Journal
HUMAN MOLECULAR GENETICS
Volume 27, Issue 16, Pages 2893-2912Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy202
Keywords
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Funding
- National Institutes of Health [R21 NS081089-01]
- National Institute of Mental Health [PBR06]
- Taube Philanthropies
- Koret Foundation [12-0160]
- Wilma Marvelle Jones Huntington Disease Research Fund and Jean Perkins Foundation
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Huntington's disease (HD) is an inherited neurodegenerative disorder that has no cure. HD therapeutic development would benefit from a non-invasive translatable biomarker to track disease progression and treatment response. A potential biomarker is using positron emission tomography (PET) imaging with a translocator protein 18 kDa (TSPO) radiotracer to detect microglial activation, a key contributor to HD pathogenesis. The ability of TSPO PET to identify microglial activation in HD mouse models, essential for a translatable biomarker, or therapeutic efficacy in HD patients or mice is unknown. Thus, this study assessed the feasibility of utilizing PET imaging with the TSPO tracer, [F-18]PBR06, to detect activated microglia in two HD mouse models and to monitor response to treatment with LM11A-31, a p75(NTR) ligand known to reduce neuroinflammation in HD mice. [F-18]PBR06-PET detected microglial activation in striatum, cortex and hippocampus of vehicle-treated R6/2 mice at a late disease stage and, notably, also in early and mid-stage symptomatic BACHD mice. After oral administration of LM11A-31 to R6/2 and BACHD mice, [F-18]PBR06-PET discerned the reductive effects of LM11A-31 on neuroinflammation in both HD mouse models. [F-18]PBR06-PET signal had a spatial distribution similar to ex vivo brain autoradiography and conelated with microglial activation markers: increased IBA-1 and TSPO immunostaining/blotting and striatal levels of cytokines IL-6 and TNFpc. These results suggest that [F-18]PBR06-PET is a useful surrogate marker of therapeutic efficacy in HD mice with high potential as a translatable biomarker for preclinical and clinical HD trials.
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