Neurofilament light chain protein (NfL) is currently the most accurate cerebrospinal fluid (CSF) biomarker in amyotrophic lateral sclerosis (ALS) in terms of both diagnostic and prognostic values, but the mechanism underlying its increase is still a matter of debate. Similarly, emerging CSF biomarkers of neurodegeneration and neuroinflammation showed promising results, although further studies are needed to clarify their clinical and pathophysiological roles. In the present study we compared the diagnostic accuracy of CSF NfL, phosphorylated (p)-tau/total (t)-tau ratio, chitinase-3like protein 1 (YKL-40) and chitotriosidase 1 (CHIT1), in healthy controls (n = 43) and subjects with ALS (n = 80) or ALS mimics (n=46). In ALS cases, we also investigated the association between biomarker levels and clinical variables, the extent of upper motor neuron (UMN) and lower motor neuron (LMN) degeneration, and denervation activity through electromyography (EMG). ALS patients showed higher levels of CSF NfL, YKL-40, CHIT1, and lower values of p-tau/ttau ratio compared to both controls and ALS mimics. Among all biomarkers, NfL yielded the highest diagnostic performance (> 90% sensitivity and specificity) and was the best predictor of disease progression rate and survival in ALS. NfL levels showed a higher correlation with the extent of LMN involvement, whereas YKL-40 levels increased together with the number of areas showing both UMN and LMN damage. EMG denervation activity did not correlate with any CSF biomarker change. These findings confirm the highest value of NfL among currently available CSF biomarkers for the diagnostic and prognostic assessment of ALS and contribute to the understanding of the pathophysiological and electrophysiological correlates of biomarker changes.

Recent studies suggest that heterozygous female Fabry disease (FD) patients develop peripheral neuropathy. We used skin biopsy to define somatic and autonomic peripheral nerve characteristics in 21 females with FD who were mainly asymptomatic and had normal renal function. Somatic epidermal and dermal autonomic nerve fiber reductions were found, prevalently in the leg, and no differences were found between symptomatic and asymptomatic individuals. Our findings suggest that females with FD, although asymptomatic, may have somatic and autonomic small fiber neuropathy.

Skin biopsy has gained widespread use for the diagnosis of somatic small-fiber neuropathy, but it also provides information on sympathetic fiber morphology. We aimed to ascertain the diagnostic accuracy of skin biopsy in disclosing sympathetic nerve abnormalities in patients with autonomic neuropathy. Peripheral nerve fiber autonomic involvement was confirmed by routine autonomic laboratory test abnormalities. Punch skin biopsies were taken from the thigh and lower leg of 28 patients with various types of autonomic neuropathy for quantitative evaluation of skin autonomic innervation. Results were compared with scores obtained from 32 age-matched healthy controls and 25 patients with somatic neuropathy. The autonomic cutoff score was calculated using the receiver operating characteristic curve analysis. Skin biopsy disclosed a significant autonomic innervation decrease in autonomic neuropathy patients versus controls and somatic neuropathy patients. Autonomic innervation density was abnormal in 96% of patients in the lower leg and in 79% of patients in the thigh. The abnormal findings disclosed by routine autonomic tests ranged from 48% to 82%. These data indicate the high sensitivity and specificity of skin biopsy in detecting sympathetic abnormalities; this method should be useful for the diagnosis of autonomic neuropathy, together with currently available routine autonomic testing.