Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies
- PMID: 35115992
- PMCID: PMC8804092
- DOI: 10.3389/fneur.2021.750543
Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. In the last decade, it has become clear that cognitive and behavioral changes in patients with ALS are more frequent than previously recognized. Significantly, these non-motor features can impact the diagnosis, prognosis, and management of ALS. Partially overlapping neuropathological staging systems have been proposed to describe the distribution of TAR DNA-binding protein 43 (TDP-43) aggregates outside the corticospinal tract. However, the relationship between TDP-43 inclusions and neurodegeneration is not absolute and other pathophysiological processes, such as neuroinflammation (with a prominent role of microglia), cortical hyperexcitability, and synaptic dysfunction also play a central role in ALS pathophysiology. In the last decade, imaging and biofluid biomarker studies have revealed important insights into the pathophysiological underpinnings of extra-motor neurodegeneration in the ALS-FTLD continuum. In this review, we first summarize the clinical and pathophysiological correlates of extra-motor neurodegeneration in ALS. Next, we discuss the diagnostic and prognostic value of biomarkers in ALS and their potential to characterize extra-motor neurodegeneration. Finally, we debate about how biomarkers could improve the diagnosis and classification of ALS. Emerging imaging biomarkers of extra-motor neurodegeneration that enable the monitoring of disease progression are particularly promising. In addition, a growing arsenal of biofluid biomarkers linked to neurodegeneration and neuroinflammation are improving the diagnostic accuracy and identification of patients with a faster progression rate. The development and validation of biomarkers that detect the pathological aggregates of TDP-43 in vivo are notably expected to further elucidate the pathophysiological underpinnings of extra-motor neurodegeneration in ALS. Novel biomarkers tracking the different aspects of ALS pathophysiology are paving the way to precision medicine approaches in the ALS-FTLD continuum. These are essential steps to improve the diagnosis and staging of ALS and the design of clinical trials testing novel disease-modifying treatments.
Keywords: TDP-43 = TAR DNA-binding protein 43; amyotrophic lateral sclerosis (ALS); biomarker (BM); cerebrospinal fluid (CSF); frontotemporal dementia (FTD); frontotemporal lobar degeneration; neuroimage; neuropathology.
Copyright © 2022 Reyes-Leiva, Dols-Icardo, Sirisi, Cortés-Vicente, Turon-Sans, de Luna, Blesa, Belbin, Montal, Alcolea, Fortea, Lleó, Rojas-García and Illán-Gala.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Figures
Similar articles
-
Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis.JAMA Neurol. 2014 Feb;71(2):172-9. doi: 10.1001/jamaneurol.2013.5489. JAMA Neurol. 2014. PMID: 24378564
-
The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients.Acta Neuropathol. 2012 Nov;124(5):717-32. doi: 10.1007/s00401-012-1045-x. Epub 2012 Sep 21. Acta Neuropathol. 2012. PMID: 22993125 Free PMC article.
-
Clinical and neuropathological features of ALS/FTD with TIA1 mutations.Acta Neuropathol Commun. 2017 Dec 7;5(1):96. doi: 10.1186/s40478-017-0493-x. Acta Neuropathol Commun. 2017. PMID: 29216908 Free PMC article.
-
Towards a TDP-43-Based Biomarker for ALS and FTLD.Mol Neurobiol. 2018 Oct;55(10):7789-7801. doi: 10.1007/s12035-018-0947-6. Epub 2018 Feb 19. Mol Neurobiol. 2018. PMID: 29460270 Free PMC article. Review.
-
The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD.Front Neurosci. 2019 Apr 11;13:335. doi: 10.3389/fnins.2019.00335. eCollection 2019. Front Neurosci. 2019. PMID: 31031584 Free PMC article. Review.
Cited by
-
In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use.Transl Neurodegener. 2024 Jun 3;13(1):29. doi: 10.1186/s40035-024-00419-8. Transl Neurodegener. 2024. PMID: 38831349 Free PMC article. Review.
-
Microglia in brain aging: An overview of recent basic science and clinical research developments.J Biomed Res. 2024 Feb 26;38(2):122-136. doi: 10.7555/JBR.37.20220220. J Biomed Res. 2024. PMID: 38403286 Free PMC article.
-
Understanding depression with amyotrophic lateral sclerosis: a short assessment of facts and perceptions.J Neural Transm (Vienna). 2024 Feb;131(2):107-115. doi: 10.1007/s00702-023-02714-6. Epub 2023 Nov 3. J Neural Transm (Vienna). 2024. PMID: 37922093 Review.
-
Iron quantification in basal ganglia using quantitative susceptibility mapping in a patient with ALS: a case report and literature review.Front Neurosci. 2023 Sep 27;17:1229082. doi: 10.3389/fnins.2023.1229082. eCollection 2023. Front Neurosci. 2023. PMID: 37877011 Free PMC article.
-
The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update.Int J Mol Sci. 2023 Sep 27;24(19):14647. doi: 10.3390/ijms241914647. Int J Mol Sci. 2023. PMID: 37834094 Free PMC article. Review.
References
Publication types
LinkOut - more resources
Full Text Sources
Miscellaneous