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

Michael Benatar; Joanne Wuu; Caroline McHutchison; Ronald B. Postuma; Bradley F. Boeve; Ronald Petersen; Christopher A. Ross; Howard Rosen; Jalayne J. Arias; Stephanie Fradette; Michael P. McDermott; Jeremy Shefner; Christine Stanislaw; Sharon Abrahams; Stephanie Cosentino; Peter M. Andersen; Richard S. Finkel; Volkan Granit; Anne-Laure Grignon; Jonathan D. Rohrer; Corey T. McMillan; Murray Grossman; Ammar Al-Chalabi; Martin R. Turner

Disclosures

Brain. 2022;145(1):27-44.

Abstract and Introduction

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.

Introduction

Emerging evidence from the study of a host of neurodegenerative diseases has made it abundantly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are preceded by periods of variable duration during which the underlying disease process is active despite the absence of even mild, prodromal symptoms. The same may also be true of all but the most severe type of spinal muscular atrophy (SMA). The impact of this understanding has been profound, revealing a disjunction between the presence of disease at the molecular, cellular and network levels versus its clinical manifestations, the latter being influenced by a variety of adaptive processes permitting functional tolerance despite underlying pathology. Increasing opportunity and ability to study the pre-symptomatic phases of these diseases (Figure 1) has heightened interest in the possibility that early therapeutic intervention—or even prevention—may offer the best hope for the millions predisposed to these devastating neurodegenerative diseases.

(Enlarge Image)

Figure 1.

Terminologies most commonly used in different neurodegenerative diseases. Different fields have used different terms to describe the prodromal phase of disease that precedes clinically overt disease. For Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and FTD, this period is designated as MCI, prodromal Parkinson's disease, prodromal Huntington's disease and prodromal FTD, respectively. In some parlance, prodromal FTD encompasses both MCI-cognition and MCI-behaviour. Similarly, each of these disorders is also characterized by an even earlier stage of asymptomatic disease (pre-MCI, preclinical Parkinson's disease, pre-symptomatic Huntington's disease and preclinical FTD, respectively), during which clinical symptoms and signs are absent, but biomarker evidence may be present. Terminology for SMA is less well-defined.

This background served as the impetus for the First International Pre-Symptomatic ALS Workshop (27 January 2020, in Miami, FL; Supplementary material) and on which this paper is based. First, we review the state-of-the-field as well as experiences and lessons shared by attendees who study the pre-symptomatic phases of various neurodegenerative diseases and their relevance for the study of pre-symptomatic ALS. We then summarize our recommendations for the study of motor, cognitive and behavioural manifestations of early ALS; the critical importance of biomarkers to this endeavour; the challenges of genetic and biomarker counselling; the pertinent ethical, legal and social implications; and considerations for the design of early intervention or disease prevention clinical trials.

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Abstract and Introduction
Pre-symptomatic Neurodegenerative Diseases
Pre-symptomatic Amyotrophic Lateral Sclerosis
Conclusion
References

Table 1. Neuropsychological assessment for MCI in pre-symptomatic ALS
Cognitive domain	Cognitive processes	Neuropsychological tests^a	Recommended number of tests
Multi-domain	Multiple	Edinburgh Cognitive and Behavioural ALS Screen (ECAS)^136,b	One test
Executive	Concept formation	Card Sort from the Delis Kaplan Executive Function System¹¹² or Wisconsin Card Sorting Test: 128- or 64-item^113,114,b	Three tests of different cognitive processes
	Set-shifting	Trail Making Test^b,c,d,e
	Inhibition	Stroop Test^b,c,f,g
	Social cognition	Reading the Mind in the Eyes^116,b
Fluency^h	Executive and language functioning	FAS letter fluency^b,c	One test
Language	Naming	Boston Naming Test^115,b,i	Two non-overlapping tests
	Comprehension	Token Test subtest from the Multilingual Aphasia Examination¹¹⁷
	Semantic processing	Semantic fluency^b,c,j
Visuospatial	Spatial perception	Judgement of Line Orientation^118,b	Two tests
Visuospatial	Object perception	Object Decision subtest from the Visual Object and Space Perception Battery^119,b	Two tests
Memory	Visual and verbal	Visual Reproduction subtest from the Wechsler Memory Scale–IV^120,b,k	Two tests
Memory	Immediate, delayed and recognition	California Auditory Verbal Learning Test^121,b	Two tests

^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
ⁱMay 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.

Table 2. Protections afforded by the Genetic Information Nondiscrimination Act, Affordable Care Act and Americans with Disabilities Act in the USA
Applicable party	Context	Information category	GINA	ACA	ADA
Employers	Employment	Genetic status	Yes^a	N/A	N/A
		Biomarker status	No^b	N/A	Maybe^c
		Functional status	N/A	N/A	Yes
Insurers	Health insurance	Genetic status	Yes	N/A	N/A
		Biomarker status	No^b	No	N/A
		Functional status	N/A	Yes	N/A
	Long-term care insurance	Genetic status	No	No	N/A
		Biomarker status	No	No	N/A
		Functional status	N/A	No	N/A
	Life insurance	Genetic status	No	N/A	N/A
		Biomarker status	No	N/A	N/A
		Functional status	N/A	N/A	N/A

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.

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

Abstract and Introduction

Abstract

Introduction

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Figure 1.

Figure 1.

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