CSF chitinase proteins in amyotrophic lateral sclerosis

Thompson, Alexander G.; Gray, Elizabeth; Bampton, Alexander; Raciborska, Dominika; Talbot, Kevin; Turner, Martin R

doi:10.1136/jnnp-2019-320442

Cited by 82 publications

(123 citation statements)

References 24 publications

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“…Previous cross-sectional studies have shown elevated CSF chitinase protein levels in ALS patients versus controls and no elevation in asymptomatic gene carriers compared with healthy controls. 11,12 The cross-sectional analysis in this study concurs with these findings, showing levels of ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association CHIT1, CHI3L1 and CHI3L2 concentrations, as well as CHIT1 activity, to be similar in healthy controls and atrisk individuals who have not yet phenoconverted (irrespective of genotype), but elevated in symptomatic ALS compared to both healthy controls and at-risk individuals.…”

Section: Discussionsupporting

confidence: 88%

“…The different chitinase proteins reflect different facets of microglial and astroglial activity in ALS. [8][9][10][11][12][13][14][15] At least 10% of all cases of ALS are attributable to mutations in one of four genes: C9ORF72, SOD1, TARDBP, and FUS. Studying the carriers of these genetic mutations provides a unique opportunity to define the biochemical landscape preceding the development of clinically manifest neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

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CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis

Thompson

Wuu

et al. 2020

Ann Clin Transl Neurol

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Objective To evaluate the CSF levels of chitinase proteins during the presymptomatic and early symptomatic phases of amyotrophic lateral sclerosis (ALS). Methods CSF samples were obtained from 16 controls, 55 individuals at‐risk for ALS (including 18 carrying a mutation in C9ORF72, 33 in SOD1), 12 ALS patients, and 7 phenoconverters (individuals diagnosed with ALS during follow‐up). At‐risk individuals and phenoconverters were enrolled through the Pre‐fALS study, which includes individuals carrying an ALS‐associated gene mutation without disease manifestations at initial assessment. Longitudinal CSF collections, where possible, took place every 3‐12 months for ALS patients and every 1‐2 years for others. CSF levels of chitotriosidase 1 (CHIT1), chitinase‐3‐like protein 1 (CHI3L1, YKL‐40) and chitinase‐3‐like protein 2 (CHI3L2, YKL‐39) were measured by ELISA, along with CHIT1 activity. Longitudinal changes in at‐risk individuals and phenoconverters were fitted to linear mixed effects models. Results Slowly rising levels of CHIT1 were observed over time in the at‐risk individuals (slope 0.059 log10[CHIT1] per year, P < 0.001). Among phenoconverters, CHIT1 levels and activity rose more sharply (0.403 log10[CHIT1] per year, P = 0.005; 0.260 log10[CHIT1 activity] per year, P = 0.007). Individual levels of both CHI3L1 and CHI3L2 remained relatively stable over time in all participant groups. Interpretation The CHIT1 neuroinflammatory response is a feature of the late presymptomatic to early symptomatic phases of ALS. This study does not suggest a long prodrome of upregulated glial activity in ALS pathogenesis, but strengthens the place of CHIT1 as part of a panel of biomarkers to objectively assess the impact of immune‐modulatory therapeutic interventions in ALS.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis

Thompson

Wuu

et al. 2020

Ann Clin Transl Neurol

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“…CHIT1 levels and activity in ALS have repeatedly been associated with neurofilament levels and with a faster disease progression rate in large study populations. 10,28,29,[46][47][48] Our results demonstrate the correlation between baseline CSF CHIT1 levels and neuronal damage and prognosis in MS.…”

Section: Discussionsupporting

confidence: 58%

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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“…Interestingly, these chitinases are neuroinflammatory biomarkers which have been previously shown to be consistently increased in CSF of ALS patients compared to neurologically healthy subjects (7,8). These results indicate that, among the unbiased signature of RNA…”

Section: Discussionmentioning

confidence: 57%

“…Recently, a study using single-cell RNA sequencing of brain tissue from an ALS mouse model reported that a specific microglial subpopulation, known as disease associated microglia (DAM), was the cell-type responsible for ALS-related microgliosis and that is enhanced by triggering receptor expressed on myeloid cells 2 (TREM2) (4). In support of this scenario, some chitinase proteins, which are known markers of microglial activation (5,6), have been consistently shown to be increased in the cerebrospinal fluid (CSF) of ALS patients (7,8).…”

Section: Introductionmentioning

confidence: 98%

Characterization of the motor cortex transcriptome supports microgial-related key events in amyotrophic lateral sclerosis

Dols‐Icardo

Montal

Sirisi

et al. 2020

Preprint

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400w)Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. A major neuropathological finding in ALS is the coexistence of glial activation and aggregation of the phosphorylated transactive response DNA-binding protein 43-kDa (pTDP43) in the motor cortex at the earliest stages of the disease. Despite this, the transcriptional alterations associated with these pathological changes in this major vulnerable brain region have yet to be fully characterized. Here, we have performed massive RNA sequencing of the motor cortex of ALS (n=11) and healthy controls (HC; n=8). We report extensive RNA expression alterations at gene and isoform levels, characterized by the enrichment of neuroinflammatory and synapse related pathways.The assembly of gene co-expression modules confirmed the involvement of these two principal transcriptomic changes, and showed a strong negative correlation between them.Furthermore, cell-type deconvolution using human single-nucleus RNA sequencing data as reference demonstrated that microglial cells are overrepresented in ALS compared to HC. Importantly, we also show for the first time in the human ALS motor cortex, that microgliosis is mostly driven by the increased proportion of a microglial subpopulation characterized by gene markers overlapping with the recently described disease associated microglia (DAM).Using immunohistochemistry, we further evidenced that this microglial subpopulation is overrepresented in ALS and that variability in pTDP43 aggregation among patients negatively correlates with the proportion of microglial cells. In conclusion, we report that neuroinflammatory changes in ALS motor cortex are dominated by microglia which is concomitant with a reduced expression of postsynaptic transcripts, in which DAM might have a prominent role. Microgliosis therefore represents a promising avenue for therapeutic intervention in ALS.

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CSF chitinase proteins in amyotrophic lateral sclerosis

Cited by 82 publications

References 24 publications

CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis

CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Characterization of the motor cortex transcriptome supports microgial-related key events in amyotrophic lateral sclerosis

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