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Magnetic resonance spectroscopy reveals mitochondrial dysfunction in amyotrophic lateral sclerosis
- Source :
- Brain : a journal of neurology. 143(12)
- Publication Year :
- 2020
-
Abstract
- Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in people living with amyotrophic lateral sclerosis using phosphorus-31 magnetic resonance spectroscopy, the modality of choice to assess energy metabolism in vivo. We recruited twenty patients and 10 healthy age and gender-matched controls in this cross-sectional clinico-radiological study. Phosphorus-31 magnetic resonance spectroscopy was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: adenosine triphosphate, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of adenosine triphosphate hydrolysis, phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in brainstem where Gibbs free energy of adenosine triphosphate hydrolysis and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting Gibbs free energy of adenosine triphosphate hydrolysis, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in amyotrophic lateral sclerosis in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. Phosphorus-31 magnetic resonance spectroscopy represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in amyotrophic lateral sclerosis and a potential tool for future clinical trials targeting bioenergetic dysfunction.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Magnetic Resonance Spectroscopy
Mitochondrial Diseases
Phosphocreatine
Walking
Oxidative Phosphorylation
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Adenosine Triphosphate
Tibialis anterior muscle
Internal medicine
medicine
Humans
Muscle Strength
Amyotrophic lateral sclerosis
Muscle, Skeletal
Aged
Brain Chemistry
Motor Neurons
Upper motor neuron
Amyotrophic Lateral Sclerosis
Skeletal muscle
Middle Aged
medicine.disease
Magnetic Resonance Imaging
Mitochondria
Adenosine diphosphate
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Cross-Sectional Studies
chemistry
Female
Neurology (clinical)
Energy Metabolism
Adenosine triphosphate
030217 neurology & neurosurgery
Phosphomonoesters
Muscle Contraction
Subjects
Details
- ISSN :
- 14602156
- Volume :
- 143
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Brain : a journal of neurology
- Accession number :
- edsair.doi.dedup.....e189d626bc295ea090a93189ce9b74c1