Energy metabolism in amyotrophic lateral sclerosis: assessment of body composition and energy expenditure

Abstract

Background and objectives: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the relentless loss of upper motor neurones (UMN) and lower motor neurones (LMN), leading to progressive weakness. The cause of ALS is unknown and there are currently no curative treatments. The median survival is 18 months from diagnosis, however, the rate of disease progression and survival vary significantly among individual ALS patients. In the absence of a cure for ALS, discovery of factors that modify disease progression is critical. An understanding of processes that influence the course of ALS could shed light on disease mechanisms and identify therapeutic targets that could be manipulated in order to prolong survival. Systemic energy metabolism is emerging as an important modifying factor in ALS. Of clinical significance, adiposity [in the form of fat mass (FM)] and nutritional status modify survival in ALS. Therefore, the assessment of FM and implementation of nutritional interventions to maintain FM are important components of routine care in ALS patients. Anthropometric measurements, including body mass index (BMI) and body adiposity index (BAI) are commonly used to predict adiposity in order to guide nutritional management. However, the accuracy of these measurements in ALS patients is currently unknown. Hypermetabolism [an increase in measured resting energy expenditure (REE) compared to a predicted REE] has been reported in some ALS patients and is also a possible modifier of disease progression. If this is a causal relationship, then strategies to correct or compensate for increased energy expenditure could possibly modify disease course. However, further studies to clarify the incidence, clinical correlations and consequences of hypermetabolism must be established. The objectives of this thesis were to determine whether commonly used anthropometric measurements are accurate predictors of FM in ALS patients and to study the incidence and clinical correlations of hypermetabolism in ALS patients. Methodology and main findings: Anthropometric measurements of BMI and BAI were compared to percentage FM derived from air displacement plethysmography (ADP) in 44 ALS patients and 35 age- and sex- matched healthy controls. Using Bland-Altman analyses it was found that both anthropometric measurements were less accurate predictors of FM in ALS patients than in controls and that BMI and BAI provided a poor estimate of FM in ALS patients. In a longitudinal assessment of 29 ALS patients, neither BMI nor BAI consistently reflected the change in FM. These results indicate that an isolated measure of BMI and BAI is not an accurate indicator of adiposity in ALS and that longitudinal measurements could be misleading. REE was measured via indirect calorimetry (mREE) and compared to a predicted REE (pREE, derived from a model that accounts for body composition) in 50 ALS patients and 50 age- and sex- matched healthy controls. Hypermetabolism was defined as a metabolic index (mREE/pREE x100) ≥ 120. Individuals with a metabolic index <120 were considered to be normometabolic. Hypermetabolism was found in 16% of controls and 40% of ALS patients. Hypermetabolic ALS patients had a higher LMN disease burden (assessed by clinical examination) and a greater short-term functional decline (assessed by the revised ALS functional rating scale, ALSFRS-R) than normometabolic patients. Conclusions and future directions: This study found that in ALS patients, BMI and BAI are not accurate predictors of FM and that they provide a poor indicator of change in FM over time. It is therefore likely that changes in BMI and BAI in ALS patients occur independent to changes in FM alone and could depend on muscle atrophy and re-distribution of fat. It was also found that when body composition is accounted for, the incidence of hypermetabolism is greater in ALS patients than in healthy matched controls. An association between hypermetabolism and LMN disease burden was observed in ALS patients. As LMN disease burden reflects dysfunction of motor units, it is hypothesized that hypermetabolism in ALS could arise from abnormal motor units which include dysfunctional LMNs, disrupted neuromuscular junctions and denervated muscle. Furthermore, hypermetabolism was associated with a greater functional decline in ALS patients who were studied over time. In the light of these findings it is hypothesized that hypermetabolism could drive progression of ALS and lead to a vicious cycle of denervation, hypermetabolism and further disease progression. Overall, the results of this thesis suggest that BMI and BAI are inadequate markers of nutritional status in ALS and that hypermetabolism is an important metabolic consideration in ALS patients. More accurate ALS-specific predictors of FM are required to guide nutritional therapies and further clinical and physiological studies are needed to understand the cause and prognostic implications of changes in body composition and hypermetabolism.