Does sympathetic dysfunction occur before denervation in pure autonomic failure?

Area of Science:

• Neurology
• Neuroscience
• Autonomic Function

Background:

• Pure autonomic failure (PAF) is a rare disorder of autonomic dysfunction without movement disorders or dementia.
• It is characterized by very low plasma norepinephrine (NE) levels, suggesting sympathetic denervation, but its pathology is poorly understood.
• Multiple systems atrophy (MSA) serves as a control, as its sympathetic nerves are considered intact.

Purpose of the Study:

• To correlate clinical and neurochemical findings with sympathetic nerve protein levels in PAF patients.
• To investigate sympathetic nerve protein abundances in PAF, MSA, and healthy controls using forearm vein biopsies.
• To elucidate the underlying pathology of sympathetic dysfunction in Pure autonomic failure.

Main Methods:

• Forearm vein biopsy specimens were obtained from 11 PAF patients, 8 MSA patients, and 9 healthy controls.
• Sympathetic nerve protein abundances, including NE transporter (NET), tyrosine hydroxylase (TH), and vesicular monoamine transporter 2 (VMAT2), were analyzed.
• Clinical evaluation, head-up tilt (HUT) testing, plasma catecholamine measurements, and muscle sympathetic nerve activity (MSNA) were performed.

Main Results:

• PAF patients showed normal NET protein abundance but significantly reduced TH and VMAT2 expression compared to controls and MSA.
• A higher plasma 3,4-dihydroxyphenylglycol (DHPG):NE ratio was observed in PAF participants.
• These findings indicate reduced NE synthesis and a shift towards intraneuronal NE metabolism in PAF.

Conclusions:

• Normal NET abundance in PAF suggests sympathetic nerves are intact but exhibit reduced NE synthesis.
• Elevated DHPG:NE ratio and reduced VMAT2 in PAF point to altered intraneuronal NE metabolism.
• Sympathetic dysfunction in PAF may occur before overt denervation, challenging previous assumptions.