| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 105 === Background: Alcohol dependence (AD) is a complex and heterogeneous mental disorder that is confounded by several factors. Previous studies suggest that the dopamine transporter (DAT) plays a crucial role in the pathogenesis of alcohol dependence (AD) and major depression (MD), inflammatory cytokines play an important role in the development of alcohol-related illness. Memantine is an uncompetitive antagonist for the N-methyl-D-aspartate (NMDA) receptors, many increasing evidences support that NMDA receptor antagonists are effective in the treatment of alcohol dependence. However, imaging studies on brain DAT availability in males with pure AD and AD comorbid with MD (AD/MD) are limited, and the associations of DAT availability with cognitive function and depressive scores in patients with pure AD and AD/MD have not been analyzed. The purpose of the present study examined the relationship of brain DAT availability, cognitive function, and depressive symptoms in different subgroups of males with AD. This study also evaluate cytokine concentrations in patients with AD at different stages and the influence of gender on cytokine levels in healthy controls and evaluate the clinical efficacy of memantine in patients with AD.
Methods: We recruited 26 AD patients and 22 healthy controls in the first experiment, 49 AD patients and 24 healthy controls in secondary experiment, 78 AD patients and 136 healthy controls in the third experiment and 54 AD patients in the fourth experiment. Single-photon emission computed tomography imaging with 99mTc- TRODAT-1 as a ligand was used to measure striatal DAT availability in patients with AD and healthy volunteers. The Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT) and 17-item Hamilton Depression Rating Scale were used to assess neurocognitive function and depressive scores. Tridimensional Personality Questionnaire (TPQ) was administrated to assess personality traits. Inflammatory cytokine expression in all participants was assessed using a multiple magnetic bead assay.
Results: Pure AD patients showed a significant reduction in dopamine transporter availability, as well as diminished performance on the WCST. Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls. Only pure AD patients showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Patients with AD showed a significant reduction of DAT availability in 3 brain regions; this reduction was more pronounced in the patients with pure AD than AD/MD compared to healthy controls. There were significant differences in the concentration of cytokines (except IL-1β) between healthy males and females. In addition, AD patients at the early withdrawal state demonstrated higher cytokine levels than the healthy controls, these cytokine levels decreased in patients during the early remission state. Memantine significantly reduced drinking consumption and frequency in AD patients compared to placebo group.
Conclusions: DAT availability is associated with neurocognitive functions, and incongruent reduction of DAT may play a pathophysiological role in different subgroups of AD. Healthy female may have a higher cellular and humoral response than healthy males due to high concentration of relevant inflammatory cytokines in females. Inflammation and cognitive impairment were observed in AD patients and these conditions can be improved by early abstinence from alcohol. Our data support the efficacy of memantine for the treat of male AD patients. Memantine might be a suitable therapy for AD patients in the future.
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