Multimodal assessment of mitochondrial function in Parkinson's disease.

The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parkinson's disease by applying a multimodal approach, combining standardized clinical assessment with midbrain and putaminal 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and deep phenotyping of mitochondrial and lysosomal function in peripheral tissue in patients with recent-onset Parkinson's disease and control subjects. Sixty participants (35 patients with Parkinson's disease and 25 healthy controls) underwent 31P-MRS for quantification of energy-rich metabolites [ATP, inorganic phosphate (Pi) and phosphocreatine] in putamen and midbrain. In parallel, skin biopsies were obtained from all research participants to establish fibroblast cell lines for subsequent quantification of total intracellular ATP and mitochondrial membrane potential (MMP) as well as mitochondrial and lysosomal morphology, using high content live cell imaging. Lower MMP correlated with higher intracellular ATP (r = -0.55, P = 0.0016), higher mitochondrial counts (r = -0.72, P < 0.0001) and higher lysosomal counts (r = -0.62, P = 0.0002) in Parkinson's disease patient-derived fibroblasts only, consistent with impaired mitophagy and mitochondrial uncoupling. 31P-MRS-derived posterior putaminal Pi/ATP ratio variance was considerably greater in Parkinson's disease than in healthy controls (F-tests, P = 0.0036). Furthermore, elevated 31P-MRS-derived putaminal, but not midbrain Pi/ATP ratios (indicative of impaired oxidative phosphorylation) correlated with both greater mitochondrial (r = 0.37, P = 0.0319) and lysosomal counts (r = 0.48, P = 0.0044) as well as lower MMP in both short (r = -0.52, P = 0.0016) and long (r = -0.47, P = 0.0052) mitochondria in Parkinson's disease. Higher 31P-MRS midbrain phosphocreatine correlated with greater risk of rapid disease progression (r = 0.47, P = 0.0384). Our data suggest that impaired oxidative phosphorylation in the striatal dopaminergic nerve terminals exceeds mitochondrial dysfunction in the midbrain of patients with early Parkinson's disease. Our data further support the hypothesis of a prominent link between impaired mitophagy and impaired striatal energy homeostasis as a key event in early Parkinson's disease.

Mapping the Evidence for Measuring Energy Expenditure and Indicating Hypermetabolism in Motor Neuron Disease: A Scoping Review.

OBJECTIVE: To map the international methods used to measure energy expenditure of adults living with motor neuron disease (MND) and to highlight discrepancies when indicating hypermetabolism in the MND literature. BACKGROUND: A decline in the nutritional status of patients is associated with exacerbated weight loss and shortened survival. Assessments of energy expenditure, using a variety of methods, are important to ensure an adequate energy intake to prevent malnutrition-associated weight loss. Assessments of energy expenditure are also commonly used to indicate hypermetabolism in MND, although these approaches may not be optimal. METHODS: A protocol based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews Guidelines was developed. Three electronic databases (Medline [Ovid], CINAHL [EBSCO], and Web of Science) were exhaustively searched. Identified publications were systematically screened according to predefined PICOS eligibility criteria. The primary outcome was the identification of methods used to measure energy expenditure in MND. The secondary outcome was the identification of applications of energy expenditure assessments to indicate hypermetabolism in MND. RESULTS: Thirty-two observational primary research publications were identified. Thirteen (40.6%) were longitudinal in design, with data on repeated measurements of energy expenditure presented in 3 (9.4%). Thirteen (40.6%) were case-control studies, of which 11 use a matched control group. Pulmonary function was used to assess eligibility in 10 publications. Energy expenditure was measured using indirect calorimetry (IC) in 31 studies. Discrepancies in the durations of fasted, measurement, and washout periods were observed. Of all included publications, 50% used assessments of resting energy expenditure to identify hypermetabolism. Bioelectrical impedance analysis was used to assess body composition alongside energy expenditure in 93.8% of publications. CONCLUSIONS: Resting energy expenditure is most frequently measured using an open-circuit IC system. However, there is a lack of a standardized, validated protocol for the conduct and reporting of IC and metabolic status in patients with MND.

A critical view of the use of predictive energy equations for the identification of hypermetabolism in motor neuron disease: A pilot study.

BACKGROUND AND AIMS: People living with motor neuron disease (MND) frequently struggle to consume an optimal caloric intake. Often compounded by hypermetabolism, this can lead to dysregulated energy homeostasis, prompting the onset of malnutrition and associated weight loss. This is associated with a poorer prognosis and reduced survival. It is therefore important to establish appropriate nutritional goals to ensure adequate energy intake. This is best done by measuring resting energy expenditure (mREE) using indirect calorimetry. However, indirect calorimetry is not widely available in clinical practice, thus dietitians caring for people living with MND frequently use energy equations to predict resting energy expenditure (pREE) and estimate caloric requirements. Energy prediction equations have previously been shown to underestimate resting energy expenditure in over two-thirds of people living with MND. Hypermetabolism has previously been identified using the metabolic index. The metabolic index is a ratio of mREE to pREE, whereby an increase of mREE by ≥110% indicates hypermetabolism. We aim to critically reflect on the use of the Harris-Benedict (1919) and Henry (2005) energy prediction equations to inform a metabolic index to indicate hypermetabolism in people living with MND. METHODS: mREE was derived using VO2 and VCO2 measurements from a GEMNutrition indirect calorimeter. pREE was estimated by Harris-Benedict (HB) (1919), Henry (2005) and kcal/kg/day predictive energy equations. The REE variation, described as the percentage difference between mREE and pREE, determined the accuracy of pREE ([pREE-mREE]/mREE) x 100), with accuracy defined as ≤ ± 10%. A metabolic index threshold of ≥110% was used to classify hypermetabolism. All resting energy expenditure data are presented as kcal/24hr. RESULTS: Sixteen people living with MND were included in the analysis. The mean mREE was 1642 kcal/24hr ranging between 1110 and 2015 kcal/24hr. When REE variation was analysed for the entire cohort, the HB, Henry and kcal/kg/day equations all overestimated REE, but remained within the accuracy threshold (mean values were 2.81% for HB, 4.51% for Henry and 8.00% for kcal/kg/day). Conversely, inter-individual REE variation within the cohort revealed HB and Henry equations both inaccurately reflected mREE for 68.7% of participants, with kcal/kg/day inaccurately reflecting 41.7% of participants. Whilst the overall cohort was not classified as hypermetabolic (mean values were 101.04% for HB, 98.62% for Henry and 95.64% for kcal/kg/day), the metabolic index ranges within the cohort were 70.75%-141.58% for HB, 72.82%-127.69% for Henry and 66.09%-131.58% for kcal/kg/day, indicating both over- and under-estimation of REE by these equations. We have shown that pREE correlates with body weight (kg), whereby the lighter the individual, the greater the underprediction of REE. When applied to the metabolic index, this underprediction biases towards the classification of hypermetabolism in lighter individuals. CONCLUSION: Whilst predicting resting energy expenditure using the HB, Henry or kcal/kg/day equations accurately reflects derived mREE at group level, these equations are not suitable for informing resting energy expenditure and classification of hypermetabolism when applied to individuals in clinical practice.

A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations.

A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.