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 (VT) 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 VT, in the hippocampus (F(1,24) 5.694; P=0.025), but no difference in VT in other ROIs. Hippocampal [11C]PBR28 VT 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 VT, raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP.

Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation

“…However, while a plethora of human and preclinical studies support TSPO as a glial marker, it is important to note that not all studies have detected TSPO upregulation in neuropathologies with a hypothesized inflammatory component. For instance, previous work showed no differences in TSPO PET signal in cocaine dependence (Narendran et al, 2014), and decreased signal in alcohol dependence (Hillmer et al, 2017; Kalk et al, 2017). In patients with psychosis, initial studies with first generation TSPO tracers showed an increase, whereas recent studies using second-generation radioligands are supportive of a decrease in TSPO levels (Plaven-Sigray et al, 2018).…”

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

“…However, the author’s reported [ 11 C]PBR28 binding was unaffected among those subjects [143]. In the third study, Kalk et al[146] imaged 9 alcohol-dependent subjects approximately three weeks since their last drink (ad libitum cigarette smoking prior to scanning) and healthy controls. This [ 11 C]PBR28 study reported significantly lower TSPO availability (partial-volume corrected V T ) by 19% in the hippocampus relative to age-matched healthy controls, with similar trends in the midbrain, thalamus, ACC, and cerebellum.…”

“…This [ 11 C]PBR28 study reported significantly lower TSPO availability (partial-volume corrected V T ) by 19% in the hippocampus relative to age-matched healthy controls, with similar trends in the midbrain, thalamus, ACC, and cerebellum. On average, subjects were imaged 14 days since last benzodiazepine dose, and thus, benzodiazepines were unlikely to alter TSPO availability in this study [146]. …”

“…First, preclinical research indicates acute alcohol exposure increases proinflammatory markers systemically [151, 152] and in the brain [153, 154]. Second, human studies of long-term alcohol consumption observe significantly lower TSPO levels [142, 143, 146], which remain lower than controls 3 weeks since last drink [146]. Third, in vivo gray matter volume is lower among alcohol-dependent subjects versus healthy controls [155].…”

“…However, no TSPO PET studies of cannabis users were identified. In the case of alcohol, the MRS literature is mixed, while 3 independent TSPO PET studies reported alcohol-dependent individuals reliably exhibited suppressed or impaired neuroimmune system relative to controls [142, 143, 146]. Alcohol’s osmotic effects and/or overlapping resonance with myo- inositol may contribute to the discordant MRS and PET findings.…”