Study Rationale: In the era where we aim to define diseases by biology and modifying treatment options become available for neurodegenerative diseases, the clinicopathological heterogeneity in alpha-synucleinopathies such as Parkinson’s disease (PD), PD dementia (PDD) and dementia with Lewy Bodies (DLB) highlights the need for pathology-specific biomarkers that can be assessed during lifetime. Misfolded and aggregated alpha-synuclein (α-Syn) represents the hallmark of pathology in PD. Yet, Alzheimer’s Disease (AD) co-pathology modifies disease progression, including the development of cognitive decline. While the classical CSF and blood markers for AD pathology, such as Amyloid-β and phospho‑Tau species, have been widely available for some time, it was only recently that seed amplification assays (SAA), detecting misfolded α-Syn in CSF and other biospecimens have been successfully implemented.
Hypothesis: Investigating the isolated and/or combined prevalence of α-Syn and AD pathology based on CSF biomarker profiles offer the opportunity to characterize the various pathologies underlying disease progression as a basis for heterogenous clinical trajectories and treatment responses in clinical trials. However, whether the prevalence of an isolated or combined pathology changes with age and/or with disease progression and whether pathology profiles differ between PD and DLB participants with and without genetic variants is unclear.
Study Design: We here aim to advance our understanding on (I) α-Syn and AD co-pathology across different synucleinopathies and against clinically related diseases (PSP, MCI, AD), (II) the contribution of varying pathology to endophenotypes and clinical trajectories, (III) the newly proposed NSD-ISS staging system (Neuronal α-Synuclein Disease Integrated Staging System). To this end we will analyze 5 large longitudinal cohorts from the German Center for Neurodegenerative Disease (DZNE; ttps://www.dzne.de/en/research): DESCRIBE PD (PD, PDD, DLB), DESCRIBE MSA, DESCRIBE PSP, DELCODE (healthy elderly, MCI, AD), DANCER (healthy elderly).
Impact on Diagnosis/Treatment of Parkinson’s Disease: By combining different α-Syn-related cohorts with various CSF biomarker profiles along with genetic and longitudinal phenotyping data, this study will advance the field in identifying pathology-driven molecular endophenotypes and their impact on disease progression of motor and non-motor symptoms in sporadic and in genetic cases.
Next Steps for Development: Results from this study will help to stratify participants for clinical trials and to estimate effect sizes and treatment responses based on the underlying pathology.