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Imaging Immune-Mediated Depression and Cognitive Impairment in Autoimmune Neurologic Diseases: – Dana Foundation

Imaging Immune-Mediated Depression and Cognitive Impairment in Autoimmune Neurologic Diseases:

MRS of Patients with Multiple Sclerosis and Transverse Myselitis

Adam I. Kaplin, M.D., Ph.D.

Johns Hopkins University School of Medicine

Funded in March 2003: $100,000 for 4 years
ABSTRACT · THESIS · RESULTS · PUBLICATIONS

ABSTRACT
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Imaging Immune-Mediated Depression and Cognitive Impairment in Autoimmune Neurologic Diseases: MRS of Patients with Multiple Sclerosis and Transverse Myselitis

Despite the dramatic individual and global impact of depression, scientific investigation of this disorder has been hampered by the heterogeneity of its causes and presentations. To overcome these impediments, a lesion model of depression would significantly enhance our understanding of this illness.

Multiple sclerosis (MS) has a higher rate of depression than any other chronic medical or neurological disease yet documented. Research findings point to immune-mediated insults to the brain as a primary cause of depression in patients with MS. Evidence supports both demyelinated brain lesions and cytokine effects as being capable of causing depression in MS patients. Transverse Myelitis (TM) is an autoimmune demyelinating disorder related to MS but is currently thought to affect only the spinal cord. Because it can reasonably be assumed that the brain regulates mood and cognition, no one has previously investigated the neuropsychiatric sequelae of patients with TM. We found rates of severe depression in patients with TM to be higher than that of MS controls. Reasoning that depression in TM was a marker for brain involvement through immune activation we performed preliminary neurocognitive testing on these patients. We found similar, selective cognitive impairments in patients with TM compared to their MS counterparts.

Interestingly, in animal models cytokines have been shown to induce a stereotypical response that resembles the behavioral symptoms of clinical depression, such as weight-loss, social isolation, and decreased interest. These animal models also have impaired memory and concentration. Correspondingly, the human therapeutic uses of cytokines are often hampered by treatment-induced depression and cognitive impairment. Elevated levels of cytokines have been found in depressed patients, even in the absence of autoimmune disorders. These observations provide a plausible link in autoimmune disorders between immune system activation with cytokine production and changes in emotional brain states and cognition.

Magnetic Resonance Spectroscopy (MRS) provides for the visualization of brain biochemistry, and has proven to be a much more sensitive indicator of brain perturbations in patients with MS than standard Magnetic Resonance Imaging (MRI). Recently, using MRS it has been possible to correlate cognitive performance and brain metabolic concentrations in MS patients, who showed little or no correlation of their neuropsychiatric symptoms with conventional MRI.

We hypothesize that Transverse Myelitis (TM) provides a model of cytokine-mediated brain involvement that results in high rates of major depression and cognitive impairment. Our study will employ structured neuropsychiatric evaluations, CSF and blood pro-inflammatory cytokine profiling, and Magnetic Resonance Spectroscopy of TM patients to try to elucidate cytokine-mediated brain metabolic changes that correlate with depression and cognitive dysfunction. These patients will be followed longitudinally to monitor changes during the course of disease progression. As controls, MS patients and non-autoimmune myelopathy patients will be investigated.

By characterizing a clinical model of cytokine-mediated neuropsychiatric deficits in TM, this study attempts to elucidate how the immune system affects the brain, and how such effects can result in clinical depression and intellectual impairment. We anticipate the results of this study will have direct implications for the neuropsychiatric comorbidities of MS, which in young adults in the United States is the most common severe CNS disease and second only to trauma as the leading cause of neurologic disability.

By utilizing cytokine profiling and MRSI to distinguish immune-mediated mood and cognitive perturbations, these findings could significantly expand our ability to diagnose, prognosticate, and treat neurospychiatric sequelae in patients with diverse types of autoimmune disorders.

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