The PI's long-term career interests are to help elucidate the biological mechanisms underlying disorders of mood regulation and cognitive function. The goal of this career development award is to allow the Principle Investigator (PI), who has a basic science background, to become a clinical investigator in neuropsychiatric translational research studying immune-mediated depression and cognitive impairment in autoimmune CNS diseases. To accomplish his goals the PI will obtain additional training in neuroimmunology, neuroimaging, and methods of clinical investigation. The Johns Hopkins School of Medicine will provide the PI with expert mentorship in all of these areas of training. In order to study the biological basis of mood and cognition, depression and cognitive impairment will be investigated in patients with Multiple Sclerosis (MS) and Transverse Myelitis (TM). Multiple Sclerosis (MS) has the highest rate of depression of any chronic disease, and a 50% prevalence of cognitive impairment. Transverse Myelitis (TM) is an autoimmune disorder like MS but with demyelinating lesions present only in the spinal cord. We found rates of severe depression in subjects with TM to be higher than those of MS controls and selective cognitive impairments in TM subjects comparable to their MS counterparts. Cytokines are chemical messengers that immune cells use to coordinate their responses. In addition to their role in modulating immune system function, recent studies have shown that cytokines also influence the CNS and the HPA axis. There is a growing body of evidence in human and animal investigations supporting a role for proinflammatory cytokines in mediating depression and cognitive impairment. We propose that MS and TM provide a model of cytokine-mediated depression and cognitive impairment. We plan to employ neuropsychiatric evaluations, cytokine profiling, and Magnetic Resonance Spectroscopy (MRS) of MS, TM and control subjects to elucidate cytokine elevations and brain neurochemical changes that correlate with depression and cognitive dysfunction. Subjects will be followed longitudinally to determine if changes in cytokine levels and brain metabolites parallel changes in mood, cognition and neurologic outcomes. Neuroendocrine correlates of depression in TM and MS subjects will be ascertained through examination of the function of their HPA axis. We anticipate that the results of this study will have direct implications for the neuropsychiatric comorbidities of MS, TM and other CNS autoimmune diseases. These findings could significantly expand our ability to diagnose, prognosticate, and treat neuropsychiatric sequelae in patients with diverse types of autoimmune disorders. Furthermore, these studies have the potential to illuminate immune mechanisms in idiopathic Major Depression that could result in novel therapeutic strategies.
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| Rahn, Kristen A; Watkins, Crystal C; Alt, Jesse et al. (2012) Inhibition of glutamate carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis. Proc Natl Acad Sci U S A 109:20101-6 |
