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 (0.2-190) 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) = 70.8, p < 0.001; mean (SD) 0.17 (0.04) vs. 0.2 (0.03), F(1) = 14.3, p < 0.001], 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 ≥ 2.5, p ≤ 0.01; for the ptau/ttau ratio: [0.13 (0.04) vs. 0.17 (0.04) vs. 0.18 (0.03), p ≤ 0.02]. 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 - 0.6), the ptau/ttau ratio (0.7), CST FA (0.8) and UMND ALS phenotype (- 2.8). 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.

the upper cervical spinal cord is measured in a large longitudinal amyotrophic lateral sclerosis (ALS) cohort to evaluate its role as a biomarker. Specifically, the cervical spinal cord´s cross-sectional area (CSA) in plane of the segments C1-C3 was measured semi-automatically with T1-weighted 3T MRI sequences in 158 ALS patients and 86 controls. Six-month longitudinal follow-up MRI scans were analyzed in 103 patients. Compared to controls, in ALS there was a significant mean spinal cord atrophy (63.8 mm² vs. 60.8 mm², p = 0.001) which showed a trend towards worsening over time (mean spinal cord CSA decrease from 61.4 mm² to 60.6 mm² after 6 months, p = 0.06). Findings were most pronounced in the caudal segments of the upper cervical spinal cord and in limb-onset ALS. Baseline CSA was related to the revised ALS functional rating scale, disease duration, precentral gyrus thickness and total brain gray matter volume. In conclusion, spinal cord atrophy as assessed in brain MRIs in ALS patients mirrors the extent of overall neurodegeneration and parallels disease severity. Spinal cord involvement is a well-known and prominent feature of amyotrophic lateral sclerosis (ALS), that reflects both anterior horn cell ("amyotrophy") and pyramidal tract degeneration/sclerosis of the lateral columns ("lateral sclerosis")-which has been highlighted since Charcot's pathology studies in 1865 1. Autopsy studies correspondingly reveal mild to marked loss of motor neurons in around 80% of the ALS patients which can affect the anterior horn of the entire spinal cord from the level of C2 to the level of its caudal sacral segments 2. Anterior horn cell loss is furthermore closely associated with large myelinated fiber degeneration of the pyramidal tract 2-4. In-vivo studies applying magnetic resonance imaging (MRI) correspondingly display a reduction of the spinal cord cross-sectional area (CSA) in ALS, i.e. showing spinal cord atrophy together with pyramidal tract integrity loss in diffusion tensor imaging (DTI) 5-7. Controversies remain, however, on the relationship of in-vivo MRI spinal cord atrophy to clinical features and biomarkers in ALS. While some studies reported an association between CSA reduction and worse motor performance or longer disease duration 8,9 , others failed to find such a clinical correlation 10,11. Conflicting or negative results might stem from small sample sizes in that most studies included less than 30 patients 8,9,12. Additionally, only a few ALS studies thus far took advantage of the capability of spinal cord in-vivo MRI to monitor CSA evolution over time 5,12,13. In consideration of these uncertainties, we conducted a retrospective analysis of the upper cervical spinal cord within brain MRIs that were acquired during a large cross-sectional (N = 158) and longitudinal (N = 103) multicenter study to understand how in-vivo spinal cord atrophy relates to clinical features, other biomarkers, and, how it evolves over time in ALS.

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In ALS, dissociated forearm muscle weakness could aid in the disease's diagnosis. Nerve ultrasound did not provide additional information on the differential involvement of finger-extension and finger-flexion strength.