Faculty Bibliography

Late-Life Major Depression (LLMD) is a complex heterogeneous disorder that has multiple pathophysiological mechanisms such as medical comorbidity, vascular-related factors and Alzheimer's disease (AD). There is an association between LLMD and AD, with LLMD possibly being a risk factor for, or early symptom of AD and vascular dementia. Whether depression is an etiologic risk factor for dementia, or part of the dementia prodrome remains controversial. AD has a long prodromal period with the neuropathologic features of the disease preceding the onset of clinical symptoms by as much as 15-20 years. Clinicopathological studies have provided robust support for the importance of Abeta42 in the pathogenesis of AD, but several other risk factors have also been identified. Given the relationship between Abeta42 and AD, a potential relationship between Abeta42 and LLMD would improve the understanding of the association between LLMD and AD. We reviewed 15 studies that analyzed the relationship between soluble Abeta42 and LLMD. For studies looking at plasma and/or cerebrospinal fluid (CSF) levels of Abeta42, the relationship between LLMD and soluble Abeta42 was equivocal, with some studies finding elevated Abeta42 levels associated with LLMD and others finding the opposite, decreased levels of Abeta42 associated with LLMD. It may be that there is poor reliability in the diagnosis of depression in late life, or variability in the criteria and the scales used, or subtypes of depression in late life such as early vs. late onset depression, vascular-related depression, and preclinical/comorbid depression in AD. The different correlations associated with each of these factors would be causing the inconsistent results for soluble Abeta42 levels in LLMD, but it is also possible that these patterns derive from disease stage-dependent differences in the trajectory of CSF Abeta42 during older age, or changes in neuronal activity or the sleep/wake cycle produced by LLMD that influence Abeta42 dynamics.

Background/Study Context: A frequently observed age-related effect is a preference in older individuals for positive stimuli. The cognitive control model proposes that this positivity effect may be mediated by executive functions. We propose that cognitive reserve, operationally defined as years of education, which tempers cognitive decline and has been linked to executive functions, should also influence the age-related positivity effect, especially as age advances. Methods: An emotional free recall test was administered to a group of 84 cognitively intact individuals aged 60 to 88, who varied in years of education. As part of a larger test battery, data were obtained on measures of executive functioning and depression. Results: Multiple regression and moderation analyses were performed, controlling for general cognitive function, severity of depressive symptoms, and executive function. In our data, years of education appeared to moderate the effect of age on the positivity effect; age was negatively associated with recall of positive words in participants with fewer years of education, whereas a nonsignificant positive correlation was observed between age and positivity in participants with more education. Conclusion: Cognitive reserve appears to play a role in explaining individual differences in the positivity effect in healthy older individuals. Future studies should investigate whether cognitive reserve is also implicated in the ability to process a wide range of emotional stimuli and whether greater reserve is reflected in improved emotional regulation.

Background: An upregulation of monocyte chemoattractant protein-1 (MCP-1) and other chemokines (Interleukin-8 [IL-8] and Interferon gamma-induced protein 10 [IP-10]) has been reported in MCI and mild Alzheimer's disease (AD). MCP-1 is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. In AD, higher CSF MCP-1, and IP-10 have been associated with higher MMSE scores, suggesting potential beneficial effects of chemokine upregulation. This may include possible effects on AD biomarkers (Abeta and tau indices), which are known to be implicated in preclinical AD. This study examined the relationship between CSF chemokine levels and established AD biomarkers in older individuals with Major Depressive Disorder (MDD), which is a risk factor for AD, and in healthy controls. Methods: CSF was obtained from 47 older subjects with intact cognition and a Mini-Mental State Exam score of at least 28; 29 with MDD and 19 controls. MRI scans were performed to rule out structural brain abnormalities. No subject had gross MRI abnormalities other than white matter hyperintensities. CSF MCP-1, IP-10, IL-8, were determined using Luminex Corporation multiplexed beadbased immunoassays. Abeta40, Abeta42, total-tau, and ptau were determined using previously published methods. Results: MCP-1 was negatively correlated with CSF Abeta40 (r=-0.376, p=0.011), total tau (r=-0.361, p=0.014), and p-tau (r=-0.361, p=0.014); IL-8 was positively correlated with t-tau (r=0.357, p=0.015); IP-10 was positively correlated with t-tau (r=0.380, p=0.009) and p-tau (r=0.323, p=0.027). None of the chemokines showed a significant correlation with Abeta42 or significant group differences. Conclusions: Our findings suggest complex and differential associations between these chemokines and CSF AD Abeta and tau indices and highlight the need for further studies to determine their prognostic significance

Background: Major depressive disorder (MDD) is a chronic and frequently recurrent illness that is associated with considerable psychiatric and medical morbidity. Although several antidepressant medications are available to treat MDD, many patients do not achieve full symptom resolution with currently available SSRIs and SNRIs. Vilazodone, a serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is approved by the US Food and Drug Administration for the treatment of MDD in adults. The efficacy and safety of vilazodone in MDD were demonstrated in 2 positive placebo-controlled Phase III trials. The current study was conducted to further characterize symptom improvement, safety, and tolerability of vilazodone in patients with moderate to severe MDD. Methods: A multicenter, 1 : 1 randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study comparing vilazodone 40 mg/day with placebo; outpatients aged 18-70 years with DSM-IV-TR-defined MDD and a baseline total score >= 26 on the Montgomery-Asberg Depression Rating Scale (MADRS) were included. The study had 3 phases: 1- to 4-week no-drug screening, 8-week doubleblind treatment, and 1-week double-blind down-taper. Patients randomized to vilazodone received 10mg/day for Week 1, 20 mg/day for Week 2, and 40 mg/day for Weeks 3- 8; all study drug was taken once daily with food. The primary efficacy outcome was MADRS total score change from baseline to Week 8; the secondary efficacy outcomes were Clinical Global Impressions-Severity (CGI-S) score change from baseline to Week 8 and MADRS sustained response rate (MADRS total score <=12 for at least the last 2 consecutive visits during double-blind treatment). Safety assessments included adverse event (AE) recording, clinical laboratory and vital sign measures, electrocardiograms (ECGs), and the Columbia-Suicide Severity Rating Scale (C-SSRS). MADRS and CGI-S change from baseline were analyzed using a mixed-effects model for repeated measures (MMRM); between-group comparison for MA!

One of the cognitive changes associated with Alzheimer's disease is a diminution of the primacy effect, i.e., the tendency toward better recall of items studied early on a list compared with the rest. We examined whether learning and recall of primacy words predicted subsequent cognitive decline in 204 elderly subjects who were non-demented and cognitively intact when first examined. Our results show that poorer primacy performance in the Rey Auditory Verbal Learning Test delayed recall trials, but not in immediate recall trials, is an effective predictor of subsequent decline in general cognitive function. This pattern of performance can be interpreted as evidence that failure to consolidate primacy items is a marker of cognitive decline.