Preventing Amyotrophic Lateral Sclerosis: Insights From Pre-symptomatic Neurodegenerative Diseases

^aIncludes examples of tests that may be used to assess cognition in ALS gene carriers. Alternative tests are available and should be selected depending on research study requirements.
^bCurrently used for longitudinal neuropsychological assessment in the ongoing Pre-Symptomatic Familial ALS (Pre-fALS) study.^133
cTimed tests may limit their continued utility following motor dysfunction onset.
^dComparison between Parts A and B would allow continued testing following motor dysfunction onset.
^ePart A assesses processing speed.
^fComparison between interference and control conditions would allow continued testing following motor dysfunction onset.
^gMay be affected by colour-blindness.
^hFluency assesses both executive and language functioning and does not represent a stand-alone domain. We include it separately due to its sensitivity to cognitive deficits in ALS and FTD.^{122,123,125
i}May be substituted with the Multilingual Naming Test (MINT)¹²⁴; however, no alternate forms are available for longitudinal assessment.
^jPerformance on this task may contribute to the criteria for impairment in fluency.
^kMay be substituted with the Benson Complex Figure task¹²⁶; however, the recognition component of this test is very simple.

ACA = Affordable Care Act; ADA = Americans with Disabilities Act; GINA = Genetic Information Nondiscrimination Act; N/A = designated legislation is not applicable/relevant; No = protection not afforded; Yes = protection afforded.
^aThe protections afforded by GINA apply only so long as disease has not yet become manifest. If a biomarker is taken to imply evidence of disease, then GINA no longer applies.
^bThe protections afforded by GINA relate to genetic risk for disease, but do not cover non-genetic biomarkers that indicate risk of disease.
^cIf the biomarker evidence of disease is (i) 'regarded as' a disability; or (ii) is taken to represent impairment of a 'major bodily function', then the Americans with Disabilities Act might provide protection (but this argument is legally unproven).

Authors and Disclosures

Michael Benatar¹, Joanne Wuu¹, Caroline McHutchison,^2,3, Ronald B. Postuma,⁴, Bradley F. Boeve,⁵, Ronald Petersen,⁵, Christopher A. Ross,^6–9, Howard Rosen,¹⁰, Jalayne J. Arias,¹⁰, Stephanie Fradette,¹¹, Michael P. McDermott,^12,13, Jeremy Shefner,¹⁴, Christine Stanislaw,¹⁵, Sharon Abrahams,^2,3, Stephanie Cosentino,¹⁶, Peter M. Andersen,¹⁷, Richard S. Finkel,¹⁸, Volkan Granit,¹, Anne-Laure Grignon,¹, Jonathan D. Rohrer,¹⁹, Corey T. McMillan,²⁰, Murray Grossman,²⁰, Ammar Al-Chalabi^21,22 and Martin R. Turner²³, on behalf of the attendees of the First International Pre-Symptomatic ALS Workshop

1 Department of Neurology, University of Miami, Miami, FL, USA
2 Human Cognitive Neuroscience, Department of Psychology, University of Edinburgh, Edinburgh, UK
3 Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, UK
4 Department of Neurology, Montreal Neurological Institute, McGill University, Montreal, Canada
5 Department of Neurology, Mayo Clinic, Rochester, MN, USA
6 Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
7 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
8 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
9 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
10 Department of Neurology, University of California San Francisco, CA, USA
11 Biogen, Cambridge, MA, 02142, USA
12 Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
13 Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
14 Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA
15 Department of Human Genetics, Emory University, Atlanta, GA, USA
16 Department of Psychiatry, Columbia University, New York, NY, USA
17 Department of Clinical Science, Neurosciences, Umea° University, Sweden
18 Department of Pediatric Medicine, Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA
19 Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK
20 Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
21 Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK
22 Department of Neurology, King's College Hospital, London, UK
23 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Correspondence to
Michael Benatar, MD, PhD Department of Neurology, Miller School of Medicine, University of Miami 1120 NW 14 Street, CRB1318, Miami, FL 33136, USA E-mail: mbenatar@med.miami.edu

Competing interests
M.B. reports grants from The ALS Association, Muscular Dystrophy Association, Motor Neuron Disease Association, Association for Frontotemporal Degeneration, Biogen and AveXis to support the First International Pre-Symptomatic ALS Workshop; as well as personal fees from Biogen outside the submitted work. The University of Miami has licensed intellectual property to Biogen to support design of the ATLAS study. C.M. reports grants from the CReATe Consortium and the ALS Association. R.B.P. reports grants and personal fees from Fonds de la Recherche en Sante, the Canadian Institute of Health Research, Parkinson Canada, the Weston-Garfield Foundation, the Michael J. Fox Foundation, the Webster Foundation and personal fees from Takeda, Roche/Prothena, Teva Neurosciences, Novartis, Biogen, Boehringer Ingelheim, Theranexus, Merck, Abbvie, Jannsen, Curasen and Inception Sciences outside the submitted work. B.F. B. reports funding for clinical trials sponsored by Alector and EIP Pharma. He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr Lewy Body Dementia Program and the Little Family Foundation. R.P. reports grant funding from the National Institute on Aging, P30 AG062677, U01 AG006786 and consults for Roche Inc., Merck Inc., Genentech Inc. and Biogen. C.A.R. reports consulting or Scientific Advisory Boards for Huntington Study Group (HSG), Annexon, Mitoconix, NeuBase, NeuExcell, Roche/Genentech, SAGE, Spark, TEVA, uniQure and Wave, all unrelated to this paper. J.J.A. reports grants from the National Institutes of Health–National Institute on Aging and the National Cancer Institute, the Alzheimer's Association, the Aging Research in Criminal Health Network and the Global Brain Health Institute. S.F. reports being employed by and holding stock in Biogen. J.S. reports research support from Amylyx, Biogen, Biotie Therapies (now Acorda Therapeutics), Cytokinetics Incorporated, Mitsubishi Tanabe Pharma America, Alexion, Medicinova, Ionis, Alector and Orphazyme, compensation received as a consultant for Apic Biosciences, Neurosense, Cytokinetics, Denali, GSK, Mitsubishi Tanabe Pharma America, Orphazyme, Pinteon, RRD, Swanbio, Helixsmith and royalties for serving as Neuromuscular Section Editor for UpToDate. S.A. reports grants from MND Scotland, the Motor Neuron Disease Association and the ALS Association. S.C. reports consulting fees from Sage Therapeutics and the Association for Frontotemporal Degeneration. P.M. A. reports grants from the Knut and Alice Wallenberg Foundation, the Swedish Research Council, Ulla-Carin Lindquist patient organization, the Umeå University Research Foundation and the Swedish Neuro Patient Organization; as well as consultancies for Biogen and Orphazyme A/S. R.S.F. reports grants to his institution to support his participation in clinical trials sponsored by AveXis/Novartis Gene Therapies, Biogen, Catabasis, Cytokinetics, Ionis, Muscular Dystrophy Association, National Institutes of Health, Lilly, ReveraGen, Roche, Sarepta, Scholar Rock and Summit. He has received honoraria for participating in symposia and on advisory boards from these same pharmaceutical companies. He serves without compensation as an advisor to the n-Lorem and EveryLife Foundations. His institution received funding from Biogen for the coordination of a SMA registry. He receives licensing fees from the Children's Hospital of Philadelphia and publishing royalty fees from Elsevier. J.D.R. reports grants from the Bluefield Project, Medical Research Council, JPND and Brain Research UK. He has sat on medical advisory boards for Wave Life Sciences, Alector, Prevail Therapeutics and Arkuda Therapeutics. C.T.M. reports research funding outside the submitted work from NIH and Biogen, and provides consulting services for personal fees from Invicro and Axon Advisors on behalf of Translational Bioinformatics, LLC. He also receives an honorarium as Associate Editor of NeuroImage: Clinical. M.G. reports support from NIH, Biogen, Samuel Newhouse Foundation, Robinson Family Foundation, Wyncote Foundation; support in kind from LMI and Avid; consultant for Passage Bio, Bracco, Daneli; and participation in trials sponsored by Biogen, Alector, Passage Bio, Prevail. A.A.-C. reports grants from the MRC through the Joint Programme on Neurodegeneration (JPND) to support work contributing to the First International Pre-Symptomatic ALS Workshop; as well as consultancies for Biogen Idec, Wave Pharmaceuticals Ltd, Cytokinetics, OrionPharma, Amylyx, GSK, Novartis, Lilly, Brainstorm Therapeutics, Apellis Inc and Quralis outside the submitted work. M.R.T. reports grants from the Motor Neurone Disease Association and My Name'5 Doddie Foundation. He sits on the Scientific Advisory Board for Orphazyme. All other authors report no competing interests.

Figure 1.