Lessons learned from various presymptomatic neurodegenerative diseases may provide opportunities for early intervention, and perhaps even disease prevention of amyotrophic lateral sclerosis (ALS), according to a review published in the journal Brain.

Studies have shown that many neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), spinal muscular atrophy (SMA), and frontotemporal dementia, are preceded by a presymptomatic or prodromal period. 

Development of biomarkers reflecting the underlying biology of AD and positron emission tomography-ligands have led to a shift in conceptualizing AD framework, as disease is defined on the basis of amyloid and tau, and progression is based on neurodegeneration. These biomarkers may be used as inclusion criteria for study entry and as outcome measures in studies to assess new potential disease-modifying therapies. Studies to assess potential disease modifying therapies in amyloid-positive patients with intact cognition may provide valuable data on the potential prevention of symptomatic AD.

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There are several potential predictors of PD, including olfactory loss, urinary and erectile dysfunction, neurogenic orthostatic hypotension, and subtle motor impairment. The strongest predictor of PD of dementia with Lewy bodies is REM sleep behavior disorder. As there are no neuroprotective therapies for PD, research criteria for prodromal PD are used for research purposes.

HD may be preceded by structural changes in various brain regions as captured by MRI. Furthermore, cerebrospinal fluid and blood biomarkers may help in tracking natural history and treatment response. Levels of mutant huntingtin and neurofilament light chain in cerebrospinal fluid or blood may serve as predictors of disease status. There is an increasing interest in the possibility of early intervention studies in an effort to prevent disease manifestations with antisense oligonucleotide-based approaches showing promising results, though additional studies were less optimistic.

Interventional studies in presymptomatic patients with SMA were promising.

Given their overlapping genetic risk, pathology and clinical manifestations, frontotemporal dementia has the most in common with ALS. Furthermore, those with frontotemporal dementia are at risk for developing ALS, and vice versa.

The presymptomatic phase of ALS includes a premanifest (or clinically silent) stage, and a potential prodromal stage, characterized by mild motor, cognitive, or behavioral changes. The symptomatic phase is characterized by the clinical syndrome of ALS with progressive weakness. Phenoconversion to clinically manifest ALS is typically abrupt but recognition of the prodromal stage may improve the understanding of the progression from presymptomatic disease into clinically manifest disease and may provide opportunities for early therapeutic intervention and disease prevention.

Identifying prodromal clinical markers that predict the future emergence of clinical ALS may have an important role in the study of presymptomatic sporadic ALS and the prevention of its clinical onset.

“The challenges ahead are significant. We can, however, forge a path forward by building upon what we have learned through the study of other neurodegenerative diseases, as well as the study of individuals at genetic risk for ALS,” concluded the researchers.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Benatar M, Wuu J, McHutchison C, et al. Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases. Brain. Published online October 2, 2021. doi: 10.1093/brain/awab404.

This article originally appeared on Neurology Advisor