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ORIGINAL RESEARCH article

Front. Neurol.
Sec. Neuromuscular Disorders and Peripheral Neuropathies
Volume 15 - 2024 | doi: 10.3389/fneur.2024.1418320

Neuroinflammation and glycosylation-related cerebrospinal fluid proteins for predicting functional decline in amyotrophic lateral sclerosis: a proteomic study

Provisionally accepted
Kimie Nakamura Kimie Nakamura 1Koji Fujita Koji Fujita 2*Motohisa Suzuki Motohisa Suzuki 1Akiyoshi Kunugi Akiyoshi Kunugi 1Yoshihiko Hirozane Yoshihiko Hirozane 1Tomonori Kunikata Tomonori Kunikata 3Bitoku Takahashi Bitoku Takahashi 3Genta Narazaki Genta Narazaki 3Hirofumi Kondo Hirofumi Kondo 3Shotaro Haji Shotaro Haji 2Keisuke Hirai Keisuke Hirai 1Yuishin Izumi Yuishin Izumi 2
  • 1 Takeda Pharmaceutical Company Limited, Capital Federal, Argentina
  • 2 Tokushima University, Tokushima, Japan
  • 3 Daiichi Sankyo (Japan), Tokyo, Tôkyô, Japan

The final, formatted version of the article will be published soon.

    Background: The rate of disease progression varies widely among patients with amyotrophic lateral sclerosis (ALS). Prognostic assessment using biomarkers is highly anticipated to improve clinical trial design. We aimed to explore the cerebrospinal fluid (CSF) for prognostic biomarkers to predict future functional decline in patients with ALS. Methods: We collected CSF samples from 64 patients with ALS and 25 disease controls. The prospective progression rate was calculated using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) at CSF collection and in 6 months. The ALS patients were classified into slow, intermediate, and fast progression groups. We performed comprehensive proteomic analyses of the CSF samples. Factors with significant changes between slow and fast progression groups were investigated via receiver operating characteristic curve analyses. Moreover, the correlation of the CSF factors with progression rate was evaluated by multiple regression analyses. Results: In total, 26 proteins changed significantly (p < 0.05 and q < 0.10), with levels varying within a large dynamic range (fold change of > 1.5 or < 0.5). A receiver operating characteristic curve analyses showed that the following proteins showed high discrimination power between slow and fast progression groups: glycoprotein non-metastatic melanoma protein B (GPNMB; area under the curve [AUC], 0.88), glial fibrillary acidic protein (AUC, 0.81), glypican-1 (GPC1; AUC, 0.79), alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (AUC, 0.74), and chitinase-3-like protein 2 (CHI3L2; AUC, 0.73). Of these, GPNMB, GPC1, and CHI3L2 were significantly correlated to prognostic progression rate. Conclusions: This study demonstrated that CSF levels of neuroinflammation and glycosylation-related proteins were significantly correlated with prospective progression rates in patients with ALS. These proteins could be useful prognostic biomarkers for ALS.

    Keywords: Amyotrophic Lateral Sclerosis, biomarker, Cerebrospinal Fluid, Glycosylation, Progression rate

    Received: 16 Apr 2024; Accepted: 23 Jul 2024.

    Copyright: © 2024 Nakamura, Fujita, Suzuki, Kunugi, Hirozane, Kunikata, Takahashi, Narazaki, Kondo, Haji, Hirai and Izumi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Koji Fujita, Tokushima University, Tokushima, Japan

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.