Metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal model
<p><strong>Background</strong> Despite widespread searches, there are currently no validated biofluid markers for the detection of subclinical neuroinflammation in multiple sclerosis (MS). The dynamic nature of human metabolism in response to changes in homeostasis, as measured by...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2022
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| _version_ | 1826309368173297664 |
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| author | Yeo, T Bayuangga, H Augusto-Oliveira, M Sealey, M Claridge, TDW Tanner, RL Leppert, D Palace, J Kuhle, J Probert, F Anthony, DC |
| author_facet | Yeo, T Bayuangga, H Augusto-Oliveira, M Sealey, M Claridge, TDW Tanner, RL Leppert, D Palace, J Kuhle, J Probert, F Anthony, DC |
| author_sort | Yeo, T |
| collection | OXFORD |
| description | <p><strong>Background</strong>
Despite widespread searches, there are currently no validated biofluid markers for the detection of subclinical neuroinflammation in multiple sclerosis (MS). The dynamic nature of human metabolism in response to changes in homeostasis, as measured by metabolomics, may allow early identification of clinically silent neuroinflammation. Using the delayed-type hypersensitivity (DTH) MS rat model, we investigated the serum and cerebrospinal fluid (CSF) metabolomics profiles and neurofilament-light chain (NfL) levels, as a putative marker of neuroaxonal damage, arising from focal, clinically silent neuroinflammatory brain lesions and their discriminatory abilities to distinguish DTH animals from controls.<br><br>
<strong>Methods</strong>
<sup>1</sup>H nuclear magnetic resonance (NMR) spectroscopy metabolomics and NfL measurements were performed on serum and CSF at days 12, 28 and 60 after DTH lesion initiation. Supervised multivariate analyses were used to determine metabolomics differences between DTH animals and controls. Immunohistochemistry was used to assess the extent of neuroinflammation and tissue damage.<br><br>
<strong>Results</strong>
Serum and CSF metabolomics perturbations were detectable in DTH animals (vs. controls) at all time points, with the greatest change occurring at the earliest time point (day 12) when the neuroinflammatory response was most intense (mean predictive accuracy [SD]—serum: 80.6 [10.7]%, <em>p</em> < 0.0001; CSF: 69.3 [13.5]%, <em>p</em> < 0.0001). The top discriminatory metabolites at day 12 (serum: allantoin, cytidine; CSF: glutamine, glucose) were all reduced in DTH animals compared to controls, and correlated with histological markers of neuroinflammation, particularly astrogliosis (Pearson coefficient, <em>r</em>—allantoin: <em>r</em> = − 0.562, <em>p</em> = 0.004; glutamine: <em>r</em> = − 0.528, <em>p</em> = 0.008). Serum and CSF NfL levels did not distinguish DTH animals from controls at day 12, rather, significant differences were observed at day 28 (mean [SEM]—serum: 38.5 [4.8] vs. 17.4 [2.6] pg/mL, <em>p</em> = 0.002; CSF: 1312.0 [379.1] vs. 475.8 [74.7] pg/mL, <em>p</em> = 0.027). Neither serum nor CSF NfL levels correlated with markers of neuroinflammation; serum NfL did, however, correlate strongly with axonal loss (<em>r</em> = 0.641, <em>p</em> = 0.001), but CSF NfL did not (<em>p</em> = 0.137).<br><br>
<strong>Conclusions</strong>
While NfL levels were elevated later in the pathogenesis of the DTH lesion, serum and CSF metabolomics were able to detect early, clinically silent neuroinflammation and are likely to present sensitive biomarkers for the assessment of subclinical disease activity in patients.</p> |
| first_indexed | 2024-03-07T07:33:08Z |
| format | Journal article |
| id | oxford-uuid:3ceea178-df52-4600-b799-c873278dd509 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:33:08Z |
| publishDate | 2022 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:3ceea178-df52-4600-b799-c873278dd5092023-02-17T12:42:56ZMetabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal modelJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3ceea178-df52-4600-b799-c873278dd509EnglishSymplectic ElementsBioMed Central2022Yeo, TBayuangga, HAugusto-Oliveira, MSealey, MClaridge, TDWTanner, RLLeppert, DPalace, JKuhle, JProbert, FAnthony, DC<p><strong>Background</strong> Despite widespread searches, there are currently no validated biofluid markers for the detection of subclinical neuroinflammation in multiple sclerosis (MS). The dynamic nature of human metabolism in response to changes in homeostasis, as measured by metabolomics, may allow early identification of clinically silent neuroinflammation. Using the delayed-type hypersensitivity (DTH) MS rat model, we investigated the serum and cerebrospinal fluid (CSF) metabolomics profiles and neurofilament-light chain (NfL) levels, as a putative marker of neuroaxonal damage, arising from focal, clinically silent neuroinflammatory brain lesions and their discriminatory abilities to distinguish DTH animals from controls.<br><br> <strong>Methods</strong> <sup>1</sup>H nuclear magnetic resonance (NMR) spectroscopy metabolomics and NfL measurements were performed on serum and CSF at days 12, 28 and 60 after DTH lesion initiation. Supervised multivariate analyses were used to determine metabolomics differences between DTH animals and controls. Immunohistochemistry was used to assess the extent of neuroinflammation and tissue damage.<br><br> <strong>Results</strong> Serum and CSF metabolomics perturbations were detectable in DTH animals (vs. controls) at all time points, with the greatest change occurring at the earliest time point (day 12) when the neuroinflammatory response was most intense (mean predictive accuracy [SD]—serum: 80.6 [10.7]%, <em>p</em> < 0.0001; CSF: 69.3 [13.5]%, <em>p</em> < 0.0001). The top discriminatory metabolites at day 12 (serum: allantoin, cytidine; CSF: glutamine, glucose) were all reduced in DTH animals compared to controls, and correlated with histological markers of neuroinflammation, particularly astrogliosis (Pearson coefficient, <em>r</em>—allantoin: <em>r</em> = − 0.562, <em>p</em> = 0.004; glutamine: <em>r</em> = − 0.528, <em>p</em> = 0.008). Serum and CSF NfL levels did not distinguish DTH animals from controls at day 12, rather, significant differences were observed at day 28 (mean [SEM]—serum: 38.5 [4.8] vs. 17.4 [2.6] pg/mL, <em>p</em> = 0.002; CSF: 1312.0 [379.1] vs. 475.8 [74.7] pg/mL, <em>p</em> = 0.027). Neither serum nor CSF NfL levels correlated with markers of neuroinflammation; serum NfL did, however, correlate strongly with axonal loss (<em>r</em> = 0.641, <em>p</em> = 0.001), but CSF NfL did not (<em>p</em> = 0.137).<br><br> <strong>Conclusions</strong> While NfL levels were elevated later in the pathogenesis of the DTH lesion, serum and CSF metabolomics were able to detect early, clinically silent neuroinflammation and are likely to present sensitive biomarkers for the assessment of subclinical disease activity in patients.</p> |
| spellingShingle | Yeo, T Bayuangga, H Augusto-Oliveira, M Sealey, M Claridge, TDW Tanner, RL Leppert, D Palace, J Kuhle, J Probert, F Anthony, DC Metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal model |
| title | Metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal model |
| title_full | Metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal model |
| title_fullStr | Metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal model |
| title_full_unstemmed | Metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal model |
| title_short | Metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal model |
| title_sort | metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament light chain in a focal multiple sclerosis animal model |
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