Studies of Environmental Risk Factors in Amyotrophic Lateral Sclerosis (ALS) and a Phase I Clinical Trial of l-Serine

Background: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both environmental and genetic factors. Our study aimed at summarising the environmental risk factors for ALS, assessing the evidence for diverse biases, and pinpointing risk factors with high epidemiological credibility. Methods: We searched PubMed from inception to August 20, 2015, to identify systematic reviews and meta-analyses of observational studies examining associations between environmental factors and ALS. For each meta-analysis, we estimated the summary effect size by the use of random-effects and fixed-effects models, the 95% CI, the 95% prediction interval (PI), and the between-study heterogeneity. We assessed the evidence of small-study effects and excess significance bias. Results: Sixteen unique meta-analyses of different risk factors and ALS were considered. Of them, 5 were statistically significant at p < 0.001 under the random-effects model. Only one factor presented robust evidence for a convincing association. This association pertained to chronic occupational exposure to lead (random-effects OR 1.81, 95% CI 1.39-2.35). Conclusions: A small number of published meta-analyses on environmental factors and risk of ALS was identified, a phenomenon that could be attributed to the challenges in studying a rare neurological disease. More observational studies with adequate sample size and study design are needed to clarify the environmental component of ALS pathogenesis.

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Environmental Risk Factors and Amyotrophic Lateral Sclerosis (ALS): A Case-Control Study of ALS in Michigan

PLoS ONE ◽

10.1371/journal.pone.0101186 ◽

2014 ◽

Vol 9 (6) ◽

pp. e101186 ◽

Cited By ~ 27

Author(s):

Yu Yu ◽

Feng-Chiao Su ◽

Brian C. Callaghan ◽

Stephen A. Goutman ◽

Stuart A. Batterman ◽

...

Keyword(s):

Risk Factors ◽

Amyotrophic Lateral Sclerosis ◽

Environmental Risk ◽

Case Control Study ◽

Case Control ◽

Environmental Risk Factors ◽

Control Study ◽

Lateral Sclerosis

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Transplantation of Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial

Cell Transplantation ◽

10.3727/096368916x693716 ◽

2017 ◽

Vol 26 (4) ◽

pp. 647-658 ◽

Cited By ~ 63

Author(s):

Eva Syková ◽

Petr Rychmach ◽

Ivana Drahorádová ◽

ŠImona Konrádová ◽

Kateřina Růžičková ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Phase I ◽

Lumbar Puncture ◽

Stromal Cells ◽

Adverse Reactions ◽

Rating Scale ◽

Neurodegenerative Disorder ◽

Safe Procedure ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive untreatable neurodegenerative disorder, leading to the death of the cortical and spinal motoneurons (MNs). Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) may represent a new approach to slowing down the progression of ALS by providing neurotrophic support to host MNs and by having an anti-inflammatory effect. We have designed a prospective, nonrandomized, open-label clinical trial (phase I/IIa, EudraCT No. 2011-000362-35) to assess the safety and efficacy of autologous multipotent BM-MSCs in ALS treatment. Autologous BM-MSCs were isolated and expanded under GMP conditions. Patients received 15 ± 4.5 × 106 of BM-MSCs via lumbar puncture into the cerebrospinal fluid. Patients were monitored for 6 months before treatment and then for an 18-month follow-up period. Potential adverse reactions were assessed, and the clinical outcome was evaluated by the ALS functional rating scale (ALSFRS), forced vital capacity (FVC), and weakness scales (WSs) to assess muscle strength on the lower and upper extremities. In total, 26 patients were enrolled in the study and were assessed for safety; 23 patients were suitable for efficacy evaluation. After intrathecal BM-MSC application, about 30% of the patients experienced a mild to moderate headache, resembling the headaches after a standard lumbar puncture. No suspected serious adverse reactions (SUSAR) were observed. We found a reduction in ALSFRS decline at 3 months after application ( p < 0.02) that, in some cases, persisted for 6 months ( p < 0.05). In about 80% of the patients, FVC values remained stable or above 70% for a time period of 9 months. Values of WS were stable in 75% of patients at 3 months after application. Our results demonstrate that the intrathecal application of BM-MSCs in ALS patients is a safe procedure and that it can slow down progression of the disease.

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What causes amyotrophic lateral sclerosis?

F1000Research ◽

10.12688/f1000research.10476.1 ◽

2017 ◽

Vol 6 ◽

pp. 371 ◽

Cited By ~ 31

Author(s):

Sarah Martin ◽

Ahmad Al Khleifat ◽

Ammar Al-Chalabi

Keyword(s):

Risk Factors ◽

Amyotrophic Lateral Sclerosis ◽

Respiratory Failure ◽

Neurodegenerative Disease ◽

Motor Neurons ◽

Environmental Risk ◽

Age Of Onset ◽

Genetic Associations ◽

Male Predominance ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis and death from respiratory failure within 2 to 3 years. The peak age of onset is 55 to 70 years, with a male predominance. The causes of amyotrophic lateral sclerosis are only partly known, but they include some environmental risk factors as well as several genes that have been identified as harbouring disease-associated variation. Here we review the nature, epidemiology, genetic associations, and environmental exposures associated with amyotrophic lateral sclerosis.

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