Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the PREDIGT score. (27th December 2016)

• Record Type: Journal Article
• Authors: Schlossmacher, Michael G.; Tomlinson, Julianna J.; Santos, Goncalo; Shutinoski, Bojan; Brown, Earl G.; Manuel, Douglas; Mestre, Tiago
• Editors: Bolam, Paul
• Is Part Of: European journal of neuroscience. Volume 45:Number 1(2017)
• Page Start: 175
• Page End: 191
• Publication Date: 2016-12-27
• Subjects: aetiology -- exposome -- genetics -- neurodegeneration -- parkinsonism -- probability -- toxin; Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.13476
• Languages: English
• ISSNs: 0953-816X

Abstract

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 ( P R ) can be calculated in healthy adults, using the formula: P R (%) = ( 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. Abstract : The PR EDIGT score quantifies the probability for the risk ( P R ) of Parkinson disease (PD) as a function of five factors: E (Exposome); D (Genetics); I (Initiation); G (Sex/Gender); and T (Time). The disease projection curve for a case of idiopathic PD is shown (solid line), where a P R of 100% is reached at 66 years of age. The curve shifts based on values for the five factors, thus changing the incidence risk at a given age, for example, to a P R = 80% at 52 years, 70% at 72 years and 60% at 88 years.