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Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies.

Authors :
Reyes-Leiva D
Dols-Icardo O
Sirisi S
Cortés-Vicente E
Turon-Sans J
de Luna N
Blesa R
Belbin O
Montal V
Alcolea D
Fortea J
Lleó A
Rojas-García R
Illán-Gala I
Source :
Frontiers in neurology [Front Neurol] 2022 Jan 18; Vol. 12, pp. 750543. Date of Electronic Publication: 2022 Jan 18 (Print Publication: 2021).
Publication Year :
2022

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.<br />Competing Interests: 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.<br /> (Copyright © 2022 Reyes-Leiva, Dols-Icardo, Sirisi, Cortés-Vicente, Turon-Sans, de Luna, Blesa, Belbin, Montal, Alcolea, Fortea, Lleó, Rojas-García and Illán-Gala.)

Details

Language :
English
ISSN :
1664-2295
Volume :
12
Database :
MEDLINE
Journal :
Frontiers in neurology
Publication Type :
Academic Journal
Accession number :
35115992
Full Text :
https://doi.org/10.3389/fneur.2021.750543