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The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers  in-vivo . Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in  GBA ,  parkin ,  PINK1 ,  DJ1, and  LRRK2 . A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe  GBA  mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe  GBA  mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with  GBA  mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF. These findings highlight the value of α-Syn seeding activity as an  in-vivo  marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.

Seed amplification assays have been implemented in Parkinson’s disease to reveal disease-specific misfolded alpha-synuclein aggregates in biospecimens. While the assays’ qualitative dichotomous seeding response is valuable to stratify and enrich cohorts for alpha-synuclein pathology in general, more quantitative parameters that are associated with clinical dynamics of disease progression and that might potentially serve as exploratory outcome measures in clinical trials targeting alpha-synuclein would add important information. To evaluate whether the seeding kinetic parameters time required to reach the seeding threshold (LAG phase), the peak of fluorescence response (Imax), and the area under the curve (AUC) are associated with clinical trajectories, we analyzed LAG, Imax, and AUC in relation to the development of cognitive decline in a longitudinal cohort of 199 people with Parkinson’s disease with positive CSF alpha-synuclein seeding status. Patients were stratified into tertiles based on their individual CSF alpha-synuclein seeding kinetic properties. The effect of the kinetic parameters on longitudinal development of cognitive impairment defined by MoCA ≤25 was analyzed by Cox-Regression. Patients with a higher number of positive seeding replicates and tertile groups of shorter LAG, higher Imax, and higher AUC showed a higher prevalence of and a shorter duration until cognitive impairment longitudinally (3, 6, and 3 years earlier with p  ≤ 0.001, respectively). Results remained similar in separate subgroup analyses of patients with and without GBA mutation. We conclude that a more prominent alpha-synuclein seeding kinetic profile translates into a more rapid development of cognitive decline.

The muscle‐specific RING finger proteins MuRF1 and MuRF2 have been proposed to regulate protein degradation and gene expression in muscle tissues. We have tested the in vivo roles of MuRF1 and MuRF2 for muscle metabolism by using knockout (KO) mouse models. Single MuRF1 and MuRF2 KO mice are healthy and have normal muscles. Double knockout (dKO) mice obtained by the inactivation of all four MuRF1 and MuRF2 alleles developed extreme cardiac and milder skeletal muscle hypertrophy. Muscle hypertrophy in dKO mice was maintained throughout the murine life span and was associated with chronically activated muscle protein synthesis. During ageing (months 4–18), skeletal muscle mass remained stable, whereas body fat content did not increase in dKO mice as compared with wild‐type controls. Other catabolic factors such as MAFbox/atrogin1 were expressed at normal levels and did not respond to or prevent muscle hypertrophy in dKO mice. Thus, combined inhibition of MuRF1/MuRF2 could provide a potent strategy to stimulate striated muscles anabolically and to protect muscles from sarcopenia during ageing.

Based on animal and ex-vivo experiments, Growth/Differentiation Factor-15 (GDF15, also called Macrophage Inhibitory Cytokine-1, MIC1), a member of the transforming growth factor-beta family, and Matrix Metalloproteinase-9 (MMP9), a member of the matrix metalloprotease family may be potential markers for Lewy body disorders, i.e. Parkinson's disease with (PDD) and without dementia (PDND) and Lewy body dementia (DLB). GDF15 has a prominent role in development, cell proliferation, differentiation, and repair, whereas MMP9 degrades, as a proteolytic enzyme, components of the extracellular matrix. In this study, cerebrospinal fluid GDF15 and MMP9 levels of 59 PDND, 17 PDD and 23 DLB patients, as well as of 95 controls were determined, and associated with demographic, clinical and biochemical parameters. Our analysis confirmed the already described association of GDF15 levels with age and gender. Corrected GDF15 levels were significantly higher in PDD than in PDND patients, and intermediate in DLB patients. Within Lewy body disorders, GDF15 levels correlated positively with age at onset of Parkinsonism and dementia, Hoehn & Yahr stage and cerebrospinal fluid t-Tau and p-Tau levels, and negatively with the Mini Mental State Examination. Remarkably, it does not relevantly correlate with disease duration. MMP9 was not relevantly associated with any of these parameters. Cerebrospinal GDF15, but not MMP9, may be a potential marker of and in Lewy body disorders.

With age, sensory, cognitive, and motor abilities decline, and the risk for neurodegenerative disorders increases. These impairments influence the quality of life and increase the need for care, thus putting a high burden on society, the economy, and the healthcare system. Therefore, it is important to identify factors that influence healthy aging, particularly ones that are potentially modifiable through lifestyle choices. However, large-scale studies investigating the influence of multi-modal factors on a global description of healthy aging measured by multiple clinical assessments are sparse. We propose a machine learning model that simultaneously predicts multiple cognitive and motor outcome measurements on a personalized level recorded from one learned composite score. This personalized composite score is derived from a large set of multi-modal components from the TREND cohort, including genetic, biofluid, clinical, demographic, and lifestyle factors. We found that a model based on a single composite score was able to predict cognitive and motor abilities almost as well as a classical flexible regression model specifically trained for each single clinical score. In contrast to the flexible regression model, our composite score model is able to identify factors that globally influence cognitive and motoric abilities as measured by multiple clinical scores. The model identified several risk and protective factors for healthy aging and recovered physical exercise as a major, modifiable, protective factor. We conclude that our low parametric modeling approach successfully recovered known risk and protective factors of healthy aging on a personalized level while providing an interpretable composite score. We suggest validating this modeling approach in other cohorts.

•Sports activity was associated with mood, sleep, cognitive flexibility, single and dual-tasking markers.•The positive effect of baseline physical activity on mood and cognition was still present after six years.•Our results strengthen the potential role of sports activity as a positive disease modifier for neurodegenerative diseases. 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. 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. 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. 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.

Quantitative pathology-specific biomarkers are needed for patients with Parkinson’s disease (PD). We estimated the α-syn seeding dose giving 50% of positive seed amplification assay (SAA) reactions (SD50) in serially diluted samples from 260 PD participants, of whom 54 had longitudinal samples. We then evaluated the associations between SD50 values and demographic and clinical parameters, including motor and cognitive scales, REM sleep behaviour disorder (RBD), and hyposmia. Higher SD50 values were significantly associated with older age, longer disease duration, worse motor and cognitive scores, and presence of RBD and visual hallucinations. Baseline SD50 values predicted the development of motor wearing-off and severe cognitive impairment. In participants with longitudinal samples, SD50 values remained substantially stable over time. Quantification of α-syn through endpoint dilution SAA may serve as a potential surrogate marker of LB pathological burden, which may support prognostication and patient stratification.

Inflammation modifies the incidence and progression of Parkinson’s disease (PD). By using 30 inflammatory markers in CSF in 498 people with PD and 67 people with dementia with Lewy bodies (DLB) we show that: (1) levels of ICAM-1, Interleukin-8, MCP-1, MIP-1 beta, SCF and VEGF were associated with clinical scores and neurodegenerative CSF biomarkers (Aβ1-42, t-Tau, p181-Tau, NFL and α-synuclein). (2) PD patients with GBA mutations show similar levels of inflammatory markers compared to PD patients without GBA mutations, even when stratified by mutation severity. (3) PD patients who longitudinally developed cognitive impairment during the study had higher levels of TNF-alpha at baseline compared to patients without the development of cognitive impairment. (4) Higher levels of VEGF and MIP-1 beta were associated with a longer duration until the development of cognitive impairment. We conclude that the majority of inflammatory markers is limited in robustly predicting longitudinal trajectories of developing cognitive impairment.

Parkinson’s disease (PD) exhibits substantial phenotypic variability, likely influenced, at least in part, by proteins associated with pathways integral to aging processes. Plasminogen activator inhibitor-1 (SERPIN E1) is known for its association with aging processes and exacerbated α-Synuclein pathology. We examined whether SERPIN E1 levels in cerebrospinal fluid (CSF) differ among controls (CON, N  = 16) and patients with PD ( N  = 479) or Dementia with Lewy bodies (DLB, N  = 67), considering that these conditions represent a spectrum of α-Synuclein pathology. Kaplan-Meier survival analysis stratified by SERPIN E1 tertile levels was conducted to evaluate phenotype-modifying effects. Elevated levels of SERPIN E1 exhibited an association with increased age and lower MOCA scores. Heightened SERPIN E1 levels were observed in individuals diagnosed with DLB, followed by PD and CON, and in males compared to females. The quantification of SERPIN E1 in CSF could potentially serve as a surrogate marker, depicting (pathological) aging processes.

We studied the age- and genetic-related prevalence of CSF alpha-Synuclein seeding and Alzheimer profiles in 188 samples from PD participants without GBA1 variants (PD wildtype ) and in 129 samples from PD participants with GBA1 variants (PD GBA1 ). While Alzheimer profiles increased with age in PD wildtype , it was sparse in PD GBA1 . Alpha-Synuclein profiles remained stable with age in both cohorts. In PD wildtype , combined alpha-Synuclein/Alzheimer profiles were associated with earlier onset of cognitive impairment.