Cardiac sympathetic innervation and vesicular storage in pure autonomic failure

Ann Clin Transl Neurol. 2020 Oct;7(10):1908-1918. doi: 10.1002/acn3.51184. Epub 2020 Sep 10.

Abstract

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 11 C-methylreboxetine (11 C-MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using 18 F-dopamine (18 F-DA) to assess intraneuronal vesicular storage in the same subjects.

Methods: Seven comprehensively tested PAF patients and 11 controls underwent 11 C-MRB PET scanning for 45 minutes (dynamic 5X1', 3X5', 1X10', static 15 minutes) and 18 F-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 11 C-MRB-derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of 11 C-MRB, the PAF group had a 41.1% mean decrease in myocardial 11 C-MRB-derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of 18 F-DA-derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p < 0.0001). At all time points after infusion of 18 F-DA and 11 C-MRB mean 18 F/11 C 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Aged
  • Autonomic Nervous System Diseases / diagnostic imaging
  • Autonomic Nervous System Diseases / metabolism*
  • Catecholamines / metabolism*
  • Female
  • Heart / innervation*
  • Humans
  • Hypotension, Orthostatic / diagnosis
  • Male
  • Middle Aged
  • Myocardium / metabolism*
  • Norepinephrine / metabolism
  • Parkinson Disease / diagnostic imaging
  • Pure Autonomic Failure / diagnostic imaging
  • Pure Autonomic Failure / metabolism*
  • Sympathetic Nervous System / metabolism
  • Tomography, X-Ray Computed / methods

Substances

  • Catecholamines
  • Norepinephrine

Grants and funding

This work was funded by Division or Intramural Research, NINDS, NIH grant .