International Workshop Focuses on Defining Prodromal Phases of ALS, FTD
Delineating the pre-symptomatic phases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two related neurodegenerative disorders, is critically important to efforts to reduce diagnostic delay and initiate treatment as early as possible, according to Michael Benatar, M.D., Ph.D., professor of neurology, the Walter Bradley Chair in ALS Research and executive director of the ALS Center of the University of Miami Miller School of Medicine.
The neurodegenerative process in ALS and FTD begins well before symptoms emerge. During this pre-symptomatic period, however, the disease may not be entirely clinically silent. Mild and subtle abnormalities can sometimes be detected that are insufficient to diagnose ALS or FTD, marking a prodromal stage of disease that is as yet poorly understood.
As a follow-up to the very successful and productive first workshop in January 2020, Dr. Benatar organized and hosted the Second International Pre-Symptomatic ALS Workshop on February 27, which focused on defining the prodromal stages of ALS and FTD. The workshop brought together more than 50 specialists in the fields of ALS, FTD, other neurodegenerative disorders, discovery science, biostatistics, genetic counseling, neuroanatomy, law/policy and philosophy.
Other participants included representatives from the pharmaceutical industry, the ALS Association, the Muscular Dystrophy Association, the Association for FTD and the National Institutes of Health. Several pre-symptomatic mutation carriers, who are at elevated genetic risk for developing ALS or FTD, also attended the workshop.
“Bringing together stakeholders from across the ALS and FTD community ensured the inclusion of diverse perspectives in our discussions on advancing our understanding of these diseases and how to define their prodromal phases,” said Dr. Benatar.
The workshop opened with Dr. Benatar presenting a conceptual framework for mild motor impairment (MMI), mild cognitive impairment (MCI) and mild behavioral impairment (MBI), which may precede clinically manifest ALS or FTD. Ronald Petersen, M.D., Ph.D., director of the Alzheimer’s Disease Research Center and the Mayo Clinic Study of Aging, gave an overview of MCI as a prodromal clinical syndrome in Alzheimer’s disease and offered insights into the relevance of MCI to the fields of ALS and FTD.
This was followed by a talk on “What Makes It ALS?” by Martin Turner, M.D., Ph.D., professor of clinical neurology and neuroscience at Oxford University in the U.K. Dr. Turner discussed the nature of abnormal clinical examination findings and minimal diagnostic criteria for ALS. “He raised important questions about whether established diagnostic criteria for ALS might benefit from some revision,” said Dr. Benatar.
Dr. Benatar then presented preliminary research criteria for MMI, based on extensive experience and data from the ongoing Pre-fALS study, which he leads with Joanne Wuu, Sc.M., research associate professor of neurology and associate director of research at the University of Miami ALS Center.
Henry Houlden, M.D., Ph.D., professor at University College London, described the movement disorder phenotypes in certain genetic carriers, which might also represent a manifestation of MMI. His talk was followed by the presentations of two different approaches to defining MCI/MBI by Edward (Ted) Huey, M.D., professor of psychiatry and human behavior at Brown University and director of the Memory and Aging Program at Butler Hospital; and Caroline McHutchison, Ph.D., post-doctoral research fellow at University of Edinburgh, U.K.
Sharon Abrahams, Ph.D., chair of neuropsychology at the University of Edinburgh, moderated a discussion of these two frameworks for defining MCI and MBI, as well as opportunities for harmonizing these approaches in research studies.
An afternoon session featured a panel discussion on how to approach communication about MMI, MCI and MBI to pre-symptomatic mutation carriers. Panelists included David Benatar, Ph.D., professor of philosophy at the University of Cape Town in South Africa; Laynie Dratch, Sc.M., CGC, genetic counselor at the University of Pennsylvania; Jalayne Arias, J.D., associate professor in health policy and behavioral sciences at Georgia State University; and Anita Crawley, a pre-symptomatic gene mutation carrier. The panelists emphasized the importance of recognizing individual preferences for this knowledge (or not) as well as how information is communicated, and the challenge of sharing information about these prodromal syndromes that clinicians are still trying to define.
The workshop concluded with development of an action plan that included further refinement of the research criteria for the three prodromal syndromes in ALS and FTD, and alignment of diagnostic criteria for MMI and ALS.
Dr. Benatar thanked the generous support of the workshop sponsors: the ALS Association, Biogen, Eli Lilly, Novartis, Regeneron, UniQure, the Muscular Dystrophy Association, the Association for FTD, the Motor Neuron Disease Association and the National Institutes of Health.