We searched MEDLINE for papers published in English between Jan 1, 1966, and Oct 31, 2015, using the search terms “neurodegeneration”, “amyotrophic lateral sclerosis”, “frontotemporal dementia”, and “metabolism” in combination with “eating”, “neuroendocrine”, “diet”, “insulin resistance”, “cholesterol”, and “lifestyle factors”. We searched article reference lists, review articles, and major textbook chapters for additional references. Abstracts and reports from relevant meetings were also
Personal ViewAmyotrophic lateral sclerosis and frontotemporal dementia: distinct and overlapping changes in eating behaviour and metabolism
Introduction
Increasing evidence suggests that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with a higher prevalence of metabolic changes—including fluctuations in weight, insulin resistance, and cholesterol—than in the general population; these higher frequencies have also been reported in several other neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease (figure 1).1, 2, 3, 4, 5 The nature of the relation between these metabolic changes and how they might affect disease progression and thereby prognosis—whether they result from the process of neurodegeneration or have a modulating effect on neurodegeneration—are unsolved questions. Typically, insulin resistance and metabolic changes have been viewed as a consequence of obesity.6 However, peripheral insulin resistance and diabetes are more frequently reported in patients with neurodegenerative disease than in the general population,1, 2, 3, 4, 5 despite patients with many of these disorders losing substantial weight, often before diagnosis.7, 8 As such, insulin resistance might be independently associated with the processes of neurodegeneration.9, 10 Common mechanisms associated with both metabolic dysfunction and neurodegeneration include oxidative stress, inflammation, and vascular dysfunction.10 Whether these or other mechanisms promote metabolic dysfunction and neurodegeneration is unclear.
Although limited in-vivo evidence exists for the exact metabolic mechanisms that might promote neurodegeneration, emerging data show great metabolic variability associated with different neurodegenerative phenotypes. Evidence for some convergence of clinical characteristics and pathological mechanisms in ALS and FTD has raised the possibility of the existence of a continuum between these two diseases,11, 12 and research from the past 5 years suggests that the range of metabolic changes and eating behaviours in ALS and FTD might parallel the clinical and pathological associations between these two disorders. This phenotypic range also suggests that these disorders could potentially be used as a model to study such changes in other neurodegenerative diseases.
In this Personal View, we examine the available evidence for the different eating and metabolic changes apparent in ALS and FTD, and the associations with disease pathology, progression, and survival in the two disorders. We then discuss the potential convergence in metabolic and eating changes between these diseases, and finally, we propose a way forward for investigating metabolic disorders in these conditions to answer the crucial question of whether metabolic derangements are the result of, or conversely promote, neurodegeneration.
Section snippets
The ALS–FTD clinical spectrum
Mounting evidence points towards a clinical and neuropathological overlap between ALS and FTD.13 These two diseases could be conceptualised as representing the extremes of a disease spectrum.11, 12 Patients diagnosed with ALS typically have limb or bulbar symptoms at initial presentation.14, 15, 16 Reports vary on the extent of cognitive changes in ALS (ie, behavioural, cognitive, and language), with estimates of at least 5% of patients being affected,17, 18 and up to 15% of patients with this
Eating behaviour and nutritional intake
ALS has generally been regarded as a disease associated with malnutrition, with suggestions that nutritional intake might decrease as the disease progresses, particularly in patients with reduced functional capability.30 This reduction in food intake might be secondary to dysphagia,31 or might result from loss of appetite32 or difficulty consuming food due to weakness of the hands. A study33 published in 2015 showed that patients presymptomatic for ALS might have increased total daily energy
Eating behaviour and nutritional intake
Research on eating and metabolic changes in FTD, compared with ALS, has so far focused more on eating abnormalities and less on their metabolic effect. Hyperorality and dietary changes form one of the six criteria for the diagnosis of bvFTD83 and are reported in more than 60% of patients at initial presentation.84 These criteria are helpful in the diagnosis of patients with this variant and in discrimination of this condition from other forms of dementia, such as Alzheimer's disease.85 Changes
Eating behaviour, metabolism, and the ALS–FTD spectrum
Given the clinical and pathological overlap between FTD and ALS,11, 120 the metabolic changes might be viewed to represent additional components of the spectrum of these two diseases.121 At one end of the continuum, patients with ALS are likely to develop weight loss, hypermetabolism, malnutrition, hyperlipidaemia, and insulin resistance. At the other end, patients with FTD are likely to develop insulin resistance, and potentially less weight gain than would be expected in light of their
Conclusions and future directions
The central question remains as to whether metabolic changes are the result of or, alternatively, exacerbate neurodegeneration in ALS and FTD. These metabolic changes might represent a secondary effect of neurodegeneration in vital brain regions, with some behavioural changes potentially having a protective effect against disease development or progression. For example, eating changes (hyperphagia) noted in FTD might act as an adaptive mechanism to stave off a hypermetabolic state. Without more
Search strategy and selection criteria
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2022, Neurobiology of AgingCitation Excerpt :The pathophysiology underlying the extent of upper and lower motor neuron involvement and the site of disease onset in ALS are poorly understood, underscoring the need for further research on this topic. In contrast, metabolic alterations in ALS patients have already been highlighted by previous studies, which found hypothalamic atrophy in MRI, alterations in the melanocortin pathway, TDP-43 pathology in the hypothalamus, and a hypermetabolic state in patients with ALS (Ahmed et al., 2016; Bouteloup et al., 2009; Cykowski et al., 2014; Desport et al., 2005; Gorges et al., 2017; Vercruysse et al., 2016). Targeting metabolism with a high caloric fatty diet might prolong survival in patients with fast disease progression (Ludolph et al., 2020).
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2022, Molecular and Cellular NeuroscienceCitation Excerpt :A recent study indicates that hypermetabolism may be an important weight loss mechanism (Wei et al., 2021). Indeed, about half of ALS patients have hypermetabolism with increased energy waste (Ahmed et al., 2016; Bouteloup et al., 2009; Steyn et al., 2018). The cerebellum is an understudied brain region in ALS/FTD compared to upper and lower motor neurons.
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