Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [ ¹¹C]PBR28 PET study

Abstract

Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [ ¹¹C]PBR28 positron emission tomography (PET), selective for the 18kDa translocator protein (TSPO) highly expressed in activated microglia and astrocytes. We investigated the relationship between microglial activation and cognitive performance. Twenty healthy control (HC) subjects (45±13; M:F 14:6) and nine ADP (45±6, M:F 9:0) were evaluated. Dynamic PET data were acquired for 90 min following an injection of 331±15 MBq [ ¹¹C]PBR28. Regional volumes of distribution ( V _T) for regions of interest (ROIs) identified a priori were estimated using a two-tissue compartmental model with metabolite-corrected arterial plasma input function. ADP had an ~20% lower [ ¹¹C]PBR28 V _T, in the hippocampus (F(1,24) 5.694; P=0.025), but no difference in V _T in other ROIs. Hippocampal [ ¹¹C]PBR28 V _T was positively correlated with verbal memory performance in a combined group of HC and ADP ( r=0.720, P<0.001), an effect seen in HC alone ( r=0.738; P=0.001) but not in ADP. We did not find evidence for increased microglial activation in ADP, as seen pre-clinically. Instead, our findings suggest lower glial density or an altered activation state with lower TSPO expression. The correlation between verbal memory and [ ¹¹C]PBR28 V _T, raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP.