Research Publications

The amyotrophic lateral sclerosis-health index (ALS-HI): development and evaluation of a novel outcome measure. Varma A, Weinstein J, Seabury J, Rosero S, Zizzi C, Alexandrou D, Wagner E, Dilek N, Heatwole J, Wuu J, Caress J, Bedlack R, Granit V, Statland J, Mehta P, Benatar M, Kaat A, Heatwole C. Amyotroph Lateral Scler Frontotemporal Degener. 2023 Aug;24(5-6):514-522. doi: 10.1080/21678421.2023.2204871. Epub 2023 May 15. PMID: 37190795

Amyotrophic lateral sclerosis (ALS) patients experience a wide variety of physical, mental, emotional, and social symptoms of the disease. Tools to track a patient’s subtle but important changes over time are important for managing the disease burden as well as assessing promising new therapeutic agents. Therefore, highly reliable, sensitive, and valid disease-specific outcome measures for ALS are vital for clinicians and researchers, as well as patients and family members.

In this study, the authors report the development of the Amyotrophic Lateral Sclerosis-Health Index (ALS-HI), which was created and validated in accordance with FDA guidance. This is a multifactorial, disease-specific patient-reported outcome measure capable of measuring meaningful changes in how an ALS patient feels and functions.

To develop the ALS-HI, the authors surveyed a national cross section of 497 individuals with ALS. After identifying the most important symptoms of ALS, they performed factor analysis, qualitative patient interviews, test-retest reliability assessment, and known groups analysis to evaluate and validate the ALS-HI. Fifteen participants took part in a beta test and found the ALS-HI to be clear, easy to use, and relevant.

The study supports use of the ALS-HI as a valid, sensitive, and reliable instrument to assess the disease burden of individual patients with ALS. The ALS-HI could also serve as an effective mechanism to track disease progression and treatment efficacy during therapeutic trials.

Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4. Kessler C, Serna-Higuita LM, Wilke C, Rattay TW, Hengel H, Reichbauer J, Stransky E, Leyva-Gutiérrez A, Mengel D, Synofzik M, Schöls L, Martus P, Schüle R. Ann Clin Transl Neurol. 2022 Mar;9(3):326-338. doi: 10.1002/acn3.51518. Epub 2022 Feb 16. PMID: 35171517; PMCID: PMC8935322.

Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders characterized by muscle weakness and tightness (spasticity) in the legs. Easily accessible fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent form of HSP. In this study, researchers investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4. The team assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. They found that sNfL levels are not suitable to monitor disease progression in SPG4, but may be valuable as a therapy response biomarker. Authors note that because sNfL levels appear to be most dynamic around the onset of SPG4, the ability to detect a therapy response is especially promising in younger patients, matching the need to initiate treatment in early disease stages.

Defining cognitive impairment in amyotrophic lateral sclerosis: an evaluation of empirical approaches. McMillan CT, Wuu J, Rascovsky K, Cosentino S, Grossman M, Elman L, Quinn C, Rosario L, Stark JH, Granit V, Briemberg H, Chenji S, Dionne A, Genge A, Johnston W, Korngut L, Shoesmith C, Zinman L; Canadian ALS Neuroimaging Consortium (CALSNIC), Kalra S, Benatar M. Amyotroph Lateral Scler Frontotemporal Degener. 2022 Mar 7:1-10. doi: 10.1080/21678421.2022.2039713. Online ahead of print.

Mild motor impairment as prodromal state in amyotrophic lateral sclerosis: a new diagnostic entity. Benatar M, Granit V, Andersen PM, Grignon AL, McHutchison C, Cosentino S, Malaspina A, Wuu J. Brain. 2022 May 20:awac185. doi: 10.1093/brain/awac185. Epub ahead of print. PMID: 35594156.

Amyotrophic lateral sclerosis (ALS) is traditionally regarded as a clinical syndrome. Emerging biomarker evidence of disease prior to clinical manifestations of disease, however, have fostered the view that ALS should be considered a biological entity with pre-symptomatic and clinically manifest stages of disease. New data from Pre-fALS, a natural history and biomarker study of people at genetic risk for ALS, now indicate that pre-symptomatic should not necessarily be taken to mean “clinically silent.” Systematic clinical characterization of 20 phenoconverters–pre-symptomatic gene mutation carriers who have been followed from the pre-symptomatic to the clinically manifest stages of disease–reveals evidence of a prodromal state of mild motor impairment (MMI). MMI is characterized by symptoms, signs, or electromyographic findings that represent a departure from normal, but which are insufficiently severe or widespread to clearly indicate ALS. The duration of prodromal MMI varies among carriers of different genetic mutations. Based on these findings, the authors conclude that in three of the most common genetic forms of ALS, MMI is an observable state that is prodromal to clinically manifest disease. The authors hypothesize that this may also be true for all genetic ALS and non-genetic forms of ALS as well. Importantly, MMI is considered both an intermediate (transitional) and an indeterminate state, as not everyone with MMI will progress to develop ALS. As a new diagnostic label, MMI should generate fresh urgency for developing diagnostic biomarkers that might permit earlier therapeutic intervention.

Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers in Primary Progressive Multiple Sclerosis and Hereditary Spastic Paraplegia Type 4. Kessler C, Ruschil C, Abdelhak A, Wilke C, Maleska A, Kuhle J, Krumbholz M, Kowarik MC, Schüle R. Serum. Int J Mol Sci. 2022 Nov 3;23(21):13466. doi: 10.3390/ijms232113466. PMID: 36362248; PMCID: PMC9657281.

Primary progressive multiple sclerosis (PPMS) and hereditary spastic paraplegia (HSP) are inherited disorders affecting nerves that send messages to the muscles. Because patients with both disorders can present with slowly progressive spastic paraparesis (weakness in the legs), accurate diagnoses are often challenging. In this study, researchers investigated the use of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) as biomarkers to support diagnosis. The team assessed sNfl and sGFAP levels in 25 patients with PPMS, 25 patients with spastic paraplegia type 4 (SPG4, the most common type of HSP), and 60 control subjects. Results showed that sNfl levels were significantly higher in patients with PPMS compared to patients with SPG4. Researchers also observed a trend toward relatively higher sGFAP levels in patients with PPMS. However, because both groups of patients showed overlapping biomarker values, the team did not find sNfL and sGFAP to be useful biomarkers. As findings indicate that sNfL and sGFAP are most significantly elevated in the early disease stages of PPMS, authors note that further investigation is warranted.

Neurofilament light chain in drug development for amyotrophic lateral sclerosis: a critical appraisal. Benatar M, Wuu J, Turner MR. Brain. 2022 Oct 31:awac394. doi: 10.1093/brain/awac394. Epub ahead of print. PMID: 36310538.

Interest in amyotrophic lateral sclerosis (ALS) biomarkers has grown exponentially over the course of the last 25 years, with great hope that they might serve as tools to facilitate the development of meaningful therapies for this otherwise progressive and fatal disease. Effective use of biomarkers, however, requires an understanding of what it means for them to be “fit-for-purpose,” as well as an appreciation of the nuances of the clinical contexts in which they will be applied. Neurofilament light chain (NfL) has emerged as a leading candidate with enormous potential to aid ALS therapy development. However, Nfl is also profoundly misunderstood. Within the conceptual framework of the BEST (Biomarkers, EndpointS, and other Tools) Resource developed by the National Institutes of Health and the Food & Drug Administration in the United States, authors consider the evidence supporting the use of NfL for a variety of purposes in different clinical contexts. Authors conclude that NfL may serve as a susceptibility/risk biomarker in populations at elevated risk for ALS, and that NfL has value as a prognostic biomarker when measured early in the course of established disease. Authors also conclude that NfL may serve as a pharmacodynamic biomarker, as a reduction in NfL in response to an experimental therapeutic might aid go/no-go decisions in phase 2 clinical trials. A reduction in NfL may also be a reasonably likely surrogate endpoint for experimental therapeutics administered early in the course of disease.

Occupational lead exposure and survival with amyotrophic lateral sclerosis. Wang TW, Wuu J, Cooley A, Yeh TS, Benatar M, Weisskopf M. Amyotroph Lateral Scler Frontotemporal Degener. 2022 Apr 9;1-8. doi: 10.1080/21678421.2022.2059379. Online ahead of print.

Environmental risk factors are thought to play a role in ALS risk but may also impact the rate of disease progression and survival. Lead, given its known neurotoxicity, is one such exposure. Prior studies that have relied on biomarkers of lead exposure have yielded conflicting results. In this study, researchers evaluated the relationship between occupational lead exposure prior to onset of ALS on the one hand, and disease progression and survival following onset of ALS on the other hand. Lead exposure was determined using a job-exposure matrix based on occupations held prior to onset of ALS. This approach avoids the potential for reverse causation bias that may result from reliance on lead biomarkers after disease onset. The impact on disease progression was quantified through both survival analysis and estimation of the rate of functional decline. Results suggest that lead exposure before onset of ALS is associated with more rapid functional decline and shorter survival following onset of ALS, even after adjusting for other factors known to influence disease progression.

Patient reported impact of symptoms in amyotrophic lateral sclerosis (PRISM-ALS): A national, cross-sectional study. Zizzi C, Seabury J, Rosero S, Alexandrou D, Wagner E, Weinstein JS, Varma A, Dilek N, Heatwole J, Wuu J, Caress J, Bedlack R, Granit V, Statland JM, Mehta P, Benatar M, Heatwole C. EClinicalMedicine. 2022 Dec 13;55:101768. doi: 10.1016/j.eclinm.2022.101768. PMID: 36531982; PMCID: PMC9755057.

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases. Benatar M, Wuu J, McHutchison C, Postuma RB, Boeve BF, Petersen R, Ross CA, Rosen H, Arias JJ, Fradette S, McDermott MP, Shefner J, Stanislaw C, Abrahams S, Cosentino S, Andersen PM, Finkel RS, Granit V, Grignon AL, Rohrer JD, McMillan CT, Grossman M, Al-Chalabi A, Turner MR; First International Pre-Symptomatic ALS Workshop. Brain. 2022 Mar 29;145(1):27-44. doi: 10.1093/brain/awab404. PMID: 34677606; PMCID: PMC8967095.

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis (ALS). Much is still unknown, however, and advances in other neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), spinal muscular atrophy (SMA), and frontotemporal dementia (FTD)—highlight opportunities for discovery in ALS. This article builds on discussions at the First International Pre-Symptomatic ALS Workshop (January 2020, Miami, Florida). Lessons from AD illustrate the importance of conceptualizing neurodegenerative diseases as biological entities. PD and HD, respectively, highlight the value of prodromal clinical markers and the value of tools to predict age of onset. FTD elucidates nuanced differences in pre-symptomatic disease based on genotype, and SMA underscores the value of early therapeutic intervention. The authors discuss a conceptual framework for pre-symptomatic ALS that includes clinically silent and prodromal stages of disease. They also provide recommendations for the study of motor, cognitive, and behavioral manifestations of early ALS; emphasize the critical importance of biomarkers; discuss the challenges of genetic and biomarker counseling as well as a range of ethical, legal, and social issues relevant to pre-symptomatic disease. Last, but not least, they present ideas about the design of early intervention and disease prevention clinical trials. Ultimately, the authors present a road map to early intervention—and perhaps even disease prevention—for all forms of ALS.

Rates of longitudinal change in (18) F-flortaucipir PET vary by brain region, cognitive impairment, and age in atypical Alzheimer's disease. Phillips JS, Nitchie FJ 4th, Da Re F, Olm CA, Cook PA, McMillan CT, Irwin DJ, Gee JC, Dubroff JG, Grossman M, Nasrallah IM; Alzheimer's Disease Neuroimaging Initiative. Alzheimers Dement. 2022 Jun;18(6):1235-1247. doi: 10.1002/alz.12456. Epub 2021 Sep 13.

Revealing the Mutational Spectrum in Southern Africans with Amyotrophic Lateral Sclerosis. Nel M, Mahungu AC, Monnakgotla N, Botha GR, Mulder NJ, Wu G, Rampersaud E, van Blitterswijk M, Wuu J, Cooley A, Myers J, Rademakers R, Taylor JP, Benatar M, Heckmann JM. Neurol Genet. 2022 Jan 12;8(1):e654. doi: 10.1212/NXG.0000000000000654. PMID: 35047667; PMCID: PMC8756565.

Amyotrophic Lateral Sclerosis Survival Associates With Neutrophils in a Sex-specific Manner. Murdock BJ, Goutman SA, Boss J, Kim S, Feldman EL. Neurol Neuroimmunol Neuroinflamm. 2021 Feb 2;8(2):e953. doi: 10.1212/NXI.0000000000000953. Print 2021 Mar.

Challenges and opportunities for Multi-National Investigator-Initiated clinical trials for ALS: European and United States collaborations. Lingor P, Koch JC, Statland JM, Hussain S, Hennecke C, Wuu J, Langbein T, Ahmed R, Günther R, Ilse B, Kassubek J, Kollewe K, Kuttler J, Leha A, Lengenfeld T, Meyer T, Neuwirth C, Tostmann R, Benatar M. Amyotroph Lateral Scler Frontotemporal Degener. 2021 Aug;22(5-6):419-425. doi: 10.1080/21678421.2021.1879866. Epub 2021 Feb 3.

Epigenetic small moleculars rescue nucleocytoplasmic transport and DNA damage phenotypes in C9ORF72 ALS/FTD. Melina Ramic, Nadja S Andrade, Matthew J Rybin, Rustam Esanov, Claes Wahlestedt, Michael Benatar, Zane Zeier. Brain Sci. 2021 Nov 20;11(11):1543. doi: 10.3390/brainsci11111543. PMID: 34827542.

FGF23, a novel muscle biomarker detected in the early stages of ALS. Si Y, Kazamel M, Benatar M, Wuu J, Kwon Y, Kwan T, Jiang N, Kentrup D, Faul C, Alesce L, King PH. Sci Rep. 2021 Jun 8;11(1):12062. doi: 10.1038/s41598-021-91496-6.

Harnessing the power of the electronic health record for ALS research and quality improvement: CReATe CAPTURE-ALS and the ALS Toolkit. Granit V, Grignon AL, Wuu J, Katz J, Walk D, Hussain S, Hernandez J, Jackson C, Caress J, Yosick T, Smider N, Benatar M. Muscle Nerve. 2022 Feb;65(2):154-161. doi: 10.1002/mus.27454. Epub 2021 Nov 16. PMID: 34730240; PMCID: PMC8752483.

Effective use of electronic health record (EHR) data for research purposes has been a long-standing goal of physicians caring for patients with amyotrophic lateral sclerosis (ALS). Several barriers, however, have impeded progress toward this goal, including the limited quality and completeness of clinical documentation, as well as the burden of duplicative entry of clinical data into a research database. To address these barriers, researchers developed the ALS Toolkit, a set of interactive digital forms integrated into the EHR. Used routinely during clinic visits, the ALS Toolkit enables seamless, structured and consistent collection of data elements relevant to ALS patient care, with the expectation that these will also be suitable for research purposes. Since it incorporates AAN quality measures for the care of ALS patients, the ALS Toolkit may also be used to facilitate quality improvement initiatives. CReATe’s Clinical Procedures to Support Research in ALS (CAPTURE-ALS) study utilizes the ALS Toolkit to facilitate multi-center aggregation of data collected at the point of clinical care, empowering research and driving quality improvement. With the goal of collecting data from all patients receiving care through multidisciplinary clinics, CAPTURE-ALS will yield data that reflects the true diversity of populations affected by ALS, rather than the restricted subset of patients currently participating in dedicated research studies.

Humoral response to neurofilaments and dipeptide repeats in ALS progression. Puentes F, Lombardi V, Lu CH, Yildiz O, Fratta P, Isaacs A, Bobeva Y, Wuu J; ALS Biomarker Consortium; CReATe Consortium, Benatar M, Malaspina A. Ann Clin Transl Neurol. 2021 Sep;8(9):1831-1844. doi: 10.1002/acn3.51428. Epub 2021 Jul 27.

Neurofilaments, both light chain (NfL) and phosphorylated neurofilament heavy (pNfH), are structural components of axons. Both NfL and pNfH are known to increase during the pre-symptomatic and early symptomatic phases of disease and then to reach a stable but elevated plateau despite continued progression of disease. Although these proteins, most notably NfL, have emerged as the most promising prognostic and potential pharmacodynamic biomarkers, it remains unclear why neurofilament levels do not change as disease progresses. The current study focused on the immune response to neurofilaments (and dipeptide repeat proteins in patients with the C9orf72 genetic form of ALS), quantifying levels of antibodies and immune complexes that represent the humeral response to the release of these proteins. The investigators observed a trend towards increasing concentrations of NfL antibodies and immune complexes over the course of longitudinal follow among patients with faster progressing disease, raising the possibility that the immune response is partially responsible for clearing NfL and stabilizing plasma levels of this protein despite increased production as neurodegeneration progresses.

Long-read targeted sequencing ucnovers clinicopathological associations for Cr0rf72-linked diseases. DeJesus-Hernandez M, Aleff RA, Jackson JL, Finch NA, Baker MC, Gendron TF, Murray ME, McLaughlin IJ, Harting JR, Graff-Radford NR, Oskarsson B, Knopman DS, Josephs KA, Boeve BF, Petersen RC, Fryer JD, Petrucelli L, Dickson DW, Rademakers R, Ebbert MTW, Wieben ED, van Blitterswijk M.. Brain. 2021 May 7;144(4):1082-1088. doi: 10.1093/brain/awab006. PMID: 33889947.

Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis. Placek K, Benatar M, Wuu J, Rampersaud E, Hennessy L, Van Deerlin VM, Grossman M, Irwin DJ, Elman L, McCluskey L, Quinn C, Granit V, Statland JM, Burns TM, Ravits J, Swenson A, Katz J, Pioro EP, Jackson C, Caress J, So Y, Maiser S, Walk D, Lee EB, Trojanowski JQ, Cook P, Gee J, Sha J, Naj AC, Rademakers R; CReATe Consortium, Chen W, Wu G, Paul Taylor J, McMillan CT. EMBO Mol Med. 2020 Dec 3;e12595. PMID: 3327098.

NK cells associate with ALS in a sex- and age-dependent manner. Murdock BJ, Famie JP, Piecuch CE, Raue KD, Mendelson FE, Pieroni CH, Iniguez SD, Zhao L, Goutman SA, Feldman EL. JCI Insight. 2021 Jun 8;6(11):e147129. doi: 10.1172/jci.insight.147129.

Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia. Kessler C, Serna-Higuita LM, Rattay TW, Maetzler W, Wurster I, Hayer S, Wilke C, Hengel H, Reichbauer J, Armbruster M, Schöls L, Martus P, Schüle R. Ann Clin Transl Neurol. 2021 May;8(5):1122-1131. doi: 10.1002/acn3.51358. Epub 2021 Apr 5.

Repeat expansions in ATXN2, NOP56, NIPA1 and ATXN1 are not associated with ALS in Africans. Nel M, Mavundla T, Gultig K, Botha G, Mulder N, Benatar M, Wuu J, Cooley A, Myers J, Rampersaud E, Wu G, Heckmann JM.. IBRO Neurosci Rep. 2021 Feb 10;10:130-135. doi: 10.1016/j.ibneur.2021.02.002. PMID: 34179866.

Urinary neopterin: A novel biomarker of disease progression in amyotrophic lateral sclerosis. Shepheard SR, Karnaros V, Benyamin B, Schultz DW, Dubowsky M, Wuu J, Chataway T, Malaspina A, Benatar M, Rogers ML. Eur J Neurol. 2021 Dec 29. doi: 10.1111/ene.15237. Epub ahead of print. PMID: 34967083.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that leads to progressive muscle weakness. There are currently no meaningfully effective treatments for ALS, which is invariably fatal. Biomarkers that are suitably fit-for-purpose have great potential to enhance therapy development efforts. A research team led by Dr. Mary Louise-Rogers at Flinders University in Australia has found that urinary neopterin, a marker of an underlying pro-inflammatory state, is elevated in ALS compared to age-matched controls, and progressively increases as the disease advances. In addition to its potential utility as a biomarker of disease progression, neopterin might also have potential as a predictive biomarker, identifying a subset of patients who may stand to benefit from therapeutics that target inflammatory pathways.

Dipeptide repeat proteins inhibit homology-directed DNA double strand break repair in C9ORF72 ALS/FTD. Andrade N, Ramic M, Esanov R, et al. Mol Neurodegener. 2020; 15: 13. PMCID:PMC7041170, PMID: 32093728.

Disentangling Heterogeneity in Alzheimer's Disease and Related Dementias Using Data-Driven Methods. Habes M, Grothe MJ, Tunc B, McMillan C, Wolk DA, Davatzikos C. Biol Psychiatry. 2020 Jul 1;88(1):70-82. doi: 10.1016/j.biopsych.2020.01.016. Epub 2020 Jan 31.

Metabolite Profiling Reveals Predictive Biomarkers and the Absence of β-Methyl Amino-l-alanine in Plasma from Individuals Diagnosed with Amyotrophic Lateral Sclerosis. Bereman MS, Kirkwood KI, Sabaretnam T, Furlong S, Rowe DB, Guillemin GJ, Mellinger AL, Muddiman DC. J Proteome Res. 2020 Aug 7;19(8):3276-328. PMID: 32418425.

Temporal evolution of the microbiome, immune system and epigenome with disease progression in ALS mice. Figueroa-Romero C,1, Guo K,2, Murdock BJ, et al. Dis Model Mech. 2020 Feb 1; 13(2). PMCID: PMC6906635, PMID: 31597644.

The potential of neurofilaments analysis using dry-blood and plasma spots. Lombardi V, Carassiti D, Giovannoni G, Lu CH, Adiutori R, Malaspina A. Sci Rep. 2020 Jan 9;10(1):97. PMID: 31919375, PMCID: PMC6952412.

Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS. Benatar M, Zhang L, Wang L, Granit V, Statland J, Barohn R, Swenson A, Ravits J, Jackson C, Burns TM, Trivedi J, Pioro EP, Caress J, Katz J, McCauley JL, Rademakers R, Malaspina A, Ostrow LW, Wuu J; CReATe Consortium. Neurology. 2020 Jul 7;95(1):e59-e69. PMID: 32385188, PMCID: PMC7371380.

Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study. Aladesuyi Arogundade O, Stauffer JE, Saberi S, Diaz-Garcia S, Malik S, Basilim H, Rodriguez MJ, Ohkubo T, Ravits J. Acta Neuropathol. 2019. PMID: 30666413.

Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein. Farhan SMK, Howrigan DP, Abbott LE, Klim JR, Topp SD, Byrnes AE, Churchhouse C, Phatnani H, Smith BN, Rampersaud E, Wu G, Wuu J, Shatunov A, Iacoangeli A, Al Khleifat A, Mordes DA, Ghosh S; ALSGENS Consortium; FALS Consortium; Project MinE Consortium; CReATe Consortium, Eggan K, Rademakers R, McCauley JL, Schüle R, Züchner S, Benatar M, Taylor JP, Nalls M, Gotkine M, Shaw PJ, Morrison KE, Al-Chalabi A, Traynor B, Shaw CE, Goldstein DB, Harms MB, Daly MJ, Neale BM. Nat Neurosci. 2019 Dec; 22(12): 1966–1974. PMCID: PMC6919277, PMID: 31768050.

Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants. Edmonson MN, Patel AN, Hedges DJ, Wang Z, Rampersaud E, Kesserwan CA, Zhou X, Liu Y, Newman S, Rusch MC, McLeod CL, Wilkinson MR, Rice SV, Soussi T, Taylor JP, Benatar M, Becksfort JB, Nichols KE, Robison LL, Downing JR, Zhang J.. Genome Res. 2019 Sep;29(9):1555-1565. doi: 10.1101/gr.250357.119. Epub 2019 Aug 22. PMID: 31439692.

ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double- Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis. Lingor P, Weber M, Camu W, et al. Front Neurol. 2019; 10: 293. PMCID: PMC6446974, PMID: 30972018.

UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis. Placek K, Baer GM, Elman L, McCluskey L, Hennessy L, Ferraro PM, Lee EB, Lee VMY, Trojanowski JQ, Van Deerlin VM, Grossman M, Irwin DJ, McMillan CT. Neurobiol Aging. 2019; 73:190-199. PMID:30368160, PMCID: PMC6251755.

G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. Simone R, Balendra R, Moens TG, et al. EMBO Mol Med. 2018;10(1):22-31. PMID: 29113975, PMCID: PMC5760849.

GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia. Eidhof I, Baets J, Kamsteeg EJ, Deconinck T, van Ninhuijs L, Martin JJ, Schüle R, Züchner S, De Jonghe P, Schenck A, van de Warrenburg BP. Brain. 2018 Sep 1;141(9):2592-2604. doi: 10.1093/brain/awy198.

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, Dominov JA, Kenna BJ, Nalls MA, Keagle P, Rivera AM, van Rheenen W, Murphy NA, van Vugt JJFA, Geiger JT, Van der Spek RA, Pliner HA, Shankaracharya, Smith BN, Marangi G, Topp SD, Abramzon Y, Gkazi AS, Eicher JD, Kenna A; ITALSGEN Consortium, Mora G, Calvo A, Mazzini L, Riva N, Mandrioli J, Caponnetto C, Battistini S, Volanti P, La Bella V, Conforti FL, Borghero G, Messina S, Simone IL, Trojsi F, Salvi F, Logullo FO, D'Alfonso S, Corrado L, Capasso M, Ferrucci L; Genomic Translation for ALS Care (GTAC) Consortium, Moreno CAM, Kamalakaran S, Goldstein DB; ALS Sequencing Consortium, Gitler AD, Harris T, Myers RM; NYGC ALS Consortium, Phatnani H, Musunuri RL, Evani US, Abhyankar A, Zody MC; Answer ALS Foundation, Kaye J, Finkbeiner S, Wyman SK, LeNail A, Lima L, Fraenkel E, Svendsen CN, Thompson LM, Van Eyk JE, Berry JD, Miller TM, Kolb SJ, Cudkowicz M, Baxi E; Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Benatar M, Taylor JP, Rampersaud E, Wu G, Wuu J; SLAGEN Consortium, Lauria G, Verde F, Fogh I, Tiloca C, Comi GP, Sorarù G, Cereda C; French ALS Consortium, Corcia P, Laaksovirta H, Myllykangas L, Jansson L, Valori M, Ealing J, Hamdalla H, Rollinson S, Pickering-Brown S, Orrell RW, et al. Neuron. 2018;97(6):1268-1283.e1266. PMID: 29566793, PMCID: PMC5867896.

Identification of compound heterozygous variants in OPTN in an ALS-FTD patient from the CReATe consortium: a case report. Pottier C, Rampersaud E, Baker M, Wu G, Wuu J, McCauley JL, Zuchner S, Schule R, Bermudez C, Hussain S, Cooley A, Wallace M, Zhang J, Taylor JP, Benatar M, Rademakers R. Amyotrophic lateral sclerosis & frontotemporal degeneration. 2018:1-3. PMID: 29558868.

MR Imaging-based Estimation of Upper Motor Neuron Density in Patients with Amyotrophic Lateral Sclerosis: A Feasibility Study. Chen J, Kostenko V, Pioro EP, Trapp BD. Radiology. 2018. PMID: 29361242.

Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. Lassuthova P, Rebelo AP, Ravenscroft G, Lamont PJ, Davis MR, Manganelli F, Feely SM, Bacon C, Brožková DŠ, Haberlova J, Mazanec R, Tao F, Saghira C, Abreu L, Courel S, Powell E, Buglo E, Bis DM, Baxter MF, Ong RW, Marns L, Lee YC, Bai Y, Isom DG, Barro-Soria R, Chung KW, Scherer SS, Larsson HP, Laing NG, Choi BO, Seeman P, Shy ME, Santoro L, Zuchner S. Am J Hum Genet. 2018;102(3):505-514. PMID: 29499166, PMCID: PMC5985288.

Sense and antisense RNA are not toxic in Drosophila models of C9orf72-associated ALS/FTD. Moens TG, Mizielinska S, Niccoli T, et al. Acta Neuropathol. 2018;135(3):445-457. PMID:29380049.

Serum neurofilament light chain is increased in hereditary spastic paraplegias. Wilke C, Rattay TW, Hengel H, Zimmermann M, Brockmann K, Schöls L, Kuhle J, Schüle R, Synofzik M. Annals of clinical and translational neurology. 2018;5(7):876-882. PMID:30009206, PMCID: PMC6043776.

Using automated electronic medical record data extraction to model ALS survival and progression. Karanevich AG, Weisbrod LJ, Jawdat O, Barohn RJ, Gajewski BJ, He J, Statland JM. BMC Neurol. 2018;18(1):205. PMID:30547800, PMCID: PMC6295028.

A C9ORF72 BAC mouse model recapitulates key epigenetic perturbations of ALS/FTD. Esanov R, Cabrera GT, Andrade NS, Gendron TF, Brown RH Jr, Benatar M, Wahlestedt C, Mueller C, Zeier Z. Mol Neurodegener. 2017;12(1):46. PMID: 28606110, PMCID: PMC5468954.

Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers. Finch NA, Wang X, Baker MC, Heckman MG, Gendron TF, Bieniek KF, Wuu J, DeJesus-Hernandez M, Brown PH, Chew J, Jansen-West KR, Daughrity LM, Nicholson AM, Murray ME, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Petrucelli L, Boeve BF, Graff-Radford NR, Asmann YW, Dickson DW, Benatar M, Bowser R, Boylan KB, Rademakers R, van Blitterswijk M. Neurology Genetics. 2017;3(4):e161. PMID: 28660252, PMCID. PMC5479438.

Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria. Strong MJ, Abrahams S, Goldstein LH, Woolley S, Mclaughlin P, Snowden J, Mioshi E, Roberts-South A, Benatar M, HortobáGyi T, Rosenfeld J, Silani V, Ince PG, Turner MR. Amyotrophic lateral sclerosis & frontotemporal degeneration. 2017;18(3-4):153-174. PMID: 28054827.

Correlation of Peripheral Immunity With Rapid Amyotrophic Lateral Sclerosis Progression. Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL. JAMA neurology. 2017. PMID: 28973548, PMCID: PMC5822195.

Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death. Jacquier A, Delorme C, Belotti E, Juntas-Morales R, Solé G, Dubourg O, Giroux M, Maurage CA, Castellani V, Rebelo A, Abrams A, Züchner S, Stojkovic T, Schaeffer L, Latour P. Acta neuropathologica communications. 2017;5(1):55. PMID: 28709447, PMCID: PMC5513089.

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Schols L, Rattay TW, Martus P, et al. Brain. 2017;140(12):3112-3127. PMID:29126212, PMCID: PMC5841036.

In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers. DeJesus-Hernandez M, Finch NA, Wang X, Gendron TF, Bieniek KF, Heckman MG, Vasilevich A, Murray ME, Rousseau L, Weesner R, Lucido A, Parsons M, Chew J, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Boeve BF, Graff-Radford NR, de Boer J, Asmann YW, Petrucelli L, Boylan KB, Dickson DW, van Blitterswijk M, Rademakers R. Acta Neuropathol. 2017;134(2):255-269. PMID: 28508101, PMCID: PMC5508036.

Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis. Gendron TF; C9ORF72 Neurofilament Study Group, Daughrity LM, Heckman MG, Diehl NN, Wuu J, Miller TM, Pastor P, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Benatar M, Silani V, Glass JD, Floeter MK, Jeromin A, Boylan KB, Petrucelli L. Ann Neurol. 2017;82(1):139-146. PMID: 28628244, PMCID: PMC5676468.

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Gendron TF, Chew J, Stankowski JN, Hayes LR, Zhang YJ, Prudencio M, Carlomagno Y, Daughrity LM, Jansen-West K, Perkerson EA, O'Raw A, Cook C, Pregent L, Belzil V, van Blitterswijk M, Tabassian LJ, Lee CW, Yue M, Tong J, Song Y, Castanedes-Casey M, Rousseau L, Phillips V, Dickson DW, Rademakers R, Fryer JD, Rush BK, Pedraza O, Caputo AM, Desaro P, Palmucci C, Robertson A, Heckman MG, Diehl NN, Wiggs E, Tierney M, Braun L, Farren J, Lacomis D, Ladha S, Fournier CN, McCluskey LF, Elman LB, Toledo JB, McBride JD, Tiloca C, Morelli C, Poletti B, Solca F, Prelle A, Wuu J, Jockel-Balsarotti J, Rigo F, Ambrose C, Datta A, Yang W, Raitcheva D, Antognetti G, McCampbell A, Van Swieten JC, Miller BL, Boxer AL, Brown RH, Bowser R, Miller TM, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Traynor BJ, Disney MD, Benatar M, Silani V, Glass JD, Floeter MK, Rothstein JD, Boylan KB, Petrucelli L. Sci Transl Med. 2017;9(383). PMID: 28356511, PMCID: PMC5576451.

Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. Prudencio M, Gonzales PK, Cook CN, Gendron TF, Daughrity LM, Song Y, Ebbert MTW, van Blitterswijk M, Zhang YJ, Jansen-West K, Baker MC, DeTure M, Rademakers R, Boylan KB, Dickson DW, Petrucelli L, Link CD. Hum Mol Genet. 2017;26(17):3421-3431. PMID: 28637276.

Research Toolkit: Capturing clinical data to advance ALS research. Michael Benatar, Jonathan Katz, David Walk CReATe Consortium ALS Association Muscular Dystrophy Association (MDA). Capturing clinical data to advance ALS research. https://galaxy.epic.com/Redirect.aspx?DocumentID=3701881&Version=Epic 2017, EpicCare Ambulatory, 2017.

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics. Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, Pottier C, Annu K, Baker M, Perkerson RB, Kurti A, Matchett BJ, Mittag T, Temirov J, Hsiung GR, Krieger C, Murray ME, Kato M, Fryer JD, Petrucelli L, Zinman L, Weintraub S, Mesulam M, Keith J, Zivkovic SA, Hirsch-Reinshagen V, Roos RP, Züchner S, Graff-Radford NR, Petersen RC, Caselli RJ, Wszolek ZK, Finger E, Lippa C, Lacomis D, Stewart H, Dickson DW, Kim HJ, Rogaeva E, Bigio E, Boylan KB, Taylor JP, Rademakers R. Neuron. 2017;95(4):808-816.e809. PMID: 28817800, PMCID: PMC5576574.

Urinary p75(ECD): A prognostic, disease progression, and pharmacodynamic biomarker in ALS. Shepheard SR, Wuu J, Cardoso M, Wiklendt L, Dinning PG, Chataway T, Schultz D, Benatar M, Rogers ML. Neurology. 2017;88(12):1137-1143. PMID: 28228570, PMCID: PMC5373786.

ALS biomarkers for therapy development: State of the field and future directions. Benatar M, Boylan K, Jeromin A, Rutkove SB, Berry J, Atassi N, Bruijn L. Muscle Nerve. Feb 2016;53(2):169-182. PMID: 26574709, PMCID: PMC4718795.

C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Liu Y, Pattamatta A, Zu T, et al. Neuron. 2016;90(3):521-534. PMID: 27112499.

C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells. Esanov R, Belle KC, van Blitterswijk M, Belzil VV, Rademakers R, Dickson DW, Petrucelli L, Boylan KB, Dykxhoorn DM, Wuu J, Benatar M, Wahlestedt C, Zeier Z. Exp Neurol. Mar 2016;277:171-177. PMID: 26746986, PMCID: PMC4761318.

Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy. Rebelo AP, Abrams AJ, Cottenie E, Horga A, Gonzalez M, Bis DM, Sanchez-Mejias A, Pinto M, Buglo E, Markel K, Prince J, Laura M, Houlden H, Blake J, Woodward C, Sweeney MG, Holton JL, Hanna M, Dallman JE, Auer-Grumbach M, Reilly MM, Zuchner S. Am J Hum Genet. 2016; 98(4):597-614. PMID: 27040688, PMCID: PMC4833435.

Increased ratio of circulating neutrophils to monocytes in amyotrophic lateral sclerosis. Murdock BJ, Bender DE, Kashlan SR, et al. Neurology(R) neuroimmunology & neuroinflammation. 2016;3(4):e242. PMID: 27308304, PMCID: PMC4897983.

Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers. Gendron TF, van Blitterswijk M, Bieniek KF, Daughrity LM, Jiang J, Rush BK, Pedraza O, Lucas JA, Murray ME, Desaro P, Robertson A, Overstreet K, Thomas CS, Crook JE, Castanedes-Casey M, Rousseau L, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Boeve BF, Graff-Radford NR, Rademakers R, Lagier-Tourenne C, Edbauer D, Cleveland DW, Dickson DW, Petrucelli L, Boylan KB. Acta Neuropathol. Oct 2015;130(4):559-573. PMID: 26350237, PMCID: PMC4575385.

Ensuring continued progress in biomarkers for amyotrophic lateral sclerosis. Turner MR, Benatar M. Muscle Nerve. Jan 2015;51(1):14-18. PMID: 25288265, PMCID: PMC4270289.

Neurodegenerative disease: C9orf72 repeats compromise nucleocytoplasmic transport. van Blitterswijk M, Rademakers R. Nature reviews. Neurology. Dec 2015;11(12):670-672. PMID: 26526532.

Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72. van Blitterswijk M, Gendron TF, Baker MC, DeJesus-Hernandez M, Finch NA, Brown PH, Daughrity LM, Murray ME, Heckman MG, Jiang J, Lagier-Tourenne C, Edbauer D, Cleveland DW, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Petrucelli L, Boeve BF, Graff-Radford NR, Boylan KB, Dickson DW, Rademakers R. Acta Neuropathol. Oct 5 2015. PMID: 26437865, PMCID: PMC4655160.

Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Rossor AM, Oates EC, Salter HK, Liu Y, Murphy SM, Schule R, Gonzalez MA, Scoto M, Phadke R, Sewry CA, Houlden H, Jordanova A, Tournev I, Chamova T, Litvinenko I, Zuchner S, Herrmann DN, Blake J, Sowden JE, Acsadi G, Rodriguez ML, Menezes MP, Clarke NF, Auer Grumbach M, Bullock SL, Muntoni F, Reilly MM, North KN. Brain. Feb 2015;138(Pt 2):293-310. PMID: 25497877, PMCID: PMC4306822.