Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications
Abstract
:1. Introduction
2. Biomarkers in ALS: Categories, Conceptualization and Rational Application
- A diagnostic biomarker is a disease feature that categorizes an individual as affected or unaffected or classifies them into subcategories based on the disease.
- A susceptibility or risk biomarker would be used to represent an individual with no apparent evidence of disease to reflect the risk of developing this kind of medical condition.
- A prognostic biomarker would be used in the baseline assessment of a patient with a confirmed diagnosis to predict the risk of occurrence of a clinical event.
- Predictive biomarkers would allow patients to be classified as candidates for medical intervention according to their probability of response.
- A biomarker of response can be measured in a patient who has already been exposed to pharmacological intervention to assess the biological response. They can be further classified into pharmacodynamics and surrogate endpoint biomarkers.
3. Fluid-Based Biomarkers in ALS: The Importance of the Study Sampling
4. Recent Developments of ALS Prognostic, Predictive and Response Biomarkers in Biological Fluids
4.1. Neurofilaments
4.2. Neuroinflammation
4.3. Metabolism
4.4. Muscle Injury Biomarkers
4.5. Non-Coding micro-RNA (miRNA)
4.6. Specific Biomarkers in Genetic Subtypes of ALS
4.7. Urinay Biomarkers
5. New Horizons in ALS Biomarker Research: An Insight into the Pathology Associated with TDP-43
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Biomarker Category | Time Point of Measurement | Description | Illustrative Example |
---|---|---|---|
Diagnostic Biomarker | One-off measurement (during the diagnostic study process) | A disease characteristic that classifies an individual according to the existence or lack of a particular condition. It should be a useful measure for the clinician to make diagnostic decisions in individuals with subtle or inconclusive impairment. | Needle EMG findings demonstrating subclinical lower motor neuron pathology (active and chronic denervation) are included in the commonly used diagnostic criteria. |
Susceptibility/Risk Biomarker | One-off measurement | A marker that reflects the likelihood of a specific medical condition or clinical event (progression) in an individual with no evidence of that particular disease. | The elevation of NfL in patients carrying pathogenic variants in certain ALS-associated genes could identify patients at risk of disease onset and to select them for early targeted therapies, such as SOD1 variants in the ATLAS clinical trial with Tofersen. |
Prognostic biomarkers | One-off measurement (baseline) | A baseline measure that allows a patient to be categorized into different risk levels based on the probability of occurrence of a clinical event, which could be for example rate of progression, death, etc. | Selected pathogenic variants in the SOD1 (A4V) gene or UCL13A SNPs have been associated with a poor prognosis. |
Predictive biomarker | One-off measurement (baseline or stratification for trial design) | A marker that, when performed at the time of a patient’s baseline assessment, allows the estimation of the likelihood of benefiting from a medical intervention. | UNC13A genotype may have a positive modifying effect on ALS patients in post hoc analysis of lithium clinical trials. |
Response biomarker | Longitudinal measurements |
| Tracking of the protein encoded by ALS-associated genes may be a valuable biomarker in both preclinical studies and human trials, such as dipeptide repeat protein poly-GP in C9orf72-ALS. |
Pathophysiological Pathway | Biomarker | Biological Fluid | Prognostic Performance Commentary | Key References |
---|---|---|---|---|
Neuro-axonal damage | NfL | Blood and CSF |
| Thompson et al., 2022 [24] Benatar et al., 2020 [19] Benatar et al., 2020 [19] |
pNfH | Blood and CSF |
| Falzone et al., 2020 [23] Shi et al., 2022 [21] | |
Neuroinflammation | Chitinases | CSF |
| Thompson et al., 2019 [46] Masrori et al., 2021 [48] |
Antibodies and immunocomplexes against Nfs | Blood |
| Puentes et al., 2021 [54] | |
Immunophenotyping | Blood |
| Gustafson et al., 2017 [49] Murdock et al., 2017 [50] | |
Tregs | Blood |
| Sheean et al., 2017 [53] | |
Neopterine and p75ECD | Urine |
| Shepheard et al., 2017 [101] Shepheard et al., 2022 [107] | |
Metabolism | Lipid metabolism | Blood |
| Janse van Mantgem et al., 2022 [61] |
Glucose metabolism | Blood |
| Sun et al., 2020 [42] | |
Iron metabolism | Blood |
| Cheng et al., 2021 [70] Paydarnia et al., 2021 [71] | |
Albumin | Blood |
| Ong et al., 2017 [74] | |
Skeletal muscle damage | Plasma creatinine | Blood |
| Van Eijk et al., 2018 [75] |
Creatine Kinase | Blood |
| Ceccanti et al., 2020 [80] Ong et al., 2017 [74] | |
RNA metabolism | miRNA-181 | Blood |
| Magen et al., 2021 [88] |
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Sanchez-Tejerina, D.; Llaurado, A.; Sotoca, J.; Lopez-Diego, V.; Vidal Taboada, J.M.; Salvado, M.; Juntas-Morales, R. Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications. Cells 2023, 12, 1180. https://doi.org/10.3390/cells12081180
Sanchez-Tejerina D, Llaurado A, Sotoca J, Lopez-Diego V, Vidal Taboada JM, Salvado M, Juntas-Morales R. Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications. Cells. 2023; 12(8):1180. https://doi.org/10.3390/cells12081180
Chicago/Turabian StyleSanchez-Tejerina, Daniel, Arnau Llaurado, Javier Sotoca, Veronica Lopez-Diego, Jose M. Vidal Taboada, Maria Salvado, and Raul Juntas-Morales. 2023. "Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications" Cells 12, no. 8: 1180. https://doi.org/10.3390/cells12081180
APA StyleSanchez-Tejerina, D., Llaurado, A., Sotoca, J., Lopez-Diego, V., Vidal Taboada, J. M., Salvado, M., & Juntas-Morales, R. (2023). Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications. Cells, 12(8), 1180. https://doi.org/10.3390/cells12081180