Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases

Abstract

Background: Pure autonomic failure (PAF) and Parkinson disease (PD) both are Lewy body diseases, and both entail substantia nigra dopaminergic, locus ceruleus noradrenergic, and cardiac sympathetic denervation. Multiple system atrophy (MSA) is a non-Lewy body disease in which alpha-synuclein accumulates in glial cells, with central catecholamine deficiency but preserved cardiac sympathetic innervation in most patients. PD is associated with more severe and consistent olfactory dysfunction than in MSA; whether PAF entails olfactory dysfunction has been unknown. In this study we assessed olfactory function in PAF in comparison with the two other synucleinopathies and whether olfactory dysfunction correlates with neuroimaging evidence of cardiac noradrenergic or nigrostriatal dopaminergic denervation.

Method: The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 8 patients with PAF, 23 with PD, and 20 with MSA. 6-[(18)F]Fluorodopamine positron emission tomographic (PET) scanning was used to indicate cardiac noradrenergic innervation and the putamen:occipital cortex (PUT:OCC) and substantia nigra (SN):OCC ratios of 6-[(18)F]fluorodopa-derived radioactivity to indicate nigrostriatal dopaminergic innervation.

Results: The PAF group had a low mean UPSIT score (22+/-3), similar to that in PD (20+/-2) and lower than in MSA (31+/-2, p=0.004). Individual UPSIT scores correlated positively with cardiac 6-[(18)F]fluorodopamine-derived radioactivity (r=0.63 in the septum, p<0.0001; r=0.64 in the free wall, p<0.0001) but not with PUT:OCC or SN:OCC ratios of 6-[(18)F]fluorodopa-derived radioactivity.

Discussion: In synucleinopathies, olfactory dysfunction is related to Lewy body pathology and cardiac sympathetic denervation, independently of parkinsonism or striatal dopamine deficiency.

Fig. 1

(A) University of Pennsylvania Smell Identification Test (UPSIT) scores in patients with pure autonomic failure (PAF, black), Parkinson disease (PD, white), or multiple system atrophy (MSA, gray). Horizontal bars show group mean values and boxes ± SEM. (B) Percents of patients in UPSIT olfactory categories. Note decreased UPSIT scores in PAF and PD compared to MSA, with the majority of PAF or PD patients having anosmia or severe microsmia and the majority of MSA patients having normal olfaction or mild microsmia.

Fig. 2

University of Pennsylvania Smell Identification Test (UPSIT) scores, expressed as a function of (A) cardiac septal 6-[¹⁸F]fluorodopamine-derived radioactivity and (B) the putamen:occipital cortex (PUT:OCC) ratio of 6-[¹⁸F]fluorodopa-derived radioactivity in patients with pure autonomic failure (PAF, black), Parkinson disease (PD, white), or multiple system atrophy (MSA, gray). Dashed line shows the line of best fit, with the linear regression equation displayed. Note positive correlation of UPSIT scores with cardiac septal 6-[¹⁸F]fluorodopamine-derived radioactivity but not with the PUT:OCC ratio.