RESUMEN

Human African trypanosomiasis or sleeping sickness is a severe, neglected tropical disease caused by the extracellular parasite Trypanosoma brucei. The disease, which leads to chronic neuroinflammation, is characterized by sleep and wake disturbances, documented also in rodent models. In rats and mice infected with Trypanosoma brucei brucei, we here tested the hypothesis that the disease could target neurons of the lateral hypothalamus (LH) containing orexin (OX)-A or melanin-concentrating hormone (MCH), implicated in sleep/wake regulation. In the cerebrospinal fluid of infected rats, the OX-A level was significantly decreased early after parasite neuroinvasion, and returned to the control level at an advanced disease stage. The number of immunohistochemically characterized OX-A and MCH neurons decreased significantly in infected rats during disease progression and in infected mice at an advanced disease stage. A marked reduction of the complexity of dendritic arborizations of OX-A neurons was documented in infected mice. The evaluation of NeuN-immunoreactive neurons did not reveal significant neuronal loss in the LH of infected mice, thus suggesting a potential selective vulnerability of OX-A and MCH neurons. Immunophenotyping and quantitative analysis showed in infected mice marked activation of microglial cells surrounding OX-A neurons. Day/night oscillation of c-Fos baseline expression was used as marker of OX-A neuron activity in mice. In control animals Fos was expressed in a higher proportion of OX-A neurons in the night (activity) phase than in the day (rest) phase. Interestingly, in infected mice the diurnal spontaneous Fos oscillation was reversed, with a proportion of OX-A/Fos neurons significantly higher at daytime than at nighttime. Altogether the findings reveal a progressive decrease of OX-A and MCH neurons and dysregulation of OX-A neuron diurnal activity in rodent models of sleeping sickness. The data point to the involvement of these peptidergic neurons in the pathogenesis of sleep/wake alterations in the disease and to their vulnerability to inflammatory signaling.

Asunto(s)

Hormonas Hipotalámicas/metabolismo , Melaninas/metabolismo , Neuronas/fisiología , Orexinas/metabolismo , Hormonas Hipofisarias/metabolismo , Trypanosoma brucei brucei , Tripanosomiasis Africana/fisiopatología , Animales , Recuento de Células , Ritmo Circadiano/fisiología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inmunohistoquímica , Masculino , Ratones Endogámicos C57BL , Microglía/parasitología , Microglía/patología , Microglía/fisiología , Neuronas/parasitología , Neuronas/patología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Sprague-Dawley , Tripanosomiasis Africana/patología

RESUMEN

In chronic diseases such as Alzheimer's disease (AD), the arsenal of biomarkers available to determine the effectiveness of symptomatic treatment is very limited. Interpretation of the results provided in literature is cumbersome and it becomes difficult to predict their standardization to a larger patient population. Indeed, cognitive assessment alone does not appear to have sufficient predictive value of drug efficacy in early clinical development of AD treatment. In recent years, research has contributed to the emergence of new tools to assess brain activity relying on innovative technologies of imaging and electrophysiology. However, the relevance of the use of these newer markers in treatment response assessment is waiting for validation. This review shows how the early clinical assessment of symptomatic drugs could benefit from the inclusion of suitable pharmacodynamic markers. This review also emphasizes the importance of re-evaluating a step-by-step strategy in drug development.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Biomarcadores Farmacológicos , Humanos , Resultado del Tratamiento

RESUMEN

Personal problem solving has emerged as an important construct in the cognitive-behavioral literature, yet there is a lack of clinically useful, performance-based measures practitioners can use to assess the personal problem-solving skills of their clients. Two studies evaluated the validity and reliability of a scoring system for measuring personal problem-solving processes via the Thematic Apperception Test (TAT; Morgan & Murray, 1935). In Experiment 1, undergraduate students (N = 87) completed two measures of personal problem solving, as well as three TAT cards, which were scored using the Personal Problem-Solving System (PPSS; Renan, 1990). In Experiment 2, an additional group of undergraduates (N = 56) responded to three TAT cards on two separate occasions and also completed a different measure of personal problem solving. Results from both studies supported the use of the PPSS for scoring TAT responses to assess personal problem-solving processes. Suggestions for future research are highlighted.