Abstract
Various studies have suggested that a neurotoxic cerebrospinal fluid profile could be implicated in amyotrophic lateral sclerosis. Here, we systematically review the evidence for cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis and explore its clinical correlates. We searched the following databases with no restrictions on publication date: PubMed, Embase and Web of Science. All studies that investigated cytotoxicity in vitro following exposure to cerebrospinal fluid from amyotrophic lateral sclerosis patients were considered for inclusion. Meta-analysis could not be performed, and findings were instead narratively summarized. Twenty-eight studies were included in our analysis. Both participant characteristics and study conditions including cerebrospinal fluid concentration, exposure time and culture model varied considerably across studies. Of 22 studies assessing cell viability relative to controls, 19 studies reported a significant decrease following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, while three early studies failed to observe any difference. Seven of eight studies evaluating apoptosis observed significant increases in the levels of apoptotic markers following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, with the remaining study reporting a qualitative difference. Although five studies investigated the possible relationship between cerebrospinal fluid cytotoxicity and patient characteristics, such as age, gender and disease duration, none demonstrated an association with any of the factors. In conclusion, our analysis suggests that cerebrospinal fluid cytotoxicity is a feature of sporadic and possibly also of familial forms of amyotrophic lateral sclerosis. Further research is, however, required to better characterize its underlying mechanisms and to establish its possible contribution to amyotrophic lateral sclerosis pathophysiology.
Highlights
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal neurodegenerative condition, characterized by the loss of motor neurons in both the brain and spinal cord, leading to paralysis
ALS is associated with several genes, for example, C9ORF72, TARDBP, SOD1 and FUS, with some genes contributing to the presence of frontotemporal dementia (FTD)
Our summary of findings in this study suggests that cerebrospinal fluid (CSF) cytotoxicity is a feature of sporadic and possibly of familial ALS, with ALS–CSF appearing to exert cytotoxicity at a wide range of concentrations and exposure times, as well as across different culture models
Summary
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal neurodegenerative condition, characterized by the loss of motor neurons in both the brain and spinal cord, leading to paralysis. Advances made in the last decade have led to a much improved understanding of ALS pathophysiology, with various mechanisms apparently involved (Hardiman et al, 2017). These include glutamate excitotoxicity, abnormal RNA metabolism, oxidative stress and mitochondrial dysfunction, amongst others. Given the involvement of impaired protein homeostasis, ALS, similar to other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease, is viewed as a proteinopathy, with most cases characterized pathologically by the presence of TAR DNA-binding protein 43 (TDP43)-containing ubiquitinated inclusions (Neumann et al, 2006). Pertains to the extent to which each of the above processes contributes to the overall pathophysiology
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