Life-Satisfaction, Engagement, Mindfulness, Flourishing, and Social Support: Do they Predict Depression, Suicide Ideation, and History of Suicide Attempt in Late Life?

OBJECTIVE: Suicide is an outcome arising from a combination of risk and protective factors. Examining psychological resilience traits associated with successful aging may help to better understand late-life suicide and depression. We examined self-reported protective factors including mindfulness, life satisfaction and engagement, flourishing, and subjective and objective social support in a high suicide-risk sample of depressed older adults. METHODS: Participants were 297 individuals aged 55+ (mean age: 64.2): 92 depressed suicide attempters, 138 depressed individuals who never attempted suicide, and 67 non-psychiatric comparisons. Using linear and binomial logistic regression, we examined the effects of a combined Protective Factor value on presence and severity of depression and suicidal ideation, and history of suicide attempt. RESULTS: Relative to the non-psychiatric comparison group, all depressed participants had significantly lower Protective Factor values. Higher Protective Factor value was associated with lower likelihood of depression, depression severity, and likelihood of ideation, but was not associated with ideation severity or history of suicide attempt. Participants with one standard deviation higher Protective Factor had lower odds of ideation incidence by a factor of OR=0.68 (95%CI=0.48-0.96). CONCLUSION: Resiliency characteristics relevant to psychological wellbeing and successful aging may mitigate the emergence of depression and suicidal ideation, as well as the severity of depression in late-life. The Resilience Factor used in this study can help clinicians nuance their appraisal of depression and suicide risk.

Hematologic safety of chronic brain-penetrating erythropoietin dosing in APP/PS1 mice.

INTRODUCTION: Low blood-brain barrier (BBB) penetration and hematopoietic side effects limit the therapeutic development of erythropoietin (EPO) for Alzheimer's disease (AD). A fusion protein of EPO and a chimeric monoclonal antibody targeting the mouse transferrin receptor (cTfRMAb) has been engineered. The latter drives EPO into the brain via receptor-mediated transcytosis across the BBB and increases its peripheral clearance to reduce hematopoietic side effects of EPO. Our previous work shows the protective effects of this BBB-penetrating EPO in AD mice but hematologic effects have not been studied. Herein, we investigate the hematologic safety and therapeutic effects of chronic cTfRMAb-EPO dosing, in comparison to recombinant human EPO (rhu-EPO), in AD mice. METHODS: Male APPswe PSEN1dE9 (APP/PS1) mice (9.5 months) were treated with saline (n = 11), and equimolar doses of cTfRMAb-EPO (3 mg/kg, n = 7), or rhu-EPO (0.6 mg/kg, n = 9) 2 days/week subcutaneously for 6 weeks, compared to saline-treated wild-type mice (n = 10). At 6 weeks, exploration and memory were assessed, and mice were sacrificed at 8 weeks. Spleens were weighed, and brains were evaluated for amyloid beta (Aß) load and synaptophysin. Blood was collected at 4, 6 and 8 weeks for a complete blood count and white blood cells differential. RESULTS: cTfRMAb-EPO transiently increased reticulocyte counts after 4 weeks, followed by normalization of reticulocytes at 6 and 8 weeks. rhu-EPO transiently increased red blood cell count, hemoglobin and hematocrit, and significantly decreased mean corpuscular volume and reticulocytes at 4 weeks, which remained low at 6 weeks. At 8 weeks, a significant decline in red blood cell indices was observed with rhu-EPO treatment. Exploration and cognitive deficits were significantly worse in APP/PS1-rhu-EPO mice. Both cTfRMAb-EPO and rhu-EPO decreased 6E10-positive brain Aß load; however, cTfRMAb-EPO and not rhu-EPO selectively reduced brain Aß1-42 and elevated synaptophysin expression. DISCUSSION: Chronic treatment with cTfRMAb-EPO results in better hematologic safety, behavioral, and therapeutic indices compared with rhu-EPO, supporting the development of this BBB-penetrable EPO analog for AD.