Assessment of disease progression and functional benefit in neurodegenerative disease: Can we tell the difference?

Therapeutic strategies for neurodegenerative diseases include modalities intended to modulate disease progression as well as those whose intent is to improve or maintain functional capacity. As the search for pharmacodynamic markers has proved elusive, treatment outcomes most commonly reflect patient function. As a result, even when clinical trials show a beneficial effect, the underlying etiology of that benefit can be difficult to determine. This review summarizes recent trials in ALS and Parkinson's disease, with the goal of increasing understanding of how the choice of outcome measures influences what can be concluded from the results. Although most ALS trials have been negative in recent years, outcomes are reviewed in terms of potential conclusions that could have been drawn. Functional benefit has been established in a number of recent trials; however, the outcomes used have lead to uncertainty as to whether specific agents modify disease or alter function. In the absence of specific markers sensitive to alteration of disease specific pathways, the distinction between agents that alter underlying disease versus those that affect function may depend on underlying hypotheses rather than clinical trial results.