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1. Identifying patterns in amyotrophic lateral sclerosis progression from sparse longitudinal data.

Author

Divya Ramamoorthy, Kristen Severson, Soumya Ghosh, Karen Sachs, Emily G. Baxi, Alyssa N. Coyne, Elizabeth Mosmiller, Lindsey Hayes, Aianna Cerezo, Omar Ahmad, Promit Roy, Steven Zeiler, John W. Krakauer, Jonathan Li 0008, Aneesh Donde, Nhan Huynh, Miriam Adam, Brook T. Wassie, Alexander LeNail, Natasha Leanna Patel-Murray, Yogindra Raghav, Velina Kozareva, Stanislav Tsitkov, Tobias Ehrenberger, Julia A. Kaye, Leandro Lima, Stacia K. Wyman, Edward Vertudes, Naufa Amirani, Krishna Raja, Reuben Thomas, Ryan G. Lim, Ricardo Miramontes, Jie Wu, Vineet Vaibhav, Andrea Matlock, Vidya Venkatraman, Ronald Holewenski, Niveda Sundararaman, Rakhi Pandey, Danica-Mae Manalo, Aaron Frank, Loren Ornelas, Lindsey Panther, Emilda Gomez, Erick Galvez, Daniel Pérez, Imara Meepe, Susan Lei, Louis Pinedo, Chunyan Liu, Ruby Moran, Dhruv Sareen, Barry Landin, Carla Agurto, Guillermo A. Cecchi, Raquel Norel, Sara Thrower, Sarah Luppino, Alanna Farrar, Lindsay Pothier, Hong Yu, Ervin Sinani, Prasha Vigneswaran, Alexander V. Sherman, S. Michelle Farr, Berhan Mandefro, Hannah Trost, Maria G. Banuelos, Veronica Garcia, Michael Workman, Richie Ho, Robert Baloh, Jennifer Roggenbuck, Matthew B. Harms, Carolyn Prina, Sarah Heintzman, Stephen Kolb, Jennifer Stocksdale, Keona Wang, Todd Morgan, Daragh Heitzman, Arish Jamil, Jennifer Jockel-Balsarotti, Elizabeth Karanja, Jesse Markway, Molly McCallum, Tim Miller, Ben Joslin, Deniz Alibazoglu, Senda Ajroud-Driss, Jay C. Beavers, Mary Bellard, Elizabeth Bruce, Nicholas J. Maragakis, Merit E. Cudkowicz, James D. Berry, Terri Thompson, Steven Finkbeiner, Leslie M. Thompson, Jennifer E. Van Eyk, Clive N. Svendsen, Jeffrey D. Rothstein, Jonathan D. Glass, Christina N. Fournier, Alexander Sherman, Christian Lunetta, David Walk, Ghazala Hayat, James Wymer, Kelly Gwathmey, Nicholas Olney, Terry Heiman-Patterson, Ximena Arcila-Londono, Kenneth Faulconer, Ervin Sanani, Alex Berger, Julia Mirochnick, Todd M. Herrington, Kenney Ng, and Ernest Fraenkel

Published
2022
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4. Edaravone efficacy in amyotrophic lateral sclerosis with reduced forced vital capacity: Post-hoc analysis of Study 19 (MCI186-19) [clinical trial NCT01492686]

Author

Benjamin Rix Brooks, Terry Heiman-Patterson, Martina Wiedau-Pazos, Shawn Liu, Jeffrey Zhang, and Stephen Apple

Subjects
Medicine, Science
Abstract

Background Edaravone slowed the rate of functional decline in subjects with amyotrophic lateral sclerosis (ALS) in phase 3 study MCI186-19 (Study 19). One of the Study 19 inclusion criteria was forced vital capacity (FVC) ≥80% of predicted (≥80%p). Therefore, the study provided no information on edaravone efficacy in subjects with FVC Objective To address the question of the efficacy of edaravone in ALS patients with FVC Methods Post-hoc analysis of Study 19 comparing edaravone efficacy at week 48 in subjects with FVC24 ≥80%p vs Results With edaravone treatment, subjects in both the FVC24 ≥80%p and the FVC24 Conclusion ALS subjects in the Study 19 placebo arm had a slowing in disease progression, even when edaravone was added with an FVC of

Published
2022

5. An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Author

Jonathan Li, Ryan G. Lim, Julia A. Kaye, Victoria Dardov, Alyssa N. Coyne, Jie Wu, Pamela Milani, Andrew Cheng, Terri G. Thompson, Loren Ornelas, Aaron Frank, Miriam Adam, Maria G. Banuelos, Malcolm Casale, Veerle Cox, Renan Escalante-Chong, J. Gavin Daigle, Emilda Gomez, Lindsey Hayes, Ronald Holewenski, Susan Lei, Alex Lenail, Leandro Lima, Berhan Mandefro, Andrea Matlock, Lindsay Panther, Natasha Leanna Patel-Murray, Jacqueline Pham, Divya Ramamoorthy, Karen Sachs, Brandon Shelley, Jennifer Stocksdale, Hannah Trost, Mark Wilhelm, Vidya Venkatraman, Brook T. Wassie, Stacia Wyman, Stephanie Yang, Jennifer E. Van Eyk, Thomas E. Lloyd, Steven Finkbeiner, Ernest Fraenkel, Jeffrey D. Rothstein, Dhruv Sareen, Clive N. Svendsen, Leslie M. Thompson, Hemali Phatnani, PhD, Justin Kwan, MD, Dhruv Sareen, PhD, James R. Broach, PhD, Zachary Simmons, MD, Ximena Arcila-Londono, MD, Edward B. Lee, MD, PhD, Vivianna M. Van Deerlin, MD, PhD, Neil A. Shneider, MD, PhD, Ernest Fraenkel, PhD, Lyle W. Ostrow, MD, PhD, Frank Baas, MD, PhD, Noah Zaitlen, PhD, James D. Berry, MD, MPH, Andrea Malaspina, MD, PhD, Pietro Fratta, MD, PhD, Gregory A. Cox, PhD, Leslie M. Thompson, PhD, Steve Finkbeiner, MD, PhD, Efthimios Dardiotis, MD, PhD, Timothy M. Miller, MD, PhD, Siddharthan Chandran, PhD, Suvankar Pal, MD, Eran Hornstein, MD, PhD, Daniel J. MacGowan, MD, Terry Heiman-Patterson, MD, Molly G. Hammell, PhD, Nikolaos.A. Patsopoulos, MD, PhD, Oleg Butovsky, PhD, Joshua Dubnau, PhD, Avindra Nath, MD, Robert Bowser, PhD, Matt Harms, MD, Mary Poss, DVM, PhD, Jennifer Phillips-Cremins, PhD, John Crary, MD, PhD, Nazem Atassi, MD, Dale J. Lange, MD, Darius J. Adams, MD, Leonidas Stefanis, MD, PhD, Marc Gotkine, MD, Robert H. Baloh, MD. PhD, Suma Babu, MBBS, MPH, Towfique Raj, PhD, Sabrina Paganoni, MD, PhD, Ophir Shalem, PhD, Colin Smith, MD, Bin Zhang, PhD, Brent Harris, MD, PhD, Iris Broce, PhD, Vivian Drory, MD, John Ravits, MD, Corey McMillan, PhD, Vilas Menon, PhD, Lani Wu, PhD, and Steven Altschuler, PhD

Subjects
Biological sciences, Neuroscience, Systems neuroscience, Systems biology, Omics, Science
Abstract

Summary: Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.

Published
2021
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6. COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success

Author

Jeremy M. Shefner, Ammar Al-Chalabi, Jinsy A. Andrews, Adriano Chio, Mamede De Carvalho, Bettina M. Cockroft, Philippe Corcia, Philippe Couratier, Merit E. Cudkowicz, Angela Genge, Orla Hardiman, Terry Heiman-Patterson, Robert D. Henderson, Caroline Ingre, Carlayne E. Jackson, Wendy Johnston, Noah Lechtzin, Albert Ludolph, Nicholas J. Maragakis, Timothy M. Miller, Jesus S. Mora Pardina, Susanne Petri, Zachary Simmons, Leonard H. Van Den Berg, Lorne Zinman, Stuart Kupfer, Fady I. Malik, Lisa Meng, Tyrell J. Simkins, Jenny Wei, Andrew A. Wolff, and Stacy A. Rudnicki

Subjects
Neurology, Neurology (clinical)
Published
2023
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7. ALSUntangled # 69: astaxanthin

Author

Timothy Fullam, Carmel Armon, Paul Barkhaus, Benjamin Barnes, Morgan Beauchamp, Michael Benatar, Tulio Bertorini, Robert Bowser, Mark Bromberg, Javier Mascias Cadavid, Gregory T. Carter, Mazen Dimachkie, Dave Ennist, Eva L. Feldman, Terry Heiman-patterson, Sartaj Jhooty, Isaac Lund, Christopher Mcdermott, Gary Pattee, Dylan Ratner, Paul Wicks, and Richard Bedlack

Subjects
Neurology, Neurology (clinical)
Published
2023
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8. ALSUntangled #68: ozone therapy

Author

Yuyao Sun, Paul Barkhaus, Benjamin Barnes, Morgan Beauchamp, Michael Benatar, Tulio Bertorini, Mark Bromberg, Gregory T. Carter, Jesse Crayle, Merit Cudkowicz, Mazen Dimachkie, Eva L. Feldman, Timothy Fullam, Terry Heiman-Patterson, Sartaj Jhooty, Isaac Lund, Christopher Mcdermott, Gary Pattee, Kaitlyn Pierce, Dylan Ratner, Paul Wicks, and Richard Bedlack

Subjects
Neurology, Neurology (clinical)
Abstract

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review ozone therapy. Ozone therapy has possible mechanisms for slowing ALS progression based on its antioxidant, anti-inflammatory, and mitochondrial effects. A non-peer-reviewed report suggests that ozone treatment may slow progression in a mTDP-43 mouse model of ALS. One verified "ALS reversal" occurred on a cocktail of alternative treatments including ozone. There are no ALS trials using ozone to treat PALS. There can be potentially serious side effects associated with ozone therapy, depending on the dose. Based on the above information, we support an investigation of ozone therapy in ALS cell or animal models but cannot yet recommend it as a treatment in PALS.

Published
2022
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9. Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Author

Oliver H. Tam, Nikolay V. Rozhkov, Regina Shaw, Duyang Kim, Isabel Hubbard, Samantha Fennessey, Nadia Propp, Delphine Fagegaltier, Brent T. Harris, Lyle W. Ostrow, Hemali Phatnani, John Ravits, Josh Dubnau, Molly Gale Hammell, Justin Kwan, Dhruv Sareen, James R. Broach, Zachary Simmons, Ximena Arcila-Londono, Edward B. Lee, Vivianna M. Van Deerlin, Neil A. Shneider, Ernest Fraenkel, Frank Baas, Noah Zaitlen, James D. Berry, Andrea Malaspina, Pietro Fratta, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Robert Bowser, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Robert Baloh, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, and Bin Zhang

Subjects
Biology (General), QH301-705.5
Abstract

Summary: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast majority of ALS cases have no family history of disease. Thus, for most ALS cases, the disease may be a product of multiple pathways contributing to varying degrees in each patient. Using machine learning algorithms, we stratify the transcriptomes of 148 ALS postmortem cortex samples into three distinct molecular subtypes. The largest cluster, identified in 61% of patient samples, displays hallmarks of oxidative and proteotoxic stress. Another 19% of the samples shows predominant signatures of glial activation. Finally, a third group (20%) exhibits high levels of retrotransposon expression and signatures of TARDBP/TDP-43 dysfunction. We further demonstrate that TDP-43 (1) directly binds a subset of retrotransposon transcripts and contributes to their silencing in vitro, and (2) pathological TDP-43 aggregation correlates with retrotransposon de-silencing in vivo. : Tam et al. present transcriptome profiling results from a large set of amyotrophic lateral sclerosis (ALS) patient cortex samples, finding 3 distinct groups. Two ALS subtypes are marked by gene pathways previously associated with ALS disease, while a third group shows elevated retrotransposon expression linked to TDP-43 pathology. Keywords: amyotrophic lateral sclerosis, retrotransposons, transposable elements, TDP-43, neurodegenerative disease, neurodegeneration, genetics and genomics of ALS

Published
2019
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12. ALSUntangled #63: ketogenic diets

Author

Tulio E. Bertorini, Christopher J McDermott, Isaac Lund, Steven Novella, Gleb Levitsky, Gregory T. Carter, Ce Jackson, Merit Cudkowicz, Lyle Ostrow, Vinay Chaudry, Anne-Marie Wills, Kristiana Salmon, Richard Bedlack, Morgan Beauchamp, Mark B. Bromberg, Terry Heiman-Patterson, Dylan Ratner, Natasha J. Olby, Benjamin Barnes, Paul E. Barkhaus, Paul Wicks, Mark Terrelonge, Susan Steves, and Gary L. Pattee

Subjects
Neurology, business.industry, medicine.medical_treatment, medicine, Neurology (clinical), Amyotrophic lateral sclerosis, Bioinformatics, medicine.disease, business, Ketogenic diet
Abstract

ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

Published
2021
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13. Use of a new ALS specific respiratory questionnaire: the ARES score

Author

Edward J. Kasarskis, Terry Heiman-Patterson, Asha George, Daohai Yu, Carlayne E. Jackson, and Michael Sherman

Subjects
medicine.medical_specialty, Scale (ratio), business.industry, Amyotrophic Lateral Sclerosis, Vital Capacity, medicine.disease, humanities, respiratory tract diseases, Respiratory symptom, Neurology, Spirometry, Surveys and Questionnaires, Breathing, Physical therapy, medicine, Humans, Neurology (clinical), Respiratory system, Amyotrophic lateral sclerosis, business
Abstract

Objective: To develop an ALS respiratory symptom scale (ARES) and evaluate how ARES compares to Medical Research Council Modified Dyspnea Scale (MRC), Borg dyspnea scale, and respiratory subscores ...

Published
2021
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14. Real-world Adherence to Nusinersen in Adults with Spinal Muscular Atrophy in the US: A Multi-site Chart Review Study

Author

Lauren Elman, Bora Youn, Crystal M. Proud, Margaret R. Frey, Senda Ajroud-Driss, M. Eileen McCormick, David Michelson, Michael S. Cartwright, Terry Heiman-Patterson, Joseph M. Choi, Aastha Chandak, Artak Khachatryan, Marta Martinez, and Angela D. Paradis

Subjects
Adult, Muscular Atrophy, Spinal, Neurology, Oligonucleotides, Humans, Neurology (clinical), Retrospective Studies
Abstract

Limited evidence exists on real-world adherence to nusinersen for the treatment of spinal muscular atrophy (SMA). Data are presented from a multi-site retrospective chart review of 86 adults with SMA initiating nusinersen at nine US centers between January 2017 and February 2019. Seventy-nine (92%) adults remained on nusinersen during the study; 454 (92%) of 493 total nusinersen doses were received on time. Fifty-eight (67%) adults received all nusinersen doses on time. The majority of patients with at least one nonadherent dose resumed nusinersen on time. Most patients followed the dosing schedule across the loading and maintenance dose periods.

Published
2022

15. ALSUntangled 59: Tamoxifen

Author

Michael S. Bereman, Terry Heiman Patterson, Paul Wicks, Paul E. Barkhaus, Kristiana Salmon, Richard Bedlack, James B. Caress, Sky Kihuwa-mani, Gregory T. Carter, Gary L. Pattee, Neta Zach, and Jesse Crayle

Subjects
Oncology, medicine.medical_specialty, Off-Label Treatment, business.industry, Cancer, medicine.disease, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Neurology, Internal medicine, medicine, Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery, Tamoxifen, medicine.drug
Abstract

Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.

Published
2021
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16. Long‐term survival of participants in the <scp>CENTAUR</scp> trial of sodium phenylbutyrate‐taurursodiol in <scp>amyotrophic lateral sclerosis</scp>

Author

Meghan Hall, Janet P. Wittes, Gary L. Pattee, Eric A. Macklin, Eric Tustison, Tuan Vu, Zi-Fan Yu, Samuel P. Dickson, Rudolph E. Tanzi, Liberty Jenkins, Suma Babu, Michael A. Elliott, Jonathan S. Katz, Chafic Karam, Patricia L. Andres, Terry Heiman-Patterson, Stephen N. Scelsa, Christina Fournier, Joseph Ostrow, Timothy M. Miller, Joshua N Cohen, Daragh Heitzman, Edward J. Kasarskis, Derek Dagostino, Patrick D. Yeramian, Colin Quinn, Rebecca Randall, Lindsay Pothier, James Wymer, Hong Yu, Gale Kittle, Newman Knowlton, Michelle McGovern, Shafeeq Ladha, Jason Walker, Jeffrey D. Rothstein, Adam Quick, James Chan, Kent L. Leslie, Prasha Vigneswaran, Maria E. St. Pierre, Kristin M. Johnson, Walter Gilbert, Namita Goyal, James B. Caress, Marianne Chase, Sabrina Paganoni, Jonathan D. Glass, Justin Klee, Merit Cudkowicz, Jeremy M. Shefner, Suzanne Hendrix, Carlayne E. Jackson, Margaret Owegi, James D. Berry, David A. Schoenfeld, Alexander Sherman, Stephen A. Goutman, Matthew Eydinov, Andrea Swenson, and Samuel Maiser

Subjects
0301 basic medicine, amyotrophic lateral sclerosis, medicine.medical_specialty, Physiology, CENTAUR, 030105 genetics & heredity, Placebo, survival analysis, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Physiology (medical), Internal medicine, Long term survival, Medicine, Amyotrophic lateral sclerosis, Clinical Research Articles, Survival analysis, sodium phenylbutyrate‐taurursodiol, Clinical Research Article, business.industry, Hazard ratio, Sodium phenylbutyrate, medicine.disease, Confidence interval, motor neuron disease, Neurology (clinical), business, 030217 neurology & neurosurgery, Median survival, medicine.drug
Abstract

An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

Published
2020
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17. A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS

Author

Gary L. Pattee, Ashley Whyte-Rayson, Andrew A. Wolff, Jeremy M. Shefner, Lisa Meng, Jesus S. Mora, Lorne Zinman, Steve Vucic, Terry Heiman-Patterson, Stephen J. Kolb, James Caress, Bettina M. Cockroft, Carlayne E. Jackson, Timothy M. Miller, Michael D. Weiss, Ghazala Hayat, Shumaila Sultan, Benjamin Rix Brooks, Daragh Heitzman, Tuan Vu, Merrilee Needham, Dianna Quan, Genevieve Matte, Shafeeq Ladha, Orla Hardiman, Fady I. Malik, Zachary Simmons, Wendy Johnston, Christen Shoesmith, Namita Goyal, Erik P. Pioro, James Wymer, David Schultz, Leonard H. van den Berg, Cynthia Bodkin, Lawrence Korngut, Jeffrey Statland, Michael Pulley, Bjorn Oskarsson, Chafic Karam, Angela Genge, Matthew C. Kiernan, Jenny Wei, Annie Dionne, Jinsy A. Andrews, Noah Lechtzin, Stephen A. Goutman, Andrea Swenson, Dominic B. Fee, Kerri Schellenberg, Robert D. Henderson, Kourosh Rezania, and Stacy A. Rudnicki

Subjects
business.industry, medicine.disease, law.invention, Double blind, 03 medical and health sciences, 0302 clinical medicine, Neurology, Randomized controlled trial, law, Anesthesia, medicine, In patient, Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery
Abstract

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow...

Published
2020
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18. Primary lateral sclerosis natural history study – planning, designing, and early enrollment

Author

Hiroshi, Mitsumoto, Grace, Jang, Ikjae, Lee, Zachary, Simmons, Alexander V, Sherman, Daragh, Heitzman, Eric, Sorenson, Ken, Cheung, Jinsy, Andrews, Matthew, Harms, Neil A, Shneider, Regina, Santella, Sabrina, Paganoni, Senda, Ajroud-Driss, J Americo M, Fernandes, Katherine M, Burke, Kelly, Gwathmey, Ali A, Habib, Nicholas J, Maragakis, David, Walk, Christina, Fournier, Terry, Heiman-Patterson, James, Wymer, Frank, Diaz, Stephen N, Scelsa, Lauren, Elman, Angela, Genge, Stephen A, Goutman, Ghazala, Hayat, Omar, Jawdat, Wendy S, Johnston, Nanette C, Joyce, Edward J, Kasarskis, Yaz Y, Kisanuki, Catherine, Lomen-Hoerth, Michael T, Pulley, Jaimin S, Shah, Christen, Shoesmith, and Lorne, Zinman

Abstract

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Published
2022
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19. Pulmonary function decline in amyotrophic lateral sclerosis

Author

Daohai Yu, Ossama Khazaal, Edward J. Kasarskis, Michael E Sherman, Carlayne E. Jackson, and Terry Heiman-Patterson

Subjects
Vital capacity, medicine.medical_specialty, Longitudinal study, Maximal Respiratory Pressures, business.industry, Amyotrophic Lateral Sclerosis, Vital Capacity, Sitting, medicine.disease, Maximum expiratory pressure, Medicare, United States, Pulmonary function testing, FEV1/FVC ratio, Neurology, Internal medicine, Cardiology, medicine, Respiratory muscle, Humans, Neurology (clinical), Longitudinal Studies, Amyotrophic lateral sclerosis, business, Aged
Abstract

Background: There has been no comprehensive longitudinal study of pulmonary functions (PFTS) in ALS determining which measure is most sensitive to declines in respiratory muscle strength. Objective: To determine the longitudinal decline of PFTS in ALS and which measure supports Medicare criteria for NIV initiation first. Methods: Serial PFTs (maximum voluntary ventilation (MVV), maximum inspiratory pressure measured by mouth (MIP) or nasal sniff pressure (SNIP), maximum expiratory pressure (MEP), and Forced Vital Capacity (FVC)) were performed over 12 months on 73 ALS subjects to determine which measure showed the sentinel decline in pulmonary function. The rate of decline for each measure was determined as the median slope of the decrease over time. Medicare-based NIV initiation criteria were met if %FVC was ≤ 50% predicted or MIP was ≤ 60 cMH2O. Results: 65 subjects with at least 3 visits were included for analyses. All median slopes were significantly different than zero. MEP and sitting FVC demonstrated the largest rate of decline. Seventy subjects were analyzed for NIV initiation criteria, 69 met MIP criteria first; 11 FVC and MIP criteria simultaneously and none FVC criteria first. Conclusions: MEP demonstrated a steeper decline compared to other measures suggesting expiratory muscle strength declines earliest and faster and the use of airway clearance interventions should be initiated early. When Medicare criteria for NIV initiation are considered, MIP criteria are met earliest. These results suggest that pressure-based measurements are important in assessing the timing of NIV and the use of pulmonary clearance interventions.

Published
2021

20. Long‐term edaravone efficacy in amyotrophic lateral sclerosis: Post‐hoc analyses of Study 19 (MCI186‐19)

Author

Martina Wiedau-Pazos, Shawn Liu, Terry Heiman-Patterson, Wendy Agnese, Erik P. Pioro, Jeffrey Zhang, Stephen Apple, and Jeremy M. Shefner

Subjects
Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Post hoc, Physiology, Phases of clinical research, 030105 genetics & heredity, medicine.disease_cause, Placebo, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, disease progression, Double-Blind Method, ALSFRS‐R, Physiology (medical), Internal medicine, Edaravone, Medicine, oxidative stress, Humans, Functional decline, Amyotrophic lateral sclerosis, Aged, business.industry, Disease progression, Amyotrophic Lateral Sclerosis, Middle Aged, medicine.disease, chronic, Treatment Outcome, Neuroprotective Agents, chemistry, Clinical Research Short Report, functional decline, Clinical Research Short Reports, linear regression, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Oxidative stress
Abstract

Background In a Phase 3 study, amyotrophic lateral sclerosis (ALS) patients experienced significantly less physical functional decline with 24‐week edaravone vs placebo, followed by open‐label treatment for an additional 24 weeks. Methods Outcome (the change in ALS Functional Rating Scale–Revised, ALSFRS‐R, from baseline) was projected for placebo patients through 48 weeks and compared with 48‐week edaravone or 24‐week edaravone after switching from placebo. Results A total of 123 patients received open‐label treatment (65 edaravone‐edaravone; 58 placebo‐edaravone). The projected ALSFRS‐R decline for placebo from baseline through week 48 was greater than for 48‐week edaravone (P, https://doi.org/10.1002/mus.26770.

Published
2019

21. Radicava (edaravone) for amyotrophic lateral sclerosis: US experience at 1 year after launch

Author

Carlayne E. Jackson, Tatyana Baranovsky, Glenn McAnanama, Pamela Kittrell, Wendy Agnese, Mike Martin, Laura Bower, and Terry Heiman-Patterson

Subjects
medicine.medical_specialty, Time Factors, MEDLINE, Survey result, Patient care, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, Physicians, Surveys and Questionnaires, Edaravone, Product Surveillance, Postmarketing, medicine, Humans, Disease management (health), Amyotrophic lateral sclerosis, Infusions, Intravenous, Adverse effect, Fatigue, Muscle Weakness, business.industry, Amyotrophic Lateral Sclerosis, Disease progression, Free Radical Scavengers, medicine.disease, United States, Neurology, chemistry, Emergency medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background: Radicava® (edaravone), approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2017, may be administered intravenously at clinic sites, infusion centers or at home. Objective: To gain insights into the utilization of Radicava® at 1 year post-launch. Methods: Radicava® usage data were collected, and a survey was conducted among 75 physicians. Adverse events (AEs) were identified from a post-marketing safety database from 8 August 2017 through 3 August 2018 (cutoff date). Results: As of 6 August 2018, 3007 ALS patients were treated with Radicava®. Survey results indicated that 43% of patients received infusions at home, 32% in a clinician's office, and 26% at a referred site. Infusions were administered mainly via implanted port. The most commonly reported AEs were drug ineffective, death (not specified), therapeutic response unexpected, asthenia, fatigue, gait disturbance, disease progression, muscular weakness, fall, and dyspnea. Conclusions: The first year of Radicava® availability to ALS patients in the US provided many key learnings that will help shape strategies for improved patient care.

Published
2019
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22. ALSUntangled 59: Tamoxifen

Author

Richard, Bedlack, Sky, Kihuwa-Mani, Paul E, Barkhaus, Michael, Bereman, James B, Caress, Jesse, Crayle, Gary L, Pattee, Terry, Heiman Patterson, Paul, Wicks, Neta, Zach, Gregory T, Carter, and Kristiana, Salmon

Subjects
Tamoxifen, Amyotrophic Lateral Sclerosis, Humans
Abstract

Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.

Published
2021

23. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

Author

Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A. Hickman, Thor D. Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S. Sabir, Makayla K. Portley, Arianna Tucci, Kristina Ibáñez, F.N.U. Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L. Waldo, Per M. Johansson, Christer F. Nilsson, James B. Rowe, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D. Glass, Andrew B. Singleton, Vincenzo Silani, Owen A. Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M. Resnick, Stuart Pickering-Brown, Christopher B. Brady, Neil Kowal, John A. Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B. Harms, Huw R. Morris, Raffaele Ferrari, John E. Landers, Adriano Chiò, J. Raphael Gibbs, Clifton L. Dalgard, Sonja W. Scholz, Bryan J. Traynor, Adelani Adeleye, Camille Alba, Dagmar Bacikova, Daniel N. Hupalo, Elisa McGrath Martinez, Harvey B. Pollard, Gauthaman Sukumar, Anthony R. Soltis, Meila Tuck, Xijun Zhang, Matthew D. Wilkerson, Bradley N. Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon D. Topp, Jason Kost, Emma L. Scotter, Kevin P. Kenna, Jack W. Miller, Cinzia Tiloca, Caroline Vance, Eric W. Danielson, Claire Troakes, Claudia Colombrita, Safa Al-Sarraj, Elizabeth A. Lewis, Andrew King, Daniela Calini, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Zorica Stevic, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Wouter van Rheenen, Frank P. Diekstra, Rosa Rademakers, Marka van Blitterswijk, Kevin B. Boylan, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Cinzia Gellera, Antonia Ratti, Robert H. Brown, Christopher E. Shaw, John C. Ambrose, Prabhu Arumugam, Emma L. Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, H. Brittain, Mark J. Caulfield, Georgia C. Chan, Clare E.H. Craig, Louise C. Daugherty, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió-Tarí, Joanne M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E. Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Chris A. Odhams, Christine Patch, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R. Smith, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Ellen R.A. Thomas, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Sampath Arepalli, Pavan Auluck, Robert H. Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, John Cooper-Knock, Philippe Corcia, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Faraz Faghri, Jennifer Farren, Eva Feldman, Mary Kay Floeter, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Stephen A. Goutman, Terry D. Heiman-Patterson, Dena G. Hernandez, Ben Hoover, Lilja Jansson, Freya Kamel, Janine Kirby, Neil W. Kowall, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel JL. MacGowan, Nicholas J. Maragakis, Gabriele Mora, Kevin Mouzat, Liisa Myllykangas, Mike A. Nalls, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Alan E. Renton, Wim Robberecht, Ian Robey, Ekaterina Rogaeva, Jeffrey D. Rothstein, Michael Sendtner, Katie C. Sidle, Zachary Simmons, David J. Stone, Pentti J. Tienari, John Q. Trojanowski, Juan C. Troncoso, Miko Valori, Philip Van Damme, Ludo Van Den Bosch, Lorne Zinman, Diego Albani, Barbara Borroni, Alessandro Padovani, Amalia Bruni, Jordi Clarimon, Oriol Dols-Icardo, Ignacio Illán-Gala, Alberto Lleó, Adrian Danek, Daniela Galimberti, Elio Scarpini, Maria Serpente, Caroline Graff, Huei-Hsin Chiang, Behzad Khoshnood, Linn Öijerstedt, Christopher M. Morris, Benedetta Nacmias, Sandro Sorbi, Jorgen E. Nielsen, Lynne E. Hjermind, Valeria Novelli, Annibale A. Puca, Pau Pastor, Ignacio Alvarez, Monica Diez-Fairen, Miquel Aguilar, Robert Perneczky, Janine Diehl-Schimd, Mina Rossi, Agustin Ruiz, Mercè Boada, Isabel Hernández, Sonia Moreno-Grau, Johannes C. Schlachetzki, Dag Aarsland, Marilyn S. Albert, Johannes Attems, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Lilah M. Besser, Eileen H. Bigio, Sandra E. Black, Bradley F. Boeve, Ryan C. Bohannan, Francesca Brett, Maura Brunetti, Chad A. Caraway, Jose-Alberto Palma, Andrea Calvo, Antonio Canosa, Dennis Dickson, Charles Duyckaerts, Kelley Faber, Tanis Ferman, Margaret E. Flanagan, Gianluca Floris, Tatiana M. Foroud, Juan Fortea, Ziv Gan-Or, Steve Gentleman, Bernardino Ghetti, Jesse Raphael Gibbs, Alison Goate, David Goldstein, Isabel González-Aramburu, Neill R. Graff-Radford, Angela K. Hodges, Heng-Chen Hu, Daniel Hupalo, Jon Infante, Alex Iranzo, Scott M. Kaiser, Horacio Kaufmann, Julia Keith, Ronald C. Kim, Gregory Klein, Rejko Krüger, Walter Kukull, Amanda Kuzma, Carmen Lage, Suzanne Lesage, James B. Leverenz, Giancarlo Logroscino, Grisel Lopez, Seth Love, Qinwen Mao, Maria Jose Marti, Elisa Martinez-McGrath, Mario Masellis, Eliezer Masliah, Patrick May, Ian McKeith, Marek-Marsel Mesulam, Edwin S. Monuki, Kathy L. Newell, Lucy Norcliffe-Kaufmann, Laura Palmer, Matthew Perkins, Olga Pletnikova, Laura Molina-Porcel, Regina H. Reynolds, Eloy Rodríguez-Rodríguez, Jonathan D. Rohrer, Pascual Sanchez-Juan, Clemens R. Scherzer, Geidy E. Serrano, Vikram Shakkottai, Ellen Sidransky, Nahid Tayebi, Alan J. Thomas, Bension S. Tilley, Ronald L. Walton, Randy Woltjer, Zbigniew K. Wszolek, Georgia Xiromerisiou, Chiara Zecca, Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Neil A. Shneider, Ernest Fraenkel, Noah Zaitlen, James D. Berry, Andrea Malaspina, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Khaled Amar, Neil Archibald, Oliver Bandmann, Erica Capps, Alistair Church, Jan Coebergh, Alyssa Costantini, Peter Critchley, Boyd CP. Ghosh, Michele T.M. Hu, Christopher Kobylecki, P. Nigel Leigh, Carl Mann, Luke A. Massey, Uma Nath, Nicola Pavese, Dominic Paviour, Jagdish Sharma, Jenny Vaughan, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, Clinicum, Pentti Tienari / Principal Investigator, Parkinson's UK, Human Genetics, ARD - Amsterdam Reproduction and Development, ANS - Complex Trait Genetics, Pathology, ANS - Cellular & Molecular Mechanisms, AII - Inflammatory diseases, Universidad de Cantabria, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Huntington's Disease, Pathology, amyotrophic lateral sclerosis, Huntingtin, Neurology, 1702 Cognitive Sciences, International ALS/FTD Genomics Consortium, Neurodegenerative, frontotemporal dementia, 3124 Neurology and psychiatry, 0302 clinical medicine, Medicine, 2.1 Biological and endogenous factors, Psychology, Amyotrophic lateral sclerosis, Aetiology, Alzheimer's Disease Related Dementias (ADRD), NYGC ALS Consortium, Huntingtin Protein, DNA Repeat Expansion, General Neuroscience, Frontotemporal Dementia (FTD), International FTD Genetics Consortium, whole-genome sequencing, Frontotemporal Dementia, Neurological, Cognitive Sciences, Lewy body dementia, huntingtin, repeat expansions, Amyotrophic Lateral Sclerosis, Humans, Mutation, Whole Genome Sequencing, Frontotemporal dementia, Huntington’s disease, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, FALS Sequencing Consortium, Article, 03 medical and health sciences, Atrophy, Rare Diseases, American Genome Center, Clinical Research, mental disorders, Genetics, Acquired Cognitive Impairment, Dementia, PROSPECT Consortium, Neurology & Neurosurgery, Lewy body, business.industry, International LBD Genomics Consortium, Neurosciences, 3112 Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genomics England Research Consortium, 1701 Psychology, ALS, business, 1109 Neurosciences, 030217 neurology & neurosurgery
Abstract

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Published
2020
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24. A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of

Author

Jeremy M, Shefner, Jinsy A, Andrews, Angela, Genge, Carlayne, Jackson, Noah, Lechtzin, Timothy M, Miller, Bettina M, Cockroft, Lisa, Meng, Jenny, Wei, Andrew A, Wolff, Fady I, Malik, Cynthia, Bodkin, Benjamin R, Brooks, James, Caress, Annie, Dionne, Dominic, Fee, Stephen A, Goutman, Namita A, Goyal, Orla, Hardiman, Ghazala, Hayat, Terry, Heiman-Patterson, Daragh, Heitzman, Robert D, Henderson, Wendy, Johnston, Chafic, Karam, Matthew C, Kiernan, Stephen J, Kolb, Lawrence, Korngut, Shafeeq, Ladha, Genevieve, Matte, Jesus S, Mora, Merrilee, Needham, Bjorn, Oskarsson, Gary L, Pattee, Erik P, Pioro, Michael, Pulley, Dianna, Quan, Kourosh, Rezania, Kerri L, Schellenberg, David, Schultz, Christen, Shoesmith, Zachary, Simmons, Jeffrey, Statland, Shumaila, Sultan, Andrea, Swenson, Leonard H Van Den, Berg, Tuan, Vu, Steve, Vucic, Michael, Weiss, Ashley, Whyte-Rayson, James, Wymer, Lorne, Zinman, and Stacy A, Rudnicki

Subjects
amyotrophic lateral sclerosis, Double-Blind Method, reldesemtiv, Humans, Muscle Strength, Randomized clinical trial, Article
Abstract

Objective: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength megascore, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

Published
2020

25. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis

Author

Michael A. Elliott, Jeffrey D. Rothstein, Joshua D. Cohen, Kent Allen Hendrix, Stephen A. Goutman, James D. Berry, Jeremy M. Shefner, Terry Heiman-Patterson, Patrick D. Yeramian, Andrea Swenson, Janet Wittes, Samuel P. Dickson, Patricia L. Andres, Tuan Vu, Samuel Maiser, Rudolph E. Tanzi, Rebecca Randall, Christina Fournier, Merit Cudkowicz, Joseph Ostrow, Suzanne Hendrix, James Wymer, Liberty Jenkins, Jonathan S. Katz, Daragh Heitzman, Alexander Sherman, Colin Quinn, Chafic Karam, Michelle McGovern, Derek Dagostino, Timothy M. Miller, Stephen N. Scelsa, Marianne Chase, Jason Walker, Edward J. Kasarskis, Eric A. Macklin, Margaret A. Owegi, Shafeeq Ladha, Lindsay Pothier, Adam Quick, Meghan Hall, Noel Ellison, James Chan, Suma Babu, Gary L. Pattee, Kristin M. Johnson, Prasha Vigneswaran, Walter Gilbert, James B. Caress, David A. Schoenfeld, Eric Tustison, Kent L. Leslie, Namita Goyal, Gale Kittle, Carlayne E. Jackson, Sabrina Paganoni, Jonathan D. Glass, Justin Klee, and Hong Yu

Subjects
Male, Neurodegenerative, 030204 cardiovascular system & hematology, Medical and Health Sciences, Severity of Illness Index, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Medicine, 030212 general & internal medicine, Amyotrophic lateral sclerosis, Sodium phenylbutyrate, General Medicine, Middle Aged, Phenylbutyrates, Intention to Treat Analysis, Drug Combinations, Treatment Outcome, 6.1 Pharmaceuticals, Disease Progression, Female, medicine.drug, medicine.medical_specialty, Clinical Trials and Supportive Activities, Taurochenodeoxycholic acid, Phenylbutyrate, Article, Taurochenodeoxycholic Acid, 03 medical and health sciences, Rare Diseases, Double-Blind Method, Clinical Research, General & Internal Medicine, Internal medicine, Severity of illness, Humans, Aged, Intention-to-treat analysis, business.industry, Amyotrophic Lateral Sclerosis, Neurosciences, Evaluation of treatments and therapeutic interventions, medicine.disease, Brain Disorders, Clinical trial, chemistry, ALS, business
Abstract

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate–taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate–taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was −1.24 points per month with the active drug and −1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate–taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR Clinicaltrials.gov number, NCT03127514.)

Published
2020

26. The clinical spectrum of primary lateral sclerosis

Author

Terry Heiman-Patterson, Richard J. Barohn, Lauren Elman, Martin R Turner, John K. Fink, Edward D. Huey, Jeffrey Statland, and Jennifer Murphy

Subjects
Leg, business.industry, Amyotrophic Lateral Sclerosis, Cognition, Disease, medicine.disease, 03 medical and health sciences, Phenotype, 0302 clinical medicine, Neurology, Time course, Humans, Medicine, Neurology (clinical), Motor Neuron Disease, Presentation (obstetrics), Amyotrophic lateral sclerosis, business, Upper motor neuron involvement, Neuroscience, 030217 neurology & neurosurgery, Primary Lateral Sclerosis
Abstract

Primary lateral sclerosis is a distinct entity that has recently been classified as a "restricted phenotype" of ALS. It is characterized by a pattern of isolated upper motor neuron involvement that often begins in the legs and spreads diffusely. Distinction from other conditions requires careful consideration of clinical presentation and time course of disease. Mills' Syndrome is a rare unilateral variant of primary lateral sclerosis. Cognitive and behavioral involvement may occur.

Published
2020

27. Real-world evidence of riluzole effectiveness in treating amyotrophic lateral sclerosis

Author

Paolo Bettica, Erik P. Pioro, Terry Heiman-Patterson, Benjamin Rix Brooks, Jinsy A. Andrews, and Carlayne E. Jackson

Subjects
Oncology, medicine.medical_specialty, education.field_of_study, Riluzole, business.industry, Population, Amyotrophic Lateral Sclerosis, Real world evidence, medicine.disease, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Neuroprotective Agents, Neurology, Internal medicine, Medicine, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, business, education, 030217 neurology & neurosurgery, Median survival, medicine.drug
Abstract

To compare the effect of riluzole on median survival in population studies of patients with amyotrophic lateral sclerosis (ALS) with that observed in clinical trials. Methods: Two independent PubMe...

Published
2020

28. Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design

Author

Michael Benatar, Terry Heiman-Patterson, Merit Cudkowicz, Stephen Apple, Stanley H. Appel, James D. Berry, Jeremy M. Shefner, Jurjen Westra, Robert Bowser, Sally K. Nelson, Angela Genge, Clifton L. Gooch, Benjamin Rix Brooks, Wendy Agnese, and Charlotte Merrill

Subjects
Oncology, medicine.medical_specialty, business.industry, Research, Interim analysis, medicine.disease, chemistry.chemical_compound, Regimen, chemistry, Internal medicine, Edaravone, Medicine, Biomarker (medicine), Observational study, Neurology (clinical), Biomarker discovery, Amyotrophic lateral sclerosis, business, Adverse effect
Abstract

ObjectivesTo identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes.MethodsThis is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration–approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale–Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported.ResultsThe study is estimated to be completed in 2022 with an interim analysis planned.ConclusionsFindings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment.

Published
2020

29. Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse

Author

Gerardo Morfini, Lanfranco Leo, Guillermo M. Alexander, Hemalatha Muralidharan, Michelle Swift, Terry Heiman-Patterson, Laura E Hennessy, Liang Qiang, Emanuela Piermarini, Peter W. Baas, Wenqian Yu, Philip L Yates, Michael A. Lane, Theresa Connors, Lyandysha V. Zholudeva, and Silvia Fernandes

Subjects
0301 basic medicine, Genetically modified mouse, Spastin, Hereditary spastic paraplegia, Mutant, Mice, Transgenic, Haploinsufficiency, Biology, medicine.disease_cause, Axonal Transport, Microtubules, Mice, 03 medical and health sciences, 0302 clinical medicine, Microtubule, Genetics, medicine, Animals, Molecular Biology, Genetics (clinical), Neurons, Mutation, Spastic Paraplegia, Hereditary, General Medicine, medicine.disease, Axons, Cell biology, Disease Models, Animal, 030104 developmental biology, Haplotypes, Gain of Function Mutation, Knockout mouse, Mutant Proteins, General Article, 030217 neurology & neurosurgery
Abstract

Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of hereditary spastic paraplegia (HSP). Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility. Here, we report a new transgenic mouse (termed SPAST(C448Y) mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of HSP (not observed in spastin knockout mice) were adult onset, as is typical of human patients. Results of histological and tracer studies on the mouse are consistent with progressive dying back of corticospinal axons, which is characteristic of the disease. The C448Y-mutated spastin alters microtubule stability in a manner that is opposite to the expectations of haploinsufficiency. Neurons cultured from the mouse display deficits in organelle transport typical of axonal degenerative diseases, and these deficits were worsened by depletion of endogenous mouse spastin. These results on the SPAST(C448Y) mouse are consistent with a gain-of-function mechanism underlying HSP, with spastin haploinsufficiency exacerbating the toxicity of the mutant spastin proteins. These findings reveal the need for a different therapeutic approach than indicated by haploinsufficiency alone.

Published
2018
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30. Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges

Author

Alice B. Schindler, Chioma Nnamdi-Emeratom, Ami Mankodi, Christopher Grunseich, Nivedita U. Jerath, Michael E. Shy, Hasna Baloui, Roman Chrast, Terry Heiman-Patterson, and Thomas O. Crawford

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, Physiology, business.industry, Scoliosis, Disease, medicine.disease, Phenotype, 03 medical and health sciences, Cellular and Molecular Neuroscience, Charcot-Marie-Tooth disease type 4C, 030104 developmental biology, 0302 clinical medicine, Physiology (medical), SH3TC2, Nerve conduction study, Medicine, Neurology (clinical), business, Hereditary motor and sensory neuropathy, 030217 neurology & neurosurgery, Genetic testing
Abstract

Introduction This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C). Methods We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2. Results All patients manifested scoliosis, and nerve conduction study indicated results in the demyelinating range. All patients exhibited signs of motor impairment within the first years of life. We describe 2 or more different genetic diseases in the same patient, atypical presentations of CMT, and 3 new mutations in CMT4C patients. Discussion A new era of unbiased genetic testing has led to this small case series of individuals with CMT4C and highlights the recognition of different genetic diseases in CMT4C patients for accurate diagnosis, genetic risk identification, and therapeutic intervention. The phenotype of CMT4C, in addition, appears to be enriched by a number of features unusual for the broad CMT category. Muscle Nerve 57: 749-755, 2018.

Published
2017
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31. Preface: promoting research in PLS: current knowledge and future challenges

Author

Vincenzo Silani, Omar Jawdat, Sheena Chew, Annemarie Hübers, Jerome E. Kurent, Leonard H. van den Berg, Kourosh Rezania, Raghav Govindarajan, Osamu Kano, Teepu Siddique, Juan Marcos Solano Atehortua, Bjorn Oskarsson, Matthew B. Harms, John K. Fink, David Walk, Orla Hardiman, Senda Ajroud-Driss, Stephen N. Scelsa, Vivian E. Drory, Bryan Hill, Jose Americo M. Fernandes, Richard J. Barohn, Hiroshi Mitsumoto, Jennifer Murphy, Pam Factor-Litvak, and Family, James Wymer, Volkan Granit, Mitsuya Morita, Patricia L. Andres, Michael Benatar, Terry Heiman-Patterson, Frank Davis, Albert C. Ludolph, Philippe Corcia, Georg Haase, Nailah Siddique, Angela Genge, Justin Kwan, Dominic A. Ferrey, Christina Fournier, Bryan J. Traynor, Ian R. A. Mackenzie, Jinsy Andrews, Marka van Blitterswijk, David Pellerin, Ghazala Hayat, Dale J. Lange, John Ravits, Sabrina Paganoni, Edward D. Huey, Yasushi Kisanuki, Estela Area Gomez, Mamede de Carvalho, Mary Kay Floeter, Jeffrey Statland, Deborah L. Warden, Merit Cudkowicz, Giovanni Manfredi, Kristen Kau, Lauren Elman, Martin R Turner, Matthew C. Kiernan, Guy A. Rouleau, Sharon P. Nations, Robin Conwit, David Marren, Zachary Simmons, Suma Babu, Eoin Finegan, and Peter Bede

Subjects
medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, MEDLINE, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Neurology, Humans, Medicine, Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery, Primary Lateral Sclerosis
Abstract

Primary lateral sclerosis (PLS) is a condition that most neurologists will never personally diagnose. For the estimated several thousand people living with PLS globally, while it may not be life-sh...

Published
2020
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32. Primary lateral sclerosis (PLS) functional rating scale: PLS-specific clinimetric scale

Author

Zachary Simmons, Codruta Chiuzan, David Walk, Stephen N. Scelsa, Bjorn Oskarsson, Nicholas J. Maragakis, Yuan Zhang, Sharon P. Nations, Ghazala Hayat, Mary Kay Floeter, Jonathan Hupf, Terry Heiman-Patterson, Christina Fournier, Brittany McHale, Yasushi Kisanuki, Daragh Heitzman, Madison Gilmore, J. Americo M. Fernandes Filho, Sabrina Paganoni, Hiroshi Mitsumoto, Lorne Zinman, Nanette C. Joyce, Lauren Elman, Omar Jawdat, Erik P. Pioro, and Eric J. Sorenson

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Activities of daily living, Certification, Physiology, 030105 genetics & heredity, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Rating scale, Physiology (medical), Activities of Daily Living, Medicine, Humans, Primary lateral sclerosis (PLS), Motor Neuron Disease, Reliability (statistics), Primary Lateral Sclerosis, Aged, Observer Variation, business.industry, Construct validity, Reproducibility of Results, Middle Aged, medicine.disease, Telephone, Clinical trial, Caregivers, Clinical Global Impression, Physical therapy, Disease Progression, Quality of Life, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Introduction Our research aim was to develop a novel clinimetric scale sensitive enough to detect disease progression in primary lateral sclerosis (PLS). Methods A prototype of the PLS Functional Rating Scale (PLSFRS) was generated. Seventy-seven participants with PLS were enrolled and evaluated at 21 sites that comprised the PLSFRS study group. Participants were assessed using the PLSFRS, Neuro-Quality of Life (QoL), Schwab-England Activities of Daily Living (ADL), and the Clinical Global Impression of Change scales. Participants completed telephone assessments at 12, 24, and 48 weeks after enrollment. Results The PLSFRS demonstrated internal consistency as well as intrarater, interrater, telephone test-retest reliability, and construct validity. Significant changes in disease progression were detected at 6 and 12 months; changes measured by the PLSFRS vs the ALSFRS-R were significantly higher. Discussion The PLSFRS is a valid tool to assess the natural history of PLS in a shorter study period.

Published
2019

33. Intracerebral Hemorrhage in a Young Urban Population: Etiologies and Outcomes in Patients 50 and Younger

Author

Guillermo Linares, Daohai Yu, Terry Heiman-Patterson, Paul Jarvis, Xiaoning Lu, and Aron Gedansky

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Subarachnoid hemorrhage, Adolescent, Population, Severity of Illness Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, Prevalence, Medicine, Humans, In patient, Risk factor, education, Stroke, Cerebral Hemorrhage, Retrospective Studies, Intracerebral hemorrhage, Philadelphia, education.field_of_study, business.industry, Rehabilitation, Age Factors, Urban Health, Middle Aged, medicine.disease, Prognosis, Cohort, Hypertension, Etiology, Surgery, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract

Goal: There is limited research on intracerebral hemorrhage in young urban populations. There is reduced access to healthcare and a high prevalence of multiple comorbidities in this vulnerable population. We studied the etiologies and outcomes of spontaneous intracerebral hemorrhage in an urban North Philadelphia cohort aged 50 years old and younger. Materials and methods: A retrospective chart review of subjects 50 years old and younger who presented with spontaneous intracerebral hemorrhage at Temple University Hospital was conducted. A novel scoring system was used to classify the cause of each intracerebral hemorrhage. This system was used to assign a degree of likelihood that hypertension, amyloid angiopathy, tumor, oral anticoagulants, vascular malformations, infrequent causes, or cryptogenic etiologies were present. Aneurysmal subarachnoid hemorrhage was excluded. The prevalence of each risk factor and outcomes were analyzed. Findings: Of the 110 patients in the study, the most common etiology was hypertension (82.7%). There was no statistically significant difference in mortality between patients with multiple possible etiologies for their hemorrhage. Vascular malformations and cavernomas were rare (5.5%). Conclusions: Hypertension was the most common cause of intracerebral hemorrhage in a young urban population. The presence of multiple possible etiologies does not correlate with a worse prognosis of mortality. There is a need for further research into hemorrhagic stroke in young populations.

Published
2019

34. List of Contributors

Author

Nounagnon F. Agbangla, Atahan Agrali, Cédric T. Albinet, Awad Aljuaid, Guillaume Andéol, Jean M. André, Pietro Aricò, Branthomme Arnaud, Romain Artico, Michel Audiffren, Hasan Ayaz, Fabio Babiloni, Wendy Baccus, Carryl L. Baldwin, Hubert Banville, Klaus Bengler, Bruno Berberian, Jérémy Bergeron-Boucher, Ali Berkol, Pierre Besson, Siddharth Bhatt, Arianna Bichicchi, Martijn Bijlsma, Nikolai W.F. Bode, Vincent Bonnemains, Gianluca Borghini, Guillermo Borragán, Marc-André Bouchard, Angela Bovo, Eric Brangier, Anne-Marie Brouwer, Heinrich H. Bülthoff, Christopher Burns, Vincent Cabibel, Tuna E. Çakar, Daniel Callan, Aurélie Campagne, Travis Carlson, William D. Casebeer, Deniz Zengin Çelik, Cindy Chamberland, Caroline P.C. Chanel, Peter Chapman, Luc Chatty, Laurent Chaudron, Philippe Chevrel, Lewis L. Chuang, Caterina Cinel, Bernard Claverie, Antonia S. Conti, Yves Corson, Johnathan Crépeau, Adrian Curtin, Frédéric Dehais, Arnaud Delafontaine, Gaétane Deliens, Arnaud Delorme, Stefano I. Di Domenico, Gianluca Di Flumeri, Jean-Marc Diverrez, Manh-Cuong Do, Mengxi Dong, Andrew T. Duchowski, Anirban Dutta, Lydia Dyer, Sonia Em, Kate Ewing, Stephen Fairclough, Brian Falcone, Tiago H. Falk, Sara Feldman, Ying Xing Feng, Victor S. Finomore, Nina Flad, Alice Formwalt, Alexandra Fort, Paul Fourcade, Marc A. Fournier, Jérémy Frey, C. Gabaude, Olivier Gagey, Marc Garbey, Liliana Garcia, Thibault Gateau, Lukas Gehrke, Nancy Getchell, Evanthia Giagloglou, Christiane Glatz, Kimberly Goodyear, Robert J. Gougelet, Jonas Gouraud, Klaus Gramann, Dhruv Grewal, Carlos Guerrero-Mosquera, Céline Guillaume, Martin Hachet, Alain Hamaoui, Gabriella M. Hancock, Peter A. Hancock, Ahmad Fadzil M. Hani, Amanda E. Harwood, Mitsuhiro Hayashibe, Terry Heiman-Patterson, Girod Hervé, Maarten A.J. Hogervorst, Amy L. Holloway, Jean-Louis Honeine, Keum-Shik Hong, Klas Ihme, Kurtulus Izzetoglu, Meltem Izzetoglu, Philip L. Jackson, Christophe Jallais, Christian P. Janssen, Branislav Jeremic, Meike Jipp, Evelyn Jungnickel, Hélio Kadogami, Gozde Kara, Waldemar Karwowski, Quinn Kennedy, Theresa T. Kessler, Muhammad J. Khan, Rayyan A. Khan, Marius Klug, Amanda E. Kraft, Michael Krein, Ute Kreplin, Bartlomiej Kroczek, Lauens R. Krol, Frank Krueger, Ombeline Labaune, Daniel Lafond, Claudio Lantieri, Paola Lanzi, Amine Laouar, Dargent Lauren, Rachel Leproult, Véronique Lespinet-Najib, Ling-Yin Liang, Fabien Lotte, Ivan Macuzic, Nicolas Maille, Horia A Maior, S. Malin, Alexandre Marois, Franck Mars, Nicolas Martin, Nadine Matton, Magdalena Matyjek, Kevin McCarthy, Ryan McKendrick, Tom McWilliams, Bruce Mehler, Ranjana Mehta, Ranjana K. Mehta, Mathilde Menoret, Yoshihiro Miyake, Alexandre Moly, Rabia Murtza, Makii Muthalib, Mark Muthalib, Noman Naseer, Jordan Navarro, Roger Newport, Anton Nijholt, Michal Ociepka, Morellec Olivier, Ahmet Omurtag, Banu Onaral, Hiroki Ora, Bob Oudejans, Özgürol Öztürk, Martin Paczynski, Nico Pallamin, Raja Parasuraman, Mark Parent, René Patesson, Kou Paul, Philippe Peigneux, Matthias Peissner, G. Pepin, Stephane Perrey, Vsevolod Peysakhovich, Markus Plank, Riccardo Poli, Kathrin Pollmann, Simone Pozzi, Nancy M. Puccinelli, Jean Pylouster, Kerem Rızvanoğlu, Martin Ragot, Bryan Reimer, Emanuelle Reynaud, Joohyun Rhee, Jochem W. Rieger, Anthony J. Ries, Benoit Roberge-Vallières, Achala H. Rodrigo, Anne L. Roggeveen, Ricardo Ron-Angevin, Guillaume Roumy, Raphaëlle N. Roy, Anthony C. Ruocco, Bartlett A. Russell, Jon Russo, Richard M. Ryan, Amanda Sargent, Kelly Satterfield, Ben D. Sawyer, Sébastien Scannella, Menja Scheer, Melissa Scheldrup, Alex Schilder, Nicolina Sciaraffa, Lee Sciarini, Magdalena Senderecka, Sarah Sharples, Tyler H. Shaw, Patricia A. Shewokis, Andrea Simone, Hichem Slama, Alastair D. Smith, Bertille Somon, Hiba Souissi, Moritz Späth, Kimberly L. Stowers, Clara Suied, Junfeng Sun, Rajnesh Suri, Tong Boon Tang, Yingying Tang, Emre O. Tartan, Nadège Tebbache, Franck Techer, Cengiz Terzibas, Catherine Tessier, Claudine Teyssedre, Hayley Thair, Jean-Denis Thériault, Alexander Toet, Shanbao Tong, Jonathan Touryan, Amy Trask, Sébastien Tremblay, Anirudh Unni, François Vachon, Davide Valeriani, Benoît Valéry, Helma van den Berg, Valeria Vignali, Mathias Vukelić, Jijun Wang, Max L. Wilson, Emily Wusch, Petros Xanthopoulos, Eric Yiou, Amad Zafar, Thorsten O. Zander, Matthias D. Ziegler, and Ivana Živanovic-Macuzic

Published
2019
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35. ALSUntangled No. 36: Accilion

Author

Gary L. Pattee, Muddasir Quereshi, Paul Wicks, Todd Levine, Chafic Karam, Edor Kabashi, Christen Shoesmith, Jonathan Goldstein, John T. Kissel, Jim Wymer, Fernando G. Vieira, Pamela Kittrell, Carmel Armon, Josep Gamez, Laurie Gutmann, Lisa Kinsley, Gleb Levitsky, Katherine Tindall, Janice Robertson, Yunxia Wang, Emma Fixsen, Carlayne E. Jackson, Stacy A. Rudnicki, Michael Benatar, Robert Bowser, Robin Conwit, Michael J. Strong, Bjorn Oskarsson, Rob Goldstein, Eric J. Sorenson, Alexander Sherman, Neta Zach, Kathy Mitchell, Peter M Andersen, Ahmad Ghavanini, Kristiana Salmon, Richard Bedlack, Nicholas J. Maragakis, Bonnie Gerecke, Jeffrey D. Rothstein, Leo McClusky, Paul E. Barkhaus, Efrat Carmi, Ginna Gonzalez, Jonathan Licht, Steve Perrin, Hiroshi Mitsumoto, Brett M. Morrison, Meraida Polak, Melanie Leitner, Tahseen Mozaffar, Lyle Ostrow, Orla Hardiman, Lorne Zinman, Daniel M. Pastula, Michael H. Rivner, Mazen M. Dimachkie, Steven Nash, Megan Grosso, Ashok Verma, James Heywood, Vivian E. Drory, Erik P. Pioro, Larry Phillips, Gregory T. Carter, Michael D. Weiss, Nazem Atassi, Jeffrey V. Rosenfeld, Khema Sharma, Yvonne Baker, Jon Baker, Christina Fournier, Kevin Boylan, Mark Bromberg, Tulio E. Bertorini, L. P. Rowland, Eric Valor, Sith Sathornsumetee, Rup Tandan, Colin Quinn, Jeremy M. Shefner, James A. Russell, Steve Kolb, Steven Novella, James Caress, Robert G. Miller, Mieko Ogino, George Sachs, Jonathan D. Glass, David Saperstein, Dan Moore, John Ravits, Terry Heiman-Patterson, Dallas Forshew, Catherine Lomen-Hoerth, Daniel MacGowan, Kate Dalton, Merit Cudkowicz, and Noah Lechtzin

Subjects
Risk, 0301 basic medicine, Clinical Trials as Topic, Pathology, medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, 03 medical and health sciences, Treatment Outcome, 030104 developmental biology, 0302 clinical medicine, Neurology, medicine, Animals, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery
Published
2016
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36. Relationships between slow vital capacity and measures of respiratory function on the ALSFRS-R

Author

Terry Heiman-Patterson, Andrew A. Wolff, Jenny Wei, Angela Genge, Mamede de Carvalho, Carlayne E. Jackson, Jeremy M. Shefner, and Repositório da Universidade de Lisboa

Subjects
Adult, Male, medicine.medical_specialty, Canada, Time Factors, Vital Capacity, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Predictive Value of Tests, Internal medicine, Outcome Assessment, Health Care, medicine, Respiratory muscle, Humans, Respiratory function, 030212 general & internal medicine, Amyotrophic lateral sclerosis, Retrospective Studies, Slow vital capacity, Alsfrs r, business.industry, Disease progression, Amyotrophic Lateral Sclerosis, Australia, medicine.disease, Respiration Disorders, United States, Respiratory Function Tests, Europe, Neurology, Respiratory measurements, Cardiology, Disease Progression, Female, Neurology (clinical), ALS, business, 030217 neurology & neurosurgery
Abstract

© 2018 University of Texas Health Science Center at San Antonio. Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way., Objective: As declining respiratory muscle function commonly leads to disability and death in amyotrophic lateral sclerosis (ALS), respiratory measurements such as slow vital capacity (SVC) may predict disease progression. This study evaluated the relationship between SVC and symptoms measured by the revised ALS Functional Rating Scale (ALSFRS-R). Methods: About 453 ALS placebo-treated patients from the EMPOWER trial (NCT01281189) were evaluated. Correlations between %predicted SVC and individual respiratory ALSFRS-R subdomain items, respiratory subdomain score (maximum score of 12), and total ALSFRS-R score (maximum score of 48) were evaluated using the Pearson correlation coefficient. Pearson's chi-squared test was used to evaluate changes from baseline to week 48 in ALSFRS-R respiratory symptom and respiratory subdomain scores in patients with baseline %predicted SVC above/below the median at baseline and with more slowly/more rapidly decreasing %predicted SVC. Results: The %predicted SVC showed significant correlations with dyspnea, orthopnoea, respiratory insufficiency, respiratory subdomain score, and total ALSFRS-R score (all p < 0.0001). Patients with baseline SVC values < median were significantly more likely than those with baseline SVC ≥ median to have a change in total ALSFRS-R respiratory subdomain score from 12 to

Published
2018

37. Author response: Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism

Author

Andrea Malaspina, Timothy M. Miller, Joshua Dubnau, Eran Hornstein, Julia Davis-Porada, Frank Baas, Dhruv Sareen, Zachary Simmons, Kristy Kang, Avindra Nath, Daniel J. L. MacGowan, Leslie M. Thompson, James D. Berry, James Gardner Gregory, Pietro Fratta, Hemali Phatnani, Nikolaos A. Patsopoulos, Justin Y. Kwan, Neil A. Shneider, Steve Finkbeiner, Ernest Fraenkel, Edward B. Lee, Lyle Ostrow, Noah Zaitlen, James R. Broach, Isabel Hubbard, Phaedra Agius, Delphine Fagegaltier, Ximena Arcila-Londono, Duyang Kim, Vivianna M. Van Deerlin, Terry Heiman-Patterson, Erin G Conlon, James L. Manley, Molly G Hammell, Siddharthan Chandran, Efthimios Dardiotis, Gregory A. Cox, and Suvankar Pal

Subjects
C9orf72, Mechanism (biology), Common disease, Biology, Neuroscience
Published
2018
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38. 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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39. Mental Fatigue Assessment in Prolonged BCI Use Through EEG and fNIRS

Author

Amanda Sargent, Sara Feldman, Terry Heiman-Patterson, Hasan Ayaz, and Patricia A. Shewokis

Subjects
Weakness, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Mental fatigue, Electroencephalography, Neurophysiology, medicine.disease, Physical medicine and rehabilitation, medicine, Amyotrophic lateral sclerosis, medicine.symptom, Controlled experiment, business, Brain–computer interface
Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes loss of motor neurons and progressive weakness including loss of speech. The use of a brain computer interface (BCI) can enable communication and increase quality of life but to date the effects of mental fatigue have been ignored. Mental fatigue due to prolonged BCI use can reduce the accuracy and increase the response time which leads to a decrease in the utility and usability of the BCI. This study is aimed to investigate biomarkers for electrophysiological and hemodynamic correlates of mental fatigue in a controlled experiment with ALS patients and healthy participants. These preliminary results indicated that EEG and fNIRS based biomarkers can be used to capture neurophysiological changes due to prolonged BCI use.

Published
2018
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40. Understanding the use of NIV in ALS: results of an international ALS specialist survey

Author

Sarah Kulke, Vincenzo Silani, Stacy A. Rudnicki, Carlayne E. Jackson, Terry Heiman-Patterson, Leonard H. van den Berg, Dafeng Chen, Angela Genge, Orla Hardiman, Mamede de Carvalho, Jinsy A. Andrews, Hiroshi Mitsumoto, Merit Cudkowicz, and Noah Lechtzin

Subjects
Male, medicine.medical_specialty, Time Factors, Neurology, International Cooperation, Clinical Neurology, 03 medical and health sciences, 0302 clinical medicine, respiratory function, medicine, Humans, Respiratory function, Oximetry, Amyotrophic lateral sclerosis, Intensive care medicine, business.industry, vital capacity, noninvasive ventilation, medicine.disease, Health Surveys, United States, Respiratory status, Clinical neurology, Europe, 030228 respiratory system, Quality of Life, Female, Noninvasive ventilation, Neurology (clinical), Blood Gas Analysis, Respiratory Insufficiency, business, 030217 neurology & neurosurgery
Abstract

Objective: To identify common practices of noninvasive ventilation (NIV) use among ALS specialists and how they follow respiratory status in their patients. Methods: A 25-item questionnaire on NIV indications/initiation was sent via SurveyMonkey® to ALS specialists identified through membership in NEALS (114 sites in the US) and ENCALS (39 sites in Europe). Descriptive statistics and Cochran–Mantel–Haenszel test for general association were performed. Results: In their initial evaluation, US and European specialists (n = 186) use upright forced vital capacity (FVC) most (92.8% vs 91.1%; p = 0.752). Upright FVC results are most important for US respondents when deciding to prescribe NIV; European respondents consider symptoms of orthopnea and/or dyspnea as most important. European respondents use overnight pulse oximetry (69.8% vs 7.9%; p < 0.001) and arterial blood gas analyses (62.8% vs 3.2%; p < 0.001) more than US respondents. Insurance regulations/national health care coverage impact NIV initiation more in the US than in Europe (70.0% vs 47.5%; p = 0.025). When asked if insurance/other financial constraints affects when they prescribe NIV, more US respondents answered positively (77.2% vs 15.4%; p < 0.001). In patients with no respiratory symptoms, most US specialists (68.3%) initiated NIV at VC

Published
2018
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41. Exposure to hazardous air pollutants and the risk of amyotrophic lateral sclerosis

Author

Aaron Barchowsky, Sandeep Rana, Angela M. Malek, David Lacomis, Terry Heiman-Patterson, Ada O. Youk, Evelyn O. Talbott, and Robert Bowser

Subjects
Adult, Male, Health, Toxicology and Mutagenesis, Toxicology, Hazardous air pollutants, Annual incidence, Risk Factors, Air Pollution, Environmental health, Odds Ratio, medicine, Humans, Pesticides, Amyotrophic lateral sclerosis, Air Pollutants, Chemistry, Amyotrophic Lateral Sclerosis, Case-control study, Environmental Exposure, General Medicine, Odds ratio, Environmental exposure, Middle Aged, medicine.disease, Pollution, Confidence interval, Logistic Models, Metals, Case-Control Studies, Solvents, Female, Conditional logistic regression
Abstract

Background : Amyotrophic lateral sclerosis (ALS) is a serious and rapidly fatal neurodegenerative disorder with an annual incidence of 1–2.6/100,000 persons. Few known risk factors exist although gene–environment interaction is suspected. We investigated the relationship between suspected neurotoxicant hazardous air pollutants (HAPs) exposure and ALS. Methods : A case–control study involving sporadic ALS cases ( n = 51) and matched controls ( n = 51) was conducted from 2008 to 2011. Geocoded residential addresses were linked to U.S. EPA NATA data (1999, 2002, and 2005) by census tract. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Results : Residential exposure to aromatic solvents significantly elevated the risk of ALS among cases compared to controls in 2002 (OR = 5.03, 95% CI: 1.29, 19.53) and 1999 (OR = 4.27, 95% CI: 1.09, 16.79) following adjustment for education, smoking, and other exposure groups. Metals, pesticides, and other HAPs were not associated with ALS. Conclusions : A potential relationship is suggested between residential ambient air aromatic solvent exposure and risk of ALS in this study.

Published
2015
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42. ALSUntangled No. 35: Hyperbaric Oxygen Therapy*

Author

Lisa Kinsley, Christen Shoesmith, Steven Nash, Peter M Andersen, John T. Kissel, Daniel M. Pastula, Josep Gamez, Nicholas J. Maragakis, Michael H. Rivner, Michael D. Weiss, Jeffrey V. Rosenfeld, James A. Russell, Kathy Mitchell, Steve Kolb, Melanie Leitner, Jim Wymer, Larry Phillips, Jon Baker, Jeffrey D. Rothstein, Erik P. Pioro, Katherine Tindall, Khema Sharma, Stacy A. Rudnicki, Jonathan D. Glass, James Caress, Janice Robertson, Meraida Polak, Tulio E. Bertorini, Paul Wicks, Yunxia Wang, Carlayne E. Jackson, L. P. Rowland, Megan Grosso, Bjorn Oskarsson, Carmel Armon, Leo McClusky, David Saperstein, Lorne Zinman, Laurie Gutmann, Gregory T. Carter, Robert Bowser, Gary L. Pattee, Kristiana Salmon, Brett M. Morrison, Richard Bedlack, Fernando G. Vieira, Orla Hardiman, Edor Kabashi, Sith Sathornsumetee, Vivian E. Drory, Jeremy M. Shefner, Emma Fixsen, Robert G. Miller, Steve Perrin, Michael Benatar, Hiroshi Mitsumoto, Alexander Sherman, Colin Quinn, Todd Levine, Neta Zach, Christina Fournier, Jonathan Goldstein, Lyle Ostrow, Mark Bromberg, Terry Heiman-Patterson, Dallas Forshew, Steven Novella, Mieko Ogino, George Sachs, John Ravits, Dan Moore, James Heywood, Merit Cudkowicz, Noah Lechtzin, Catherine Lomen-Hoerth, Daniel MacGowan, Kate Dalton, Ashok Verma, Yvonne Baker, Muddasir Quereshi, Kevin Boylan, Pamela Kittrell, Gleb Levitsky, Eric J. Sorenson, Robin Conwit, Rob Goldstein, Eric Valor, Rup Tandan, Nazem Atassi, Ahmad Ghavanini, Paul E. Barkhaus, Ginna Gonzalez, Efrat Carmi, Tahseen Mozaffar, Chafic Karam, Mazen M. Dimachkie, Michael J. Strong, Jonathan Licht, and Bonnie Gerecke

Subjects
Complementary Therapies, Male, 0301 basic medicine, Mice, Mice, Neurologic Mutants, 03 medical and health sciences, Clinical Trials, Phase II as Topic, 0302 clinical medicine, Hyperbaric oxygen, Animals, Humans, Medicine, Single-Blind Method, Amyotrophic lateral sclerosis, Hyperbaric Oxygenation, Clinical Trials, Phase I as Topic, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Disease Models, Animal, Oxidative Stress, Treatment Outcome, 030104 developmental biology, Neurology, Anesthesia, Neurology (clinical), business, 030217 neurology & neurosurgery
Published
2016
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43. ALSUntangled 43: copper

Author

Carmel Armon, Jeffrey D. Rothstein, Erik P. Pioro, Pamela Kittrell, Nicholas J. Maragakis, Kristiana Salmon, Mark B. Bromberg, Stephen J. Kolb, Robert Bowser, Fernando Viera, Christopher J McDermott, Sabrina Paganoni, Tulio E. Bertorini, Terry Heiman-Patterson, Gary L. Pattee, Jim Caress, Eric Valor, Rup Tandan, Neta Zach, Ceri Weber, Vernoica Peschansky, Jon Glass, and Greg Carter

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Amyotrophic Lateral Sclerosis, chemistry.chemical_element, medicine.disease, Copper, Trace Elements, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, chemistry, medicine, Animals, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, 030217 neurology & neurosurgery
Published
2017

44. Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges

Author

Nivedita U, Jerath, Ami, Mankodi, Thomas O, Crawford, Christopher, Grunseich, Hasna, Baloui, Chioma, Nnamdi-Emeratom, Alice B, Schindler, Terry, Heiman-Patterson, Roman, Chrast, and Michael E, Shy

Subjects
Adult, Male, Adolescent, Intracellular Signaling Peptides and Proteins, Proteins, Sciatic Nerve, Article, Rats, Rats, Sprague-Dawley, Animals, Newborn, Scoliosis, Charcot-Marie-Tooth Disease, Mutation, Animals, Humans, Female, Genetic Testing, Child, Demyelinating Diseases
Abstract

This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C).We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2.All patients manifested scoliosis, and nerve conduction study indicated results in the demyelinating range. All patients exhibited signs of motor impairment within the first years of life. We describe 2 or more different genetic diseases in the same patient, atypical presentations of CMT, and 3 new mutations in CMT4C patients.A new era of unbiased genetic testing has led to this small case series of individuals with CMT4C and highlights the recognition of different genetic diseases in CMT4C patients for accurate diagnosis, genetic risk identification, and therapeutic intervention. The phenotype of CMT4C, in addition, appears to be enriched by a number of features unusual for the broad CMT category. Muscle Nerve 57: 749-755, 2018.

Published
2017

45. ALSUntangled 41: 'Eric Is Winning'

Author

Paul E. Barkhaus, Yvonne Baker, Carlayne E. Jackson, Martina Wiedau, Fernando G. Vieira, Michael H. Rivner, Larry Phillips, Stephen J. Kolb, Terry Heiman-Patterson, Kristiana Salmon, Paul Wicks, Richard Bedlack, Eric Valor, John T. Kissel, Gleb Levitsky, Lucie Bruijn, Meraida Polak, Gregory Ringkamp, Mark B. Bromberg, Nicholas J. Maragakis, Carmel Armon, Laurie Gutmann, Michael Benatar, Gregory T. Carter, Kathy Mitchell, Sabrina Paganoni, Jonathan D. Glass, Jeff Rothstein, Tulio E. Bertorini, Lyle Ostrow, and James Caress

Subjects
0301 basic medicine, Aged, 80 and over, Male, medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, Brain, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Physical medicine and rehabilitation, Neurology, Spinal Cord, medicine, Disease Progression, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, Age of Onset, business, 030217 neurology & neurosurgery
Published
2017

46. Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population

Author

Terry Heiman-Patterson, Catherine Lomen-Hoerth, Erin McDonnell, Tawfiq Al-Lahham, Jinsy A. Andrews, Merit Cudkowicz, Alyssa Murphy, Lorena Loci, Hiroshi Mitsumoto, Zachary Simmons, April McVey, Christina Fournier, Nazem Atassi, Yasushi Kisanuki, and Nicholas J. Maragakis

Subjects
0301 basic medicine, Male, Electromyography, Neurodegenerative, Severity of Illness Index, Cohort Studies, 0302 clinical medicine, Amyotrophic lateral sclerosis, Primary Lateral Sclerosis, education.field_of_study, medicine.diagnostic_test, Upper motor neuron, General Medicine, Middle Aged, Upper motor neuron syndrome, medicine.anatomical_structure, Neurology, Neurological, Female, medicine.medical_specialty, Hereditary spastic paraplegia, Population, Clinical Trials and Supportive Activities, Clinical Sciences, Autoimmune Disease, Article, 7.3 Management and decision making, 03 medical and health sciences, Physical medicine and rehabilitation, Rare Diseases, Clinical Research, medicine, Humans, Motor Neuron Disease, education, Aged, Neurology & Neurosurgery, business.industry, Neurosciences, EMG abnormality, medicine.disease, Brain Disorders, 030104 developmental biology, Cross-Sectional Studies, Neurology (clinical), Management of diseases and conditions, ALS, business, 030217 neurology & neurosurgery
Abstract

Objectives The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Methods Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. Results Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. Conclusions Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

Published
2017

47. ALSUntangled: Introducing The Table of Evidence

Author

Hubert Kwieciński, Dan Moore, Gary L. Pattee, Edor Kabashi, Chafic Karam, James Caress, Ashok Verma, Brett M. Morrison, Mieko Ogino, George Sachs, Orla Hardiman, Bonnie Gerecke, Vivian E. Drory, Hiroshi Mitsumoto, Gleb Levitsky, Josep Gamez, James Heywood, Nazem Atassi, Michael D. Weiss, Jeffrey V. Rosenfeld, Colin Quinn, Kathy Mitchell, Robin Conwit, Steven Novella, Mark B. Bromberg, Lewis P. Rowland, Jerry M. Belsh, Michael J. Strong, Todd Levine, Jonathan D. Glass, Yunxia Wang, Carlayne E. Jackson, Jon Baker, Muddasir Quereshi, Melanie Leitner, David Saperstein, Carmel Armon, Leo McClusky, Jonathan Licht, Terry Heiman-Patterson, Dallas Forshew, Laurie Gutmann, Pamela Kittrell, Jonathan Goldstein, Khema Sharma, Alexander Sherman, Efrat Carmi, Tahseen Mozaffar, James A. Russell, Merit Cudkowicz, Meraida Polak, Lorne Zinman, Michael Benatar, Jim Wymer, Christina Fournier, Noah Lechtzin, Eric Valor, Mazen M. Dimachkie, Steve Kolb, Megan Grosso, Katherine Tindall, Gregory T. Carter, Stacy A. Rudnicki, Lyle Ostrow, Eric J. Sorenson, Jeffrey D. Rothstein, Robert Bowser, Bjorn Oskarsson, Rup Tandan, Catherine Lomen-Hoerth, Daniel MacGowan, Peter M Andersen, Kate Dalton, Daniel M. Pastula, Craig Oster, Paul Wicks, Richard Bedlack, Michael H. Rivner, Nicholas J. Maragakis, John Ravits, Erik P. Pioro, Christen Shoesmith, John T. Kissel, Tulio E. Bertorini, Jeremy M. Shefner, Paul E. Barkhaus, Kevin Boylan, Jeff Dietz, Ginna Gonzalez, Sith Sathornsumetee, Larry Phillips, Steven Nash, Robert G. Miller, Janice Robertson, and Lisa Kinsley

Subjects
PubMed, medicine.medical_specialty, Evidence-Based Medicine, Physical medicine and rehabilitation, Neurology, business.industry, Amyotrophic Lateral Sclerosis, Humans, Medicine, Table (landform), Neurology (clinical), business
Published
2014
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48. Cardiopulmonary Response to Videogaming: Slaying Monsters Using Motion Sensor Versus Joystick Devices

Author

Terry Heiman-Patterson, Jeffrey D. Sherman, and Michael Sherman

Subjects
Health (social science), Energy expenditure, Joystick, Rehabilitation, Heart rate, Public Health, Environmental and Occupational Health, Physical activity, Aerobic exercise, Motion sensors, Simulation, Respiratory minute volume, Computer Science Applications, Mathematics
Abstract

Objective: Replacing physical activity with videogaming has been implicated in causing obesity. Studies have shown that using motion-sensing controllers with activity-promoting videogames expends energy comparable to aerobic exercise; however, effects of motion-sensing controllers have not been examined with traditional (non–exercise-promoting) videogames. Materials and Methods: We measured indirect calorimetry and heart rate in 14 subjects during rest and traditional videogaming using motion sensor and joystick controllers. Results: Energy expenditure was higher while subjects were playing with the motion sensor (1.30±0.32 kcal/kg/hour) than with the joystick (1.07±0.26 kcal/kg/hour; P

Published
2014
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49. Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy

Author

Teepu Siddique, Albert J. Tahmoush, Faisal Fecto, Irfan Lalani, Han Xiang Deng, Kaouther Ajroud, Vamsi K. Mootha, Sarah E. Calvo, Senda Ajroud-Driss, Terry Heiman-Patterson, and Nailah Siddique

Subjects
Male, Candidate gene, Nuclear gene, Chromosomes, Human, Pair 22, Mitochondrial disease, Mutant, Locus (genetics), Mitochondrion, Biology, Human mitochondrial genetics, Article, Mitochondrial Proteins, Cellular and Molecular Neuroscience, Mitochondrial myopathy, Genetics, medicine, Humans, Family, Genetics (clinical), Genes, Dominant, Puerto Rico, Mitochondrial Myopathies, medicine.disease, Molecular biology, Mitochondria, Mutation, Female
Abstract

Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5 % of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.

Published
2014
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50. A major QTL on mouse chromosome 17 resulting in lifespan variability in SOD1-G93A transgenic mouse models of amyotrophic lateral sclerosis

Author

Gregory A. Cox, Jeffrey S. Deitch, Terry Heiman-Patterson, Elizabeth A. Blankenhorn, Guillermo M. Alexander, Juliann Jiang, and Roger B. Sher

Subjects
Genetically modified mouse, Candidate gene, DNA Copy Number Variations, Transgene, Longevity, Quantitative Trait Loci, SOD1, Mice, Transgenic, Locus (genetics), Motor Activity, Quantitative trait locus, Biology, Mice, medicine, Animals, Humans, Amyotrophic lateral sclerosis, Genetics, Mice, Inbred BALB C, Euthanasia, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, medicine.disease, Survival Analysis, Mice, Inbred C57BL, Chromosome 17 (human), Disease Models, Animal, Neurology, Mice, Inbred DBA, Neurology (clinical), Chromosomes, Human, Pair 17
Abstract

Amyotrophic lateral sclerosis is a late-onset degenerative disease affecting motor neurons in the spinal cord, brainstem, and motor cortex. There is great variation in the expression of ALS symptoms even between siblings who both carry the same Cu/Zn superoxide dismutase (SOD1) mutations. One important use of transgenic mouse models of SOD1-ALS is the study of genetic influences on ALS severity. We utilized multiple inbred mouse strains containing the SOD1-G93A transgene to demonstrate a major quantitative trait locus (QTL) on mouse chromosome 17 resulting in a significant shift in lifespan. Reciprocal crosses between long- and short-lived strains identified critical regions, and we have narrowed the area for potential genetic modifier(s) to < 2Mb of the genome. Results showed that resequencing of this region resulted in 28 candidate genes with potentially functional differences between strains. In conclusion, these studies provide the first major modifier locus affecting lifespan in this model of FALS and, once identified, these candidate modifier genes may provide insight into modifiers of human disease and, most importantly, define new targets for the development of therapies.

Published
2014
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