PPMI study to add a new prodromal cohort

The PPMI Steering Committee has recently decided to expand PPMI to include a prodromal PD cohort.  Defining a pre-diagnostic or prodromal phase for PD presents both an immediate challenge ? how to reliably identify individuals during this prodromal period at high risk to phenoconvert to PD ? and an eventual opportunity:  can we ultimately treat these individuals at high risk for PD prior to the onset of symptoms of disease to prevent or delay the development of manifest PD? It is hoped that this additional cohort, called P-PPMI, will provide researchers with the opportunity to examine biomarker progression prior to the onset of motor symptoms.  The PPMI study has built a robust infrastructure of sites and cores with well-defined processes to ensure standardization across sites that will be to support the prodromal Parkinson cohort.

RATIONALE: As scientists have long recognized, PD has a prolonged pre-diagnostic period during which nigral dopamine degeneration and likely brainstem and olfactory bulb pathology has occurred several years in advance of typical motor symptoms. Numerous studies have demonstrated that at clinical diagnosis of PD, a 40-60% loss of dopaminergic neurons has already occurred during a prodromal period estimated to be 5-15 years in duration.

Several lines of evidence demonstrate that dopaminergic imaging can reliably identify subjects with a reduction in dopamine transporter density during this prodromal phase of their disease. Early non-motor symptoms like olfactory loss, autonomic dysfunction, sleep disturbance, cognitive and behavioral impairment may also occur prior to typical PD motor symptoms, reflecting early brainstem or extra-nigral pathology. Recent understanding of both these early non-motor manifestations and the molecular genetics of PD have provided several specific strategies to identify those individuals without typical PD motor symptoms, but at increased risk to develop PD. Several proof of concept studies have demonstrated that enriching a population for PD risk by combining non-motor symptoms (olfaction or REM Sleep Behavior Disorder (RBD)) or genetic risk with dopamine transporter imaging (DAT) may successfully identify individuals at high risk to phenoconvert to manifest PD.

STUDY DESIGN:  Subjects with either hyposmia (< 10th percentile by age and gender), RBD (defined by Polysomnography (PSG) criteria) and/or LRRK2 mutation who also have a dopamine transporter deficit based on brain imaging are at high risk to phenoconvert to motor PD within two years. Approximately 100 individuals with hyposmia, RBD or LRRK2 with a dopamine transporter deficit will be enrolled. Subjects will be followed for four years and will follow the same schedule of events as is outlined for PD subjects in the study. Based on preliminary data we anticipate that approximately 30% of prodromal subjects will develop motor PD within 2 years.

P-PPMI is currently in the planning phase. Recruitment for the study is expected to begin in early 2013.