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Hypermetabolism may be linked to neurodegenerative processes in ALS
Amyotrophic lateral sclerosis (ALS) is a disease of paradoxes. Patients usually have little or no medical history and tend to be fit and athletic,1 2 yet undergo a rapid, unrelenting decline. Patients predominantly present with progressive weakness, with involvement of cortical motor neurons and as the disease progresses, patients develop denervation, muscle atrophy, decreased muscle mass and decreased free fat mass, all of which would be expected to decrease energy expenditure.3 Yet patients with ALS are consistently hypermetabolic, with increased resting energy expenditure evident in up to 50% of patients.4
Several variables have been hypothesised to contribute to this hypermetabolic state, including uncontrolled fasciculations, increased respiratory work and mitochondrial dysfunction,4 yet the exact mechanism remains to be elucidated. In their JNNP paper Steyn and colleagues5 aim to determine the prevalence of hypermetabolism in ALS and to determine the relationship between hypermetabolism and functional decline. They find that hypermetabolism is more prevalent in ALS (41% vs 12% in controls), and that hypermetabolic patients have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival compared with normometabolic patients with ALS. The authors hypothesise that the presence of hypermetabolism may be multifactorial related to peripheral denervation and central factors.
The study by Steyn and colleagues provides strong evidence that hypermetabolism in ALS is associated with worsened disease prognosis. Hypermetabolic patients with ALS are likely to have a more severe disease and earlier death, and this adds evidence to the argument that the hypermetabolic state is intrinsically linked to the process of neurodegeneration. Such statement is supported by studies in several genetic animal models exhibiting hypermetabolism and weight loss.4 6 What we do not yet understand relates to primacy, that is, is hypermetabolism a by-product of the neurodegenerative process or does it promote neurodegeneration, thus constituting a potential therapeutic target? Further confounding the issue are recent findings that energy expenditure in patients with ALS are dependent on body composition and physical activity,7 meaning that some patients with ALS may have reduced energy expenditure in advanced ALS, suggesting that longitudinal studies measuring metabolic changes in both presymptomatic and symptomatic patients are desperately needed.
As stated by Steyn and colleagues in their discussion, it is also likely that central factors play a role in the development of hypermetabolism in addition to peripheral factors. Of relevance, hypothalamic atrophy was identified in ALS in both symptomatic and presymptomatic cohorts and correlated with body mass index.8 9 Similar findings have been identified in frontotemporal dementia10 11 and suggest that changes in neural pathways and central factors may have a pivotal role in controlling food intake and energy metabolism,12 either as pathogenic drivers or as adaptive mechanisms. Disentangling pathogenic pathways from compensatory responses will be challenging in future studies as it seems likely that the body tries to adapt to the imbalance of increased energy metabolism by rewiring hypothalamic neural circuits leading to increased food intake.13 An increase in food and fat intake is able to secondarily affect blood lipid levels,14 which in turn have been associated with improved survival.15 As such, it seems likely that ALS may provide an ideal model to study the interaction between energy metabolism, food intake, neurodegeneration and the adaptive mechanisms that try to preserve function. Understanding these aspects of ALS physiology16 and disease mechanisms may in turn provide novel treatment targets to help modify the prognosis in this devastating disease. In all, the study by Steyn and colleagues provides impetus for further research to understand the mechanisms underlying metabolic changes and how we may target these changes in clinical trials.
Contributors All authors drafted and reviewed the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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