Background : Women with breast cancer commonly experience fatigue and depressive symptoms before, during, and after treatment. Many studies have found that fatigue and depression are correlated in women with breast cancer throughout treatment, but there are few studies that have investigated the temporal nature of this relationship. Methods : As part of a larger study investigating sleep and fatigue in breast cancer, 89 women (mean age=51.9 yrs) with breast cancer were assessed for fatigue and depressive symptoms before beginning chemotherapy and in the last week of cycle 4 of chemotherapy. Fatigue was assessed using the Multidimensional Fatigue Scale - Short Form (MFSI-SF). Depressive symptoms were assessed with the Center for Epidemiological Studies-Depression (CES-D) questionnaire, and only women with a baseline CES-D score less than 16, suggestive of no depressive symptoms, were included in the study. The relationship between baseline MFSI-SF scores and the final CES-D scores was modeled with multiple regression models adjusted for demographic and disease related confounders. Results : The MFSI-SF mental subscale was the only fatigue measure to remain significantly associated with either the final CES-D score (B=0.156, p=0.002) or final CES-D score ≥16 (O.R.=1.20, 95% C.I.=1.01-1.42) after adjustment for baseline CES-D score, antidepressant use, and ethnicity in a multiple regression model. Conclusion : This study suggests that women with breast cancer who have higher levels of mental fatigue prior to chemotherapy are more likely to experience higher levels of depressive symptoms and progression to clinically significant depression following chemotherapy. Future studies should investigate if interventions that decrease fatigue prior to or early in cancer treatment will prevent worsening of depressive symptoms.

Abstract Background Recent studies suggest that the pathogenic process in neurodegenerative disorders may disrupt mature neuronal circuitries and neurogenesis in the adult brain. Abnormal activation of CDK5 is associated with neurodegenerative disorders, and recently a critical role for CDK5 in adult neurogenesis has been identified. We have developed an in vitro model of abnormal CDK5 activation during adult hippocampal neurogenesis, and here we used this model to investigate aberrantly phosphorylated downstream targets of CDK5. Results Abnormal CDK5 activation in an in vitro model of adult neurogenesis results in hyperphosphorylation of collapsin-response mediator protein-2 (CRMP2) and impaired neurite outgrowth. Inhibition of CDK5, or expression of a non-phosphorylatable (S522A) CRMP2 construct reduced CRMP2 hyperphosphorylation, and reversed neurite outgrowth deficits. CRMP2 plays a role in microtubule dynamics; therefore we examined the integrity of microtubules in this model using biochemical and electron microscopy techniques. We found that microtubule organization was disrupted under conditions of CDK5 activation. Finally, to study the relevance of these findings to neurogenesis in neurodegenerative conditions associated with HIV infection, we performed immunochemical analyses of the brains of patients with HIV and transgenic mice expressing HIV-gp120 protein. CDK5-mediated CRMP2 phosphorylation was significantly increased in the hippocampus of patients with HIV encephalitis and in gp120 transgenic mice, and this effect was rescued by genetic down-modulation of CDK5 in the mouse model. Conclusions These results reveal a functional mechanism involving microtubule destabilization through which abnormal CDK5 activation and CRMP2 hyperphosphorylation might contribute to defective neurogenesis in neurodegenerative disorders such as HIV encephalitis.