Ulnar nerve ultrasound in ALS subgroups revealed significant differences in distal CSA values, which suggests it has value as a marker of LMN involvement. Its potential was particularly evident in the UMND and PLS groups, which can be hard to separate clinically, yet their accurate separation has major prognostic implications.

Summary:Purpose: For the antiepileptic drug (AED) topiramate (TPM), neuroprotective effects have been reported in models of focal cerebral ischemia and experimental status epilepticus, but the putative mechanism of action has remained elusive.Methods: We studied the effects of TPM on mitochondrial function in the pilocarpine rat model of chronic epilepsy and in isolated mitochondria from rat brain.Results: TPM treatment in status epilepticus at doses ranging from 20 to 100 mg/kg considerably improved the survival of rats and improved CA1 and CA3 pyramidal cell survival in a dose-dependent manner. This treatment increased the activity of mitochondrial respiratory chain complex I in the CA1 and CA3 pyramidal subfields and resulted in lower seizure frequencies in chronic epileptic rats. In vitro investigations of the action of TPM on isolated rat brain mitochondria ruled out any direct effects of the drug on mitochondrial oxidative phosphorylation but revealed a protective effect on hippocampal mitochondria against an external calcium challenge. This can explain its observed neuroprotective action in the concentration range tested. The in vitro effects of TPM on the calcium handling of isolated brain mitochondria was found to be comparable to the action of cyclosporin A.Conclusions: The neuroprotective action of TPM seems to be directly related to its inhibitory effect on the mitochondrial permeability transition pore.

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.

In the PI(3,5)P2 biosynthetic complex, the lipid kinase PIKFYVE and the phosphatase FIG4 are bound to the dimeric scaffold protein VAC14, which is composed of multiple heat-repeat domains. Mutations of FIG4 result in the inherited disorders Charcot-Marie-Tooth disease type 4J, Yunis-Varón syndrome, and polymicrogyria with seizures. We here describe inherited variants of VAC14 in two unrelated children with sudden onset of a progressive neurological disorder and regression of developmental milestones. Both children developed impaired movement with dystonia, became nonambulatory and nonverbal, and exhibited striatal abnormalities on MRI. A diagnosis of Leigh syndrome was rejected due to normal lactate profiles. Exome sequencing identified biallelic variants of VAC14 that were inherited from unaffected heterozygous parents in both families. Proband 1 inherited a splice-site variant that results in skipping of exon 13, p.Ile459Profs(∗)4 (not reported in public databases), and the missense variant p.Trp424Leu (reported in the ExAC database in a single heterozygote). Proband 2 inherited two missense variants in the dimerization domain of VAC14, p.Ala582Ser and p.Ser583Leu, that have not been previously reported. Cultured skin fibroblasts exhibited the accumulation of vacuoles that is characteristic of PI(3,5)P2 deficiency. Vacuolization of fibroblasts was rescued by transfection of wild-type VAC14 cDNA. The similar age of onset and neurological decline in the two unrelated children define a recessive disorder resulting from compound heterozygosity for deleterious variants of VAC14.