Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer's disease.
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Abstract
The cannabinoid type 2 receptor (CB<sub>2</sub>R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB<sub>2</sub>R is primarily found on microglia. CB<sub>2</sub>R upregulation has been reported in animal models of Alzheimer's disease, with a preferential localization near amyloid beta (Aβ) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB<sub>2</sub>R tracer [<sup>11</sup>C]NE40 in healthy controls (HC) and in patients with Alzheimer's disease (AD) to investigate whether higher CB<sub>2</sub>R availability regionally colocalized to Aβ deposits is present in vivo. Dynamic 90-min [<sup>11</sup>C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [<sup>11</sup>C]PIB scan 40 min after injection. In four HC, a retest scan with [<sup>11</sup>C]NE40 PET was performed within 9 weeks to investigate test-retest characteristics. [<sup>11</sup>C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time-activity curves best; both binding potential (BP<sub>ND</sub>) and distribution volume (V <sub>T</sub>) parameters could be used. Brain uptake was generally low with an average K <sub>1</sub> value of 0.07 ml/min/ml tissue. V <sub>T</sub> and BP<sub>ND</sub> were in the range of 0.7 - 1.8 and 0.6 - 1.6, respectively. Test values in HC were about 30 % for V <sub>T</sub> and BP<sub>ND</sub>. AD patients showed overall significantly lower CB<sub>2</sub>R binding. No relationship was found between regional or global amyloid load and CB<sub>2</sub>R availability. Kinetic modelling of [<sup>11</sup>C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [<sup>11</sup>C]NE40 PET shows lower CB<sub>2</sub>R availability in vivo in AD patients, with no relationship to Aβ plaques. A possible explanation for these findings is that [<sup>11</sup>C]NE40 binds to CB<sub>2</sub>R with lower affinity and/or selectivity than to CB<sub>1</sub>R.
Medical subject headings
- Alzheimer Disease
- Brain
- Models, Neurological
- Plaque, Amyloid
- Quinolines
- Receptor, Cannabinoid, CB2