We demonstrate the significance of peripheral benzodiazepine receptor (PBR) imaging in living mouse models of Alzheimer's disease (AD) as biomarkers and functional signatures of glial activation. By radiochemically and immunohistochemically analyzing murine models of the two pathological hallmarks of AD, we found that AD-like A␤ deposition is concurrent with astrocyte-dominant PBR expression, in striking contrast with nonastroglial PBR upregulation in accumulations of AD-like phosphorylated tau. Because tauinduced massive neuronal loss was distinct from the marginal neurodegeneration associated with A␤ plaques in these models, cellular localization of PBR reflected deleterious and beneficial glial reactions to tau versus A␤ pathologies, respectively. This notion was subsequently examined in models of various non-AD neuropathologies, revealing the following reactive glial dynamics underlying differential PBR upregulation: (1) PBR(Ϫ) astrogliosis uncoupled with microgliosis or coupled with PBR(ϩ) microgliosis associated with irreversible neuronal insults; and (2) PBR(ϩ) astrogliosis coupled with PBR(Ϫ or Ϯ) microgliosis associated with minimal or reversible neuronal toxicity. Intracranial transplantation of microglia also indicated that nontoxic microglia drives astroglial PBR expression. Moreover, levels of glial cell line-derived neurotrophic factor (GDNF) in astrocytes were correlated with astroglial PBR, except for increased GDNF in PBR(-) astrocytes in the model of AD-like tau pathology, thereby suggesting that PBR upregulation in astrocytes is an indicator of neurotrophic support. Together, PBR expressions in astrocytes and microglia reflect beneficial and deleterious glial reactions, respectively, in diverse neurodegenerative disorders including AD, pointing to new applications of PBR imaging for monitoring the impact of gliosis on the pathogenesis and treatment of AD.

Peripheral benzodiazepine receptor (PBR) is expressed in most organs and its expression is reported to be increased in activated microglia in the brain. [(11)C]PK11195 has been widely used for the in vivo imaging of PBRs, but its signal in the brain was not high enough for stable quantitative analysis. We synthesized a novel positron emission tomography (PET) ligand, [(11)C]DAA1106, for PBR and investigated its in vivo properties in rat and monkey brain. High uptake of [(11)C]DAA1106 was observed in the olfactory bulb and choroid plexus area, followed by the pons/medulla and cerebellum by in vivo autoradiography of rat brain, correlating with the binding in vitro. [(11)C]DAA1106 binding was increased in the dorsal hippocampus with neural destruction, suggesting glial reaction. [(11)C]DAA1106 binding was both inhibited and displaced by 1.0 mg/kg of DAA1106 and 5 mg/kg of PK11195 by 80% and 70%, respectively. Specific binding was estimated as 80% of total binding. [(11)C]DAA1106 binding was four times higher compared to the binding of [(11)C]PK11195 in the monkey occipital cortex. These results indicated that [(11)C]DAA1106 might be a good ligand for in vivo imaging of PBR.

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Recent investigations have indicated the importance of secondary brain damage in the pathophysiology of intracerebral hemorrhage (ICH), which includes ischemic brain damage and edema formation around a hematoma. The purpose of the current study is to investigate chronological changes of perihematomal edema in patients with human ICH and also the correlation between volume of perihematomal edema and neurological status. Fourteen patients with medium-sized putaminal hemorrhage (29.4 ± 13.2 ml) without hematoma enlargement were included in this study. To investigate chronological changes of perihematomal edema, we performed CT scans prospectively on the day of hemorrhage and repeated them on days I, 3, 7, 14, and 28. We evaluated the patients neurologically using the NIH stroke scale on the day a CT scan was performed. The volume of perihematomal edema in human ICH increased rapidly three days after hemorrhage and the score on the NIH stroke scale showed a deterioration. The volume of perihematomal edema then increased slowly until day 14 after hemorrhage, and decreased thereafter. Despite progression of perihematomal edema , the score on the NIH stroke scale improved gradually after day 3.