Details

Autor(en) / Beteiligte

• Thompson, Alexander G.
• Gray, Elizabeth
• Thézénas, Marie‐Laëtitia
• Charles, Philip D.
• Evetts, Samuel
• Hu, Michele T.
• Talbot, Kevin
• Fischer, Roman
• Kessler, Benedikt M.
• Turner, Martin R.

Titel

Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis

Ist Teil von

• Annals of neurology, 2018-02, Vol.83 (2), p.258-268

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2018

Quelle

Access via Wiley Online Library

Beschreibungen/Notizen

• Objective The neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is a heterogeneous clinical syndrome involving multiple molecular pathways. The development of biomarkers for use in therapeutic trials is a priority. We sought to use a high‐throughput proteomic method to identify novel biomarkers in individual cerebrospinal fluid (CSF) samples. Methods Liquid chromatography/tandem mass spectrometry with label‐free quantification was used to identify CSF proteins using samples from a well‐characterized longitudinal cohort comprising patients with ALS (n = 43), the upper motor neuron variant, primary lateral sclerosis (PLS; n = 6), and cross‐sectional healthy (n = 20) and disease controls (Parkinsons' disease, n = 20; ALS mimic disorders, n = 12). Results Three macrophage‐derived chitinases showed increased abundance in ALS: chitotriosidase (CHIT1), chitinase‐3‐like protein 1 (CHI3L1), and chitinase‐3‐like protein 2 (CHI3L2). Elevated CHI3L1 was common to ALS and PLS, whereas CHIT1 and CHI3L2 levels differed. Chitinase levels correlated with disease progression rate (CHIT1, r = 0.56, p < 0.001; CHI3L1, r = 0.31; p = 0.028; CHI3L2, r = 0.29, p = 0.044). CHIT1, CHI3L1, and CHI3L2 levels correlated with phosphorylated neurofilament heavy chain (pNFH; r = 0.62, p < 0.001; r = 0.49, p < 0.001; r = 0.41, p < 0.001). CHI3L1 levels, but not CHIT1 or CHI3L2, increased over time in those with low initial levels (gradient = 0.005 log abundance units/month, p = 0.001). High CHIT1 was associated with shortened survival (hazard ratio [HR] 2.84; p = 0.009). Inclusion of pNFH in survival models left only an association of pNFH and survival (HR 1.26; p = 0.019). Interpretation Neuroinflammatory mechanisms have been consistently implicated through various experimental paradigms. These results support a key role for macrophage activity in ALS pathogenesis, offering novel target engagement and pharmacodynamic biomarkers for neuroinflammation‐focused ALS therapy. Ann Neurol 2018;83:258–268