Motor complications in Parkinson's disease: 13-year follow-up of the CamPaIGN cohort.

BACKGROUND: Long-term population-representative data on motor fluctuations and levodopa-induced dyskinesias in Parkinson's disease is lacking. METHODS: The Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) cohort comprises incident PD cases followed for up to 13 years (n = 141). Cumulative incidence of motor fluctuations and levodopa-induced dyskinesias and risk factors were assessed using Kaplan-Meyer and Cox regression analyses. RESULTS: Cumulative incidence of motor fluctuations and levodopa-induced dyskinesias was 54.3% and 14.5%, respectively, at 5 years and 100% and 55.7%, respectively, at 10 years. Higher baseline UPDRS-total and SNCA rs356219(A) predicted motor fluctuations, whereas higher baseline Mini-mental State Examination and GBA mutations predicted levodopa-induced dyskinesias. Early levodopa use did not predict motor complications. Both early motor fluctuations and levodopa-induced dyskinesias predicted reduced mortality in older patients (age at diagnosis >70 years). CONCLUSIONS: Our data support the hypothesis that motor complications are related to the severity of nigrostriatal pathology rather than early levodopa use and indicate that early motor complications do not necessarily confer a negative prognosis. © 2019 International Parkinson and Movement Disorder Society.This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013-R1A1A2010499). CWG is supported by a Medical Research Council Clinician Scientist Fellowship. The CamPaIGN study was supported by the Wellcome Trust, the Medical Research Council, the Patrick Berthoud Trust, and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre Dementia and Neurodegeneration Theme (Grant Reference Number 146281). RAB is an NIHR Senior Investigator

Association between MAPT haplotype and memory function in patients with Parkinson's disease and healthy aging individuals.

Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in MAPT is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging.This work was funded by Parkinson's UK, the Medical Research Council, the Wellcome Trust (088324), and the NIHR Comprehensive Biomedical Research Centre (RG64473). The BCNI is co-funded by the MRC and Wellcome Trust. Sophie E. Winder-Rhodes received PhD funding from a Merck Sharp and Dohme studentship.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.006

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

The role of tau in the pathological process and clinical expression of Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington's disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington's disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington's disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington's disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype-phenotype analysis of a large cohort of patients with Huntington's disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington's disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington's disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington's disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT haplotypes affect the rate of cognitive decline in a large cohort of patients with Huntington's disease. Our findings therefore highlight a novel important role of tau in the pathogenic process and clinical expression of Huntington's disease, which in turn opens up new therapeutic avenues for this incurable condition.The authors thank the EHDN REGISTRY Study Group investigators (listed in the Supplementary material) for collecting the data and all participating REGISTRY patients for their time and efforts, the Cambridge Brain Bank for the post-mortem tissue which is supported by a grant to the NIHR Cambridge Biomedical Research Centre and in particular to J. Wilson and Dr D. O’ Donovan. We are grateful to S. Sawcer and M. Ban in the Neurology Unit at the University of Cambridge, for their help with the genotyping, C.H. Williams-Gray at the John van Geest Centre for Brain Repair, University of Cambridge, for her help with the statistical analyses, J. Hardy, J.L. Holton, and T. Revesz at the UCL Institute of Neurology for their helpful discussions as well as K. Strand, F. Javad and A. Posada Bórbon, at the UCL Institute of Neurology, for their support with the experimental work, R. Kayed at the University of Texas Medical Branch, Galveston, for providing the TOMA and T22 antibodies. Finally, P. Tyers, R. Raha-Chowdhury, A. Tolkovsky, B. Ossola and J. Simpson for their support and encouragement throughout this work.This is the final version of the article. It was first available from Oxford University Press viahttp://dx.doi.org/10.1093/brain/awv10

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

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

Association between MAPT haplotype and memory function in patients with Parkinson's disease and healthy aging individuals.

Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in MAPT is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging.This work was funded by Parkinson's UK, the Medical Research Council, the Wellcome Trust (088324), and the NIHR Comprehensive Biomedical Research Centre (RG64473). The BCNI is co-funded by the MRC and Wellcome Trust. Sophie E. Winder-Rhodes received PhD funding from a Merck Sharp and Dohme studentship.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.006

Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study.

Parkinson's disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the 'Dual Syndrome' hypothesis for cognitive impairment in Parkinson's disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson's disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson's disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-ε2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson's disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson's disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson's disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson's disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson's disease.This study was supported by Parkinson’s UK (C.N.), Lockhart Parkinson’s Disease Research Fund (T.K.K.), Michael J. Fox Foundation (A.J.Y.), the National Institute for Health Research (NIHR, RG64473) Cambridge Biomedical Research Centre, the Wellcome Trust (JBR 088324); the Medical Research Couciil Cognition and Brain Sciences Unit, Cambridge (MC-A060-5PQ30); the NIHR Newcastle, Biomedical Research Unit based at Newcastle-upon-Tyne Hospitals, NHS Foundation Trust and Newcastle University; the NIHR Dementias and Neurodegenerative Diseases Research Network (J.T.O.) and Raymond and Beverly Sackler studentship (D.P.B.). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/brain/awu20