Prediagnostic plasma branched-chain amino acids and the risk of amyotrophic lateral sclerosis

Bjørnevik, Kjetil; O’Reilly, Éilis J.; Berry, James; Clish, Clary B.; Jeanfavre, Sarah; Kato, Ikuko; Kolonel, Laurence N.; Marchand, Loı̈c Le; McCullough, Marjorie L.; Paganoni, Sabrina; Schwarzschild, Michael A.; Talbott, Evelyn O.; Wallace, Robert B.; Zhang, Zhongli; Manson, JoAnn E.; Ascherio, Alberto

doi:10.1212/wnl.0000000000006669

Cited by 6 publications

(9 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A later epidemiological study attempted to address the relationship between prediagnostic BCAA levels and ALS in a population cohort but found no evidence of a significant relationship. 78 It should be noted that the only relationship in this study with a risk ratio >1 indicating a possible positive association with the development of ALS, was for serum isoleucine measured less than 5 years before ALS was diagnosed. In addition, this study included only 275 individuals who developed ALS, whereas our MR experiments aggregated data from a minimum of 12 577 ALS patients; it is, therefore, possible that the population cohort study was underpowered.…”

Section: Discussionmentioning

confidence: 50%

Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Boddy

Islam

Moll

et al. 2022

Brain Communications

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease which affects 1/350 individuals in the United Kingdom. The cause of ALS is unknown in the majority of cases. Two sample Mendelian randomisation (MR) enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study (GWAS) summary statistics for serum concentrations of 566 metabolites which were population matched with a GWAS study of ALS. For each metabolite we performed MR using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction our unbiased screen revealed three metabolites which were significantly linked to risk of ALS: Estrone-3-sulfate and bradykinin were protective, which is consistent with literature describing a male preponderance of ALS and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit breakdown of bradykinin. Serum isoleucine was positively associated with ALS risk. All three metabolites were supported by robust MR measures and sensitivity analyses; estrone-3-sulfate and isoleucine were confirmed in a validation ALS GWAS. Estrone-3-sulfate is metabolised to the more active estradiol by the enzyme 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1); further MR demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17β-HSD1, modify risk for ALS. Finally, in a zebrafish model of C9ORF72-ALS we present evidence that estradiol is neuroprotective. Isoleucine is metabolised via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction which consumes vitamin B12. Multivariable MR revealed that the toxic effect of isoleucine is dependent on depletion of vitamin B12; consistent with this, rare variants which reduce function of MMUT are protective against ALS. We propose that ALS patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12.

show abstract

Section: Discussionmentioning

confidence: 50%

Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Boddy

Islam

Moll

et al. 2022

Brain Communications

View full text Add to dashboard Cite

show abstract

“…We found that ALS-associated essential nutrients were concentrated in polyunsaturated fatty acids and fat-soluble vitamins, providing supportive evidence of the importance of lipid metabolism in ALS. No evidence has shown that diet-derived circulating essential amino acids and minerals influence the risk of ALS in the general population, even though some of them (e.g., branched-chain amino acids [ 77 ], iron, zinc, and selenium [ 78 ]) have attracted widespread attention. However, our research has certain limitations.…”

Section: Discussionmentioning

confidence: 99%

Dietary-Derived Essential Nutrients and Amyotrophic Lateral Sclerosis: A Two-Sample Mendelian Randomization Study

et al. 2022

View full text Add to dashboard Cite

Previous studies have suggested a close but inconsistent relationship between essential nutrients and the risk of amyotrophic lateral sclerosis (ALS), and whether this association is causal remains unknown. We aimed to investigate the potential causal relation between essential nutrients (essential amino acids, essential fatty acids, essential minerals, and essential vitamins) and the risk of ALS using Mendelian randomization (MR) analysis. Large-scale European-based genome-wide association studies’ (GWASs) summary data related to ALS (assembling 27,205 ALS patients and 110,881 controls) and essential nutrient concentrations were separately obtained. MR analysis was performed using the inverse variance–weighted (IVW) method, and sensitivity analysis was conducted by the weighted median method, simple median method, MR–Egger method and MR–PRESSO method. We found a causal association between genetically predicted linoleic acid (LA) and the risk of ALS (OR: 1.066; 95% CI: 1.011–1.125; p = 0.019). An inverse association with ALS risk was noted for vitamin D (OR: 0.899; 95% CI: 0.819–0.987; p = 0.025) and for vitamin E (OR: 0.461; 95% CI: 0.340–0.626; p = 6.25 × 10−7). The sensitivity analyses illustrated similar trends. No causal effect was observed between essential amino acids and minerals on ALS. Our study profiled the effects of diet-derived circulating nutrients on the risk of ALS and demonstrated that vitamin D and vitamin E are protective against the risk of ALS, and LA is a suggested risk factor for ALS.

show abstract

“…High doses of BCAAs over an extended period led to increased excitability in cultured cortical neurons and pyramidal neurons from the motor cortex slices of mice, suggesting a shared phenotype between neurons treated with BCAAs and neurons from genetic ALS mouse models [ 109 ]. However, a recent study investigating pre-diagnostic plasma levels of BCAAs from five extensive cohort studies did not find any association between these compounds and the risk of ALS [ 110 ].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Soccer (football) and brain health

Pensato,

Cortelli

2024

J Neurol

View full text Add to dashboard Cite

Soccer is one of the most popular sports worldwide, played by over 270 million people and followed by many more. Several brain health benefits are promoted by practising soccer and physical exercise at large, which helps contrast the cognitive decline associated with ageing by enhancing neurogenesis processes. However, sport-related concussions have been increasingly recognised as a pressing public health concern, not only due to their acute impact but also, more importantly, due to mounting evidence indicating an elevated risk for the development of neurological sequelae following recurrent head traumas, especially chronic traumatic encephalopathy (CTE). While soccer players experience less frequent concussions compared with other contact or combat sports, such as American football or boxing, it stands alone in its purposeful use of the head to hit the ball (headings), setting its players apart as the only athletes exposed to intentional, sub-concussive head impacts. Additionally, an association between soccer and amyotrophic lateral sclerosis has been consistently observed, suggesting a potential “soccer-specific” risk factor. In this review, we discuss the neurological sequelae related to soccer playing, the emerging evidence of a detrimental effect related to recurrent headings, and the need for implementation of comprehensive strategies aimed at preventing and managing the burden of head impact in soccer.

show abstract

Prediagnostic plasma branched-chain amino acids and the risk of amyotrophic lateral sclerosis

Cited by 6 publications

References 37 publications

Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Dietary-Derived Essential Nutrients and Amyotrophic Lateral Sclerosis: A Two-Sample Mendelian Randomization Study

Soccer (football) and brain health

Contact Info

Product

Resources

About