Scott Mackin

Problem solving therapy for the depression-executive dysfunction syndrome of late life

The ‘depression executive dysfunction syndrome’ afflicts a considerable number of depressed elderly patients and may be resistant to conventional pharmacotherapy. Non‐pharmacological approaches addressing their behavioral deficits may reduce disability and experienced stress and improve depression.

Treating depression in disabled, low-income elderly: a conceptual model and recommendations for care.

The treatment of depression in low‐income older adults who live in poverty is complicated by several factors. Poor access to resources, disability, and mild cognitive impairment are the main factors that moderate treatment effects in this population. Interventions that not only address the depressive syndrome but also manage social adversity are sorely needed to help this patient population recover from depression.

The Role of Cognitive Functioning and Distress in Suicidal Ideation in Older Adults

OBJECTIVES: To evaluate the role of cognitive functioning and other clinical and demographic characteristics as potential predictors of suicidal ideation in older primary care patients.

Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2

Alzheimers Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimers disease (AD) and related disorders.

Evidence for disrupted gray matter structural connectivity in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is characterized by atrophy within the prefrontal-limbic network. Graph analysis was used to investigate to what degree atrophy in PTSD is associated with impaired structural connectivity within prefrontal limbic network (restricted) and how this affects the integration of the prefrontal limbic network with the rest of the brain (whole-brain). 85 male veterans (45 PTSD neg, 40 PTSD pos) underwent volumetric MRI on a 3T MR. Subfield volumes were obtained using a manual labeling scheme and cortical thickness measurements and subcortical volumes from FreeSurfer. Regression analysis was used to identify regions with volume loss. Graph analytical Toolbox (GAT) was used for graph-analysis. PTSD pos had a thinner rostral anterior cingulate and insular cortex but no hippocampal volume loss. PTSD was characterized by decreased nodal degree (orbitofrontal, anterior cingulate) and clustering coefficients (thalamus) but increased nodal betweenness (insula, orbitofrontal) and a reduced small world index in the whole brain analysis and by orbitofrontal and insular nodes with increased nodal degree, clustering coefficient and nodal betweenness in the restricted analysis. PTSD associated atrophy in the prefrontal-limbic network results in an increased structural connectivity within that network that negatively affected its integration with the rest of the brain.

The Independent Contributions of Cognitive Impairment and Neuropsychiatric Symptoms to Everyday Function in Older Adults

The everyday functional capacities of older adults are determined by multiple factors. The primary goal of the present study was to evaluate whether apathy and depression have unique influences on degree of functional impairment, independent of the effects of specific cognitive impairments. Participants included 344 older adults (199 normal, 87 with MCI, 58 with dementia). The Everyday Cognition (ECog) scales were used to measure both global and domain-specific functional abilities. Neuropsychiatric symptoms of depression and apathy were measured by the Neuropsychiatric Inventory (NPI), and specific neuropsychological domains measured included episodic memory and executive functioning. Results indicated that worse memory and executive function, as well as greater depression and apathy, were all independent and additive determinants of poorer functional abilities. Apathy had a slightly more restricted effect than the other variables across the specific functional domains assessed. Secondary analysis suggested that neuropsychiatric symptoms may be more strongly associated with everyday function within cognitively normal and MCI groups, while cognitive impairment is more strongly associated with everyday function in dementia. Thus, a somewhat different set of factors may be associated with functional status across various clinical groups.

Brain structure and function as mediators of the effects of amyloid on memory

Objective: The objective of this study was to test whether effects of β-amyloid (Aβ) pathology on episodic memory were mediated by metabolism and gray matter volume in the early stages of Alzheimer disease. Methods: This was a prospective cohort study. We measured baseline Aβ (using florbetapir-PET), brain function (using fluorodeoxyglucose-PET), and brain structure (using MRI). A mediation analysis was performed to test whether statistical effects of Aβ positivity on cross-sectional and longitudinal episodic memory were mediated by hypometabolism or regional gray matter volume in cognitively healthy controls (CN, n = 280) and mild cognitive impairment (MCI, n = 463). Results: Lower memory scores were associated with Aβ positivity (CN, mildly; MCI, strongly), smaller gray matter volumes (CN, few regions, including hippocampus; MCI, widespread), and hypometabolism. Smaller volumes and hypometabolism mediated effects of Aβ in MCI but not in CN. The strongest individual regions mediated up to approximately 25%. A combination of brain structure and function mediated up to approximately 40%. In several regions, gray matter atrophy and hypometabolism predicted episodic memory without being associated (at p < 0.05) with Aβ positivity. Conclusions: Changes in brain structure and function appear to be, in part, downstream events from Aβ pathology, ultimately resulting in episodic memory deficits. However, Aβ pathology is also strongly related to memory deficits through mechanisms that are not quantified by these imaging measurements, and episodic memory decline is partly caused by Alzheimer disease–like brain changes independently of Aβ pathology.

PBMC telomerase activity, but not leukocyte telomere length, correlates with hippocampal volume in major depression.

Accelerated cell aging, indexed in peripheral leukocytes by telomere shortness and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic resonance imaging-estimated hippocampal volume in un-medicated depressed individuals and healthy controls. We predicted that, to the extent peripheral and central telomerase activity are directly related, PBMC telomerase activity would be positively correlated with hippocampal volume, perhaps due to hippocampal telomerase-associated neurogenesis, neuroprotection or neurotrophic facilitation, and that this effect would be clearer in individuals with increased PBMC telomerase activity, as previously reported in un-medicated MDD. We did not have specific hypotheses regarding the relationship between leukocyte telomere length and hippocampal volume, due to conflicting reports in the published literature. We found, in 25 un-medicated MDD subjects, that PBMC telomerase activity was significantly positively correlated with hippocampal volume; this relationship was not observed in 18 healthy controls. Leukocyte telomere length was not significantly related to hippocampal volume in either group (19 unmedicated MDD subjects and 17 healthy controls). Although the nature of the relationship between peripheral telomerase activity and telomere length and the hippocampus is unclear, these preliminary data are consistent with the possibility that PBMC telomerase activity indexes, and may provide a novel window into, hippocampal neuroprotection and/or neurogenesis in MDD.

Differences in prefrontal, limbic, and white matter lesion volumes according to cognitive status in elderly patients with first-onset subsyndromal depression.

The purpose of this preliminary study was to test the hypothesis that subsyndromal depression is associated with the volume of medial prefrontal regional gray matter and that of white matter lesions (WMLs) in the brains of cognitively normal older people. We also explored the relationships between subsyndromal depression and medial prefrontal regional gray matter volume, limbic regional gray matter volume, and lobar WMLs in the brains of patients with mild cognitive impairment (MCI) and Alzheimers disease (AD). We performed a cross-sectional study comparing patients with subsyndromal depression and nondepressed controls with normal cognition (n = 59), MCI (n = 27), and AD (n = 27), adjusting for sex, age, years of education, and results of the Mini-Mental State Examination. Frontal WML volume was greater, and right medial orbitofrontal cortical volume was smaller in cognitively normal participants with subsyndromal depression than in those without subsyndromal depression. No volume differences were observed in medial prefrontal, limbic, or WML volumes according to the presence of subsyndromal depression in cognitively impaired patients. The absence of these changes in patients with MCI and AD suggests that brain changes associated with AD pathology may override the changes associated with subsyndromal depression.

Cortisol Predicts Antidepressant Treatment Outcome, Memory Improvement, and Brain Response to Negative Emotions: The Importance of Aging

Background Studies testing the relationship between cortisol levels, depression, and antidepressant treatment response have yielded divergent results suggesting the possibility of moderators of a cortisol effect. Several studies indicate that age may moderate the relationship between cortisol and psychopathology. In patients with Major Depressive Disorder (MDD), we studied the interactive effects of age and cortisol on predicting diagnostic status, improvement in mood and memory function with antidepressant treatment, and brain response to negative emotional stimuli. Methods 66 unmedicated patients with MDD and 75 matched healthy controls had serum assayed at pre-treatment baseline for cortisol. Logistic regression was used to determine an association of age, cortisol and their interaction with MDD diagnosis. Thirty-four of the MDD participants (age range: 19-65 years; median: 36) underwent treatment with a selective serotonin reuptake inhibitor (SSRl) for 8 weeks. Clinician and self-ratings of depression symptoms, as well as tests of verbal and visual delayed recall were obtained at baseline and post treatment. Moderation analyses determined the effect of age on the relationship between baseline cortisol and treatment outcome. A separate sample of 8 MDD participants prospectively underwent fMRI neuroimaging and cortisol collection while viewing negative emotional faces. Results Age moderated the effects of cortisol on predicting MDD diagnosis (p<.05), treatment-associated reduction of depression symptoms (p<.001), improvement of delayed recall (p<.001), and baseline brain response to negative emotions (p<.05, whole brain corrected). Modeling the Age X Cortisol interaction suggested that for the participants below the median age of our sample, lower cortisol levels predicted a lower rate of MDD diagnosis, higher antidepressant effects and decreased brain reactivity in emotion regulation regions such as the anterior cingulate gyrus. On the contrary, in those above the median sample age, lower cortisol predicted a higher rate of MDD, less improvement in depression symptoms and memory performance, and more brain reactivity in the anterior cingulate. Conclusions Our results indicate that age moderates the relationship between peripheral cortisol levels and (1) MDD diagnosis, (2) brain reactivity to emotional stimuli, and (3) antidepressant-associated improvement in depression and memory symptoms. These results indicate that previous disparities in the literature linking peripheral cortisol levels with depression characteristics and treatment response may critically relate, at least in part, to the age of the patients studied.