Association of anosmia with autonomic failure in Parkinson disease

Abstract

Background: Olfactory dysfunction and autonomic failure are gaining recognition as nonmotor manifestations of Parkinson disease (PD). This observational study assessed whether in PD anosmia and autonomic failure are related to each other or to neuroimaging evidence of striatal dopamine deficiency.

Methods: Olfactory function was assessed by the University of Pennsylvania Smell Identification Test (UPSIT) in 23 patients with sporadic PD. Baroreflex-cardiovagal gain was quantified from the relationship between cardiac interbeat interval and systolic pressure during the Valsalva maneuver and baroreflex-sympathoneural function by responses of systolic pressure to the Valsalva maneuver and of hemodynamics and plasma norepinephrine (NE) and dihydroxyphenylglycol (DHPG) levels to orthostasis. 6-[(18)F]Fluorodopamine PET and plasma and skeletal muscle microdialysate NE and DHPG were used to indicate cardiac and extracardiac noradrenergic innervation and brain 6-[(18)F]fluorodopa PET to indicate striatal dopaminergic innervation. Parkinsonism was assessed by UPDRS scores.

Results: Compared to patients with PD and normal to moderately decreased sense of smell, patients with anosmic PD had lower mean baroreflex-cardiovagal gain (p = 0.04), larger falls in systolic pressure during the Valsalva maneuver and orthostasis (p = 0.04, p = 0.02), smaller orthostatic increments in plasma NE and DHPG (p = 0.003, p = 0.03), lower cardiac septal:hepatic and renal cortical:hepatic ratios of 6-[(18)F]fluorodopamine-derived radioactivity (p = 0.01, p = 0.06), and lower microdialysate NE and DHPG (p = 0.01; p = 0.006). Neither clinical severity of parkinsonism nor the putamen:occipital cortex ratio of 6-[(18)F]fluorodopa-derived radioactivity was related to the UPSIT category.

Conclusions: In Parkinson disease, anosmia is associated with baroreflex failure and cardiac and organ-selective extracardiac noradrenergic denervation, independently of parkinsonism or striatal dopaminergic denervation.

Figure 1 Measures of baroreflex function vs olfactory category (A) Mean (±SEM) data for baroreflex-cardiovagal gain, calculated from the slope of the relationship between cardiac interbeat interval and systolic blood pressure during the decline of pressure in phase II of the Valsalva maneuver. (B–F) Data for measures of baroreflex-sympathoneural function. *Significant difference between anosmia and normal–moderately decreased sense of smell, p < 0.05; **p < 0.01; ***p < 0.001. ΔSBPs = change in systolic blood pressure; Fx ΔTPR = fractional change in total peripheral resistance; Fx ΔNE = fractional change in plasma norepinephrine level; Fx ΔDHPG = fractional change in plasma dihydroxyphenylglycol level; moderate = moderate microsmia. Note that by all 6 measures, anosmic patients had evidence for decreased baroreflex function compared to patients with normal–moderately decreased sense of smell.

Figure 2 Measures of sympathetic noradrenergic innervation vs olfactory category (A–D) Results for organ ratios of 6-[¹⁸F]fluorodopamine-derived radioactivity. (E, F) Results from skeletal muscle microdialysate concentrations of norepinephrine (NE) and dihydroxyphenylglycol (DHPG). *Significant difference between anosmia and normal–moderately decreased sense of smell, p < 0.05; **p < 0.01. Microdialysis = skeletal muscle microdialysate. Note that by all 6 measures, anosmic patients had evidence for decreased sympathetic noradrenergic innervation compared to patients with normal–moderately decreased sense of smell.