Objective: To assess the frequency of pathological α-synuclein (αSyn) in various movement disorders and neurodegenerative diseases from a specialized movement disorder clinic by αSyn seed amplification assay (αSyn-SAA) in CSF.

Background: Neuropathological studies revealed that αSyn-pathology is not exclusive to Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and Multiple System Atrophy (MSA). It is detected as a co-pathology to a variable degree in other forms of neurodegenerative disorders[1].

Method: Between 2008-2022, 605 (219 f, 386 m) consecutive patients were recruited at the Paracelsus-Elena Klinik Kassel, Germany. Diagnoses were finalized after comprehensive evaluations (e.g. clinical examination, lumbar puncture, levodopa response, imaging) and according to established diagnostic criteria. αSyn-SAA was performed blindly by Amprion using assay conditions reported before[2].

Results: A clinical diagnosis was reached in 583/605 (96.4%) patients. The highest rates of αSyn-SAA positivity were found in synucleinopathies: PD (96.8% positive [+], n=93), DLB (94.7%+, 75), MSA (91.9%+, 37). Moderate frequency of αSyn-SAA+ was also detected in tauopathies (TP) (31.3%+, 96), Alzheimer’s disease (AD) (38.1%+, 21), vascular PD/vascular dementia (25.5%+, 55) and idiopathic normal pressure hydrocephalus (iNPH) (27.5%+, 102). All PD with concomitant iNPH were αSyn-SAA+ (100%+, 13). Patients with chorea (14.3%+, 7) dystonia (11.1%+, 9), multifactorial gait disorder (8.3%+, 12), cerebellar ataxia (8.0%+, 25) and essential tremor (0%+, 6) were αSyn-SAA+ to a lesser extent. Rare miscellaneous diagnoses (e.g. myoclonus, restless-legs syndrome, etc.) were mostly negative (9.4%+, 32).  A high number of αSyn-SAA+ was found in cases with unresolved diagnoses: unclear dementia with movement disorder (80.0%+, 5), unclear neurodegeneration (42.9%+, 7) and unclear hypokinetic movement disorder (30.0%+, 10).

Conclusion: Our study provides an important reference of αSyn-pathology by CSF αSyn-SAA in a large real-life diagnostic cohort. We show that αSyn-pathology is common in AD, TP, and iNPH. Furthermore, the high rate of αSyn-SAA+ in cases not meeting diagnostic criteria for a specific disease is a reminder that many syndromes are not caused by a single type of protein accumulation, and are rather the result of complex relationships between underlying proteinopathies and affected neuronal pathways.

References: 1. Moda, F. et al. Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception. Front. Biosci.-Landmark 28, 255 (2023).
2. Bellomo, G. et al. Investigating alpha-synuclein co-pathology in Alzheimer’s disease by means of cerebrospinal fluid alpha-synuclein seed amplification assay. Alzheimers Dement. J. Alzheimers Assoc. (2024) doi:10.1002/alz.13658.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/%ce%b1-synuclein-pathology-across-movement-disorders-and-neurodegenerative-diseases-by-seed-amplification-assay/