Review
Immunology
Zongzhi Jiang, Ziyi Wang, Xiaojing Wei, Xue-Fan Yu
Summary: This review article summarizes the role and application of inflammatory markers in amyotrophic lateral sclerosis (ALS). Inflammatory molecules and proteins play a key role in the pathogenesis of ALS and may serve as indicators for predicting patient survival and evaluating treatment response. Furthermore, inflammatory markers have the potential to be used as new therapeutic targets and strategies to expand the therapeutic interventions for ALS.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Clinical Neurology
Lindsey R. Hayes, Petr Kalab
Summary: Nuclear clearance and cytoplasmic mislocalization of TDP-43 protein are pathological features of neurodegenerative disorders. The mislocalization of TDP-43 leads to neurodegeneration through disruption of RNA processing and cellular functions. Therapies for TDP-43 primarily focus on clearing TDP-43 aggregates, and future strategies aim to address the upstream causes of TDP-43 disruption.
Review
Chemistry, Medicinal
Kazumoto Shibuya, Ryo Otani, Yo-ichi Suzuki, Satoshi Kuwabara, Matthew C. Kiernan
Summary: Amyotrophic lateral sclerosis (ALS) is a devastating disease involving degeneration of upper and lower motor neurons. Riluzole and edaravone have been shown to slow disease progression in ALS by inhibiting glutamate and eliminating free radicals, respectively. Excessive activation of glutamate receptors generates free radicals, leading to excitotoxicity and neurodegeneration, which are key mechanisms in ALS.
Review
Cell Biology
Pedro Soares, Catia Silva, Daniel Chavarria, Filomena S. G. Silva, Paulo J. Oliveira, Fernanda Borges
Summary: Amyotrophic lateral sclerosis (ALS) is a progressive disease that leads to paralysis and death due to respiratory failure. Current ALS drugs only provide mild relief to patients. Recent advances in understanding ALS biology have identified potential targets for drug development, including mitochondria and oxidative stress, iron metabolism and ferroptosis, and regulators of hypoxia and inflammation. This review focuses on discussing the latest advances in ALS drug development and proposes the rational design of multi-target ligands as a potential effective therapy for ALS.
AGEING RESEARCH REVIEWS
(2023)
Article
Clinical Neurology
Philippe Corcia, Pascal Lejeune, Patrick Vourc'h, Stephane Beltran, Anne-Sophie Piegay, Helene Blasco, Vincent Meininger
Summary: This study characterized the prototypical phenotype of patients with amyotrophic lateral sclerosis (ALS) associated with PFN1 mutations and identified clinical indications for testing mutations in this gene. The main clinical findings for familial ALS linked to PFN1 were identified as pedigrees with over five cases, an onset age around 50 years, onset in the lower limbs, and the absence of cognitive impairment. The similarities with other ALS mutations prompt a review of ALS classifications based on both phenotype and genotype.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Neurosciences
Yahui Zhu, Mao Li, Hongfen Wang, Fei Yang, RongRong Du, Xinyuan Pang, Jiongming Bai, Xusheng Huang
Summary: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) currently lack effective treatments. Drug repurposing provides a rapid solution to address the therapeutic needs of ALS and FTD. Through genetic analysis, several potential therapeutic targets for repurposing have been identified.
MOLECULAR NEUROBIOLOGY
(2023)
Review
Cell Biology
Nancy Tarantino, Ileana Canfora, Giulia Maria Camerino, Sabata Pierno
Summary: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons and muscle function. The disease involves a complex cascade of events among motor neurons, glia, and muscles, and is associated with mitochondrial dysfunction and other mechanisms. Currently, there are limited treatment options, and there is a need to find effective treatments.
Review
Endocrinology & Metabolism
Nader Akbari Dilmaghani, Bashdar Mahmud Hussen, Saeedeh Nateghinia, Mohammad Taheri, Soudeh Ghafouri-Fard
Summary: ALS, a deadly motor neuron disease, is classified into familial and sporadic types, with genetic risk factors not fully identified in sporadic cases. Studies have shown dysregulation of multiple miRNAs in ALS patients' serum samples and brain tissues, some of which may serve as potential biomarkers for sporadic ALS.
METABOLIC BRAIN DISEASE
(2021)
Review
Biochemistry & Molecular Biology
Shinji Miwa, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Kentaro Igarashi, Hiroyuki Tsuchiya
Summary: Chondrosarcomas develop resistance to standard anticancer drugs, making it challenging to control the disease. New treatment approaches, such as molecule-targeting agents and immunotherapy, are needed. Recent studies have identified promising biomarkers and therapeutic targets for chondrosarcoma, and various molecule-targeting agents and immunotherapies have shown favorable antitumor activity in clinical studies. This review summarizes recent research on biomarkers and therapeutic targets, as well as clinical studies on the treatment of chondrosarcomas.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cell Biology
Takashi Hosaka, Hiroshi Tsuji, Shin Kwak
Summary: Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by the death of upper and lower motor neurons. Age-dependent changes in RNA metabolism and dysregulation of RNA editing have been found to play crucial roles in the pathogenesis of ALS. Furthermore, circRNAs have been identified as potential biomarkers and therapeutic targets for ALS based on their age-related changes and involvement in neurodegeneration.
Review
Biochemistry & Molecular Biology
Barbara Teruel-Pena, Jose Luis Gomez-Urquiza, Nora Suleiman-Martos, Isabel Prieto, Francisco Jose Garcia-Cozar, Manuel Ramirez-Sanchez, Carmen Fernandez-Martos, German Dominguez-Vias
Summary: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons and biomarkers for ALS are important for disease detection and therapeutic targets. This study conducted a systematic review and meta-analyses of genetic loci associated with ALS using genome-wide association studies (GWASs). Aminopeptidases were identified as possible biomarkers, but the meta-analyses did not show a risk association between the genetic variation rs1060404 in the DPP6 gene and ALS.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Clinical Neurology
Thomas H. Julian, Sarah Boddy, Mahjabin Islam, Julian Kurz, Katherine J. Whittaker, Tobias Moll, Calum Harvey, Sai Zhang, Michael P. Snyder, Christopher McDermott, Johnathan Cooper-Knock, Pamela J. Shaw
Summary: Mendelian randomization studies on amyotrophic lateral sclerosis show a causal link between blood lipids and the disease risk, while factors like smoking and immune function require further investigation for confirmation. The use of high methodological standards and replication across different datasets are essential for reliable results in Mendelian randomization studies.
Review
Biochemistry & Molecular Biology
Katarina Maksimovic, Mohieldin Youssef, Justin You, Hoon-Ki Sung, Jeehye Park
Summary: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Recent research has shown that ALS is not only limited to motor neurons, but also involves systemic metabolic dysfunction. This review examines the metabolic dysfunction in ALS at various levels, including muscle tissue, adipose tissue, liver, pancreas, and the central nervous system. It also discusses the future prospects of metabolic research in ALS and potential treatment options.
Review
Medicine, General & Internal
Can Cui, Jiangwei Sun, Kyla A. McKay, Caroline Ingre, Fang Fang
Summary: This systematic review investigated the association between medication use and ALS risk, and found no strong evidence linking any medication use with the risk of ALS.
Article
Neurosciences
Shuangwu Liu, Yuying Zhao, Qingguo Ren, Dong Zhang, Kai Shao, Pengfei Lin, Ying Yuan, Tingjun Dai, Yongqing Zhang, Ling Li, Wei Li, Peiyan Shan, Xiangshui Meng, Qian Wang, Chuanzhu Yan
Summary: This study investigated amygdala abnormalities in ALS patients, revealing distinct patterns at different clinical disease stages and highlighting their impact on anxiety and cognitive dysfunction.
HUMAN BRAIN MAPPING
(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.
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
Marta Garcia-Montojo, Elena Rita Simula, Saeed Fathi, Cynthia McMahan, Anubrata Ghosal, James D. Berry, Merit Cudkowicz, Abdel Elkahloun, Kory Johnson, Gina Norato, Peter Jensen, Tony James, Leonardo A. Sechi, Avindra Nath
Summary: This study found that individuals with amyotrophic lateral sclerosis (ALS) had a stronger antibody response against HML-2 env compared to healthy controls. Lower levels of HML-2 antibodies in ALS were associated with poor prognosis and decreased survival probability.
ANNALS OF NEUROLOGY
(2022)
Meeting Abstract
Clinical Neurology
Pamela Shaw, Timothy Miller, Merit Cudkowicz, Angela Genge, Gen Sobue, Ivan Nestorov, Danielle Graham, Laura Fanning, Stephanie Fradette, Manjit McNeill
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(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)
Article
Oncology
Corinne E. Griguer, Claudia R. Oliva, Christopher S. Coffey, Merit E. Cudkowicz, Robin A. Conwit, Anna L. Gudjonsdottir, Dixie J. Ecklund, Janel K. Fedler, Tina M. Neill-Hudson, Louis B. Nabors, Melanie Benge, James R. Hackney, Marianne Chase, Timothy P. Leonard, Toral Patel, Howard Colman, Macarena de la Fuente, Rekha Chaudhary, Karen Marder, Teri Kreisl, Nimish Mohile, Milan G. Chheda, Katharine McNeill, Priya Kumthekar, Aclan Dogan, Jan Drappatz, Vinay Puduvalli, Agnes Kowalska, Jerome Graber, Elizabeth Gerstner, Stephen Clark, Michael Salacz, James Markert
Summary: Through a prospective study of 152 newly diagnosed GBM patients, it was found that tumor CcO activity alone is not a prognostic marker for GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may indicate improved long-term survival in a subgroup of GBM patients, which warrants further investigation.
NEURO-ONCOLOGY ADVANCES
(2022)
Article
Clinical Neurology
Jamie K. Wong, Anna K. Roselle, Taylor M. Shue, Serena J. E. Shimshak, Joseph M. Beaty, Nadia M. Celestin, Ivy Gao, Rose P. Griffin, Merit E. Cudkowicz, Saud A. Sadiq
Summary: This study demonstrates that apolipoprotein B-100 induces motor disability and motor neuron degeneration in a novel cerebrospinal fluid-mediated mouse model of sporadic amyotrophic lateral sclerosis. Targeted removal of apolipoprotein B-100 in cerebrospinal fluid attenuates its neurotoxic capacity, thereby preventing disability and motor neuron degeneration.
BRAIN COMMUNICATIONS
(2022)
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)
