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1. The mitochondrial citrate carrier SLC25A1 regulates metabolic reprogramming and morphogenesis in the developing heart

Author

Chiemela Ohanele, Jessica N. Peoples, Anja Karlstaedt, Joshua T. Geiger, Ashley D. Gayle, Nasab Ghazal, Fateemaa Sohani, Milton E. Brown, Michael E. Davis, George A. Porter, Victor Faundez, and Jennifer Q. Kwong

Subjects
Biology (General), QH301-705.5
Abstract

Abstract The developing mammalian heart undergoes an important metabolic shift from glycolysis towards mitochondrial oxidation that is critical to support the increasing energetic demands of the maturing heart. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mitochondrial citrate carrier (SLC25A1) knockout mice. Slc25a1 null embryos displayed impaired growth, mitochondrial dysfunction and cardiac malformations that recapitulate the congenital heart defects observed in 22q11.2 deletion syndrome, a microdeletion disorder involving the SLC25A1 locus. Importantly, Slc25a1 heterozygous embryos, while overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 haploinsuffiency and dose-dependent effects. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of gene expression to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of cardiac morphogenesis and metabolic maturation, and suggests a role in congenital heart disease.

Published
2024
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2. Balloon-expandable covered stenting of a large right hepatic artery aneurysm

Author

Baqir J. Kedwai, BHSc, Matthew Byrne, MD, Joshua T. Geiger, MD, Sam Najjar, BS, Michael C. Stoner, MD, and Doran S. Mix, MD

Subjects
Hepatic artery, Aneurysm, Endovascular, Stent, Balloon expandable, Surgery, RD1-811, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Hepatic artery aneurysms (HAAs) are rare visceral aneurysms with a high rupture rate. We report the case of an 88-year-old man with a 4.2-cm right HAA treated with covered stenting. Balloon-expandable covered stents effectively excluded the HAA with excellent proximal and distal seals. Our case is one of a limited number of reports on successfully repairing a hepatic aneurysm with a balloon-expandable stent graft. This case demonstrates that balloon expandable covered stenting is a viable approach in patients with appropriate anatomy and may be favorable in patients precluded from open bypass.

Published
2024
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3. Stenting of a hepatic artery pseudoaneurysm rupture secondary to a celiac artery dissection

Author

Baqir J. Kedwai, BHSc, Matthew Byrne, MD, Joshua T. Geiger, MD, Daniel J. Lehane, BA, Doran S. Mix, MD, and Michael C. Stoner, MD

Subjects
Endovascular, Hepatic artery, Pseudoaneurysm, Stent, Vasculitis, Surgery, RD1-811, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Hepatic artery (HA) pseudoaneurysm rupture is a rare and potentially lethal pathology. We present the case of a celiac artery dissection complicated by an HA pseudoaneurysm rupture that was treated successfully with endovascular stenting. The patient's postoperative course was uncomplicated, and he was further evaluated for an underlying connective tissue disorder. There is no standard treatment for a ruptured HA pseudoaneurysm, although transarterial embolization is most frequently reported. This report demonstrates that self-expanding stent grafts are effective in the emergent repair of HA pseudoaneurysm rupture.

Published
2024
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4. TUBB2B Mutation in an Adult Patient with Myoclonus-Dystonia

Author

Joshua T. Geiger, Alice B. Schindler, Cornelis Blauwendraat, Harvey S. Singer, and Sonja W. Scholz

Subjects
Tubulinopathy, TUBB2B, Dystonia, Myoclonus, Neuronal migration disorder, Genetic testing, Genotype-phenotype correlation, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Tubulin mutations are a cause of neuronal migrational disorders referred to as tubulinopathies. Mutations in tubulin genes can have a severe impact on microtubule function and result in heterogeneous clinical presentations. Current understanding of the clinical spectrum of tubulinopathies is predominantly based on research in fetal tissue and early-childhood cases. Methods: Testing of candidate genes followed by whole-exome sequencing was performed in an adult woman with a neurodevelopmental, hyperkinetic movement disorder, to identify the underlying genetic cause. Bioinformatic modeling and a systematic review of literature was conducted to investigate genotype-phenotype correlations. Results: The patient was found to carry a heterozygous, de novo c.722G>A, p.R241H mutation in a conserved domain of TUBB2B, encoding the β-isoform of tubulin. In silico analysis indicated that this mutation was pathogenic. On neuroimaging, the patient had asymmetric pachygyria and dysmorphic basal ganglia. Her neurological examination demonstrated mild cognitive impairment, myoclonus-dystonia, and skeletal anomalies. Conclusions: Here, we report the unique phenotype of an adult TUBB2B mutation carrier. This case illustrates a relatively mild phenotype compared to previously described fetal and early childhood cases. This highlights the importance of obtaining molecular genetic testing in individuals with a high probability of a genetic disease, including undiagnosed adult patients.

Published
2017
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5. Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Author

Joshua T. Geiger, Jinhui Ding, Barbara Crain, Olga Pletnikova, Christopher Letson, Ted M. Dawson, Liana S. Rosenthal, Alexander Pantelyat, J. Raphael Gibbs, Marilyn S. Albert, Dena G. Hernandez, Argye E. Hillis, David J. Stone, Andrew B. Singleton, John A. Hardy, Juan C. Troncoso, and Sonja W. Scholz

Subjects
Dementia with Lewy bodies, Exome sequencing, Alzheimer dementia, Lewy body dementia, GBA, PSEN1, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value

Published
2016
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6. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040

Author

Karissa C. Arthur, Andrea Calvo, T. Ryan Price, Joshua T. Geiger, Adriano Chiò, and Bryan J. Traynor

Subjects
Science
Abstract

The socioeconomic burden of amyotrophic lateral sclerosis (ALS) is high, but the projected number of cases in the upcoming years is unclear. Here, the authors estimate the number and distribution of ALS cases to 2040, and show that cases are projected to increase, particularly in developing nations.

Published
2016
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7. Mitochondrial citrate carrier SLC25A1 is a dosage-dependent regulator of metabolic reprogramming and morphogenesis in the developing heart

Author

Chiemela Ohanele, Jessica N. Peoples, Anja Karlstaedt, Joshua T. Geiger, Ashley D. Gayle, Nasab Ghazal, Fateemaa Sohani, Milton E. Brown, Michael E. Davis, George A. Porter, Victor Faundez, and Jennifer Q. Kwong

Subjects
Article
Abstract

SUMMARYThe developing mammalian heart undergoes an important metabolic shift from glycolysis toward mitochondrial oxidation, such that oxidative phosphorylation defects may present with cardiac abnormalities. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mice with systemic loss of the mitochondrial citrate carrier SLC25A1.Slc25a1null embryos displayed impaired growth, cardiac malformations, and aberrant mitochondrial function. Importantly,Slc25a1haploinsufficient embryos, which are overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggestingSlc25a1dose-dependent effects. Supporting clinical relevance, we found a near-significant association between ultrarare human pathogenicSLC25A1variants and pediatric congenital heart disease. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of PPARγ to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of ventricular morphogenesis and cardiac metabolic maturation and suggests a role in congenital heart disease.

Published
2023
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8. Association Between the Atherosclerotic Disease Risk Score and Carotid Artery Stenosis

Author

Joshua T. Geiger, Mark D. Balceniuk, Michael C. Stoner, Armand Sebastian, Claire M. Motyl, Roan J. Glocker, Adam J. Doyle, and Brian Ayers

Subjects
Male, medicine.medical_specialty, Multivariate analysis, Youden's J statistic, Disease, Risk Assessment, Severity of Illness Index, Asymptomatic, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Carotid Stenosis, Aged, Retrospective Studies, Ultrasonography, Aged, 80 and over, Framingham Risk Score, business.industry, Area under the curve, Atherosclerotic disease, Middle Aged, Atherosclerosis, medicine.disease, Stenosis, Carotid Arteries, Logistic Models, ROC Curve, 030220 oncology & carcinogenesis, Cardiology, Female, 030211 gastroenterology & hepatology, Surgery, medicine.symptom, business
Abstract

Carotid artery stenosis (CAS) is the most frequently detected treatable cause of ischemic stroke. However, there are no recommendations to screen asymptomatic patients. The atherosclerotic cardiovascular disease (ASCVD) risk score estimates individuals' 10-year risk for developing cardiovascular disease. The objective of this study is to identify a relationship between the ASCVD risk score and moderate/severe CAS based on ultrasound findings.We performed a single-institution retrospective review of patients who underwent a surveillance ultrasound for CAS between 2015 and 2018. We used Strandness velocity criteria to separate patients into two cohorts: none to mild CAS (50%) and moderate/severe CAS (≥50%). We performed Student's t-test, multivariate analysis, and receiver operator characteristic (ROC) curve analysis to determine a relationship between the ASCVD risk score and degree of CAS. We evaluated a new risk score model based on stepwise logistic regression of significant variables on univariate analysis.Two thousand eight hundred and fifty-six patients with carotid ultrasounds (1623 with none to mild, 1161 with moderate, and 72 with severe disease) were included in the study. The ASCVD risk score significantly predicted moderate/severe CAS in an adjusted multivariate analysis. Each 10% increase in the ASCVD risk score corresponded to an additional 11% likelihood of moderate/severe stenosis (OR: 1.11 [1.04-1.20], P = 0.004). The ROC area under the curve for predicting moderate/severe CAS based on the ASCVD risk score was 0.59 (Youden index (J) = 0.14); the optimized ASCVD cutoff point was 28.4%. Our new atherosclerotic disease model demonstrated increased odds of moderate/severe CAS with scores greater than zero (ROC area under the curve = 0.57).This is the first study to demonstrate an association between atherosclerotic disease risk factors as measured by the ASCVD risk score and moderate/severe CAS. However, this tool is not sensitive or specific for using the ASCVD risk score as a screening mechanism for moderate/severe CAS.

Published
2021
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9. Neither cardiac mitochondrial DNA variation nor copy number contribute to congenital heart disease risk

Author

Jon A.L. Willcox, Joshua T. Geiger, Sarah U. Morton, David McKean, Daniel Quiat, Joshua M. Gorham, Angela C. Tai, Steven DePalma, Daniel Bernstein, Martina Brueckner, Wendy K. Chung, Alessandro Giardini, Elizabeth Goldmuntz, Jonathan R. Kaltman, Richard Kim, Jane W. Newburger, Yufeng Shen, Deepak Srivastava, Martin Tristani-Firouzi, Bruce Gelb, George A. Porter, J.G. Seidman, and Christine E. Seidman

Subjects
Heart Defects, Congenital, DNA Copy Number Variations, Cardiovascular, DNA, Mitochondrial, Medical and Health Sciences, Congenital, Clinical Research, Report, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), Heart Defects, Pediatric, Genetics & Heredity, DNA, mitochondrial copy number, Biological Sciences, congenital heart disease, Mitochondria, Mitochondrial, genome sequencing, Heart Disease, mitochondrial genome, Mutation, Congenital Structural Anomalies
Abstract

The well-established manifestation of mitochondrial mutations in functional cardiac disease (e.g., mitochondrial cardiomyopathy) prompted the hypothesis that mitochondrial DNA (mtDNA) sequence and/or copy number (mtDNAcn) variation contribute to cardiac defects in congenital heart disease (CHD). MtDNAcns were calculated and rare, non-synonymous mtDNA mutations were identified in 1,837 CHD-affected proband-parent trios, 116 CHD-affected singletons, and 114 paired cardiovascular tissue/blood samples. The variant allele fraction (VAF) of heteroplasmic variants in mitochondrial RNA from 257 CHD cardiovascular tissue samples was also calculated. On average, mtDNA from blood had 0.14 rare variants and 52.9 mtDNA copies per nuclear genome per proband. No variation with parental age at proband birth or CHD-affected proband age was seen. mtDNAcns in valve/vessel tissue (320 ± 70) were lower than in atrial tissue (1,080 ± 320, p= 6.8E-21), which were lower than in ventricle tissue (1,340 ± 280, p= 1.4E-4). The frequency of rare variants in CHD-affected individual DNA was indistinguishable from the frequency in an unaffected cohort, and proband mtDNAcns did not vary from those of CHD cohort parents. In both the CHD and the comparison cohorts, mtDNAcns were significantly correlated between mother-child, father-child, and mother-father. mtDNAcns among people with European (mean= 52.0), African (53.0), and Asian haplogroups (53.5) were calculated and were significantly different for European and Asian haplogroups (p= 2.6E-3). Variant heteroplasmic fraction (HF) in blood correlated well with paired cardiovascular tissue HF (r= 0.975) and RNA VAF (r= 0.953), which suggests blood HF is a reasonable proxy for HF in heart tissue. We conclude that mtDNA mutations and mtDNAcns are unlikely to contribute significantly to CHD risk.

Published
2022

11. Surgeon volume and established hospital perioperative mortality rate together predict for superior outcomes after open abdominal aortic aneurysm repair

Author

Adam J. Doyle, Joshua T. Geiger, Fergal J. Fleming, and Michael C. Stoner

Subjects
Relative risk reduction, Male, medicine.medical_specialty, Time Factors, New York, Workload, Risk Assessment, Postoperative Complications, medicine, Humans, Hospital Mortality, Aged, Quality Indicators, Health Care, Retrospective Studies, Surgeons, business.industry, Proportional hazards model, Mortality rate, Hazard ratio, Postoperative complication, Perioperative, Vascular surgery, medicine.disease, Abdominal aortic aneurysm, Surgery, Treatment Outcome, Female, Clinical Competence, Cardiology and Cardiovascular Medicine, business, Vascular Surgical Procedures, Hospitals, High-Volume, Aortic Aneurysm, Abdominal, Follow-Up Studies
Abstract

BACKGROUND In 2018, the Society for Vascular Surgery (SVS) published hospital volume guidelines for elective open abdominal aortic aneurysm (AAA) repair, recommending that elective open surgical repair of AAAs should be performed at centers with an annual volume of ≥10 open aortic operations of any type and a documented perioperative mortality of ≤5%. Recent work has suggested a yearly surgeon volume of at least seven open aortic cases for improved outcomes. The objective of the present study was to assess the importance of hospital volume and surgeon volume at these cut points for predicting 1-year mortality after open surgical repair of AAAs. METHODS We evaluated patients who had undergone elective open AAA repair using the New York Statewide Planning and Research Cooperative System database from 2003 to 2014. The effect of the SVS guidelines on postoperative mortality and complications was evaluated. Confounding between the hospital and surgeon volumes was identified using mixed effects multivariate Cox proportional hazards analysis. The effect of the interactions between hospital volume, established hospital perioperative survival, and surgeon volume on postoperative outcomes was also investigated. RESULTS The cohort consisted of 7594 elective open AAA repairs performed by 542 surgeons in 137 hospitals during the 12-year study period. Analysis of the 2018 guidelines using the Statewide Planning and Research Cooperative System database revealed 1-year and 30-day mortality rates of 9.2% (range, 8.3%-10.1%) and 3.5% (range, 2.9%-4.1%) for centers that were within the SVS guidelines and 13.6% (range, 12.5%-14.7%) and 6.9% (range, 6.1%-7.8%) for those that were outside the guidelines, respectively (P < .001 for both). Multivariate survival analysis revealed a hazard ratio for a surgeon volume of ≥7, hospital volume of ≥10, and hospital 3-year perioperative mortality of ≤5% of 0.80 (95% confidence interval [CI], 0.70-0.93; P = .003), 0.91 (95% CI, 0.77-1.08; P = .298), and 0.72 (95% CI, 0.62-0.82; P < .001), respectively. Additionally, procedures performed by surgeons with a yearly average volume of open aortic operations of at least seven and at hospitals with an established elective open AAA repair perioperative mortality rate of ≤5% showed improved 1-year (33.2% relative risk reduction; P < .001) and 30-day (P = .001) all-cause survival and improved postoperative complication rates. CONCLUSIONS These data have demonstrated that centers that meet the SVS AAA volume guidelines are associated with improved 1-year and 30-day all-cause survival. However, the results were confounded by surgeon volume. A surgeon open aortic volume of at least seven procedures and an established hospital perioperative mortality of ≤5% each independently predicted for 1-year survival after open AAA repair, with the hospital volume less important. These results indicate that surgeons with an annual volume of at least seven open aortic operations of any type should perform elective open AAA repair at centers with a documented perioperative mortality of ≤5%.

Published
2021

12. A Reappraisal of CT Angiography Derived Duplex Ultrasound Velocity Criteria With a Comparison to Digital Subtraction Angiography in Patients With Carotid Artery Stenosis

Author

Claire M. Motyl, Christian L. Dohring, Michael C. Stoner, Adam J. Doyle, Maxwell L. Wang, and Joshua T. Geiger

Subjects
Male, Computed Tomography Angiography, 030204 cardiovascular system & hematology, Severity of Illness Index, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, medicine.artery, medicine, Humans, Carotid Stenosis, cardiovascular diseases, Common carotid artery, Computed tomography angiography, Aged, Retrospective Studies, Aged, 80 and over, Ultrasonography, Doppler, Duplex, medicine.diagnostic_test, Receiver operating characteristic, business.industry, Ultrasound, Angiography, Digital Subtraction, Reproducibility of Results, General Medicine, Digital subtraction angiography, Middle Aged, medicine.disease, Stenosis, Duplex (building), Regional Blood Flow, Angiography, Surgery, Female, Cardiology and Cardiovascular Medicine, business, Nuclear medicine, Blood Flow Velocity
Abstract

Background Traditionally, carotid duplex ultrasound (CDUS) velocity criteria have been derived from angiography. Recent studies support a shift toward computed tomography angiography (CTA) derived velocity criteria; however, they lack a comparison to angiography. The purposes of this study are to validate CTA derived measurements with digital subtraction angiography (DSA) and to update our previous CTA-derived velocity criteria for 50% and 80% stenosis. Methods All patients between 2010 and 2019 who underwent CDUS and a neck CTA within 6 months were identified for a retrospective review. Vessel diameter and corresponding CDUS data were recorded. Additional DSA measurements were recorded for a subset of patients. Data from this cohort were added to a previously reported deidentified data set from patients between 2000 and 2009. Receiver operating characteristic (ROC) curves were generated to determine optimal velocity thresholds. Spearman rank correlation was used to correlate measurements obtained by CTA to those obtained by DSA. Results A total of 1139 vessels from 636 patients were analyzed. ROC analysis to identify ≥ 50% stenosis resulted in optimized thresholds of 143 cm/sec, 46.2 cm/sec, and 2.15 for peak systolic velocity (PSV), end-diastolic velocity (EDV), and PSV to common carotid artery PSV ratio (PSVR), respectively. ROC analysis to identify ≥ 80% stenosis resulted in optimized thresholds of 319 cm/sec, 87.2 cm/sec, and 3.49 for PSV, EDV, and PSVR, respectively. The degree of carotid artery stenosis for a subset of 124 vessels on CTA correlated well with that of DSA (ρ = 0.89, P Conclusions These data demonstrate a high correlation between measurements obtained on CTA and DSA while forming reliable CTA-derived CDUS velocity criteria.

Published
2021

13. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture

Author

Pentti J. Tienari, James B. Leverenz, Nahid Tayebi, Gabriele Mora, Bradley F. Boeve, Laura Palmer, Steve M. Gentleman, Ellen Sidransky, Pau Pastor, Liana S. Rosenthal, G. Xiromerisiou, Sara Saez-Atienzar, Francesco Landi, Scott M. Kaiser, Qinwen Mao, Claire Troakes, Peter St George-Hyslop, Andrea Calvo, Suzanne Lesage, Mario Masellis, Randy Woltjer, Marilyn S. Albert, Thomas T. Warner, Lorraine N. Clark, Gregory Klein, Charles Duyckaerts, Seth Love, Ed Monuki, Lawrence S. Honig, Kelley Faber, Dennis W. Dickson, Lucy Norcliffe-Kaufmann, Cornelis Blauwendraat, Ronald C. Kim, Kevin Morgan, Clifton L. Dalgard, Joshua T. Geiger, Ali Torkamani, Jinhui Ding, Juan Fortea, Eliezer Masliah, Ekaterina Rogaeva, Matthew H. Perkins, Clemens R. Scherzer, John Q. Trojanowski, Zbigniew K. Wszolek, Glenda M. Halliday, Jordi Clarimón, Sonja W. Scholz, Olaf Ansorge, Makayla K. Portley, Toshiko Tanaka, Mary B. Makarious, Safa Al-Sarraj, Giancarlo Logroscino, John D. Eicher, Neill R. Graff-Radford, Carmen Lage, Ziv Gan-Or, Francesca Brett, Alison Goate, Raffaele Ferrari, John C. Morris, J. Raphael Gibbs, Lynn M. Bekris, Jose-Alberto Palma, Angela K. Hodges, Regina H. Reynolds, Alexis Brice, Monica Diez-Fairen, Coralie Viollet, Patrick May, Minna Oinas, Erika Salvi, Vivianna M. Van Deerlin, Estrella Morenas-Rodríguez, Anni Moore, Zane Jaunmuktane, Eileen H. Bigio, Daniele Cusi, Douglas Galasko, Ruth Chia, Kathy L. Newell, Isabel Santana, Claudia Schulte, David Goldstein, Thomas Gasser, Owen A. Ross, Walter A. Kukull, Tatiana Foroud, Chad A. Caraway, David A. Bennett, Samreen Ahmed, Lilah M. Besser, Antonio Canosa, Daniel Alcolea, Yevgeniya Abramzon, Elisabet Londos, Laura Parkkinen, Sandra E. Black, Eric Topol, Marya S. Sabir, Olga Pletnikova, Grisel Lopez, Tanis J. Ferman, Johannes Attems, Matthew J. Barrett, Margaret E. Flanagan, Horacio Kaufmann, Stuart Pickering Brown, Jon Infante, Ryan C. Bohannan, Alberto Lleó, Eloy Rodríguez-Rodríguez, Huw R. Morris, Gianluca Floris, Ted M. Dawson, Maura Brunetti, Alan E. Renton, Andrew B. Singleton, Karen Marder, Alan J. Thomas, Pascual Sanchez-Juan, Adriano Chiò, Nigel J. Cairns, David J. Stone, Tammaryn Lashley, Mike A. Nalls, Bernardino Ghetti, Sara Bandres-Ciga, Zalak Shah, Ian G. McKeith, Susan M. Resnick, Julia Keith, Liisa Myllykangas, Diego Albani, Christopher M. Morris, Vikram Shakkottai, M. Ryten, Ronald L. Walton, Isabel González-Aramburu, Luigi Ferrucci, Bryan J. Traynor, Amanda B. Kuzma, Afina W. Lemstra, Thomas G. Beach, Juan C. Troncoso, Emil K. Gustavsson, Maurizio Grassano, John Hardy, Geidy E. Serrano, Rejko Krüger, Dag Aarsland, Bension S. Tilley, and Dena G. Hernandez

Subjects
0303 health sciences, Lewy body, Disease, Computational biology, Biology, medicine.disease, DNA sequencing, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, medicine, Dementia, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Published
2020
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15. Surgeon Volume And Established Hospital Peri-operative Mortality Rate Together Predict Superior Outcomes After Open AAA Repair

Author

Michael C. Stoner, Fergal J. Fleming, Joshua T. Geiger, and Adam J. Doyle

Subjects
Surgical repair, medicine.medical_specialty, Proportional hazards model, business.industry, General surgery, Mortality rate, General Medicine, Perioperative, medicine.disease, Abdominal aortic aneurysm, Hospital volume, Cohort, medicine, Surgery, Cardiology and Cardiovascular Medicine, business, Surgeon volume
Abstract

BACKGROUND In 2018, the SVS published hospital volume guidelines for elective open abdominal aortic aneurysm (AAA) repair, recommending elective open surgical repair for AAA be performed at centers with an annual volume of at least 10 open aortic operations of any type and a documented perioperative mortality of 5% or less. Recent work suggests a yearly surgeon volume of ≥7 open aortic cases for improved outcomes. The objective of this study is to assess the importance of hospital volume and surgeon volume at these cut points in predicting 1-year mortality after OSR for AAA. METHODS We evaluated patients undergoing elective open AAA repair using The New York Statewide Planning and Research Cooperative System database from 2003 to 2014. The effect of the SVS guidelines on postoperative mortality and complications was evaluated. Confounding between hospital and surgeon volume was identified using mixed-effects multivariate cox proportional hazards analysis. The effect of interactions between hospital volume, established hospital perioperative survival, and surgeon volume on post-operative outcomes was investigated. RESULTS The cohort consisted of 7,594 elective open AAA repairs performed by 542 surgeons in 137 hospitals over the 12 years. Analysis of the 2018 guidelines using the SPARCS database resulted in 1-year and 30-day mortality rates of 9.2% (8.3–10.1) and 3.5% (2.9-4.1) for centers that were within the guidelines and 13.6% (12.5–14.7) and 6.9% (6.1-7.8) for those that were outside the guidelines, respectively (both p CONCLUSIONS These data demonstrate centers that meet the SVS AAA volume guidelines are associated with improved 1-year and 30-day all-cause survival; however, are confounded by surgeon volume. Surgeon open aortic volume ≥7 and established hospital perioperative mortality of ≤5% each independently predict 1-year survival after open AAA repair, while hospital volume is less important. Surgeons with an annual volume of at least 7 open aortic operations of any type should perform elective open AAA repair at centers with a documented perioperative mortality of 5% or less.

Published
2021
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16. Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Author

Sonja W. Scholz, Dena G. Hernandez, Juan C. Troncoso, David J. Stone, Alexander Pantelyat, Ted M. Dawson, Olga Pletnikova, J. Raphael Gibbs, John Hardy, Barbara J. Crain, Christopher Letson, Argye E. Hillis, Liana S. Rosenthal, Andrew B. Singleton, Marilyn S. Albert, Joshua T. Geiger, and Jinhui Ding

Subjects
Lewy Body Disease, Male, Exome sequencing, 0301 basic medicine, Dementia with Lewy bodies, Biology, Article, lcsh:RC321-571, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Humans, Missense mutation, Dementia, Genetic Predisposition to Disease, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Allele frequency, Aged, Genetic testing, Aged, 80 and over, PSEN1, Genetics, Alzheimer dementia, Lewy body, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, 030104 developmental biology, Neurology, Mutation, North America, Mutation (genetic algorithm), Female, Lewy Bodies, GBA, Lewy body dementia, 030217 neurology & neurosurgery
Abstract

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value

Published
2016
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17. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Published
2018
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18. C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

Author

Sonja W. Scholz, Olga Pletnikova, Alexander Pantelyat, Barbara J. Crain, Liana S. Rosenthal, Juan C. Troncoso, Joshua T. Geiger, Ted M. Dawson, Marilyn S. Albert, Argye E. Hillis, and Karissa C. Arthur

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, business.industry, Dementia with Lewy bodies, Extramural, medicine.disease, C9orf72 Protein, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, C9orf72, mental disorders, medicine, Neurology (clinical), Amyotrophic lateral sclerosis, Repeat analysis, Neurodegenerative dementia, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion. Objective: To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients. Methods: We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay. Results: No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB. Conclusion: Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases.

Published
2016
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19. Genetic analysis of neurodegenerative diseases in a pathology cohort

Author

Cornelis Blauwendraat, Olga Pletnikova, Joshua T. Geiger, Natalie A. Murphy, Yevgeniya Abramzon, Gay Rudow, Adamantios Mamais, Marya S. Sabir, Barbara Crain, Sarah Ahmed, Liana S. Rosenthal, Catherine C. Bakker, Faraz Faghri, Ruth Chia, Jinhui Ding, Ted M. Dawson, Alexander Pantelyat, Marilyn S. Albert, Mike A. Nalls, Susan M. Resnick, Luigi Ferrucci, Mark R. Cookson, Argye E. Hillis, Juan C. Troncoso, and Sonja W. Scholz

Subjects
Male, 0301 basic medicine, Aging, Genotyping Techniques, Disease, Biology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Genetic analysis, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, C9orf72, PSEN1, medicine, Humans, Genotyping, Genetic Association Studies, Aged, Aged, 80 and over, Genetics, DNA Repeat Expansion, C9orf72 Protein, General Neuroscience, Neurodegeneration, Neurodegenerative Diseases, Middle Aged, medicine.disease, LRRK2, High-Throughput Screening Assays, 030104 developmental biology, Molecular Diagnostic Techniques, Mutation, Cohort, Female, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Molecular genetic research provides unprecedented opportunities to examine genotype-phenotype correlations underlying complex syndromes. To investigate pathogenic mutations and genotype-phenotype relationships in diverse neurodegenerative conditions, we performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center (n = 1243 patients). We used NeuroChip genotyping and C9orf72 hexanucleotide repeat analysis to rapidly screen our cohort for disease-causing mutations. In total, we identified 42 individuals who carried a pathogenic mutation in LRRK2, GBA, APP, PSEN1, MAPT, GRN, C9orf72, SETX, SPAST, or CSF1R, and we provide a comprehensive description of the diverse clinicopathological features of these well-characterized cases. Our study highlights the utility of high-throughput genetic screening arrays to establish a molecular diagnosis in individuals with complex neurodegenerative syndromes, to broaden disease phenotypes and to provide insights into unexpected disease associations.

Published
2019
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20. C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

Author

Joshua T, Geiger, Karissa C, Arthur, Ted M, Dawson, Liana S, Rosenthal, Alexander, Pantelyat, Marilyn, Albert, Argye E, Hillis, Barbara, Crain, Olga, Pletnikova, Juan C, Troncoso, and Sonja W, Scholz

Subjects
Aged, 80 and over, Lewy Body Disease, Male, DNA Repeat Expansion, C9orf72 Protein, Mutation, Humans, Proteins, Female, White People, Article, Aged
Abstract

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion.To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients.We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay.No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB.Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases.

Published
2016

21. Contents Vol. 16, 2016

Author

Marilyn S. Albert, Kah-Leong Lim, Genny Orso, Eniko Veronika Kovari, Alessandro Padovani, Sonja W. Scholz, Chiara Mattei, José Berciano, François Herrmann, Davide Massucco, Matteo Pardini, Hans Wilhelm Müller, Markus Beu, Shyuan T. Ngo, Karissa C. Arthur, Jasper Verbree, Joshua T. Geiger, Zeeshan Mushtaq, Bing-Han Chai, Stefano Ferrea, Chee-Hoe Ng, Juan C. Troncoso, Jian-xiu Zhu, Carlo Scialò, José Manuel López-Vega, Olga Pletnikova, Panteleimon Giannakopoulos, Federica Rossi, Francesca Benassi, Zhi-jian Su, Caroline G.L. Lee, Druckerei Stückle, Samuel S. Chong, Peng Lei, Constantin Bouras, Richard G. Wise, Pamela A. McCombe, Saumitra Dey Choudhury, Jacqueline A.M. Wubben, Eduards Mamlins, Qi-hao Zhang, Silvia Compostella, William L. Klein, Leonardo Emberti Gialloreti, Peng-hui Yang, Mingjue Zhao, Ana Santurtún, Pascual Sánchez-Juan, Henry Basil Adeline, Liana S. Rosenthal, Ingrid H.C.H.M. Philippens, Davide Sassos, Matthis Synofzik, Vimlesh Kumar, August B. Smit, Maura Brunetti, Lars Wojtecki, Sven Hammesfahr, Xian-ying Zhang, Ezio Giacobini, Lars Dinkelbach, Jordan Grafman, Christina Antke, Barbara Borroni, Javier Riancho, Jochen Klenk, Alexia-Sabine Moldovan, Frank Krueger, Armand Savioz, Robert D. Henderson, Cheng-Wu Zhang, Clemens Becker, Barbara J. Crain, Ashley I. Bush, Ilaria Callegari, Zara A. Ioannides, Pablo Lozano-Cuesta, Massimiliano Filosto, Ronald E. van Kesteren, Mario Amore, Adriano Chiò, Sigrid K. Franke, Craig Blackstone, Alfons Schnitzler, Sri Krishna Gangwar, Matthias J.P. van Osch, Alexander Pantelyat, J M Polo, Flavio Nobili, Fabrizio Rinaldi, Hai-Yang Law, Ya-dong Huang, Özgür Yaldizli, Qi Xiang, Frederik J. Steyn, Andrea Pilotto, Carlo Serrati, Cornelia Schatton, Sam Hofman, Massimo Filippi, Matthew J. Fraidakis, Satz Mengensatzproduktion, Esther A. H. Warnert, Karin Srulijes, Argye E. Hillis, Lars Schwickert, Martin Südmeyer, Walter Maetzler, Eugenia T.E. Hong, Ted M. Dawson, Leonardo Cocito, and Maura Cosseddu

Subjects
Neurology, Neurology (clinical)
Published
2016
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22. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040

Author

Adriano Chiò, Bryan J. Traynor, Karissa C. Arthur, Joshua T. Geiger, Andrea Calvo, and T. Ryan Price

Subjects
Male, 0301 basic medicine, Aging, Science, Population, General Physics and Astronomy, Developing country, Disease, Global Health, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Age Distribution, 0302 clinical medicine, Health care, Prevalence, Global health, medicine, Humans, Amyotrophic lateral sclerosis, education, Socioeconomic status, Aged, education.field_of_study, Multidisciplinary, business.industry, Incidence, Incidence (epidemiology), Amyotrophic Lateral Sclerosis, General Chemistry, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Female, business, 030217 neurology & neurosurgery, Demography
Abstract

Although amyotrophic lateral sclerosis (ALS) is relatively rare, the socioeconomic significance of the disease is extensive. It is therefore vital to project the epidemiologic trend of ALS. To date, there have been few published studies attempting to estimate the number and distribution of ALS cases in the upcoming years. Here we show that the number of ALS cases across the globe will increase from 222,801 in 2015 to 376,674 in 2040, representing an increase of 69%. This increase is predominantly due to ageing of the population, particularly among developing nations. This projection is likely an underestimate due to improving healthcare and economic conditions. The results should be used to inform healthcare policy to more efficiently allocate healthcare resources., The socioeconomic burden of amyotrophic lateral sclerosis (ALS) is high, but the projected number of cases in the upcoming years is unclear. Here, the authors estimate the number and distribution of ALS cases to 2040, and show that cases are projected to increase, particularly in developing nations.

Published
2016

23. ADORA1mutations are not a common cause of Parkinson's disease and dementia with Lewy bodies

Author

Cornelis Blauwendraat, Dena G. Hernandez, Mike A. Nalls, Juan C. Troncoso, J. Raphael Gibbs, Monica Federoff, Javier Simón-Sánchez, Christopher Letson, Sonja W. Scholz, Joshua T. Geiger, Jinhui Ding, and Olga Pletnikova

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Parkinson's disease, business.industry, Dementia with Lewy bodies, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Published
2016
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