A ferroptosis–based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis
David Devos
(1, 2, 3)
,
Caroline Moreau
(2, 1, 3)
,
Maeva Kyheng
(1)
,
Guillaume Garçon
(4, 5, 1)
,
Anne Sophie Rolland
(1, 2)
,
Hélène Blasco
(6, 7, 8)
,
Patrick Gelé
(9)
,
T. Timothée Lenglet
(10)
,
C. Veyrat-Durebex
,
Philippe Corcia
(7, 8, 6)
,
Mary M. Dutheil
(2, 1)
,
Peter Bede
(11, 12, 13)
,
Andreas Jeromin
,
Patrick Oeckl
,
Markus Otto
(14)
,
Vincent Meninger
(10)
,
Véronique Danel-Brunaud
(2, 1, 3)
,
Jean-Christophe Devedjian
(1, 2)
,
James A Duce
(15, 16)
,
Pierre François Pradat
(17, 10, 11, 12)
1
CHRU Lille -
Centre Hospitalier Régional Universitaire [CHU Lille]
2 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
3 Département de neurologie [Lille]
4 IMPECS - Impact de l'environnement chimique sur la santé humaine - ULR 4483
5 Institut Pasteur de Lille
6 Université Francois Rabelais [Tours]
7 iBraiN - Imaging, Brain & Neuropsychiatry
8 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
9 Université de Lille
10 CHU Pitié-Salpêtrière [AP-HP]
11 LIB - Laboratoire d'Imagerie Biomédicale [Paris]
12 SU - Sorbonne Université
13 Trinity College Dublin
14 Universität Ulm - Ulm University [Ulm, Allemagne]
15 CAM - University of Cambridge [UK]
16 University of Leeds
17 University of Ulster
2 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
3 Département de neurologie [Lille]
4 IMPECS - Impact de l'environnement chimique sur la santé humaine - ULR 4483
5 Institut Pasteur de Lille
6 Université Francois Rabelais [Tours]
7 iBraiN - Imaging, Brain & Neuropsychiatry
8 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
9 Université de Lille
10 CHU Pitié-Salpêtrière [AP-HP]
11 LIB - Laboratoire d'Imagerie Biomédicale [Paris]
12 SU - Sorbonne Université
13 Trinity College Dublin
14 Universität Ulm - Ulm University [Ulm, Allemagne]
15 CAM - University of Cambridge [UK]
16 University of Leeds
17 University of Ulster
David Devos
- Fonction : Auteur
- PersonId : 13309
- IdHAL : david-devos
- ORCID : 0000-0002-2417-799X
- IdRef : 091996309
Maeva Kyheng
- Fonction : Auteur
- PersonId : 1260234
- ORCID : 0000-0002-8915-0915
- IdRef : 250816040
Hélène Blasco
- Fonction : Auteur
- PersonId : 770152
- ORCID : 0000-0001-6107-0035
- IdRef : 128057602
C. Veyrat-Durebex
- Fonction : Auteur
Philippe Corcia
- Fonction : Auteur
- PersonId : 889823
Peter Bede
- Fonction : Auteur
- PersonId : 900586
Andreas Jeromin
- Fonction : Auteur
Patrick Oeckl
- Fonction : Auteur
Markus Otto
- Fonction : Auteur
- PersonId : 761030
- ORCID : 0000-0002-6647-5944
Jean-Christophe Devedjian
- Fonction : Auteur
- PersonId : 975652
Résumé
Accurate patient stratification into prognostic categories and targeting Amyotrophic Lateral Sclerosis (ALS)-associated pathways may pave the way for promising trials. We evaluated blood-based prognostic indicators using an array of pathological markers. Plasma samples were collected as part of a large, phase III clinical trial (Mitotarget/TRO19622) at months 1, 6, 12 and 18. The ALSFRS-r score was used as a proxy of disease progression to assess the predictive value of candidate biological indicators. First, established clinical predictors were evaluated in all 512 patients. Subsequently, pathologic markers, such as proxies of neuronal integrity (Neurofilament light chain and phosphorylated heavy chain), DNA oxidation (8-oxo-2'-desoxyguanosine), lipid peroxidation (4-hydroxy-2-nonenal, isoprostane), inflammation (interleukin-6) and iron status (ferritin, hepcidin, transferrin) were assessed in a subset of 109 patients that represented the whole cohort. Markers of neuronal integrity, DNA and lipid oxidation, as well as iron status at baseline are accurate predictors of disability at 18-month follow-up. The composite scores of these markers in association with established clinical predictors enable the accurate forecasting of functional decline. The identified four biomarkers are all closely associated with 'ferroptosis', a recently discovered form of programmed cell death with promising therapeutic targets. The predictive potential of these pathophysiology-based indicators may offer superior patient stratification for future trials, individualised patient care and resource allocation.