Abstract
Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson’s disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative 31P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo 31P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment.
Highlights
Energy metabolism is a fundamental process of life, and adenosine triphosphate (ATP)produced by mitochondrial oxidative phosphorylation (OXPHOS) is the main source of chemical energy for all cellular activities in the brain [1,2,3]
We found that the ATPase enzyme activity represented by the forward rate constant kf,ATPase was higher in Parkinson’s disease (PD) brains, while there was no significant difference in CMRATP values between the PD
By performing metabolic and energetic assessments of PD patients and age-sex matched healthy controls, we have provided compelling evidences showing abnormal energy metabolism in cortical brain region of the PD patients
Summary
Energy metabolism is a fundamental process of life, and adenosine triphosphate (ATP)produced by mitochondrial oxidative phosphorylation (OXPHOS) is the main source of chemical energy for all cellular activities in the brain [1,2,3]. In vivo 31 P MRS can directly detect constituents of endogenous phosphorous metabolites, including ATP, phosphocreatine (PCr), inorganic phosphate (Pi), phosphoethanolamine (PE) and glycerophosphocholine (GPC), as well as intracellular pH and free magnesium content ([Mg2+ ]). It should, provide an ideal tool for assessing the link between energy failure and neurodegenerative diseases [4,22]. Only a small number of such studies have been reported and most of them were performed on relatively low-field (≤3 Tesla (T)) MR imaging (MRI) scanners with limited signal-to-noise ratio (SNR) and sub-optimal spectral quality [18,23,24,25,26,27,28,29,30,31]
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