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2. The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology

Author

Benatar, Michael, Wuu, Joanne, Huey, Edward D., McMillan, Corey T., Petersen, Ronald C., Postuma, Ronald, McHutchison, Caroline, Dratch, Laynie, Arias, Jalayne J., Crawley, Anita, Houlden, Henry, McDermott, Michael P., Cai, Xueya, Thakur, Neil, Boxer, Adam, Rosen, Howard, Boeve, Bradley F., Dacks, Penny, Cosentino, Stephanie, Abrahams, Sharon, Shneider, Neil, Lingor, Paul, Shefner, Jeremy, Andersen, Peter M., Al-Chalabi, Ammar, and Turner, Martin R.

Published
2024
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3. Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit

Author

Sattler, Rita, Traynor, Bryan J., Robertson, Janice, Van Den Bosch, Ludo, Barmada, Sami J., Svendsen, Clive N., Disney, Matthew D., Gendron, Tania F., Wong, Philip C., Turner, Martin R., Boxer, Adam, Babu, Suma, Benatar, Michael, Kurnellas, Michael, Rohrer, Jonathan D., Donnelly, Christopher J., Bustos, Lynette M., Van Keuren-Jensen, Kendall, Dacks, Penny A., and Sabbagh, Marwan N.

Published
2023
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4. Publisher Correction: The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology

Author

Benatar, Michael, Wuu, Joanne, Huey, Edward D., McMillan, Corey T., Petersen, Ronald C., Postuma, Ronald, McHutchison, Caroline, Dratch, Laynie, Arias, Jalayne J., Crawley, Anita, Houlden, Henry, McDermott, Michael P., Cai, Xueya, Thakur, Neil, Boxer, Adam, Rosen, Howard, Boeve, Bradley F., Dacks, Penny, Cosentino, Stephanie, Abrahams, Sharon, Shneider, Neil, Lingor, Paul, Shefner, Jeremy, Andersen, Peter M., Al-Chalabi, Ammar, and Turner, Martin R.

Published
2024
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5. Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Author

Granit, Volkan, Steele, Julie, Levy, Wendy, Paredes, Maria Elena, Hernandez, Jessica, Bilsker, Martin, Szacka, Katarzyna, Ronert, Adam, Jablońska, Dorota, Łuczak, Alina Zuzanna, Chaverri, Delia, Janse van Mantgem, Mark R, Bunte, Tommy M, Broere, Bianca, de Fockert, Arianne, Sanchez-Tejerina, Daniel, Landabaso, Carmen, Calvo, Andrea, Moglia, Cristina, Manera, Umberto, Canosa, Antonio, Vasta, Rosario, Salamone, Paolina, Fuda, Giuseppe, DeMarco, Giovanni, Casale, Federico, ME Forsberg, Karin, Winroth, Ivar, Almgren Stenberg, Erica, Holmgren, Monica, Amador, Maria del Mar, Lenglet, Timothee, Querin, Giorgia, Coudoin, Sylvie, Pavlakis, Pantelis, Holzberg, Shara, Sideri, Riccardo, Marinou, Kalliopi, Czarnecki, Maciej, Ługiewicz, Renata, Biel-Czarnecka, Marta, Boczkowska, Marcelina, Schotte, Caroline, Vynckier, Jan, Van Daele, Sien, Claeys, Thomas, Delmotte, Koen, Swinnen, Bart, Serrien, Anouk, D'Hondt, Ann, Lamaire, Nikita, Debien, Elisa, Jones, Sarah, Vachon, Chris, Grogan, James, Solorzano, Guillermo, Crowell, Allison, Rakocevic, Goran, Wagoner, Mary, Alma, Osmanovic, Flavia, Wiehler, Sonja, Körner, Olivia, Schreiber-Katz, Camilla, Wohnrade, Anastasia, Sarikidi, Carola, Kassebaum, Chantal, Fischer, Adamo, Ashley, Turcotte, Nicole, Duncan, Jessie, Turner, Ivone, Elman, Lauren, Massie, Rami, Berube, Maxime, Saunders, Natalie, Salmon, Kristiana, Foucher, Juliette, Agessandro, Abrahao, Shirley, Pham, Jahan, Mookshah, Phung, Liane, Statland, Jeffrey, Jawdat, Omar, Dimachkie, Mazen, Pasnoor, Mamatha, Farmakidis, Constantine, Heim, Andrew, Lillig, Katie, Lackey, Alyssa, Weber, Markus, Kurz, Martina, Levine, Todd, Benatar, Michael, Hansen, Thomas, Rom, Dror, Geist, Marie A, Blaettler, Thomas, Camu, William, Kuzma-Kozakiewicz, Magdalena, van den Berg, Leonard H, Morales, Raul Juntas, Chio, Adriano, Andersen, Peter M, Pradat, Pierre-Francois, Lange, Dale, Van Damme, Philip, Mora, Gabriele, Grudniak, Mariusz, Elliott, Matthew, Petri, Susanne, Olney, Nicholas, Ladha, Shafeeq, Goyal, Namita A, Meyer, Thomas, Hanna, Michael G, Quinn, Colin, Genge, Angela, Zinman, Lorne, Jabari, Duaa, Shoesmith, Christen, Ludolph, Albert C, Neuwirth, Christoph, Nations, Sharon, Shefner, Jeremy M, Turner, Martin R, Wuu, Joanne, Bennett, Richard, Dang, Hoang, and Sundgreen, Claus

Published
2024
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6. Modeling seeding and neuroanatomic spread of pathology in amyotrophic lateral sclerosis

Author

Pandya, Sneha, Maia, Pedro D, Freeze, Benjamin, Menke, Ricarda AL, Talbot, Kevin, Turner, Martin R, and Raj, Ashish

Subjects
Biomedical and Clinical Sciences, Health Sciences, Neurosciences, Neurodegenerative, Genetics, Rare Diseases, ALS, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, Brain, Connectome, Frontotemporal Dementia, Humans, Motor Neurons, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

The neurodegenerative disorder amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurons, with pathological involvement of cerebral motor and extra-motor areas in a clinicopathological spectrum with frontotemporal dementia (FTD). A key unresolved issue is how the non-random distribution of pathology in ALS reflects differential network vulnerability, including molecular factors such as regional gene expression, or preferential spread of pathology via anatomical connections. A system of histopathological staging of ALS based on the regional burden of TDP-43 pathology observed in postmortem brains has been supported to some extent by analysis of distribution of in vivo structural MRI changes. In this paper, computational modeling using a Network Diffusion Model (NDM) was used to investigate whether a process of focal pathological 'seeding' followed by structural network-based spread recapitulated postmortem histopathological staging and, secondly, whether this had any correlation to the pattern of expression of a panel of genes implicated in ALS across the healthy brain. Regionally parcellated T1-weighted MRI data from ALS patients (baseline n=79) was studied in relation to a healthy control structural connectome and a database of associated regional cerebral gene expression. The NDM provided strong support for a structural network-based basis for regional pathological spread in ALS, but no simple relationship to the spatial distribution of ALS-related genes in the healthy brain. Interestingly, OPTN gene was identified as a significant but a weaker non-NDM contributor within the network-gene interaction model (LASSO). Intriguingly, the critical seed regions for spread within the model were not within the primary motor cortex but basal ganglia, thalamus and insula, where NDM recapitulated aspects of the postmortem histopathological staging system. Within the ALS-FTD clinicopathological spectrum, non-primary motor structures may be among the earliest sites of cerebral pathology.

Published
2022

8. Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases

Author

Benatar, Michael, Wuu, Joanne, McHutchison, Caroline, Postuma, Ronald B, Boeve, Bradley F, Petersen, Ronald, Ross, Christopher A, Rosen, Howard, Arias, Jalayne J, Fradette, Stephanie, McDermott, Michael P, Shefner, Jeremy, Stanislaw, Christine, Abrahams, Sharon, Cosentino, Stephanie, Andersen, Peter M, Finkel, Richard S, Granit, Volkan, Grignon, Anne-Laure, Rohrer, Jonathan D, McMillan, Corey T, Grossman, Murray, Al-Chalabi, Ammar, Turner, Martin R, Arias, Jalayne, Boeve, Bradley, Dave, Kuldip, Ferguson, Toby, Floeter, Mary-Kay, Rohrer, Jonathan, Gendron, Tania, Gubitz, Amelie, Kaufman, Petra, Le Ber, Isabelle, Lee, Suzee, Malaspina, Andrea, McMillan, Corey, Nicholson, Katie, Postuma, Ronald, Robinson, Richard, Ross, Christopher, Tatton, Nadine, Thakur, Neil, Turner, Martin, and Weishaupt, Jochen

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Neurodegenerative, Dementia, Genetics, Alzheimer's Disease, Rare Diseases, Aging, Prevention, Brain Disorders, Neurosciences, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), ALS, Acquired Cognitive Impairment, Biotechnology, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Neurological, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Asymptomatic Diseases, Frontotemporal Dementia, Humans, Neurodegenerative Diseases, neurodegeneration, amyotrophic lateral sclerosis, pre-symptomatic, disease prevention, First International Pre-Symptomatic ALS Workshop, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

Published
2022

10. The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Author

Chen, Zhongbo, Reynolds, Regina H., Pardiñas, Antonio F., Gagliano Taliun, Sarah A., van Rheenen, Wouter, Lin, Kuang, Shatunov, Aleksey, Gustavsson, Emil K., Fogh, Isabella, Jones, Ashley R., Robberecht, Wim, Corcia, Philippe, Chiò, Adriano, Shaw, Pamela J., Morrison, Karen E., Veldink, Jan H., van den Berg, Leonard H., Shaw, Christopher E., Powell, John F., Silani, Vincenzo, Hardy, John A., Houlden, Henry, Owen, Michael J., Turner, Martin R., Ryten, Mina, and Al-Chalabi, Ammar

Published
2023
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11. Tensor image registration library: Deformable registration of stand‐alone histology images to whole‐brain post‐mortem MRI data

Author

Huszar, Istvan N., Pallebage-Gamarallage, Menuka, Bangerter-Christensen, Sarah, Brooks, Hannah, Fitzgibbon, Sean, Foxley, Sean, Hiemstra, Marlies, Howard, Amy F.D., Jbabdi, Saad, Kor, Daniel Z.L., Leonte, Anna, Mollink, Jeroen, Smart, Adele, Tendler, Benjamin C., Turner, Martin R., Ansorge, Olaf, Miller, Karla L., and Jenkinson, Mark

Published
2023
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13. The cortical neurophysiological signature of amyotrophic lateral sclerosis

Author

Trubshaw, Michael, primary, Gohil, Chetan, additional, Yoganathan, Katie, additional, Kohl, Oliver, additional, Edmond, Evan, additional, Proudfoot, Malcolm, additional, Thompson, Alexander G, additional, Talbot, Kevin, additional, Stagg, Charlotte J, additional, Nobre, Anna C, additional, Woolrich, Mark, additional, and Turner, Martin R, additional

Published
2024
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15. Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials

Author

van den Berg, Leonard H, Sorenson, Eric, Gronseth, Gary, Macklin, Eric A, Andrews, Jinsy, Baloh, Robert H, Benatar, Michael, Berry, James D, Chio, Adriano, Corcia, Philippe, Genge, Angela, Gubitz, Amelie K, Lomen-Hoerth, Catherine, McDermott, Christopher J, Pioro, Erik P, Rosenfeld, Jeffrey, Silani, Vincenzo, Turner, Martin R, Weber, Markus, Brooks, Benjamin Rix, Miller, Robert G, Mitsumoto, Hiroshi, and Group, for the Airlie House ALS Clinical Trials Guidelines

Subjects
ALS, Clinical Research, Neurosciences, Brain Disorders, Neurodegenerative, Clinical Trials and Supportive Activities, Rare Diseases, Amyotrophic Lateral Sclerosis, Biomarkers, Clinical Trials as Topic, Delphi Technique, Guidelines as Topic, Humans, Outcome Assessment, Health Care, Patient Selection, Research Design, Statistics as Topic, Airlie House ALS Clinical Trials Guidelines Group, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo revise the 1999 Airlie House consensus guidelines for the design and implementation of preclinical therapeutic studies and clinical trials in amyotrophic lateral sclerosis (ALS).MethodsA consensus committee comprising 140 key members of the international ALS community (ALS researchers, clinicians, patient representatives, research funding representatives, industry, and regulatory agencies) addressed 9 areas of need within ALS research: (1) preclinical studies; (2) biological and phenotypic heterogeneity; (3) outcome measures; (4) disease-modifying and symptomatic interventions; (5) recruitment and retention; (6) biomarkers; (7) clinical trial phases; (8) beyond traditional trial designs; and (9) statistical considerations. Assigned to 1 of 8 sections, committee members generated a draft set of guidelines based on a "background" of developing a (pre)clinical question and a "rationale" outlining the evidence and expert opinion. Following a 2-day, face-to-face workshop at the Airlie House Conference Center, a modified Delphi process was used to develop draft consensus research guidelines, which were subsequently reviewed and modified based on comments from the public. Statistical experts drafted a separate document of statistical considerations (section 9).ResultsIn this report, we summarize 112 guidelines and their associated backgrounds and rationales. The full list of guidelines, the statistical considerations, and a glossary of terms can be found in data available from Dryad (appendices e-3-e-5, doi.org/10.5061/dryad.32q9q5d). The authors prioritized 15 guidelines with the greatest potential to improve ALS clinical research.ConclusionThe revised Airlie House ALS Clinical Trials Consensus Guidelines should serve to improve clinical trial design and accelerate the development of effective treatments for patients with ALS.

Published
2019

17. Amyotrophic Lateral Sclerosis

Author

Turner, Martin R., Pagani, Marco, Dierckx, Rudi A. J. O., editor, Otte, Andreas, editor, de Vries, Erik F. J., editor, van Waarde, Aren, editor, and Leenders, Klaus L., editor

Published
2021
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18. Understanding Quality of Life for People with Motor Neurone Disease Who Use Tracheostomy Ventilation and Family Members: A Scoping Review.

Author

Turner, Nicola, Faull, Christina, Palmer, Jonathan, Armstrong, Alison, Bedford, Jennifer, Turner, Martin R., and Wilson, Eleanor

Subjects
AMYOTROPHIC lateral sclerosis, MEDICAL personnel, QUALITY of life, WELL-being, DECISION making
Abstract

Tracheostomy ventilation (TV) can increase survival time for people living with motor neurone disease (MND); however, the use of TV varies between countries. Concerns regarding anticipated quality of life (QoL) are among the reasons given by healthcare professionals for not recommending this intervention, yet little is known about QoL in this context. This scoping review was conducted to examine the evidence on QoL for those with MND who use TV and family members involved in their care. Using the methodological guidance of the Joanna Briggs Institute, 23 papers were identified for inclusion, and findings were inductively analysed to identify key themes. We found that people living with MND tend to rate QoL post TV more positively than anticipated by healthcare professionals or family members. QoL was found to be related to positive relationships and activities the person could maintain. Feeling able to make a choice and an adequate level of financial resources were also important factors. Family members tended to experience lower QoL, associated with the uncertainty surrounding an emergency procedure and the complexity of subsequently required care. More evidence on QoL from the perspectives of people with MND who use TV is needed to support decision making and inform guidance. [ABSTRACT FROM AUTHOR]

Published
2024
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20. Genetic screening in sporadic ALS and FTD

Author

Turner, Martin R, Al-Chalabi, Ammar, Chio, Adriano, Hardiman, Orla, Kiernan, Matthew C, Rohrer, Jonathan D, Rowe, James, Seeley, William, and Talbot, Kevin

Subjects
Genetics, Frontotemporal Dementia (FTD), Brain Disorders, Rare Diseases, Neurodegenerative, Dementia, Acquired Cognitive Impairment, Neurosciences, Clinical Research, ALS, Neurological, Amyotrophic Lateral Sclerosis, C9orf72 Protein, Frontotemporal Dementia, Genetic Testing, Humans, Reproducibility of Results, C9ORF, FRONTOTEMPORAL DEMENTIA, GENETICS, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The increasing complexity of the genetic landscape in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) presents a significant resource and physician training challenge. At least 10% of those diagnosed with ALS or FTD are known to carry an autosomal dominant genetic mutation. There is no consensus on what constitutes a positive family history, and ascertainment is unreliable for many reasons. However, symptomatic individuals often wish to understand as much as possible about the cause of their disease, and to share this knowledge with their family. While the right of an individual not to know is a key aspect of patient autonomy, and despite the absence of definitive therapy, many newly diagnosed individuals are likely to elect for genetic testing if offered. It is incumbent on the practitioner to ensure that they are adequately informed, counselled and supported in this decision.

Published
2017

28. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

Author

Allen, Claire, Archibald, Neil, Arkell, James, Arthur-Farraj, Peter, Baker, Mark, Ball, Harriet, Bradley-Barker, Verity, Brown, Zoe, Bruno, Stefania, Carey, Lois, Carswell, Christopher, Chakrabarti, Annie, Choulerton, James, Daher, Mazen, Davies, Ruth, Di Marco Barros, Rafael, Dima, Sofia, Dunley, Rachel, Dutta, Dipankar, Ellis, Richard, Everitt, Alex, Fady, Joseph, Fearon, Patricia, Fisniku, Leonora, Gbinigie, Ivie, Gemski, Alan, Gillies, Emma, Gkrania-Klotsas, Effrossyni, Grigg, Julie, Hamdalla, Hisham, Hubbett, Jack, Hunter, Neil, Huys, Anne-Catherine, Ihmoda, Ihmoda, Ispoglou, Sissi, Jha, Ashwani, Joussi, Ramzi, Kalladka, Dheeraj, Khalifeh, Hind, Kooij, Sander, Kumar, Guru, Kyaw, Sandar, Li, Lucia, Littleton, Edward, Macleod, Malcolm, Macleod, Mary Joan, Madigan, Barbara, Mahadasa, Vikram, Manoharan, Manonmani, Marigold, Richard, Marks, Isaac, Matthews, Paul, Mccormick, Michael, Mcinnes, Caroline, Metastasio, Antonio, Milburn-McNulty, Philip, Mitchell, Clinton, Mitchell, Duncan, Morgans, Clare, Morris, Huw, Morrow, Jasper, Mubarak Mohamed, Ahmed, Mulvenna, Paula, Murphy, Louis, Namushi, Robert, Newman, Edward, Phillips, Wendy, Pinto, Ashwin, Price, David Ashley, Proschel, Harald, Quinn, Terry, Ramsey, Deborah, Roffe, Christine, Ross Russell, Amy, Samarasekera, Neshika, Sawcer, Stephen, Sayed, Walee, Sekaran, Lakshmanan, Serra-Mestres, Jordi, Snowdon, Victoria, Strike, Gayle, Sun, James, Tang, Christina, Vrana, Mark, Wade, Ryckie, Wharton, Chris, Wiblin, Lou, Boubriak, Iryna, Herman, Katie, Plant, Gordon, Varatharaj, Aravinthan, Thomas, Naomi, Ellul, Mark A, Davies, Nicholas W S, Pollak, Thomas A, Tenorio, Elizabeth L, Sultan, Mustafa, Easton, Ava, Breen, Gerome, Zandi, Michael, Coles, Jonathan P, Manji, Hadi, Al-Shahi Salman, Rustam, Menon, David K, Nicholson, Timothy R, Benjamin, Laura A, Carson, Alan, Smith, Craig, Turner, Martin R, Solomon, Tom, Kneen, Rachel, Pett, Sarah L, Galea, Ian, Thomas, Rhys H, and Michael, Benedict D

Published
2020
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34. Data‐independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis.

Author

Dellar, Elizabeth R., Vendrell, Iolanda, Talbot, Kevin, Kessler, Benedikt M., Fischer, Roman, Turner, Martin R., and Thompson, Alexander G.

Subjects
CEREBROSPINAL fluid examination, AMYOTROPHIC lateral sclerosis, CEREBROSPINAL fluid, ENDOPLASMIC reticulum, PROTEOMICS, PROPORTIONAL hazards models, PROGNOSIS
Abstract

While unbiased proteomics of human cerebrospinal fluid (CSF) has been used successfully to identify biomarkers of amyotrophic lateral sclerosis (ALS), high‐abundance proteins mask the presence of lower abundance proteins that may have diagnostic and prognostic value. However, developments in mass spectrometry (MS) proteomic data acquisition methods offer improved protein depth. In this study, MS with library‐free data‐independent acquisition (DIA) was used to compare the CSF proteome of people with ALS (n = 40), healthy (n = 15) and disease (n = 8) controls. Quantified protein groups were subsequently correlated with clinical variables. Univariate analysis identified 7 proteins, all significantly upregulated in ALS versus healthy controls, and 9 with altered abundance in ALS versus disease controls (FDR < 0.1). Elevated chitotriosidase‐1 (CHIT1) was common to both comparisons and was proportional to ALS disability progression rate (Pearson r = 0.41, FDR‐adjusted p = 0.035) but not overall survival. Ubiquitin carboxyl‐terminal hydrolase isozyme L1 (UCHL1; upregulated in ALS versus healthy controls) was proportional to disability progression rate (Pearson r = 0.53, FDR‐adjusted p = 0.003) and survival (Kaplan Meier log‐rank p = 0.013) but not independently in multivariate proportional hazards models. Weighted correlation network analysis was used to identify functionally relevant modules of proteins. One module, enriched for inflammatory functions, was associated with age at symptom onset (Pearson r = 0.58, FDR‐adjusted p = 0.005) and survival (Hazard Ratio = 1.78, FDR = 0.065), and a second module, enriched for endoplasmic reticulum proteins, was negatively correlated with disability progression rate (r = −0.42, FDR‐adjusted p = 0.109). DIA acquisition methodology therefore strengthened the biomarker candidacy of CHIT1 and UCHL1 in ALS, while additionally highlighted inflammatory and endoplasmic reticulum proteins as novel sources of prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Published
2024
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36. Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model

Author

Westeneng, Henk-Jan, Debray, Thomas P A, Visser, Anne E, van Eijk, Ruben P A, Rooney, James P K, Calvo, Andrea, Martin, Sarah, McDermott, Christopher J, Thompson, Alexander G, Pinto, Susana, Kobeleva, Xenia, Rosenbohm, Angela, Stubendorff, Beatrice, Sommer, Helma, Middelkoop, Bas M, Dekker, Annelot M, van Vugt, Joke J F A, van Rheenen, Wouter, Vajda, Alice, Heverin, Mark, Kazoka, Mbombe, Hollinger, Hannah, Gromicho, Marta, Körner, Sonja, Ringer, Thomas M, Rödiger, Annekathrin, Gunkel, Anne, Shaw, Christopher E, Bredenoord, Annelien L, van Es, Michael A, Corcia, Philippe, Couratier, Philippe, Weber, Markus, Grosskreutz, Julian, Ludolph, Albert C, Petri, Susanne, de Carvalho, Mamede, Van Damme, Philip, Talbot, Kevin, Turner, Martin R, Shaw, Pamela J, Al-Chalabi, Ammar, Chiò, Adriano, Hardiman, Orla, Moons, Karel G M, Veldink, Jan H, and van den Berg, Leonard H

Published
2018
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37. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, Georgios, Appel, Stanley H., Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard, Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Allen, Andrew S., Appel, Stanley, Bedlack, Richard S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Ticozzi, Nicola, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, D’Alfonso, Sandra, Corrado, Lucia, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Mazzini, Letizia, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Al Kheifat, Ahmad, Al-Chalabi, Ammar, Andersen, Peter, Basak, A. Nazli, Blair, Ian P., Chio, Adriano, Cooper-Knock, Jonathan, de Carvalho, Mamede, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hardiman, Orla, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Kooyman, Maarten, Landers, John, McLaughlin, Russell, Middelkoop, Bas, Mill, Jonathan, Neto, Miguel Mitne, Moisse, Mattieu, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shatunov, Aleksey, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van der Spek, Rick, van Eijk, Kristel, van Es, Michael, van Rheenen, Wouter, van Vugt, Joke, Veldink, Jan, Weber, Markus, Williams, Kelly L., Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., Murphy, Natalie A., van Vugt, Joke J.F.A., Geiger, Joshua T., Van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Messina, Sonia, Simone, Isabella L., Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Wyman, Stacia K., LeNail, Alex, Van Eyk, Jennifer E., Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L.M.A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J.L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Van Eijk, Kristel R., Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Fifita, Jennifer A., Nicholson, Garth A., Esteban-Pérez, Jesús, García-Redondo, Alberto, Rogaeva, Ekaterina, Zinman, Lorne, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Van Damme, Philip, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.

Published
2018
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38. Mechanisms, models and biomarkers in amyotrophic lateral sclerosis

Author

Turner, Martin R, Bowser, Robert, Bruijn, Lucie, Dupuis, Luc, Ludolph, Albert, McGrath, Michael, Manfredi, Giovanni, Maragakis, Nicholas, Miller, Robert G, Pullman, Seth L, Rutkove, Seward B, Shaw, Pamela J, Shefner, Jeremy, and Fischbeck, Kenneth H

Subjects
Biomedical and Clinical Sciences, Neurosciences, Biomedical Imaging, Clinical Research, Biotechnology, Neurodegenerative, Genetics, Rare Diseases, Brain Disorders, Orphan Drug, ALS, Neurological, Amyotrophic Lateral Sclerosis, Animals, Biomarkers, Disease Models, Animal, Humans, Mitochondrial Diseases, Neuroimaging, Oxidative Stress, Clinical Sciences
Abstract

The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery.

Published
2013

42. Objectively Monitoring Amyotrophic Lateral Sclerosis Patient Symptoms During Clinical Trials With Sensors: Observational Study

Author

Garcia-Gancedo, Luis, Kelly, Madeline L, Lavrov, Arseniy, Parr, Jim, Hart, Rob, Marsden, Rachael, Turner, Martin R, Talbot, Kevin, Chiwera, Theresa, Shaw, Christopher E, and Al-Chalabi, Ammar

Subjects
Information technology, T58.5-58.64, Public aspects of medicine, RA1-1270
Abstract

BackgroundObjective symptom monitoring of patients with Amyotrophic Lateral Sclerosis (ALS) has the potential to provide an important source of information to evaluate the impact of the disease on aspects of real-world functional capacity and activities of daily living in the home setting, providing useful objective outcome measures for clinical trials. ObjectiveThis study aimed to investigate the feasibility of a novel digital platform for remote data collection of multiple symptoms—physical activity, heart rate variability (HRV), and digital speech characteristics—in 25 patients with ALS in an observational clinical trial setting to explore the impact of the devices on patients’ everyday life and to record tolerability related to the devices and study procedures over 48 weeks. MethodsIn this exploratory, noncontrolled, nondrug study, patients attended a clinical site visit every 3 months to perform activity reference tasks while wearing a sensor, to conduct digital speech tests and for conventional ALS monitoring. In addition, patients wore the sensor in their daily life for approximately 3 days every month for the duration of the study. ResultsThe amount and quality of digital speech data captured at the clinical sites were as intended, and there were no significant issues. All the home monitoring sensor data available were propagated through the system and were received as expected. However, the amount and quality of physical activity home monitoring data were lower than anticipated. A total of 3 or more days (or partial days) of data were recorded for 65% of protocol time points, with no data collected for 24% of time points. At baseline, 24 of 25 patients provided data, reduced to 13 of 18 patients at Week 48. Lower-than-expected quality HRV data were obtained, likely because of poor contact between the sensor and the skin. In total, 6 of 25 patients had mild or moderate adverse events (AEs) in the skin and subcutaneous tissue disorders category because of skin irritation caused by the electrode patch. There were no reports of serious AEs or deaths. Most patients found the sensor comfortable, with no or minimal impact on daily activities. ConclusionsThe platform can measure physical activity in patients with ALS in their home environment; patients used the equipment successfully, and it was generally well tolerated. The quantity of home monitoring physical activity data was lower than expected, although it was sufficient to allow investigation of novel physical activity end points. Good-quality in-clinic speech data were successfully captured for analysis. Future studies using objective patient monitoring approaches, combined with the most current technological advances, may be useful to elucidate novel digital biomarkers of disease progression.

Published
2019
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46. Variants of the elongator protein 3 ( ELP3 ) gene are associated with motor neuron degeneration

Author

Simpson, Claire L, Lemmens, Robin, Miskiewicz, Katarzyna, Broom, Wendy J, Hansen, Valerie K, van Vught, Paul WJ, Landers, John E, Sapp, Peter, Van Den Bosch, Ludo, Knight, Joanne, Neale, Benjamin M, Turner, Martin R, Veldink, Jan H, Ophoff, Roel A, Tripathi, Vineeta B, Beleza, Ana, Shah, Meera N, Proitsi, Petroula, Van Hoecke, Annelies, Carmeliet, Peter, Horvitz, H Robert, Leigh, P Nigel, Shaw, Christopher E, van den Berg, Leonard H, Sham, Pak C, Powell, John F, Verstreken, Patrik, Brown, Robert H, Robberecht, Wim, and Al-Chalabi, Ammar

Subjects
Rare Diseases, Genetics, Neurodegenerative, Biotechnology, Brain Disorders, Neurosciences, ALS, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Animals, Drosophila, Female, Genetic Predisposition to Disease, Genetic Variation, Histone Acetyltransferases, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Motor Neurons, Mutation, Nerve Tissue Proteins, White People, Zebrafish, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P=1.96 x 10(-9)). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: -0.49, P=1.83 x 10(-12) (start codon morpholino) and -0.46, P=4.05 x 10(-9) (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P=0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.

Published
2009

47. The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Author

Neurologen, Brain, Neuromuscular Disorders, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Chen, Zhongbo, Reynolds, Regina H, Pardiñas, Antonio F, Gagliano Taliun, Sarah A, van Rheenen, Wouter, Lin, Kuang, Shatunov, Aleksey, Gustavsson, Emil K, Fogh, Isabella, Jones, Ashley R, Robberecht, Wim, Corcia, Philippe, Chiò, Adriano, Shaw, Pamela J, Morrison, Karen E, Veldink, Jan H, van den Berg, Leonard H, Shaw, Christopher E, Powell, John F, Silani, Vincenzo, Hardy, John A, Houlden, Henry, Owen, Michael J, Turner, Martin R, Ryten, Mina, Al-Chalabi, Ammar, Neurologen, Brain, Neuromuscular Disorders, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Chen, Zhongbo, Reynolds, Regina H, Pardiñas, Antonio F, Gagliano Taliun, Sarah A, van Rheenen, Wouter, Lin, Kuang, Shatunov, Aleksey, Gustavsson, Emil K, Fogh, Isabella, Jones, Ashley R, Robberecht, Wim, Corcia, Philippe, Chiò, Adriano, Shaw, Pamela J, Morrison, Karen E, Veldink, Jan H, van den Berg, Leonard H, Shaw, Christopher E, Powell, John F, Silani, Vincenzo, Hardy, John A, Houlden, Henry, Owen, Michael J, Turner, Martin R, Ryten, Mina, and Al-Chalabi, Ammar

Published
2023

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