Hyposmia is one of the most important non-motor symptoms of Parkinson’s disease (PD) with a prevalence ranging from 50 to 96% of PD patients (Doty et al., 1988; Wenning et al., 1995; Hawkes et al., 1997; Boesveldt et al., 2008; Duda, 2010). It generally predates motor symptoms and the olfactory testing is useful in differentiating PD from non-PD patients with a sensitivity ranging from 79 to 100% and a specificity from 80 to 89% (Doty, 2012). Therefore, hyposmia is reported to be a critical clinical marker of PD.

In recent years olfactory dysfunction is found to be associated with other non-motor symptoms in PD patients such as chronic constipation, clinical possible rapid eye movement behavior disorder (RBD) (Chen et al., 2015) and psychotic symptoms (Morley et al., 2011). Notably, increasing evidence suggests that hyposmia is strongly associated with cognitive impairment in PD patients and may be a risk factor for PD dementia (Bohnen et al., 2010; Stephenson et al., 2010; Morley et al., 2011; Parrao et al., 2012; Domellof et al., 2017). In fact, the association between olfaction and cognition has been long reported in mild cognitive impairment and Alzheimer’s disease which was evidenced by prominent atrophy in the primary olfactory cortex and hippocampus (Vasavada et al., 2015) as well as a strong correlation between tau pathology in the olfactory bulb and limbic systems (Attems et al., 2005). However, the role of hyposmia in cognitive impairment in PD patients is not clear.

Event-related potentials (ERP) have been widely used for assessing cognitive functions and brain ability. ERP wave latency and amplitude represent respectively the length of time spent and the amount of neural resources participating during information processing. There were increasing studies of ERP in PD patients owning to its independence of motor speed and disability. The abnormal P300 was reported to be associated with cognitive impairment in PD (Katsarou et al., 2004; Matsui et al., 2007) while other ERP measures were barely studied in PD. It remained unclear whether the ERP components were altered in PD with hyposmia, especially the early ERP components reflecting visuospatial processing which was one of the mostly impaired cognitive domains in PD.

The delayed match to sample (DMS) task, one of the most popular tasks during ERP records in PD patients (Seer et al., 2016), was used in our study to test working memory which related to several cognitive abilities including storage capacity, retrieval strategies (Unsworth and Engle, 2007) and visuospatial attention (Bleckley et al., 2003; Giuliano et al., 2014). And Chinese characters applied in our DMS task were more acceptable for Chinese participants and more dependable on visual working memory (Opitz et al., 2014). What’s more, we focused on retrieval epoch rather than encoding epoch in view of impaired retrieval process and reserved encoding ability of memory deficit in PD (Mahurin et al., 1993).

To our knowledge, there was no research focusing on cognitive ERP measures in PD patients with hyposmia. The aim of this study was to improve our understanding of the role of hyposmia in cognitive impairment in PD using the ERP technique with DMS task. Our study investigated difference in ERP components and its association with cognitive domains between PD patients with and without hyposmia.

To our knowledge, our study was the first to compare cognitive ERP measures between PD patients with and without hyposmia. No significant difference in ERP performance was found between the two groups. Among all subjects, N1 latency was significantly negatively related to visuospatial-executive function and there was a significant positive correlation between P1 amplitude and language ability. Within the normosmic group, N1 and P1 also associated with visuospatial-executive and language functions while a significant correlation was only found between N1 latency and clock drawing test performance rather than visuospatial-executive item score in the hyposmic group. What’s more, odor identification ability was not found to be significantly related to visuospatial-executive function or language ability.

Hyposmia is an important clinical biomarker of PD and there are four subtypes of olfactory dysfunction reported in PD including impairment of odor identification, odor discrimination, odor threshold detection and odor recognition memory (Mesholam et al., 1998; Haehner et al., 2009). Odor identification deficit is the most prevalent form of hyposmia and is tested mainly by University of Pennsylvania Smell Identification Test (UPSIT) in PD patients (Doty et al., 1988) and SS-16 (Haehner et al., 2009) which was used in our study considering its advantage in cross-cultural application.

Previous studies found a significant association between hyposmia and cognitive impairment in PD patients. The percentage of cognitive decline was significantly higher in PD patients with hyposmia than those without (Bohnen et al., 2010; Stephenson et al., 2010; Morley et al., 2011; Parrao et al., 2012). And olfactory dysfunction significantly increased the risk of dementia in PD patients regardless the cognitive functions at baseline according to a 10-year follow up study (Domellof et al., 2017). The underlying mechanism remained unclear. The olfactory bulb was known to be one of the onset sites with appearance of Lewy body pathology during PD progression in Braak’s stage (Braak et al., 2003). And over expression of alpha-synuclein in the olfactory bulb was reported to initiate hyposmia and other prodromal symptoms of PD in rats (Niu et al., 2018). A hypothesis was proposed that severe olfactory dysfunction might be related to abundant cortical Lewy body deposition (Morley et al., 2011) which was found to be associated with PD dementia (Tsuboi et al., 2007). What’s more, the relation between hyposmia and cognitive impairment could also be explained by cholinergic denervation of the limbic archicortex (Bohnen et al., 2010) and dopaminergic denervation of the hippocampus (Bohnen et al., 2008). In our study, no significant difference was found in MMSE or MOCA score between PD with and without hyposmia, which may be associated with limits of our sample size and sensitivities of MMSE and MOCA in cognitive impairment of PD patients (Burdick et al., 2014; Wyman-Chick et al., 2017). Interestingly, no significant difference was found in parameters of ERP components including N1, N2, P1, P2 and P300 recorded during DMS tasks between these two groups. Therefore, the association between cognitive domains and ERP measures in PD with and without hyposmia was important to be investigated.

N1 and P1 were found to respectively associate with visuospatial-executive functions and language in our study while no significant correlation was found between the other components including P2, N2, and P300 and specific cognitive functions. N1 and P1 are the earliest components in ERP representing visual sensory input. The generator of visual N1 is probably located in lateral extrastriate cortex (Gomez Gonzalez et al., 1994), dorsal occipito-parietal and ventral occipito-temporal areas (Yamazaki et al., 2000) and the visual P1 may be generated in fusiform gyrus (Heinze et al., 1994). N1 and P1 were reported to be associated with visual perceptual processing (Vogel and Luck, 2000; Taylor, 2002) especially in visuospatial attention according to previous reports (Naatanen and Picton, 1987; Luck et al., 1990). Luck et al. (1990) found that N1 was related to attention orienting to relevant stimulus and P1 possibly reflected a facilitation of early sensory processing with attention already focused. On the other hand, several studies demonstrated the role of N1 and P1 in language perception. Selpien et al. (2015) found that N1 and P1 were significantly related to language lateralization. In an auditory ERP study, the association between P1 amplitude and attention was found in linguistic probes stimulation but not in non-linguistic probes (Giuliano et al., 2014).

Abnormal N1 and P1 components in PD patients were observed in several studies. Wright et al. (1996) found attenuated N1 amplitudes during Auditory Oddball Task in 17 PD patients. However, enlarged N1 and P1 amplitudes as well as shortened N1 latency in 34 PD patients were demonstrated in a visual ERP study with oddball and S1–S2 tasks (Li et al., 2003). The discrepancy may be explained by the differences of tasks used in ERP, sample size and analytical approach of component parameters. Unfortunately, the clinical significance of N1 and P1 components in PD patients was investigated in very few studies. Wang et al. (2001) reported the association between N1 and cognitive visual processing in PD patients evidenced by its correlation with the regional cerebral blood flow. Consistent to previous studies, our study found a significant negative correlation between N1 latency and visuospatial-executive function in PD patients and P1 amplitude was significantly positively related to language ability. Therefore N1 latency and P1 amplitude during DMS task were possible to be used for assessing visuospatial-executive functions and language abilities in PD patients. Interestingly, the significant association between these cognitive functions and N1 and P1 components were also found in the normosmic group while in the hyposmic group, there was only a significant correlation between N1 and clock drawing test score rather than visuospatial-executive item score. To explain difference in clinical significance of N1 and P1 components between the two groups, one hypothesis could be that there exists different cognitive processing between these normosmic and hyposmic participants. Increasing evidence shows that PD with and without hyposmia may be two subtypes of PD patients. Lee et al. (2015) found that normosmic PD represented a unique clinical phenotype with a more benign with fewer motor deficits and higher dopamine transporter activity. On the other hand, hyposmia in PD was reported to be associated with tremor-dominant type (Iijima et al., 2011), SNCA rs11931074 and specific non-motor symptoms such as RBD and chronic constipation (Chen et al., 2015). From the aspect of cognition, a good olfactory performance in PD was found to compensate gray matter volume loss (Lee et al., 2014) and there were cholinergic and dopaminergic denervations in PD with hyposmia (Bohnen et al., 2008, 2010). Therefore, some components underlying a cognitive process such as visuospatial-executive and language functions could be different between PD with and without hyposmia.

The impaired cognitive domains in PD with hyposmia were under debate. Bohnen et al. (2010) found that UPSIT scores were significantly related to episodic verbal learning in 58 PD patients but not other cognitive performance including visuospatial function, visual non-verbal memory, attention and executive function. However, poorer memory and executive functions were reported to be associated with worse olfactory identification in other studies (Morley et al., 2011; Parrao et al., 2012). Our study demonstrated no significant association between SS-16 score and visuospatial-executive or language item score of MOCA in PD patients. The discrepancy is possibly explained by difference in sample size and neurocognitive test batteries which may be avoided by using ERP measures.

There were several limitations of our study. A larger sample size is expected in further studies to confirm our results. In addition, only MOCA with relatively high reliability and validation reported (Nie et al., 2012) was used for cognitive assessment in our study as the psychometric properties of neurocognitive test batteries were rarely studied in Chinese PD patients. What’s more, only odor identification was tested which was the mostly impaired olfactory function in PD (Doty et al., 1988). However, in view of possibly different mechanisms underlying four subtypes of hyposmia (Kareken et al., 2003; Hedner et al., 2010), the association between cognitive domains and the other three olfactory functions in PD warrants further investigation.

In conclusion, our study compared ERP measures recorded during DMS tasks at retrieval period and its association with cognitive domains between PD patients with and without hyposmia. No significant difference in ERP components was found between the two groups in the present study. Among all participants, N1 latency was significantly negatively related to visuospatial-executive functions and there was also a significantly positive correlation between P1 amplitude and language ability. In PD without hyposmia, N1 latency and P1 amplitude were respectively associated with visuospatial-executive and language functions while in PD with hyposmia, only a significant correlation was found between N1 latency and clock drawing test performance rather than visuospatial-executive item score in MOCA. What’s more, no significant association was found between odor identification ability and visuospatial-executive or language item score of MOCA.

All the authors cooperated and contributed to the design and plan of the present study. Y-QL, S-SC, J-JD, GL, Y-XH, P-CZ, YF, PH, and CG performed the research. S-DC was in charge of clinical diagnosis. Y-QL and B-YL analyzed the data. Y-QL wrote the original article. S-DC and B-YL were in charge of manuscript verifying.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.