Introduction: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD). Methods: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing. Results: In AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles. Conclusion: We report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.

Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that ␣-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of major depression with melancholic features. M ajor depression is a complex disorder with an estimated lifetime prevalence of 15% in women and 8% in men (1). Depression is the main cause of suicide: Ϸ70% of all suicides are attributed to untreated depression. Studies in the United States suggest that, at any given time, Ϸ2-3% of the population is hospitalized or seriously impaired by affective illness. The World Health Organization has declared major depression as the single largest cause of morbidity for women and the leading cause of disability worldwide.The current standard diagnostic instrument for psychiatry, the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV) (2), lists two subtypes of major depression, melancholic and atypical. The features of melancholic depression include insomnia (most often early morning awakening), loss of appetite, weight loss, inappropriate guilt, and lack of pleasure (anhedonia). The second major subtype is major depression with atypical features, characterized in part by hypersomnia, hyperphagia, lethargy, and fatigue. The subclassification of depression provides direction for the appropriate choice of antidepressant medication. Studies in identical twins show a significantly higher concordance for ...

Objective. To examine basal and stimulated hypothalamic-pituitary-adrenal (HPA) axis and related hormone levels, including adrenocorticotropin (ACTH), cortisol, arginine vasopressin (AVP), and neuropeptide Y (NPY), in patients with fibromyalgia (FM).Methods. Basal and ovine corticotropin-releasing hormone (oCRH)-stimulated HPA axis function were assessed in 12 patients with FM and in age-and sexmatched normal subjects. Basal plasma AVP levels and AVP release after postural change were assessed, and plasma NPY levels were measured in the same samples.Results. Patients with FM had low 24-hour urinary free cortisol, but normal peak and elevated trough plasma cortisol levels, compared with normal subjects. The net integrated ACTH response to oCRH in FM was not significantly different from that in normal subjects, but tended toward an exaggerated response. There was a significant decrease in net integrated cortisol response to oCRH in FM patients, indicating adrenal hyporesponsiveness. AVP levels were not significantly different between FM patients and control subjects, but variability was greater among the FM patients. Plasma NPY levels were significantly lower in FM patients than in normal subjects.