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.

Background Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha‐synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As disease‐modifying treatment options such as alpha‐synuclein lowering compounds are under way, patient stratification according to alpha‐synuclein‐specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite. Objective Are GBA1 mutations associated with a CSF alpha‐synuclein profile in PD? Methods Screening of the GBA1 gene and analysis of CSF levels of total alpha‐synuclein were performed in 80 PDGBA, 80 PDGBA_wildtype and 39 healthy controls cross‐sectionally. Subgroup analyses based on mutation severity was done for PDGBA. Results Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha‐synuclein. Conclusion The effects of GBA1 mutations on CSF alpha‐synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. © 2019 International Parkinson and Movement Disorder Society

BackgroundNeurofilament light protein is an unspecific biofluid marker that reflects the extent of neuronal/axonal damage and thereby offers the chance monitor disease severity and progression. The objective of this study was to investigate cerebrospinal fluid (CSF) levels of neurofilament light protein in Parkinson’s disease (PD) patients with clinical trajectories of motor and cognitive function longitudinally.MethodsCSF neurofilament light protein levels were assessed in 371 PDsporadic, 126 genetic PD patients (91 PDGBA, 8 PDLRRK2, 21 PDPRKN/PINK1/DJ1_heterozygous, 6 PDPRKN/PINK1/DJ1_homozygous), and 71 healthy controls. Participants were followed up longitudinally for up to 8 years.ResultsAt baseline, mean CSF neurofilament light protein levels were highest in PD patients with cognitive impairment (Montreal Cognitive Assessment score ≤ 25; 1207 pg/mL) but also higher in PD patients with normal cognitive function (757 pg/mL) compared with healthy controls (593 pg/mL; P ≤ 0.001). In healthy controls and in PD patients older age was associated with higher CSF levels of neurofilament light protein (P ≤ 0.001). In PD patients, male gender, older age at onset, longer disease duration, higher Hoehn and Yahr stages, higher UPDRS‐III scores, and lower Montreal Cognitive Assessment scores were associated with higher CSF levels of neurofilament light protein (P < 0.01). In patients who developed cognitive impairment during study, CSF neurofilament light protein levels prior to conversion to cognitive impairment were not significantly different compared with CSF neurofilament light protein levels of patients who remained cognitively normal.ConclusionsIncreased CSF levels of neurofilament light protein are associated with cognitive decline and motor impairment in PD. However, this increase seems not a very early event and does not mark the conversion to cognitive impairment beforehand. Therefore, the predictive value needs to be discussed critically. © 2020 International Parkinson and Movement Disorder Society