The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer's disease: A post-mortem autoradiographic study

Abstract

Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimer's disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[(18)F]FMeNER-D(2). (S,S)-[(18)F]FMeNER-D(2) appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[(18)F]FMeNER-D(2) in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[(18)F]FMeNER-D(2) as a molecular imaging biomarker in AD.

Noradrenergic dysfunction in Alzheimer's disease

“…One finding has been that norepinephrine transporter sites are decreased in AD patients. In autoradiograph studies (Gulyas et al, 2010) and radioligand binding studies of post-mortem tissues (Tejani-Butt et al, 1993), the norepinephrine transporter sites were significantly reduced in AD brains compared to normal control samples. As norepinephrine transporter is responsible for norepinephrine reuptake to the presynaptic neurons, a decrease in norepinephrine transporter sites would increase the amount of norepinephrine in the synapse.…”

PET Quantification of the Norepinephrine Transporter in Human Brain with (S,S)-18F-FMeNER-D2

“…In the current study, we used the entire data from the 3 dynamic scans as a gold standard to validate the NET density estimations in deep brain regions from the 90-min scan data. We also validated the regional BP ND values estimated with 90-min scans by comparing their rank order with that of a postmortem study (16). NET density estimations for the superficial cerebral cortex from the entire 240-min scan data may not be reliable because of defluorination effects.…”

Nuclear Medicine Methods in Dementia

“…(S,S)-[F-18]FMeNER-D NET selektif yeni bir PET ligandıdır. AH' lı hastaların postmortem otoradyolojik incelemesinde locus coeruleus ve talamusda sağlıklı bireylerle kıyaslandığında NET yoğunluğunda anlamlı azalma gösterilmiştir (38). HistaminerjikReseptörGörüntüleme…”