there is a remarkable similarity in the markers assessed and evaluation methods applied in the risk/prodromal and clinical PD cohorts. CONCLUSIONS: The inventory of the longitudinal cohorts that are part of the BioLoC-PD consortium reveals that there is a growing consensus on the markers that should be assessed in longitudinal cohort studies in PD. However, controversy still exists on the specific type of assessment. To allow comparison of data and common analyses it will be essential to harmonize scales and assessment outcomes.