Amyloid-Beta Radiotracer [18F]BF-227 Does Not Bind to Cytoplasmic Glial Inclusions of Postmortem Multiple System Atrophy Brain Tissue.

Mathieu Verdurand,Fabien Chauveau,Armand Perret-Liaudet,Sophie Lancelot,Elise Levigoureux,Luc Zimmer,Isabelle Quadrio,Thierry Billard,Waël Zeinyeh

doi:10.1155/2018/9165458

Abstract

The accumulation of aggregated alpha-synuclein (α-syn) in multiple brain regions is a neuropathological hallmark of synucleinopathies. Multiple system atrophy (MSA) is a synucleinopathy characterized by the predominant cerebral accumulation of aggregated α-syn as cytoplasmic glial inclusions (CGI). A premortem diagnosis tool would improve early diagnosis and help monitoring disease progression and therapeutic efficacy. One Positron Emission Tomography (PET) study suggested [11C]BF-227 as a promising radiotracer for monitoring intracellular α-syn deposition in MSA patients. We sought to confirm the binding of this radiotracer to α-syn using state-of-the-art autoradiography. Medulla sections were obtained from 9 MSA patients and 9 controls (London Neurodegenerative Diseases Brain Bank). [18F]BF-227, chemically identical to [11C]BF-227, was used at nanomolar concentrations to perform in vitro autoradiography assays. Autoradiograms were superimposed on fluorescent staining from the conformational anti-α-syn antibody 5G4 and quantified after immunofluorescence-driven definition of regions of interest. Autoradiography showed no specific signals in MSA patients in comparison to controls despite widespread pathology detected by immunofluorescence. Autoradiography does not support a significant binding of [18F]BF-227 to CGI at concentrations typically achieved in PET experiments.

Highlights

Most neurodegenerative diseases are proteinopathies or protein misfolding diseases that lead to the formation of insoluble protein aggregates in the brain
Proteinopathies with α-synuclein (α-syn) aggregates form a heterogeneous group of diseases called “synucleinopathies.” Alpha-synuclein is deposited as intracellular inclusions (i) inside neurons in Parkinson’s disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB) and (ii) inside oligodendroglial cells in multiple system atrophy (MSA)
All MSA sections presented a high density of α-syn staining, with typical flameshaped morphology

Summary

Introduction

Most neurodegenerative diseases are proteinopathies or protein misfolding diseases that lead to the formation of insoluble protein aggregates in the brain. Proteinopathies with α-synuclein (α-syn) aggregates form a heterogeneous group of diseases called “synucleinopathies.” Alpha-synuclein is deposited as intracellular inclusions (i) inside neurons in Parkinson’s disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB) and (ii) inside oligodendroglial cells in multiple system atrophy (MSA). Subsequent neuropathological lesions are termed Lewy bodies and neurites (LB/LN) and cytoplasmic glial inclusions (CGI), respectively. Alpha-synuclein aggregation is supposed to drive neuronal dysfunction and death and may start long before the first clinical symptoms appear. In vivo imaging of α-syn deposits is a critical need for early and differential diagnosis of synucleinopathies.

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