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Journal ArticleDOI

Significance of CSF NfL and tau in ALS

05 Sep 2018-Journal of Neurology (J Neurol)-Vol. 265, Iss: 11, pp 2633-2645

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.

AbstractCerebrospinal 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

  • 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 [7].
  • 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.

Data availability

  • 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 measures

  • 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) [11].
  • CV was calculated using the root mean square method, described e.g. in [19].
  • 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 [16] 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).

Results

  • 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.

Figures

  • 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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Supplemental
Methods
ALS sample
Penn UMN score
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) [1]. In detail, for
the bulbar segment, single points were allocated for an abnormal jaw-jerk reflex, an
abnormal facial reflex, the existence of the palmomental sign and the existence of an
abnormal pseudobulbar affect. For the upper extremity subscore, single points were given for
each, pathologically brisk biceps reflex, triceps reflex, presence of finger flexors, Hoffmann’s
sign or the existence of a clonus anywhere in the limb. Additionally, spasticity was rated
according to the Ashworth Spasticity Scale (0-2 points, with adding 0 points for Ashworth 1
(normal tone), 1 point for Ashworth 2-3, 2 points for Ashworth 4-5) [2]. For the lower
extremity subscore, single points were allocated for each, pathologically brisk plantar reflex,
ancle reflex, crossed adduction, Babinski’s sign and a clonus anywhere in the limb. For the
lower extremity, spasticity was rated the same way as described for the upper extremity
subscore.
Clinical phenotypes
Clinical phenotypes were classified according to recent specifications [3, 4]. At the time of
study inclusion, a variable combination of UMN signs (spastic tone, clonus, etc.) and LMN
signs (wasting, weakness, fasciculations) in the upper and lower limbs were found in those
designated as classic ALS who, in turn, fulfilled the El Escorial criteria of definite or probable
ALS. UMND ALS patients had either no LMN signs, or, if present (1) they were restricted to
only 1 neuraxis level (bulbar, cervical, or lumbosacral); and (2) electromyographic
abnormalities were limited to sparse fibrillation potentials/positive sharp waves or minor
enlargement of motor unit potentials in 1 or at most 2 muscles [5, 6] for at least 12 months
after symptom onset. 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 [7]. All
patients with LMND ALS had clinical and electrophysiological evidence of sporadic
progressive pure LMN involvement in 1 or more regions without clinical signs of UMN
dysfunction. To differentiate this condition from early limb-onset ALS, we specified that LMN
involvement must be the predominant finding for at least 12 months after the symptom onset.
LMND ALS comprised patients with flail arm phenotype (n=4), flail leg phenotype (n=2) and
progressive muscular atrophy (n=3). Other LMN diseases, such as multifocal motor
neuropathy, spinal muscular atrophy, monomelic amyotrophy, Kennedy’s disease, and post-
polio syndrome, were excluded by extensive clinical and laboratory examinations [7, 8].
Data availability
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 our 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.
Survival data could be identified in n=86 subjects (97%) with n=53 (62%) having died after a
median survival time of 35.8 months. C9orf72 and SOD1 status was available in n=64
patients (72%), comprising n=6 (9%) suffering from familial ALS (n=2 with C9orf72 positivity
and n=4 with SOD1 positivity). Nerve CSA was available in n=72 (81%) cases, CMAP
amplitudes in n=65 (73%) and MPRAGE images in n=61 (69%) subjects of whom n=51
(57%) had also cerebral DTI measures. Constellations of individual data availability in ALS
are indicated in Supplemental Figure 1.
CSF measures
Within 20 minutes of lumbar puncture, CSF samples were centrifuged at 4 C, aliquoted and
stored at -80 C until analysis. 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 we determined the intra-assay coefficient of
variability (CV; =reproducibility, within-assay performance) and the inter-assay CV
(=repeatability, between-assay performance) [11]. CV was calculated using the root mean
square method, described e.g. in [19]. 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. Intra-assay CV of duplicates was 3.1%, inter-assay CV was 10.6%, which is
in line with the literature [11]. 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. 3D MPRAGE images were
acquired using the following parameters: acquisition time 9 min, 20 s, repetition time 2500
ms, echo time 4.82 ms, inversion time 1100 ms, flip angle 7 °, voxel size = 1×1×1 mm
3
. DWI
data were acquired with a resolution of 2×2×2 mm
3
. Diffusion gradients were applied along
30 non-collinear directions with b = 1000 s/mm
2
, one scan without diffusion weighting (b =
0 s/mm
2
) was also acquired. The data were averaged across two repetitions (for full details
see [12, 13]). A T2-weighted FLASH sequence was acquired during the same session to
investigate the presence of white matter hyperintensities.
Diffusion tensor imaging analysis
Diffusion tensor images were processed using the FMRIB software library (FSL [14];
Analysis Group, FMRIB, University of Oxford, UK). In brief, each diffusion weighted volume
was affined-aligned to its corresponding b0 image using FSL's linear image co-registration
tool (FLIRT v5.4.2) to correct for motion artifacts and eddy-current distortions. Using FSL’s
brain-extraction tool (BET v2.1) a binary brain mask of each b0 image was generated, with
fractional threshold f = 0.1 and vertical gradient g = 0. The original b-matrix was reoriented

using an in-house script to adjust it for rotations induced by the previous transformations.
FSL's diffusion toolbox (FDT v2.0) was used to fit a single tensor model, taking a weighted
linear approach, and to compute the maps of DTI scalars (FA, mean diffusivity (MD), radial
diffusivity (RD), axial diffusivity (AD)). Load of white matter lesion was evaluated on a T2-
weighted FLASH sequence employing the Fazekas scale [15].
The analyses were performed employing tract-based spatial statistics [16] that warped all the
FA images to the FMRIB58_FA standard template (FMRIB; resolution: 1×1×1 mm
3
) in
MNI152 space using FSL's non-linear registration tool (FNIRT v1.0). The warped FA maps
were averaged to create a mean FA template, from which the FA skeleton was computed,
imposing an FA threshold of 0.2. All the FA maps as well as the maps of the other DTI
scalars were then projected onto the skeleton. The whole-brain regression analysis was
conducted employing the Randomise tool version 2.9 available in FSL with 5000
permutations, threshold-free cluster enhancement (TFCE) and 2D optimization for tract-
based DTI analysis. The CST region of interest (ROI) analysis was performed using the CST
mask (bilateral) included in the JHU white matter tractography atlas available in FSL,
thresholded at 0.5. The JHU-CST mask was further intersected with the study- specific
skeleton and the resulting mask was used for extracting the median values of DTI scalars in
the CST for each participant.
Cortical thickness and volumetric measures
For each patient cortical thickness of the bilateral precentral gyrus was obtained from the
native-space MPRAGE scans using the automated FreeSurfer 6.0 parcellation [18]. Total
brain volume (TBV), GM volume (GMV) and WM volume (WMV), normalized for head size,
were estimated using the SIENAX algorithm from the SIENA-package of FSL v5.0.
Results
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. Unfortunately, in our cohort the group
of LMND ALS and UMND ALS was too small, lacking the power to perform phenotype-wise
analysis. However, correlation between DTI metrics in the CST and NfL level was present
also when restricting the analysis to the classic ALS cases (NfL and FA: rho=-0.4, p=0.03;
NfL and RD: rho=0.4, p=0.05; Supplemental Figure 2). Results in classic ALS are
convincing, overall supporting our main findings of a significant relationship between CSF
NfL and CST integrity.
Relationship between CSF NfL and survival across ALS phenotypes
The distribution of observed survival times over measured NfL levels is shown in
Supplemental Figure 3A for the distinct phenotypes. Classic phenotypes with survival times
greater than 8 years were excluded as they seem to exhibit a somewhat different course of
disease. Within that plot, the distribution of the values of the UMND ALS phenotype is
seemingly different from that of the scatter pattern of the classic phenotype. To elucidate this,
a principal component analysis with the variables NfL and survival time was performed
yielding the eigenvectors shown as arrows in black. 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. The scatter plot in factor coordinates in Supplemental Figure 3B reveals that
patients with the classic phenotype tend to scatter along the factor 1 axis, displaying low NfL
and relatively long survival times or for negative factor 1 values a combination of high NfL
with short survival times. The UMND group displays a negative mean for factor 1, so that
they also seem to exhibit elevated NfL levels corresponding to decreased survival times. But
this is somewhat offset by a positive mean value in their factor 2 components, allowing for
constellations with higher NfL levels than comparably long-lived classic cases or the ability to
survive longer than would be expected for a classic case with these NfL levels (or a
combination of those two). One may thus hypothesize that these results point to the

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