Combination of CSF Neurofilament and TDP-43 Improves ALS Diagnostic Performance

Toshiki Mizuno, MD, professor, Division of Neurology and Gerontology, Kyoto Prefectural University of Medicine

Toshiki Mizuno, MD

New study results suggest that cerebrospinal fluid (CSF) and plasma neurofilament light chain (NfL), as well as CSF TAR DNA‐binding protein 43 (TDP‐43), may serve well as diagnostic biomarkers in amyotrophic lateral sclerosis (ALS). Notably, the results also imply that CSF and plasma NfL can provide a measurement of disease progression.

As such, the use of them in combination holds potential as a possible biomarker for the diagnosis of ALS, author Toshiki Mizuno, MD, professor, Division of Neurology and Gerontology, Kyoto Prefectural University of Medicine, and colleagues wrote. Ultimately, levels of TDP-43 and NfL in CSF were significantly higher among those with ALS.

“The diagnostic or prognostic value of plasma TDP‐43 or plasma t‐tau in ALS has remained uncertain because of the difficulty of stable measurement,” Mizuno and co. wrote. “To the best of our knowledge, this study is the first to comprehensively measure levels of all of these 3 candidate biomarkers, not only in CSF but also, simultaneously, in plasma.”

The prospective, single-center, longitudinal study included a discovery cohort of 29 patients with ALS and a group of age-matched healthy individuals. As well, there was a validation cohort of 46 participants with ALS and 46 controls, not age-matched, with motor weakness from neuromuscular disease. The only significant difference between groups was in the validation cohort, as the median age of the control group was significantly younger (P <.0001).

TDP-43 was elevated in both CSF (P <.0001) and plasma (P = .0035) in the discovery cohort compared to the control group, as was NfL in plasma (P = .0299) and CSF (P <.0001). T-tau levels were significantly lower for those in the ALS group in plasma only (P = .0178).

When the levels of regarding the levels of plasma TDP&#8208;43, plasma t&#8208;tau, and CSF t&#8208;tau when comparing the 2 cohorts, the following was identified: Levels of plasma TDP&#8208;43 in the combined ALS group were higher than those in the combined control group (P = 0.0137), as was CSF t&#8208;tau (P = 0.0006). Levels of plasma t&#8208;tau were not different between these groups (P = 0.228).

When recalculating survival analyses in the combined ALS group, both plasma NfL (P = .0002) and CSF NfL (P = 0.0193) levels were linked with shorter survival. After age-adjustment, those significant relationships remained (plasma NfL: hazard ratio [HR] 7.611, P <.001; CSF NfL: HR 4.567, P <.001). No significant difference in survival between the high— and low–level groups based on TDP&#8208;43 and t&#8208;tau levels in plasma and CSF was observed.

“Furthermore, the potential prognostic value of elevated levels of CSF NfL, in terms of shorter survival time, was observed after stratifying cohorts according to the median CSF NfL levels. These confirm the findings gathered in retrospective case-control studies and prospective observations,” Mizuno et al. wrote. They additionally noted that the data support that NfL in both plasma and CSF can serve as a progression-monitoring and diagnostic biomarker for ALS.

Due to TDP-43’s standing as a disease-specific biomarker reflective of TDP&#8208;43 pathology, the group noted that the ability to discriminate those with ALS from controls using CSF NfL and TDP-43 can be improved, as measured by area under the curve (AUC) values, was expected. The combination of the pair offered AUC values of 0.8430 and 0.9493 in the discovery and validation cohorts, respectively.

“This observation was found consistently across both cohorts, suggesting that CSF TDP&#8208;43 could serve as a biomarker complementary to NfL, for the diagnosis of ALS,” the group wrote. The discriminability for the product of CSF NfL × plasma NfL (AUC = 0.7598) was inferior to that of CSF NfL alone in the discovery cohort, though the value for the combination of plasma NfL and CSF TDP&#8208;43 (AUC = 0.6813) did not exceed that for CSF TDP&#8208;43 alone.

“Plasma TDP&#8208;43 and CSF t&#8208;tau may be elevated in ALS patients and, therefore, be of diagnostic value; however, the results of this study still need future validation in a larger cohort,” Mizuno and colleagues concluded.

REFERENCE

Kasai T, Kojima Y, Ohmichi T, et al. Combined use of CSF NfL and CSF TDP&#8208;43 improves diagnostic performance in ALS. Ann Clin Transl Neurol. Published online November 19, 2019. doi: 10.1002/acn3.50943.