Significance of CSF NfL and tau in ALS
TL;DR: The findings that higher CSF NfL levels and a reduced ptau/ttau ratio are more associated with clinical UMN involvement and with reduced CST FA offer strong converging evidence that both are markers of central motor degeneration.
Abstract: Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has emerged as putative diagnostic biomarker in amyotrophic lateral sclerosis (ALS), but it remains a matter of debate, whether CSF total tau (ttau), tau phosphorylated at threonine 181 (ptau) and the ptau/ttau ratio could serve as diagnostic biomarker in ALS as well Moreover, the relationship between CSF NfL and tau measures to further axonal and (neuro)degeneration markers still needs to be elucidated Our analysis included 89 ALS patients [median (range) age 63 (33-83) years, 61% male, disease duration 10 (02-190) months] and 33 age- and sex-matched disease controls [60 (32-76), 49%] NfL was higher and the ptau/ttau ratio was lower in ALS compared to controls [8343 (1795-35,945) pg/ml vs 1193 (612-2616), H(1) = 708, p < 0001; mean (SD) 017 (004) vs 02 (003), F(1) = 143, p < 0001], as well as in upper motor neuron dominant (UMND, n = 10) compared to classic (n = 46) or lower motor neuron dominant ALS [n = 31; for NfL: 16,076 (7447-35,945) vs 8205 (2651-35,138) vs 8057 (1795-34,951)], Z ≥ 25, p ≤ 001; for the ptau/ttau ratio: [013 (004) vs 017 (004) vs 018 (003), p ≤ 002] In ALS, NfL and the ptau/ttau ratio were related to corticospinal tract (CST) fractional anisotropy (FA) and radial diffusivity (ROI-based approach and whole-brain voxelwise analysis) Factor analysis of mixed data revealed a co-variance pattern between NfL (factor load - 06), the ptau/ttau ratio (07), CST FA (08) and UMND ALS phenotype (- 28) NfL did not relate to any further neuroaxonal injury marker (brain volumes, precentral gyrus thickness, peripheral motor amplitudes, sonographic cross-sectional nerve area), but a lower ptau/ttau ratio was associated with whole-brain gray matter atrophy and widespread white matter integrity loss Higher NfL baseline levels were associated with greater UMN disease burden, more rapid disease progression, a twofold to threefold greater hazard of death and shorter survival times The findings that higher CSF NfL levels and a reduced ptau/ttau ratio are more associated with clinical UMN involvement and with reduced CST FA offer strong converging evidence that both are markers of central motor degeneration Furthermore, NfL is a marker of poor prognosis, while a low ptau/ttau ratio indicates extramotor pathology in ALS
Summary (2 min read)
- Clinical phenotypes were classified according to recent specifications [3, 4].
- The diagnostic criteria for PLS required a period of at least 4 years in which there were only UMN signs on examination.
- Other conditions that mimic PLS, such as hereditary spastic paraplegia (HSP) were excluded by appropriate investigations .
- To differentiate this condition from early limb-onset ALS, the authors specified that LMN involvement must be the predominant finding for at least 12 months after the symptom onset.
- CSF data were on hand for all ALS patients, of those 89 cases, 58 (69%) and 13 (15%) patients, respectively, have already been included in their previous cross-sectional and longitudinal peripheral nerve sonography ALS studies [3, 9, 10].
- Out of the 84 patients with available baseline ALSFRS-R scores, longitudinal ALSFRS-R scoring was performed in n=71 cases (80%) with at least two follow-ups and n=46 cases (52%) with at least three follow-ups.
- CSF biomarkers were measured with commercially available ELISA (for NfL: NF-light® ELISA, IBL International GmbH, Hamburg, Germany; for total tau [ttau] or ptau: Innotest hTauAg or Innotest p-Tau, Innogenetics, Ghent, Belgium), following the instructions provided by the manufacturer.
- To assess the performance of the NfL assay the authors determined the intra-assay coefficient of variability (CV; =reproducibility, within-assay performance) and the inter-assay CV (=repeatability, between-assay performance) .
- CV was calculated using the root mean square method, described e.g. in .
- CSF samples of 2 controls and four ALS patients were measured twice on the first assay, and procedure was repeated 24 hours later taking a second assay.
- Detailed CSF NfL values of each sample are given in Supplemental Table 1.
3T MRI measures of the brain
- All MRI scans were performed on the same Siemens Verio 3 T system (Siemens Medical Systems, Erlangen, Germany) with a 32-channel head coil.
- Diffusion gradients were applied along 30 non-collinear directions with b = 1000 s/mm2, one scan without diffusion weighting (b = 0 s/mm2) was also acquired.
- A T2-weighted FLASH sequence was acquired during the same session to investigate the presence of white matter hyperintensities.
- The original b-matrix was reoriented using an in-house script to adjust it for rotations induced by the previous transformations.
- The analyses were performed employing tract-based spatial statistics  that warped all the FA images to the FMRIB58_FA standard template (FMRIB; resolution: 1×1×1 mm3) in MNI152 space using FSL's non-linear registration tool (FNIRT v1.0).
- Relationship between CSF NfL and DTI metrics across ALS phenotypes.
- Out of the whole sample n=29 classic ALS, n=14 LMND ALS and n=6 UMND ALS cases had available both, measures of CSF NfL and DTI metrics.
- The distribution of observed survival times over measured NfL levels is shown in Supplemental Figure 3A for the distinct phenotypes.
- The factor loads of [-0.7, 0.7] and [0.7, 0.7] lead to factor 1 describing constellations with low NfL values and comparatively longer survival times and factor 2 pointing to individuals with longer survival times despite higher NfL values.
- One may thus hypothesize that these results point to the existence of distinct groups displaying high CSF NfL: UMND ALS with longer survival despite high CSF NfL and ALS patients with combined UMN and LMN pathology (classic disease phenotype), high CSF NfL and worse prognosis.
Subject code A1M1 A1M2 A2M1 A2M2
- Unless otherwise reported, medians and are given.
- ALS, amyotrophic lateral sclerosis; ALSFRS-R, revised ALS functional rating scale; LMND, lower motor neuron dominant; UMND, upper motor neuron dominant; *ANOVA, #binary logistic regression analysis.
- P-values <0.05 were deemed to be statistically significant.
- Availability of multimodal data in the ALS sample Constellations of data availability for the various measurements within the ALS sample.
- CSF, clinical and genetic measures are colored in blue, measures to obtain PNS neuroaxonal injury are colored in green and measures to obtain CNS neuroaxonal injury are colored in orange.
- Scatter plot of observed survival times vs. NfL measurement.
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"Significance of CSF NfL and tau in ..." refers methods in this paper
...) according to 149 the revised El Escorial criteria comprising the assessment of the number of regions (bulbar, 150 thoracic, upper limb, lower limb) with UMN (clinically) or lower motor neuron (LMN) 151 involvement (clinically or via electromyography) ....
"Significance of CSF NfL and tau in ..." refers background in this paper
...in thin unmyelinated axons of the neocortical gray 345 matter, providing axonal transport and maintenance of the neurons’ structure/morphology 346 [52, 53]....
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The Penn UMN score ranged from 0 to 32 points and comprised items from the bulbar segment ( 0-4 points ) and from each of the four limbs ( 0 -7 points per limb ) this paper.