TY - JOUR
T1 - Preventing amyotrophic lateral sclerosis
T2 - insights from pre-symptomatic neurodegenerative diseases
AU - Benatar, Michael
AU - Wuu, Joanne
AU - McHutchison, Caroline
AU - Postuma, Ronald B.
AU - Boeve, Bradley F.
AU - Petersen, Ronald
AU - Ross, Christopher A.
AU - Rosen, Howard
AU - Arias, Jalayne J.
AU - Fradette, Stephanie
AU - McDermott, Michael P.
AU - Shefner, Jeremy
AU - Stanislaw, Christine
AU - Abrahams, Sharon
AU - Cosentino, Stephanie
AU - Andersen, Peter M.
AU - Finkel, Richard S.
AU - Granit, Volkan
AU - Grignon, Anne Laure
AU - Rohrer, Jonathan D.
AU - McMillan, Corey T.
AU - Grossman, Murray
AU - Al-Chalabi, Ammar
AU - Turner, Martin R.
AU - Andersen, Peter M.
AU - Arias, Jalayne
AU - Benatar, Michael
AU - Boeve, Bradley
AU - Cosentino, Stephanie
AU - Dave, Kuldip
AU - Ferguson, Toby
AU - Floeter, Mary Kay
AU - Rohrer, Jonathan
AU - Fradette, Stephanie
AU - Gendron, Tania
AU - Granit, Volkan
AU - Grignon, Anne Laure
AU - Grossman, Murray
AU - Gubitz, Amelie
AU - Kaufman, Petra
AU - Le Ber, Isabelle
AU - Lee, Suzee
AU - Malaspina, Andrea
AU - McDermott, Michael P.
AU - McHutchison, Caroline
AU - McMillan, Corey
AU - Nicholson, Katie
AU - Petersen, Ronald
AU - Robinson, Richard
AU - Rosen, Howard
AU - Ross, Christopher
AU - Shefner, Jeremy
AU - Stanislaw, Christine
AU - Tatton, Nadine
AU - Thakur, Neil
AU - Weishaupt, Jochen
AU - Wuu, Joanne
N1 - Publisher Copyright:
© 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - 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.
AB - 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.
KW - amyotrophic lateral sclerosis (ALS)
KW - disease prevention
KW - neurodegeneration
KW - pre-symptomatic
UR - http://www.scopus.com/inward/record.url?scp=85127479942&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127479942&partnerID=8YFLogxK
U2 - 10.1093/brain/awab404
DO - 10.1093/brain/awab404
M3 - Review article
C2 - 34677606
AN - SCOPUS:85127479942
SN - 0006-8950
VL - 145
SP - 27
EP - 44
JO - Brain
JF - Brain
IS - 1
ER -