Epidemiological study of young and later onset Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative condition and the risk of developing it is age dependent, the prevalence increasing with advancing age. There are relatively little published data on frequency and clinical features of Young Onset Parkinson's disease (YOPD) and it is uncertain whether this subgroup of PD is a different disease entity to later onset Lewy body PD. Investigation of this question is the main focus of this research thesis. This work has two components—the first provides an estimate of the prevalence of PD in Cardiff and describes age at onset, the second is a community based case control study of YOPD and later onset PD (LOPD) using the prevalence cohort as the main source of cases. The prevalence of PD in Cardiff is similar to the weighted average of previous PD prevalence studies in the UK over the past 42 years. Our crude prevalence estimate was 130 per 105 (95% CI 117,144) and the age standardised prevalence 142 per 105 (95% CI 128,156) using 1997 England and Wales population figures as a standard population. Significant clinical differences were identified in YOPD as compared to LOPD. YOPD patients reported less hyposmia, constipation and sleep disturbance in the pre-motor stage, but more depression, paraesthesiae and sleep disturbance and less dementia in established disease than LOPD. YOPD presented more commonly with akinetic rigid symptoms and had a lower frequency of tremor. YOPD was much more likely to involve dystonia and treatment related dyskinesia than LOPD. These results support the hypothesis that PD is a clinically heterogeneous condition and that significant differences are seen according to age at onset

Epidemiological study of young and later onset Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative condition and the risk of developing it is age dependent, the prevalence increasing with advancing age. There are relatively little published data on frequency and clinical features of Young Onset Parkinson's disease (YOPD) and it is uncertain whether this subgroup of PD is a different disease entity to later onset Lewy body PD. Investigation of this question is the main focus of this research thesis. This work has two components—the first provides an estimate of the prevalence of PD in Cardiff and describes age at onset, the second is a community based case control study of YOPD and later onset PD (LOPD) using the prevalence cohort as the main source of cases. The prevalence of PD in Cardiff is similar to the weighted average of previous PD prevalence studies in the UK over the past 42 years. Our crude prevalence estimate was 130 per 105 (95% CI 117,144) and the age standardised prevalence 142 per 105 (95% CI 128,156) using 1997 England and Wales population figures as a standard population. Significant clinical differences were identified in YOPD as compared to LOPD. YOPD patients reported less hyposmia, constipation and sleep disturbance in the pre-motor stage, but more depression, paraesthesiae and sleep disturbance and less dementia in established disease than LOPD. YOPD presented more commonly with akinetic rigid symptoms and had a lower frequency of tremor. YOPD was much more likely to involve dystonia and treatment related dyskinesia than LOPD. These results support the hypothesis that PD is a clinically heterogeneous condition and that significant differences are seen according to age at onset.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A two-stage meta-analysis identifies several new loci for Parkinson's Disease

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5×10−10, PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Systemic delivery of human GlyR IgG antibody induces GlyR internalization into motor neurons of brainstem and spinal cord with motor dysfunction in mice

Aims Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a life‐threatening condition often associated with highly raised serum antibodies to glycine receptors (GlyRs); these bind to the surface of large neurons and interneurons in rodent brain and spinal cord sections and, in vitro, inhibit function and reduce surface expression of the GlyRs. The effects in vivo have not been reported. Methods Purified plasma IgG from a GlyR antibody‐positive patient with PERM, and a healthy control (HC), was injected daily into the peritoneal cavity of mice for 12 days; lipopolysaccharide (LPS) to open the blood–brain barrier, was injected on days 3 and 8. Based on preliminary data, behavioural tests were only performed 48 h post‐LPS on days 5–7 and 10–12. Results The GlyR IgG injected mice showed impaired ability on the rotarod from days 5 to 10 but this normalized by day 12. There were no other behavioural differences but, at termination (d13), the GlyR IgG‐injected mice had IgG deposits on the neurons that express GlyRs in the brainstem and spinal cord. The IgG was not only on the surface but also inside these large GlyR expressing neurons, which continued to express surface GlyR. Conclusions Despite the partial clinical phenotype, not uncommon in passive transfer studies, the results suggest that the antibodies had accessed the GlyRs in relevant brain regions, led to antibody‐mediated internalization and increased GlyR synthesis, compatible with the temporary loss of function

Familial early onset frontotemporal dementia caused by a novel S356T MAPT mutation, initially diagnosed as schizophrenia

Autosomal dominant frontotemporal dementia (FTD) due to mutations in the MAPT gene is referred to as FTD with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). Typically the disease begins in the sixth decade of life. We report a novel exon 12 mutation in MAPT (S356T), in a family with an exceptionally early age at onset (27 and 29 years), causing familial behavioural variant frontotemporal dementia. Both the proband and the proband's father were initially diagnosed as having schizophrenia. Pathological examination showed frontotemporal lobar degeneration with extensive neuronal and glial tau deposition. This mutation is one of a small group of MAPT mutations (including P301S, G335V and S352L) that cause very early onset FTDP-17T. It is likely that the early age at onset reflects a marked pathogenic effect of the mutation involving a disturbance of microtubule binding, tau phosphorylation or a major acceleration of tau aggregation

Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1)and LRRK2 in early-onset Parkinson's disease

Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early-onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late-onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high-ascertainment regional and community-based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ-1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) &lt; 40 (9.5%), an affected first-degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from &gt;5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ-1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity