Cortical Beta-Amyloid Deposition in Late-Life Depression

Introduction: Late-life depression (LLD) has major public health consequences given its association with serious disability, mortality in the medically ill elderly, and an increased rate of completed suicide. Despite the availability of effective antidepressant agents, many patients with LLD are refractory to treatment. Cognitive impairment is also a common feature of LLD and frequently persists even after mood symptom remission. Furthermore, substantial evidence indicates that LLD is both a risk factor and/or a prodrome of dementia including Alzheimer’s disease (AD). Molecular imaging studies to evaluate whether persistent cognitive impairment in LLD is associated with AD neuropathology are a logical focus of study. Positron Emission Tomography (PET) studies in LLD patients with mild cognitive impairment (MCI) have shown greater cortical beta-amyloid (Ab) in patients than controls (Butters, et al. Alzheimer Dis Assoc Disord. 22(3):261-8, 2008). Serial PET imaging studies performed during the course of antidepressant treatment demonstrate that changes in regional cerebral glucose metabolism in a medial temporal-parietalfrontal network are associated with improved cognition in LLD (Diaconsecu et al. Hum Brain Mapp. 32(10):1677-91, 2011). This network overlaps with the brain regions affected in AD, as well as the regional distribution of Ab in AD. The present study tested the hypothesis that cortical Ab was higher in LLD patients without MCI than non-depressed, non-cognitively impaired comparison subjects. Methods: Sixteen un-medicated LLD patients (10 females/6 males, age 66.2 5.8, Mini Mental State Examination [MMSE] score 29.2 1.1) who met DSM-IV criteria for a major depressive episode but did not meet Petersen criteria for MCI as well as 13 non-depressed age-matched comparison subjects (5 female/8 males, age 66.2 7.6, MMSE score 28.5 1.3) enrolled in the study. All participants underwent baseline cognitive assessment, brain magnetic resonance imaging and PET scans to measure Ab. PET scans were acquired with the CPS/Siemens High Resolution Research Tomograph (HRRT) scanner (2mm spatial resolution) using the radiotracer [11C]-Pittsburgh Compound B ([11C]-PIB; N-methyl-[11C]2-(40-methylaminophenyl)-6-hydroxybenzothiazole). LLD patients then began a flexibly dosed citalopram course beginning at 10mg daily with titration based on clinical response (mean dose 21.9 9.1 mg). LLD patients underwent follow-up cognitive testing at 8-10 weeks of treatment, after achieving a stable clinical response for at least 2 weeks. Both hypothesis driven, volume of interest (VOI) and data driven, voxel-wise PET data analysis methods were performed (Zhou et al., Neuroimage 36(2):298-312, 2007). Distribution volume ratio (DVR), an index of tracer specific binding to Ab, was estimated using a simplified reference tissue model (SRTM) using the cerebellum as the reference region. Voxel-wise analyses of the parametric DVR images were performed with Statistical Parametric Mapping (SPM5; p 50). Results: In LLD patients, depressive symptoms decreased significantly with citalopram treatment as measured with the 17-item Hamilton Depression Rating Scale (HAM-D; baseline: 17.5 1.83; follow-up: 3.56 2.16; p < 0.01). LLD patients performed worse on verbal (letter) fluency and visuospatial memory than controls. LLD patients improved in verbal fluency during citalopram treatment (p < 0.05). ROI analysis showed significantly greater Ab in LLD patients than controls in the anterior cingulate gyrus, superior and middle frontal and temporal gyri, and precuneus (DVR range: controls: 1.11-1.19 and LLD patients: 1.39-1.55; p < 0.05). Voxel-wise analyses confirmed greater Ab in these areas, as well as in the left insula, bilateral superior and inferior parietal lobule, and left parahippocampal gyrus (p < 0.05). Higher Ab correlated with lower baseline immediate and delayed verbal memory (CVLT), visuospatial memory (BVMT-R) and executive function (Stroop) in the LLD patients. Higher Ab also correlated with less improvement in verbal fluency with citalopram treatment but did not correlate with mood response to citalopram. Conclusions:We observed greater Ab deposition in non-MCI, LLD patients than controls in similar cortical regions that: 1) have increased regional cerebral glucose metabolism in LLD; 2) correlate with improvement in cognition with antidepressant treatment; and 3) demonstrate Ab deposition in non-depressed MCI patients. Correlations between higher regional Ab and worse cognitive function and less improvement with citalopram treatment (letter fluency) may suggest that Ab is associated with cognitive impairment in LLD. Future studies with a larger sample size will relate the Ab measures to other measures associated with cognitive decline (including ApoE4, cerebral atrophy and vascular disease), as well as to affective and cognitive responses to treatment.