CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.

Maitake Beta-Glucan Enhances the Therapeutic Effect of Trastuzumab via Antibody-Dependent Cellular Cytotoxicity and Complement-Dependent Cytotoxicity.

Trastuzumab, an anti-HER2 monoclonal antibody, is the mainstay treatment for of HER2-positive breast cancer. However, trastuzumab resistance is often observed during treatment. Therefore, new therapeutic strategies are needed to enhance the clinical benefits of trastuzumab. Maitake ß-glucan MD-Fraction, isolated from Grifola frondosa, inhibits tumor growth by enhancing immune responses. In this study, we examined the effect of MD-Fraction on trastuzumab treatment of HER2-positive breast cancer. MD-Fraction did not directly inhibit the survival of HER2-positive breast cancer cells, alone or in the presence of trastuzumab in vitro. In HER2-positive xenograft models, the combination of MD-Fraction and trastuzumab was more effective than trastuzumab alone. Peripheral blood lymphocytes and splenic natural killer cells isolated from BALB/c nu/nu mice treated with MD-Fraction showed enhanced trastuzumab-induced antibody-dependent cellular cytotoxicity (ADCC) ex vivo. MD-Fraction-treated macrophages and neutrophils did not show enhanced trastuzumab cytotoxicity in the presence of heat-inactivated serum, but they showed enhanced cytotoxicity in the presence of native serum. These results suggest that MD-Fraction-treated macrophages and neutrophils enhance trastuzumab-induced complement-dependent cellular cytotoxicity (CDCC). Treatment of HER2-positive breast cancer cells with MD-Fraction in the presence of trastuzumab and native serum increased C3a release and tumor cell lysis in a dose-dependent manner, indicating that MD-Fraction enhanced trastuzumab-induced complement-dependent cytotoxicity (CDC) by activating the complement system. This study demonstrates that the combination of trastuzumab and MD-Fraction exerts a greater antitumor effect than trastuzumab alone by enhancing ADCC, CDCC, and CDC in HER2-positive breast cancer.

[Guillain-Barré syndrome associated with Epstein-Barr virus and cytomegalovirus reactivation during treatment for chronic graft-versus-host disease after allogeneic bone marrow transplantation].

Guillain-Barré syndrome (GBS) is a rare neurological complication of allogeneic hematopoietic stem cell transplantation (HSCT). The pathogenesis of post-HSCT GBS is unclear. Here, we report a case of GBS coincident with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation that occurred after HSCT in a patient with myelodysplastic syndrome. A 61-year-old man was admitted to our hospital because of gait disturbance due to lower limb muscle weakness, which arose during treatment for chronic graft-versus-host disease (GVHD) five months after allogeneic HSCT. He was diagnosed with GBS based on his clinical course, cerebrospinal fluid analysis, and a nerve conduction study. At that time, he exhibited EBV and CMV reactivation. GBS improved after intravenous injection of immunoglobulins. Our case suggests that reactivation of EBV and CMV during treatment for chronic GVHD may induce GBS, and that rapidly progressive muscular weakness coincident with EBV or CMV reactivation can be a diagnostic sign of GBS after allogeneic HSCT.

Structural and thermodynamical insights into the binding and inhibition of FIH-1 by the N-terminal disordered region of Mint3.

Mint3 is known to enhance aerobic ATP production, known as the Warburg effect, by binding to FIH-1. Since this effect is considered to be beneficial for cancer cells, the interaction is a promising target for cancer therapy. However, previous research has suggested that the interacting region of Mint3 with FIH-1 is intrinsically disordered, which makes investigation of this interaction challenging. Therefore, we adopted thermodynamic and structural studies in solution to clarify the structural and thermodynamical changes of Mint3 binding to FIH-1. First, using a combination of circular dichroism, nuclear magnetic resonance, and hydrogen/deuterium exchange-mass spectrometry (HDX-MS), we confirmed that the N-terminal half, which is the interacting part of Mint3, is mostly disordered. Next, we revealed a large enthalpy and entropy change in the interaction of Mint3 using isothermal titration calorimetry (ITC). The profile is consistent with the model that the flexibility of disordered Mint3 is drastically reduced upon binding to FIH-1. Moreover, we performed a series of ITC experiments with several types of truncated Mint3s, an effective approach since the interacting part of Mint3 is disordered, and identified amino acids 78 to 88 as a novel core site for binding to FIH-1. The truncation study of Mint3 also revealed the thermodynamic contribution of each part of Mint3 to the interaction with FIH-1, where the core sites contribute to the affinity (ΔG), while other sites only affect enthalpy (ΔH), by forming noncovalent bonds. This insight can serve as a foothold for further investigation of intrinsically disordered regions (IDRs) and drug development for cancer therapy.

Comparison of two families with and without ataxia harboring novel variants in PRKCG.

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant SCA caused by variants of the PRKCG encoding protein kinase C gamma (PKCγ). Although the toxic gain-of-function mechanism is the main cause of SCA14, its molecular pathophysiology remains unclear. To elucidate the molecular pathogenesis of SCA14, we analyzed two families with the variants in PRKCG. Clinical symptoms and neurological findings of two Japanese families were evaluated by neurologists. Exome sequencing was performed using the BGI platform. GFP-tagged PRKCGs harboring the identified variants were transfected into the HeLa cells, and aggregation of PKCγ was analyzed using confocal laser microscopy. Solubility of PKCγ was evaluated by assessing the proportion of insoluble fraction present in1% Triton-X. Patients in family 1 presented with only cerebellar atrophy without ataxia; however, patients in family 2 exhibited cerebellar ataxia, dystonia, and more severe cerebellar atrophy than those in family 1. Exome sequencing identified two novel missense variants of PRKCG:c.171 G > C,p.W57C (family 1), and c.400 T > C,p.C134R (family 2). Both the mutant PKCγ aggregated in the cytoplasm. Although the solubility of PKCγ of the C134R variant was lower than that of the wild-type, PKCγ of W57C retained its solubility. In conclusion, we identified two novel variants of PRKCG. The difference in severity between the two families may be due to the difference in solubility changes observed between the two variants. Decreased solubility of the PKCγ may play an important role in the pathogenesis of SCA14.

Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan.

Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.

Autoimmune polyglandular syndrome type 2 and autoimmune hepatitis with thymoma-associated myasthenia gravis: case report.

BACKGROUND: Autoimmune polyglandular syndrome type 2 (APS-2) is a rare and complex clinical entity, and little is known about its etiology and progression. CASE PRESENTATION: A 52-year-old woman with autoimmune hepatitis (AIH) and bronchial asthma was diagnosed with APS-2; autoimmune Addison's disease (AD), and Hashimoto's thyroiditis (HT), and she underwent prednisolone (PSL) treatment. Five months later, she presented ptosis and was diagnosed with thymoma-associated myasthenia gravis (MG). Thymectomy and PSL treatment with immuno-suppressants appeared to ameliorate MG, AD, AIH, HT, and bronchial asthma. HLA typing analysis revealed that the patient had susceptible HLA alleles to MG, AIH, and HT in a Japanese population. CONCLUSIONS: This case suggests common endocrinological and autoimmune aspects of APS-2 and AIH with thymoma-associated MG, which are considered to be extremely rare complications.

Expression of Fgf23 in activated dendritic cells and macrophages in response to immunological stimuli in mice.

Fibroblast growth factors (Fgfs) are polypeptide growth factors with diverse biological activities. While several studies have revealed that Fgf23 plays important roles in the regulation of phosphate and vitamin D metabolism, the additional physiological roles of Fgf23 remain unclear. Although it is believed that osteoblasts/osteocytes are the main sources of Fgf23, we previously found that Fgf23 mRNA is also expressed in the mouse thymus, suggesting that it might be involved in the immune system. In this study we examined the potential roles of Fgf23 in immunological responses. Mouse serum Fgf23 levels were significantly increased following inoculation with Escherichia coli or Staphylococcus aureus or intraperitoneal injection of lipopolysaccharide. We also identified activated dendritic cells and macrophages that potentially contributed to increased serum Fgf23 levels. Nuclear factor-kappa B (NF-κB) signaling was essential for the induction of Fgf23 expression in dendritic cells in response to immunological stimuli. Moreover, we examined the effects of recombinant Fgf23 protein on immune cells in vitro. Fgfr1c, a potential receptor for Fgf23, was abundantly expressed in macrophages, suggesting that Fgf23 might be involved in signal transduction in these cells. Our data suggest that Fgf23 potentially increases the number in macrophages and induces expression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine. Collectively, these data suggest that Fgf23 might be intimately involved in inflammatory processes.

Sialyltransferase ST3Gal IV deletion protects against temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) often becomes refractory, and patients with TLE show a high incidence of psychiatric symptoms, including anxiety and depression. Therefore, it is necessary to identify molecules that were previously unknown to contribute to epilepsy and its associated disorders. We previously found that the sialyltransferase ST3Gal IV is up-regulated within the neural circuits through which amygdala-kindling stimulation propagates epileptic seizures. In contrast, this study demonstrated that kindling stimulation failed to evoke epileptic seizures in ST3Gal IV-deficient mice. Furthermore, approximately 80% of these mice failed to show tonic-clonic seizures with stimulation, whereas all littermate wild-type mice showed tonic-clonic seizures. This indicates that the loss of ST3Gal IV does not cause TLE in mice. Meanwhile, ST3Gal IV-deficient mice exhibited decreased acclimation in the open field test, increased immobility in the forced swim test, enhanced freezing during delay auditory fear conditioning, and sleep disturbances. Thus, the loss of ST3Gal IV modulates anxiety-related behaviors. These findings indicate that ST3Gal IV is a key molecule in the mechanisms underlying anxiety - a side effect of TLE - and may therefore also be an effective target for treating epilepsy, acting through the same circuits.

Contrast enrichment of spinal cord MR imaging using a ratio of T1-weighted and T2-weighted signals.

PURPOSE: We aimed to assess if the T1-weighted (T1w)/T2-weighted (T2w) signal ratio could be used to improve image contrast in MR spinal cord imaging. MATERIALS AND METHODS: T1w and T2w cervical spinal cord MR images were acquired from 23 normal subjects using 3 Tesla (T) MR scanner. In addition, a multiple sclerosis patient, and a cervical spondylotic myelopathy patient were evaluated. White matter (WM) and gray matter (GM) signal intensities were measured for each image (T1w, T2w, and T1w/T2w) for seven cervical segments in each subject to calculate the contrast. Age-related changes in signal intensity were assessed at each location (lateral column, anterior column, dorsal column, and GM) for each image. Additionally, the imaging results of two subjects with spinal diseases and the controls were numerically compared. RESULTS: The contrast between the WM and GM in the T1w/T2w ratio image was approximately twice as much as that in the T1w and T2w images (mean ± SD = 1.8 ± 0.4). The signal intensity ratio was related to age. For both clinical patients, the signal intensities were significantly lower in the lesion areas in the ratio images. CONCLUSION: The T1w/T2w ratio images demonstrated increased image contrast compared with T1w and T2w images alone and, reduced inter-individual signal intensity differences.

Persistence of Kii amyotrophic lateral sclerosis after the 2000s and its characteristic aging-related tau astrogliopathy.

Kii amyotrophic lateral sclerosis (ALS) is a unique disease that occurs in the southern portion of the Kii Peninsula and exhibits a dual pathology of TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy and tauopathy. The incidence of ALS in this region was very high in the 1960s, briefly decreased through the 1980s, but began increasing again after 2000 with a change of high-concentration geographic foci. It is unclear, however, whether the unique pathological features have changed along with the incidence changes. This study analyzed postmortem specimens from neuropathologically confirmed Kii ALS cases from the 1970s (n = 4) and those after 1999 (n = 12) from the southern Kii Peninsula or outside of the area. Our results confirm the continued occurrence of Kii ALS after 2000 in the southern Kii Peninsula and the preservation of disease-specific neuronal tau pathology, including the widespread occurrence throughout the brain and spinal cord, sparse neuropil threads, and predominance in superficial layers. Furthermore, we assessed the glial tau pathology of Kii and non-Kii ALS in accordance with the aging-related tau astrogliopathy classification method for the first time and detected a unique brainstem predominant appearance of gray matter aging-related tau astrogliopathy in Kii ALS cases, which may provide clues to pathogenetic mechanisms.

A secretory protein neudesin regulates splenic red pulp macrophages in erythrophagocytosis and iron recycling.

Neudesin, originally identified as a neurotrophic factor, has primarily been studied for its neural functions despite its widespread expression. Using 8-week-old neudesin knockout mice, we elucidated the role of neudesin in the spleen. The absence of neudesin caused mild splenomegaly, shortened lifespan of circulating erythrocytes, and abnormal recovery from phenylhydrazine-induced acute anemia. Blood cross-transfusion and splenectomy experiments revealed that the shortened lifespan of erythrocytes was attributable to splenic impairment. Further analysis revealed increased erythrophagocytosis and decreased iron stores in the splenic red pulp, which was linked to the upregulation of Fcγ receptors and iron-recycling genes in neudesin-deficient macrophages. In vitro analysis confirmed that neudesin suppressed erythrophagocytosis and expression of Fcγ receptors through ERK1/2 activation in heme-stimulated macrophages. Finally, we observed that 24-week-old neudesin knockout mice exhibited severe symptoms of anemia. Collectively, our results suggest that neudesin regulates the function of red pulp macrophages and contributes to erythrocyte and iron homeostasis.

BACH1 inhibits senescence, obesity, and short lifespan by ferroptotic FGF21 secretion.

Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation. A model cell system is constructed to induce ferroptosis by re-expressing the transcription factor BACH1, a potent ferroptosis inducer, in immortalized mouse embryonic fibroblasts (iMEFs). The transfer of the culture supernatant from ferroptotic iMEFs activates the proliferation of hepatoma cells and other fibroblasts and suppresses cellular senescence-like features. The BACH1-dependent secretion of the longevity factor FGF21 is increased in ferroptotic iMEFs. The anti-senescent effects of the culture supernatant from these iMEFs are abrogated by Fgf21 knockout. BACH1 activates the transcription of Fgf21 by promoting ferroptotic stress and increases FGF21 protein expression by suppressing its autophagic degradation through transcriptional Sqstm1 and Lamp2 repression. The BACH1-induced ferroptotic FGF21 secretion suppresses obesity in high-fat diet-fed mice and the short lifespan of progeria mice. The inhibition of these aging-related phenotypes can be physiologically significant regarding ferroptosis.

Noise Pareidolia Test in Parkinson's Disease and Atypical Parkinsonian Syndromes: A Retrospective Study.

INTRODUCTION: Pareidolias, or visual misperceptions, are a non-motor symptom of Parkinson's disease (PD) with unclear pathophysiology. The noise pareidolia test (NPT) is a tool for screening pareidolias. The usefulness of the NPT in differentiating PD from atypical parkinsonian syndromes (APS) is also unknown. METHODS: We retrospectively investigated 74 patients with PD and 18 patients with APS who took the NPT. Correlations between the number of pareidolic responses, gray matter volume, and cerebral blood flow were also examined in the patients with PD. RESULTS: The median number of pareidolic responses in patients with PD and patients with APS was 0 (interquartile range (IQR): 0-3) and 0 (IQR: 0-1), respectively, and tended to be higher in patients with PD than in those with APS (p = 0.077). It was significantly higher in patients with PD who had hallucinations (2; IQR: 0-9) (p = 0.016). The area under the receiver operating characteristic curve for the number of pareidolic responses in the NPT was 0.62 when used to differentiate PD and APS, and the optimal cutoff number of pareidolic responses was 2/3. Sensitivity and specificity were 25.7% and 100%, respectively. In the PD group, the number of pareidolic responses was correlated with age (r = 0.27; p = 0.021) and the Frontal Assessment Battery (FAB) score (r = -0.34; p = 0.0099). Magnetic resonance imaging showed no significant correlation between the number of pareidolic responses and the volume of focal gray matter. On cerebral hypoperfusion mapping, the left parietal lobe had a significant correlation with the number of pareidolic responses (r = 0.35; p = 0.027). CONCLUSION: The number of pareidolic responses in NPT was suggested to be useful as a red flag to rule out APS in differentiating PD from APS. In PD without dementia, the number of pareidolic responses was associated with reduced blood flow in the left parietal lobe.

A putative polypeptide N-acetylgalactosaminyltransferase/Williams-Beuren syndrome chromosome region 17 (WBSCR17) regulates lamellipodium formation and macropinocytosis.

We previously identified a novel polypeptide N-acetylgalactosaminyltransferase (GalNAc-T) gene, which is designated Williams-Beuren syndrome chromosome region 17 (WBSCR17) because it is located in the chromosomal flanking region of the Williams-Beuren syndrome deletion. Recent genome-scale analysis of HEK293T cells treated with a high concentration of N-acetylglucosamine (GlcNAc) demonstrated that WBSCR17 was one of the up-regulated genes possibly involved in endocytosis (Lau, K. S., Khan, S., and Dennis, J. W. (2008) Genome-scale identification of UDP-GlcNAc-dependent pathways. Proteomics 8, 3294-3302). To assess its roles, we first expressed recombinant WBSCR17 in COS7 cells and demonstrated that it was N-glycosylated and localized mainly in the Golgi apparatus, as is the case for the other GalNAc-Ts. Assay of recombinant WBSCR17 expressed in insect cells showed very low activity toward typical mucin peptide substrates. We then suppressed the expression of endogenous WBSCR17 in HEK293T cells using siRNAs and observed phenotypic changes of the knockdown cells with reduced lamellipodium formation, altered O-glycan profiles, and unusual accumulation of glycoconjugates in the late endosomes/lysosomes. Analyses of endocytic pathways revealed that macropinocytosis, but neither clathrin- nor caveolin-dependent endocytosis, was elevated in the knockdown cells. This was further supported by the findings that the overexpression of recombinant WBSCR17 stimulated lamellipodium formation, altered O-glycosylation, and inhibited macropinocytosis. WBSCR17 therefore plays important roles in lamellipodium formation and the regulation of macropinocytosis as well as lysosomes. Our study suggests that a subset of O-glycosylation produced by WBSCR17 controls dynamic membrane trafficking, probably between the cell surface and the late endosomes through macropinocytosis, in response to the nutrient concentration as exemplified by environmental GlcNAc.

GTDC2 modifies O-mannosylated α-dystroglycan in the endoplasmic reticulum to generate N-acetyl glucosamine epitopes reactive with CTD110.6 antibody.

Hypoglycosylation is a common characteristic of dystroglycanopathy, which is a group of congenital muscular dystrophies. More than ten genes have been implicated in α-dystroglycanopathies that are associated with the defect in the O-mannosylation pathway. One such gene is GTDC2, which was recently reported to encode O-mannose ß-1,4-N-acetylglucosaminyltransferase. Here we show that GTDC2 generates CTD110.6 antibody-reactive N-acetylglucosamine (GlcNAc) epitopes on the O-mannosylated α-dystroglycan (α-DG). Using the antibody, we show that mutations of GTDC2 identified in Walker-Warburg syndrome and alanine-substitution of conserved residues between GTDC2 and EGF domain O-GlcNAc transferase resulted in decreased glycosylation. Moreover, GTDC2-modified GlcNAc epitopes are localized in the endoplasmic reticulum (ER). These data suggested that GTDC2 is a novel glycosyltransferase catalyzing GlcNAcylation of O-mannosylated α-DG in the ER. CTD110.6 antibody may be useful to detect a specific form of GlcNAcylated O-mannose and to analyze defective O-glycosylation in α-dystroglycanopathies.

Maitake α-glucan promotes differentiation of monocytic myeloid-derived suppressor cells into M1 macrophages.

AIMS: Myeloid-derived suppressor cells (MDSCs) are major components of the tumor microenvironment and systemically accumulate in tumor-bearing hosts and patients with cancer, facilitating cancer progression. Maitake macromolecular α-glucan YM-2A, isolated from Grifola frondosa, inhibits tumor growth by enhancing immune responses. The present study investigated the effects of YM-2A on the immunosuppressive potential of MDSCs. MAIN METHODS: YM-2A was orally administered to CT26 tumor-bearing mice, and the number of immune cells in the spleen and tumor was measured. Splenic MDSCs isolated from the CT26 tumor-bearing mice were treated with YM-2A and co-cultured with T cells to measure their inhibitory effect on T cell proliferation. For adoptive transfer of monocytic MDSCs (M-MDSCs), YM-2A-treated M-MDSCs mixed with CT26 cells were implanted subcutaneously in the mice to measure the tumor growth rate. KEY FINDINGS: YM-2A selectively reduced the accumulation of M-MDSCs but not that of polymorphonuclear MDSCs (PMN-MDSCs) in CT26 tumor-bearing mice. In tumor tissues, YM-2A treatment induced the polarity of immunostimulatory M1-phenotype; furthermore, it increased the infiltration of dendritic, natural killer, and CD4+ and CD8+ T cells. YM-2A treatment of purified M-MDSCs from CT-26 tumor-bearing mice induced dectin-1-dependent differentiation into M1 macrophages. YM-2A-treated M-MDSCs lost their inhibitory activity against proliferation and activation of CD8+ T cells. Furthermore, adoptive transfer of M-MDSCs treated with YM-2A inhibited CT26 tumor growth. SIGNIFICANCE: YM-2A promotes the differentiation of M-MDSCs into immunostimulatory M1 macrophages, thereby enhancing the efficacy of cancer immunotherapy.

Diagnostic utility of susceptibility-weighted imaging in amyotrophic lateral sclerosis.

Susceptibility-weighted imaging (SWI) was developed as a diagnostic tool for amyotrophic lateral sclerosis (ALS). However, its sensitivity and specificity are insufficient for accurate diagnosis. Herein, we investigated a new, simple evaluation method for SWI as a diagnostic marker for ALS. We retrospectively investigated 36 patients with ALS and 19 healthy controls. The low signal intensity was semi-quantitatively evaluated on SWI using the motor cortex low intensity (MCLI) score: the sum score of the visual evaluation for the signal intensity of the bilateral primary motor cortices (orofacial, upper-limb, and lower-limb regions) from 0 (isointense) to 2 (markedly hypointense) with a total of 12 points. The mean MCLI score of two independent raters was significantly higher in ALS (median [interquartile range]; 5 [4-6]) than in controls (0 [0-1]), p < 0.0001. When the cutoff value of the MCLI score was set to 3, the area under the receiver operating characteristic curve was 0.973, and the sensitivity and specificity were 0.92 and 1.00, respectively. The MCLI score was not significantly correlated with age, disease duration, and ALS functional rating scale-revised (FRS-R), but was significantly correlated with the progression rate (∆FRS) (ρ = 0.39, p = 0.021) and upper motor neuron score (ρ = 0.51, p = 0.0014). Therefore, MCLI scoring is a useful diagnostic marker for ALS as the MCLI score was correlated with the UMN and ∆FRS scores.

Predictive value of the neutrophil-to-lymphocyte ratio for treatment response in patients diagnosed with definite or probable autoimmune encephalitis/encephalopathy.

Introduction: Autoimmune encephalitis/encephalopathy (AE) is a complex and heterogeneous disease, making it difficult to predict the prognosis. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential prognostic tool, but its usefulness remains a matter of debate. This study aimed to explore prognostic factors in cases of clinically definite or probable AE, including those with autoantibody-negative, or unknown status. Methods: Data on patients diagnosed with definite or probable AE, including those with autoantibody-negative, or unknown status, were retrospectively collected from the admission records of our department between January 2013 and December 2022. These patients were then categorized into either a good- or poor-response group, based on their short-term treatment response. Clinical characteristics, auxiliary examinations, and treatments were compared between the two groups. A multivariable logistic regression model was constructed to identify independent predictors of poor short-term treatment response by Akaike information criterion backward stepwise method. Results: A total of 31 patients were included in the final analysis, with 18 of them included in the poor-response group. In the univariable analysis, the poor-response group had a higher proportion of patients with a modified Rankin Scale (mRS) high score upon admission, female, epileptic seizures, or NLRs of 3.93 or higher than the good-response group (all p < 0.10). Furthermore, the multivariable logistic regression analysis revealed that the mRS score upon admission [OR: 5.51, 95% confidence intervals (CI): 1.29-23.50, p = 0.02], epileptic seizures (OR: 10.01, 95% CI: 1.16-86.66, p = 0.04), and NLRs of 3.93 or higher (OR: 11.37, 95% CI: 1.12-114.68, p = 0.04) were significantly associated with poor short-term treatment response. Conclusion: The NLR may play a supplementary role in predicting the short-term treatment response in patients diagnosed with definite or probable AE, including those with autoantibody-negative, or unknown status.