Establishing an 'at risk' Cohort for Parkinson's Disease Neuroprevention Using Olfactory Testing and DAT Imaging

Principal Investigator:
Charles H. Adler, MD, PhD

Co-investigators:
John N. Caviness, MD, Virgilio Evidente, MD, Erika Driver-Dunckley, MD

Study Centers
15-17 clinical centers including academic centers, VA Parkinson's Disease, Research, Education and Clinical Centers (PADRECCs) and high-volume community practices. The primary sites are IND and UPENN.

Study Objectives
The overall goal of this project is to develop a strategy to detect pre-symptomatic Parkinson’s disease (PD) in a large population of individuals at increased risk for PD.

The specific objectives are to:

  1. To estimate the frequency of olfactory loss of first-degree relatives of PD patients without signs or symptoms of PD using the University of Pennsylvania Smell Identification Test (UPSIT);
  2. To compare striatal DAT density using [123I] beta-CIT and SPECT imaging in first-degree relatives of PD patients without signs or symptoms of PD with olfactory loss based on UPSIT testing with age-matched healthy control cohort.
  3. To determine if a reduction in DAT density using [123I] beta-CIT and SPECT imaging in first-degree relatives of PD patients without signs or symptoms of PD at baseline predicts progressive loss of DAT density on imaging at 2 years follow-up.
  4. To determine if a reduction in DAT density using [123I] beta CIT and SPECT imaging in first-degree relatives of PD patients without signs or symptoms of PD at baseline predicts the onset of clinical PD at 2-year follow-up.

Study Population
1st degree relatives of PD patients.

Subjects
The study subjects will consist of first-degree relatives drawn from PD patients at the sites and national advertising and recruitment of unaffected first-degree relatives of PD patients:

  1. The initial contact will be with 7,500 1st degree relatives of PD patients
  2. Approximately 3,000 relatives that meet eligibility criteria for the study will be sent UPSIT tests by mail
  3. We anticipate 2,100 relatives will return valid UPSIT tests (70% response rate)
  4. 300 relatives (225 with abnormal olfaction and 75 with normal olfaction) will be included in the cohort for serial imaging and clinical follow-up.

PD patients at Mayo Clinic will be asked whether they are willing to contact their first-degree relatives for participation in the study. If they are willing to do so then the Mayo Clinic investigators will give the PD patient a packet of information to give to the first-degree relative that will include study information and information on how the relative can participate. This will require the relative to contact Mayo Clinic and/or IND/UPENN, Mayo Clinic investigators will not contact the relative nor will Mayo Clinic send any information to the IND/PENN until the relative enrolled in the study.

Study Design
The study is designed as a two-phase screening program followed by a 2-year longitudinal cohort study.

In the screening phase, 1st degree relatives of PD patients will first have olfactory testing using the UPSIT. This part of the study will be conducted by mail by the IND and UPENN staff. Subjects with abnormal olfaction, and a sub-set of subjects with normal olfaction will then be asked to have beta-CIT imaging and clinical evaluations.

For the longitudinal portion of the study, clinical evaluations will be completed annually for two years including repeat olfactory testing and diagnostic evaluations. Imaging will be performed at baseline once and at two years of follow-up. All imaging will be performed at IND and will involve contact between the subject and IND, Mayo Clinic will not be involved in making these arrangements.

The clinical evaluations of the first-degree relatives will occur at the site most convenient to the relative. In some cases this will be Mayo Clinic and in others it will be another participating center.

Significance
This study will extend findings of a pilot study performed at IND and UPENN and other previous studies by characterizing the performance of the 40-item UPSIT in a cohort of first-degree relatives of PD patients. The results may allow us to identify individuals in the presymptomatic stages of PD. Once identified, individuals with a loss of olfaction will be followed as an at-risk cohort with both clinical evaluations and dopamine transporter imaging to determine if the screening evaluation was predictive of later developing PD. The results from this study have the potential to validate the use of olfactory testing using the UPSIT as a screening tool followed by dopamine transporter imaging as a 2 step screening process for presymptomatic PD.

Identifying subjects with an increased risk of developing PD may contribute to the development of neuroprotective treatment strategies. A presymptomatic diagnosis would not only allow neuroprotective agents to be administered earlier in the disease process, but would also enable us to study the etiology of the neurodegeneration closer to the onset of neuronal loss.