[F-18]PBR06 TSPO-PET Reveals Region-specific Neuroinflammation in Multiple System Atrophy and Relates to Clinical Severity and Brain Atrophy
Steven Cicero1, Diego Rodriguez1, Alain Ndayisaba1, Nicolas Horan1, Olivia Laun1, Hong Pan1, Eero Rissanen1, Shipra Dubey1, Geoffrey Young1, Jisoo Kim1, Ashlan Willett1, Ariana Pitaro1, Howard Weiner1, Vikram Khurana1, Tarun Singhal1
1Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
Objective:

To evaluate region-specific microglial activation in Multiple System Atrophy (MSA) using [F-18]PBR06 -PET targeting 18kiloDalton-translocator protein (TSPO) and examine its association with clinical severity, regional atrophy, and survival.

Background:

MSA lacks fully validated in-vivo biomarkers for disease staging or progression monitoring. Microglial activation and neuroinflammation are consistently observed in postmortem cohorts and experimental models of MSA. Second-generation TSPO ligands such as [F-18]PBR06 enable sensitive, regional quantification of neuroinflammation in vivo.

Design/Methods:

Cross-sectional study of 18 MSA (MSA-C=12; MSA-P=6) and 9 controls. TSPO genotyping excluded low-affinity binders. [F-18]PBR06 PET images were co-registered to brain MRI and globally-normalized 60-90 minute standardized-uptake-value ratios (SUVRs) were calculated. Regional analyses used nonparametric-tests and voxel-wise statistical parametrical mapping (SPM) adjusting for age, sex, and TSPO affinity. Disease severity was assessed with the Unified MSA rating scale (UMSARS).

Results:

Compared with controls, MSA showed elevated [F-18]PBR06 uptake in the putamen (+14.1%, p=0.01), pallidum (+12.5%, p=0.006), cerebellar white matter (CWM; +9%, p=0.03), and hippocampus (+8%, p=0.04), all with large effect sizes. After covariate adjustment, differences in the putamen and pallidum remained significant. Voxel-wise SPM confirmed widespread increases across the thalamus, hippocampus, basal ganglia, and midbrain (p<0.05). Putaminal uptake correlated with both UMSARS Part II (R=0.57) and total scores (R=0.56). Regions showing elevated PET signal also exhibited marked atrophy on MRI (putamen −43%; CWM −45%), and CWM PET-uptake inversely correlated with its volume (ρ=−0.61, p=0.04). Receiver-operating-curve analyses demonstrated good discrimination between MSA and controls (AUC: pallidum 0.85; putamen 0.82). Higher putaminal SUVRs showed a trend for predicting shorter survival (HR = 1.85 per 0.1 SUVR, p=0.051)

Conclusions:

[F-18]PBR06 TSPO-PET identifies region-specific neuroinflammation in MSA correlates with clinical severity, regional atrophy, and may have predictive value for disease course, supporting it as a promising biomarker for MSA. Larger, longitudinal studies of [F-18]PBR06-PET in MSA are warranted.

10.1212/WNL.0000000000217287
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