Cortical/Subcortical Circuits in Late-Life Depression

Major depressive disorder (MDD) and other clinically significant forms of "minor depression" are among the most common mental disorders in the elderly. Data from the Epidemiologic Catchment Area Studies indicate that in the community dwelling elderly, the prevalence of MDD is approximately 1-2 percent. The prevalence of dysthymia and "clinically significant" depressive symptoms is estimated to be 2-3% and 5-10% respectively. Clinically significant mood disorders are responsible for considerable medical and psychosocial morbidity. These include frequent medical and psychiatric hospitalizations, visits to the emergency room, suicide attempts, and use of alcohol, and other prescription medications with psychotropic effects. The clinical impact of these disorders is comparable to those caused by other chronic medical disorders.

The vast majority of patients with mood disorders are managed at ambulatory care/primary care settings around the country. Ambulatory care clinics have become "defacto" settings for the diagnosis and management of psychiatric problems, especially in the elderly. Depression, particularly in the elderly, is associated with several chronic medical illnesses including malignancies, chronic obstructive pulmonary disease, and gastrointestinal, vascular, autoimmune and demyelinating disorders. Acknowledging the overall robust association between medical illness and mood disorders, the NIH consensus statement on depression in the elderly states, "The hallmark of depression in late-life is its association with medical comorbidity." While the precise mechanisms by which coexisting medical illnesses contribute to depression remain unclear, neuroanatomical, vascular, immunologic, psychosocial and /or a combination of these mechanisms have been invoked as possible pathways by which medical disorders may lead to depression in the elderly.

Late-life MDD is characterized by 1) Neuroanatomical changes in neocortical and subcortical regions of the brain. These principally comprise a decrease in focal brain volumes and an increase in the volume of high intensity lesions in the parenchyma; 2) The increase in high intensity lesions occurs largely, though not exclusively, in the white matter; 3) Preliminary studies suggest that there are abnormalities in white matter regions and tracts even in areas that appear normal in MR images in patients with late-life MDD when compared with controls; 4) Biochemical and biophysical changes in the white matter are likely related to the pathophysiology of major psychiatric disorders independent of the impact of cerebrovascular disease/risk factors.

TRIAL OBJECTIVES AND PURPOSE

Specific Aim 1: To estimate absolute levels and ratios (metabolite/creatine) of NAA, Ch and Ml bilaterally in the dorsolateral white matter and subcortical nuclei in patients with MDD and non-depressed controls.

Hypothesis: Absolute levels and ratios of Ch and Ml will be higher and levels of NAA will be lower in the dorsolateral white matter and the subcortical nuclei in patients with MDD when compared with controls.

Specific Aim 2: To estimate magnetization transfer ratios (MTR) bilaterally in the frontal white matter/head of the caudate nucleus and the putamen in patients with MDD and controls and to examine the relationship between MTR and MRS measures in the dorsolateral white matter. Hypothesis a: MTR will be significantly lower in normal appearing dorsolateral white matter regions and subcortical nuclei (caudate nucleus and putamen) in patients with MDD when compared with controls.

Hypothesis b: There will be an inverse relationship between MTR and normalized levels of Ml in patients diagnosed with MDD in the dorsolateral white matter bilaterally.

Specific Aim 3: To examine the neurocognitive correlates of frontal and striatal compromise identified using MRS and MT ratio measures in patients with MDD and controls. The associations between NAA and a global cognitive scale and MT ratios from the bilateral dorsolateral white matter and subcortical nuclei and subscales targeted to dorsolateral and striatal cognitive functioning will be examined.

Hypothesis a: Among healthy and depressed elderly, NAA/Cr with be positively related to a global scale of cognitive function.

Hypothesis b: Among healthy and depressed elderly, MT ratios of the dorsolateral cortices will be positively related to a subscale of dorsolateral function (working memory, executive function, nonverbal recall).

Hypothesis c: Among healthy and depressed elderly, MT ratios of subcortical nuclei will be positively related to a subscale of striatal function (processing, learning).

Exploratory analyses: In addition to the specific aims above, the investigators will conduct two three exploratory analyses.

Analysis 1: A more finely grained analysis in which the investigators examine the relationship of NAA, Ml and Cho ratios to dorsolateral and striatal subscales after examining their relationship to global cognitive function. The investigators will also study the relationship of the relative concentrations of NAA to Ml (NAA/MI) and Ch (NAA/Ch) to global and regional subscales. In addition, the preliminary MTR data suggest that there may be laterally effects, which the investigators will examine.

Analysis 2: A comparison of blood samples of the healthy versus depressed subject groups, to see if there is evidence of differences in the neurotransmitter system, hypothalamic-pituitary-adrenals (HAP) axis, and immune function between these two groups of elderly persons.

Analysis 3: To examine whether neuroimaging and cognitive measures associated with major depression are reversed by antidepressant treatment.