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.

Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

“…Being one of the most promising fluid-based biomarkers in ALS, neurofilaments (Nf) as markers of axonal damage have been studied extensively. In general, Nf levels are increased in ALS compared to healthy controls and similar diseases, and their prognostic value nowadays is indisputable [ 115 , 116 ]. Nf levels are highest in ALS patients with a more aggressive disease course, which correlates to certain clinical and/or genetic phenotypes (i.e.…”

Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis

“…At the moment, there are several hypotheses about the site of origin of ALS in the body [3,46,47]. Among them, there are "dying forward" and "dying back" hypotheses of the development of ALS-depending on which structures in the chain "upper motor neuron-lower motor neuron-skeletal muscle" are affected first (Figure 1).…”

Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Patients: Insights from High-Resolution Respirometry

“…Amyotrophic sclerosis is a fatal neurodegenerative disease with a median survival of 3 to 5 years [ 1 ]. The disease is characterized by the progressive neurodegeneration of motor neurons in the brain and spinal cord at all levels of the motor system.…”

“…This questionnaire includes questions targeting bulbar function, fine and gross motor tasks, and respiratory function. However, more advanced staging systems are now available (King’s Staging System, Milano Torino Staging System, Rasch Overall ALS Disability Scale) [ 1 ]. Nerve conduction studies are required as part of electrodiagnostic methods to demonstrate motor nerve involvement, indicated by reduced action potential of the compound muscle, prolonged distal motor latency, and reduced conduction velocity without evidence of conduction blocks.…”

“…Another method is genetic testing, which can find confirmed genetic variants and rule out other genetic disorders. Within laboratory diagnostics, potentially promising biomarkers in diagnosing this disease are neurofilaments, inflammatory biomarkers, Chitinase, Tau Protein, TDP-43, and Creatine Kinase [ 1 ]. There are currently three drugs approved for the treatment of ALS (Riluzole and Edavarone, Sodium phenylbutyrate, and Taurursodiol PB/TURSO), which do not cure the disease but help slow the progression of this serious disease.…”