Zara A. Ioannides

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research.

Susac syndrome and multifocal motor neuropathy first manifesting in pregnancy

Susac Syndrome (SS) and multifocal motor neuropathy (MMN) are rare autoimmune neurological conditions which can affect women of childbearing years. The effect of pregnancy on these disorders is poorly characterised. We report a case of SS first manifesting in pregnancy with challenges in diagnosis and management and a poor clinical outcome, and a case of MMN manifesting in pregnancy then relapsing in a subsequent pregnancy. A summary of other cases in the literature and the postulated underlying immune mechanisms is presented.

Hypermetabolism in ALS is associated with greater functional decline and shorter survival

Objective To determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival. Methods Fifty-eight patients with clinically definite or probable ALS as defined by El Escorial criteria, and 58 age and sex-matched control participants underwent assessment of energy expenditure. Our primary outcome was the prevalence of hypermetabolism in cases and controls. Longitudinal changes in clinical parameters between hypermetabolic and normometabolic patients with ALS were determined for up to 12 months following metabolic assessment. Survival was monitored over a 30-month period following metabolic assessment. Results Hypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4; p<0.01). Change in body weight, body mass index and fat mass (%) was similar between normometabolic and hypermetabolic patients with ALS. Mean lower motor neuron score (SD) was greater in hypermetabolic patients when compared with normometabolic patients (4 (0.3) vs 3 (0.7); p=0.04). In the 12 months following metabolic assessment, there was a greater change in Revised ALS Functional Rating Scale score in hypermetabolic patients when compared with normometabolic patients (−0.68 points/month vs −0.39 points/month; p=0.01). Hypermetabolism was inversely associated with survival. Overall, hypermetabolism increased the risk of death during follow-up to 220% (HR 3.2, 95% CI 1.1 to 9.4, p=0.03). Conclusions and relevance Hypermetabolic patients with ALS have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival. The metabolic index could be important for informing prognosis in ALS.

Anthropometric measures are not accurate predictors of fat mass in ALS

Abstract Background: Anthropometric measurements including body mass index (BMI) and body adiposity index (BAI) are widely employed as indicators of fat mass (FM). Metabolic abnormalities in amyotrophic lateral sclerosis (ALS) impact disease progression, therefore assessment of FM informs care. The aim of this study was to determine whether BMI and BAI are accurate predictors of FM in ALS. Methodology and main findings: BMI, BAI and percentage FM (determined by air displacement plethysmography; FM-ADP) were measured in control (n = 35) and ALS (n = 44) participants. While BMI and BAI correlated significantly with FM-ADP, neither index provided an accurate estimate of FM. In longitudinally assessed ALS participants (n = 29; ∼six-month repeat assessment interval), although a change in BMI (r2 = 0.62 r = 0.79 p < 0.01) and BAI (r2 = 0.20 r = 0.44, p = 0.02) correlated with a change in FM-ADP, the anthropometric measures did not consistently reflect increases or decreases observed in FM-ADP. Conclusions/significance: Using FM-ADP as the standard, this study suggests that BMI and BAI are not accurate measures of FM in ALS. Furthermore, longitudinal assessments indicate that changes in BMI and BAI do not consistently reflect true changes of FM in ALS.

When does ALS start? A novel SOD-1 p.Gly142Arg mutation causing motor neurone disease with prominent premorbid cramps and spasms

Amyotrophic lateral sclerosis (ALS) is characterised by progressive muscle weakness and degeneration of upper and lower motor neurones. The risk of developing ALS is partly genetic and partly environmental. Approximately 10% of cases of ALS are familial and a number of causative genes have been identified.1 Many of the causative genes encode proteins that accumulate in cells in ALS. Mutations of the copper-zinc (Cu, Zn) superoxide dismutase type 1 (SOD1) gene account for approximately 20% of familial and 3% of sporadic ALS cases. Over 150 mutations in the coding region of SOD1 have been found in patients with ALS worldwide, with variation of the frequency of SOD1 mutations in different populations. However, not all SOD1 mutations are pathogenic and there is a variety of clinical presentations of patients with pathogenic mutations. Furthermore, the different mutations have diverse effects on the structure of the SOD1 protein, and some cause no abnormality other than decreasing the net charge of the protein. We now describe two sisters, from a family of Caucasian genetic background, with a novel SOD1 mutation, and unusual clinical features before the onset of weakness. The proband developed painful leg and hand cramps and leg stiffening in her sixth decade. After about 10 years, she …

Predictions of resting energy expenditure in amyotrophic lateral sclerosis are greatly impacted by reductions in fat free mass

Abstract Background: Hypermetabolism, defined as an increase in measured resting energy expenditure (mREE) relative to predicted REE (pREE), is recognised as an important feature of amyotrophic lateral sclerosis (ALS). Previous predictions of REE in ALS have not accounted for differences in fat free mass (FFM). This study aimed to investigate the effect of accounting for FFM on pREE in ALS patients and a matched control population. Methodology and findings: Body composition and pREE data were obtained from 50 ALS and 50 age- and sex-matched healthy control participants. We contrast conventional models for predicting REE that rely on anthropometric measures, age, and sex, with models that predict REE relative to FFM. Given that a significantly lower FFM was observed in ALS, models that consider FFM predicted significantly lower REE in ALS participants when compared to controls. Using Bland-Altman analysis, we demonstrate a prediction bias between models that do not account for FFM between the ALS and control populations. We also demonstrate greater agreement in predictions between control and ALS populations when correcting for FFM. Conclusions/significance: Future studies should correct for reductions in FFM when predicting REE in ALS.

Hypermetabolism in motor neurone disease is associated with a greater functional decline but not weight loss

Objectives Motor Neurone Disease (MND) is fatal neurological disease. Hypermetabolism (increased resting energy expenditure (REE)) and loss of body weight occur in MND. We aimed to determine whether hypermetabolism correlates with disease severity and weight loss. Methods Patients (n=44) and control participants (n=45) presented at the MND clinic at the CCR following an overnight fast. Body composition was assessed using air displacement plethysmography (BodPod; COSMED). REE was assessed by indirect calorimetry (Quark RMR, COSMED) and a metabolic index (MI;% change in measured REE versus predicted REE) determined. Hypermetabolism was defined as MI>120%. Disease severity was assessed using the Amyotrophic Lateral Sclerosis Functional Rating scale (ALSFRS-R) and respiratory function tests (RFTs). A subset of MND patients (n=30) returned for a repeat assessment ~4 months later. Results Hypermetabolism was more prevalent in MND (41%) when compared with control (18%) participants. In longitudinal analyses, hypermetabolism was not associated with a change in RFTs (including forced vital capacity, p=0.91 and sniff nasal pressure, p=0.40), loss of body weight (p=0.79) or a reduction in% fat mass (p=0.78). Strikingly, hypermetabolic individuals experienced a greater decline in ALSFRS-R over the sampling interval (p<0.01). Conclusions We confirm a greater prevalence of hypermetabolism in MND when compared with matched controls. Hypermetabolism in MND patients is associated with a greater functional decline but not a change in RFTs or weight loss. While challenging the notions that hypermetabolism is a consequence of respiratory dysfunction and that it contributes to weight loss, our emerging insights suggest that hypermetabolism contributes to disease progression. Thus, hypermetabolism could have major implications for quality of life and possibly disease survival. Ongoing studies aim to clarify the cause for and consequence of hypermetabolism in MND.

The risk of overestimating fatness in motor neurone disease: longitudinal assessments of body composition

Objectives Loss of fat mass (FM) in motor neurone disease (MND) is common and could impact disease progression. Thus, accurate predictions of FM in MND could inform strategies to manage body weight throughout disease course. The aim of this study was to determine whether anthropometric measurements of body mass index (BMI) and body adiposity index (BAI) are accurate predictors of FM in MND patients. Methods BMI, BAI and percentage FM (determined by air displacement plethesmography (ADP)) were measured in control (n=46) and MND (n=42) study participants. Results BMI and BAI correlated significantly with FM (p<0.01). Bland Altman analysis showed that BMI and BAI overestimated FM in MND (mean bias of 8.59 for BMI comparisons and 8.47 for BAI comparisons). In longitudinally assessed MND participants (n=23; 6 month assessment interval), a change in BMI (r2=0.61, p<0.01) but not BAI (r2=0.07, p<0.24), correlated significantly with a change in FM. Conclusions Results from this study suggest that a single measurement of BAI and BMI is likely to overestimate FM in MND. Importantly, longitudinal assessment of BMI in MND patients could be used as an indicator of change in FM over time. Knowledge of limitations and strengths in using BMI and BAI could inform nutritional and dietary strategies to manage body weight in MND.

Comparison of Faecal Microbe Diversity Between Motor Neurone Disease (Mnd) and Control Participants

Objectives Imbalances in the composition and function of intestinal microbes have been reported in neurological and other diseases. We sought to determine whether faecal microbe composition differs between motor neuron disease (MND) patients and an age- and sex-matched control population. Methods MND (n=26) and control participants (n=24) provided faecal samples for 16S gDNA analysis of the presence of bacteria and archaeal species. For MND participants, body composition, metabolic status, site of symptom onset, and functional capacity (as determined by ALSFRS-R) was recorded. 16S metagenomics aggregate reports were completed for each sample (2017 Illumina, Inc.), and the entropy of species-level classifications determined across all samples using the Shannon Species Diversity index. Functional and species diversity interactions are currently under assessment using PICRUSt and QIIME data analysis pipelines. Results In all participants metagenomics aggregate reports revealed an increase in species diversity within individuals with increasing age. Compared with control participants, a higher number of faecal microbial species, and a greater species diversity were observed in MND patients. The greater species diversity was primarily seen in patients with bulbar onset disease. Conclusions Greater diversity of faecal microbe content in MND participants with bulbar onset disease suggest that changes in the gut microbiome composition in this cohort of patients could occur secondary to changes in dietary intake as a consequence of dysphagia. Ongoing studies aim to clarify these findings in a larger cohort of individuals, while considering the functional implications of a shift in gut microbe diversity in MND.

The utility of FDG-PET in complex neurological conditions: Letters to the Editor

demulcent (substance having soothing effect) and protects the intestinal walls. The protective role of flour against herb poisons has been confirmed in two series of experiments using dogs which received C. colocynthis or E. elaterium infusions through a stomach-tube. These experiments reveal the reliability of the biblical narrative. Although this incident, from the theological point of view, is one of the miracles of the prophet Elisha, which happened to protect the faithful prophets of the Lord from any harm (cf. Mark. 16:18: ‘And if they drink anything deadly, it will by no means hurt them’), it undoubtedly highlights the possible harmful effects on human health that could be caused by the consumption of unknown wild plants. In conclusion, the accidental poisoning of the prophets’ sons in the Old Testament and its successful management with flour by the prophet Elisha is an excellent case of herb poisoning in the history of medical toxicology.