Despite advances in basic neuroscience and clinical psychiatry, treatments for schizophrenia (SCZ) remain limited. One main reason for these limitations is the lack of biomarkers capable of measuring SCZ pathophysiology and target engagement of experimental agents. Therefore, as part of this Mentored Career Development Award (K23), I propose to obtain training in multimodal Magnetic Resonance (MR) imaging of the glutamate system in schizophrenia, with the following specific training goals: 1) Obtain in depth knowledge of using high resolution, steady-state, gadolinium enhanced functional magnetic resonance imaging [i.e., cerebral blood volume (CBV)] in SCZ; 2) Obtain in depth knowledge of using proton Magnetic Resonance Spectroscopy (MRS) to examine the glutamate system in SCZ; 3) Develop expertise in the role of the glutamate system in the neurobiology of SCZ and its treatment. These training and scientific goals, combined with the training in PET and therapeutics that I have obtained as part of my three year T32 fellowship and three year KL2 training, will put me in an ideal position to use multimodal imaging of the glutamate system to assess target engagement of novel glutamatergic compounds for SCZ. The scientific focus in this Mentored Patient-Oriented Research Career Development Award will be on the glutamate system with a focus on the effects of chronicity of disease on glutamate in hippocampal and medial prefrontal cortex (mPFC) regions in SCZ. An additional aim will be to examine the relationship between CBV and glutamate (Glu) MRS in these two brain regions. I recently senior authored two important reviews on glutamate in SCZ and in particular on imaging glutamate in SCZ. Findings from imaging studies of the glutamate system in SCZ strongly support a role for glutamate in SCZ. In particular, CBV in the CA1 region of the hippocampus was found to predict conversion to psychosis among a clinical high risk (CHR) cohort, and glutamate was implicated as the pathogenic driver. In addition, MRS has identified elevated glutamate in hippocampus and mPFC as key pathophysiological markers in SCZ. However, CBV has never been used to study potential differences in the glutamate system at different stages along the SCZ spectrum (e.g., in chronic vs. early stage SCZ), and while the CBV signal has been shown to be glutamatergic in rodents, a similar validation has not been performed in humans. This work is critical for a full understanding of glutamate in SCZ. For example, they may help to explain why an mGluR 2/3 agonist demonstrated benefit in only an early stage SCZ population (presentation by Dr. Bruce Kinon at the biannual meeting of the Schizophrenia International Research Society, Florence, Italy, April, 2014) but not in the full group. In addition, while an age effect n glutamate as measured by MRS has been suggested in a meta-analysis and by our own ketamine data in which acute ketamine challenge leads to increases in glutamate as measured by MRS while this is not observed in chronic ketamine users, an exploratory analysis of our own MRS data suggests that it is medication status (i.e., on or off medications) rather than age that effects glutamate levels. Therefore, my specific aims are to: 1) To examine the effects of age and chronicity of illness on Glu MRS and CBV in hippocampus and mPFC in individuals with SCZ. We hypothesize that there will be an inverse relationship between age/chronicity of disease and CBV/Glu in individuals with SCZ. 2) To examine relationships between CBV and Glu MRS in hippocampus and mPFC. We hypothesize that there will be a direct, positive relationship between CBV and Glu MRS in individuals with SCZ. 3) To examine differences between CBV and Glu MRS in hippocampus and mPFC between patients with SCZ and control subjects and to examine relationships between CBV and Glu MRS in hippocampus and mPFC and clinical (PANSS) and neurocognitive (MATRICS) measures in patients. We hypothesize that both CBV and Glu MRS in both areas will be greater in individuals with SCZ than in controls, and that higher levels of CBV and Glu in both regions will correlate with greater symptomatology and worse neurocognitive functioning in patients. To obtain training in multimodal CBV/MRS imaging, examine age/chronicity of illness effects on CBV and Glu MRS, and examine the relationships between CBV and Glu MRS, we propose to recruit 30 medication-free individuals with SCZ and 30 matched healthy control subjects and perform whole brain CBV and Glu MRS in mPFC and hippocampus. These career, training, and research goals build on the training and data that I have obtained to date as a T32 fellow and K12 scholar. I will perform the proposed research projects and implement the career development plan in a nurturing environment at the New York State Psychiatric Institute and Columbia University Medical Center. These institutions have the resources and track record needed to enable me to acquire the skills and experience necessary to establish myself as an independent, patient-oriented researcher, expert in using multimodal glutamate imaging to examine the pathophysiology of SCZ and target engagement of experimental treatments, and with a focus that is different from that of my mentors.
Schizophrenia is a prevalent psychiatric illness and leading cause of disability in the USA and worldwide, and therefore represents a very significant public health problem. This Mentored Patient-Oriented Research Career Development Award (K23) will enable Dr. Ragy Girgis to learn how to use magnetic resonance based imaging modalities to identify and develop novel targets for new medications for schizophrenia. These studies and line of work have the potential to decrease the overall burden of the disease and may suggest future research regarding promising, novel treatment targets for schizophrenia.
