Myelin, Glia and Depression in Type 2 Diabetes

Diabetes is a major health problem affecting approximately 18 million Americans. It is a growing crisis that has devastating complications including heart disease, peripheral neuropathy and renal failure. According to a literature review by Gavard et al, the prevalence of major depression in a sample diabetic population in controlled studies was 8.5 to 27.3% (mean prevalence of 14.0%). This was estimated to be up to three times the prevalence of major depression in the general U.S. adult population. Diabetes and major depression are mutual risk factors, with diabetic patients more likely to develop major depression with an odds ratio of 2.5 and depressed patients being more likely to develop type 2 diabetes with an estimated relative risk of 2.2. Depression also has a significant impact on the course of diabetes, leading to higher rates of hyperglycemia and diabetic complications. Depression in patients with diabetes is also associated with poor compliance, decreased quality of life, increased disability and greater health care utilization. A recent 8-year follow-up study of patients with diabetes and depression concluded that the coexistence of these illnesses is associated with a significantly increased risk of death from all causes beyond that due to either depression or diabetes alone. In this study, patients with diabetes and depression had a 1.3-fold increased risk of death from all causes when compared with patients with diabetes alone and a 2-fold increased risk of death when compared with patients with only depression. Reports from a prospective, community-based study in western Australia suggest that the behavioral consequences of depression, including non-compliance with medication and exercise regimens, contribute to increased mortality in these patients.

TRIAL OBJECTIVES AND PURPOSE Specific Aim 1: To study the biophysical properties of the white and gray matter in critical cortical and subcortical regions using magnetization transfer in patients with type 2 diabetes and MDD, non-depressed diabetic controls, patients with unipolar depression without diabetes and nondiabetic healthy controls. The investigators are interested in the separate and cumulative effects of both diabetes and depression on Magnetization Transfer Ratios (MTR) in different brain regions.

Hypothesis: The overarching hypothesis is that both diabetes and depression have the effect of lowering magnetization transfer ratios (MTR) in the anterior cingulate cortex, subcortical nuclei (head of the caudate nucleus and putamen) and the frontal white matter. These effects are cumulative and may not be additive in some regions. Our pilot data suggest that MTR will be lower in these regions in patients with type 2 diabetes (both with and without depression) when compared with healthy controls. In some regions (eg. head of the caudate nucleus - see preliminary data) the investigators anticipate that patients with diabetes and MDD will have the lowest and healthy controls will have the highest MT ratios. The group with unipolar depression without diabetes and the diabetic controls will have MT ratios that fall between these two groups. In other regions of interest, both groups with diabetes will have values significantly different from healthy controls, with patients diagnosed with unipolar depression falling between the healthy and diabetic groups.

Specific Aim 2: To examine levels of glutamate and aspartate (creatine ratios) in two regions involved in the regulation of mood and cognition - the bilateral anterior cingulate cortex and the left subcortical region (the head of the caudate nucleus and the putamen) in patients with type 2 diabetes and our three comparison groups.

Hypothesis: Levels of glutamate and aspartate (creatine ratios) will be lower in patients with combined Type 2 Diabetes and MDD when compared with non-depressed diabetic patients and healthy controls. Our pilot data provide little basis to expect a simple effect of diabetes alone but do not rule out an interaction such that effects are only seen, or are worsened, by the combination of diabetes and depression. The inclusion of a depressed non-diabetic group in the current design will make it possible to evaluate whether the observed effect in the doubly-diagnosed group is best viewed as an effect of depression alone or as an interaction in which diabetes plays a role.

Specific Aim 3: To examine the relationship between regional MTRs and specific cognitive domains in subjects in all four groups.

Hypothesis: There will be direct correlations in all study groups between MT ratios in the subcortical nuclei, anterior cingulate cortex and the dorsolateral white matter and performance on specific cognitive domains, including attention, executive functions, learning and memory and psychomotor processing.

Exploratory Aim 1: In an exploratory manner the investigators will estimate cerebral blood volume, a measure of the cerebral microvasculature, in critical brain regions involved in frontal-subcortical circuitry (anterior cingulate, dorsolateral white, head of the caudate nucleus and the putamen) in subjects in our depressed diabetic group and the three comparison groups using dynamic susceptibility contrast MR imaging (perfusion-weighted MR imaging).

Exploratory Aim 2: A comparison of blood samples from healthy controls, diabetic subjects, depressed subjects and subjects with both depression and diabetes to see if there is evidence of differences in plasma neurotransmitter levels, hypothalamic-pituitary-adrenals (HPA) axis, and immune function between these four subject groups