Mechanisms, models and biomarkers in amyotrophic lateral sclerosis

Abstract

The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery.

Challenges in the Understanding and Treatment of Amyotrophic Lateral Sclerosis/Motor Neuron Disease

“…The multisystem involvement of patients affected by ALS/ MND, as well as the varied mechanisms attributed to the disease has led to a multitude of clinical and biological markers proposed as indices of disease progression and/or severity [4,12,14]. Despite this, one of the primary challenges in studying ALS/MND is the absence of an accepted marker with both the appropriate sensitivity and specificity applicable to the wide range of affected patients.…”

“…Since the earliest description in the mid 1800s, our understanding, diagnosis, and management of patients with amyotrophic lateral sclerosis (ALS) and the related motor neuron diseases (MNDs) has progressed dramatically [1][2][3][4][5]. The rate of discovery of novel pathogenic mechanisms, new phenotypes, mutations, and therapeutic interventions has escalated more in the last 15 years than ever before.…”

“…Our inability to find effective therapeutics that fundamentally alter the disease course of ALS/MND is often attributed to this heterogeneity of the patient population; thus, there is a need for better diagnostic definitions that will allow for the prognostically relevant categorizations of the disease [3][4][5][7][8][9][10][11]. Our difficulty in identifying reliable biomarkers of disease progression and therapeutic benefit further confound this challenge [4,[12][13][14].…”

Evaluating the levels of CSF and serum factors in ALS

“…Most of these studies have examined changes of individual biomarkers that might distinguish patients with ALS from healthy control subjects (Lu et al., 2015; Takahashi et al., 2015), but it is likely more appropriate to identify panels of biomarkers rather than focusing on a single factor to increase their specificity to ALS. Some studies were limited by the number of samples in the analysis (Turner et al., 2013), and some chose a different control population into the study (Tateishi et al., 2010). In addition, a panel of biomarkers has been detected in either the CSF or serum in some recent studies, but they were either more concerned with a diagnosis rather than a clinically relevant prognosis (Gray et al., 2015; Kuhle et al., 2009; Lawton et al., 2012) or only measuring factors either the CSF or serum (Ehrhart et al., 2015; Mitchell et al., 2009).…”

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

“…While there is evidence of numerous pathologic mechanisms associated with ALS, excitoxicity continues to be one of the accepted mediators of disease progression and MN death and has been studied extensively [74][75][76]. Excitoxicity is a result of overstimulation of glutamate receptors, thereby increasing intracellular calcium levels leading to increased cell death.…”