11C‐PBR28 brain PET imaging with lipopolysaccharide challenge for the study of microglia function in Alzheimer’s disease

Abstract

AbstractBackgroundThe study of neuroimmune function in Alzheimer’s disease (AD) has been challenging, partly because the underlying mechanisms are still incompletely understood. Here we present the results of a novel imaging study in human subjects to assess microglial activity in cognitively normal (CN) participants compared to participants with mild cognitive impairment (MCI) or mild dementia (MD) due to AD.MethodThis pilot study used positron emission tomography (PET) imaging with the radioligand 11C‐PBR28, which is specific for the 18 kDa‐translocator protein (TSPO), a marker sensitive to acute immune effects of lipopolysaccharide (LPS). The 11C‐PBR28 volume of distribution (VT) was measured from two scans, one at baseline and a second at 180 minutes after intravascular administration of lipopolysaccharide (LPS‐ 0.4 ng/Kg). We calculated microglia activation reserve index (MARI) as the proportional increase in binding of 11C‐PBR28, 180 minutes after the administration of the LPS: MARI = [(VT,LPS‐VT,Baseline)/ VT,Baseline] x 100.ResultsCN participants had a significantly higher global cerebral MARI of 35% (SD 13%, n=5) compared to the AD group (MARI=15%, SD 15%, n=5, p=0.030). We found no significant differences between global 11C‐PBR‐28 VT at baseline in CN participants compared to the AD group. MARI values correlated with clinical dementia rating (CDR) ‐ sum of boxes (CDR‐SB) score (R2=0.55, p=0.013), but not with MOCA scores. Conversely baseline 11C‐PBR‐28 VT correlated with MOCA scores (R2=0.44, p=0.025) but not CDR‐SB. TSPO gene polymorphism (high vs. medium affinity binding) did not make a difference in the response pattern. Measurements of serum cytokines indicated that the response differences between the two groups were central and not related to the peripheral immune response.ConclusionOur experiment presents preliminary human data on reduced brain microglial activity in AD.. Our novel method provides a unique opportunity to test the dynamic response of microglia in vivo. However, further investigations with larger sample sizes are required for better understanding of the role of microglia in AD.