Quantitative Assessment of Occipital Metabolic and Energetic Changes in Parkinson's Patients, Using In Vivo 31P MRS-Based Metabolic Imaging at 7T

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.

Keywords: cerebral ATP energy metabolism; human brain; in vivo 31P MRS-based metabolic imaging; neurodegenerative disease; ursodeoxycholic acid (UDCA).

Figure 1

(A) ¹H MR image (sagittal orientation) of a subject brain showing the size and location of the ³¹P surface coil used in the study; (B) a representative ³¹P MR spectrum obtained from a PD patient; and (C) expanded original and fitted spectra covering the chemical shift range of a-ATP, NAD⁺ and NADH (gray trace: original data, red trace: spectral fitting, blue/black/green traces: decomposed a-ATP, NAD⁺ and NADH signals).

Figure 2

Occipital phosphorous metabolites profile in Parkinson’s patients (PD, n = 8) and age/gender-matched healthy controls (CT, n = 8) of Cohort I. (A) Metabolite concentrations of ATP, Pi, PCr, PE, GPC and (B) their ratios; (C) intracellular NAD⁺, NADH and total NAD contents, (D) NAD⁺/NADH redox ratio; and (E) intracellular pH are presented. * p < 0.01 and ** p < 0.001 indicate that statistic significant differences were detected with 2-tailed student t-test; and all data are presented as Mean ± SD.

Figure 3

Summary of phosphorous metabolites concentration (A), intracellular pH (B), forward rate constant (C) and cerebral metabolic rate of ATPase (D) and CK (E) reactions measured in the occipital lobe of PD patients (PD, n = 11) and age-/gender-matched control subjects (CT, n = 11) of Cohort II. All data are presented as Mean ± SD. * p < 0.05 and ** p < 0.005 indicate that significant differences were detected with 2-tailed Student t-test.

Figure 4

Summarized ATP, PCr and Pi concentrations (A), intracellular pH, free [Mg²⁺] and PE/GPC ratio (B) obtained from all participants in Cohorts I–II showing the distribution of the these values from individual PD patients (n = 19) and healthy controls (n = 19). * p < 0.05, ** p < 0.01 and *** p < 0.001 indicate that significant differences between the PD and CT groups were detected with 2-tailed student t-test.