Progression in ALS is not linear but is curvilinear

Abstract

The aim of the study is to determine the shape of the progression curve in ALS, assess the impact of clinical variables on the rate of progression, and evaluate the association between functional decline and survival. Data were prospectively collected and entered into a clinical database from all patients seen in 2002-2008 at the Centre SLA, Hôpital de la Salpêtrière, Paris. Variables analyzed were demographic and baseline information, the ALS functional rating scale (ALSFRS-R), strength testing (MMT), and survival. Generalized additive mixed models characterized changes in ALSFRS-R and MMT scores over time. Linear mixed effects assessed the impact of demographic and clinical measures on rate of progression and Cox models examined their effect on survival. Of 2,452 patients with ALS identified, 1,884 had adequate data for analysis. The ALSFRS-R and MMT declined in a curvilinear way; a quadratic fit described the trends but a linear fit did not. The total ALSFRS-R score was negatively associated with age-of-onset (p < 0.001), and positively associated with baseline ALSFRS-R (p < 0.001) as well as more severe bulbar features (p < 0.001). Higher rate of decline in ALSFRS-R and MMT, older age-at-onset and bulbar-onset predicted shorter survival. Deterioration in ALS is non-linear. The early and late phases of the illness show the most rapid rates of decline. Older age and bulbar signs are associated with a steeper decline, and along with more rapid initial rate of decline, but not current functional status, also predict survival.

Being PRO-ACTive: What can a Clinical Trial Database Reveal About ALS?

“…Using the PRO-ACT database allowed for validation of these findings; for example, site of onset has been shown to affect the slope of ALSFRS and overall survival time [33][34][35][36][37][38][39][40][41], with bulbar onset leading to poor prognosis compared with limb onset. Similarly, age of onset was predictive of prognosis (with poorer prognosis for patients with an later disease onset [34][35][36][37][38][39][40][41][42][43][44]). Other factors connected to prognosis in previous reports included body mass index or absolute weight [42,45]; cognitive functioning [46]; level of uric acid [42,47]; and levels of albumin and creatinine [48,49].…”

“…Understanding the development of ALSFRS over time is relevant for understanding disease progression. Reports vary regarding the linearity of ALSFRS-R measure over time [34,43,54,55], and these reports likely depend on number of patients, distribution of disease progression, and frequency of measuring ALSFRS-R.…”

RandomForest4Life: A Random Forest for predicting ALS disease progression

“…This model depicted in the left part of Figure 5 (A) indeed suggested a nonlinear ALSFRS trajectory; however, we found a faster instead of a slower disease progression, as reported earlier (cf. Figure 1 in Gordon et al 2010). The random slope parameters necessary for the definition of the ALSFRS slope between the linear and the quadratic model were highly correlated.…”

“…Gordon et al Gordon et al (2010) reported that the mean ALSFRS trajectory over time is nonlinear. We also modelled deviations from a linear ALSFRS trajectory by allowing an additional fixed effect in quadratic time β 2 t 2 in model (2).…”

“…Two approaches have been used in the past, namely the search for prognostic factors for the overall survival time after diagnosis (Kimura et al 2006;Zoccolella et al 2008;Fujimura-Kiyono et al 2011, among many others) and the prognosis of a functional assessment of patients via the ALSFRS (ALS functional rating scale; Brooks et al 1996) and ALSFRS-R scores (Cedarbaum et al 1999). Among the published prognostic factors for ALS disease progression are bulbar rather than limb onset (Qureshi et al 2006;Gordon et al 2010), body mass index (Reich-Slotky et al 2013), early disease progression (Kimura et al 2006;Kollewe et al 2008), age at onset (Gordon et al 2010), uric acid level (Paganoni et al 2012), and amount of repeat expansion in gene C9ORF72 (Brettschneider et al 2012).…”