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Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis
  1. Rebekah Ahmed1,
  2. I Sadaf Farooqi2
  1. 1 Brain and Mind Centre and Sydney Medical School, University of Sydney, Sydney, Australia
  2. 2 University of Cambridge Metabolic Research Laboratories and the NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
  1. Correspondence to Dr Rebekah Ahmed, ForeFront Clinic Brain and Mind Centre 94 Mallett St Camperdown, NSW Australia 2050; rebekah.ahmed{at}sydney.edu.au

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The hypothalamus, energy balance and neurodegeneration

There is growing interest in understanding the specific brain regions underlying the association between metabolic changes and a range of neurodegenerative diseases.1–3 Atrophy of the hypothalamus, a region critical to the regulation of energy balance, has been observed in Huntington’s disease4 and frontotemporal dementia (FTD).5 6 In their JNNP paper, Gorges and colleagues7 found that people with amyotrophic lateral sclerosis (ALS), part of the spectrum of neurodegenerative disease that includes FTD, also had substantially decreased hypothalamic volumes measured by 3 T MRI.

Why is this finding important? The hypothalamus contains neurons that regulate eating behaviour and autonomic function and has functional projections to the striatum, thalamus, brainstem, orbitofrontal cortex and other brain regions,8 involved in reward processing and decision-making.8 As such structural changes in the hypothalamus (such as a loss of volume/atrophy) could contribute to changes in eating behaviour and body weight and metabolism, as well as to disruption of the sleep/wake cycle, disordered thermoregulation and pain perception. Interestingly, Dupuis and colleagues found that hypothalamic atrophy in ALS is correlated with body mass index. Potential mechanisms that might explain this association include changes in food intake and/or energy expenditure. Comparison with studies in FTD where increased food intake and increased energy expenditure and changes in hypothalamic volume have been observed would also be useful to explore.5

Changes in energy homeostasis are modulated by neural circuits involving the hypothalamus which respond to nutritional state (through the adipose tissue-derived hormone leptin) and meal consumption (via neural and hormonal signals from the gut) (figure 1). Primary leptin-responsive neurons in the arcuate nucleus of the hypothalamus expressing the anorectic peptide pro-opiomelanocortin (POMC) or the orexigen agouti-related peptide (AgRP) project to the paraventricular nucleus of the hypothalamus where they synapse with neurons expressing the melanocortin 4 receptor (MC4R) to regulate food intake.9

Figure 1

Interaction of peripheral hormones and neural networks proposed to influence eating behaviour in FTD. Given the overlap with ALS, these structures may also influence eating behaviour in ALS. Red arrow pathways inhibit eating behaviour, green arrow pathways promote eating behaviour. ARC, arcuate nucleus; bvFTD, behavioural variant FTD; CART, cocaine-regulated and amphetamine-regulated transcript; CCK, cholecystokinin; MCR, melanocortin receptor; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus; PYY, peptide YY; svPPA, semantic variant primary progressive aphasia.

Increased serum AgRP levels (suggestive of the starved/fasted state) have previously been identified in patients with FTD (both behavioural variant and semantic variant primary progressive aphasia)5 (figure 1). A recent study by Dupuis’s group10 found that hypothalamic expression of AgRP was increased in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1 (G86R); these findings were also replicated in TDP-43 (Tardbp) and FUS mutations. Additionally, Dupuis et al have shown the presence of atrophy of the hypothalamus in presymptomatic carriers, with the majority carrying mutations in the C9orf72 and SOD1 genes which predispose to ALS.11 Longitudinal studies of mutation carriers (vs non-mutation carrier family members) are needed to investigate the potential significance of these findings and the contribution of neural and neuroendocrine changes to disease onset and progression.

Further research is also warranted into commonalities and differences in the metabolic and neuroendocrine profiles across neurodegeneration, particularly in presymptomatic cohorts.12 Such studies could potentially provide new understanding into the mechanisms underlying these diseases and could identify novel therapeutic targets.

References

Footnotes

  • Contributors RA and ISF wrote and critically appraised the manuscript for publication.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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