C E Millett1, J Harder1, J J Locascio2, M Shanahan3, G Santone4, R N Fichorova4, A Corrigan5, C Baecher-Allan6, K E Burdick7. 1. Mood and Psychosis Research Program, Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States. 2. Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital and Harvard Medical School, United States. 3. Mood and Psychosis Research Program, Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, United States; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital and Harvard Medical School, United States. 4. Laboratory of Genital Tract Biology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States. 5. Mood and Psychosis Research Program, Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, United States. 6. Ann Romney Center for Neurologic Disease, Harvard Medical School, Boston, MA 02115, USA; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. 7. Mood and Psychosis Research Program, Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States. Electronic address: kburdick1@bwh.harvard.edu.
Abstract
BACKGROUND: Bipolar disorder (BD) is one of the most disabling mental health conditions in the world. Symptoms of cognitive impairment in BD contribute directly to occupational and social deficiencies and are very difficult to treat. Converging evidence suggests that BD patients have increased peripheral markers of inflammation. The hypothesis of neuroprogression in BD postulates that cognitive deficits develop over the course of the illness and are influenced by prior severe mood episodes, leading to wear-and-tear on the brain- however, there exists a paucity of data statistically testing a mediating role of immune molecules in cognitive dysfunction in BD. METHODS: This is a cross-sectional study. We measured serum levels of tumor necrosis factor alpha (TNF-α), and soluble (s) TNF receptors one and two (sTNF-R1 and sTNF-R2) in 219 euthymic BD patients and 52 Healthy Controls (HCs). Structural equation modeling (SEM) was used for the primary purpose of assessing whether TNF markers (measured by the multiple indicators TNF-α, sTNF-R1 and sTNF-R2) mediate the effect or number of prior severe mood episodes (number of prior psychiatric hospitalizations) on cognitive performance. RESULTS: BD and HC groups did not differ on circulating levels of TNF molecules in the present study. However, we found higher sTNF-R1 concentration in 'late-stage' BD illness (>1 prior psychiatric hospitalization) compared to those in early stage illness. In the subsequent SEM, we found that the model fits the data acceptably (Chi-square = 49.2, p = 0.3), and had a 'close fit' (RMSEA = 0.02, PCLOSE = 0.9). Holding covariates constant (age, sex, premorbid IQ, education, and race), we found that the standardized indirect effect was significant, p = 0.015, 90%CI [-0.07, -0.01], indicating that the estimated model was consistent with peripheral TNF markers partially mediating a causal effect of severe mood episodes on executive function. CONCLUSIONS: Our results indicate that circulating levels of TNF molecules partially mediate the relationship between prior severe mood episodes and executive function in BD. These results may implicate TNF variables in the neuroprogressive course of BD and could point to novel interventions for cognition.
BACKGROUND: Bipolar disorder (BD) is one of the most disabling mental health conditions in the world. Symptoms of cognitive impairment in BD contribute directly to occupational and social deficiencies and are very difficult to treat. Converging evidence suggests that BD patients have increased peripheral markers of inflammation. The hypothesis of neuroprogression in BD postulates that cognitive deficits develop over the course of the illness and are influenced by prior severe mood episodes, leading to wear-and-tear on the brain- however, there exists a paucity of data statistically testing a mediating role of immune molecules in cognitive dysfunction in BD. METHODS: This is a cross-sectional study. We measured serum levels of tumor necrosis factor alpha (TNF-α), and soluble (s) TNF receptors one and two (sTNF-R1 and sTNF-R2) in 219 euthymic BD patients and 52 Healthy Controls (HCs). Structural equation modeling (SEM) was used for the primary purpose of assessing whether TNF markers (measured by the multiple indicators TNF-α, sTNF-R1 and sTNF-R2) mediate the effect or number of prior severe mood episodes (number of prior psychiatric hospitalizations) on cognitive performance. RESULTS: BD and HC groups did not differ on circulating levels of TNF molecules in the present study. However, we found higher sTNF-R1 concentration in 'late-stage' BD illness (>1 prior psychiatric hospitalization) compared to those in early stage illness. In the subsequent SEM, we found that the model fits the data acceptably (Chi-square = 49.2, p = 0.3), and had a 'close fit' (RMSEA = 0.02, PCLOSE = 0.9). Holding covariates constant (age, sex, premorbid IQ, education, and race), we found that the standardized indirect effect was significant, p = 0.015, 90%CI [-0.07, -0.01], indicating that the estimated model was consistent with peripheral TNF markers partially mediating a causal effect of severe mood episodes on executive function. CONCLUSIONS: Our results indicate that circulating levels of TNF molecules partially mediate the relationship between prior severe mood episodes and executive function in BD. These results may implicate TNF variables in the neuroprogressive course of BD and could point to novel interventions for cognition.
Authors: Keith H Nuechterlein; Michael F Green; Robert S Kern; Lyle E Baade; Deanna M Barch; Jonathan D Cohen; Susan Essock; Wayne S Fenton; Frederick J Frese; James M Gold; Terry Goldberg; Robert K Heaton; Richard S E Keefe; Helena Kraemer; Raquelle Mesholam-Gately; Larry J Seidman; Ellen Stover; Daniel R Weinberger; Alexander S Young; Steven Zalcman; Stephen R Marder Journal: Am J Psychiatry Date: 2008-01-02 Impact factor: 18.112