The Parkinson's progression markers initiative (PPMI) – establishing a PD biomarker cohort

Abstract

ObjectiveThe Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker‐defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease‐modifying therapeutic trials.MethodsA total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org.ResultsApproximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS‐UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α‐synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P < 0.03). Similarly, t‐tau (45/53) and p‐tau (16/18) were reduced in PD versus HC (P < 0.01),Interpretation PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials.

Clinical and Dopamine Transporter Imaging Characteristics of Leucine Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson's Disease Participants in the Parkinson's Progression Markers Initiative: A Cross‐Sectional Study

“…Data used in the preparation of this manuscript were obtained from the PPMI database (http://www.ppmi-info.org/data). The aims and methodology of the study have been published elsewhere . The study protocol and manuals are available at http://www.ppmi-info.org/study-design.…”

“…Participants were excluded if they had conditions that precluded safe performance of lumbar puncture. The sPD cohort recruited at baseline newly diagnosed, untreated PD patients who were aged 30 or older and had a disease duration less than 2 years at baseline and Hoehn and Yahr stage ≤2 . The sPD cohort recruitment was completed between June 2010 and April 2013.…”

“…All participants are expected to undergo DAT SPECT to assess DAT binding analyzed according to the PPMI imaging technical operations manual (http://ppmi-info.org/). All participants have quantitative analysis using previously described methods to determine the minimum putamen specific binding ratio (SBR) . The PPMI also collects an array of cerebrospinal fluid biomarkers, but these measures are currently available only for a small subset of participants in the genetic cohort (as they are processed in batches) and as such were not included in this report.…”

Deep sncRNA-seq of the PPMI cohort to study Parkinson’s disease progression

“…Of the participants 440 were diagnosed with idiopathic PD, 81 with Parkinsonism (atypical forms of PD), and 485 are age-matched healthy controls. Among the Parkinsonism sub-cohort, there are cases of Progressive Supranuclear Palsy (25), unspecified Parkinsonism (13), Cerebrovascular Disease with Parkinsonism features (13), Multiple System Atrophy (10), Lewy Body Dementia (10), Cortical-basal Syndrome (7), and Drug-Induced Parkinsonism (3). In total, 640 miRNAs passed QC (Supplementary Table 10) and 416 of those overlapped with miRNAs detected in the PPMI cohort.…”

CSF sTREM2 correlates with CSF tau in advancing Parkinson’s disease

“…These non-motor symptoms do not improve with dopamine enhancing therapies and contribute significantly to late morbidity, loss of quality of life, and mortality. Although at initial diagnosis, 6.5% of PD patients show abnormal CSF levels of Aβ 42 and tau (Marek et al, 2018), at autopsy, 60-80% of PD subjects will have developed brain pathology consistent with AD, with prominent accumulation of amyloid plaques and/or tau containing neurofibrillary tangles (Tsuang et al, 2013;Dickson et al, 2018;Robinson et al, 2018). Thus in a vast majority of patients with PD, AD pathophysiologic processes are initiated at some point after diagnosis.…”