Patients with the greatest olfactory impairment at baseline were at higher risk for developing visual hallucinations and cognitive decline over the course of clinical follow-up. After adjustment for covariates, there was no significant relationship between baseline olfactory performance and risk of motor progression indicated by incident dyskinesias and falls. Our results suggest that olfactory testing can provide useful prognostic information regarding neuropsychiatric features of PD. In addition, the observed clinical associations suggest that olfactory performance may be a marker for extranigral pathology to a greater extent than for nigrostriatal dysfunction.
There was a pattern of increasing risk of neuropsychiatric complications with each quartile drop in olfactory performance. The greatest risk was for patients in the lowest quartile of smell loss, with UPSIT scores of 16 or lower. This level of smell loss represents nearly complete anosmia, since a score of ~10 of 40 is expected simply by guessing. Although there was no association between impaired olfaction and motor performance in adjusted analysis, subjects in the lowest quartile of olfactory performance were more likely to develop falls in the data of the unadjusted analysis. In previous research, axial symptoms have been more associated with neuropsychiatric features of PD than other motor aspects of the disease.14
The present data suggest that the risk of dyskinesias is unrelated to olfactory impairment. Our results do not entirely exclude a modest association between impaired olfaction and subsequent risk of falls.
Prior studies have investigated the relationship between olfaction and motor features of PD, and to a lesser extent, olfaction and cognition in Lewy Body disorders. Several studies have shown that odor identification deficits appear early in the course of PD1
and are modestly related to severity of motor disability.15
One study showed that olfactory deficits and cognitive impairment are independent factors in PD patients.16
However, severe odor identification deficits are present in patients with dementia with Lewy Bodies (DLB),17,18
and they may be more common and pronounced in the Lewy Body variant of Alzheimer’s disease (AD) than in typical AD.19
These studies show that olfactory deficits occur in cognitive disorders associated with extranigral LB pathology.
Our findings are consistent with the pathological staging system proposed by Braak et al.20
in which the olfactory bulb and anterior olfactory nucleus are among the first sites of Lewy body pathology, while nigral pathways are affected later. In this context, it is possible that lower brainstem pathology leads more directly to nigral disease, whereas olfactory system pathology is more related to extranigral degeneration.
The results of this study have clinically relevant implications. Nonmotor features of PD are increasingly recognized as important determinants of impaired function and reduced health-related quality of life (HRQL) in PD.21,22
Patients with visual hallucinations are at higher risk for institutionalization and mortality 23
than patients without visual hallucinations. Cognitive impairment in PD has been associated with greater disability, 24,25
higher caregiver burden,27
and increased mortality.28
If PD patients at increased risk for developing these problems could be identified earlier, it is possible that they could be managed more appropriately. In the future, these at-risk individuals could be targeted to receive disease-modifying therapies that might delay or mitigate the devastating effects of dementia and psychosis in PD.
Several limitations of this study should be noted. Inclusion criteria were based in part on UPDRS, part I items which is not as accurate as formal neuropsychological testing. As a result, some subjects with mild dementia or psychosis that would have been detected with more sensitive measures may have been included in this cohort. Furthermore, it is possible that subjects with mildly impaired cognition at baseline may have had worse olfactory performance due to impaired attention or memory. While this potential source of bias can not be excluded, the uniformly high scores on the PIT in the subset to whom this test was administered suggest that it was not a major problem in this cohort. Outcome data were collected retrospectively by review of clinical charts, and a number of the clinical charts were not available for review. In addition, outcomes may not always be accurately recorded in medical charts. Although these problems are a potential source of bias, there are several reasons why it is unlikely that they would lead to finding false associations. First, assessment of outcomes was performed blinded to baseline olfactory status. Second, it is unlikely that subjects would be lost to follow-up based on performance on their olfactory testing. Thus, while both of these limitations are important, and we can not completely exclude the possibility that low baseline olfaction is associated with a greater probability of remaining in the cohort and developing psychosis, neither would be likely to produce “false positive” results. The more likely problem is that our study underestimates the magnitude of the relationship between olfaction and nonmotor outcomes, and may have failed to detect smaller associations between olfactory deficits and motor features. This may have occurred in the case of falls. However, our data do not support any association between olfaction and risk of dyskinesias. Another limitation is that a treatment history was not included in the analysis. Treatment with dopaminergic medications is clearly associated with visual hallucinations in PD patients. However, it is unlikely that treatment would be related to baseline olfactory performance, and therefore, it is unlikely that the relationship between baseline olfactory performance and subsequent emergence of visual hallucinations would be confounded by dopaminergic treatment.
To address these limitations, our results should be confirmed in prospective longitudinal studies. Particularly in the setting of effective medical and surgical treatments for the cardinal motor features of PD, non-motor problems are major determinants of disability and mortality. Accurate prediction of these problems would have substantial research and clinical impact. Olfactory testing, perhaps combined with other tests, could be used to identify at-risk patients. With better prognostic information, these patients could be managed more effectively and potentially enrolled in research to better understand the evolution and treatments of neuropsychiatric complications of PD.