title: Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the PREDIGT score.
abstract: Fifty-five years after the concept of dopamine replacement therapy was introduced, Parkinson disease (PD) remains an incurable neurological disorder. To date, no disease-modifying therapeutic has been approved. The inability to predict PD incidence risk in healthy adults is seen as a limitation in drug development, because by the time of clinical diagnosis ≥ 60% of dopamine neurons have been lost. We have designed an incidence prediction model founded on the concept that the pathogenesis of PD is similar to that of many disorders observed in ageing humans, i.e. a complex, multifactorial disease. Our model considers five factors to determine cumulative incidence rates for PD in healthy adults: (i) DNA variants that alter susceptibility (D), e.g. carrying a LRRK2 or GBA risk allele; (ii) Exposure history to select environmental factors including xenobiotics (E); (iii) Gene-environment interactions that initiate pathological tissue responses (I), e.g. a rise in ROS levels, misprocessing of amyloidogenic proteins (foremost, α-synuclein) and dysregulated inflammation; (iv) sex (or gender; G); and importantly, (v) time (T) encompassing ageing-related changes, latency of illness and propagation of disease. We propose that cumulative incidence rates for PD (PR) can be calculated in healthy adults, using the formula: PR(%) = (E + D + I) × G × T. Here, we demonstrate six case scenarios leading to young-onset parkinsonism (n = 3) and late-onset PD (n = 3). Further development and validation of this prediction model and its scoring system promise to improve subject recruitment in future intervention trials. Such efforts will be aimed at disease prevention through targeted selection of healthy individuals with a higher prediction score for developing PD in the future and at disease modification in subjects that already manifest prodromal signs.
authors.affiliation: Neuroscience Program, Ottawa Hospital Research Institute, 451 Smyth Road, RGH #1414, Ottawa, ON, K1H 8M5, Canada.|Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.|University of Ottawa Brain & Mind Research Institute, Ottawa, Canada.|Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlossmacher
authors.affiliation: Neuroscience Program, Ottawa Hospital Research Institute, 451 Smyth Road, RGH #1414, Ottawa, ON, K1H 8M5, Canada.|University of Ottawa Brain & Mind Research Institute, Ottawa, Canada.
authors.forename: Julianna J
authors.initials: JJ
authors.lastname: Tomlinson
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Goncalo
authors.initials: G
authors.lastname: Santos
authors.affiliation: Neuroscience Program, Ottawa Hospital Research Institute, 451 Smyth Road, RGH #1414, Ottawa, ON, K1H 8M5, Canada.|University of Ottawa Brain & Mind Research Institute, Ottawa, Canada.
authors.forename: Bojan
authors.initials: B
authors.lastname: Shutinoski
authors.affiliation: Neuroscience Program, Ottawa Hospital Research Institute, 451 Smyth Road, RGH #1414, Ottawa, ON, K1H 8M5, Canada.|Faculty of Medicine, University of Ottawa, Ottawa, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Earl G
authors.initials: EG
authors.lastname: Brown
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, Canada.|Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Douglas
authors.initials: D
authors.lastname: Manuel
authors.affiliation: Neuroscience Program, Ottawa Hospital Research Institute, 451 Smyth Road, RGH #1414, Ottawa, ON, K1H 8M5, Canada.|Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.|University of Ottawa Brain & Mind Research Institute, Ottawa, Canada.|Faculty of Medicine, University of Ottawa, Ottawa, Canada.|Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Tiago
authors.initials: T
authors.lastname: Mestre
mesh_terms: D004298:Dopamine / Q000378:metabolism; D059647:Gene-Environment Interaction; D006801:Humans; D015994:Incidence; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
keywords: aetiology; exposome; genetics; neurodegeneration; parkinsonism; probability; toxin