Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase

Oeckl, Patrick; Weydt, Patrick; Steinacker, Petra; Anderl‐Straub, Sarah; Nordin, Frida; Volk, Alexander E; Diehl‐Schmid, Janine; Andersen, Peter M.; Kornhuber, Johannes; Danek, Adrian; Faßbender, Klaus; Fließbach, Klaus; Jahn, Holger; Lauer, Martin; Müller, Kathrin; Knehr, Antje; Prudlo, Johannes; Schneider, Anja; Thal, Dietmar Rudolf; Yilmazer-Hanke, Deniz; Weishaupt, Jochen H.; Ludolph, Albert C.; Otto, Markus

doi:10.1136/jnnp-2018-318868

Cited by 100 publications

(152 citation statements)

References 31 publications

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“…Correlation between chitotriosidase (CHIT1) 24bp duplication (rs150192398) and CHIT1 levels. X‐axis depicts copies of the minor allele (24bp duplication), which was previously demonstrated to affect RNA stability and protein levels . The logarithmic transformation (base 10) was applied for CHIT1 (pg/ml) levels.…”

Section: Resultsmentioning

confidence: 99%

“…This leads to less stable RNA, an 87 amino acid in-frame deletion, and lower enzyme levels as well as lower enzyme activity. [26][27][28][29] Allele dosages for CHI3L1 variant rs4950928 and the 24bp duplication (rs150192398) in CHIT1 for N = 604 patients were extracted from the post-QC imputed dataset. Imputation info scores were 0.98 and 0.95, respectively.…”

Section: Mri and Image Analysismentioning

confidence: 99%

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CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Oldoni

Smets

Mallants

et al. 2020

Annals of Neurology

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Objective Evidence for a role of microglia in the pathogenesis of multiple sclerosis (MS) is growing. We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity (relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients. Methods In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia‐related proteins, chitotriosidase (CHIT1), chitinase‐3–like protein 1 (CHI3L1 or YKL‐40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme‐linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia‐related markers in publicly available RNA expression data from postmortem brain tissue. Results CHIT1 levels at diagnostic LP correlated with 2 aspects of long‐term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E‐04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E‐04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL. Interpretation CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity. ANN NEUROL 2020;87:633–645

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Section: Resultsmentioning

confidence: 99%

Section: Mri and Image Analysismentioning

confidence: 99%

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Oldoni

Smets

Mallants

et al. 2020

Annals of Neurology

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“…The proteins that we quantified here are important indicators of health status relevant for different diseases: FGF21 for example is a known key regulator in lipid and glucose metabolism, which is increased in conditions such as type 2 diabetes, obesity, and nonalcoholic fatty liver disease . CHIT1 serves as a neuroinflammatory marker and shows increased concentrations in sALS (sporadic amyotrophic lateral sclerosis) . ER stress is hypothesized to lead to hereditary pancreatitis may promote the development of pancreatic ductal adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Systematic Development of Sandwich Immunoassays for the Plasma Secretome

et al. 2019

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The plasma proteome offers a clinically useful window into human health. Recent advances from highly multiplexed assays now call for appropriate pipelines to validate individual candidates. Here, a workflow is developed to build dual binder sandwich immunoassays (SIA) and for proteins predicted to be secreted into plasma. Utilizing suspension bead arrays, ≈1800 unique antibody pairs are first screened against 209 proteins with recombinant proteins as well as EDTA plasma. Employing 624 unique antibodies, dilution‐dependent curves in plasma and concentration‐dependent curves of full‐length proteins for 102 (49%) of the targets are obtained. For 22 protein assays, the longitudinal, interindividual, and technical performance is determined in a set of plasma samples collected from 18 healthy subjects every third month over 1 year. Finally, 14 of these assays are compared with with SIAs composed of other binders, proximity extension assays, and affinity‐free targeted mass spectrometry. The workflow provides a multiplexed approach to screen for SIA pairs that suggests using at least three antibodies per target. This design is applicable for a wider range of targets of the plasma proteome, and the assays can be applied for discovery but also to validate emerging candidates derived from other platforms.

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“…In this issue of the journal, Oeckl and colleagues14 demonstrate significant neuroinflammatory changes in both ALS and FTD, which are linked to the symptomatic phase of disease, although the inflammatory profile appears to be varied. In patients with sporadic and familial ALS, there was a marked increase in both blood and Cerebrospinal fluid (CSF) chitotriosidase 1 levels, which correlated with biomarkers of axonal degeneration (neurofilaments).…”

Section: Neuroinflammation Contributes To Als and Ftd Pathophysiologymentioning

confidence: 98%

“…Findings from the study of Oeckl and colleagues14 would suggest the importance of neuroinflammation in the pathogenesis of ALS and FTD, with diverse neuroinflammatory profiles contributing to phenotypic heterogeneity. Specifically, microglial activation was evident in sporadic and familial forms of ALS and FTD, thereby suggesting that neuroinflammation was important in regulating disease progression rather than triggering disease onset, in keeping with previous studies 7 11.…”

Section: Neuroinflammation Contributes To Als and Ftd Pathophysiologymentioning

confidence: 99%

Differences in inflammatory profiles between ALS and FTD

Vucic

2018

J Neurol Neurosurg Psychiatry

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Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase

Cited by 100 publications

References 31 publications

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Systematic Development of Sandwich Immunoassays for the Plasma Secretome

Differences in inflammatory profiles between ALS and FTD

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