August 26, 2026

@michaelokun

What resonates with me about this important JAMA Neurology review and accompanying editorial is the provocative idea that we may need to stop thinking about ALS, FTD, LATE, inclusion body myositis and related disorders only as separate clinical diagnoses, and begin asking whether some are different faces of a shared biology centered on TDP-43. Benatar and colleagues propose TDP-43–associated neurodegenerative disease (TAND) as an umbrella framework that could eventually classify and stage disease by underlying TDP-43 biology, potentially even before symptoms emerge, rather than waiting for the late clinical phenotype to tell us what to call it. This matters because a biologically defined TAND could accelerate biomarker discovery and ultimately enable mechanism-based “basket” trials in which therapies targeting TDP-43 could cross traditional diagnostic boundaries. But the accompanying editorial appropriately asks, “Are we there yet?” TDP-43 diseases remain remarkably heterogeneous, TDP-43 may be a primary driver in some settings and a co-pathology in others, and most importantly we still lack validated in-vivo biomarkers capable of reliably defining TAND and its proposed stages in living people. Alzheimer’s disease taught us how powerful it can be to move from a syndrome to a biological definition once biomarkers mature. We may not be there yet with TAND, but these papers make a compelling case that we are moving in that direction. https://cutt.ly/ZygFs8Jq