Cerebrospinal fluid alpha-synuclein seed amplification assay positivity identifies a prognostically distinct subgroup in amyotrophic lateral sclerosis
Abstract
Background-synuclein (Lewy body-type) co-pathology has been identified at autopsy in a subset of patients with amyotrophic lateral sclerosis (ALS). However, its prevalence and prognostic relevance in vivo remain poorly characterized.
MethodsWe analyzed baseline cerebrospinal fluid (CSF) -synuclein seed amplification assay (Syn SAA) status in 443 patients with ALS from two cohorts (Nagoya, Japan, n = 248; Bologna, Italy, n = 195). Samples were classified as strong-positive, weak-positive, or negative based on RT-QuIC reactivity across replicate wells, using the assays established a priori criteria at initial and repeat testing; classifications were corroborated by quantitative kinetic parameters. We compared age- and sex-adjusted odds of positivity in ALS with those in cognitively unimpaired (CU; n = 999; stratified by amyloid-{beta} [A{beta}] status), A{beta}-positive mild cognitive impairment (n = 224), and Alzheimers disease dementia (n = 319) groups from the Swedish BioFINDER cohort. In ALS, we examined tracheostomy-free survival and longitudinal functional decline using cohort-stratified Cox and linear mixed-effects models, respectively. We also assessed interactions between Syn SAA status and baseline CSF neurofilament light chain (NfL). Prognostic analyses were performed in sporadic ALS and repeated after including familial or genetic cases.
ResultsStrong Syn SAA positivity was detected in 24/443 patients with ALS (5.4%); overall positivity, including weak-positive samples, was 37/443 (8.4%). Patients with ALS did not have significantly higher odds of SAA positivity than A{beta}-negative CU participants (age- and sex-adjusted odds ratio [OR] 1.33, 95% CI [0.82, 2.14]) and had significantly lower odds than patients with Alzheimers disease dementia (OR 0.44, [0.27, 0.70]). Among patients with sporadic ALS, strong Syn SAA positivity was associated with shorter tracheostomy-free survival after adjustment for established predictors including NfL (adjusted HR 2.08 [1.25, 3.45]), whereas weak positivity showed no clear survival association. In linear mixed-effects models, strong Syn SAA positivity modified the association between NfL and ALSFRS-R decline (NfL x Syn SAA x time interaction {beta}-0.70 points/month [-1.26, -0.14] per SD NfL). These findings persisted in analyses including familial or genetic ALS cases and in those restricted to A{beta}-negative patients. Neuropathological findings (n = 5) were concordant with the CSF Syn SAA classification.
ConclusionsA strong -synuclein seeding profile was uncommon in ALS but identified a subgroup with shorter survival and a stronger association between NfL and functional decline. These findings provide ante-mortem evidence that -synuclein co-pathology may contribute to prognostic heterogeneity in ALS.
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BibTeX
@misc{obara2026cerebrospinal,
title = {{Cerebrospinal fluid alpha-synuclein seed amplification assay positivity identifies a prognostically distinct subgroup in amyotrophic lateral sclerosis}},
author = {Kazuki Obara and Andrea Mastrangelo and Agustina Ranieri and Shorena Janelidze and Daisuke Ito and Munetaka Yamamoto and Veria Vacchiano and Rocco Liguori and Serena Caldera and Yuichi Riku and Yasushi Iwasaki and Sinh Tran and Takahiro Kawase and Yu Mori and Keita Hiraga and Shinichiro Yamada and Koyo Tsujikawa and Yosuke Nishio and Tomoo Ogi and Ryoichi Nakamura and Naoki Atsuta and Gen Sobue and Erik Stomrud and Sebastian Palmqvist and Oskar Hansson and Piero Parchi and Masahisa Katsuno and Niklas Mattsson-Carlgren},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.23.26366349},
url = {https://www.medrxiv.org/content/10.64898/2026.10.23.26366349v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cerebrospinal fluid alpha-synuclein seed amplification assay positivity identifies a prognostically distinct subgroup in amyotrophic lateral sclerosis
AU - Kazuki Obara
AU - Andrea Mastrangelo
AU - Agustina Ranieri
AU - Shorena Janelidze
AU - Daisuke Ito
AU - Munetaka Yamamoto
AU - Veria Vacchiano
AU - Rocco Liguori
AU - Serena Caldera
AU - Yuichi Riku
AU - Yasushi Iwasaki
AU - Sinh Tran
AU - Takahiro Kawase
AU - Yu Mori
AU - Keita Hiraga
AU - Shinichiro Yamada
AU - Koyo Tsujikawa
AU - Yosuke Nishio
AU - Tomoo Ogi
AU - Ryoichi Nakamura
AU - Naoki Atsuta
AU - Gen Sobue
AU - Erik Stomrud
AU - Sebastian Palmqvist
AU - Oskar Hansson
AU - Piero Parchi
AU - Masahisa Katsuno
AU - Niklas Mattsson-Carlgren
PY - 2026
DA - 2026/10/23
PB - medRxiv
DO - 10.64898/2026.10.23.26366349
UR - https://www.medrxiv.org/content/10.64898/2026.10.23.26366349v1
AB - Background-synuclein (Lewy body-type) co-pathology has been identified at autopsy in a subset of patients with amyotrophic lateral sclerosis (ALS). However, its prevalence and prognostic relevance in vivo remain poorly characterized. MethodsWe analyzed baseline cerebrospinal fluid (CSF) -synuclein seed amplification assay (Syn SAA) status in 443 patients with ALS from two cohorts (Nagoya, Japan, n = 248; Bologna, Italy, n = 195). Samples were classified as strong-positive, weak-positive, or negative based on RT-QuIC reactivity across replicate wells, using the assays established a priori criteria at initial and repeat testing; classifications were corroborated by quantitative kinetic parameters. We compared age- and sex-adjusted odds of positivity in ALS with those in cognitively unimpaired (CU; n = 999; stratified by amyloid-{beta} [A{beta}] status), A{beta}-positive mild cognitive impairment (n = 224), and Alzheimers disease dementia (n = 319) groups from the Swedish BioFINDER cohort. In ALS, we examined tracheostomy-free survival and longitudinal functional decline using cohort-stratified Cox and linear mixed-effects models, respectively. We also assessed interactions between Syn SAA status and baseline CSF neurofilament light chain (NfL). Prognostic analyses were performed in sporadic ALS and repeated after including familial or genetic cases. ResultsStrong Syn SAA positivity was detected in 24/443 patients with ALS (5.4%); overall positivity, including weak-positive samples, was 37/443 (8.4%). Patients with ALS did not have significantly higher odds of SAA positivity than A{beta}-negative CU participants (age- and sex-adjusted odds ratio [OR] 1.33, 95% CI [0.82, 2.14]) and had significantly lower odds than patients with Alzheimers disease dementia (OR 0.44, [0.27, 0.70]). Among patients with sporadic ALS, strong Syn SAA positivity was associated with shorter tracheostomy-free survival after adjustment for established predictors including NfL (adjusted HR 2.08 [1.25, 3.45]), whereas weak positivity showed no clear survival association. In linear mixed-effects models, strong Syn SAA positivity modified the association between NfL and ALSFRS-R decline (NfL x Syn SAA x time interaction {beta}-0.70 points/month [-1.26, -0.14] per SD NfL). These findings persisted in analyses including familial or genetic ALS cases and in those restricted to A{beta}-negative patients. Neuropathological findings (n = 5) were concordant with the CSF Syn SAA classification. ConclusionsA strong -synuclein seeding profile was uncommon in ALS but identified a subgroup with shorter survival and a stronger association between NfL and functional decline. These findings provide ante-mortem evidence that -synuclein co-pathology may contribute to prognostic heterogeneity in ALS.
ER -