Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.

Background: Persistent postural-perceptual dizziness (PPPD) is a chronic functional neuro-otologic disorder marked by persistent dizziness, unsteadiness, and visual dependence. Its electrophysiological mechanisms remain unclear. This study examined resting-state EEG spectral power and functional connectivity in PPPD and their associations with postural stability and clinical symptoms. Methods: Forty patients with PPPD and 40 age- and sex-matched healthy controls were studied with an eyes-closed resting state EEG recording. Static postural stability was measured with Pro-Kin system. Spectral power was calculated for delta, theta, alpha, beta, and gamma bands. Functional connectivity was assessed using weighted phase lag index. Results: Static posturography showed impaired postural stability in patients with PPPD compared with healthy controls，especially under eyes-closed conditions. Spectral power analysis showed increased theta-band relative power over the frontal and right parieto-occipital regions. Connectivity analysis showed increased prefrontal–temporal and decreased temporal–occipital connectivity in the theta band, increased fronto-parieto-occipital and decreased parietal -temporal connectivity in the alpha band, and decreased cerebellar and temporal, central connectivity in the gamma band. Frontal spectral power was positively correlated with HAMA scores in the PPPD group. Conclusions: PPPD was associated with frequency-specific alterations in resting-state cortical oscillations and functional connectivity involving cognitive-affective, visual, and sensorimotor networks. Resting-state EEG may help characterize network-level abnormalities in PPPD.

TAR DNA-binding protein (TDP-43) is a multifunctional protein that binds DNA and RNA within the nucleus. In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), TDP-43 is mislocalized to the cytoplasm, forming inclusions. Current TDP-43 transgenic mouse models generally fail to exhibit significant cytoplasmic accumulation and loss of nuclear TDP-43, which hampers the investigation of cytoplasmic TDP-43 pathology. We previously discovered that primate-specific caspase-4 (CASP4) can cleave TDP-43, producing truncated fragments that are mislocalized to the cytoplasm. Here we show that a transgenic mouse model that expresses human CASP4 and recapitulates the cytoplasmic mislocalization of endogenous TDP-43 and motor dysfunction in an age-dependent manner. Moreover, CASP4 mice exhibited gene expression changes and neuropathology similar to patients with sporadic ALS. Inhibition of CASP4 by its antisense oligonucleotide ameliorated TDP-43 pathology and subsequent neurotoxicity in CASP4 mice. Thus, CASP4 mice present a valuable animal model for exploring endogenous TDP-43-mediated pathogenesis and therapeutics.

Objective Summarize the pathological and clinical characteristics of muscle disorder cases with nemaline-shaped structure,to improve the diagnosis and differential diagnosis of the disease.Methods and Results A total of 22 cases with nemaline-shaped structure underwent muscle biopsy were selected from May 2021 to May 2024.As to final diagnosis,there were 3 cases(13.64%)of congenital nemaline myopathy,12 cases(54.54%)of amyotrophic lateral sclerosis(ALS),2 cases(9.09%)of limb-girdle muscular dystrophy(LGMD),one case(1.45%)of desminopathy,one case(1.45%)of charcot-marie-tooth disease(CMT),one case(1.45%)of non-specific myositis,one case(1.45%)of frontotemporal dementia(FTO)caused by GRN,and one case(1.45%)of hypothyroid myopathy.The muscle biopsy of all 22 cases revealed various granular,rod-shape or flaky purplish-red depositions in the sarcoplasm as nemaline-shaped structure in modified Gomori trichrome(MGT)staining and positive immunohistochemistry staining of myotilin and/or α-actin.Under electron microscopy,some cases had the ultrastructural characteristics of nemaline body or nemaline-shaped structure.Muscle biopsy that confirmed congenital nemaline myopathy had more typical nemaline,besides myotilin and α-actin were both immunopositively.Besides nemaline myopathy,the pathological changes of other muscle diseases also had specific characteristics,such as neurogenic atrophy was often present in ALS;abnormal aggregation of desmin protein was often present in desminopathy;circular atrophy,large amount internalized nuclei and interstitial fibrosis were often present in LGMD;in addition,obvious inflammatory cell infiltration was common in non-specific myositis.Therefore,the diagnosis of nemaline myopathy could not be relied on HE staining and electron microscopy alone.Apart from 14 patients that diagnosed with ALS,non-specific myositis and hypothyroid myopathy,NEB gene mutation(3 cases),CAPN3 gene mutation(one case),DYSF gene mutation(one case),SH3TC2 gene mutation(one case),GRN gene mutation(one case),and DES gene heterozygous mutation(one case)were detected by whole exome sequencing(WES)in the remaining 8 cases.Conclusions Nemaline-shaped structure can appear in a variety of muscular disorder and neurodegenerative diseases.Combined with clinicopathological characteristics are contribute to recognize nemaline myopathy,and the genetic test by WES is strong evidence for nemaline myopathy.

Lobar intracerebral hemorrhage (ICH) is associated with a high risk of recurrence, particularly in elderly patients, where cerebral amyloid angiopathy (CAA) is often the primary cause. Diagnostic markers of CAA-related ICH, including subarachnoid hemorrhage (SAH) and finger-like projection (FLP), have recently been developed. Here, we aimed to explore the associations between SAH, FLP and the risk of ICH recurrence in lobar ICH patients. We analyzed data from consecutive lobar ICH patients using the method of cohort study. We divided them into 4 groups on the basis of the presence or absence of SAH and FLP on CT imaging. The Cox regression model and competing risk model were used to analyze the associations of SAH and FLP with the risk of ICH recurrence at 1 year. In total, 353 patients with lobar ICH (median age 74 [62, 81] years, 57.2

Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by the degeneration of spinal cord and brain neurons. Proteomics combined with Mendelian randomization (MR) is an effective method for finding disease treatment targets. Methods: We aimed to seek new therapeutic targets for ALS. A large-scale GWAS on proteomics (4907 circulatory protein) with 35,559 individuals was included as the exposure data; a GWAS with 138,086 ALS patients was used as the outcome data; we found that a high level of sex hormone-binding globulin (SHBG) is a risk factor by MR analysis. Colocalization analyses were used to validate the causality between SHBG and ALS further. Functional enrichment found a high level of SHBG was associated with a low level of bioavailable testosterone. Two-sample MR confirmed the association of SHBG (400,210 samples), bioavailable testosterone (367,289 samples), and ALS. Results: A high level of SHBG, and a low level of bioavailable testosterone are risk factors for ALS. Conclusions: A low level of bioavailable testosterone is a risk factor for ALS. Although our study is relatively limited and cannot fully confirm that testosterone supplementation has a therapeutic effect on ALS, it offers a promising direction for ALS therapy.

Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons. Early bilateral limb involvement significantly affects patients' daily lives and may lead them to be confined to bed. However, the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear. To address this issue, we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022. A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis. We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients. Multiple factor analyses revealed that higher upper motor neuron scores(hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.01–1.09, P = 0.018), onset in the left limb(HR = 0.72, 95% CI = 0.58–0.89, P = 0.002), and a horizontal pattern of progression(HR = 0.46, 95% CI = 0.37–0.58, P < 0.001) were risk factors for a shorter interval until bilateral limb involvement. The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients. These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.

Pathological proteins in amyotrophic lateral sclerosis (ALS), such as superoxide dismutase 1, TAR DNA-binding protein 43, and fused in sarcoma, exhibit a prion-like pattern. All these proteins have a low-complexity domain and seeding activity in cells. In this review, we summarize the studies on the prion-like effect of these proteins and list six prion-like protein targeting strategies that we believe have potential for ALS therapy, including antisense oligonucleotides, antibody-based technology, peptide, protein chaperone, autophagy enhancement, and heteromultivalent compounds. Considering the pathological complexity and heterogeneity of ALS, we believe that the final solution to ALS therapy is most likely to be an individualized cocktail therapy, including clearance of toxicity, blockage of pathological progress, and protection of neurons.

BackgroundUpper motor neuron-dominant ALS (UMND ALS) is recognized to have early onset and good prognosis, but may have a rapid decline in motor function due to gait instability in the early stage. We investigated changes in lower extremity function in UMND ALS, particularly UMND ALS patients accompanied with postural instability or repeated falls (UMND ALS plus).ResultsAmong the 2,353 ALS patients reviewed, 211 (9.0%) had UMND ALS. UMND ALS had a longer diagnosis delay and restricted symptoms. Although UMND ALS patients had better lower extremity function and strength than matched classic ALS patients on first evaluation, there was no difference in the time of needing assistance or not being able to walk after disease onset. In contrast, UMND ALS plus has severe UMN symptoms and a more rapid decline in motor function. The lower extremity function was no better than that in the matched classic ALS. The prognosis of UMND ALS and UMND ALS plus were significantly better than those of overall ALS.ConclusionUMND ALS has restricted symptoms but has a rapid decline in lower extremity function in the early stage of the disease. The motor function decline of UMND ALS plus is as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation.

ObjectivesThe aims of this study were to investigate whether CSF sTREM2 may be a potential marker of disease monitoring for amyotrophic lateral sclerosis (ALS).MethodsWe investigated whether CSF sTREM2 levels are altered in ALS patients and are correlated with upper motor neuron (UMN) burden and disease progression.ResultsCSF sTREM2 was greater in the ALS patients than in the controls (p = 0.002). Elevated CSF sTREM2 was associated with the UMN score (r = 0.38, p = 0.009), ΔFS (r = 0.30, p = 0.04) and serum NFL (lg) (r = 0.35, p = 0.015). As the motor band sign (MBS) score increased, the CSF sTREM2 level increased (p-trend = 0.014). Furthermore, the correlations became stronger (UMN score (r = 0.50, p = 0.01) ΔFRS (r = 0.52, p = 0.008) and serum NFL (lg) (r = 0.55, p = 0.004) when estimated only among patients with a disease duration >12 months.ConclusionWe found that CSF sTREM2 is elevated in ALS patients and may be a novel marker, probably reflecting upper motor unit severity and prognosis.

Cytoplasmic aggregation of the transactive response DNA-binding protein-43 (TDP-43) in neurons, a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, has been found in some Alzheimer’s patients. Protein disulfide isomerase (PDI) functions as both an enzyme and a molecular chaperone to correct or eliminate misfolded proteins under pathological conditions. Here, we report that TDP-43 is mislocalized to the cytoplasm and colocalizes with PDI in the brain and spinal cord of two ALS patients and the brain of six Alzheimer’s patients compared to controls. TDP-43 selectively recruits wild-type PDI into its phase-separated condensate, which in turn slows down in vitro liquid–liquid phase separation of TDP-43, shifting the equilibrium phase boundary to higher protein concentrations. Importantly, wild-type PDI decreases oxidative stress-induced interaction between TDP-43 and G3BP1 to disassemble stress granules containing TDP-43 in neuronal cells. Wild-type PDI blocks the oxidative stress-induced mislocalization of TDP-43 to the cytoplasm, and blocks subsequent pathological phosphorylation and aggregation of TDP-43. We demonstrate that under pathological stress conditions, wild-type PDI disassembles stress granules, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppresses mitochondrial damage and TDP-43 toxicity. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS patients and some Alzheimer’s patients. Teaser PDI disassembles SGs, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppress TDP-43 toxicity in ALS. ### Competing Interest Statement The authors have declared no competing interest.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by neuronal degeneration of the spinal cord and brain and believed to be related to the immune system. In this study, our aim is to use Mendelian randomization (MR) to search for immune markers related to ALS. A total of 731 immune cell traits were included in this study. MR analysis was used to identify the causality between 731 immune cell traits (with 3,757 Europeans) and ALS (with 138,086 Europeans). Colocalization analysis was used to verify the found causality, protein-protein interaction prediction was used to look for the interacting proteins that are known to be involved in ALS. We found low expression levels of CD3 on central memory CD8+ T cell is risk factor for ALS (OR = 0.90, 95% CI: 0.86-0.95, P = 0.0000303). CD3 can interact with three ALS-related proteins: VCP, HLA-DRA and HLA-DRB5, which are associated with adaptive immune response. Our study reported for the first time that low-level CD3 is a risk factor for ALS and the possible mechanism, which could provide a potential strategy for ALS diagnosis and therapy.

Background: Hereditary spastic paraplegia (HSP) constitutes a group of clinically and genetically rare neurodegenerative diseases characterized by progressive corticospinal tract degeneration. The phenotypes and genotypes of HSP are still expanding. In this study, we aimed to analyse the differential diagnosis, clinical features, and genetic distributions of a Chinese HSP patients in a 14-year cohort and to improve our understanding of the disease.Methods: The clinical data of patients with a primary diagnosis of HSP at the initial visit to the Department of the Neurology, Peking University Third Hospital, from 2008 to 2022 were retrospectively collected. Next-generation sequencing gene panels (NGS) combined with a multiplex ligation-amplification assay (MLPA) were conducted. Epidemiological and clinical features and candidate variants in HSP-related genes were analyzed and summarized.Results: 54 cases (probands from 25 different pedigrees and 29 sporadic cases) from 95 patients with a primary diagnosis of HSP were finally confirmed to have a clinical diagnosis of HSP based on clinical criteria, including their clinical findings, family history and long-term follow-up. Earlier disease onset was associated with longer diagnostic delay and longer disease duration and was associated with a lower risk of loss of ability to walk independently. In addition, 20 candidate variants in reported HSP-related genes were identified in these clinically diagnosed HSP patients, including variants in SPAST, ALT1, WASHC5, SPG11, B4GALNT1, and REEP1. The genetic diagnostic rate in these 54 patients was 35.18%.Conclusion: Hereditary spastic paraplegia has high clinical and genetic heterogeneity and is prone to misdiagnosis. Long-term follow-up and genetic testing can partially assist in diagnosing HSP. Our study summarized the clinical features of Chinese HSP patients in a 14-year cohort, expanded the genotype spectrum, and improved our understanding of the disease.

Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional "belly-tendon" montage does not accurately and completely reflect the action potential of the ulnar nerve dominating the abductor digiti minimi muscle due to the effects of far-field potentials of intrinsic hand muscles. A new method of ulnar nerve compound muscle action potential measurement was developed in 2020, which adjusts the E2 electrode from the distal tendon of the abductor digitorum to the middle of the back of the proximal wrist. This new method may reduce the influence of the reference electrode and better reflect the actual ulnar nerve compound muscle action potential. In this prospective cross-sectional study, we included 64 patients with amyotrophic lateral sclerosis and 64 age- and sex-matched controls who underwent conventional and novel ulnar nerve compound muscle action potential measurement between April 2020 and May 2021 in Peking University Third Hospital. The compound muscle action potential waveforms recorded by the new montage were unimodal and more uniform than those recorded by traditional montage. In the controls, no significant difference in the compound muscle action potential waveforms was found between the traditional montage and new montage recordings. In amyotrophic lateral sclerosis patients presenting with abductor digiti minimi spontaneous activity and muscular atrophy, the amplitude of compound muscle action potential-pE2 was significantly lower than that of compound muscle action potential-dE2 (P < 0.01). Using the new method, damaged axons were more likely to exhibit more severe amplitude decreases than those measured with the traditional method, in particular for patients in early stage amyotrophic lateral sclerosis. In addition, the decline in compound muscle action potential amplitude measured by the new method was correlated with a decrease in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores. These findings suggest that the new ulnar nerve compound muscle action potential measurement montage reduces the effects of the reference electrode through altering the E2 electrode position, and that this method is more suitable for monitoring disease progression than the traditional montage. This method may be useful as a biomarker for longitudinal follow-up and clinical trials in amyotrophic lateral sclerosis.

Background and Objective In amyotrophic lateral sclerosis (ALS), progressive weakness significantly limits the ability to exercise. However, measurements of the impaired exercise function and their practical value to assess disease progression in ALS are scarce. Cardiopulmonary exercise testing (CPET) is a non-invasive accurate method used to comprehensively quantify exercise physiology in a variety of diseases. This study aimed to evaluate the clinical value of CPET and to explore its association with disease severity and prognosis prediction in ALS. Methods A total of 319 participants were enrolled in this 3-year prospective study. After strict quality control, 109 patients with ALS and 150 age- and sex-matched healthy controls were included with comprehensive clinical assessment and follow-ups. The incremental ramp protocol for symptom-limited CPET was applied in both groups. The exercise physiology during peak effort exercise was systematically measured, including the overall aerobic capacity of exercise (VO2 peak) and the respective capacity of the exercise-involved organs [cardiac response (heart rate peak—HR peak), ventilatory efficiency (VE/VCO2 slope), breathing economy (VE/VO2 peak), and other relevant parameters]. Disease severity and progression were evaluated using recognized scales. Survival was monitored with regular follow-ups every 6 months. Results Decreased exercise capacity (VO2 peak < 16 ml/kg/min) occurred more frequently in patients with ALS than in controls (44.95% vs. 9.33%, p < 0.01). In patients with ALS, the average VO2 peak (16.16 ± 5.43 ml/kg/min) and HR peak [135 (112–153) bpm] were significantly lower (p < 0.01) than in controls [22.26 ± 7.09 ml/kg/min; 148 (135–164) bpm], but the VE/VCO2 slope was significantly higher [28.05 (25.03–32.16) vs. 26.72 (24.37–29.58); p = 0.03]. In patients with ALS, the VO2 peak and HR peak were significantly correlated with disease severity and progression scores (p < 0.05). Survival analyses revealed the VO2 peak and HR peak as protective indicators while the VE/VO2 peak as a detrimental indicator for the prognostic prediction in ALS (HR = 0.839, p = 0.001; HR = 0.967, p < 0.001; HR = 1.137, p = 0.028, respectively). Conclusion Our prospective study quantified the significantly decreased exercise capacity in ALS through non-invasive CPET. The impaired VO2 peak and HR peak closely correlated with disease severity and independently predicted a worse prognosis. Our findings identified the clinical value of CPET as an objective indicator of disease progression in ALS.

Background GNE myopathy is a rare distal myopathy caused by mutations of the GNE gene. A few cases of GNE myopathy accompanied by neurogenic features of electrophysiology mimicking hereditary motor neuropathy were reported recently. We confirmed this feature and described the clinical phenotype and mutations of GNE myopathy in these rare cases. Results The absence of lower limb tendon reflexes, decreased compound muscle action potentials in lower leg motor nerves, and neurogenic pattern of electromyography suggested neuropathy in four patients. However, muscle pathology revealed a predominantly myogenic pattern. The follow-up electroneurography results implied that the compound motor action potential amplitudes deteriorated over time. Next-generation sequencing identified three novel variants of the GNE gene, c.2054T > C (p.Val685Ala), c.424G > A (p.Gly142Arg) and c.944T > C (p.Phe315Ser), as well as two hotspot mutations, c.115C > T(p.Arg39*) and c.620A > T(p.Asp207Val), in these patients. These novel mutations cosegregated with disease in the family. Conclusions These rare cases supported the existence of neurogenic features of electrophysiology different from the typical myopathic pattern of GNE myopathy.

ERBB4 is related to amyotrophic lateral sclerosis (ALS) in patients with a family history and is thought to cause ALS-19. We screened 448 ALS patients, including 364 sporadic ALS (sALS) and 84 familial ALS (fALS) patients with ERBB4 variants, in a Chinese cohort. In total, 12 missense variants were identified in this study. Of these, 3 (p.Arg106His, p.Gln164Pro, and p.Val212Leu) were absent from the in-house healthy control cohort and population databases and predicted to be likely pathogenic. Genetic burden analysis did not reveal an increase in damaging variants of the ERBB4 gene. We considered that most of the missense variants in ERBB4 were not pathogenic, but certain variants, such as p.Arg106His, p.Gln164Pro, and p.Val212Leu, were likely pathogenic. The phenotype of these three patients carrying ERBB4 variants revealed the typical clinical manifestations of ALS without cognitive dysfunction. We concluded that ERBB4 likely pathogenic variants account for ~0.67% of ALS patients in China. It is necessary to interpret the relationship between the disease and variants carefully for ALS patients with ERBB4 gene variants.

Introduction: Alterations in the visual pathway involving the retina have been reported in amyotrophic lateral sclerosis (ALS) but they lack consistency and subgroup analysis. We aimed to assess the retinal nerve fiber layer (RNFL) and retinal ganglion cells (RGCs) alterations in different stages of ALS patients and their association with ALS progression parameters. Methods: The study population consisted of 70 clinically diagnosed ALS patients and 55 age, sex matched controls. All of them underwent ophthalmic assessments and optical coherence tomography imaging. Four quadrants of the peripapillary RNFL and ganglion cell/inner plexiform complex (GCIP) were observed and automatically measured. Early-stage distal motor neuron axon dysfunction in ALS was detected by compound muscle action potential (CMAP) of the distal limbs within 12 months. The ALS disease parameters included the ALSFRS-R score and the disease progression rate (ΔFS). Results: Generally compared with controls, the nasal (p = 0.016) quadrant of the RNFL was thicker in ALS patients. When controlling for age and ΔFS, the RNFL(r = 0.37, p = 0.034) and GCIP(r = 0.40, p = 0.021) were significantly thickened as disease progressed within 12 months, while the RNFL declined with time after one year (r = −0.41, p = 0.037). ALS patients was subclassified into thickened RNFL (T-RNFL, >95th percentile of normal), impaired RNFL (I-RNFL, <5th percentile of normal) and normal RNFL. There were significant differences in the GCIP among the three groups (p < 0.001). In the T-RNFL group (n = 18), the RNFL was negatively correlated with the abductor pollicis brevis-CMAP amplitude within 12 months (r = −0.56, p = 0.01). Patients within 12 months in this group progressed faster than others (p = 0.039). In the normal RNFL group (n = 22), 13 patients were diagnosed beyond 12 months, whose ΔFS was remarkably lower (p = 0.007). In I-RNFL group (n = 30), the early stage patients (<12 months) had significant higher ΔFS (p = 0.006). One patient was with SOD1 pathogenic variant (p.A5V). Conclusion: Alterations of retinal nerve were not consistent in ALS patients with diverse phenotypes and progression rates. Generally speaking, the RNFL thickened during the first year and then gradually declined, which is related to but preceding the thickness change of the RGCs. Patients with a significant RNFL thinning in the early stage may have a faster progression rate. The inverse U-shaped curve transformation might be in accordance with early-stage motor neuron axonopathy.

It is generally believed that eye movements are completely spared in amyotrophic lateral sclerosis (ALS). Although a series of eye movement abnormalities has been recognized in recent years, the findings are highly controversial, and bulbar disabilities should be considered in relation to eye movement abnormalities. The present study aimed to determine whether eye movement abnormalities are present in ALS and, if so, to investigate their characteristics and their association with bulbar disability in ALS patients. A total of 60 patients and 30 controls were recruited and underwent the standardized evaluations of the oculomotor system using videonystagmography. Square-wave jerks (OR: 16.20, 95% CI: 3.50–74.95, p < 0.001) and abnormal cogwheeling during smooth pursuit (OR: 14.04, 95% CI: 3.00–65.75, p = 0.001) were more frequently observed in ALS patients than in the control subjects. In subgroup analyses, square-wave jerks (OR: 26.51, 95% CI: 2.83–248.05, p = 0.004) and abnormal cogwheeling during smooth pursuit (OR: 6.56, 95% CI: 1.19–36.16, p = 0.031) were found to be more common in ALS patients with bulbar involvement (n = 44) than in those without bulbar involvement (n = 16). There were no significant differences in the investigated eye movement parameters between bulbar-onset (n = 12) and spinal-onset patients (n = 48). ALS patients showed a range of eye movement abnormalities, affecting mainly the ocular fixation and smooth pursuit systems. Our pioneering study indicates that the region of involvement could better indicate the pathophysiological essence of the abnormalities than the type of onset pattern in ALS. Eye movement abnormalities may be potential clinical markers for objectively evaluating upper brainstem or supratentorial cerebral lesion neurodegeneration in ALS.

Objectives The aims of this study were to investigate whether serum neurofilament light chain (NfL) levels were correlated with the severity of the axonal degeneration of lower motor neurons (LMNs) in the early symptomatic phase of amyotrophic lateral sclerosis (ALS). Methods In this prospective study, the serum samples used for NfL measurement were obtained from 103 sporadic ALS outpatients within 2 years of disease duration. The severity of axonal degeneration was assessed by assessing the decrease in the compound muscle action potentials (CMAPs) within a 1-month interval from serum sampling. Results The NfL levels showed a significant positive correlation with the relative score as a proxy for the axonal damage of LMNs in patients with ALS (coefficient: 0.264, p = 0.009). Furthermore, this correlation became stronger (coefficient: 0.582, p = 0.037) when estimated only among patients with disease subtypes that involve only LMNs, that is, patients with flail arm or leg syndrome (FAS or FLS). The levels of NfL increased with the severity of axonal damage of LMNs (F = 6.694, P = 0.0001). Conclusions Serum NfL levels mirrored the severity of the axonal degeneration of LMNs, particularly in patients with signs of predominant LMN involvement. These results may have a profound effect on the selection of patients and the monitoring of treatment efficacy in future disease-modifying clinical trials.