Abstract
Lewy body diseases (LBDs) feature profound myocardial depletion of the sympathetic neurotransmitter norepinephrine. In addition to sympathetic neuronal loss, the norepinephrine deficiency may reflect decreased vesicular sequestration of cytoplasmic catecholamines in dysfunctional but living nerve terminals. To evaluate intraneuronal vesicular storage in patients with LBDs, we retrospectively analyzed multitracer PET data using (18)F-6-fluorodopamine ((18)F-DA, a sympathetic neuroimaging agent) and (11)C-methylreboxetine ((11)C-MRB, a ligand for the cell membrane norepinephrine transporter). If there were a vesicular storage defect, then the decrease in (18)F-DA-derived radioactivity would be greater than the decrease in (11)C-MRB-derived radioactivity. Methods: Twenty-three patients with Parkinson disease or the Lewy body form of pure autonomic failure and 15 controls underwent (18)F-DA dynamic scanning (9 frames; last frame, 10-min duration with midpoint at 25 min) and on a separate day underwent (11)C-MRB PET for 45 min (dynamic for 30 min, then a static 15-min frame with midpoint at 38 min). Results: All patients in the LBD group had interventricular septal (18)F-DA-derived radioactivity below the range of values in the control group (mean decrease, 75%; P < 0.0001). The LBD group also had a mean decrease of 37% in (11)C-MRB-derived radioactivity from the control group in the static frame with midpoint at 38 min (P < 0.0001). At all time points after tracer administration, septal myocardial (18)F-DA/(11)C-MRB ratios were lower in the LBD group (by 68% at 25 min; P < 0.0001). Conclusion: LBDs entail substantially decreased vesicular storage in cardiac sympathetic nerves. This abnormality has direct implications for disease-modifying treatment and prevention strategies, since extant but dysfunctional ("sick-but-not-dead") neurons may be salvageable.