Schizophrenia a disabling psychiatric disorder that affects approximately 1% of the population. The cost to society resulting from this illness is high Despite extensive research, the underlying biochemical causes of schizophrenia remain elusive, with evidence to suggest that the dopaminergic, glutamatergic and GABAergic neurotransmitter systems all play a role in the development of symptoms. An improved understanding of regional neurotransmitter levels is a first step towards the design of new treatments. Over the last few years, there has been particular interest in the roles of glutamate (Glu), N-acetyl aspartyl glutamate (NAAG) and ?-aminobutyric acid (GABA) in schizophrenia. Glu and GABA the primary excitatory and inhibitory neurotransmitters in the human brain, respectively. NAAG is a precursor of Glu and also binds to receptors involved in the glutamatergic system. High field (7 Telsa) magnetic resonance spectroscopy (MRS), in conjunction with spectral editing techniques, has the potential to measure various neurotransmitters in vivo in the human brain, including Glu and GABA, with higher sensitivity and specificity than at lower field strengths. We have also recently demonstrated that it is possible to reliably determine NAAG in the brain using MRS.
The aims of this proposal are therefore to (1) to establish that 7T MRS can reliably measure a 'neurotransmitter profile'of Glu, NAAG and GABA in multiple brain regions in patients with schizophrenia, (2) investigate the differences in neurotransmitter levels between healthy volunteers, early-stage, and later stage patients with schizophrenia, and to also measure the same compounds in first degree relatives of subjects with schizophrenia who demonstrate some of the same traits as patients with schizophrenia. Patients will also be thoroughly evaluated with neuropsychological testing, and neurotransmitter levels will be examined for correlations with both positive and negative symptoms of schizophrenia. An important reason for studying first degree relatives is that they will be unmedicated, allowing observation of disease related neurochemical changes free from the possible confounding effects of medication. The long term goal of this study is to firmly establish the role of Glu, NAAG and GABA (as well as other metabolites) in the pathophysiology of schizophrenia, and investigate their relationship to symptom severity. This knowledge will aid in the design of future treatment trials. We also expect that the establishment of these noninvasive biomarkers by high-field MRS will be useful in the future for evaluating disease severity, progression and treatment response in patients with schizophrenia.

Public Health Relevance

Schizophrenia is a disabling psychiatric disorder that affects approximately 1% of the US population. This research proposal will use high field magnetic resonance spectroscopy methods to measure neurotransmitter levels in patients with schizophrenia, to investigate their relationship to symptom severity, and also study 1st degree relatives of patients with schizophrenia. The long term goal is to develop biomarkers and better understand brain biochemistry in patients with schizophrenia, which in the future may lead to new and improved treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH096263-03
Application #
8627212
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rumsey, Judith M
Project Start
2012-06-18
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$501,326
Indirect Cost
$93,095
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Chiappelli, Joshua; Postolache, Teodor T; Kochunov, Peter et al. (2016) Tryptophan Metabolism and White Matter Integrity in Schizophrenia. Neuropsychopharmacology 41:2587-95
Chiappelli, Joshua; Rowland, Laura M; Wijtenburg, S Andrea et al. (2015) Evaluation of Myo-Inositol as a Potential Biomarker for Depression in Schizophrenia. Neuropsychopharmacology 40:2157-64
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Pradhan, Subechhya; Bonekamp, Susanne; Gillen, Joseph S et al. (2015) Comparison of single voxel brain MRS AT 3T and 7T using 32-channel head coils. Magn Reson Imaging 33:1013-8
Chiappelli, J; Hong, L E; Wijtenburg, S A et al. (2015) Alterations in frontal white matter neurochemistry and microstructure in schizophrenia: implications for neuroinflammation. Transl Psychiatry 5:e548
Haffey, Spenser J; Rowland, Laura M (2015) The importance of first person accounts in education: teacher and student perspectives. Schizophr Bull 41:311-2
Edden, Richard A E; Puts, Nicolaas A J; Harris, Ashley D et al. (2014) Gannet: A batch-processing tool for the quantitative analysis of gamma-aminobutyric acid–edited MR spectroscopy spectra. J Magn Reson Imaging 40:1445-52
Harris, Ashley D; Glaubitz, Benjamin; Near, Jamie et al. (2014) Impact of frequency drift on gamma-aminobutyric acid-edited MR spectroscopy. Magn Reson Med 72:941-8

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