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. 2025 Jan 3;11(1):7.
doi: 10.1038/s41531-024-00854-4.

Radiological markers of CSF α-synuclein aggregation in Parkinson's disease patients

Amgad Droby  1   2   3   4 , Avital Yoffe-Vasiliev  5   6 , Daniel Atias  5   6 , Kyle B Fraser  7 , Omar S Mabrouk  7 , Nurit Omer  5   6 , Anat Bar-Shira  5   8 , Mali Gana-Weisz  5   8 , Orly Goldstein  5   8 , Moran Artzi  9 , Dafna Ben Bashat  9 , Roy N Alcalay  5   10   8 , Avi Orr-Urtreger  10   8 , Julia C Shirvan  7 , Jesse M Cedarbaum  11 , Nir Giladi  5   6   10   12 , Anat Mirelman  5   6   10   12 , Avner Thaler  5   6   10
Affiliations

Radiological markers of CSF α-synuclein aggregation in Parkinson's disease patients

Amgad Droby et al. NPJ Parkinsons Dis. .

Abstract

Alpha-synuclein (αS) aggregation is a widely regarded hallmark of Parkinson's disease (PD) and can be detected through synuclein amplification assays (SAA). This study investigated the association between cerebrospinal fluid (CSF) radiological measures in 41 PD patients (14 iPD, 14 GBA1-PD, 13 LRRK2-PD) and 14 age-and-sex-matched healthy controls. Quantitative measures including striatal binding ratios (SBR), whole-brain and deep gray matter volumes, neuromelanin-MRI (NM-MRI), functional connectivity (FC), and white matter (WM) diffusion-tensor imaging (DTI) were calculated. Nine LRRK2-PD patients were SAA-negative (PD-SAA-). PD-SAA+ patients showed lower whole-brain gray matter, putamenal, brainstem, and substantia nigra volumes, reduced FC in the left caudate, and lower fractional anisotropy in the left fronto-occipital fasciculus compared to PD-SAA-. Taken together, αS aggregation was observed in iPD, GBA1-PD, and 38% of LRRK2-PD patients, and this was associated with reduced regional brain volumes, altered caudal FC, and SBRs. These changes were less pronounced in PD-SAA-, possibly suggesting a milder neurodegenerative process.

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Conflict of interest statement

Competing interests: AD is an Associate Editor for npj Parkinson’s Disease and receives honoria from Springer Nature. He was not involved in the journal’s review of, or decisions related to, this manuscript. AY-V, BC, NO, AB-S, MG-W, OG, and AO-U report no competing interests. KBF, OSM, and JCS are employees of and own stock in Biogen. RNA research is funded by the Michael J. Fox Foundation (MJFF) and the Parkinson’s Foundation. He received consultation fees from Genzyme/Sanofi, Takeda, and Gain Therapeutics. JMC is a former employee of Biogen, and reports no competing interests relevant to this work. NG has no competing interests pertaining to this work. He serves as a member of the editorial board for the Journal of Parkinson’s Disease. He serves as a consultant to Sionara, Accelmed, Teva, NeuroDerm, Intec Pharma, Pharma2B, Denali, and Abbvie. He received royalties from Lysosomal Therapeutics (LTI) and payment for lectures at Teva, UCB, Abbvie, Sanofi-Genzyme, Bial and Movement Disorder Society. He received research support from the Michael J Fox Foundation, the National Parkinson Foundation, the European Union 7th Framework Program, and the Israel Science Foundation, as well as from the Teva NNE program, Biogen, LTI, and Pfizer. AM reports no competing interests relevant to this work. AM is an Associate Editor for npj Parkinson’s Disease and receives Honoria from Springer Nature. She was not involved in the journal’s review of, or decisions related to, this manuscript. She reports serving as an advisor to Neuroderm. AT reports receiving honoraria from Abbvie, research funding from MJFF, and consultation fees from Capsida Inc. He reports no competing interests relevant to this work.

Figures

Fig. 1
Fig. 1. Flowchart demonstrating included participants in the final analysis.
CSF corticospinal fluid, SAA synuclein amplification assays, iPD idiopathic PD, NMNC non-manifesting non-carriers (healthy controls).
Fig. 2
Fig. 2. Box-dot plots demonstrating distribution and between-group differences in investigated radiological measures (the central line in each box represents the median score, dots represent each data point in the dataset).
a Between groups’ differences in measured striatl binding ratio (SBR) based on DaTscan. Significantly reduced SBR values were detected between HCs and both PD groups (p = 0.002; Bonferroni-corrected in all cases). b Left panel: compared to HCs, significantly higher left putamen and right volumes in the HC group compared to PD-SAA- (p = 0.003 and p = 0.004 respectively, Bonferroni-corrected) were observed. Compared to HCs, PD-SAA+ showed significantly lower volumes in the brainstem (p < 0.001 Bonferroni-corrected), and the putamen bilaterally (p < 0.001 Bonferroni-corrected in all cases). Right panel: significantly lower whole-brain GM volumes (Mann–Whitney U-test, p = 0.002, Bonferroni-corrected) in PD-SAA+ compared to HCs. c In rs-fMRI, the PD-SAA+ group showed significantly reduced FC levels in the left and right caudate nucleus compared to the PD-SAA- group (p = 0.002; Bonferroni-corrected in both cases). d In NM-MRI, reduced left SN volume was observed in the PD-SAA+ group compared to HC (p < 0.001; Bonferroni-corrected) e Significantly higher FA along the L SFOF fibers where measured in PD-SAA- vs. PD-SAA+ (p < 0.001, Bonferroni-corrected). PD-SAA+: N = 33 [14 iPD, 14 GBA1-PD, 5 LRRK2-PD], PD-SAA-: N = 8 [all LRRK2-PD], HC = 14. adenotes post hoc comparison PD-SAA- vs. HC; cdenotes post hoc comparison PD-SAA+ vs. HC; ddenotes post hoc comparison PD-SAA- vs. PD-SAA+. *denotes p ≤ 0.05; **denotes 0.05≤ p ≤ 0.001; ***denotes p < 0.001.
Fig. 3
Fig. 3. Leave one out cross-validation (LOOCV) for PD status classification based on the identified radiological features.
a Receiver operating characteristic (ROC) curve for the optimal features subset, showing the classifier’s performance. The area under the curve (AUC) was 0.74, indicating strong classification performance. b Feature importance ranking showing the contribution of the top four features identified during feature selection. The selected features contributed most significantly to the classifier’s precision.
See this image and copyright information in PMC

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