More information about text formats
Our findings demonstrate that serum C-reactive protein (CRP) does not predict survival in amyotrophic lateral sclerosis (ALS), neither in a univariate model nor in a multivariate model including other established prognostic factors for survival in ALS. In contrast, in a similar multivariate model, serum neurofilament light chain (NfL) is an independent predictor of survival in ALS. Further, we investigated the combination of serum CRP and NfL within the same multivariate survival model. The results indicated that elevated levels of serum NfL (Hazard ratio: 1.83 [95% CI: 1.23-2.74] p = 0.003), but not of serum CRP (Hazard ratio: 0.93 [95% CI = 0.63-1.37], p = 0.7), are associated with a shorter survival in ALS. From these data, we can conclude that there is no evidence that combining both markers would improve the prediction of survival in ALS.
Moreover, we determined the disease progression rate (DPR) at time of sampling for 368 patients with ALS. The DPR was calculated as (48 – ALS-FRS-R)/(disease duration). We found a significant correlation between the DPR and serum NfL levels (rs = 0.519 [95% CI = 0.437-0.592], p < 0.0001) as well as serum CRP levels (rs = 0.294 [95% CI = 0.194-0.387], p < 0.0001). Accordingly, patients with a DPR in the upper quartile had significantly elevated levels of serum NfL (median [range]: 183 [11.1-738] pg/mL vs. 67.9 [0.300-262] pg/mL, p < 0.0001) and serum CRP (median [range]: 0.336 [0.0150-30.0] mg/dL vs. 0.0775 [0.0150-2.7...
Moreover, we determined the disease progression rate (DPR) at time of sampling for 368 patients with ALS. The DPR was calculated as (48 – ALS-FRS-R)/(disease duration). We found a significant correlation between the DPR and serum NfL levels (rs = 0.519 [95% CI = 0.437-0.592], p < 0.0001) as well as serum CRP levels (rs = 0.294 [95% CI = 0.194-0.387], p < 0.0001). Accordingly, patients with a DPR in the upper quartile had significantly elevated levels of serum NfL (median [range]: 183 [11.1-738] pg/mL vs. 67.9 [0.300-262] pg/mL, p < 0.0001) and serum CRP (median [range]: 0.336 [0.0150-30.0] mg/dL vs. 0.0775 [0.0150-2.75] mg/dL, p < 0.0001) in comparison with patients with a DPR in the lower quartile.
The cross-sectional retrospective design of the study did not allow us to assess the change of serum serum NfL and CRP levels over time. However, recent publications indicate that serum NfL levels remain stable over time, confirming our observation in cerebrospinal fluid.[1–3] Furthermore, Benatar M. and colleagues have shown that baseline NfL measurements are predictive of ALSFRS-r decline. Recent studies with the experimental drug nusinersen in patients with spinal muscular atrophy and fingolimod in patients with multiple sclerosis show that neurofilament levels in blood respond to treatment.[4,5] These findings highlight the potential utility of neurofilaments as pharmacodynamic biomarkers. Interestingly, upon treatment of SOD1 ALS mice models with antisense oligonucleotides (ASO), the phosphorylated neurofilament heavy chain levels in serum were significantly lower in comparison to mice receiving the control treatment. Likewise, patients with ALS who were treated with the highest dose of Tofersen, an ASO for SOD1 mutation carriers, also showed a decrease in plasma neurofilaments upon treatment. Yet, these findings have to be confirmed in larger cohort of patients with ALS.
1 Benatar M, Zhang L, Wang L, et al. Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS. Neurology Published Online First: 8 May 2020. doi:10.1212/WNL.0000000000009559
2 Huang F, Zhu Y, Hsiao-Nakamoto J, et al. Longitudinal biomarkers in amyotrophic lateral sclerosis. Ann Clin Transl Neurol 2020;:1–14. doi:10.1002/acn3.51078
3 Poesen K, De Schaepdryver M, Stubendorff B, et al. Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology 2017;88:2302–9. doi:10.1212/WNL.0000000000004029
4 Darras BT, Crawford TO, Finkel RS, et al. Neurofilament as a potential biomarker for spinal muscular atrophy. Ann Clin Transl Neurol 2019;6:932–44. doi:10.1002/acn3.779
5 Sormani MP, Haering DA, Kropshofer H, et al. Blood neurofilament light as a potential endpoint in Phase 2 studies in MS. Ann Clin Transl Neurol 2019;6:1081–9. doi:10.1002/acn3.795
6 McCampbell A, Cole T, Wegener AJ, et al. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest 2018;128:3558–67. doi:10.1172/JCI99081
7 Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med 2020;383:109–19. doi:10.1056/NEJMoa2003715
De Schaepdryver et al. assessed the prognostic ability of serum neurofilament light chain (NfL) and C-reactive protein (CRP) in patients with amyotrophic lateral sclerosis (ALS) (1). Although two indicators can significantly predict the prognosis, the superiority by the combination of NfL and CRP should be checked for the analysis. I want to discuss NfL and ALS prognosis from recent publications.
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum NfL in patients with ALS (2). Serum NfL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NfL did not differ among patients in different ALS pathological stages, and NfL levels were stable over time within each patient.
Regarding the first query, Thouvenot et al. reported that serum NfL could be used as a prognostic marker for ALS at the time of diagnosis (3). Gille et al. recognized the relationship of serum NfL with motor neuron degeneration in patients with ALS (4). They described that serum NfL was significantly associated with disease progression rate and survival, and it could be recommended as a surrogate biomarker of ALS. These two papers presented no information whether NfL can be used for monitoring of ALS progression in each patient.
De Schaepdryver et al. used two indicators, and I suspect that the authors can present information r...
De Schaepdryver et al. used two indicators, and I suspect that the authors can present information regarding the monitoring ability for ALS progression. In combination with clinical findings, biological monitoring method might be important for medication efficacy.
1. De Schaepdryver M, Lunetta C, Tarlarini C, et al. Neurofilament light chain and C reactive protein explored as predictors of survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2020;91(4):436-437. doi: 10.1136/jnnp-2019-322309
2. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2019 Feb;90(2):157-164. doi: 10.1136/jnnp-2018-318704
3. Gille B, De Schaepdryver M, Goossens J, et al. Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2019;45(3):291-304. doi: 10.1111/nan.12511
4. Thouvenot E, Demattei C, Lehmann S, et al. Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis. Eur J Neurol. 2020;27(2):251-257. doi: 10.1111/ene.14063