Key result
Pure autonomic failure is associated with a substantial vesicular storage defect in residual cardiac sympathetic nerves, evidenced by a 70% postinfusion loss of 18F-DA-derived radioactivity by 30 minutes compared to 14% in controls.
Why the study?
Reports have disagreed about mechanisms of the noradrenergic lesion in pure autonomic failure, with neuropathological studies highlighting denervation while functional studies emphasized deficient vesicular sequestration.
Does combined 11C-MRB and 18F-DA PET imaging reveal decreased cardiac sympathetic innervation and/or a vesicular storage defect in patients with pure autonomic failure compared to controls?
Case-Control (n=18)
Single-blind
No
Does combined 11C-MRB and 18F-DA PET imaging reveal decreased cardiac sympathetic innervation and/or a vesicular storage defect in patients with pure autonomic failure compared to controls?
Absolute Event Rate: 70% vs 14%
p-value: p=<0.0001
Combined 11C-MRB and 18F-DA PET imaging demonstrates that pure autonomic failure involves both moderate cardiac sympathetic denervation and a severe vesicular storage defect in residual nerves.
Should not yet change management of pure autonomic failure; leaves open diagnostic utility of combined PET imaging.
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.
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Goldstein et al. (2020) conducted a case-control in Pure autonomic failure (n=18). Pure autonomic failure vs. Healthy volunteers and hypertensive controls without orthostatic hypotension was evaluated on Postinfusion loss of 18F-DA-derived radioactivity by 30 minutes (p=<0.0001). Pure autonomic failure is associated with a substantial vesicular storage defect in residual cardiac sympathetic nerves, evidenced by a 70% postinfusion loss of 18F-DA-derived radioactivity by 30 minutes compared to 14% in controls.
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