The Characteristics of People with Serious Mental Illness Who are at High Risk for Hospitalization or Death.

Many individuals with serious mental illness are at high risk for hospitalization or death due to inadequate treatment of medical conditions or unhealthy behaviors. The authors describe demographic and clinical characteristics associated with increased risk in this population. Electronic data were obtained for individuals in treatment at a large Veterans' healthcare system who were at high risk according to a validated model. A random sample of these individuals was assessed in person. Multivariable regressions estimated the effect of numerous demographic, health, and clinical characteristics on risk. Emergency visits and hospitalizations were common. Greater risk was associated with being male, not married, and having more diagnoses. While risk varied by race, this effect was no longer significant after controlling for other factors. Health-related quality of life worsened with increasing risk. Routine data identify a large population of high-risk individuals who may benefit from outreach to provide healthcare services.

Neuroprotection in Cerebral Cortex Induced by the Pregnancy Hormone Estriol.

In multiple sclerosis (MS), demyelination occurs in the cerebral cortex, and cerebral cortex atrophy correlates with clinical disabilities. Treatments are needed in MS to induce remyelination. Pregnancy is protective in MS. Estriol is made by the fetoplacental unit, and maternal serum estriol levels temporally align with fetal myelination. Here, we determined the effect of estriol treatment on the cerebral cortex in the preclinical model of MS, experimental autoimmune encephalomyelitis (EAE). Estriol treatment initiated after disease onset decreased cerebral cortex atrophy. Neuropathology of the cerebral cortex showed increased cholesterol synthesis proteins in oligodendrocytes, more newly formed remyelinating oligodendrocytes, and increased myelin in estriol-treated EAE mice. Estriol treatment also decreased the loss of cortical layer V pyramidal neurons and their apical dendrites and preserved synapses. Together, estriol treatment after EAE onset reduced atrophy and was neuroprotective in the cerebral cortex.

Inflammatory Markers of Geriatric Depression Response to Tai Chi or Health Education Adjunct Interventions.

BACKGROUND: Underlying inflammation is associated with an increased risk of depression in older adults. In this study, we examined the role of inflammatory biomarkers in antidepressant response in depressed older adults undergoing adjunct Tai Chi Chih (TCC) or Health education interventions. METHODS: Older adults aged 60 years and above with a diagnosis of major depression were randomized to 12 weeks of TCC versus Health and Wellness Education (HEW) as an adjunct therapy to their stable antidepressant treatment regimen. A panel of 19 cytokine/chemokines was measured at baseline and 12 weeks. Five factors were derived using factor analysis. General linear models were estimated to examine the change in factor scores and the association of these changes on depression remission rates, controlling for age, sex, and body mass index. RESULTS: Of the 170 randomized participants (TCC: n = 85 and HEW: n = 85), 55 TCC and 58 HEW completed the 3-month assessment. The groups did not differ at baseline in any measure. At follow-up, neither the changes in cytokine/chemokines scores nor the depression remission rate differed significantly between TCC and HEW. However, remitters and non-remitters differed significantly in changes in a factor composed of growth-regulated oncogene protein-alpha (GRO-alpha), epidermal growth factor (EGF), and soluble CD40 ligand (sCD40L). GRO-alpha and EGF levels (in both groups) were significantly increased in remitters compared to non-remitters. CONCLUSION: Changes in certain cytokines/chemokines may accompany improvement in depressive symptoms in older adults. Future studies will need to explore the role of these molecules in remission of late-life depression.

Grey matter volume predicts improvement in geriatric depression in response to Tai Chi compared to Health Education.

OBJECTIVES: Geriatric depression (GD) is associated with cognitive impairment and brain atrophy. Tai-Chi-Chih (TCC) is a promising adjunct treatment to antidepressants. We previously found beneficial effects of TCC on resting state connectivity in GD. We now tested the effect of TCC on gray matter volume (GMV) change and the association between baseline GMV and clinical outcome. PARTICIPANTS: Forty-nine participants with GD (>=60 y) underwent antidepressant treatment (38 women). INTERVENTION: Participants completed 3 months of TCC (N = 26) or health and wellness education control (HEW; N = 23). MEASUREMENTS: Depression and anxiety symptoms and MRI scans were acquired at baseline and 3-month follow-up. General linear models (GLMs) tested group-by-time interactions on clinical scores. Freesurfer 6.0 was used to process T1-weighted images and to perform voxel-wise whole-brain GLMs of group on symmetrized percent GMV change, and on the baseline GMV and symptom change association, controlling for baseline symptom severity. Age and sex served as covariates in all models. RESULTS: There were no group differences in baseline demographics or clinical scores, symptom change from baseline to follow-up, or treatment-related GMV change. However, whole-brain analysis revealed that lower baseline GMV in several clusters in the TCC, but not the HEW group, was associated with larger improvements in anxiety. This was similar for right precuneus GMV and depressive symptoms. CONCLUSIONS: While we observed no effect on GMV due to the interventions, baseline regional GMV predicted symptom improvements with TCC but not HEW. Longer trials are needed to investigate the long-term effects of TCC on clinical symptoms and neuroplasticity.

Regional gray matter volume correlates with anxiety, apathy, and resilience in geriatric depression.

OBJECTIVES: Geriatric depression (GD) is associated with significant medical comorbidity, cognitive impairment, brain atrophy, premature mortality, and suboptimal treatment response. While apathy and anxiety are common comorbidities, resilience is a protective factor. Understanding the relationships between brain morphometry, depression, and resilience in GD could inform clinical treatment. Only few studies have addressed gray matter volume (GMV) associations with mood and resilience. PARTICIPANTS: Forty-nine adults aged >60 years (38 women) with major depressive disorder undergoing concurrent antidepressant treatment participated in the study. MEASUREMENTS: Anatomical T1-weighted scans, apathy, anxiety, and resilience data were collected. Freesurfer 6.0 was used to preprocess T1-weighted images and qdec to perform voxel-wise whole-brain analyses. Partial Spearman correlations controlling for age and sex tested the associations between clinical scores, and general linear models identified clusters of associations between GMV and clinical scores, with age and sex as covariates. Cluster correction and Monte-Carlo simulations were applied (corrected alpha = 0.05). RESULTS: Greater depression severity was associated with greater anxiety (r = 0.53, p = 0.0001), lower resilience (r = -0.33, p = 0.03), and greater apathy (r = 0.39, p = 0.01). Greater GMV in widespread, partially overlapping clusters across the brain was associated with reduced anxiety and apathy, as well as increased resilience. CONCLUSION: Our results suggest that greater GMV in extended brain regions is a potential marker for resilience in GD, while GMV in more focal and overlapping regions may be markers for depression and anxiety. Interventions focused on improving symptoms in GD may seek to examine their effects on these brain regions.

Transcriptomic signatures of treatment response to the combination of escitalopram and memantine or placebo in late-life depression.

Drugs that target glutamate neuronal transmission, such as memantine, offer a novel approach to the treatment of late-life depression, which is frequently comorbid with cognitive impairment. The results of our recently published double-blind, randomized, placebo-controlled trial of escitalopram or escitalopram/memantine in late-life depression with subjective memory complaints (NCT01902004) indicated no differences between treatments in depression remission, but additional benefits in cognition at 12-month follow-up with combination treatment. To identify pathways and biological functions uniquely induced by combination treatment that may explain cognitive improvements, we generated transcriptional profiles of remission compared with non-remission from whole blood samples. Remitters to escitalopram compared with escitalopram/memantine combination treatment display unique patterns of gene expression at baseline and 6 months after treatment initiation. Functional enrichment analysis demonstrates that escitalopram-based remission associates to functions related to cellular proliferation, apoptosis, and inflammatory response. Escitalopram/memantine-based remission, however, is characterized by processes related to cellular clearance, metabolism, and cytoskeletal dynamics. Both treatments modulate inflammatory responses, albeit via different effector pathways. Additional research is needed to understand the implications of these results in explaining the observed superior effects of combination treatment on cognition observed with prolonged treatment.

A Randomized Controlled Trial of Tai Chi Chih or Health Education for Geriatric Depression.

OBJECTIVES: Geriatric depression is difficult to treat and frequently accompanied by treatment resistance, suicidal ideations and polypharmacy. New adjunctive mind-body treatment strategies can improve clinical outcomes in geriatric depression and reduce risk for side-effects of pharmacological treatments. METHODS: We conducted a 3-month randomized controlled trial to assess the efficacy and tolerability of combining Tai Chi Chih (TCC) or Health Education and Wellness training (HEW) with the stable standard antidepressant treatment on mood and cognitive functioning in depressed older adults (NCT02460666). Primary outcome was change in depression as assessed by the Hamilton Rating Scale for Depression (HAM-D) post-treatment. Remission was defined as HAM-D ≤ 6; naturalistic follow-up continued for 6 months. We also assessed psychological resilience, health-related quality of life and cognition. RESULTS: Of the 178 randomized participants, 125 completed the 3-month assessment and 117 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Remission rate within TCC was 35.5% and 33.3%, compared to 27.0% and 45.8% in HEW, at 3 and 6 months respectively (χ2(1) = 1.0, p = 0.3; χ2(1) = 1.9, p =0.2). Both groups improved significantly on the HAM-D at 3 and 6 months. TCC demonstrated a greater improvement in general health compared to HEW. CONCLUSIONS: Both TCC and HEW combined with a standard antidepressant treatment improved symptoms of depression in older adults. While TCC was superior to HEW in improving general health, we did not find group differences in improvement in mood and cognition.

The Effect of Cumulative Lifetime Estrogen Exposure on Cognition in Depressed Versus Non-Depressed Older Women.

OBJECTIVES: Two-thirds of individuals living with Alzheimer's disease are women. Declining estrogen levels influence mood and cognition. Cumulative lifetime estrogen exposure (CLEE) correlates with cognition later in life. We examined the relationship of CLEE to depression and cognition in older women with major depression compared to non-depressed women. DESIGN: Older women (age ≥60 years) with depression were compared to non-depressed women using a lifetime estrogen exposure questionnaire. CLEE was defined as combined durations of reproductive span (age of menopause minus age of menarche) and any post-menopausal hormone replacement therapy use. Higher vs lower CLEE groups were based on a median of 474 months of estrogen exposure. SETTING: University hospital outpatient research program. PARTICIPANTS: 135 women ≥60 years; 64 depressed and 71 non-depressed. MEASURMENTS: Participants completed a comprehensive cognitive test battery. General linear models were used to examine the association between cognitive domain scores and CLEE in depressed and non-depressed women, controlling for age, education, and ethnicity. RESULTS: Depressed and non-depressed groups had significantly different levels of CLEE, measured in months: mean 495.7 (SD 108.6) vs 456.4 (SD 66.0) months, F(1,130) = 5.01, p = .03. Within the non-depressed participants, higher CLEE was associated with improved delayed recall (F(1,59) = 5.94, p = .02, effect size = .61), while no such relationship was observed in the depressed group. CONCLUSION: Higher CLEE was associated with improvement in delayed recall among non-depressed, but not among depressed participants. This suggests a protective role of estrogen on memory in non-depressed older postmenopausal women. Further research should examine the role of the CLEE in antidepressant response and cognitive decline.

The intestinal microbiota as a predictor for antidepressant treatment outcome in geriatric depression: a prospective pilot study.

OBJECTIVES: (1) To investigate if gut microbiota can be a predictor of remission in geriatric depression and to identify features of the gut microbiota that is associated with remission. (2) To determine if changes in gut microbiota occur with remission in geriatric depression. DESIGN: Secondary analysis of a parent randomized placebo-controlled trial (NCT02466958). SETTING: Los Angeles, CA, USA (2016-2018). PARTICIPANTS: Seventeen subjects with major depressive disorder, over 60 years of age, 41.2% female. INTERVENTION: Levomilacipran (LVM) or placebo. MEASUREMENTS: Remission was defined by Hamilton Depression Rating Scale score of 6 or less at 12 weeks. 16S-ribosomal RNA sequencing based fecal microbiota composition and diversity were measured at baseline and 12 weeks. Differences in fecal microbiota were evaluated between remitters and non-remitters as well as between baseline and post-treatment samples. LVM and placebo groups were combined in all the analyses. RESULTS: Baseline microbiota showed no community level α-diversity or ß-diversity differences between remitters and non-remitters. At the individual taxa level, a random forest classifier created with nine genera from the baseline microbiota was highly accurate in predicting remission (AUC = .857). Of these, baseline enrichment of Faecalibacterium, Agathobacter and Roseburia relative to a reference frame was associated with treatment outcome of remission. Differential abundance analysis revealed significant genus level changes from baseline to post-treatment in remitters, but not in non-remitters. CONCLUSIONS: This is the first study demonstrating fecal microbiota as a potential predictor of treatment response in geriatric depression. Our findings need to be confirmed in larger prospective studies.

Predictors of Cognitive Improvement Following Treatment for Late-Life Depression.

OBJECTIVE: Cognitive impairment is frequently comorbid with late-life depression (LLD) and often persists despite remission of mood symptoms with antidepressant treatment. Increasing understanding of factors that predict improvement of cognitive symptoms in LLD is useful to inform treatment recommendations. METHODS: We used data from 2 randomized clinical trials of geriatric depression to examine the relationships between sociodemographic factors (resilience, quality of life) and clinical factors (age of depression onset, severity of depression, apathy) with subsequent cognitive outcomes. One hundred sixty-five older adults with major depression who had completed one of 2 clinical trials were included: (1) methylphenidate plus placebo, citalopram plus placebo, and citalopram plus methylphenidate or (2) citalopram combined with Tai Chi or health education. A comprehensive neuropsychiatric battery was administered; 2 measures of cognitive improvement were examined, one defined as an increase in general cognitive performance score of at least 1 standard deviation and the other 0.5 standard deviation pre-post treatment. RESULTS: At posttreatment, 59% of participants had remitted, but less than a third of those who remitted showed cognitive improvement (29%). Cognitive improvement was observed in 18% of nonremitters. Lower baseline depression severity, greater social functioning, and depression onset prior to 60 years of age were significantly associated with cognitive improvement. None of the other measures, including baseline apathy, resilience, and depression remission status, were significantly associated with cognitive improvement. CONCLUSIONS: Lower severity of depression, earlier onset, and greater social functioning may predict improvement in cognitive functioning with treatment for depression in LLD.

Sleep quality, neurocognitive performance, and memory self-appraisal in middle-aged and older adults with memory complaints.

OBJECTIVE: Because of inconsistent findings regarding the relationship between sleep quality and cognitive function in people with age-related memory complaints, we examined how self-reports of sleep quality were related to multiple domains of both objective and subjective cognitive function in middle-aged and older adults. DESIGN: A cross-sectional study involving analysis of baseline data, collected as part of a clinical trial. MEASUREMENTS: Two hundred and three participants (mean age = 60.4 [6.5] years, 69.0% female) with mild memory complaints were asked to rate their sleep quality using the Pittsburgh Sleep Quality Index (PSQI) and their memory performance using the Memory Functioning Questionnaire (MFQ), which measures self-awareness of memory ability. Neurocognitive performance was evaluated using the Continuous Performance Test (CPT), Trail Making Test, Buschke Selective Reminding Test, and the Brief Visuospatial Test - Revised (BVMT-R). RESULTS: Total PSQI scores were significantly associated with objective measures of sustained attention (CPT hit reaction time by block and standard error by block) and subjective memory loss (MFQ frequency and seriousness of forgetting). The PSQI components of (poorer) sleep quality and (greater) sleep disturbance were related to (worse) sustained attention scores while increased sleep latency and daytime sleepiness were associated with greater frequency and seriousness of forgetting. CONCLUSIONS: Sleep quality is related to both objective measures of sustained attention and self-awareness of memory decline. These findings suggest that interventions for improving sleep quality may contribute not only to improving the ability to focus on a particular task but also in reducing memory complaints in middle-aged and older adults.

[18F]FDDNP PET binding predicts change in executive function in a pilot clinical trial of geriatric depression.

OBJECTIVES: Geriatric depression often presents with memory and cognitive complaints that are associated with increased risk for Alzheimer's disease (AD). In a parent clinical trial of escitalopram combined with memantine or placebo for geriatric depression and subjective memory complaints, we found that memantine improved executive function and delayed recall performance at 12 months (NCT01902004). In this report, we used positron emission tomography (PET) to assess the relationship between in-vivo amyloid and tau brain biomarkers and clinical and cognitive treatment response. DESIGN: In a randomized double-blind placebo-controlled trial, we measured 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile ([18F]FDDNP) binding at baseline and assessed mood and cognitive performance at baseline, posttreatment (6 months), and naturalistic follow-up (12 months). PARTICIPANTS: Twenty-two older adults with major depressive disorder and subjective memory complaints completed PET scans and were included in this report. RESULTS: Across both treatment groups, higher frontal lobe [18F]FDDNP binding at baseline was associated with improvement in executive function at 6 months (corrected p = .045). This effect was no longer significant at 12 months (corrected p = .12). There was no association of regional [18F]FDDNP binding with change in mood symptoms (corrected p = .2). CONCLUSIONS: [18F]FDDNP binding may predict cognitive response to antidepressant treatment. Larger trials are required to further test the value of [18F]FDDNP binding as a biomarker for cognitive improvement with antidepressant treatment in geriatric depression.

The Effect of Memory Training on Memory Control Beliefs in Older Adults with Subjective Memory Complaints.

Objective: To study whether memory control beliefs predict response to memory training, or change as a result of participating in memory training. Methods: Eighty community based participants with subjective memory complaints Community-based study at UCLA were randomized to one of three conditions: Memory Training, the program consisted of weekly 120-minute classes featuring instruction in three specific strategies: Method of Loci; Chunking Technique; and Face-Name Association, Health Education or Wait-List over seven weeks. All participants underwent pre- and 1-week post-intervention follow-up memory testing for recalling word lists (in serial order and any order) and face-name pairs. Memory control beliefs were assessed at baseline and follow-up using the Memory Controllability Inventory, which consists of four subscales; Present Ability; Potential Improvement; Effort Utility; and Inevitable Decrement. Results: Sixty-three participants (mean age [SD] 68.3 [6.7] years) were included in the analysis. ANCOVA revealed significant group differences in the Present Ability subscale, F2,58 = 4.93, p =.01. Participants in the Memory Training group significantly improved on the Present Ability subscale compared to the Health Education group (mean difference =.96, SE =.31, p =.003, effect size = 0.93). From regression analyses, baseline Memory Controllability Inventory subscales did not significantly predict memory performance after memory training. Conclusions: Baseline memory control beliefs did not predict memory performance following the intervention, but participating in memory training enhanced memory control beliefs about current memory function. These results suggest that participating in memory training can enhance confidence in one's memory ability.

A Randomized Double-Blind Placebo-Controlled Trial of Combined Escitalopram and Memantine for Older Adults With Major Depression and Subjective Memory Complaints.

OBJECTIVE: Geriatric depression is difficult to treat and frequently accompanied by cognitive complaints that increase risk for dementia. New treatment strategies targeting both depression and cognition are urgently needed. METHODS: We conducted a 6-month double-blind placebo-controlled trial to assess the efficacy and tolerability of escitalopram + memantine (ESC/MEM) compared to escitalopram + placebo (ESC/PBO) for improving mood and cognitive functioning in depressed older adults with subjective memory complaints (NCT01902004). Primary outcome was change in depression as assessed by the HAM-D post-treatment (at 6 months). Remission was defined as HAM-D ≤6; naturalistic follow-up continued until 12 months. RESULTS: Of the 95 randomized participants, 62 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Mean daily escitalopram dose was 11.1 mg (SD = 3.7; range: 5-20 mg). Mean daily memantine dose was 19.3 mg (SD = 2.6; range 10-20 mg). Remission rate within ESC/MEM was 45.8% and 47.9%, compared to 38.3% and 31.9% in ESC/PBO, at 3 and 6 months, respectively (χ2(1) = 2.0, p = 0.15). Both groups improved significantly on the HAM-D at 3, 6, and 12 months, with no observed between-group differences. ESC/MEM demonstrated greater improvement in delayed recall (F(2,82) = 4.3, p = 0.02) and executive functioning (F(2,82) = 5.1, p = 0.01) at 12 months compared to ESC/PBO. CONCLUSIONS: The combination of memantine with escitalopram was well tolerated and as effective as escitalopram and placebo in improving depression using HAM-D. Combination memantine and escitalopram was significantly more effective than escitalopram and placebo in improving cognitive outcomes at 12 months. Future reports will address the role of biomarkers of aging in treatment response.

Cortical thickness increases with levomilnacipran treatment in a pilot randomised double-blind placebo-controlled trial in late-life depression.

BACKGROUND: Late-life depression (LLD) is associated with significant medical comorbidity, cognitive impairment, and suboptimal treatment response compared to depression experienced earlier in life. Levomilnacipran (LVM) is a novel antidepressant the effects of which on neuroplasticity have not yet been investigated. We investigated the effect of LVM on cortical thickness in a pilot randomised placebo-controlled trial in LLD. METHODS: Twenty-nine adults (≥ 60 years) with major depression (48.3% female; mean age = 71.5 ± 5.8 years; mean education = 16.0 ± 1.7 years) were randomised to either LVM or placebo for 12 weeks. T1-weighted images were acquired at baseline and 12 weeks. Thirteen subjects (six LVM and seven placebo) completed the study. Group differences in cortical thickness change across the study period were evaluated, with age and total intracranial volume included as covariates. RESULTS: Dropout rates did not differ significantly between groups. The LVM group had significantly more side effects, but no serious adverse events were reported. Lower LVM dose (≤ 40 mg) was better tolerated than higher doses (80-120 mg). Additionally, the LVM group showed a larger increase in cortical thickness in the right postcentral gyrus (primary somatosensory), supramarginal gyrus (sensory association region), and lateral occipital cortex (visual cortex) compared to the placebo group and greater reductions in the left insula. CONCLUSIONS: LVM may be less tolerable by older adults with depression and the effects on cortical thickness across sensory and sensory association regions may be related to the experience of side effects. Larger studies are necessary to evaluate treatment efficacy, tolerability, and neural effects of LVM in LLD.

Neurocognitive Correlates of Resilience in Late-Life Depression.

OBJECTIVE: Increasing understanding of the neurocognitive correlates of resilience in late-life depression (LLD) could inform interventions to promote more sustained remission. We investigated cross-sectional relations between baseline resilience and domains of neurocognitive functioning in depressed older adults enrolled in one of four trials. METHODS: Participants (N = 288) completed neurocognitive tests of memory, language performance, and executive functioning as well as measures of subjective memory performance and components of resilience (grit, active coping self-efficacy, accommodative coping self-efficacy, and spirituality). RESULTS: Medium-sized associations were observed between greater resilience (overall resilience, accommodative coping) and lower frequency of self-reported forgetting. Small positive associations were observed between language performance and total resilience, active coping self-efficacy, and accommodative coping self-efficacy. Small negative associations were observed between spirituality and each objective measure of cognitive performance. CONCLUSION: Future longitudinal studies will help elucidate the complex relation between resilience and cognitive functioning in LLD. In addition, randomized controlled trials targeting coping self-efficacy may inform the development of more effective and personalized interventions.

Clinical correlates of resilience factors in geriatric depression.

ABSTRACTBackground:Traditional perspectives conceptualize resilience as a trait and depression as resulting from resilience deficiency. However, research indicates that resilience varies substantially even among adults who are clinically depressed, as well as across the lifespan of an individual. Few studies have investigated resilience in depression, and even fewer have examined resilience in depressed older adults. METHODS: Three hundred thirty-seven adults ≥60 years with major depressive disorder completed the Connor-Davidson Resilience Scale (CD-RISC) and measures of mental health, quality of life (QOL), and medical comorbidity. Exploratory factor analysis was used to explore the factor structure of the CD-RISC. Correlations and general linear models were used to examine associations between resilience and other variables. RESULTS: The rotated component matrix indicated a four-factor model. Sorting of items by highest factor loading revealed constructs associated with (1) grit, (2) active coping self-efficacy, (3) accommodative coping self-efficacy, and (4) spirituality. Resilience was significantly correlated with increased age, lower cognitive functioning, greater cerebrovascular risk, and greater medical comorbidity. Resilience was negatively associated with mental health symptoms (depression, apathy, and anxiety) and positively associated with QOL. The final optimal model identified less depression, less apathy, greater medical comorbidity, higher QOL, and minority (non-White) race as factors that significantly explained variability in resilience. CONCLUSIONS: Resilience was significantly associated with a range of mental health constructs in a sample of older adults with depression. Future clinical trials and dismantling studies may help determine whether interventions targeting grit, active coping, accommodative coping, and spirituality can increase resilience and help prevent and treat depression in older adults.

Apathy Mediates Cognitive Difficulties in Geriatric Depression.

OBJECTIVE: Cognitive impairment associated with late-life depression can persist after remission of mood symptoms. Apathy, a common symptom of late-life depression, often leads to worse clinical outcomes. We examined if severity of apathy mediates cognitive difficulties in a cohort of older adults with major depression. METHODS: One hundred thirty-eight older adults with depression (54.4% female; mean [SD] age: 69.7 [7.4] years; mean [SD] education:15.6 [2.7] years) were recruited to participate in a treatment study, and only baseline data were analyzed. All participants received a comprehensive evaluation of depression, apathy, and cognition. We examined whether apathy mediated the relationship between depression and cognition, focusing our attention on memory and cognitive control. We then explored whether the mediation effects differed across women and men. RESULTS: Increased apathy was significantly associated with worse depression and lower performance in the cognitive control domain but not in memory. Higher depressive scores were significantly associated with worse cognitive control but not memory. Mediation analyses revealed a significant indirect effect on cognitive control by depression through increased apathy scores with the mediator accounting for 21% of the total effect. Stratifying by sex, we found that women exhibited a significant indirect effect, with the mediator accounting for 47% of the total effect, whereas there was no mediation by apathy in men. CONCLUSIONS: The findings imply that increased apathy mediates the relationship between cognition and depression. The identification of mediating effects may inform future treatment strategies and preventive interventions that can focus on decreasing apathy to improve cognition in late-life depression.

In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults.

OBJECTIVE: Growing evidence supports an association between increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. METHODS: Positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden. A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. RESULTS: Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (η2 = 0.06). However, this relationship was no longer significant after introducing FDDNP-PET binding as an additional covariate in the statistical models. In vivo plaque and tangle burden accounted for over 30% of the observed association between higher DBP and poorer cognitive performance. CONCLUSIONS: By suggesting a mediation of the relationship between DBP and cognitive functioning by FDDNP-PET binding, this study advances our understanding of some potential predictors of cognitive decline in non-demented adults, and underscores the importance of devising early multimodal interventions to more effectively combat degenerative brain disorders.

Resilience and White Matter Integrity in Geriatric Depression.

OBJECTIVE: Greater psychological resilience may protect against developing depression in a growing geriatric population. Identifying the neural correlates of resilience in geriatric depression could provide neurobiologic targets to inform clinical interventions. However, most prior neuroimaging studies have only considered the presence or absence of resilience and have not addressed the multifactorial nature of resilience. The current study aimed to establish the neural correlates of four factors of resilience in the depressed elderly. METHODS: White matter integrity was assessed using diffusion-weighted magnetic resonance imaging data collected from 70 older adults with major depressive disorder. We used four resilience factors previously derived in an exploratory factor analysis of the Connor-Davidson Resilience Scale in a large sample of depressed older adults: 1, grit; 2, active coping self-efficacy; 3, accommodative coping self-efficacy; and 4, spirituality. RESULTS: The resilience factor "grit" was positively associated with fractional anisotropy in the callosal region connecting prefrontal cortex and fractional anisotropy in cingulum fibers; however, the latter did not survive correction for multiple comparisons. CONCLUSION: Structural integrity of major white matter pathways implicated in cognitive control and emotion regulation (i.e., connecting prefrontal cortex) was positively associated with the resilience factor "grit" in our sample of older adults with depression. Prospective studies are needed to determine the utility of the structural integrity of these pathways as a biomarker in predicting risk for depression and treatment response.