Article
Clinical Neurology
Ruben P. A. van Eijk, L. H. van den Berg, Ying Lu
Summary: ALS patients have diverse preferences and needs, leading to the development of a new endpoint (PROOF) that focuses on patient function improvement. It provides a patient-centered analysis to refine risk-benefit assessment of new treatments for ALS.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Article
Clinical Neurology
Steve Vucic, Toby A. Ferguson, Catherine Cummings, Michael T. Hotchkin, Angela Genge, Robert Glanzman, Kasper C. D. Roet, Merit Cudkowicz, Matthew C. Kiernan
Summary: The diagnostic criteria for ALS have been simplified with the Gold Coast criteria, which have increased sensitivity, maintained accuracy, and differentiated atypical phenotypes. It is proposed that these criteria should be incorporated into routine practice and clinical trial settings.
Article
Clinical Neurology
Kathrin Muller, Ki-Wook Oh, Angelica Nordin, Sudhan Panthi, Seung Hyun Kim, Frida Nordin, Axel Freischmidt, Albert C. Ludolph, Chang Seok Ki, Karin Forsberg, Jochen Weishaupt, Young-Eun Kim, Peter Munch Andersen
Summary: De novo mutations in SOD1 have been identified as a cause of sporadic ALS, potentially impacting both isolated cases and smaller familial groups. While the exact origin of these mutations remains uncertain, the findings suggest the importance of genetic counseling and screening for all ALS patients to potentially benefit from personalized therapy.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Article
Genetics & Heredity
Marzieh Khani, Shahriar Nafissi, Hosein Shamshiri, Hamidreza Moazzeni, Hanieh Taheri, Elahe Elahi
Summary: This study identified a novel causative gene, RNF13, for recessively inherited ALS and found that its mutation affects protein homeostasis, contributing to the pathogenesis of neurodegeneration.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Clinical Neurology
Sri Raghav S. Sista, Shahar Shelly, Bjorn Oskarsson, Devon Rubin, Jennifer M. Martinez-Thompson, Carolina Parra-Cantu, Nathan P. Staff, Ruple S. Laughlin
Summary: This study aimed to investigate the differences between C9ORF72 gene-related ALS (C9ALS) and non-C9ALS. The study found that compared to non-C9ALS, C9ALS had a higher prevalence in women, higher family history of ALS, and a higher frequency of upper motor neuron signs. Electrophysiological testing showed higher sensory nerve and lower fibular compound muscle action potential amplitudes in C9ALS.
Article
Clinical Neurology
Adriaan D. de Jongh, Nathalie Braun, Markus Weber, Michael A. van Es, Pegah Masrori, Jan H. Veldink, Philip van Damme, Leonard H. van den Berg, Ruben P. A. van Eijk
Summary: This study aimed to characterize disease progression in amyotrophic lateral sclerosis (ALS) according to the Gold Coast criteria (GCC). The results showed that the GCC broadened the definition of ALS, allowing more patients to participate in trials, while minimally impacting population heterogeneity. However, there were variations in survival time and progression rates between different diagnostic categories, suggesting that selecting specific categories for trials may not result in a more homogeneous study population.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Review
Biochemistry & Molecular Biology
Jan Lejman, Kinga Panuciak, Emilia Nowicka, Angelika Mastalerczyk, Katarzyna Wojciechowska, Monika Lejman
Summary: Gene therapy is the administration of genetic material to modify gene expression or alter cell properties for therapeutic purposes. Recent advances in this field have led to breakthroughs in treating diseases, including motor neuron diseases (MNDs). MNDs are neurodegenerative disorders, and gene therapy shows promise in improving the treatment of these diseases such as SMA and ALS.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Clinical Neurology
Maurizio Grassano, Andrea Calvo, Cristina Moglia, Luca Sbaiz, Maura Brunetti, Marco Barberis, Federico Casale, Umberto Manera, Rosario Vasta, Antonio Canosa, Sandra D'Alfonso, Lucia Corrado, Letizia Mazzini, Clifton Dalgard, Ramita Karra, Ruth Chia, Bryan Traynor, Adriano Chio
Summary: This study evaluated the diagnostic yield and advantages of whole-genome sequencing (WGS) as a standard diagnostic test for Amyotrophic Lateral Sclerosis (ALS). The results showed that WGS had a high diagnostic yield and lower cost compared to conventional strategies. It also identified differences in mutation rates between early-onset and late-onset ALS patients, and found additional genetic factors that worsen prognosis. Therefore, WGS should be considered as the standard genetic testing for all ALS patients.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Editorial Material
Oncology
Puja R. Mehta, Tammaryn Lashley, Pietro Fratta, Alexander Bampton
Summary: In this study, the authors used transcriptomic analysis in combination with a well-curated clinical cohort to identify molecular signature differences between cognitively affected and unaffected ALS patients, revealing insights into potential novel therapeutic targets for ALS.
JOURNAL OF PATHOLOGY
(2022)
Article
Clinical Neurology
Teuta Domi, Paride Schito, Giacomo Sferruzza, Tommaso Russo, Laura Pozzi, Federica Agosta, Paola Carrera, Nilo Riva, Massimo Filippi, Angelo Quattrini, Yuri Matteo Falzone
Summary: This study aims to outline the clinical features of SOD1-ALS patients by comparing them to patients without ALS major gene variants and patients with variants in other major ALS genes. Defining the SOD1-ALS phenotype can assist clinicians in identifying patients who should be prioritized for genetic testing.
JOURNAL OF NEUROLOGY
(2023)
Article
Clinical Neurology
Avyarthana Dey, Collin C. Luk, Abdullah Ishaque, Daniel Ta, Ojas Srivastava, Dennell Krebs, Peter Seres, Chris Hanstock, Christian Beaulieu, Lawrence Korngut, Richard Frayne, Lorne Zinman, Simon Graham, Angela Genge, Hannah Briemberg, Sanjay Kalra
Summary: This study aimed to identify the structural and neurochemical properties that contribute to functional connectivity impairments in the primary motor cortex (PMC) in amyotrophic lateral sclerosis (ALS), and to understand the clinical implications of these findings. The analysis of multimodal data revealed reduced functional connectivity between the PMC and other regions in the brain, as well as alterations in neurochemical markers and diffusion metrics. Furthermore, there were correlations between neurochemical markers, diffusion metrics, and upper motor neuron function. These findings suggest that in vivo neurochemistry may serve as an effective imaging marker for assessing functional connectivity impairments in ALS.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2023)
Review
Clinical Neurology
Georgiana Soares Leandro, Mario Emilio Teixeira Dourado Junior, Glauciane Costa Santana, Luan Samy Xavier Dantas
Summary: The main coping strategy used by ALS patients is seeking social support, while Confrontive coping and Distancing are less commonly mentioned. The coping strategies of ALS patients do not seem to focus on emotions or stress-triggering problems, and age and gender do not modify the chosen strategy.
JOURNAL OF NEUROLOGY
(2022)
Article
Clinical Neurology
Safoora B. Syeda, Museer A. Lone, Payam Mohassel, Sandra Donkervoort, Pinki Munot, Marcondes C. Franca, Juan Eli Galarza-Brito, Matthias Eckenweiler, Alexander Asamoah, Kenneth Gable, Anirban Majumdar, Anke Schumann, Sita D. Gupta, Arpita Lakhotia, Perry B. Shieh, A. Reghan Foley, Kelly E. Jackson, Katherine R. Chao, Thomas L. Winder, Francesco Catapano, Lucy Feng, Janbernd Kirschner, Francesco Muntoni, Teresa M. Dunn, Thorsten Hornemann, Carsten G. Bonnemann
Summary: This study reports six patients from six independent families with juvenile amyotrophic lateral sclerosis (ALS) caused by a specific variant in the SPTLC2 gene. The findings confirm the importance of sphingolipid metabolism alterations in the pathogenesis of motor neuron diseases and suggest that avoiding serine supplementation may be a therapeutic strategy for SPT-associated ALS.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2023)
Article
Clinical Neurology
Melina Pazian Martins, Carelis Gonzalez-Salazar, Fabricio Diniz de Lima, Tauana Bernardes Leoni, Alberto R. M. Martinez, Joao Pedro Nunes Goncalves, Anamarli Nucci, Marcondes Cavalcante Franca Jr
Summary: This study characterized and compared the autonomic function of patients with sporadic ALS and familial ALS type 8. The results showed that both types of ALS patients had dysautonomia involving both sympathetic and parasympathetic divisions, but the symptoms were different between the two groups.
CLINICAL NEUROPHYSIOLOGY
(2023)
Article
Clinical Neurology
Robert David Henderson, Kasper Planeta Kepp, Andrew Eisen
Summary: Amyotrophic lateral sclerosis and frontotemporal dementia are neurodegenerative diseases with complex cellular pathology. The paper emphasizes the importance of evolution in the development of higher cortical function and the impact of factors related to increased lifespan on neuronal function.
FRONTIERS IN NEUROLOGY
(2022)
Article
Clinical Neurology
Carolyn Young, Susana Pinto, Julian Grosskreutz, Orla Hardiman, Lora L. Clawson, Merit E. Cudkowicz, Jinsy A. Andrews
Summary: The roundtable meeting discussed respiratory support in ALS patients, highlighting the potential of orally administered medication in delaying the introduction of NIV or enhancing its benefits. Furthermore, attention was given to the impact of the COVID-19 pandemic on the usual assessment and management practices for respiratory difficulties in ALS patients.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2022)
Article
Clinical Neurology
Sabrina Paganoni, James D. Berry, Melanie Quintana, Eric Macklin, Benjamin R. Saville, Michelle A. Detry, Marianne Chase, Alexander Sherman, Hong Yu, Kristin Drake, Jinsy Andrews, Jeremy Shefner, Lori B. Chibnik, Matteo Vestrucci, Merit E. Cudkowicz
Summary: The current therapeutic development in ALS faces limitations in terms of cost, time, and flexibility due to individual randomized clinical trials. Adaptive platform trials provide a novel approach to investigate multiple interventions for a single disease continuously. The Healey ALS Platform Trial is a recently launched trial that aims to identify novel treatments, biomarkers, and trial endpoints rapidly by testing multiple investigational products concurrently in ALS patients.
ANNALS OF NEUROLOGY
(2022)
Article
Clinical Neurology
Tiziana Petrozziello, Ana C. Amaral, Simon Dujardin, Sali M. K. Farhan, James Chan, Bianca A. Trombetta, Pia Kivisakk, Alexandra N. Mills, Evan A. Bordt, Spencer E. Kim, Patrick M. Dooley, Caitlin Commins, Theresa R. Connors, Derek H. Oakley, Anubrata Ghosal, Teresa Gomez-Isla, Bradley T. Hyman, Steven E. Arnold, Tara Spires-Jones, Merit E. Cudkowicz, James D. Berry, Ghazaleh Sadri-Vakili
Summary: This study found alterations in tau phosphorylation in post-mortem motor cortex of ALS patients, especially increased total tau and pTau-S396 in C9ORF72-ALS. Levels of total tau in cerebrospinal fluid were associated with disease progression speed, while the pTau-T181:tau ratio correlated with disease progression speed.
Article
Neurosciences
Tiziana Petrozziello, Evan A. Bordt, Alexandra N. Mills, Spencer E. Kim, Ellen Sapp, Benjamin A. Devlin, Abigail A. Obeng-Marnu, Sali M. K. Farhan, Ana C. Amaral, Simon Dujardin, Patrick M. Dooley, Christopher Henstridge, Derek H. Oakley, Andreas Neueder, Bradley T. Hyman, Tara L. Spires-Jones, Staci D. Bilbo, Khashayar Vakili, Merit E. Cudkowicz, James D. Berry, Marian DiFiglia, M. Catarina Silva, Stephen J. Haggarty, Ghazaleh Sadri-Vakili
Summary: Research suggests that increased levels of hyperphosphorylated tau may lead to mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis (ALS); reducing tau levels could potentially alleviate mitochondrial dysfunction in ALS.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Clinical Neurology
Robert G. Miller, Rongzhen Zhang, Paige M. Bracci, Ari Azhir, Richard Barohn, Richard Bedlack, Michael Benatar, James D. Berry, Merit Cudkowicz, Edward J. Kasarskis, Hiroshi Mitsumoto, Georgios Manousakis, David Walk, Bjorn Oskarsson, Jeremy Shefner, Michael S. McGrath
Summary: ALS is a complex disease that may be influenced by inflammation. This study found that NP001, which regulates macrophage activation, could slow down disease progression in ALS patients with higher levels of the inflammatory marker CRP. Although the phase 2B trial did not meet its primary endpoints, post hoc analysis identified a subset of patients aged 40-65 years who showed significantly slower decline in ALSFRS-R scores and vital capacity loss when treated with NP001.
Article
Clinical Neurology
Merit E. Cudkowicz, Stacy R. Lindborg, Namita A. Goyal, Robert G. Miller, Matthew J. Burford, James D. Berry, Katharine A. Nicholson, Tahseen Mozaffar, Jonathan S. Katz, Liberty J. Jenkins, Robert H. Baloh, Richard A. Lewis, Nathan P. Staff, Margaret A. Owegi, Donald A. Berry, Yael Gothelf, Yossef S. Levy, Revital Aricha, Ralph Z. Kern, Anthony J. Windebank, Robert H. Brown
Summary: This study evaluated the efficacy of mesenchymal stem cells induced to secrete neurotrophic factors in slowing the progression of ALS. The results suggest that this therapy may have a positive effect on patients with less severe disease, but did not reach statistical significance on the primary endpoint.
Article
Neurosciences
Emily G. Baxi, Terri Thompson, Jonathan Li, Julia A. Kaye, Ryan G. Lim, Jie Wu, Divya Ramamoorthy, Leandro Lima, Vineet Vaibhav, Andrea Matlock, Aaron Frank, Alyssa N. Coyne, Barry Landin, Loren Ornelas, Elizabeth Mosmiller, Sara Thrower, S. Michelle Farr, Lindsey Panther, Emilda Gomez, Erick Galvez, Daniel Perez, Imara Meepe, Susan Lei, Berhan Mandefro, Hannah Trost, Louis Pinedo, Maria G. Banuelos, Chunyan Liu, Ruby Moran, Veronica Garcia, Michael Workman, Richie Ho, Stacia Wyman, Jennifer Roggenbuck, Matthew B. Harms, Jennifer Stocksdale, Ricardo Miramontes, Keona Wang, Vidya Venkatraman, Ronald Holewenski, Niveda Sundararaman, Rakhi Pandey, Danica-Mae Manalo, Aneesh Donde, Nhan Huynh, Miriam Adam, Brook T. Wassie, Edward Vertudes, Naufa Amirani, Krishna Raja, Reuben Thomas, Lindsey Hayes, Alex Lenail, Aianna Cerezo, Sarah Luppino, Alanna Farrar, Lindsay Pothier, Carolyn Prina, Todd Morgan, Arish Jamil, Sarah Heintzman, Jennifer Jockel-Balsarotti, Elizabeth Karanja, Jesse Markway, Molly McCallum, Ben Joslin, Deniz Alibazoglu, Stephen Kolb, Senda Ajroud-Driss, Robert Baloh, Daragh Heitzman, Tim Miller, Jonathan D. Glass, Natasha Leanna Patel-Murray, Hong Yu, Ervin Sinani, Prasha Vigneswaran, Alexander V. Sherman, Omar Ahmad, Promit Roy, Jay C. Beavers, Steven Zeiler, John W. Krakauer, Carla Agurto, Guillermo Cecchi, Mary Bellard, Yogindra Raghav, Karen Sachs, Tobias Ehrenberger, Elizabeth Bruce, Merit E. Cudkowicz, Nicholas Maragakis, Raquel Norel, Jennifer E. Van Eyk, Steven Finkbeiner, James Berry, Dhruv Sareen, Leslie M. Thompson, Ernest Fraenkel, Clive N. Svendsen, Jeffrey D. Rothstein
Summary: Answer ALS is a resource that includes patient-derived iPS cell lines, multi-omic data from iPS neurons, and clinical and smartphone data from over 1,000 ALS patients. This data can be used to identify distinct disease subgroups in ALS.
NATURE NEUROSCIENCE
(2022)
Article
Clinical Neurology
Richard J. Nowak, Christopher S. Coffey, Jonathan M. Goldstein, Mazen M. Dimachkie, Michael Benatar, John T. Kissel, Gil Wolfe, Ted M. Burns, Miriam L. Freimer, Sharon Nations, Volkan Granit, A. Gordon Smith, David P. Richman, Emma Ciafaloni, Muhammad T. Al-Lozi, Laura Ann Sams, Dianna Quan, Eroboghene Ubogu, Brenda Pearson, Aditi Sharma, Jon W. Yankey, Liz Uribe, Michael Shy, Anthony A. Amato, Robin Conwit, Kevin C. O'Connor, David A. Hafler, Merit E. Cudkowicz, Richard J. Barohn
Summary: This study suggests that rituximab is safe but unlikely to significantly reduce steroid use in patients with mild to moderate symptoms of AChR-Ab+ gMG.
Review
Clinical Neurology
Richard Bedlack, Paul E. Barkhaus, Benjamin Barnes, Morgan Beauchamp, Tulio Bertorini, Mark B. Bromberg, Gregory T. Carter, Vinay Chaudry, Merit Cudkowicz, Ce Jackson, Gleb Levitsky, Isaac Lund, Christopher McDermott, Steven Novella, Natasha Olby, Lyle Ostrow, Gary L. Pattee, Terry Heiman-Patterson, Dylan Ratner, Kristiana Salmon, Susan Steves, Mark Terrelonge, Paul Wicks, Anne-Marie Wills
Summary: ALSUntangled reviews the effectiveness of ketogenic diets for ALS patients and finds that they may work by enhancing cellular energy balance and reducing excitotoxicity, neuroinflammation, and oxidative stress. However, there is currently insufficient data to recommend ketogenic diets for ALS patients, especially considering the potential side effects.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2023)
Article
Clinical Neurology
Jonathan S. Katz, Jeffrey D. Rothstein, Merit E. Cudkowicz, Angela Genge, Bjorn Oskarsson, Avis B. Hains, Chen Chen, Joshua Galanter, Braydon L. Burgess, William Cho, Geoffrey A. Kerchner, Felix L. Yeh, Arundhati Sengupta Ghosh, Sravanthi Cheeti, Logan Brooks, Lee Honigberg, Jessica A. Couch, Michael E. Rothenberg, Flavia Brunstein, Khema R. Sharma, Leonard van den Berg, James D. Berry, Jonathan D. Glass
Summary: This study investigated the safety, tolerability, and pharmacokinetics of GDC-0134, a potential therapeutic drug for ALS. Results showed good tolerability of GDC-0134 at appropriate doses, but no tolerated dose was identified. The study also found changes in plasma neurofilament light chain levels in GDC-0134-treated patients and mice.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2022)
Article
Clinical Neurology
Megan Yerton, Allison Winter, Anthony Kostov, Cassandra Lieberman, Dario Gelevski, Harli Weber, Michael Doyle, Geli Kane, Neil Parikh, Katherine M. Burke, Margot Rohrer, Taylor Stirrat, Margaret Bruno, Alison Hochman, Sarah Luppino, Jennifer Scalia, Debra Skoniecki, Derek D'Agostino, Ervin Sinani, Hong Yu, Alexander Sherman, Suma Babu, James D. Berry, Mark G. Midei, Peter G. Milner, Merit E. Cudkowicz, Sabrina Paganoni
Summary: This study reports on the use of 11,11 Di-deuterated linoleic ethyl ester (RT001) in patients with amyotrophic lateral sclerosis (ALS) under expanded access. The results show that RT001 can prevent lipid peroxidation in cellular and mitochondrial membranes and has a therapeutic effect in some patients. The observed adverse events were mostly gastrointestinal and considered to have a low correlation with the use of RT001.
Editorial Material
Clinical Neurology
Merit Cudkowicz
Article
Geriatrics & Gerontology
Frank W. Pun, Bonnie Hei Man Liu, Xi Long, Hoi Wing Leung, Geoffrey Ho Duen Leung, Quinlan T. Mewborne, Junli Gao, Anastasia Shneyderman, Ivan V. Ozerov, Ju Wang, Feng Ren, Alexander Aliper, Evelyne Bischof, Evgeny Izumchenko, Xiaoming Guan, Ke Zhang, Bai Lu, Jeffrey D. Rothstein, Merit E. Cudkowicz, Alex Zhavoronkov
Summary: In this study, an AI-driven target discovery platform called PandaOmics was used to analyze the expression profiles of CNS samples and direct iPSC-derived motor neurons from public datasets and Answer ALS. The study identified 17 high-confidence and 11 novel therapeutic targets, and verified their therapeutic effects in a fruit fly model. The research provides new insights into ALS pathophysiology and demonstrates the ability of AI to speed up the target discovery process.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Review
Clinical Neurology
Xiaoyan Li, Carmel Armon, Paul Barkhaus, Benjamin Barnes, Michael Benatar, Tulio Bertorini, Mark Bromberg, Gregory T. Carter, Jesse Crayle, Merit Cudkowicz, Mazen Dimachkie, Eva L. Feldman, Jonathan Glass, Jill Goslinga, Terry Heiman-Patterson, Sartaj Jhooty, Rachel Lichtenstein, Isaac Lund, Christopher Mcdermott, Gary Pattee, Kaitlyn Pierce, Dylan Ratner, Kristiana Salmon, Paul Wicks, Richard Bedlack
Summary: ALSUntangled reviews alternative and off-label treatments for ALS and finds that rituximab, a drug depleting B lymphocytes, lacks evidence of efficacy in ALS. One patient's experience with rituximab showed no benefit. Due to the known risks, we advise against using rituximab as an ALS treatment.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2023)
Meeting Abstract
Clinical Neurology
Gordon Smith, J. R. Singleton, Marianne Chase, Christopher Coffey, Robin Conwit, Merit Cudkowicz, Dixie Ecklund, Janel Fedler, Anna Godjonsdottir, Tom Greene, Peter Hauer, Elizabeth Klingner, Cathy Revere
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)