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Patterns of Mitochondrial TSPO Binding in Cerebral Small Vessel Disease: An in vivo PET Study With Neuropathological
Paul Wright1, Mattia Veronese1, Ndabezinhle Mazibuko1
1Department of Neuroimaging, Institute of Psychiatry Psychology & Neuroscience, King's College London, London, United Kingdom.
Abstract:
Small vessel disease (SVD) is associated with cognitive impairment in older age and be implicated in vascular dementia. Post-mortem studies show proliferation of activated microglia in the affected white matter. However, the role of inflammation in SVD pathogenesis is incompletely understood and better biomarkers are needed. We hypothesized that expression of the 18 kDa translocator protein (TSPO), a marker of microglial activation, would be higher in SVD. Positron emission tomography (PET) was performed with the second-generation TSPO ligand [11C]PBR28 in 11 participants with SVD. TSPO binding was evaluated by a two-tissue compartment model, with and without a vascular binding component, in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM). In post-mortem tissue, in a separate cohort of individuals with SVD, immunohistochemistry was performed for TSPO and a pan-microglial marker Iba1. Kinetic modeling showed reduced tracer volume and blood volume fraction in WMH compared with NAWM, but a significant increase in vascular binding. Vascular [11C]PBR28 binding was also increased compared with normal-appearing white matter of healthy participants free of SVD. Immunohistochemistry showed a diffuse increase in microglial staining (with Iba1) in sampled tissue in SVD compared with control samples, but with only a subset of microglia staining positively for TSPO. Intense TSPO staining was observed in the vicinity of damaged small blood vessels, which included perivascular macrophages. The results suggest an altered phenotype of activated microglia, with reduced TSPO expression, in the areas of greatest white matter ischemia in SVD, with implications for the interpretation of TSPO PET studies in older individuals or those with vascular risk factors.
Insights
Small vessel disease (SVD) involves inflammation and microglial activation. TSPO PET imaging revealed altered microglial phenotypes and increased vascular binding in SVD white matter, impacting biomarker interpretation.
Area of Science:
- Neuroscience
- Neuropathology
- Medical Imaging
Background:
- Small vessel disease (SVD) is linked to cognitive decline and vascular dementia.
- Activated microglia are observed in SVD white matter, but inflammation's role is unclear.
- Biomarkers for SVD-related inflammation are needed.
Purpose of the Study:
- To investigate the expression of the 18 kDa translocator protein (TSPO), a microglial activation marker, in SVD.
- To assess TSPO binding using [11C]PBR28 positron emission tomography (PET) in SVD patients.
Main Methods:
- PET imaging with [11C]PBR28 in 11 SVD participants.
- Kinetic modeling of TSPO binding in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM).
- Immunohistochemistry for TSPO and Iba1 in post-mortem SVD and control tissues.
Main Results:
- Kinetic modeling showed reduced tracer volume but increased vascular binding in WMH compared to NAWM.
- Vascular [11C]PBR28 binding was elevated in SVD WMH versus controls.
- Immunohistochemistry revealed increased overall microglial presence but reduced TSPO expression on microglia in SVD WMH, with TSPO staining near damaged vessels.
Conclusions:
- Activated microglia in SVD white matter ischemia exhibit an altered phenotype with reduced TSPO expression.
- TSPO PET studies in SVD may be confounded by increased vascular binding and altered microglial TSPO expression.
- Findings have implications for interpreting TSPO PET in older adults and those with vascular risk factors.
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