Blood-brain barrier dysfunction and myelin basic protein in survival of amyotrophic lateral sclerosis with or without frontotemporal dementia.

OBJECTIVE: We aim to investigate blood-brain barrier (BBB) dysfunction and myelin basic protein (MBP) in amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD) and further determine the effect of these factors on the survival of ALS. METHODS: This was a retrospective study of 113 ALS patients, 12 ALS-FTD patients, and 40 disease controls hospitalized between September 2013 and October 2020. CSF parameters including total protein (TP), albumin (Alb), immunoglobulin-G (IgG), and MBP were collected and compared between groups. The CSF-TP, CSF-Alb, CSF-IgG, and CSF/serum quotients of Alb and IgG (QAlb, QIgG) were used to reflect the BBB status. Patients were followed up until December 2020. Cox regression and Kaplan-Meier method were used for survival analysis. RESULTS: The CSF-TP, CSF-Alb, and CSF-IgG concentrations were significantly higher in patients than controls (p < 0.01). Increased CSF-TP and CSF-IgG was found in 45 (39.8%) and 27 (23.9%) ALS patients, while in 7 (58.3%) and 5 (41.7%) ALS-FTD patients. The level of CSF-Alb, CSF-IgG, and CSF-MBP were significantly higher in patients with ALS-FTD than ALS. MBP showed a moderate accuracy in the distinction between ALS-FTD and ALS (AUC = 0.715 ± 0.101). No difference in MBP was found between patients and controls. Kaplan-Meier analysis indicated that a higher CSF-TP, CSF-IgG, QIgG, or QAlb was significantly associated with shorter survival. Cox regression model showed that CSF-TP, CSF-IgG, and QIgG were independent predictors of survival. CONCLUSION: Our findings suggested that BBB dysfunction was more prominent in ALS-FTD than ALS and associated with a worse prognosis. Further studies are needed to determine the role of CSF-MBP as a biomarker in ALS.

Anti-NMDAR encephalitis after resection of melanocytic nevi: report of two cases.

BACKGROUND: Encephalitis with antibodies against N-methyl D-aspartate receptor (NMDAR) is recognized as a group of antibody-mediated neuropsychiatric syndromes, which occurs with and without a tumor association. Neoplasm may contribute to the pathogenesis of Anti-NMDAR encephalitis in tumor-positive patients. However, the underlying causes in tumor-negative patients are largely unknown. This is the first report, of which we are aware, of two cases of anti-NMDAR encephalitis after the resection of melanocytic nevus. CASE PRESENTATION: We describe 2 female patients in their 20s confirmed with anti-NMDAR encephalitis. They shared two points in common: About several weeks (2 weeks and 5 weeks respectively) before the initial symptom, both of them underwent a resection of melanocytic nevi; the screening tests for an ovarian teratoma and other tumors were all negative. A 25 year-old woman presented with seizure, psychiatric symptoms and behavioral change for 2 weeks. Electroencephalogram indicated electrographic seizures. Anti-NMDAR antibodies were all positive in the cerebrospinal fluid and serum. Her symptoms relieved gradually after the treatment with steroids and mycophenolate mofetil. Another patient admitted to our hospital with psychosis, behavioral change and complex partial seizure over a period of 5 months. Electroencephalogram demonstrated generalized slow activities. High titres of anti-NMDAR antibodies were both detected in the cerebrospinal fluid and serum. She responded well to the first-line immunotherapy and got substantial recovery. CONCLUSION: Our cases provided an observational link between anti-NMDAR encephalitis and resection of nevi. We postulate that the exposure of certain antigen on nevus cell caused by nevi excision, which might be NMDA receptor or other mimic cross-reactive antigens, may trigger an autoimmune response resulting in encephalitis. This suggested a potential site of antigen exposure triggering the immune response in non-tumor associated anti-NMDAR encephalitis, which may lend support to elucidating the underlying immunopathological mechanisms. Further studies are expected for investigating the expression of NMDA receptor on nevus cell and evaluating the validity of this hypothesis.

Multifocal hemosiderin depositions on T2*-weighted magnetic resonance imaging in a patient with pathology-proven systemic diffuse large B-cell lymphoma.

BACKGROUND: Intracranial hemorrhage in central nervous system lymphoma is extremely rare. T2*-weighted gradient-echo magnetic resonance imaging is of particularly use in detecting silent hemorrhage as hypointense signals due to the deposition of paramagnetic hemosiderin or mineralization. Multifocal hemosiderin depositions caused by chronic silent hemorrhage have not yet been identified in patients with central nervous system involvement of systemic lymphoma. We present an unexpected radiographic feature on T2*-weighted gradient-echo magnetic resonance imaging in a patient with central nervous system involvement of pathologically confirmed systemic diffuse large B-cell lymphoma. CASE PRESENTATION: A 56-year-old woman presented with lower extremities weakness and progressive cognitive decline for four months. Conventional brain magnetic resonance imaging demonstrated multiple lesions with hypointensities on T1-weighted images and hyperintensities on T2-weighted images and fluid attenuated inversion recovery in both hemispheres. She was then transferred to our hospital. CONCLUSION: This is the first report of pathologically confirmed case of CNS involvement of systemic diffuse large B-cell lymphoma with multifocal silent hemosiderin depositions detected by T2*-weighted gradient-echo magnetic resonance imaging. Even though uncommon, our report offers an insight that CNS lymphoma could present with multifocal silent hemosiderin depositions on T2*-weighted gradient-echo magnetic resonance imaging. Further studies were expected for exploring the association between this radiologic feature and systemic lymphoma and their underlying mechanisms.

Comparison of neurofilament light and heavy chain in spinal muscular atrophy and amyotrophic lateral sclerosis: A pilot study.

BACKGROUND: Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) were two major motor neuron diseases with similar symptoms and poor outcomes. This study aimed to identify potential biomarkers in disease monitoring and differential diagnosis of adult SMA patients with sporadic ALS patients. METHODS: This was a pilot study with ten adult SMA patients and ten ALS patients consecutively enrolled during hospitalization. Serum and cerebrospinal fluid (CSF) samples were collected for assessment of neurofilament light (NFL) and phosphorylated neurofilament heavy chain (pNFH). Serum creatine kinase (CK) and creatinine (Cr) were also compared between groups. The receiver operating characteristic (ROC) curves were used to identify differentiated values among ALS and SMA patients. RESULTS: Serum Cr, CSF NFL, and CSF pNFH levels of ALS patients were significantly higher than those of the adult SMA patients (p < .01). Serum CK and Cr were strongly correlated with baseline ALSFRS-R scores in SMA patients (p < .001). The ROC curves revealed an area under the curve (AUC) of 0.94 in serum Cr with a cut-off value of 44.5 µmol/L (Sensitivity 90%, Specificity 90%). AUC from the ROC curve of CSF NFL and CSF pNFH were 1.0 and 0.84, with cut-off values of 1275 pg/mL and 0.395 ng/mL, respectively (Sensitivity and Specificity of 100% and 100% in CSF NFL; Sensitivity and Specificity of 90% and 80% in CSF pNFH). CONCLUSION: CSF NFL and pNFH might be useful biomarkers for differential diagnosis of adult SMA and ALS.

Alterations in metabolic biomarkers and their potential role in amyotrophic lateral sclerosis.

BACKGROUND: Metabolic dysfunction has been suggested to be involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). This study aimed to investigate the potential role of metabolic biomarkers in the progression of ALS and understand the possible metabolic mechanisms. METHODS: Fifty-two patients with ALS and 24 normal controls were included, and blood samples were collected for analysis of metabolic biomarkers. Basal anthropometric measures, including body composition and clinical features, were measured in ALS patients. The disease progression rate was calculated using the revised ALS functional rating scale (ALSFRS-R) during the 6-month follow-up. RESULTS: ALS patients had higher levels of adipokines (adiponectin, adipsin, resistin, and visfatin) and other metabolic biomarkers [C-peptide, glucagon, glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide, and plasminogen activator inhibitor type 1] than controls. Leptin levels in serum were positively correlated with body mass index, body fat, and visceral fat index (VFI). Adiponectin was positively correlated with the VFI and showed a positive correlation with the ALSFRS-R and a negative correlation with baseline disease progression. Patients with lower body fat, VFI, and fat in limbs showed faster disease progression during follow-ups. Lower leptin and adiponectin levels were correlated with faster disease progression. After adjusting for confounders, lower adiponectin levels and higher visfatin levels were independently correlated with faster disease progression. INTERPRETATION: The current study found altered levels of metabolic biomarkers in ALS patients, which may play a role in ALS pathogenesis. Adiponectin and visfatin represent potential biomarkers for prediction of disease progression in ALS.

Clinical characteristics and prognosis of amyotrophic lateral sclerosis with autoimmune diseases.

INTRODUCTION: The occurrence of autoimmune diseases (AIDs) in amyotrophic lateral sclerosis (ALS) patients is widely reported, but little is known about the associated clinical phenotype. This study aims to evaluate the clinical features and prognosis of ALS patients with AID. METHODS: This retrospective study was based on the ALS Registry dataset of Peking Union Medical College Hospital from 2013 to 2020. Clinical features and inflammatory biomarkers at registration were compared between ALS patients with coexisting AIDs and those without (controls). The medical records of immunotherapy were also collected. The Kaplan-Meier method and Cox proportional hazard model were used to study the survival of ALS patients. RESULTS: There are 26 (1.6%) ALS patients with AIDs in our database. The ALS patients with AIDs had older ages at onset and poorer respiratory function than controls (p<0.05). After propensity score matching by sex, onset age, and disease duration, the difference in respiratory function remained significant between groups. We found no differences in overall survival between ALS patients with and without AIDs before and after matching (p = 0.836; p = 0.395). Older age at onset, rapid disease progression, and lower erythrocyte sedimentation rate (ESR) were associated with shorter survival (p<0.05). Among ALS patients with AIDs, 8 (30.8%) had a history of immunotherapy and showed slightly prolonged survival compared with those without immunotherapy, but the results did not reach statistical significance (p = 0.355). CONCLUSIONS: Patients with coexisting ALS and AIDs had older onset age and poorer respiratory function but similar overall survival than those with pure ALS.

Correlation of weight and body composition with disease progression rate in patients with amyotrophic lateral sclerosis.

This study aims to observe the nutritional status of Chinese patients with amyotrophic lateral sclerosis (ALS), further investigating its effect on disease progression. One hundred consecutive newly diagnosed ALS patients and fifty controls were included. Weight and body composition were measured by bioelectrical impedance analysis at baseline and follow-ups. The revised ALS functional rating scale (ALSFRS-R) was used to calculate the rate of disease progression. Patients with ALS had a significantly lower BMI than controls, while no significant difference was found in body composition. Weight loss occurred in 66 (66%) and 52 (67.5%) patients at diagnosis and follow-up, respectively. Patients with significant weight loss (≥ 5%) at diagnosis had significantly lower BMI, fat mass (FM), and FM in limbs and trunk than those without. Fat-free mass (FFM), FM, and FM in limbs were significantly decreased along with weight loss at follow-up (p < 0.01). Patients with lower visceral fat index, lower proportion of FM, and higher proportion of muscle mass at baseline progressed rapidly during follow-ups (p < 0.05). Multivariate linear regression showed that FFM and weight at follow-up were independently correlated with disease progression rate at follow-up (p < 0.05). Weight loss is a common feature in ALS patients, along with muscle and fat wasting during the disease course. Body composition may serve as a prognostic factor and provide guidance for nutritional management in ALS patients.

Comparative physiological and root transcriptome analysis of two annual ryegrass cultivars under drought stress.

Annual ryegrass is a widely cultivated forage grass with rapid growth and high productivity. However, drought is one of the abiotic stresses affecting ryegrass growth and quality. In this study, we compared the physiological and transcriptome responses of Chuansi No.1 (drought-tolerant, DT) and Double Barrel (drought-sensitive, DS) under drought stress simulated by PEG-6000 for 7 days. The results showed that Chuansi No. 1 had stronger physiological and biochemical parameters such as root properties, water content, osmotic adjustment ability and antioxidant ability. In addition, RNA-seq was used to elucidate the molecular mechanism of root drought resistance. We identified 8588 differentially expressed genes related to drought tolerance in root, which were mainly enriched in oxidation-reduction process, carbohydrate metabolic process, apoplast, arginine and proline metabolism, and phenylpropanoid biosynthesis pathways. The expression levels of DEGs were consistent with physiological changes of ryegrass under drought stress. We found that genes related to sucrose and starch synthesis, root development, osmotic adjustment, ABA signal regulation and specifically up-regulated transcription factors such as WRKY41, WRKY51, ERF7, ERF109, ERF110, NAC43, NAC68, bHLH162 and bHLH148 in Chuansi No. 1 may be the reason for its higher drought tolerance. This study revealed the underlying physiological and molecular mechanisms of root response to drought stress in ryegrass and provided some new candidate genes for breeding rye drought tolerant varieties.

Utility and Safety of Intrathecal Methotrexate Treatment in Severe Anti-N-methyl-D-aspartate Receptor Encephalitis: A Pilot Study.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune neurologic syndrome that occurs with or without tumor association. However, some severe cases are refractory to systemic immunotherapy. This pilot study aimed to evaluate the utility and safety of intrathecal methotrexate injection for severe patients with anti-NMDAR encephalitis who did not respond to first-line immunotherapy. METHODS: Intrathecal injections with methotrexate and dexamethasone were performed weekly in four legible patients within consecutive 4 weeks. Cerebrospinal fluid (CSF) was collected at baseline and each time of intrathecal injection for identification of anti-NMDAR antibody titers. RESULTS: Significant clinical improvement was observed in three patients associated with a stepwise decrease of CSF anti-NMDAR antibody titers (maximum: 1/320 to minimum: 1/10). After 2 months of follow-up, they were able to follow simple commands and had appropriate interactions with people (modified Rankin scale [mRS] of 0-2). At 12 months of follow-up, they all had returned to most activities of daily life (mRS of 0), and no relapses were reported. One patient showed no clinical improvement and died of neurologic complications. CONCLUSIONS: Intrathecal treatment may be a potentially useful supplementary therapy in severely affected patients with anti-NMDAR encephalitis. Further large cohort study and animal experiment may help us elaborate the utility of intrathecal injection of methotrexate and its mechanism of action.

Limbic Encephalitis Associated with Anti-γ-aminobutyric Acid B Receptor Antibodies: A Case Series from China.

BACKGROUND: Autoimmune encephalitis associated with antibodies against γ-aminobutyric acid B receptor (GABA B R) in patients with limbic encephalitis (LE) was first described in 2010. We present a series of Han Chinese patients for further clinical refinement. METHODS: Serum and cerebrospinal fluid (CSF) samples from patients referred to the program of encephalitis and paraneoplastic syndrome of Peking Union Medical College Hospital were tested with indirect immunofluorescence. Clinical information of patients with anti-GABA B R antibody positivity was retrospectively reviewed, and descriptive statistical analysis was performed. RESULTS: All eighteen anti-GABA B R antibody-positive cases had limbic syndromes, and electroencephalogram (EEG) or neuroimaging evidence fulfilled the diagnostic criteria of LE. Four patients had additional antibodies against Hu in serum and one had anti-N-methyl-d-aspartate receptor antibody in both sera and CSF. Seventeen (17/18) patients presented with new-onset refractory seizure or status epileptics. Twelve (12/18) patients had memory deficits, 11 (11/18) patients had personality change, 7 (7/18) patients had disturbance of consciousness, and 3 (3/18) patients showed cerebellar dysfunction. One patient with LE had progressive motor and sensory polyneuropathy. Lung cancer was detected in 6 (6/18) patients. Ten (10/18) patients showed abnormality in bilateral or unilateral mediotemporal region on magnetic resonance imaging. Ten (10/18) patients had temporal lobe epileptic activity with or without general slowing on EEG. Seventeen patients received immunotherapy and 15 of them showed neurological improvement. Four patients with lung cancer died within 1-12 months due to neoplastic complications. CONCLUSIONS: Our study demonstrates that most Han Chinese patients with anti-GABA B R antibody-associated LE have prominent refractory epilepsy and show neurological improvement on immunotherapy. Patients with underlying lung tumor have a relatively poor prognosis. Testing for anti-GABA B R antibodies is necessary for patients with possible LE or new-onset epilepsy with unknown etiology.

De novo FUS gene mutations are associated with juvenile-onset sporadic amyotrophic lateral sclerosis in China.

Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of motor neuron disease and occurs before 25 years of age. Only very few sporadic cases of juvenile-onset ALS have been reported. Rare SOD1 mutations and several FUS mutations have been identified in juvenile-onset ALS patients. To define the genetics of juvenile-onset sporadic ALS (SALS) of Chinese origin, we sequenced all 5 exons of SOD1, exons 3-6 and 12-15 of FUS in 11 juvenile-onset SALS patients, 105 adult-onset ALS patients (including 6 familial ALS [FALS] pedigrees), and 245 healthy controls. For the 11 juvenile-onset SALS and 6 FALS cases, the other 7 exons of FUS were also screened. A heterozygous de novo missense mutation c.1574C>T (p.P525L), a heterozygous de novo 2-base pair deletion c.1509_1510delAG (p.G504Wfs*12), and a nonsense mutation c.1483C>T (p.R495X) was each identified in 1 juvenile SALS patient. A heterozygous missense mutation c.1561C>G (p.R521G) was identified in a FALS proband. In the Chinese population, the frequency of FUS mutation in FALS is 11.4% (95% confidence interval [CI], 0.9%-22.0%), higher than the Japanese (10%; 95% CI, 0.7%-19.3%), and Caucasians (4.9%; 95% CI, 3.9%-6.0%). The frequency of FUS mutation in SALS patients is 1.5% (95% CI, 0.2%-2.9%), which is similar to Koreans (1.6%; 95% CI, 0%-3.2%), but higher than in Caucasians (0.6%; 95% CI, 0.4%-0.8%). Our findings suggest that de novo FUS mutations are associated with juvenile-onset SALS of Chinese origin and that this gene should be screened in ALS patients with a young age of onset, aggressive progression, and sporadic occurrence.