Decreased urinary excretion of norepinephrine and dopamine in autonomic synucleinopathies

Abstract

Background: Autonomic synucleinopathies feature autonomic failure and intracellular deposition of the protein alpha-synuclein. Three such conditions are the Lewy body diseases (LBDs) Parkinson's disease (PD) and pure autonomic failure (PAF) and the non-LBD synucleinopathy multiple system atrophy (MSA). These diseases all entail catecholaminergic abnormalities in the brain, sympathetically innervated organs, or both; however, little is known about renal catecholaminergic functions in autonomic synucleinopathies. We measured urinary excretion rates of the sympathetic neurotransmitter norepinephrine, the hormone epinephrine, the autocrine-paracrine substance dopamine, the catecholamine precursor 3,4-dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylglycol (DHPG, the main neuronal metabolite of norepinephrine), and 3,4-dihydroxyphenylacetic acid (DOPAC, a major dopamine metabolite), in PD, PAF, and MSA groups and controls.

Methods: Data were reviewed from all research participants who had urine collections (usually 3.5 h) at the National Institutes of Health (NIH) Clinical Center from 1995 to 2024. The control cohort had neither autonomic failure nor a movement disorder.

Results: Norepinephrine excretion rates were decreased compared with controls in PD (p = 0.0001), PAF (p < 0.0001), and MSA (p < 0.0001). Dopamine excretion was also decreased in the three groups (PD: p = 0.0136, PAF: p = 0.0027, MSA: p = 0.0344). DHPG excretion was decreased in PD (p = 0.0004) and PAF (p = 0.0004) but not in MSA. DOPA and epinephrine excretion did not differ among the study groups.

Conclusions: Autonomic synucleinopathies involve decreased urinary excretion rates of norepinephrine and dopamine. Since virtually all of urinary dopamine in humans is derived from circulating DOPA, the low rates of urinary norepinephrine and dopamine excretion may reflect dysfunctions in the renal sympathetic noradrenergic system, the DOPA-dopamine autocrine-paracrine system, or both systems.

Keywords: Autonomic; Dopamine; Kidney; Norepinephrine; Synuclein.

Fig. 1

Individual values for urinary excretion rates of catechols (A-F) and for myocardial ¹⁸F-dopamine- (¹⁸F-DA)-derived radioactivity (G) in a control group (gray) and patient groups with Parkinson disease (PD, red), pure autonomic failure (PAF, green), and multiple system atrophy (MSA, blue). A–G show individual values and means ± standard error of the mean (SEM) for A norepinephrine, B 3,4-dihydroxyphenylglycol (DHPG), C dopamine, D 3,4-dihydroxyphenylacetic acid (DOPAC), E epinephrine (EPI), F 3,4-dihydroxyphenylalanine (DOPA), and G interventricular septal ¹⁸F-DA-derived radioactivity. Numbers in italics are p values for comparisons versus control on the basis of Dunnett’s post hoc test. PD, PAF, and MSA entailed decreased urinary norepinephrine and dopamine excretion with normal DOPA and EPI excretion. The PD and PAF groups also had decreased urinary DHPG excretion, whereas the MSA group did not, and the PD group had decreased urinary DOPAC excretion, whereas the MSA and PAF groups did not. ¹⁸F-DA-derived radioactivity highly efficiently separated the PD and PAF groups from the MSA and control groups

Fig. 2

Correlations among urinary excretion rates of catechols across groups of patients with autonomic synucleinopathies and control subjects. Linear regression lines of best fit (solid lines) with 95% confidence intervals (dashed lines), correlation coefficients (r), and p values for A 3,4-dihydroxyphenylglycol (DHPG) versus norepinephrine, B 3,4-dihydroxyphenylacetic acid (DOPAC) versus dopamine, C dopamine versus DOPA, D DOPAC versus norepinephrine, and E norepinephrine versus cardiac ¹⁸F-dopamine-derived radioactivity. Urinary excretion rates of catechols were strongly positively correlated. Norepinephrine excretion was weakly positively correlated with ¹⁸F-dopamine-derived radioactivity

Fig. 3

Individual values for urinary norepinephrine (NE) excretion and interventricular septal myocardial ¹⁸F-dopamine-derived radioactivity in patients with Parkinson’s disease (PD, red), pure autonomic failure (PAF, green), or multiple system atrophy (MSA, blue) and in control subjects (gray). Rectangles placed manually to highlight low urinary NE excretion with low myocardial ¹⁸F-dopamine-derived radioactivity in PD and PAF (pink) and low urinary NE excretion with normal myocardial radioactivity in MSA (blue).

Fig. 4

Concept diagram depicting sources of catechols in urine. Urinary norepinephrine (NE) excretion is derived from post-ganglionic nerves of the sympathetic noradrenergic system (SNS), glomerular filtration of circulating norepinephrine (NE), and dopamine (DA) via the enzyme dopamine-beta-hydroxylase (DBH). Urinary DA excretion is derived from proximal tubular cell uptake of circulating DOPA (DOPA) or from DOPA in the glomerular filtrate via neutral amino acid transporters (NAAT) followed by enzymatic decarboxylation via L-aromatic-amino-acid decarboxylase (LAAAD). DOPA is influenced by dietary factors, release from SNS nerves, and tyrosine hydroxylase expressed in splanchnic organs. Cytoplasmic DA is converted to the acid 3,4-dihydroxyphenylacetic acid (DOPAC) via monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH), and NE is converted to the glycol 3,4-dihydroxyphenylglycol (DHPG) via MAO and aldehyde/aldose reductase (AR). In general, urinary catechol excretion reflects a convergence of the SNS and the DOPA-DA autocrine-paracrine system. Not shown are urinary DOPAC and epinephrine derived from the circulation. The autonomic synucleinopathies Parkinson’s disease (PD, red arrows), pure autonomic failure (PAF, green arrows), and multiple system atrophy (MSA, blue arrows) were associated with decreased urinary excretion of NE and DA. PD and PAF were also associated with decreased urinary excretion of DHPG, but MSA was not