Methods in Neuroepidemiology Characterization of European Longitudinal Cohort Studies in Parkinson's Disease - Report of the JPND Working Group BioLoC-PD

Abstract

Background: Enormous effort is being put into the identification and characterization of symptoms that may be used as predictive and progression markers in Parkinson's disease (PD). An impressive number of PD patients and individuals at risk for or in the prodromal stage of PD are currently followed in longitudinal studies; however, there does not exist an overview on the kind of markers evaluated and the assessments used. Methods: Information on the design, sample size, evaluated markers and assessments of 21 studies of the Joint Programme - Neurodegenerative Disease Research BioLoC-PD working group were collected by questionnaire. The studies were classified into at risk/prodromal or clinical PD cohorts. The assessments were grouped into quantitative assessments, investigator-rated assessments, investigator interviews, patient-rated questionnaires and caregiver-rated questionnaires. Results: Compilation of these data revealed an interesting consensus on evaluated markers, but there was an enormous variability of assessments. Furthermore, there is a remarkable similarity in the markers assessed and evaluation methods applied in the risk/prodromal and clinical PD cohorts. Conclusions: The inventory of the longitudinal cohorts that are part of the BioLoC-PD consortium reveals that there is a growing consensus on the markers that should be assessed in longitudinal cohort studies in PD. However, controversy still exists on the specific type of assessment. To allow comparison of data and common analyses it will be essential to harmonize scales and assessment outcomes.

Constipation: an emerging risk factor for Parkinson's disease?

“…Future studies should be directed at finding the best combination of prodromal clinical (including constipation) and laboratory biomarkers with the highest trade‐off between specificity and sensitivity for diagnosing PD; some studies looking at cohorts of healthy individuals considered to be at high risk for PD have already been conducted . The Parkinson Associated Risk Syndrome (PARS) study tested the association between impaired olfaction and other prodromal features of PD and evaluated the relative risk of abnormal dopamine transporter (DaT) imaging for subjects with and without hyposmia; the PARS investigators showed that hyposmic subjects are more likely to manifest other NMS of PD including constipation , and that combination of multiple factors (hyposmia, male sex and constipation) significantly increases the percentage of subjects with a DaT deficit up to more than 40% .…”

New Frontiers in Parkinson's Disease: From Genetics to the Clinic

“…While the trial was not designed or powered to detect efficacy, highly debated anecdotal reports suggested that patients improved dramatically (Wyse et al, 2016). In the wake of this trial, and a growing body of scientific evidence that c-Abl inhibitors are effective in experimental PD (Brahmachari et al, 2017), a series of Phase IIa trials are now underway in both PD and other synucleinopathies (www.ClinicalTrials.gov, Identifier NCT03205488).…”

“…It has been somewhat difficult, however, to measure LRRK2 activity or its physiological regulation. Because LRRK2 is a large (288 kDa) multidomain protein that is expressed at relatively low levels, conventional assays often rely on immunoprecipitation, and they typically use artificial substrates or assess kinase autophosphorylation by autoradiography (Lee et al, 2012). As such, it has been difficult to examine the activity of LRRK2 in specific regions or cell types in the brain.…”

“…There are a growing number of precompetitive consortia focused on PD. These include initiatives led by both government and advocacy organizations including Parkinson's Progression Marker Initiative (2011), Parkinson's Disease Biomarkers Program (Rosenthal et al, 2016), Innovative Medicines Initiative (IMI) (Hofmann-Apitius et al, 2015), Joint Programme Neurodegenerative Disease (JPND) (Lerche et al, 2015;Heinzel et al, 2017), International Parkinsonism Genetics Network (http://pdgenetics.org/), and more recently Accelerating Medicines Partnership-Parkinson's Disease (https://www.nih. gov/research-training/accelerating-medicines-partnership-amp/ parkinsons-disease).…”

“…Understanding the natural progression of PD is critical for research and therapeutic development. Thus, great focus has been placed on advancing genetically defined targets, biomarkerdriven phenotypes, precision medicine strategies, and early diagnosis (Fereshtehnejad et al, 2017;Jennings et al, 2017;Postuma et al, 2017). Global databases consisting of integrated data are needed to define disease progression across the spectrum of such a heterogeneous disease.…”