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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.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive limb and/or bulbar muscular weakness and atrophy. Although ALS-related alterations of motor and extra-motor neuronal networks have repeatedly been reported, their temporal dynamics during disease progression are not well understood. Recently, we reported a decline of motor system activity and a concurrent increase of hippocampal novelty-evoked modulations across 3 months of ALS progression. To address whether these functional changes are associated with structural ones, the current study employed probabilistic fiber tractography on diffusion tensor imaging (DTI) data using a longitudinal design. Therein, motor network integrity was assessed by DTI-based tracking of the intracranial corticospinal tract, while connectivity estimates of occipito-temporal tracts (between visual and entorhinal, perirhinal or parahippocampal cortices) served to assess structural changes that could be related to the increased novelty-evoked hippocampal activity across time described previously. Complementing these previous functional observations, the current data revealed an ALS-related decrease in corticospinal tract structural connectivity compared to controls, while in contrast, visuo-perirhinal connectivity was relatively increased in the patient group. Importantly, beyond these between-group differences, a rise in the patients' occipito-temporal tract strengths occurred across a 3-month interval, while at the same time no changes in corticospinal tract connectivity were observed. In line with previously identified functional alterations, the dynamics of these structural changes suggest that the affection of motor- and memory-related networks in ALS emerges at distinct disease stages: while motor network degeneration starts primarily during early (supposedly pre-symptomatic) phases, the hippocampal/medial temporal lobe dysfunctions arise at later stages of the disease.

Previous studies using diffusion tensor imaging (DTI) have examined for differences between bulbar- and limb-onset amyotrophic lateral sclerosis (ALS). Findings between studies have been markedly inconsistent, though possibly as a consequence of poor matching for confounding variables. To address this problem, this study contrasted the DTI profiles of limb-onset (ALS-L) and bulbar-onset (ALS-B) in groups that were tightly matched for the potential confounding effects of power, age, cognitive impairment and motor dysfunction. 14 ALS-L and 14 ALS-B patients were selected from a large prospective study so as to be matched on clinical and demographic features. All subjects, including 29 controls, underwent neuropsychological and neurological assessment. Tract-based spatial statistics and region of interest techniques were used to analyse fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (λ₁). Extensive bilateral FA and RD changes along the corticospinal tract were found in ALS-B compared to controls, p (corrected) <0.05; a similar distribution was seen for ALS-L at a less stringent statistical threshold. ROI analyses also showed more significant changes in ALS-B than ALS-L when each was compared to controls; for FA, MD and RD the changes reached statistical significance in the direct contrast between the two patient groups. With careful matching for confounding factors, the results suggest that ALS-B is associated with greater central white matter degeneration than ALS-L, possibly contributing to the known worse prognosis of ALS-B. The study, however, found no evidence that the spatial distribution of white matter degeneration differs between these groups.

To determine longitudinal rates of cortical atrophy in classical Amyotrophic lateral sclerosis (ALS) and ALS variants. Rates of cortical thinning were determined between 2 scans, 3-15 months apart, in 77 ALS patients: 51 classical, 12 upper motor neuron (UMN), and 14 lower motor neuron (LMN) ALS variants. Cortical thickness at the first assessment was compared with 60 healthy controls matched by age and gender. Atrophy rates were compared between patient sub-groups and correlated with disease duration, progression, and severity. Using a cross-sectional analysis, we found a significant difference in cortical thickness between ALS patients and controls in the motor and extra-motor areas (left medial orbito frontal gyrus, left inferior parietal gyrus, bilateral insular cortex, right fusiform gyrus, bilateral precuneus). Using a longitudinal analysis, we found a significant decline of cortical thickness in frontal, temporal, and parietal regions over the course of the study in ALS patients. Effects were independent of the clinical subtype, with exception of the precentral gyrus (p < 0.001). The LMN ALS variants demonstrated the highest rates of cortical thinning in the precentral gyrus, the UMN-dominant subjects exhibited intermediate rates of atrophy, and the classical ALS patients exhibited no such change. Atrophy of the precentral gyrus in classical ALS indicates a floor effect at the first assessment, resulting in a lack of further atrophy over time. Structural loss of the precentral gyrus appears to be an early sign of classical ALS. Over time, patterns of cortical thinning in extra-motor areas can be identified in ALS, regardless of the phenotype.

Amyotrophic lateral sclerosis (ALS) is characterised by degeneration of upper (UMN) and lower motor neurons (LMN).We aimed to relate clinical variables to cortical thinning of the primary motor cortex (PMC). The PMC was defined as the region of interest in high-resolution structural MRI scans. We related vertex-wise measures of cortical thinning to UMN involvement, bulbar/limb onset, the total ALS functional rating scale (ALSFRS-R), and its bulbar and upper limb subscore. In total, 93 ALS patients were recruited (60 with classical ALS; 17 with dominant UMN, e.g., primary lateral sclerosis; 16 with pure LMN variant, e.g., progressive muscular atrophy, flail arm or leg syndrome) and compared to 67 age and gender matched healthy controls. The UMN signs in the bulbar regions were associated with bilateral thinning within the bulbar segment on the motor cortex, and UMN signs in spinal regions were associated with thinning in the limb segment of the motor cortex. The site of disease onset (bulbar/lower limb) exhibited the most pronounced thinning in the corresponding part of the motor cortex. According to our analysis, dominant UMN patients demonstrated the most distinct thinning followed by classical ALS patients. Pure LMN variants did not differ from healthy controls. The bulbar subscore of the ALSFRS-R correlated with thinning of the left inferior PMC. Focal morphological changes within the PMC correspond to clinically measured impairments and depend on disease phenotype. Measuring cortical thickness may potentially offer an objective in vivo marker to quantify disease pathology.

Hirayama disease (HirD) is a juvenile spinal muscular atrophy predominantly affecting young men with an initially progressive course followed by a stable plateau within several years. It is a matter of debate whether HirD is a widespread motor neuron or more focal cervical cord disease. Whether the supraspinal pathways of the corticospinal tract (CST) are also affected has not been studied systematically. We analyzed CST integrity in seven HirD patients and 11 controls of similar age and gender using diffusion tensor imaging at a 1.5-T scanner and central motor conduction time (CMCT) using transcranial magnetic stimulation. The apparent diffusion coefficient, fractional anisotropy, and axial and radial diffusivity coefficients were determined bilaterally at four representative CST levels and along the whole CST using a probabilistic fiber tracking approach. There were no differences between the initially affected and the contralateral side in HirD patients and no difference between HirD patients and controls for both the ROI-based and the whole CST analyses. Radial diffusivity of the CST was positively correlated with years of disease progression in HirD patients. CMCT was normal in HirD patients. Combined anatomical and functional measurements established normal integrity of the supraspinal CST in HirD patients lending support to the notion that HirD is a pure spinal motor neuron disorder.