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. 2025 Jun;40(6):1206-1213.
doi: 10.1002/mds.30184. Epub 2025 Apr 9.

Anosmia and Upper Limb Rigidity-A Potential Phenotype of Idiopathic Normal Pressure Hydrocephalus with Cerebrospinal Fluid α-Synuclein Seeds

Sandrina Weber  1   2 , Carly M Farris  3 , Yihua Ma  3 , Mohammed Dakna  1 , Maritta Starke  2 , Sebastian Schade  2 , Michael Bartl  1   4 , Claudia Trenkwalder  2   5 , Luis Concha-Marambio  3 , Brit Mollenhauer  1   2
Affiliations

Anosmia and Upper Limb Rigidity-A Potential Phenotype of Idiopathic Normal Pressure Hydrocephalus with Cerebrospinal Fluid α-Synuclein Seeds

Sandrina Weber et al. Mov Disord. 2025 Jun.

Abstract

Background: The pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) and its association with neurodegenerative disorders is poorly understood.

Objectives: The aim was to determine the prevalence of α-synuclein pathology in iNPH and its associations with clinical characteristics.

Methods: We used α-synuclein seed amplification assay (synSAA) to retrospectively analyze cerebrospinal fluid (CSF) from a large single-center iNPH cohort (n = 144). Clinical assessments comprised Unified Parkinson's Disease Rating Scale part III, Mini-Mental State Examination, levodopa-challenge test, and olfactory identification test. Degenerative biomarkers (total-tau, phospho-tau, β-amyloid 1-42, and β-amyloid 1-40) were measured in CSF.

Results: A total of 30.1% of iNPH patients were synSAA+, and presented significantly more upper limb (UL) rigidity, hallucinations, and worse olfactory performance than synSAA- cases. Anosmia was higher in synSAA+ patients (64.0%) than synSAA- patients (15.3%). Clinical assessments and other biomarkers did not significantly vary with synSAA status.

Conclusions: Underlying α-synuclein pathology is common in iNPH and presents with UL rigidity and olfactory dysfunction, suggesting a distinct synSAA+ phenotype in iNPH. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: SAA; anosmia; normal pressure hydrocephalus; seed amplification assay; α‐synuclein.

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Figures

FIG. 1
FIG. 1
Violin plots showing the number of correctly identified smells (maximum 12) in the “Sniffin’ Sticks” olfactory identification test of α‐synuclein seed amplification assay negative (synSAA‐) and α‐synuclein seed amplification assay positive (synSAA+) idiopathic normal pressure hydrocephalus (iNPH) patients. Olfactory performance: ≥10 normosmia, 9–7 hyposmia, ≤6 anosmia. [Color figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

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