Olfactory dysfunction is one of the earliest recognized signs of synucleinopathy in PD, and has garnered interest as a potential marker for other clinical manifestations that typically appear later in the disease course. In this study, we have examined the relationship of hyposmia to neuropsychiatric and cognitive outcomes in PD patients. Consistent with prior observations (9
), we found a high prevalence of olfactory dysfunction and a substantial fraction of patients in our cohort experienced clinically significant psychiatric symptoms(38
). Global cognitive function, as measured by the MMSE, was relatively unaffected in our sample (mean 28), whereas tests of verbal memory and executive functions were abnormal in a significant proportion of our subjects. A small number of subjects had MMSE scores <24, however, excluding these patients from the analysis did not affect our results (not shown). These findings are consistent with prior descriptions of domain-specific cognitive dysfunction in non-demented PD patients(39
), and also reflect the relative insensitivity of the MMSE for detection of mild cognitive impairment in PD (41
While the value of hyposmia as a biomarker of motor symptoms is currently unclear, our results, and those of others, increasingly support a link between olfactory dysfunction and non-motor symptoms. In particular, our results suggest an association between olfactory dysfunction and neuropsychiatric manifestations. Cramer and colleagues have described that apathetic PD patients exhibited worse olfactory performance than non-apathetic patients (19
). While we observed trends toward higher levels of apathy and anxiety in patients with worse olfactory function, these did not reach statistical significance (); however, our studies used different instruments to measure both olfactory function and apathy. A recent retrospective cohort analysis by Stephenson et al.
found that worse baseline olfactory function increased the risk of developing visual hallucinations (20
). We also observed that psychotic symptoms, such as illusions or visual hallucinations, were significantly more common in patients with the worst olfactory function, and given the association between hallucinations and subsequent dementia, it seems possible that very poor olfaction may herald cognitive decline in PD.
Consistent with this idea, the report from Stephenson et al.
also demonstrated an increased risk of incident cognitive dysfunction in patients with the worst baseline olfactory function (20
). Cognitive problems were identified by a score of 2 (or 1 with corroborating chart documentation of the problem) on the corresponding UPDRS item and, therefore could not further differentiate the types of problems described or cognitive domains involved. Our data demonstrating an association of UPSIT score with performance on the HVLT-R and TOL-DX suggest the link may be specific to verbal learning as well as executive functions. In addition to these clinical findings, Bohnen and colleagues recently demonstrated that olfactory dysfunction was correlated with radiologic markers of cholinergic denervation in hippocampus and other cortical areas (43
). Thus, evidence linking olfactory and cognitive dysfunction, along with potential neurochemical substrates, is developing rapidly.
The early onset of olfactory dysfunction in PD is subserved by the appearance of Lewy pathology in the olfactory system. Braak’s detailed neuropathological analyses (44
) suggest that the olfactory bulb and lower brainstem may be induction sites from which Lewy pathology spreads through the midbrain and ultimately to cortical areas. An alternative "top-down" hypothesis has been advanced suggesting that olfactory connections could allow parallel spread both "up" to higher cortical areas and "down" to other recognized induction sites, such as, the dorsal motor nucleus of the vagus nerve (46
). Variability in the pace and pattern of progression observed among different individuals with PD supports the idea that both mechanisms may coexist, and it is possible that early events in this process influence the route of pathological spread giving rise to clinical phenotypes including hallucinations or cognitive impairment (47
). One interpretation of these results is that early, severe olfactory dysfunction may be a biomarker of additional extranigral disease, such as higher cortical Lewy pathology, leading to the development of hallucinations or cognitive dysfunction. Non-motor symptoms are increasingly recognized as common, treatment-refractory and disabling (48
). Understanding early events that lead to non-motor features and, potentially the ability to predict their onset, could have tremendous clinical impact.
The results of our study must be interpreted in the context of several limitations. Using the UPSIT, we only interrogated odor identification whereas odor discrimination and threshold are also affected in PD, though there is some debate whether these tests all measure a common source of variance(51
). While our use of ten different neuropsychiatric instruments represents the first study to broadly investigate the relationship of hyposmia with specific psychiatric and cognitive domains, such an analysis necessarily introduces concerns about the influence of multiple statistical testing. However, for those relationships that persisted after adjustment for covariates (psychosis, HVLT-R, TOL-DX), the group differences were most highly significant in the bivariate comparisons (p<0.001, ). Additionally, a recent preliminary analysis in a small cohort (published as a letter to the Editor commenting on Bohnen’s paper(43
)) described a correlation between olfaction and verbal memory but not the MMSE (TOL-DX was not tested), supporting the association of hyposmia with specific cognitive domains as we observed.
The magnitudes of effect size we observed were relatively modest (adjusted ORs: 1.8–3.1). Verbaan et al.
) found small but significant differences in scores between PD patients with and without olfactory impairment on the Scale for Outcomes in Parkinson's disease cognitive and psychiatric measures (SCOPA-COG, SCOPA-PC) in the PROPARK cohort but reported "no significant moderate or strong (>0.4) correlations" between olfactory impairment and other clinical domains, consistent with a small effect size. In their study, a relationship between individual cognitive domains and olfactory impairment, as we have observed, would potentially be minimized by use of an aggregate measure cognitive of function, such as the SCOPA-COG. While these results indicate that olfactory performance, along with other clinical variables, provides some information about neuropsychiatric manifestations (and vice versa), the strength of this relationship is presently unclear.
It is tempting to speculate that the association between olfactory dysfunction (a very early event) and typically later-occurring neuropsychiatric or cognitive phenotypes implies that hyposmia might be used predicatively. The data presented here are cross-sectional and cannot directly support such a claim. However, further prospective studies to determine whether early characteristics of olfactory impairment may predict future disease course are certainly warranted.