Eating and metabolism across the frontotemporal dementia and amyotropic lateral sclerosis spectrum

Abstract

Metabolic changes have been identified across a number of neurodegenerative conditions. It is not known how these changes arise, whether they represent the result of the process of neurodegeneration affecting critical brain regions involved in metabolic regulation, or are causative, driving the process. In amyotrophic lateral sclerosis (ALS) metabolic changes have been linked to disease progression, yet there has been little investigation of changes in eating behaviour that may affect metabolism. In frontotemporal dementia (FTD), which shares a significant clinical and pathological overlap with ALS, changes in eating behaviour have been incorporated into the diagnostic criteria, but there has been no examination of changes in metabolism and energy expenditure, nor how eating behaviour may differ between the phenotypes of FTD (behavioural variant FTD: bvFTD and semantic variant primary progressive aphasia: svPPA). The following thesis, using methods adapted from obesity research quantifies the eating behavioural and metabolic changes, including changes in energy expenditure along the ALS-FTD spectrum. Key findings include that bvFTD is characterized by marked hyperphagia, with a strong sucrose preference, whilst svPPA is characterized by more rigid eating behaviour and a strong sucrose preference. These changes are mediated by complex neural networks that differ between bvFTD and svPPA, involving reward, cognitive, visual and autonomic control of food intake. These neural networks interact with the hypothalamus and key neuroendocrine peptides. In FTD there are also key changes in body mass index (BMI) and insulin and cholesterol levels. Changes in BMI are likely to be mediated by changes in the autonomic nervous system, heart rate regulation and energy expenditure, with neural correlates for these changes in FTD including the mesial temporal cortex. A spectrum of eating behavioural changes occurs along the ALS-FTD spectrum that increases with cognitive impairment, and are associated with an improved survival (3 fold decrease risk of dying). Future research focusing on longitudinal changes in eating behaviour and metabolism in presymptomatic and affected cohorts in ALS and FTD is likely to help answer the question of whether metabolic changes promote neurodegeneration or are the result of the neurodegenerative process and how we may modify these factors to affect disease progression.