Variation in Parkinson's disease : age, gender, genotype and phenotype correlations in early onset disease

There is a wide variation in the phenotypic expression, progression rates, therapy response and complications in Parkinson’s disease (PD). The primary research objective in this thesis was to analyse the variation in the 4 domains of phenotypic expression i.e. motor, non-motor, cognitive, and quality of life in a subset of early onset Parkinson’s disease (EOPD) patients from the PRoBaND study, in the United Kingdom. The secondary objective was to explore the factors responsible for this variation or heterogeneity in the clinical characteristics. Linking genotypes with phenotypes, besides evaluating environmental risk factors and iatrogenic influences, represents one mechanism of understanding this variation in the phenotypic expression of PD. We found subtle but significant variation across all domains of symptoms examined in this thesis by classifying patients into groups according to motor subtype, gender, age at diagnosis and heritability of the parkinsonian trait, despite statistically insignificant differences in risk factors such as head trauma, exposure to pesticides (including herbicides, insecticides, fungicides and fumigants), heavy metals, caffeine and a past history of oophorectomy (in females) with the exception of smoking (p=0.046) and exposure to solvents, which were more common in males compared to females (p<0.001). There were differences in the prevalence of motor symptoms such as balance problems being more prevalent in the postural instability gait difficulty (PIGD) subtype compared to the tremor dominant PD (TDPD) and ‘Mixed’ motor subtypes both subjectively (p<0.001) and objectively (p<0.001). Other axial problems such as speech difficulties and freezing were also more prevalent in those with the PIGD phenotype compared to the other motor subtypes both subjectively (p=0.004, p<0.001) and objectively (p=0.002, p<0.001). There was also variation in the prevalence of motor complications such as dyskinesia (p<0.001) and dystonia (p=0.020), being more prevalent in the PIGD subtype compared to other motor subtypes. 8 The prevalence of certain non-motor symptoms such as pain (p=0.022) and features of gastrointestinal dysfunction e.g. prandial bloating (p=0.024) and constipation (p=0.022) were more commonly reported by females compared to males. There were also differences in the prevalence of cognitive impairment (p=0.049) and neurobehavioural characteristics such as anxiety (p=0.002) and depression (p=0.006), after the diagnosis of PD, being more prevalent in PIGD compared to other motor subtypes. Finally, these differences contributed to the variation in the independence of activities of daily living scores which were lower in those with the PIGD phenotype compared to other motor subtypes (p<0.001). There were some differences in exposure to environmental risk factors for PD but not sufficient to explain all the variation. Iatrogenic influences from drugs contributed in part to the phenotypic variation. 10% of the cases in the EOPD cohort tested positive for mutations in one of three genes screened i.e. LRRK2, GBA and Parkin; their DNA remains banked and there is scope to test these cases for mutations in other genes, relevant to PD, in the future. There were too small numbers of cases in each subgroup to draw definite conclusions about the exact influence of genes on the overall phenotypic variation but differences between Parkin mutation carriers and gene test negative ‘controls’ such as early age of onset and long disease duration were obvious. PRoBaND is linked to other similar research studies in the UK, with the stated aim of sharing datasets, in the hope that larger numbers of patients and their DNA samples will increase the power, in statistical terms, to test hypotheses about the role of genetic markers in influencing the course and expression of symptoms. Our current understanding of PD as a complex trait suggests both genetic and environmental influences (including iatrogenic factors if patients are treated) play a role in the phenotypic expression of this condition. A lot more remains to be explored to improve our understanding of the finer details and molecular mechanisms underlying the variation in this disease.