TY - JOUR
T1 - Chitotriosidase as biomarker for early stage amyotrophic lateral sclerosis: a multicenter study
AU - Steinacker, Petra
AU - Feneberg, Emily
AU - Halbgebauer, Steffen
AU - Witzel, Simon
AU - Verde, Federico
AU - Oeckl, Patrick
AU - van Damme, Philip
AU - Gaur, Nayana
AU - Gray, Elizabeth
AU - Grosskreutz, Julian
AU - Jardel, Claude G.
AU - Kachanov, Mykyta
AU - Kuhle, Jens
AU - Lamari, Foudil
AU - Maceski, Aleksandra
AU - del Mar Amador, Maria
AU - Mayer, Benjamin
AU - Morelli, Claudia
AU - Petri, Susanne
AU - Poesen, Koen
AU - Raaphorst, Joost
AU - Salachas, François
AU - Silani, Vincenzo
AU - Turner, Martin R.
AU - Verbeek, Marcel M.
AU - Volk, Alexander E.
AU - Weishaupt, Jochen H.
AU - Weydt, Patrick
AU - Ludolph, Albert C.
AU - Otto, Markus
N1 - Funding Information: This study was supported by the EU Joint Programme?Neurodegenerative Diseases (JPND) research networks under Grants Prefrontals [01ED1512], GENF-Prox [01ED2008A], and ONWebDUALS; the German Federal Ministry of Education and Research under Grant [FTLDc O1GI1007A]; the foundation of the state Baden-W?rttemberg under [Grant D.3830]; the Thierry Latran foundation; the ALS Association; Boehringer Ingelheim Ulm University BioCenter under [Grant D.5009]; a TBM grant from FWO-Vlaanderen [n? T003519N]; by the German Society for Muscle Diseases (DGM); the German Neuromuscular Society; the German Israeli Foundation (GIF) for Scientific Research and Development. PVD holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga Belgi? and the KU Leuven funds "Een Hart voor ALS", "Laeversfonds voor ALS Onderzoek" and the "Val?ry Perrier Race against ALS Fund". Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD). VS receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and E-Rare Joint Transnational Call. MRT is funded by the Motor Neurone Disease Association. For their excellent technical assistance, we are grateful to Stephen Meier, Sandra H?bsch, Dagmar Schattauer, Alice Beer, and Mehtap T?redi. We are deeply indebted to the patients for participating in this study. Publisher Copyright: © 2021 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.
PY - 2021
Y1 - 2021
N2 - Objective: Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. Methods: Overall, 275 patients from 8 European neurological centers were examined. We included ALS with <6 and >6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients (N = 65). Results: Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 (p = 0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients’ progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. Conclusions: CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.
AB - Objective: Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. Methods: Overall, 275 patients from 8 European neurological centers were examined. We included ALS with <6 and >6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients (N = 65). Results: Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 (p = 0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients’ progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. Conclusions: CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.
KW - Amyotrophic lateral sclerosis
KW - chitotriosidase
KW - neurofilaments
KW - prognostic biomarker
UR - http://www.scopus.com/inward/record.url?scp=85100860183&partnerID=8YFLogxK
U2 - https://doi.org/10.1080/21678421.2020.1861023
DO - https://doi.org/10.1080/21678421.2020.1861023
M3 - Article
C2 - 33576252
SN - 2167-8421
VL - 22
SP - 276
EP - 286
JO - Amyotrophic lateral sclerosis and frontotemporal degeneration
JF - Amyotrophic lateral sclerosis and frontotemporal degeneration
IS - 3-4
ER -