STOCKHOLM, Sweden — Baseline data from the Parkinson's Progression Markers Initiative (PPMI) have shown some interesting findings characterizing biological changes that occur in Parkinson's disease.

These include early nonmotor features, reduction in dopamine transporter binding, and reductions in cerebral spinal fluid (CSF) levels of synuclein and tau.

The PPMI has been set up to identify clinical, imaging, and biospecimen biomarkers of Parkinson's disease progression. It includes patients with Parkinson's disease, matched healthy volunteers, and individuals at risk of developing Parkinson's.

The latest data from the PPMI was presented here at the International Parkinson and Movement Disorder Society (MDS) 18th International Congress of Parkinson's Disease and Movement Disorders by Ken Marek, MD, Institute for Neurodegenerative Disorders, New Haven, Connecticut.

"Parkinson's is a heterogeneous disorder that likely has different etiologies," Dr. Marek commented to Medscape Medical News. "We can't separate them out at present with the UPDRS [Unified Parkinson's Disease Rating Scale] scoring system so we need to add on different measures. This initiative is trying to identify what those new measures will be.

"This is the largest investigation into the mechanisms involved in Parkinson's ever conducted, and it is groundbreaking in that it is just being done," he added. "We are hoping to develop an array of biomarkers that will be of value to track the disease, and to identify subsets of patients that may respond to specific therapeutics."

Reduction in CSF Tau

Regarding the baseline observations so far reported, Dr. Marek noted that the reduction in tau seen in the CSF of patients with Parkinson's disease is "somewhat surprising and not fully expected."

He explained that tau is thought to be a sign of neurodegeneration and is elevated in Alzheimer's disease. "As Parkinson's is also a neurodegenerative disease, most people would expect that tau would be raised in this condition as well."

He noted that 2 other smaller studies have also suggested that tau may be reduced in Parkinson's.

"But our data is the biggest sample," he said. "It does seem to be a real finding. We can't explain it at the moment. It is leading to much discussion, and additional research is needed to understand what we are seeing."

Table. PPMI: Baseline Levels of CSF Biomarkers

Biomarker Patients With Parkinson's Disease Healthy Volunteers
Tau (pg/ml) 44.7 52.4
P-tau (pg/ml) 15.5 18.3
Synuclein (pg/ml) 1847 2197

 

Dr. Marek reported that the PPMI is looking at 4 categories of measures:

  1. Clinical measures: UPDRS and others, including cognition, depression, sleep, and autonomic disturbances

  2. Imaging: photoacoustic computed tomography, single-photon emission computed tomography, MRI

  3. Biospecimens: CSF, blood, plasma

  4. Genetic measures: how the genetic background influences other biomarkers and progression of the disease

All these measures will be monitored as participants are followed, providing the structure to conduct longitudinal follow-up and the opportunity to assess which biomarkers change over time.

The PPMI has now recruited 400 patients with Parkinson's disease and 200 age- and sex-matched healthy controls. Also included are 70 individuals who have Parkinson's symptoms but have normal findings on dopamine transporter imaging — these patients are known as having SWEDD (scans without evidence of dopaminergic deficit) — and 100 individuals believed to be at risk of developing Parkinson's on the basis of the olfactory test or REM Sleep Behaviour Disorder (RBD) measure.

Finding Treatment Targets

Dr. Marek noted that they were keen to include individuals thought to be at risk of developing Parkinson's. "We will follow them to see which patients develop the disease and which biomarkers change. In this way we are hoping to find treatment targets so we can start treatment before symptoms develop."

He noted that the SWEDD patients have a different clinical profile, and the overwhelming majority don't have Parkinson's. "But in the early stages they are often thought to have Parkinson's. We are looking for biomarkers in this group too. Parkinson's experts get the diagnosis wrong about 15% of the time in patients who come with symptoms that could be Parkinson's. We don't have a test that will tell us for sure one way or the other at the moment."

The PPMI also includes a genetic study with 600 individuals with LRRK2 and synuclein mutations.

All study data are integrated into the PPMI study database and are available at www.ppmi-info.org.

Commenting on the project, Philip Thompson, MD, professor of neurology at the University of Adelaide and Royal Adelaide Hospital in Australia, pointed out that the great need for studies to identify persons at risk for Parkinson's and for clinical trials to examine the efficacy of treatments at presymptomatic stages.

"A number of biomarkers have been identified that may make possible a study of presymptomatic neurodegenerations, such as Parkinson's disease," Dr. Thompson said. "To be effective and widely applicable such studies require considerable precision in identifying reliable predictors and biomarkers of the disease to recruit a cohort of homogenous patients in the presymptomatic stages."

He added: "To this end, this prospective study has recruited a large number of subjects in a 'premotor stage' with known risk factors for Parkinson's disease and embarked on a long-term follow-up study using various objective measures. The results of this study have the potential to change the way clinical trials in Parkinson's disease are undertaken in the future and the way in which patients with prodromal premotor of Parkinson's disease are managed."

International Parkinson and Movement Disorder Society (MDS) 18th International Congress of Parkinson's Disease and Movement Disorders. Abstract 729.

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