RT Journal Article
SR Electronic
T1 Novel Reference Region Model Reveals Increased Microglial and Reduced Vascular Binding of <sup>11</sup>C-(<em>R</em>)-PK11195 in Patients with Alzheimer's Disease
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1249
OP 1256
DO 10.2967/jnumed.108.050583
VO 49
IS 8
A1 Giampaolo Tomasi
A1 Paul Edison
A1 Alessandra Bertoldo
A1 Federico Roncaroli
A1 Poonam Singh
A1 Alexander Gerhard
A1 Claudio Cobelli
A1 David J. Brooks
A1 Federico E. Turkheimer
YR 2008
UL http://jnm.snmjournals.org/content/49/8/1249.abstract
AB 11C-(R)-PK11195 is a PET radiotracer for the quantification of peripheral benzodiazepine binding sites (PBBSs). The PBBS is a consistent marker of activated microglia, and 11C-(R)-PK11195 has been used to image microglial activity in the diseased brain and in neoplasia. However, the PBBS is also expressed in the brain vasculature (endothelium and smooth muscles), and no evidence, to our knowledge, exists of a change in the vascular PBBS in pathologic brains or of such a change having an effect on the quantification of 11C-(R)-PK11195 binding. To investigate this issue, we have used a modified reference-tissue model (SRTMV) that accounts for tracer vascular activity both in reference and target tissues and applied it for the estimation of binding potential (BP) in a cohort of patients with Alzheimer's disease (AD). Methods: A total of 10 patients with AD and 10 age-matched healthy subjects who underwent a 11C-(R)-PK11195 scan were considered in the analysis. The time–activity curves of 11 regions of interest were extracted using the Hammersmith maximum probability atlas. BPs were first estimated using the standard simplified reference-tissue model (SRTM) with the reference tissue computed with a supervised selection algorithm. Subsequently, we applied an SRTMV that models PBBS vascular activity using an additional linear term for both target (VbT) and reference (VbR) regions accounting for vascular tracer activity (CB), whereas CB was extracted directly from the images. VbR was fixed to 5%, and R1, k2, BP, and VbT were estimated. PBBS density in the vasculature was also assessed by immunocytochemistry on a separate cohort of young and elderly controls and 3 AD postmortem brains. Results: The inclusion of a vascular component in the SRTM increased BPs in all subjects, but the amount of the increase was different (about 11.9% in controls and 16.8% in patients with AD). In addition, average VbT values derived using the SRTMV were 4.22% for controls but only 2.87% in patients with AD. Immunochemistry showed reduced PBBS expression in AD due to vascular fibrosis. Conclusion: The reduction of VbT in AD can be interpreted as a consequence of 2 independent but concurring phenomena. The vascular fibrosis in the AD brain causes the well-documented decrease of the size of lumens and the reduction of blood volume. At the same time, the fibrotic process determines the loss of vascular PBBS, particularly in smooth muscles, as here documented by immunochemistry. The inclusion of the additional vascular component in the SRTM effectively models these 2 concurrent processes and amplifies the BP in AD more than in controls because of the decrease in tracer binding to the vasculature in the disease cohort.