IMPORTANCE Various factors have been proposed as possible candidates associated with the prognosis of amyotrophic lateral sclerosis (ALS); however, there is still no consensus on which biomarkers are reliable prognostic factors. C-reactive protein (CRP) is a biomarker of the inflammatory response that shows significant prognostic value for several diseases. OBJECTIVE To examine the prognostic significance of CRP in ALS. DESIGN, SETTING, AND PARTICIPANTS Patients' serum CRP levels were evaluated from January 1, 2009, to June 30, 2015, in a large cohort of patients with ALS observed by an Italian tertiary multidisciplinary center. Results were replicated in an independent cohort obtained from a population-based registry of patients with ALS. A post hoc analysis was performed of the phase 2 trial of NP001 to determine whether stratification by levels of CRP improves differentiation of responders and nonresponders to the drug. MAIN OUTCOMES AND MEASURES Serum CRP levels from the first examination were recorded to assess their effect on disease progression and survival. RESULTS A total of 394 patients with ALS (168 women and 226 men; mean [SD] age at diagnosis, 60.18 [13.60] years) were observed in a tertiary multidisciplinary center, and the analysis was replicated in an independent cohort of 116 patients with ALS (50 women and 66 men; mean [SD] age at diagnosis, 67.00 [10.74] years) identified through a regional population-based registry. Serum CRP levels in the 394 patients with ALS correlated with severity of functional impairment, as measured by total score on the ALS Functional Rating Scale-Revised, at first evaluation (r =-0.14818; P = .004), and with patient survival (hazard ratio, 1.129; 95% CI, 1.033-1.234; P = .007). Similar results were found in the independent cohort (hazard ratio, 1.044; 95% CI, 1.016-1.056; P Յ .001). Moreover, a post hoc analysis of the phase 2 trial of NP001 using the same CRP threshold showed that patients with elevated baseline CRP levels receiving the higher dose of NP001 had significantly less functional impairment after the treatment period compared with patients with normal baseline CRP, regardless of whether patients with normal CRP levels received NP001 or placebo (3.00 [3.62] vs-7.31 [6.23]; P = .04). CONCLUSIONS AND RELEVANCE These findings suggest that patients with ALS and elevated serum CRP levels progress more rapidly than do those with lower CRP levels and that this elevation may reflect a neuroinflammatory state potentially responsive to the immune regulators such as NP001.

The objective of our study was to perform a randomized controlled trial (RCT) aimed to evaluate the effects of three strictly monitored exercise programs(SMEP) compared to "usual care" (UCP) in a cohort of ALS patients. We included patients with definite and probable ALS and disease duration ≤24 months. Patients were randomized to receive a SMEPs or a UCP. SMEPs included three subgroups of treatment: active exercises associated with cycloergometer activity (1A), only active (1B) and passive (1C) exercises, respectively. Moreover, SMEP patients and their caregivers were trained to a daily home-based passive exercise program. The UCP group was treated with passive and stretching exercises twice weekly. The treatment period for both groups was 6 months (T180), and patients were assessed by revised ALS Functional Rating Scale (ALSFRS-R), % Forced Vital Capacity (FVC %), and McGill Quality of Life (MGQoL) questionnaire. ALSFRS-R score was also evaluated at 6 months after the treatment period (T360). Sixty ALS patients were randomly assigned to one of two arms: SMEP Group included 30 patients, ten subjects for each subgroup (1A, 1B, and 1C); 30 patients were included in the UCP Group.At T180 and T360, SMEPs group had significantly higher ALSFRS-R score compared to the UCP group (32.8 ± 6.5 vs 28.7 ± 7.5, p = 0.0298; 27.5 ± 7.6 vs 23.3 ± 7.6, p = 0.0338, respectively). No effects of SMEPs on survival, respiratory decline and MGQol were found. In conclusion, although no effect on survival was demonstrated,our data suggest that a strictly monitored exercise program may significantly reduce motor deterioration in ALS patients.

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ALS is a heterogeneous disease that is not well understood. Epigenetic rearrangements are important in complex disorders including motor neuron diseases. The aim of this study was to determine whether whole-blood DNA methylation (DNA MET %) is a potential modifier of age at onset in ALS. DNA MET % was measured as incorporation of [(3)H]dCTP following HpaII cut in 96 ALS patients and 87 controls, comprising: early-onset (< 55 years of age) and late-onset (> 74 years of age). Methionine (Met) and homocysteine (Hcy) plasma levels were assessed by liquid chromatography selected reaction monitoring coupled with isotope-dilution mass spectrometry. Results showed that DNA MET % was increased in ALS patients independently of age of onset. Compared to the other three groups, Hcy plasma levels were reduced in early-onset ALS patients but Met levels were similar. ROC analysis reported Met levels and DNA MET %, respectively, with a slight and moderate discriminative power. In conclusion, increased DNA MET % is a possible marker of epigenetic dysfunction in ALS independently of age of onset. Further studies dissecting biological determinants of phenotypic complexity in ALS may help in developing successful therapeutic strategies.

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