Abstract
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.
Highlights
The current gold-standard diagnosis for Parkinson’s disease (PD) is based on clinicopathological criteria that include neuronal loss in the substantia nigra pars compacta and Lewy-body (LB) pathology related to alpha-synuclein (α-Syn) aggregation [1,2,3]
real‐time quaking‐induced conversion (RT‐QuIC) seeding activity is associated with disease status and genetic mutations Association with disease Eighty-five percent of PD and 86% of dementia with Lewy bodies (DLB) patients showed a positive Real-time quaking-induced conversion (RT-QuIC) α-Syn seeding activity compared to 8% of controls (Table 1)
There were no significant differences in RT-QuIC seeding kinetics (AUC, Maximum of intensity (Imax), and lag phase (LAG)) between PD and DLB patients with positive α-Syn seeding (p > 0.05)
Summary
The current gold-standard diagnosis for Parkinson’s disease (PD) is based on clinicopathological criteria that include neuronal loss in the substantia nigra pars compacta and Lewy-body (LB) pathology related to alpha-synuclein (α-Syn) aggregation [1,2,3]. While PD patients with mutations in the GBA gene ( PDGBA) show extensive LB pathology, most PD patients with bi-allelic mutations in the recessive gene parkin (PDrecessive_bi-allelic) show nigral degeneration without LBs [4]. The histopathology in PD patients with LRRK2 mutations (PDLRRK2) is remarkably variable, including typical LB pathology, misfolded tau deposition or nigral degeneration without LBs [5,6,7]. This heterogeneity highlights the need for pathology-driven biomarkers that distinguish between the different underlying pathologies in-vivo. With disease-modifying treatment options targeting α-Syn underway, patient stratification according to α-Syn-specific enrichment strategies is a much-needed prerequisite to introduce patients to clinical trials
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