The time of the ALSFRS-R to decrease to 50% (D50) in a sigmoidal decay model sufficiently describes the complete disease course of ALS

author: Nayana Gaur, Jena University Hospital
published: July 21, 2017,   recorded: May 2017,   views: 1544


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Introduction: Deterioration in ALS is not linear but this is what the routinely used progression rate [PR = (48-ALSFRS-R/disease duration)] suggests, as it describes progression at a circumscribed time point rather than over the disease course. A model reflecting disease progression across time will facilitate theragnostic stratification of ALS patients based on severity and progression type and assist in drug development and clinical trial recruitment. Objectives: The study aimed to develop a model that uses regularly collected ALSFRS-R scores to mathematically project disease course for individual patients. Methods: The model enlists the observation that the ALSFRS-R decays slowly after symptom onset rather than dropping immediately. This transitions to a period of stable progression that has been captured by most clinical trials, owing to late inclusion of patients based on laboratory supported ALS as per the EL Escorial/ Awaji criteria. As disability progresses, ALSFRS-R appears to plateau again. Thus, we used a function which describes the transition between two states: full health to maximum disease. The model yields two parameters describing the ALS disease course: D50 = time taken for ALSFRS-R to drop to 24 and dx = slope of ALSFRS-R decrease. Capturing the disease coursebolsters the classification of disease phases: Phase I (early semistable phase), Phase II (early progressive phase), Phase III (late progressive phase) and Phase IV (late semi-stable phase). Results: Based on ALSFRS-R scores and disease duration from onset to ALSFRS-R date for our cohort (n = 393) , we were able to determine D50 and dx in 352 (90%) of patients using the Microsoft® Excel Add-In Solver tool, with dynamic presets derived using the conventional PR parameter. Mean age at symptom onset was 62.8 years. ALSFRS-R was 36.9 +/- 7.8 and 26.3 +/- 10.6 at the first and last visit, respectively. The relationship between D50 and dx was highly linear (R2 = 0.9), indicating that the entire disease course can be described using D50 alone. Conclusion: D50, defined as months taken to reach an ALSFRS-R of 24, is a more accessible and descriptive indice. Further, sampling at a given time point can be correlated to a single parameter, enabling the discovery of early prognostic markers and refining clinical endpoints. This work is supported by BMBF (Bundesministerium für Bildung and Forschung) in the framework of the E-RARE programme (PYRAMID) and JPND (OnWebDuOnWebDUALS).

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