Quality of Sleep and Coexistent Psychopathology Have Significant Impact on Fatigue Burden in Patients With Inflammatory Bowel Disease.

BACKGROUND: Fatigue is common in inflammatory bowel disease (IBD) patients and is associated with factors such as psychopathology, sleep quality, and disease activity. GOAL: To investigate the combined role of all the above factors in the burden of fatigue among IBD patients. STUDY: We conducted an observational study of adult patients enrolled in an IBD clinical research registry at a tertiary care clinic. Fatigue burden was defined by Item 1 of the Short-form IBD Questionnaire (SIBDQ), which is scored on a 7-point Likert scale. Crohn's disease (CD) and ulcerative colitis (UC) disease activity were measured with the Harvey-Bradshaw Index or the UC Activity Index, respectively. Labs were obtained to assess anemia, vitamin deficiencies, and inflammatory markers. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Use of psychotropic medications and narcotics was used as proxy measure of psychopathology and pain. RESULTS: Among 685 IBD patients enrolled in the registry, 631 (238 UC, 393 CD) had a complete SIBDQ. High fatigue burden was found in 57.5% of patients (64.4% CD, 46.2% UC). Fatigue burden was significantly associated with sleep disturbance (PSQI), SIBDQ, and disease activity. CD patients had more fatigue burden than UC patients. Multivariate regression showed that poor quality of life, sleep disturbance, and being on a psychotropic medication are significantly associated with fatigue burden for both UC and CD. CONCLUSION: Because fatigue is common in IBD patients, these findings suggest that attention to quality of sleep and psychopathology is as important as medical disease management.

Depression subtypes in pediatric inflammatory bowel disease.

OBJECTIVE: The association between inflammatory bowel disease (IBD) and depression provides a unique opportunity to understand the relation between systemic inflammation and depressive symptom profiles. METHODS: Youth (n = 226) ages 9 to 17 years with comorbid IBD and depression underwent psychiatric assessment and evaluation of IBD activity. Latent profile analysis (LPA) identified depressive subgroups based on similar responses to the Children's Depression Rating Scale-Revised. Demographic factors, depression severity, anxiety, IBD activity, inflammatory markers, IBD-related medications, and illness perception were evaluated as predictors of profile membership. RESULTS: Mean age was 14.3 years; 75% had Crohn disease; 31% were taking systemic corticosteroids. Mean depressive severity was moderate, whereas IBD activity, which reflects inflammation, was mild. LPA identified 3 subgroups: Profile-1 (mild, 75%) had diverse low-grade depressive symptoms and highest quality of life; Profile-2 (somatic, 19%) had severe fatigue, appetite change, anhedonia, decreased motor activity, and depressed mood with concurrent high-dose steroid therapy and the highest IBD activity; and Profile-3 (cognitive, 6%) had the highest rates of self-reported depressive symptoms, ostomy placements, and anxiety with IBD symptoms in the relative absence of inflammation. CONCLUSIONS: Evidence was found for 3 depression profiles in youth with IBD and depression. Our analyses determined that patients with predominantly somatic or cognitive symptoms of depression comprised 25% of our cohort. These findings may be used to design subgroup-specific interventions for depression in adolescents with IBD and other physical illnesses associated with systemic inflammation.

Characterization of relations among sleep, inflammation, and psychiatric dysfunction in depressed youth with Crohn disease.

OBJECTIVES: Recent reports demonstrate a link between inflammatory bowel disease (IBD) and sleep disturbance. Increased psychiatric dysfunction is consistently reported in patients with IBD. Our objective is to examine relations among sleep disturbance, inflammation, and psychiatric dysfunction in a pediatric population with Crohn disease (CD) and depression. METHODS: Pediatric patients with CD with depression (n = 96) and healthy controls (n = 19) completed measures of sleep (Pittsburgh Sleep Quality Index [PSQI]), depression, anxiety, and abdominal pain, and provided blood for inflammatory markers. CD activity was determined by the Pediatric Crohn's Disease Activity Index. Factor analysis was performed on subscales of the PSQI to derive measures of sleep disturbance. Univariate and multivariate regression analyses assessed relations between sleep disturbance, psychosocial, and biological measures of CD and psychiatric dysfunction. RESULTS: Sleep disturbance in depressed youth with CD was significantly greater than healthy controls, and was significantly related to measures of abdominal pain, depression, and anxiety, but not biomarkers of inflammation. Factor analysis of the PSQI demonstrated a 2-factor solution. The first factor, termed "Qualitative," included Subjective Sleep Quality, Daytime Dysfunction, Sleep Disturbance, and Sleep Latency, whereas the second factor, "Quantitative," consisted of Habitual Sleep Efficiency and Sleep Duration. This factor showed a significant relation to inflammatory markers. Multivariate modeling suggested that qualitative sleep disturbance was predicted by disease activity, pain, and anxiety, whereas quantitative sleep disturbance was predicted by disease activity. CONCLUSIONS: These results indicate that sleep disturbance in depressed youth with CD differs depending upon illness activity. Patients may require different interventions depending upon the sleep disturbance exhibited.

Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin signaling.

Two major signaling pathways that control neuronal positioning during brain development have been uncovered as a result of genetic and biochemical studies on neurological mouse mutants. Mice deficient in Reelin, Disabled 1 (Dab1), or both the very low-density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor 2 (ApoER2) exhibit identical neuroanatomic defects in laminar structures throughout the brain. These proteins function as components of the Reelin signaling pathway. Reelin is a secreted glycoprotein that binds to VLDLR and ApoER2, inducing tyrosine phosphorylation of Dab1, an intracellular adapter protein. Neuronal migration is also regulated by cyclin-dependent kinase 5 (Cdk5) and its activating subunits p35 and p39. Mice deficient in Cdk5, p35, or both p35 and p39 exhibit lamination defects that are similar but not identical to those observed in mice with a defect in the Reelin signaling pathway. Cdk5 phosphorylates proteins that maintain cytoskeletal structures and promote cell motility. To explore the possibility that Cdk5 influences the Reelin pathway, we sought to determine whether Dab1 is a substrate for Cdk5. Here we show that Cdk5 phosphorylates Dab1 on serine 491 in vitro and in vivo, independently of Reelin signaling. We also show that ectopic neurons in Cdk5-deficient mice exhibit reduced levels of Reelin signaling during later stages of cortical development, although Cdk5 is not required for Reelin-induced tyrosine phosphorylation of Dab1. Although the functional significance of Dab1 serine phosphorylation is unclear, our results suggest that there is biochemical cross-talk between two signaling pathways that control cell positioning.

Components of the reelin signaling pathway are expressed in the spinal cord.

The Reelin signaling pathway in the brain involves the binding of Reelin to very-low-density lipoprotein receptors (VLDLR) and apolipoprotein E receptor 2 (ApoER2). After Reelin binds the lipoprotein receptors on migrating neurons, the intracellular adaptor protein Disabled-1 (Dab1) becomes phosphorylated, ultimately resulting in the proper positioning of cortical neurons. Previous work showed that Reelin also affects the positioning of sympathetic preganglionic neurons (SPN) in the spinal cord (Yip et al. [2000] Proc Natl Acad Sci USA 97:8612-8616). We asked in the present study whether components of the Reelin signaling pathway in the brain also function to control SPN migration in developing spinal cord. Results showed that Reelin and reelin mRNA are found adjacent to migrating SPN. In addition, dab1 mRNA and protein are expressed by migrating SPN, and dab1-null mice show abnormal SPN migration similar to that seen in reeler. Finally, vldlr and apoER2 are also expressed in migrating SPN, and mice lacking both vldlr and apoER2 show aberrant SPN location that is identical to that of reeler and dab1-null mice. Because molecules known to be involved in Reelin signaling in the brain are present in the developing spinal cord, it is likely that the Reelin signaling pathways in the brain and spinal cord function similarly. The relative simplicity of the organization of the spinal cord makes it a potentially useful model system with which to study the molecular and cellular function of the Reelin signaling pathway in control of neuronal migration.

Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1.

Reelin, Disabled-1 (Dab1), apolipoprotein E receptor 2 (ApoER2), and very low density lipoprotein receptor (VLDLR) participate in a signaling pathway required for layer formation during mammalian brain development. Binding of Reelin to ApoER2 and VLDLR induces a rapid increase in tyrosine phosphorylation of Dab1, an adaptor protein that associates with the cytoplasmic domain of the receptors. However, Reelin has also been proposed to signal through integrin and protocadherin. Here we compare the roles of ApoER2 and VLDLR in Reelin signaling. We used layer-specific markers to identify the final positions of early- and late-born neurons in the cortices of mice lacking ApoER2, VLDLR, or both ApoER2 and VLDLR. Subtle alterations were observed in mice lacking VLDLR, whereas more severe abnormalities were detected in the absence of ApoER2, and major disruptions were obvious in mice lacking both receptors. Purified Reelin associated more readily with ApoER2 than with VLDLR and no synergy was observed in the presence of both receptors. Consistent with the binding data, the level of Reelin-induced Dab1 phosphorylation was more severely reduced in neurons lacking ApoER2 than in neurons lacking VLDLR. However, similarly low levels of Dab1 tyrosine phosphorylation were observed in ApoER2(-/-) and VLDLR(-/-) mice in vivo. Finally, there was a complete absence of Reelin-induced tyrosine phosphorylation of Dab1 in cortical neurons from mice lacking both ApoER2 and VLDLR. These findings demonstrate that ApoER2 and VLDLR are essential for Reelin signaling and that no other receptor molecules can compensate for their role in mediating tyrosine phosphorylation of Dab1.

Randomized efficacy trial of two psychotherapies for depression in youth with inflammatory bowel disease.

OBJECTIVE: Pediatric inflammatory bowel disease (IBD) is associated with high rates of depression. This study compared the efficacy of cognitive behavioral therapy (CBT) to supportive nondirective therapy (SNDT) in treating youth with comorbid IBD and depression. METHOD: Youth (51% female and 49% male; age 9-17 years, mean age 14.3 years) with depression and Crohn's disease (n = 161) or ulcerative colitis (n = 56) were randomly assigned to a 3-month course of CBT or SNDT. The primary outcome was comparative reduction in depressive symptom severity; secondary outcomes were depression remission, increase in depression response, and improved health-related adjustment and IBD activity. RESULTS: A total of 178 participants (82%) completed the 3-month intervention. Both psychotherapies resulted in significant reductions in total Children's Depression Rating Scale Revised score (37.3% for CBT and 31.9% for SNDT), but the difference between the 2 treatments was not significant (p = .16). There were large pre-post effect sizes for each treatment (d = 1.31 for CBT and d = 1.30 for SNDT). More than 65% of youth had a complete remission of depression at 3 months, with no difference between CBT and SNDT (67.8% and 63.2%, respectively). Compared to SNDT, CBT was associated with a greater reduction in IBD activity (p = .04) but no greater improvement on the Clinical Global Assessment Scale (p = .06) and health-related quality of life (IMPACT-III scale) (p = .07). CONCLUSION: This is the first randomized controlled study to suggest improvements in depression severity, global functioning, quality of life, and disease activity in a physically ill pediatric cohort treated with psychotherapy. Clinical trial registration information-Reducing Depressive Symptoms in Physically Ill Youth; http://clinical trials.gov; NCT00534911.

Differential binding of ligands to the apolipoprotein E receptor 2.

Apolipoprotein E receptor 2 (apoER2) is an important participant in the Reelin signaling pathway that directs cell positioning during embryogenesis. ApoER2 is a cell surface molecule that elicits intracellular signal transduction through binding of Reelin. The structural requirements for Reelin binding to apoER2 and the receptor domains involved in this process are unclear at present. Using a series of receptor mutants, we characterized the interaction of apoER2 with Reelin and compared this interaction to that of apoER2 with the receptor-associated protein (RAP), an apoER2 ligand that does not induce signaling. By surface plasmon resonance we demonstrate that apoER2 exhibits 6-fold higher affinity for Reelin than the very low density lipoprotein receptor (VLDLR), which also functions as a Reelin receptor (K(D) 0.2 nM versus K(D) 1.2 nM). Acidic amino acid residues in complement-type repeat domains 1 and 3 of apoER2 are required for Reelin binding. The same regions of the receptor are also bound by RAP with a 25-fold lower affinity (K(D) 5 nM). Whereas RAP binds to apoER2 with a 1:1 stoichiometry, experimental evidence suggests that Reelin associates with two or more receptor molecules simultaneously to achieve high-affinity interaction. This finding indicates that aggregation of apoER2 by multivalent ligands such as Reelin may be the structural basis for signal transduction.

Reelin promotes peripheral synapse elimination and maturation.

Reelin is an extracellular protein that is crucial for layer formation in the embryonic brain. Here, we demonstrate that Reelin functions postnatally to regulate the development of the neuromuscular junction. Reelin is required for motor end-plate maturation and proper nerve-muscle connectivity, and it directly promotes synapse elimination. Unlike layer formation, neuromuscular junction development requires a function of Reelin that is not mediated by Disabled1 or very-low-density lipoprotein receptors and apolipoprotein E receptor 2 receptors but by a distinct mechanism involving its protease activity.