A roadmap to ALS prevention: strategies and priorities

Benatar, Michael; Goutman, Stephen A.; Staats, Kim A.; Feldman, Eva L.; Weisskopf, Marc G.; Talbott, Evelyn O.; Dave, Kuldip D.; Thakur, Neil M; Al‐Chalabi, Ammar

doi:10.1136/jnnp-2022-330473

Cited by 6 publications

(2 citation statements)

References 44 publications

(52 reference statements)

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“…Indeed, there is evidence that the temporal evolution and nature of biomarkers in the presymptomatic stage of FTD also differ across the three major implicated genotypes [11]. With the study of presymptomatic genetic ALS as the starting point, the long-term goal is to parlay the insights obtained from these studies into the identification of underlying risk factors (environmental and polygenic) and development of therapeutic strategies for the larger group of apparently sporadic cases of ALS [12].…”

Section: Studying Presymptomatic Disease Through Genetic Amyotrophic ...mentioning

confidence: 99%

Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention

Benatar

Turner

Wuu

2023

Current Opinion in Neurology

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Purpose of review Significant progress in characterizing presymptomatic amyotrophic lateral sclerosis (ALS) is ushering in an era of potential disease prevention. Although these advances have largely been based on cohorts of deep-phenotyped mutation carriers at an elevated risk for ALS, there are increasing opportunities to apply principles and insights gleaned, to the broader population at risk for ALS [and frontotemporal dementia (FTD)]. Recent findings The discovery that blood neurofilament light chain (NfL) level increases presymptomatically and may serve as a susceptibility biomarker, predicting timing of phenoconversion in some mutation carriers, has empowered the first-ever prevention trial in SOD1-ALS. Moreover, there is emerging evidence that presymptomatic disease is not uniformly clinically silent, with mild motor impairment (MMI), mild cognitive impairment (MCI), and/or mild behavioral impairment (MBI) representing a prodromal stage of disease. Structural and functional brain abnormalities, as well as systemic markers of metabolic dysfunction, have emerged as potentially even earlier markers of presymptomatic disease. Ongoing longitudinal studies will determine the extent to which these reflect an endophenotype of genetic risk. Summary The discovery of presymptomatic biomarkers and the delineation of prodromal states is yielding unprecedented opportunities for earlier diagnosis, treatment, and perhaps even prevention of genetic and apparently sporadic forms of disease.

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Section: Studying Presymptomatic Disease Through Genetic Amyotrophic ...mentioning

confidence: 99%

Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention

Benatar

Turner

Wuu

2023

Current Opinion in Neurology

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“…Of increasing concern is the role the life course of environmental exposures-the exposome-plays in ALS risk [6]. This is especially important as these exposures may be modifiable and offer the hope of disease prevention for ALS [7], and other neurological diseases more broadly [8].…”

Section: Introductionmentioning

confidence: 99%

Nanoplastics and Neurodegeneration in ALS

Eisen,

Pioro,

Goutman

et al. 2024

Brain Sciences

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Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues including breast milk. MNPLs, especially weathered particles, can breach the blood–brain barrier, inducing neurotoxicity. This has been documented in non-human species, and in human-induced pluripotent stem cell lines. Within the brain, MNPLs initiate an inflammatory response with pro-inflammatory cytokine production, oxidative stress with generation of reactive oxygen species, and mitochondrial dysfunction. Glutamate and GABA neurotransmitter dysfunction also ensues with alteration of excitatory/inhibitory balance in favor of reduced inhibition and resultant neuro-excitation. Inflammation and cortical hyperexcitability are key abnormalities involved in the pathogenic cascade of amyotrophic lateral sclerosis (ALS) and are intricately related to the mislocalization and aggregation of TDP-43, a hallmark of ALS. Water and many foods contain MNPLs and in humans, ingestion is the main form of exposure. Digestion of plastics within the gut can alter their properties, rendering them more toxic, and they cause gut microbiome dysbiosis and a dysfunctional gut–brain axis. This is recognized as a trigger and/or aggravating factor for ALS. ALS is associated with a long (years or decades) preclinical period and neonates and infants are exposed to MNPLs through breast milk, milk substitutes, and toys. This endangers a time of intense neurogenesis and establishment of neuronal circuitry, setting the stage for development of neurodegeneration in later life. MNPL neurotoxicity should be considered as a yet unrecognized risk factor for ALS and related diseases.

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