Freeman L, Garcia-Lorenzo D, Bottin L, Leroy C, Louapre C, Bodini B, Papeix C, Assouad R, Granger B, Tourbah A, Dollé F, Lubetzki C, Bottlaender M, Stankoff B. The neuronal component of gray matter damage in multiple sclerosis: A [11C]-flumazenil positron emission tomography study.
Ann Neurol. 2015 Aug. doi: 10.1002/ana.24468
OBJECTIVE:Using positron emission tomography (PET) with [11 C]flumazenil ([11 C]FMZ), an antagonist of the central benzodiazepine site located within the GABA-A receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric.
METHODS:A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [11 C]FMZ PET imaging and brain magnetic resonance imaging. [11 C]FMZ binding was estimated using the partial saturation protocol providing voxel-wise absolute quantification of GABAA receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis.
RESULTS: [11 C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([11 C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [11 C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsing-remitting forms of the disease and correlated with WM T2-weighted lesion load. [11 C]FMZ cortical binding correlated with cognitive performance.
INTERPRETATION: This pilot study showed that PET with [11 C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS
Positron Emission Tomography is a method of imaging radio-active substances. Carbon 12 is the non-radio active variant but carbon 11 is a rapidly degraded radioactive isotope. Here they make a drug called flumazenil with carbon 11 and this will bind to the GABA-A receptor on nerves.
The benzodiazepines had already been in wide use as anxiolytics and anticonvulsants for more than ten years before their site of action in the central nervous system, the benzodiazepine receptor, was discovered. Simultaneously, a binding site in the peripheral organs, e.g. heart, lungs and kidneys, was found. Although some benzodiazepines, such as diazepam, bind to both central and peripheral benzodiazepine receptors with a high affinity, these two binding sites exhibit quite different properties. It is already clear that the central benzodiazepine receptors are in many regions of the brain coupled with the receptors for gamma-amino butyric acid (GABA), and they mediate the acute actions of benzodiazepines in the central nervous system. The peripheral-type receptors are present on microglia and PET ligands against the peripheral benzodiazepine receptor are used for imaging microglia.