(11)C-PBR28 imaging in multiple sclerosis patients and healthy controls: test-retest reproducibility and focal visualization of active white matter areas.

Abstract

Activated microglia play a key role in inflammatory demyelinating injury in multiple sclerosis (MS). Microglial activation can be measured in vivo using a positron emission tomography (PET) ligand (11)C-PBR28. We evaluated the test-retest variability (TRV) and lesion detectability of (11)C-PBR28 binding in MS subjects and healthy controls (HCs) with high-resolution PET. Four clinically and radiologically stable relapsing-remitting MS subjects (age 41 ± 7years, two men/two women) and four HCs (age 42 ± 8years, 2two men/two women), matched for translocator protein genotype [two high- and two medium-affinity binders according to DNA polymorphism (rs6971) in each group], were studied for TRV. Another MS subject (age 41years, male) with clinical and radiological activity was studied for lesion detectability. Dynamic data were acquired over 120min after injection of 634 ± 101MBq (11)C-PBR28. For the TRV study, subjects were scanned twice, on average 1.4weeks apart. Volume of distribution (V T) derived from multilinear analysis (MA1) modeling (t* = 30min, using arterial input data) was the main outcome measure. Mean test V T values (mlcm(-3)) were 3.9 ± 1.4 in the whole brain gray matter (GM), 3.6 ± 1.2 in the whole brain white matter (WM) or normal-appearing white matter (NAWM), and 3.3 ± 0.6 in MS WM lesions; mean retest V T values were 3.7 ± 1.0 in GM, 3.3 ± 0.9 in WM/NAWM, and 3.3 ± 0.7 in MS lesions. Test-retest results showed a mean absolute TRV ranging from 7 to 9% across GM, WM/NAWM, and MS lesions. High-affinity binders demonstrated 30% higher V T than medium-affinity binders in GM. Focal (11)C-PBR28 uptake was detected in two enhancing lesions of the active MS patient. High-resolution (11)C-PBR28 PET can visualize focal areas where microglial activation is known to be present and has good test-retest reproducibility in the human brain. (11)C-PBR28 PET is likely to be valuable for monitoring both MS disease evolution and response to therapeutic strategies that target microglial activation.