Diffusion MRI and α-Synuclein Seed Amplification Status in Parkinson's Disease

Shannon Y. Chiu; Wei en Wang; Robin Chen; Jesse C. DeSimone; Derek B. Archer; Charles H. Adler; Shyamal H. Mehta; Sara R. Dresler; Melissa J. Armstrong; Nikolaus McFarland; Michael Okun; David E. Vaillancourt; Neha Prakash; Tanya Simuni; Nabila Dahodwala; Caroline Tanner; Lana Chahine; Brit Mollenhauer; Anat Mirelman; Roy Alcalay Leaver; Marie Saint-Hilaire; Ruth Schneider; Christopher Tarolli; Werner Poewe; Aleksandar Videnovic; David Standaert; Marissa Dean; Sonja Jonsdottir; Rejko Krueger; Claire Pauly; Stewart Factor; Penelope Hogarth; Robert Hauser; Amy Amara; Michelle Fullard; Cyrus Zabetian; Hubert Fernandez; Kathrin Brockmann; Isabel Wurster; Yen Tai; Paolo Barone; Marina Picillo; Stuart Isaacson; Alberto Espay; Eduardo Tolosa; Javier Ruiz Martinez; Leonidas Stefanis; Kelvin Chou; Lorraine Kalia; Connie Marras; Parkinson's Progression Markers Initiative

doi:10.1002/ana.78252

Diffusion MRI and α-Synuclein Seed Amplification Status in Parkinson's Disease

Shannon Y. Chiu^*
, Wei en Wang
, Robin Chen
, Jesse C. DeSimone
, Derek B. Archer
, Charles H. Adler
, Shyamal H. Mehta
, Sara R. Dresler
, Melissa J. Armstrong
, Nikolaus McFarland
, Michael Okun
, David E. Vaillancourt
, Neha Prakash
, Tanya Simuni
, Nabila Dahodwala
, Caroline Tanner
, Lana Chahine
, Brit Mollenhauer
, Anat Mirelman
, Roy Alcalay Leaver

Marie Saint-Hilaire, Ruth Schneider, Christopher Tarolli, Werner Poewe, Aleksandar Videnovic, David Standaert, Marissa Dean, Sonja Jonsdottir, Rejko Krueger, Claire Pauly, Stewart Factor, Penelope Hogarth, Robert Hauser, Amy Amara, Michelle Fullard, Cyrus Zabetian, Hubert Fernandez, Kathrin Brockmann, Isabel Wurster, Yen Tai, Paolo Barone, Marina Picillo, Stuart Isaacson, Alberto Espay, Eduardo Tolosa, Javier Ruiz Martinez, Leonidas Stefanis, Kelvin Chou, Lorraine Kalia, Connie Marras, Parkinson's Progression Markers Initiative

^*Corresponding author for this work

Transversal Translational Medicine

Research output: Contribution to journal › Article › Research › peer-review

Abstract

OBJECTIVE: Positive α-synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free-water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA- status.

METHODS: We studied patients with PD with baseline diffusion imaging and α-synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA T), and clinical characteristics between SAA+ and SAA- groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status.

RESULTS: Among 462 participants (41 SAA- and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA- (pFDR < 0.05). No significant differences in FA T were found between groups.

INTERPRETATION: Positive α-synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295-304.

Original language	English
Pages (from-to)	295-304
Number of pages	10
Journal	Annals of Neurology
Volume	100
Issue number	2
Early online date	7 May 2026
DOIs	https://doi.org/10.1002/ana.78252
Publication status	Published - Aug 2026

Keywords

Humans
alpha-Synuclein/metabolism
Parkinson Disease/diagnostic imaging
Female
Aged
Diffusion Magnetic Resonance Imaging/methods
Male
Middle Aged
Brain/diagnostic imaging

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Chiu, S. Y., Wang, W. E., Chen, R., DeSimone, J. C., Archer, D. B., Adler, C. H., Mehta, S. H., Dresler, S. R., Armstrong, M. J., McFarland, N., Okun, M., Vaillancourt, D. E., Prakash, N., Simuni, T., Dahodwala, N., Tanner, C., Chahine, L., Mollenhauer, B., Mirelman, A., ... Parkinson's Progression Markers Initiative (2026). Diffusion MRI and α-Synuclein Seed Amplification Status in Parkinson's Disease. Annals of Neurology, 100(2), 295-304. https://doi.org/10.1002/ana.78252

@article{5aedce732256466fbe8ae33b8432b175,

title = "Diffusion MRI and α-Synuclein Seed Amplification Status in Parkinson's Disease",

abstract = "OBJECTIVE: Positive α-synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free-water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA- status.METHODS: We studied patients with PD with baseline diffusion imaging and α-synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA T), and clinical characteristics between SAA+ and SAA- groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status. RESULTS: Among 462 participants (41 SAA- and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4\% (n = 427, 91.6\% had SAA+) and classified 7.6\% as atypical parkinsonism (n = 35, 85.7\% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA- (pFDR < 0.05). No significant differences in FA T were found between groups. INTERPRETATION: Positive α-synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295-304. ",

keywords = "Humans, alpha-Synuclein/metabolism, Parkinson Disease/diagnostic imaging, Female, Aged, Diffusion Magnetic Resonance Imaging/methods, Male, Middle Aged, Brain/diagnostic imaging",

author = "Chiu, \{Shannon Y.\} and Wang, \{Wei en\} and Robin Chen and DeSimone, \{Jesse C.\} and Archer, \{Derek B.\} and Adler, \{Charles H.\} and Mehta, \{Shyamal H.\} and Dresler, \{Sara R.\} and Armstrong, \{Melissa J.\} and Nikolaus McFarland and Michael Okun and Vaillancourt, \{David E.\} and Neha Prakash and Tanya Simuni and Nabila Dahodwala and Caroline Tanner and Lana Chahine and Brit Mollenhauer and Anat Mirelman and Leaver, \{Roy Alcalay\} and Marie Saint-Hilaire and Ruth Schneider and Christopher Tarolli and Werner Poewe and Aleksandar Videnovic and David Standaert and Marissa Dean and Sonja Jonsdottir and Rejko Krueger and Claire Pauly and Stewart Factor and Penelope Hogarth and Robert Hauser and Amy Amara and Michelle Fullard and Cyrus Zabetian and Hubert Fernandez and Kathrin Brockmann and Isabel Wurster and Yen Tai and Paolo Barone and Marina Picillo and Stuart Isaacson and Alberto Espay and Eduardo Tolosa and Martinez, \{Javier Ruiz\} and Leonidas Stefanis and Kelvin Chou and Lorraine Kalia and Connie Marras and \{Parkinson's Progression Markers Initiative\}",

note = "{\textcopyright} 2026 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

year = "2026",

month = aug,

doi = "10.1002/ana.78252",

language = "English",

volume = "100",

pages = "295--304",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley \& Sons Inc.",

number = "2",

}

Chiu, SY, Wang, WE, Chen, R, DeSimone, JC, Archer, DB, Adler, CH, Mehta, SH, Dresler, SR, Armstrong, MJ, McFarland, N, Okun, M, Vaillancourt, DE, Prakash, N, Simuni, T, Dahodwala, N, Tanner, C, Chahine, L, Mollenhauer, B, Mirelman, A, Leaver, RA, Saint-Hilaire, M, Schneider, R, Tarolli, C, Poewe, W, Videnovic, A, Standaert, D, Dean, M, Jonsdottir, S , Krueger, R , Pauly, C, Factor, S, Hogarth, P, Hauser, R, Amara, A, Fullard, M, Zabetian, C, Fernandez, H, Brockmann, K, Wurster, I, Tai, Y, Barone, P, Picillo, M, Isaacson, S, Espay, A, Tolosa, E, Martinez, JR, Stefanis, L, Chou, K, Kalia, L, Marras, C & Parkinson's Progression Markers Initiative 2026, 'Diffusion MRI and α-Synuclein Seed Amplification Status in Parkinson's Disease', Annals of Neurology, vol. 100, no. 2, pp. 295-304. https://doi.org/10.1002/ana.78252

TY - JOUR

T1 - Diffusion MRI and α-Synuclein Seed Amplification Status in Parkinson's Disease

AU - Chiu, Shannon Y.

AU - Wang, Wei en

AU - Chen, Robin

AU - DeSimone, Jesse C.

AU - Archer, Derek B.

AU - Adler, Charles H.

AU - Mehta, Shyamal H.

AU - Dresler, Sara R.

AU - Armstrong, Melissa J.

AU - McFarland, Nikolaus

AU - Okun, Michael

AU - Vaillancourt, David E.

AU - Prakash, Neha

AU - Simuni, Tanya

AU - Dahodwala, Nabila

AU - Tanner, Caroline

AU - Chahine, Lana

AU - Mollenhauer, Brit

AU - Mirelman, Anat

AU - Leaver, Roy Alcalay

AU - Saint-Hilaire, Marie

AU - Schneider, Ruth

AU - Tarolli, Christopher

AU - Poewe, Werner

AU - Videnovic, Aleksandar

AU - Standaert, David

AU - Dean, Marissa

AU - Jonsdottir, Sonja

AU - Krueger, Rejko

AU - Pauly, Claire

AU - Factor, Stewart

AU - Hogarth, Penelope

AU - Hauser, Robert

AU - Amara, Amy

AU - Fullard, Michelle

AU - Zabetian, Cyrus

AU - Fernandez, Hubert

AU - Brockmann, Kathrin

AU - Wurster, Isabel

AU - Tai, Yen

AU - Barone, Paolo

AU - Picillo, Marina

AU - Isaacson, Stuart

AU - Espay, Alberto

AU - Tolosa, Eduardo

AU - Martinez, Javier Ruiz

AU - Stefanis, Leonidas

AU - Chou, Kelvin

AU - Kalia, Lorraine

AU - Marras, Connie

AU - Parkinson's Progression Markers Initiative

PY - 2026/8

Y1 - 2026/8

N2 - OBJECTIVE: Positive α-synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free-water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA- status.METHODS: We studied patients with PD with baseline diffusion imaging and α-synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA T), and clinical characteristics between SAA+ and SAA- groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status. RESULTS: Among 462 participants (41 SAA- and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA- (pFDR < 0.05). No significant differences in FA T were found between groups. INTERPRETATION: Positive α-synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295-304.

AB - OBJECTIVE: Positive α-synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free-water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA- status.METHODS: We studied patients with PD with baseline diffusion imaging and α-synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA T), and clinical characteristics between SAA+ and SAA- groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status. RESULTS: Among 462 participants (41 SAA- and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA- (pFDR < 0.05). No significant differences in FA T were found between groups. INTERPRETATION: Positive α-synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295-304.

KW - Humans

KW - alpha-Synuclein/metabolism

KW - Parkinson Disease/diagnostic imaging

KW - Female

KW - Aged

KW - Diffusion Magnetic Resonance Imaging/methods

KW - Male

KW - Middle Aged

KW - Brain/diagnostic imaging

UR - https://www.scopus.com/pages/publications/105038704906

UR - https://pubmed.ncbi.nlm.nih.gov/42095555/

U2 - 10.1002/ana.78252

DO - 10.1002/ana.78252

M3 - Article

C2 - 42095555

AN - SCOPUS:105038704906

SN - 0364-5134

VL - 100

SP - 295

EP - 304

JO - Annals of Neurology

JF - Annals of Neurology

IS - 2

ER -

Diffusion MRI and α-Synuclein Seed Amplification Status in Parkinson's Disease

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Keywords

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