Conversion to Parkinson Disease in the PARS Hyposmic and Dopamine Transporter-Deficit Prodromal Cohort

Abstract

Importance: Detecting individuals at risk for Parkinson disease (PD) during the prodromal phase could clarify disease mechanisms and allow for treatment earlier in the disease process to possibly slow or prevent the onset of motor PD.

Objective: To determine if the combination of smell identification testing followed by dopamine transporter (DAT) imaging can accurately and efficiently identify individuals from the general population at risk for conversion to a clinical diagnosis of PD.

Design, setting, and participants: Participants were identified from the community by olfactory testing assessed longitudinally with DAT imaging 2 and 4 years after baseline and by annual clinical follow-up to determine whether they had clinical evidence to establish a PD diagnosis. Participants were contacted by mail and completed olfactory testing at home. Longitudinal follow-up of clinical measures and DAT imaging occurred at specialty centers. There were 203 hyposmic and 100 normosmic participants. A total of 185 hyposmic and 95 normosmic individuals had at least 1 follow-up visit, and 152 hyposmic participants (82.2%) were either observed for 4 years or converted to PD during follow-up.

Main outcomes and measures: Percentage of individuals with hyposmia and a DAT deficit that converted to PD and the change in PD clinical scale scores (Unified Parkinson's Disease Rating Scale) and DAT imaging during 4-year follow-up.

Results: Of 280 total participants, 140 (50.0%) were male, and the mean (SD) age of the cohort was 63 (8.7) years. Among 21 participants with hyposmia and a DAT deficit (65% or less of age-expected lowest putamen binding ratio) at baseline, 14 (67%) converted to PD at 4 years compared with 2 of 22 participants (9%) with a DAT in an indeterminate range (greater than 65%-80%) and 3 of 109 participants (2.8%) with no DAT deficit (greater than 80%) at baseline. Individuals with a baseline DAT deficit experienced a 4-year decline in DAT binding of 20.23% (SD, 15.04%) compared with 3.68% (SD, 18.36%) and 5.45% (SD, 13.58%) for participants with an indeterminate and no DAT deficit, respectively (P = .002). The relative risk of conversion to a diagnosis of PD in hyposmic individuals with a DAT deficit was 17.47 (95% CI, 7.02-43.45) compared with individuals with either indeterminate or no DAT deficit.

Conclusions and relevance: The combination of hyposmia and DAT deficit was highly predictive of conversion to PD within 4 years of clinical follow-up. Individuals with hyposmia and a DAT deficit had a 5% reduction in DAT binding annually, similar to early PD. These results provide a framework for planning disease prevention studies in PD.

Figure 1.. Progression of Participants Through the Study

Flow diagram showing the number of hyposmic individuals and normosmic individuals observed through the study. No normosmic individuals converted to Parkinson disease (PD) during the first 2 years of follow-up, and 56 were discontinued from the study at that point to conserve resources. Subsequently, no normosmic individual who was observed for 4 years converted to a clinical diagnosis. PARS indicates Parkinson Associated Risk Study. ^aFive hyposmic individuals who converted to a diagnosis of PD (or dementia with Lewy bodies) before year 4 and did not have further follow-up are considered to have completed the study (endpointed), even if they did not have a year 4 visit.

Figure 2.. Phenoconversion Rate Depending on Degree of Baseline Dopamine Transporter (DAT) Deficit

Kaplan-Meier curves showing rates of survival to conversion to a diagnosis of Parkinson disease among 185 hyposmic individuals. Individuals are grouped into no DAT deficit (>80% of age-expected lowest putamen binding ratio), indeterminate DAT deficit (>65%-80% expected), and DAT deficit (≤65% expected). The relative hazard for conversion to Parkinson disease was significantly higher in the DAT deficit group (log-rank test, 71.3; degrees of freedom, 2; P < .001).

Figure 3.. Mean Change in Whole Striatum Specific Binding Ratio (SBR)

Percentage of change in mean SBR for 131 hyposmic individuals with complete data^a divided into 3 groups based on baseline dopamine transporter (DAT) status; 96 had no DAT deficit (>80% of age-expected lowest putamen binding ratio), 20 had an indeterminate DAT deficit (>65%-80% expected), and 15 had a DAT deficit (≤65% expected). The DAT deficit group experienced significantly greater loss of striatal DAT than the other 2 groups (χ² = 12.1; degrees of freedom, 2; P = .002). Error bars indicate standard error. ^aAt baseline, 4 hyposmic individuals and 1 normosmic individual were receiving modafinil, a drug known to bind to the DAT. Three hyposmic individuals (1 with a DAT deficit and 2 with no DAT deficit) had baseline year, year 2, and year 4 scans but were excluded. None of the 5 modafinil-exposed individuals converted to PD or had abnormal DAT imaging at year 4, when modafinil was either discontinued or withheld at the time of imaging. All individuals exposed to modafinil were excluded from this analysis.