A common polymorphism in SNCA is associated with accelerated motor decline in GBA-Parkinson's disease.

A growing number of genetic susceptibility factors have been identified for Parkinson’s disease (PD). The combination of inherited risk variants is likely to affect not only risk of developing PD but also its clinical course. Variants in the GBA gene are particularly common, being found in approximately 5 to 10% of patients, and they lead to more rapid disease progression1. However, the effect of concomitant genetic risk factors on disease course in GBA-PD is not known.The CamPaIGN study has received financial support from the Wellcome Trust, the Medical Research Council, Parkinson’s UK and the Patrick Berthoud Trust. CHWG is supported by an RCUK/UKRI Innovation Fellowship awarded by the Medical Research Council. RAB is supported by the Wellcome Trust Stem Cell Institute (Cambridge). TBS received financial support from the Cure Parkinson’s Trust. The study is also supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre Dementia and Neurodegeneration Theme (reference number 146281). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. CRS' work is supported in part by NIH grants R01AG057331, U01NS100603, R01AG057331, and the American Parkinson Disease Association. Illumina MEGA Chip genotyping was made possible by a philanthropic investment from Dooley LLC (to Brigham & Women's Hospital and CRS)

Impact of GBA1 variants on long-term clinical progression and mortality in incident Parkinson’s disease

Funder: Foundation for the National Institutes of Health; FundRef: http://dx.doi.org/10.13039/100000009Funder: Van Geest FoundationFunder: Patrick Berthoud Charitable Trust; FundRef: http://dx.doi.org/10.13039/501100004218Funder: Cure Parkinson's TrustFunder: Michael J Fox FoundationFunder: Innovate UK; FundRef: http://dx.doi.org/10.13039/501100006041Funder: Dooley LLCFunder: American Parkinson's disease associationFunder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265Funder: Cambridge Centre for Parkinson-PlusFunder: Parkinson's UK; FundRef: http://dx.doi.org/10.13039/501100000304Funder: John Black charitable foundationFunder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272Funder: Van Andel Research Institute; FundRef: http://dx.doi.org/10.13039/100006019Introduction: Variants in the GBA1 gene have been identified as a common risk factor for Parkinson’s disease (PD). In addition to pathogenic mutations (those associated with Gaucher disease), a number of ‘non-pathogenic’ variants also occur at increased frequency in PD. Previous studies have reported that pathogenic variants adversely affect the clinical course of PD. The role of ‘non-pathogenic’ GBA1 variants on PD course is less clear. In this study, we report the effect of GBA1 variants in incident PD patients with long-term follow-up. Methods: The study population consisted of patients in the Cambridgeshire Incidence of Parkinson’s disease from General Practice to Neurologist and Parkinsonism: Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire cohorts. Patients were grouped into non-carriers, carriers of ‘non-pathogenic’ GBA1 variants and carriers of pathogenic GBA1 mutations. Survival analyses for time to development of dementia, postural instability and death were carried out. Cox regression analysis controlling for potential confounders were used to determine the impact of GBA1 variants on these outcome measures. Results: GBA1 variants were identified in 14.4% of patients. Pathogenic and ‘non-pathogenic’ GBA1 variants were associated with the accelerated development of dementia and a more aggressive motor course. Pathogenic GBA1 variants were associated with earlier mortality in comparison with non-carriers, independent of the development of dementia. Discussion: GBA1 variants, including those not associated with Gaucher disease, are common in PD and result in a more aggressive disease course

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.

OBJECTIVE: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance. INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685

GBA and APOE Impact Cognitive Decline in Parkinson's Disease : A 10-Year Population-Based Study

Acknowledgments: We would like to thank all participants, study personnel from each study, and funders of individual studies and of PICC. We would like to thank Artur Wozniak and Adrian Martin from the University of Aberdeen, Data Management Department, for help in developing the PICC database. We acknowledge the contributions of members of the individual study groups as detailed below. Members of PICC Steering Group: Dr. Angus D. Macleod, Dr. Carl E. Counsell (Chair), University of Aberdeen, UK; Prof. Ole-Bjørn Tysnes, University of Bergen, Norway; Marta Camacho, Dr. Caroline WilliamsGray, University of Cambridge, UK; Dr. Rachael A. Lawson, Newcastle University, UK; Dr. Jodi Maple-Grødem, Prof. Guido Alves, Stavanger University Hospital, Norway; Prof. Lars Forgren, Umeå University, Sweden. CamPaIGN study: Roger A. Barker, Thomas Foltynie, Sarah L. Mason, Caroline H. Williams-Gray. ICICLE-PD Study: David Burn, Lynn Rochester, Alison J. Yarnall, Rachael A. Lawson, Gordon W. Duncan, Tien K. Khoo. NYPUM Study: Lars Forsgren, Jan Linder, Mona Edström, Jörgen Andersson, Linda Eriksson, David Bäckström, Gun-Marie Hariz, Magdalena Domellöf. ParkWest Study: ParkWest Principal investigators: Guido Alves (Norwegian Centre for Movement Disorders, Stavanger University Hospital) and Ole-Bjørn Tysnes (Haukeland University Hospital). Study personnel: Michaela Dreetz Gjerstad, Kenn Freddy Pedersen, Elin Bjelland Forsaa, Veslemøy Hamre Frantzen, Anita Laugaland, Jodi MapleGrødem, Johannes Lange, Karen Simonsen, Eldbjørg Fiske and Ingvild Dalen (Stavanger University Hospital); Bernd Müller, Geir Olve Skeie and Marit Renså (Haukeland University Hospital); Wenche Telstad, Aliaksei Labusau and Jane Kastet (Førde Hospital); Ineke HogenEsch, Marianne Kjerandsen and Liv Kari Håland (Haugesund Hospital); Karen Herlofson, Solgunn Ongre, and Siri Bruun (Sørlandet Hospital Arendal). PICNICS study: Roger A. Barker, Marta Camacho, Gemma Cummins, Jonathan R. Evans, David P. Breen, Ruwani S. Wijeyekoon, Caroline H. Williams-Gray. PINE Study: Medical: Carl E. Counsell, Kate S. M. Taylor, Robert Caslake, Angus D. Macleod, David J. M. McGhee, Diane Swallow; Research nurse/assistant: Joanne Gordon, Clare Harris, Ann Hayman, Nicola Johannesson, Hazel Forbes; Data management: Valerie Angus, Alasdair Finlayson, David Dawson, Katie Wilde, David Ritchie, Artur Wozniak; Statisticians: Neil Scott, Shona Fielding; Radiology: Prof. Alison Murray; Pathology: Ishbel Gall, Dr. James MacKenzie, Prof. Colin Smith; Secretarial: Aileen Sylvester, Susan Mitchell, Pam Rebecca, Ann Christie, and Diane McCosh. Funding agencies: This work was supported by the Research Council of Norway (287842). The CamPaIGN study has received funding from the Wellcome Trust, the Medical Research Council, the Patrick Berthoud Trust, and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The ICICLE-PD study was funded by Parkinson’s UK (J-0802, G-1301, G-1507) and supported by the Lockhart Parkinson’s Disease Research Fund, National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit and Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The NYPUM study was supported by grants from the Swedish Medical Research Council, Erling-Persson Foundation, the Swedish Brain Foundation (Hjärnfonden), Umeå University, Västerbotten County Council, King Gustaf V and Queen Victoria Freemason Foundation, Swedish Parkinson Foundation, Swedish Parkinson Research Foundation, Kempe Foundation, Swedish PD Association, the European Research Council, and the Knut and Alice Wallenberg Foundation. The Norwegian ParkWest study has received funding from the Research Council of Norway (177966), the Western Norway Regional Health Authority (911218), the Norwegian Parkinson’s Research Foundation, and Rebergs Legacy. The PICNICS study was funded by the Cure Parkinson’s Trust, the Van Geest Foundation, the Medical Research Council, Parkinson’s UK, and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The PINE study was funded by Parkinson’s UK (grant numbers G0502, G0914, and G1302), the Scottish Chief Scientist Office (CAF/12/05, PCL/17/10), Academy of Medical Sciences, NHS Grampian endowments, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, and SPRING. The PICC collaboration has been supported by The Chief Scientist Office of the Scottish Government (PCL/17/10), the Academy of Medical Sciences, Parkinson’s UK (initial collaborator meeting) and the Norwegian Association for Public Health. C.R.S.’s work was supported by NIH grants NINDS/NIA R01NS115144, U01NS095736, U01NS100603, and the American Parkinson Disease Association Center for Advanced Parkinson Research. This research was funded in whole, or in part by the UKRI Medical Research Council [MR/R007446/1]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD

Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts.

OBJECTIVE: To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. METHODS: We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed. RESULTS: We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69-6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04-20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16-1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19-2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (-0.72 [-1.21 to -0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27-1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21-1.03]). CONCLUSIONS: This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.The Intramural Research Program the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinson’s Researc

Differences in the Presentation and Progression of Parkinson's Disease by Sex.

BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.This study was supported by the Intramural Research Program the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinson’s Research

Identifying novel prostate cancer associated pathways based on integrative microarray data analysis

The development and diverse application of microarray and next generation sequencing technologies has made the meta-analysis widely used in expression data analysis. Although it is commonly accepted that pathway, network and systemic level approaches are more reproducible than reductionism analyses, the meta-analysis of prostate cancer associated molecular signatures at the pathway level remains unexplored. In this article, we performed a meta-analysis of 10 prostate cancer microarray expression datasets to identify the common signatures at both the gene and pathway levels. As the enrichment analysis result of GeneGo's database and KEGG database, 97.8% and 66.7% of the signatures show higher similarity at pathway level than that at gene level, respectively. Analysis by using gene set enrichment analysis (GSEA) method also supported the hypothesis. Further analysis of PubMed citations verified that 207 out of 490 (42%) pathways from GeneGo and 48 out of 74 (65%) pathways from KEGG were related to prostate cancer. An overlap of 15 enriched pathways was observed in at least eight datasets. Eight of these pathways were first described as being associated with prostate cancer. In particular, endothelin-1/EDNRA transactivation of the EGFR pathway was found to be overlapped in nine datasets. The putative novel prostate cancer related pathways identified in this paper were indirectly supported by PubMed citations and would provide essential information for further development of network biomarkers and individualized therapy strategy for prostate cancer

Fibrinogen is an independent risk factor for white matter hyperintensities in CADASIL but not in sporadic cerebral small vessel disease patients

10.14336/ad.2020.1110Aging and Disease123801-81

DNA methylation changes associated with Parkinson’s disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood

Parkinson’s Disease (PD) is a common neurodegenerative disorder currently diagnosed based on the presentation of characteristic movement symptoms. Unfortunately, patients exhibiting these symptoms have already undergone significant dopaminergic neuronal loss. Earlier diagnosis, aided by molecular biomarkers specific to PD, would improve overall patient care. Epigenetic mechanisms, which are modified by both environment and disease pathophysiology, are emerging as important components of neurodegeneration. Alterations to the PD methylome have been reported in epigenome-wide association studies. However, the extent to which methylation changes correlate with disease progression has not yet been reported; nor the degree to which methylation is affected by PD medication. We performed a longitudinal genome-wide methylation study surveying ~850,000 CpG sites in whole blood from 189 well-characterized PD patients and 191 control individuals obtained at baseline and at a follow-up visit ~2 y later. We identified distinct patterns of methylation in PD cases versus controls. Importantly, we identified genomic sites where methylation changes longitudinally as the disease progresses. Moreover, we identified methylation changes associated with PD pathology through the analysis of PD cases that were not exposed to anti-parkinsonian therapy. In addition, we identified methylation sites modulated by exposure to dopamine replacement drugs. These results indicate that DNA methylation is dynamic in PD and changes over time during disease progression. To the best of our knowledge, this is the first longitudinal epigenome-wide methylation analysis for Parkinson’s disease and reveals changes associated with disease progression and in response to dopaminergic medications in the blood methylome