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: $100000 for 4 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . FINDINGS . SELECTED 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.

HYPOTHESIS

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Hypothesis:
Depression and cognitive impairment in Transverse Myelitis (TM) and Multiple Sclerosis (MS) is the result of immune-mediated cytokine effects on the brain that can be visualized using Magnetic Resonance Spectroscopy (MRS).

Goals and Methods:
Investigation of depression 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 the highest rate of depression of any chronic disease. MS has a 50% prevalence of cognitive impairment. Evidence supports both demyelinated brain lesions and cytokine effects as causes of depression and cognitive dysfunction in MS patients. 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.

In humans and animals, cytokines induce depression (or its behavioral equivalent) and cognitive impairment. Elevated pro-inflammatory cytokine levels are found in patients with idiopathic depression, which is a state of relative hypercortisolemia. In a homeostatic regulatory cycle, pro-inflammatory cytokines stimulate the HPA axis to release cortisol, which in turn attenuates the immune response. Thus, there is a plausible link in autoimmune disorders between immune system activation with cytokine production and changes in emotional brain states and cognition.

We propose that TM provides a model of cytokine-mediated depression and cognitive impairment. We will investigate the epidemiology of these neuropsychiatric phenomena in TM subjects compared to MS and non-autoimmune myelopathy controls. Our study will then employ neuropsychiatric evaluations, cytokine profiling, and Magnetic Resonance Spectroscopy (MRS) of 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 TM and MS. These findings could significantly expand our ability to diagnose, prognosticate, and treat neuropsychiatric sequelae in patients with diverse types of autoimmune disorders. These studies also have the potential to illuminate immune mechanisms in idiopathic major depression.

Follow-on Funding: 
Johns Hopkins University School of Medicine General Clinical Research Center (GCRC) support for $300,000.

FINDINGS

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Scientific Summary

Background:

Evidence has been accumulating that immune system activation (such as through the release of chemical messengers called cytokines) can lead to neuropsychiatric changes such as depression and cognitive impairment in CNS autoimmune diseases. We predicted brain changes in Transverse Myelitis (TM) and Multiple Sclerosis (MS) that correlated with mood and cognitive changes would be demonstrated using Magnetic Resonance Spectroscopy (MRS). For example, we conjectured that participants with TM and MS with higher scores on the SCL-90R depressive symptom subscale would show correlated decreased N-Acetyl-Aspartate (NAA) and increased Choline (Cho) levels. Looking at cognitive impairment, we predicted lower performance on neuropsychological testing would correlate with decreased NAA and increased Choline levels by MRS. We further hypothesized that spinal fluid cytokine levels would correlate with both neuropsychiatric changes and their MRS correlates.

Methods:

We employed MRS-measured metabolites as surrogate markers for cytokine-induced abnormalities in patients with TM and MS around the time of diagnosis and at 6-month follow-up. Since our original proposal, we have performed 48 MRS scans on 31 patients (15MS, 11TM and 5 controls); though due to problems including motion artifact not all gave usable results. Seventeen subjects completed their follow-up, 6-month evaluation and testing.

Results:

NAA/Cr levels in frontal white matter of TM patients was inversely correlated with depression scores (r=-0.968, p=0.03) in TM. At follow-up, Cho/Cr levels correlated with Depression scores in the left Hippocampus of TM patients (r=0.99, p=0.016).

The Brief Visuospatial Memory neuropsychological tests  (Trial 1, Trial 2, Trial 3 and Delayed Recall) were inversely correlated with cytokine IL-8 levels (r = -0.77 p=.025; r=-0.923 p=.001; r= -0.957 p=.0002; r=-0.934 p=.0007, respectively) in MS patients. The California Verbal learning neuropsychological tests (Long Delay Cued Recall & D-Prime) were inversely correlated with cytokine IL-6 levels (r=-0.703 p=.05; r=-0.713 p=.05, respectively) in MS patients.

Summary:

These findings provide preliminary evidence for immune system activation induced depression and cognitive impairment in the CNS autoimmune diseases TM and MS. The evidence supports the hypothesis that cytokines elaborated by activated immune cells in the CNS mediate the changes in brain activity and function that result in changes in mood and cognition in affected individuals. Future studies will verify these initial findings and, by utilizing cytokine profiling and MRS, could significantly expand our ability to diagnose, prognosticate, and treat neuropsychiatric sequelae in patients with diverse types of autoimmune disorders.

Background:

This study was done to look at mood and thought clarity (also called cognition) in subjects with brain and/or spinal cord injury due to immune system attack, such as Transverse Myelitis (TM) and Multiple Sclerosis (MS). We examined whether subjects with these types of neurological disorders were more likely to develop depression and/or difficulties with memory and concentration. We also investigated whether there were similarities or differences between the types of depressive symptoms and cognitive impairments found in these two illnesses. How these subjects’ moods and cognition change over time was also investigated.

Cells that fight off infections produce proteins called cytokines that can stimulate the immune system to cause brain lesions in MS. We looked at cytokines in the blood and spinal fluid and markers of brain activity in the brain to see if they correlated with changes in mood and cognition. We hypothesized that cytokines were responsible for abnormal brain activity that resulted in depression and impaired cognition, which would be expected to result in correlations between these various factors.

Magnetic Resonance Spectroscopy (MRS) is a type of brain scan, which is capable of measuring metabolites in the brain to indicate how the brain is functioning. MRS is safe and uses the same technology as MRI to show the biochemistry of the brain. This allows researchers to assess the integrity and function of neurons and other brain cells.

Methods:

We performed 48 MRS scans on 31 patients (15MS, 11TM and 5 controls), though due to problems, including patient movement while scanning, not all gave usable results. Seventeen subjects completed their follow-up, 6-month evaluation and testing.

Results:

In TM patients, increased depression levels as measured by paper mood questionnaires correlated with a decrease in the brain metabolite N-Acetyl-Aspartate as measured by MRS. At follow-up presentation, increased depression levels correlated with an increase in the brain metabolite Choline in TM patients.

In MS patients, some increased cytokine levels from the spinal fluid correlated with a decrease in specific memory and learning assessments that were quantified with neurocognitive testing.

Discussion:

These comparisons helped us to better understand how immune mediated diseases (MS and TM) affect patients’ brains and how they can result in depression and cognitive impairment. Our findings support the notion that cytokines are responsible for changes in mood and cognition. Future studies will verify these initial findings and, by utilizing cytokine profiling and MRS, could significantly expand our ability to diagnose and treat neuropsychiatric symptoms in patients with different types of autoimmune disorders.

SELECTED PUBLICATIONS

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Kaplin A.I., Deshpande D.M., Scott E., Krishnan C., Carmen J.S., Shats I., Martinez T., Drummond J., Dike S., Pletnikov M., Keswani S.C., Moran T.H., Pardo C.A., Calabresi P.A., and Kerr D.A. IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis. J Clin Invest. 2005 Oct;115(10):2731-41.

Krishnan C., Kaplin A.I., Graber J.S., Darman J.S., and Kerr D.A. Recurrent transverse myelitis following neurobrucellosis: immunologic features and beneficial response to immunosuppression. J Neurovirol. 2005 Apr;11(2):225-31.

Kaplin A.I., Krishnan C., Deshpande D.M., Pardo C.A., and Kerr D.A. Diagnosis and management of acute myelopathies. Neurologist. 2005 Jan;11(1):2-18.