Objective: To detect α-synuclein (αSyn) pathology and associated clinical characteristics in patients with idiopathic normal pressure hydrocephalus (iNPH) through cerebrospinal fluid (CSF) αSyn seed amplification assay (αSyn-SAA).

Background: The pathophysiology of iNPH is still poorly understood. The variable and often not sustained response to shunt surgery and the overlap of clinical symptoms with neurodegenerative disorders have led to questioning the idiopathic nature of iNPH. In this context, recent αSyn-SAA studies with CSF of iNPH patients have revealed αSyn-pathology in 14-20.5% of iNPH patients[1,2].

Method: Consecutive patients with clinically diagnosed iNPH were recruited during an inpatient diagnostic workup at the Paracelsus-Elena Klinik Kassel, Germany, between 2008 – 2022. Clinical characteristics were assessed with MDS-UPDRS-III, MMSE, and Sniffing stick olfactory identification test. All patients underwent a diagnostic spinal tap test with removal of 30–50 cc CSF before performing temporo-spatial gait analysis. Samples were blindly analyzed with αSyn-SAA by Amprion, following previously published assay conditions[3].

Results: A total of 102 iNPH patients (71m, 31f) were recruited, of which 28 (27.5%) patients were αSyn-SAA+. The mean age in αSyn-SAA-/αSyn-SAA+ (76.2/77.9 years) and the mean disease duration (2.8/3.2 years) was similar in both groups. There was no significant difference between Syn-SAA-/αSyn-SAA+ in mean MDS-UPDRS-III score (24.9/26.0) and MMSE score (23.8/23.1). Of 12 different scents, αSyn-SAA+ patients identified significantly fewer scents (mean 3.7) than αSyn-SAA- patients (mean 8.8, p< 0.05) during olfactory testing.

Conclusion: Our study extends the findings of two previous studies and provides further evidence for underlying αSyn pathology in iNPH (27.5%). Since clinical disease trajectories and treatment responses are very variable in iNPH, patient stratification based on underlying pathology can increase our understanding of the disease and allow the identification of more targeted therapies. Moreover, αSyn-SAA+ patients had worse olfaction than patients with αSyn-SAA-. Although independent replication in additional cohorts and neuropathological confirmation is needed, our findings already suggest that hyposmia could serve as a surrogate marker for αSyn-neuropathology in iNPH.

References: 1. Fasano, A. et al. ALPHA‐SYNUCLEIN RT‐QUIC in Idiopathic Normal Pressure Hydrocephalus. Ann. Neurol. 92, 985–991 (2022).
2. Giannini, G. et al. In vivo assessment of Lewy body and beta-amyloid copathologies in idiopathic normal pressure hydrocephalus: prevalence and associations with clinical features and surgery outcome. Fluids Barriers CNS 19, 71 (2022).
3. 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/hyposmia-is-associated-with-positive-csf-%ce%b1-synuclein-seeding-in-normal-pressure-hydrocephalus/