SevereGBA1variants drive the GBA-PD clinical phenotype: implications for counselling and clinical trials

Severe GBA1 variants drive the GBA-PD clinical phenotype: implications for counselling and clinical trials | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var 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Marco Toffoli , Nadine Loefflad , Franco Valzania , View ORCID Profile Francesco Cavallieri , Valentina Fioravanti , Selen Yalkic , Naomi Limbachiya , View ORCID Profile Fabio Blandini , View ORCID Profile Micol Avenali , View ORCID Profile Anthony HV Schapira doi: https://doi.org/10.1101/2024.12.09.24318560 Elisa Menozzi 1 Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL) , London, United Kingdom 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Elisa Menozzi Sara Lucas Del Pozo 1 Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL) , London, United Kingdom 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jane Macnaughtan 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 3 Liver Failure Group, Institute for Liver and Digestive Health, University College London , London, UK MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Roxana Mezabrovschi 1 Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL) , London, United Kingdom 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sofia Koletsi 1 Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL) , London, United Kingdom 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Pierfrancesco Mitrotti 4 Department of Brain and Behavioral Sciences , University of Pavia, Pavia, Italy 5 IRCCS Mondino Foundation , Pavia, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Luca Gallo 4 Department of Brain and Behavioral Sciences , University of Pavia, Pavia, Italy 5 IRCCS Mondino Foundation , Pavia, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rosaria Calabrese 4 Department of Brain and Behavioral Sciences , University of Pavia, Pavia, Italy 5 IRCCS Mondino Foundation , Pavia, Italy PsyD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marco Toffoli 1 Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL) , London, United Kingdom 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nadine Loefflad 1 Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL) , London, United Kingdom 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Franco Valzania 6 Neurology Unit, Neuromotor and Rehabilitation Department, Azienda USL-IRCCS di Reggio Emilia , Reggio Emilia, Italy MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Francesco Cavallieri 6 Neurology Unit, Neuromotor and Rehabilitation Department, Azienda USL-IRCCS di Reggio Emilia , Reggio Emilia, Italy MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Francesco Cavallieri Valentina Fioravanti 6 Neurology Unit, Neuromotor and Rehabilitation Department, Azienda USL-IRCCS di Reggio Emilia , Reggio Emilia, Italy MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Selen Yalkic 1 Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL) , London, United Kingdom 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Naomi Limbachiya 1 Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL) , London, United Kingdom 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fabio Blandini 4 Department of Brain and Behavioral Sciences , University of Pavia, Pavia, Italy 8 Ca’ Granda IRCCS Foundation , Ospedale Maggiore Policlinico, Milan, Italy MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Fabio Blandini Micol Avenali 4 Department of Brain and Behavioral Sciences , University of Pavia, Pavia, Italy 5 IRCCS Mondino Foundation , Pavia, Italy MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Micol Avenali Anthony HV Schapira 1 Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL) , London, United Kingdom 2 Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network , Chevy Chase, MD, 20815 MD, DSc, FRCP, FMedSci Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Anthony HV Schapira For correspondence: a.schapira{at}ucl.ac.uk Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background Variants in the GBA1 gene are the commonest genetic risk factor for Parkinson disease (PD). Genotype- phenotype correlations exist but with conflicting data, particularly in the cognitive domain. Objectives Comparing clinical phenotypes in a multicentre, international cohort incorporating GBA-PD and idiopathic PD (iPD) patients. Methods Patients underwent a comprehensive assessment of motor and non-motor functions. Two-group (GBA- PD vs iPD) and multiple-group comparisons (iPD, risk, mild, and severe variant GBA-PD) were performed. Results Three hundred eleven PD patients were recruited: 183 iPD, 39 severe GBA-PD, 24 mild GBA-PD, 55 risk GBA-PD, and 10 patients carrying variants of unknown significance. Groups were matched for sex, education, disease duration and medications. Mild and severe GBA-PD were younger and developed PD earlier. Severe GBA-PD had worse depression, cognitive impairment, hyposmia, and motor complications. Conclusions Only severe variant GBA-PD have a distinctive, more severe clinical profile. Introduction Variants in the GBA1 gene are highly prevalent in the Parkinson disease (PD) population (~10-15%). 1 In recent years, the increased recourse to GBA1 genotyping in PD, 2 the different response of patients carrying GBA1 variants (GBA-PD) to advanced treatments for PD (i.e., deep brain stimulation-DBS), 3 and the growing number of clinical trials testing GBA1 -targeted therapies, 4 have created the need for standardized guidelines for genetic counselling, management and selection of patients for clinical trials. 1 Major challenges in manifest GBA-PD include the differences in clinical severity and progression according to GBA1 variant type. 4 Several case-control studies have reported that PD patients carrying severe GBA1 variants (e.g., p.L483P) compared to carriers of mild (e.g., pN409S) or risk (e.g., p.E365K) variants, present with a more severe clinical phenotype characterised by faster progression, and worse psychiatric and cognitive dysfunction, worsened by interventions such as DBS. 3 , 5 – 8 However, recent studies have contradicted these results, reporting similar cognitive and motor deterioration in GBA1 variant carriers, regardless of variant type. 9 - 12 Phase II trials are now underway evaluating changes in cognitive function at 12 months as primary outcomes, recruiting either mild or severe variant GBA-PD. 13 An understanding of the natural clinical history of PD associated with different GBA1 variants is crucial to appropriate trial design. Here, we present our experience from a large, multi-centre, international case-control study incorporating PD patients negative (idiopathic PD-iPD) or positive for GBA1 variants (GBA-PD), the latter group being representative of all variant types (risk, mild, and severe). We highlight how the severe GBA1 variant carriers represent the only group with a remarkably different and more severe clinical phenotype compared to iPD. Our findings caution the PD community to avoid generalisation and consider GBA-PD as a clinically heterogeneous condition. Methods Study design and clinical data Participants were recruited via the RAPSODI study (University College London) in the United Kingdom, 14 and two neurology tertiary centres in Italy (IRCCS Mondino Foundation, Pavia, and Azienda USL-IRCCS, Reggio Emilia). GBA1 variants were classified into four classes (severe, mild, risk, and unknown significance) as previously reported (a list of GBA1 variants included in the study is presented in Supplementary Table 1). 15 Information about family history, disease onset, and medications was collected, and levodopa equivalent daily dose (LEDD) calculated for each participant. 16 , 17 Motor and non-motor functions were evaluated through an extensive clinical examination (see Supplementary Methods). This study was approved by the local Ethics Committees (London – Queen Square REC: 15/LO/1155; EC of Pavia: code P-20210009687; EC of Area Vasta Emilia Nord: code 2021/0092531). All participants signed informed consent upon enrolment. Statistical analysis A first set of statistical analyses were completed comparing iPD to GBA-PD. In a second set, patients were stratified according to their GBA1 variant severity into risk, mild, and severe (carriers of variants of unknown significance were excluded from this comparison because of the low numbers of individuals in this group). Study data were collected and managed using REDCap electronic data capture tools. 18 Statistical analyses were performed using R version 4.2.3. 19 Full statistical analysis methods can be found in Supplementary Methods. Results Demographic and clinical features of iPD and GBA-PD groups are summarised in Table 1 . A total of 311 PD patients (183 iPD, 128 GBA-PD) were recruited. Within the GBA-PD, 43% (N=55) carried GBA1 risk variants, 30% (N=39) severe variants, 19% (N=24) mild variants, and 8% (N=10) carried variants of unknown significance. View this table: View inline View popup Download powerpoint Table 1. Demographics and clinical features of study cohort. Two-group comparison: iPD vs GBA-PD Compared with iPD, GBA-PD patients showed a significantly younger age (61 vs 65 years) and more frequent positive family history for PD (37% vs 23% of participants). No differences in sex distribution were found between groups. In terms of disease-associated features, GBA-PD patients developed the disease 5 years earlier and had undergone DBS more frequently than iPD patients. No differences in disease duration or LEDD were identified. GBA-PD patients presented with more severe mood disorders (HADS depression: OR, 1.9; 95% CI: 1.2-3.1; p=0.01, and BDI: OR, 2.3; 95% CI: 1.5-3.7; p=0.0002), anxiety (HADS anxiety: OR, 1.8; 95% CI: 1.1-3; p=0.02), olfactory dysfunction (UPSIT: β=-2.2, p=0.002), subjective motor disability (MDS- UPDRS part II: p=0.03) and motor complications (MDS-UPDRS part IV: p=0.003), and greater cardiovascular dysfunction (p=0.03). Despite similar global cognitive function as measured by the total MOCA score, the GBA-PD group performed significantly worse in tasks evaluating visuospatial and executive functions (all p values<0.05, see Table 2 ; individual p values, ORs and CIs are reported in Supplementary Table 2). View this table: View inline View popup Download powerpoint Table 2. Performances in specific cognitive abilities (MOCA sub-scores). Clinical features in stratified GBA1 -variant type groups When patients were stratified according to GBA1 variant type, severe and mild GBA-PD were significantly younger than both risk GBA-PD (p=0.02, and p=0.01, respectively) and iPD (both p<0.001), with no difference in age between severe and mild GBA-PD. Severe and mild GBA-PD also developed PD earlier than risk GBA-PD (p=0.006 and p=0.003, respectively) and iPD (both p<0.001). Severe GBA-PD patients had a more frequent positive family history for PD (44%) and were more frequently subjected to DBS procedures compared to iPD patients ( Table 1 ). Groups were homogenous in terms of disease duration and LEDD. When clinical features were compared, severe GBA-PD patients presented with a distinct clinical profile when compared to iPD patients, but not to the risk or mild GBA-PD patients ( Table 1 ). This profile was characterised by more severe depression (HADS depression: OR, 2.7; 95% CI: 1.3- 5.3; p=0.005, and BDI: OR, 3.8; 95% CI: 2-7.4; p<0.0001), olfactory dysfunction (UPSIT: β=-3.8, p=0.0006), cognitive impairment (MOCA: β=-1.5, p=0.01), motor complications (p.adj=0.04) and a trend for more severe constipation/gastrointestinal dysfunction (see Table 1 ). Cognitive performances were worse in severe GBA-PD, also compared with risk and mild GBA-PD patients (all p values<0.01); these results remained statistically significant even after removing subjects with DBS, with only a nearly significance for the comparison between mild and severe carriers (p=0.0505), which might be due to low numbers of individuals (21 and 26, respectively) and thus loss of statistical power. Severe GBA-PD were mostly affected in visuospatial and executive function and attention abilities ( Table 2 and Supplementary Table 2). No other statistically significant differences emerged among the four groups in the severity of motor and non-motor symptoms when results were adjusted for multiple comparisons. Discussion In this large, multi-centre, international case-control study, we demonstrated the importance of considering the type of GBA1 genetic variant in research studies and clinical trials conducted on GBA- PD. Reporting findings on GBA-PD without stratifying according to GBA1 variant type, can be misleading: differences can be detected related to iPD, however these are mainly driven by severe variant carriers. Our results align with previous findings showing a more severe phenotype in severe variant carriers. 6 , 8 , 20 In a previous study comparing a large cohort of GBA-PD (139 mild, 48 severe) to 152 iPD patients, more severe depression, hallucinations, worse hyposmia, and higher frequencies of REM sleep behaviour disorder (RBD) were detected in severe GBA-PD compared to the other two groups. 20 However, this study did not include risk variant carriers, who numerically represent the predominant group of GBA-PD individuals, especially in those of Caucasian background. 1 In contrast to previous reports, we did not detect any significant cognitive impairment in carriers of risk or mild variants. One study found that both pathogenic (mix of mild and severe) variant carriers (N=60) and p.E365K carriers (N=65) had higher incidence of dementia and a greater impairment in working memory/executive function and visuospatial abilities compared to iPD, however the disease duration in these groups was mostly >7.5years, so additional factors beyond GBA1 status might have contributed to these results. 11 Cognitive decline at 7 years from diagnosis was faster in pathogenic and risk variant carriers than iPD in another study, however, the association with progression rate to dementia was much smaller in the risk variant carriers group, and no distinction was made between severe and mild variant carriers. 21 Our results showed more severe cardiovascular dysfunction in GBA-PD vs iPD, but we did not see any differences across variant types. Previous reports also found more impaired cardiovascular autonomic control characterised by a lower parasympathetic modulation at rest and a lower parasympathetic modulation in response to active standing, in GBA-PD compared to iPD. 22 GBA-PD also presented a lower heart-to-mediastinum uptake ratio in 123 I-meta-iodobenzylguanidine scintigraphy suggestive of reduced cardiac sympathetic denervation, 23 and greater cardiac sympatho-vagal demodulation. 24 The latter study detected greater impairment in cardiovagal function in severe GBA-PD compared to risk and mild GBA-PD combined together, but numbers were small. 24 Nonetheless, these findings make this area worth investigating in the future. In our study, we observed higher scores in the SCOPA pupillomotor subdomain in severe GBA-PD, which might be related to a more extreme pupillary parasympathetic dysfunction in this group. Interestingly, pupillomotor abnormalities suggestive of dysfunctional parasympathetic innervation were also detected in individuals with neuronopathic Gaucher disease, caused by biallelic pathogenic variants in GBA1 , 25 or with Fabry disease, another lysosomal storage disorder. 26 Several disease-modifying therapies targeting the GBA1 pathway are in Phase II/III of clinical trial stage, aiming to halt/slow GBA-PD progression. 4 , 27 Recently, a Phase II, randomized-controlled trial (MOVES-PD), testing the effect of the glucosylceramide synthase inhibitor Venglustat in GBA-PD patients, did not meet its primary endpoint, and showed paradoxical worsening of motor symptoms in mild GBA-PD treated with Venglustat. 28 This highlight the need to refine patients’ selection and stratify individuals for variant severity in trials targeting the GBA-PD population in order to optimise chances of success. 28 Our study has some limitations. First, the relatively small number of individuals with severe and mild GBA-PD might have undermined the results. Second, this is a case-control study, however a 2-year follow-up assessment of this cohort is in progress. Despite these limitations, we believe that this study provides clinicians with useful information to approach their GBA-PD patients in the clinic, tailoring their counselling on prognosis and disease trajectories, and integrating our recent consensus guidance on PD risk. 1 Moreover, we hope that these findings will inform researchers involved in clinical trials to improve the design of such studies and guide the choice of realistic outcomes in the correct patient groups. Finally, this study provides insight into the pathophysiological mechanisms underlying disease severity in GBA-PD. Data Availability All data produced in the present study are available upon reasonable request to the authors. Conflict of Interest Statement EM, SLDP, JM, SK, PM, LG, RC, MT, NL, FV, FC, VF, NL, FB and MA have no conflicts to disclose. RM and SY are supported by a Royal Free Charity fellowship. AHVS has provided paid consultancy to Capsida, Neurocrine and Auxilius, is the Chief Investigator of the ambroxol phase III study and a Principal Investigator of the MOVES-PD study. Authors’ Roles Research project: A. Conception, B. Organization, C. Execution. Statistical Analysis: A. Design, B. Execution, C. Review and Critique. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. EM: 1A, 1B, 1C, 2A, 2B, 2C, 3A. SLDP: 1A, 1B, 1C, 3B. JM: 1A, 1B, 1C, 3B. RM: 1B, 1C, 3B. SK: 1B, 3B. PM: 1B, 1C, 3B. LG: 1B, 1C, 3B. RC: 1B, 1C, 3B. MT: 1B, 1C, 3B. NL: 1B, 1C, 3B. FV: 1C, 3B. FC: 1C, 3B. VF: 1C, 3B. SY: 1B, 1C, 3B. NL: 1B, 1C, 3B. FB: 1A, 1B, 2C, 3B. MA: 1A, 1B, 1C, 2C, 3B. AHVS: 1A, 1B, 2C, 3B. Acknowledgments This research was funded in part by Aligning Science Across Parkinson’s (Grant number: ASAP- 000420) through the Michael J. Fox Foundation for Parkinson’s Research (MJFF) and by the EU Joint Programme—Neurodegenerative Research (JPND: GBA-PaCTS) through the MRC grant code MR/T046007/1. For the purpose of open access, the author has applied a CC BY 4.0 public copyright license to all Author Accepted Manuscripts arising from this submission. Footnotes ↵ $ senior authors Table 1 and 2 revised; Supplemental files revised; part of the text revised. References 1. ↵ Vieira SRL , Mezabrovschi R , Toffoli M , et al. Consensus Guidance for Genetic Counseling in GBA1 Variants: A Focus on Parkinson’s Disease . Mov Disord 2024 . 2. ↵ Skrahina V , Gaber H , Vollstedt EJ , et al. The Rostock International Parkinson’s Disease (ROPAD) Study: Protocol and Initial Findings . Mov Disord 2021 ; 36 ( 4 ): 1005 – 1010 . OpenUrl CrossRef PubMed 3. ↵ Pal G , Mangone G , Hill EJ , et al. 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Share Severe GBA1 variants drive the GBA-PD clinical phenotype: implications for counselling and clinical trials Elisa Menozzi , Sara Lucas Del Pozo , Jane Macnaughtan , Roxana Mezabrovschi , Sofia Koletsi , Pierfrancesco Mitrotti , Luca Gallo , Rosaria Calabrese , Marco Toffoli , Nadine Loefflad , Franco Valzania , Francesco Cavallieri , Valentina Fioravanti , Selen Yalkic , Naomi Limbachiya , Fabio Blandini , Micol Avenali , Anthony HV Schapira medRxiv 2024.12.09.24318560; doi: https://doi.org/10.1101/2024.12.09.24318560 Share This Article: Copy Citation Tools Severe GBA1 variants drive the GBA-PD clinical phenotype: implications for counselling and clinical trials Elisa Menozzi , Sara Lucas Del Pozo , Jane Macnaughtan , Roxana Mezabrovschi , Sofia Koletsi , Pierfrancesco Mitrotti , Luca Gallo , Rosaria Calabrese , Marco Toffoli , Nadine Loefflad , Franco Valzania , Francesco Cavallieri , Valentina Fioravanti , Selen Yalkic , Naomi Limbachiya , Fabio Blandini , Micol Avenali , Anthony HV Schapira medRxiv 2024.12.09.24318560; doi: https://doi.org/10.1101/2024.12.09.24318560 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Neurology Subject Areas All Articles Addiction Medicine (573) Allergy and Immunology (865) Anesthesia (302) Cardiovascular Medicine (4453) Dentistry and Oral Medicine (444) Dermatology (383) Emergency Medicine (609) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1515) Epidemiology (15242) Forensic Medicine (30) Gastroenterology (1131) Genetic and Genomic Medicine (6615) Geriatric Medicine (669) Health Economics (1001) Health Informatics (4552) Health Policy (1372) Health Systems and Quality Improvement (1614) Hematology (543) HIV/AIDS (1270) Infectious Diseases (except HIV/AIDS) (15929) Intensive Care and Critical Care Medicine (1106) Medical Education (624) Medical Ethics (147) Nephrology (670) Neurology (6625) Nursing (346) Nutrition (999) Obstetrics and Gynecology (1148) Occupational and Environmental Health (957) Oncology (3344) Ophthalmology (979) Orthopedics (369) Otolaryngology (421) Pain Medicine (436) Palliative Medicine (130) Pathology (665) Pediatrics (1696) Pharmacology and Therapeutics (693) Primary Care Research (714) Psychiatry and Clinical Psychology (5461) Public and Global Health (9252) Radiology and Imaging (2207) Rehabilitation Medicine and Physical Therapy (1371) Respiratory Medicine (1197) Rheumatology (597) Sexual and Reproductive Health (715) Sports Medicine (530) Surgery (714) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a02eb7f07ba158f4',t:'MTc3OTk4NjYwOA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();