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.

Iron quantification in basal ganglia using quantitative susceptibility mapping in a patient with ALS: a case report and literature review

“…Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that affects both upper and lower motor neurons (UMN and LMN), leading to progressive muscle weakness, paralysis, and death (Bhattarai et al, 2022 ; Ghaderi et al, 2023a ; Marshall et al, 2023 ; Mohammadi and Ghaderi, 2023 ). ALS is affected by motor and extra-motor neurodegeneration (Ragagnin et al, 2019 ; Rojas et al, 2020 ; Reyes-Leiva et al, 2022 ). The neuropathological mechanisms underlying ALS involve complex interactions between genetic, environmental, and cellular factors, resulting in motor neuron vulnerability and neuroinflammation (Mejzini et al, 2019 ; Le Gall et al, 2020 ; Keon et al, 2021 ).…”

Microglia in brain aging: An overview of recent basic science and clinical research developments

“…Altogether, these data suggest that microglial activation is present in the early, rather than in the late stage. Moreover, microglial activation was correlated with neuronal and synaptic loss, as well as a quick development of motor and extra-motor illness [ 112 – 113 ] ; however, it is unclear whether these connections are causative or a result of the accelerated pathology [ 114 ] . Therefore, more investigations and improved tools are needed to fully characterize how the microglia-mediated inflammatory response occurs at different phases of ALS and where potential therapeutic interventions may be taken to delay disease progression and bring the patient functional recovery.…”

In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use

“…A TDP-43 PET radiotracer would be of utmost interest in the clinic for the differential diagnosis of TDP-43 proteinopathies, as the currently used amyloid and tau tracers in AD. Unfortunately, such radiotracers are still unavailable [ 82 ].…”