Probing Estrogen Sulfotransferase-Mediated Inflammation with [¹¹C]-PiB in the Living Human Brain

Article type: Research Article

Authors: Surmak, Andrew J.^a | Wong, Koon-Pong^a | Cole, Graham B.^a | Hirata, Kenji^{a; b} | Aabedi, Alexander A.^a | Mirfendereski, Omid^a | Mirfendereski, Payam^a | Yu, Amy S.^{a; c} | Huang, Sung-Cheng^a | Ringman, John M.^{a; d} | Liebeskind, David S.^{e; *} | Barrio, Jorge R.^{a; *}

Affiliations: [a] University of California, Los Angeles, David Geffen School of Medicine, Department of Molecular and Medical Pharmacology, Los Angeles, CA, USA | [b] Department of Nuclear Medicine, Hokkaido University, Sapporo, Japan | [c] Department of Radiation Oncology, Stanford University, Stanford, CA, USA | [d] University of Southern California, Department of Neurology, Los Angeles, CA, USA | [e] Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: David S. Liebeskind, MD, Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. E-mail: [email protected] and Jorge R. Barrio, PhD, Department of Molecular and Medical Pharmacology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. E-mail: [email protected].

Abstract: Background:2-(4’- [11C]Methylaminophenyl)-6-hydroxybenzothiazole ([11C]-PiB), purportedly a specific imaging agent for cerebral amyloid-β plaques, is a specific, high affinity substrate for estrogen sulfotransferase (SULT1E1), an enzyme that regulates estrogen homeostasis. Objective:In this work, we use positron emission tomography (PET) imaging with [11C]-PiB to assess the functional activity of SULT1E1 in the brain of moyamoya disease patients. Methods:Ten moyamoya subjects and five control patients were evaluated with [11C]-PiB PET and structural MRI scans. Additionally, a patient with relapsing-remitting multiple sclerosis (RRMS) received [11C]-PiB PET scans before and after steroidal and immunomodulatory therapy. Parametric PET images were established to assess SULT1E1 distribution in the inflamed brain tissue. Results:Increased [11C]-PiB SRTM DVR in the thalamus, pons, corona radiata, and internal capsule of moyamoya cohort subjects was observed in comparison with controls (p ≤ 0.01). This was observed in patients without treatment, with collateralization, and also after radiation. The post-treatment [11C]-PiB PET scan in one RRMS patient also revealed substantially reduced subcortical brain inflammation. In validation studies, [11C]-PiB autoradiography signal in the peri-infarct area of the rat middle cerebral arterial occlusion stroke model was shown to correlate with SULT1E1 immunohistochemistry. Conclusion:Strong [11C]-PiB PET signal associated with intracranial inflammation in the moyamoya syndrome cohort and a single RRMS patient appears consistent with functional imaging of SULT1E1 activity in the human brain. This preliminary work offers substantial and direct evidence that significant [11C]-PiB PET focal signals can be obtained from the living human brain with intracranial inflammation, signals not attributable to amyloid-β plaques.

Keywords: Inflammation, moyamoya, PET, PIB, sulfotransferase

DOI: 10.3233/JAD-190559

Journal: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1023-1033, 2020