Translational psychiatry
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Translational psychiatry · Jan 2014
Women with the Alzheimer's risk marker ApoE4 lose Aβ-specific CD4⁺ T cells 10-20 years before men.
Adaptive immunity to self-antigens causes autoimmune disorders, such as multiple sclerosis, psoriasis and type 1 diabetes; paradoxically, T- and B-cell responses to amyloid-β (Aβ) reduce Alzheimer's disease (AD)-associated pathology and cognitive impairment in mouse models of the disease. The manipulation of adaptive immunity has been a promising therapeutic approach for the treatment of AD, although vaccine and anti-Aβ antibody approaches have proven difficult in patients, thus far. CD4(+) T cells have a central role in regulating adaptive immune responses to antigens, and Aβ-specific CD4(+) T cells have been shown to reduce AD pathology in mouse models. ⋯ Notably, women who carried the AD risk marker apolipoproteinE-ɛ4 (ApoE4) showed the earliest decline, with a precipitous drop between 45 and 52 years, when menopause typically begins. Aβ-CD4see requires a standard blood draw and provides a minimally invasive approach for assessing changes in Aβ biology that may reveal AD-related changes in physiology by a decade. Furthermore, CD4see probes can be modified to target any peptide, providing a powerful new tool to isolate antigen-specific CD4(+) T cells from human subjects.
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Translational psychiatry · Jan 2014
Comparative StudyCodeine-induced hyperalgesia and allodynia: investigating the role of glial activation.
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. ⋯ This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity-although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.
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Translational psychiatry · Jan 2014
Multicenter StudyQuantitative proteomics of delirium cerebrospinal fluid.
Delirium is a common cause and complication of hospitalization in older people, being associated with higher risk of future dementia and progression of existing dementia. However relatively little data are available on which biochemical pathways are dysregulated in the brain during delirium episodes, whether there are protein expression changes common among delirium subjects and whether there are any changes which correlate with the severity of delirium. We now present the first proteomic analysis of delirium cerebrospinal fluid (CSF), and one of few studies exploring protein expression changes in delirium. ⋯ These data not only provide confirmatory evidence that the inflammatory response is a component of delirium, but also reveal dysregulation of protein expression in a number of novel and unexpected clusters of proteins, in particular the granins. Another surprising outcome of this work is the level of similarity of CSF protein profiles in delirium patients, given the diversity of causes of this syndrome. These data provide additional elements for consideration in the pathophysiology of delirium as well as potential biomarker candidates for delirium diagnosis.
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Translational psychiatry · Jan 2014
Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression.
Mitochondrial dysfunction might have a central role in the pathophysiology of depression. Phenotypically, depression is characterized by lack of energy, concentration problems and fatigue. These symptoms might be partially explained by reduced availability of adenosine triphosphate (ATP) as a consequence of impaired mitochondrial functioning. ⋯ The results suggest that mitochondrial dysfunction contributes to the biomolecular pathophysiology of depressive symptoms. The decreased immune capability observed in MD leading to a higher risk of comorbidities could be attributable to impaired energy supply due to mitochondrial dysfunction. Thus mitochondrial respiration in PBMCs and its functional consequences might be an interesting target for new therapeutical approaches in the treatment of MD and immune-related comorbidities.
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Translational psychiatry · Oct 2013
Fear conditioning, persistence of disruptive behavior and psychopathic traits: an fMRI study.
Children diagnosed with Disruptive Behavior Disorders (DBD), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Deficient fear conditioning may be a key mechanism underlying persistence, and has been associated with altered regional brain function in adult antisocial populations. In this study, we investigated the associations between the neural correlates of fear conditioning, persistence of childhood-onset DBD during adolescence and psychopathic traits. ⋯ In addition, regression analyses revealed that impulsive-irresponsible and grandiose-manipulative psychopathic traits were associated with higher activation, whereas callous-unemotional psychopathic traits were related to lower activation in fear-related areas. Finally, the association between neural activation and DBD subgroup membership was mediated by impulsive-irresponsible psychopathic traits. These results provide evidence for heterogeneity in the neurobiological mechanisms underlying psychopathic traits and antisocial behavior and, as such, underscore the need to develop personalized interventions.