Altered phospholipid and high-energy phosphate metabolism in the basal ganglia and thalamus of severe obsessive compulsive patients with treatment resistance: A phosphorus 31 nuclear magnetic resonance spectroscopy study.

https://doi.org/10.1016/j.pscychresns.2020.111217Get rights and content

Highlights

  • First study of 31P-MRS in OCD at 3 tesla.

  • Significantly increased concentrations of PC, PDE, PME, GPC, PME/PCr, PDE/PCr in OCD patients compared to controls in the striatum and thalamus.

  • Significantly decreased concentrations of PCr and tATP in OCD patients compared to controls in the striatum.

  • Modifications of the membrane and energy metabolism in the basal ganglia of severe OCD patients.

ABSTRACT

Introduction

Cerebral metabolism in obsessive-compulsive-disorder(OCD) has been the subject of numerous studies using proton magnetic resonance spectroscopy(MRS). Despite heterogeneous results, some studies have unraveled membrane turnover and energy metabolism abnormalities in different brain regions, suggesting that alterations in these processes may contribute to the pathophysiology. So far, no authors have explored phospholipids and high-energy phosphate metabolism using 31P-MRS, which allows in vivo quantification of phosphorus metabolites that are considered to be related to membrane turnover and energy metabolism.

Materials and Methods

The aim of our study was to describe and compare brain metabolic changes using 31P-MRS in the striatum and the thalamus, between 23 severe OCD patients and 22 healthy controls. All subject underwent a clinical examination and a same 31P-MRS protocol.

Results

Significantly, increased concentrations of PC, PDE,PME,GPC,PME/PCr,PDE/PCr were found in patients compared to controls in the striatum and the thalamus. PCr and tATP were decreased in the striatum. Finally, significant correlations were found in the striatum and the thalamus between illness duration and some specific measured parameters.

Conclusion

Our results showed significant modifications of the membrane and energy metabolism in the basal ganglia of severe OCD patients and suggests a link between energetic buffer and serotonin metabolism disorder.

Introduction

Despite heterogeneous results, proton magnetic resonance spectroscopy (1H-MRS) studies have suggested brain biochemical abnormalities (especially for N-AcetylAspartate, choline(Cho), and glutamate) in obsessive compulsive disorder (OCD). It is not yet possible to define the specific metabolic abnormalities in the brain of OCD patients. Our previous study found an increase of Cho and its ratios in the anterior cingulate cortex (ACC), striatum and thalamus, findings suggesting a neural membrane alteration on a large part of the cortico-striato-thalamo-cortical (CSTC) network in OCD(Hatchondo et al., 2017). While possible mechanisms for OCD symptoms have been suggested in animal models and neuropathological findings, they have not been confirmed by MRS studies(Aouizerate et al., 2004)

31P-MRS provides an in vivo assessment of two main pools of high energy phosphates(HEP), adenosine triphosphate(ATP) and phosphocreatine(PCr), as well as inorganic phosphate(Pi). ATP synthesized from adenosine diphosphate(ADP) and Pi in mitochondria is converted to PCr and is shuttled to the cytoplasm. PCr acts as a reservoir for HEP and the transfer of high-energy phosphate groups between ATP and PCr is a reversible reaction catalyzed by creatine kinases(CK) to generate ATP in response to energy demand. The reaction catalyzed by CKs given by PCr2+NDP+H+CKNTP2+Cris critical for maintaining stable ATP levels which are in turn critical for all energy requiring processes including ion pumping and the modification of the activity state of numerous enzymes. 31P-MRS also assesses differences in cellular membrane expansion and contraction by quantifying phosphocholine[PC], phosphoethanolamine[PE], phosphomonoesters[PMEs] and catabolites of membrane phospholipids with phosphodiesters[PDEs], glycerophosphocholine[GPC], and glycerophosphoethanolamine[GPE]. Because of their degree of mobility, GPE, GPC, PME and PDE can be quantified by time domain processing of the free induction decay, thus allowing a more refined analysis of the phospholipids catabolism/anabolism balance(Stanley, 2002).

Neural membrane integrity is essential to maintain synaptic transmission and therefore appropriate levels of neurotransmitters. In many neurodegenerative diseases (e.g. Alzheimer Disease or Huntington's disease), studies have shown modifications of membrane component balance(phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol)(Nitsch et al., 1992;Pettegrew, Panchalingam, Hamilton, and McClure, 2001) and increased levels of choline, suggesting a link between Cho and neuronal membrane degradation or even neuronal loss(Jenkins, Koroshetz, Beal, and Rosen, 1993;Meyerhoff et al., 1994). More specifically, multiple sclerosis patients exhibited high concentrations of Cho in the active demyelinating plaques(Arnold, Matthews, Francis, O'Connor, and Antel, 1992;Hattingen et al., 2011;Zaaraoui, Audoin, Pelletier, Cozzone, and Ranjeva, 2010a). Numerous studies have provided new insights in psychiatric disorders including bipolar disorders(Du et al., 2018;Shi et al., 2015) and schizophrenia(Haszto, Stanley, Iyengar, and Prasad, 2020;Weber-Fahr et al., 2013;Yuksel et al., 2015), highlighting alterations in both HEP and membrane phospholipids. Until now, no study has used 31P-MRS to explore brain metabolism in OCD.

The aim of our study was to describe and compare brain metabolic changes, and more specifically, phospholipid and high-energy phosphate metabolism, between severe OCD patients and healthy control subjects, using 3T 31P-MRS in basal ganglia and thalamus.

Section snippets

Materials and methods

This prospective, descriptive, transversal, comparative and single-center study was approved by the ethical committee of our Hospital and was performed in accordance with the guidelines of good clinical practice and the ethical standards of the Declaration of Helsinki(1964). All participants were provided with a complete description of the study during individual interview(written and oral information). All had given their written informed consent.

Clinical data

Fifty subjects were initially included. We subsequently excluded 3 OCD patients and 2 healthy controls due to poor MRS spectral quality. Finally, we retained 45 subjects: 23 patients with severe OCD and 22 healthy controls. All patients were taking SSRIs (Paroxetine, Fluoxetine, Sertraline, Escitalopram) and 12 patients were taking benzodiazepines in addition to the antidepressant medication. The demographic characteristics of the subjects are presented in Table 1.

31P-MRS: ocd vs healthy controls

As significant differences

Discussion

To our knowledge, this is the first 31P-MRS study performed on OCD patients. The mean age between OCD patients and controls was statistically different. As a result, we had to correct the data for age in the analysis. This study reveals modifications of phosphorus metabolites between patients with severe OCD and healthy controls in basal ganglia(striatum and thalamus). Significant results were found between the groups involving both bioenergetics and membrane metabolites. We also found

Authors’ contributions

Conceived and designed the experiments: LH, NJ, RG, CG. Performed the experiments: LH, CG, RG. Analyzed data: LH, CG. Statistical Analysis: JNV. Contributed materials/clinical analysis: NJ, LH, SM.

Declaration of Competing Interest

The authors of the paper “Altered phospholipid and high-energy phosphate metabolism in the basal ganglia and Thalamus of severe obsessive compulsive patients with treatment resistance: A phosphorus 31 nuclear magnetic resonance spectroscopy study.” report no potential conflict of interest.

Acknowledgments

We wish to thank Jeffrey Arsham, and Pr Luc Pellerin for the English-editing of this manuscript.

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