Objective To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers.
Methods The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA.
Results CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (−80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05).
Conclusion Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome.
- amyotrophic lateral sclerosis
- frontotemporal dementia
- cerebrospinal fluid
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Contributors Design or conceptualisation of the study: PO, PW, JHW, ACL, MO. Analysis or interpretation of data: PO, PW, PS, SAS, FN, AEV, JDS, PMA, HJ, JK, AD, KFa, KFl, ML, KM, AK, JP, AS, DRT, DYH, JHW, ACL, MO. Drafting or revising the manuscript for intellectual content: PO, PW, PS, SAS, FN, AEV, JDS, PMA, HJ, JK, AD, KFa, KFl, ML, KM, AK, JP, AS, DRT, DYH, JHW, ACL, MO.
Funding This study was supported by the EU Joint Programme–Neurodegenerative Disease Research (JPND) networks SOPHIA (01ED1202A), BiomarkAPD (01ED1203F), and PreFrontAls (01ED1512), the German Federal Ministry of Education and Research (FTLDcO1GI1007A, MND-Net 01GM1103A), the EU (NADINE 246513, FAIR-PARK II 633190,STRENTH/JPND), the German Research Foundation/DFG (VO2028, SFB1279), the foundation of the state Baden-Württemberg (D3830), Boehringer Ingelheim Ulm University BioCenter (D5009), Thierry Latran Foundation, Departmental Funds (GPS-ALS Study), the Charcot Foundation, the Swedish Brain Research Foundation, the Bertil Hållsten Foundation, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, and the Ulla-Carin Lindquist Foundation.
Disclaimer The funders were not involved in the study design, in the collection, analysis and interpretation of data, in the writing of the report; and in the decision to submit the paper for publication.
Competing interests DRT received consultancies from Covance Laboratories (UK) and GE Healthcare (UK), received a speaker honorarium from GE Healthcare (UK), and collaborated with Novartis Pharma Basel (Switzerland).
PO, PW, PS, SAS, FN, AEV, JDS, PMA, JK, AD, KFa, KFl, HJ, ML, KM, AK, JP, AS, DYH, JHW, ACL and MO report no competing interests.
Patient consent Not required
Ethics approval Ethics committees of the Universities of Ulm, Umea, Munich, Erlangen, Homburg, Bonn. The Medical Ethical Review Boards of the participating centers approved the study.
Provenance and peer review Not commissioned; externally peer reviewed.
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