VANCOUVER—Among patients with Parkinson’s disease, the lowest level of olfactory function is associated with subjective cognitive impairment and more rapid decline in global cognition, compared with higher levels of olfactory function, according to an analysis described at the 68th Annual Meeting of the American Academy of Neurology. Furthermore, a combination of CSF biomarkers and olfactory testing may increase neurologists’ ability to identify patients at highest risk for cognitive decline and progression to mild cognitive impairment (MCI).

These two biomarkers may reflect the dual pathology of Lewy bodies and amyloid plaques observed in Parkinson’s disease–related MCI and Parkinson’s disease dementia and come together to give a more complete clinical picture, said Michelle Fullard, MD, a fellow at the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia Veterans Affairs Medical Center.

Michelle Fullard, MD

The rate and risk of cognitive decline in Parkinson’s disease vary from person to person, and biomarkers could help identify patients at highest risk for this outcome. Data suggest that olfaction reflects the Lewy pathology present in Parkinson’s disease. In addition, approximately one-third of patients with Parkinson’s disease dementia meet the pathologic criteria for Alzheimer’s disease. Increased levels of CSF tau and decreased levels of CSF amyloid beta are associated with cognitive impairment in this population.

The Parkinson’s Progression Markers Initiative

Dr. Fullard and colleagues sought to examine the association between baseline olfaction and measures of cognition in a cohort of 423 patients with early Parkinson’s disease. The researchers investigated whether olfaction alone or in combination with CSF biomarkers predicts cognitive decline and conversion to MCI. They analyzed data from the Parkinson’s Progression Markers Initiative, an observational cohort study of patients with Parkinson’s disease. Eligible participants were untreated at enrollment, had been diagnosed within two years of enrollment, and had dopamine transporter deficit on imaging.

All participants underwent various assessments at predetermined time points. Dr. Fullard and colleagues specifically examined the University of Pennsylvania Smell Identification Test (UPSIT), which was administered at baseline, and the Montreal Cognitive Assessment (MOCA), which was administered at baseline and annually thereafter. The investigators also analyzed CSF tau and CSF beta amyloid levels at baseline.

For the data analysis, the researchers grouped the cohort into tertiles according to olfactory function. They performed a cross-sectional analysis to investigate the association between olfaction and measures of cognition. A linear mixed-effects model was used to identify predictors of cognitive decline. Finally, the investigators used Cox proportional hazards models to investigate conversion to MCI.

UPSIT Predicted Cognitive Decline

Approximately 91% of participants had olfactory impairment. About 35% of patients were anosmic, and these patients constituted the lowest tertile of olfaction. This group tended to be older and had a higher proportion of males, compared with the other tertiles. Dr. Fullard and colleagues adjusted for age and gender in subsequent analyses. Education and disease duration were similar among the three tertiles. Average disease duration was between six to seven months for the population.

Participants in the lowest tertile were more likely to report subjective nonmotor symptoms than participants in the other tertiles, as measured by Part 1A of the Unified Parkinson’s Disease Rating Scale. Patients in the lowest tertile also were more likely to report subjective cognitive impairment, compared with the rest of the cohort. After the researchers adjusted the data for age and sex, they found that MOCA scores were similar among the three tertiles.

When Dr. Fullard and colleagues considered the UPSIT and the CSF biomarkers as continuous variables, they found that each was significantly associated with decline in MOCA score. For every one-point decrease in UPSIT score, the MOCA score declined by 0.02 points per year. Using a separate linear mixed-effects model, the investigators noted that patients in the lowest amyloid beta tertile tended to have more cognitive decline, but the result was not statistically significant. Participants with the highest tau–amyloid beta ratios, however, had significantly more cognitive decline than other participants.

Next, Dr. Fullard’s group categorized the patients as having low-, medium-, or high-risk profiles based on olfaction and CSF biomarkers. When they analyzed the composite of olfaction and amyloid beta, as well as the composite for olfaction and tau–amyloid beta ratio, they noted that patients with the highest risk profiles had significantly more cognitive decline, as measured by the MOCA.

Furthermore, the researchers observed that patients with the worst olfaction, as measured by the UPSIT, appeared to have a higher rate of conversion to MCI, but the result did not reach statistical significance. Similarly, participants with the highest tau–amyloid beta ratio appeared to have a higher rate of conversion to MCI, but the finding was not significant. When the investigators combined the biomarkers using the risk profiles, participants with the highest risk profiles were 79% more likely to develop MCI during the three-year study period than other participants.

—Erik Greb

Poor Olfaction May Predict Rapid Cognitive Decline in Parkinson’s Disease