This pilot study is the first to explore the value of combined olfactory test and TCS in the differential diagnosis of PD in China. Our preliminary data indicated that the combination of hyposmia and SN hyperechogenicity could improve the diagnostic potential for discriminating patients with PD from ET. If either hyposmia or SN hyperechogenicity was present, the sensitivity reached 78.4%, surpassing the corresponding value of each biomarker. Moreover, if both were found abnormal, the specificity was 100%, suggesting that this combination might be a feasible method for more accurate diagnosis of PD.
Our results suggested that hyposmia and SN hyperechogenicity might act as complementary roles for the discriminating of PD from ET. This phenomenon could be explained by several aspects. Firstly, from a pathophysiological perspective, they may be caused by different mechanisms. hyposmia in PD was associated with alpha-synuclein accumulation in central olfactory system, especially the olfactory bulb [12
]. Whereas, SN hyperechogenicity may reflect increased SN iron content in PD, this was demonstrated in animal models and postmortem human brains [14
]. Secondly, a few cross-sectional studies [6
], as well as the present one, indicated that there was no obvious correlation between hyposmia and SN hyperechogenicity in PD. Thirdly, longitudinal follow-up studies suggested these two clinical biomarkers might reflect different prognosis. Baba and colleagues in Japan found that severe hyposmia in PD was a prominent clinical feature predicting the subsequent development of Parkinson’s disease dementia (PDD) [16
]. While SN hyperechogenicity in PD was a stable finding, its area didn’t change during the course of disease [17
]. Since these two items are independent risk factors for PD, both olfactory test and TCS could add supplementary information for the differential diagnosis.
To our knowledge, only a few studies have tried to explore the efficiency of combined two biomarkers for the early and differential diagnosis of PD. An observational study in Japan with small sample size found that the diagnostic sensitivity and specificity of olfactory test was 84.8% and 78.1%, and the corresponding value was 78.8% and 93.8% for TCS. If either one was present, the diagnostic sensitivity increased to 100% for discriminating patients with PD from normal controls [6
]; Walter and co-workers in Germany evaluated the value of combined midbrain sonography, olfactory test and motor function assessment in the differential diagnosis of PD with larger sample size. They reported that, if both hyposmia and SN hyperechogencity were present, the diagnostic specificity and PPV reached to 89% and 95%, respectively [7
]. Based on these studies, as well as the present one, it might be expected that combining olfactory test and TCS of the SN could provide a valuable method for the differential diagnosis of PD.
The present study has limitation because of its small sample size and the diagnosis of PD was clinical, without the evidence of functional neuroimaging [18
]. The frequency of hyposima and SN hyperechogencity of PD in our study was lower than the patients in Western counties and Japan [3
], which partly explains the low sensitivity of the two combined tests. Furthermore, the frequency of olfactory dysfunction in our ET patients was lower than that in German ET subjects [7
]. These discrepancies might be attributable, at least to some extent, to recruited sample size and race diversity [19
]. Selected bias might exist, since we enrolled subjects suitable for both olfactory tests and sufficient temporal bone window on TCS. This pilot study enrolled a relative low proportion of female patients with PD. In Asian subjects, the frequency of insufficient bone window on TCS was found to be higher than that in European counties, especially in elderly women [5
]. Therefore, the true nature of the prevalence of SN hyperechogencity in Chinese patients with PD and this combination in the differential diagnosis of Chinese patients merit further investigation with larger sample size in future. As these two tests are easy to perform, noninvasive, and low-cost, the combination of these two tests is beneficial to further identification of the at-risk individuals who will develop PD, such as non-symptomatic first-degree relatives of PD and idiopathic REM sleep behavior disorders [20