Cardiac sympathetic innervation and vesicular storage in pure autonomic failure

• Published in: Annals of clinical and translational neurology Vol. 7; no. 10; pp. 1908 - 1918
• Main Authors: Goldstein, David S., Isonaka, Risa, Holmes, Courtney, Ding, Yu‐Shin, Sharabi, Yehonatan
• Format: Journal Article
• Language: English
• Published: Bognor Regis John Wiley & Sons, Inc 01-10-2020; John Wiley and Sons Inc; Wiley
• Subjects: Binding sites; Defects; Dopamine; Laboratories; Neurodegeneration; Orthostatic hypotension; Patients; Rare diseases; Scanners
• ISSN: 2328-9503; 2328-9503
• DOI: 10.1002/acn3.51184

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.