Current State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.

Keywords: ALS; MND; amyotrophic lateral sclerosis; diagnosis; diagnostics; motor neuron disease.

Figure 1

Clinical signs of UMN and LMN involvement according to body regions. DTR: Deep tendon reflex; LMN: Lower motor neurons; UMN: Upper motor neurons. Created by Castro-Gomez with “BioRender.com”; accessed on 4 February 2023.

Figure 2

Current state of and future directions for the diagnosis of amyotrophic lateral sclerosis. A delayed diagnosis of ALS is still currently performed using clinical criteria such as Revised El Escorial, but the determination of fluid biomarkers such as Nf is accelerating an earlier identification of the disease. In the future, the availability of more specific biomarkers related to disease pathology onset will allow early risk assessment and definitive diagnosis in patients in prodromal phases. Additionally, an ideal biomarker should develop preventive therapies and monitor disease activity in patients under novel causative therapies. ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; Aβ: Amyloid β; bFGF: basic fibroblast growth factor; CHI3L1: chitinase-3-like protein 1; CHI3L2: chitinase-3-like protein 2; CHIT1: chitotriosidase 1; CK: creatinine kinase; cTnT: cardiac troponin T; IL-6: interleukin-6; IL-8: interleukin-18; MCP-1: monocyte chemoattractant protein-1; MMI: mild motor impairment; NfL: neurofilament light chain; pNfH: phosphorylated neurofilament heavy chain; Poly-GP: arginine containing dipeptide repeat polymers; pTau: phosphorylated tau; SPP1: secreted phosphoprotein 1; TNF-α: tumor necrosis factor; t-Tau: total tau. Created by Castro-Gomez with “BioRender.com”; accessed on 04 February 2023.