Cardiac sympathetic innervation and vesicular storage in pure autonomic failure

Objective: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine. Reports have disagreed about mechanisms of the noradrenergic lesion. Neuropathological studies have highlighted denervation, while functional studies have emphasized deficient vesicular sequestration of cytoplasmic catecholamines in extant neurons. We examined both aspects by a combined positron emission tomographic (PET) neuroimaging approach using ¹¹C-methylreboxetine (¹¹C-MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using ¹⁸F-dopamine (¹⁸F-DA) to assess intraneuronal vesicular storage in the same subjects. Methods: Seven comprehensively tested PAF patients and 11 controls underwent ¹¹C-MRB PET scanning for 45 minutes (dynamic 5X1’, 3X5’, 1X10’, static 15 minutes) and ¹⁸F-DA scanning for 30 minutes (same dynamic imaging sequence) after 3-minute infusions of the tracers on separate days. Results: In the PAF group septal ¹¹C-MRB-derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of ¹¹C-MRB, the PAF group had a 41.1% mean decrease in myocardial ¹¹C-MRB-derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of ¹⁸F-DA-derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p < 0.0001). At all time points after infusion of ¹⁸F-DA and ¹¹C-MRB mean ¹⁸F/¹¹C ratios in septal myocardium were lower in the PAF than control group. Interpretation: PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves.