Clinical Features and Classification of Neuronal Intranuclear Inclusion Disease.

Background and Objectives: Neuronal intranuclear inclusion body disease (NIID) is a neurodegenerative disease with highly heterogeneous clinical manifestations. The present study aimed to characterize clinical features and propose a classification system based on a large cohort of NIID in China. Methods: The Chinese NIID registry was launched from 2017, and participants' demographics and clinical features were recorded. Brain MRI, skin pathologies, and the number of GGC repeat expansions in the 5' untranslated region of the NOTCH2NLC gene were evaluated in all patients. Results: In total, 223 patients (64.6% female) were recruited; the mean (SD) onset age was 56.7 (10.3) years. The most common manifestations were cognitive impairment (78.5%) and autonomic dysfunction (70.9%), followed by episodic symptoms (51.1%), movement disorders (50.7%), and muscle weakness (25.6%). Imaging markers included hyperintensity signals along the corticomedullary junction on diffusion-weighted imaging (96.6%), white matter lesions (98.1%), paravermis (55.0%), and focal cortical lesions (10.1%). The median size of the expanded GGC repeats in these patients was 115 (range, 70-525), with 2 patients carrying >300 GGC repeats. A larger number of GGC repeats was associated with younger age at onset (r = -0.329, p < 0.0001). According to the proposed clinical classification based on the most prominent manifestations, the patients were designated into 5 distinct types: cognitive impairment-dominant type (34.1%, n = 76), episodic neurogenic event-dominant type (32.3%, n = 72), movement disorder-dominant type (17.5%, n = 39), autonomic dysfunction-dominant type (8.5%, n = 19), and neuromuscular disease-dominant type (7.6%, n = 17). Notably, 32.3% of the episodic neurogenic event-dominant type of NIID has characteristic focal cortical lesions on brain MRI presenting localized cortical edema or atrophy. The mean onset age of the neuromuscular disease-dominant type was 47.2 (17.6) years, younger than the other types (p < 0.001). There was no significant difference in the sizes of GGC repeats among the patients in the 5 types (p = 0.547, Kruskal-Wallis test). Discussion: This observational study of NIID establishes an overall picture of the disease regarding clinical, imaging, and genetic characteristics. The proposed clinical classification of NIID based on the most prominent manifestation divides patients into 5 types.

Application of metagenomic next-generation sequencing technique for diagnosing a specific case of necrotizing meningoencephalitis caused by human herpesvirus 2.

Reactivation of latent human herpesvirus 2 (HHV-2) can cause spontaneous recovering aseptic meningitis and recurrent meningitis in adults, but it rarely affects the brain parenchyma to cause encephalitis. Here, we report the case of a 37-year-old male patient admitted to our hospital due to fever with a progressive headache for 3 days and paroxysmal episodes of unconsciousness for 1 day. Brain magnetic resonance imaging (MRI) revealed viral meningoencephalitis. Then, metagenomics next-generation sequencing (mNGS) was applied, which detected 12,024 unique sequences of HHV-2 in cerebrospinal fluid (2022), indicating HHV-2 encephalitis. After antiviral treatment, the patient's symptoms improved, and he was discharged. During the 1-month follow-up, the patient recovered without any new symptoms, but a brain MRI revealed significant atrophy of the original foci. The patient was finally diagnosed with HHV-2 necrotizing meningoencephalitis, which is extremely rare. mNGS helped with the clinical diagnosis and strengthened our understanding of HHV-2 infections in the central nervous system.

A neglected neurodegenerative disease: Adult-onset globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD), or Krabbe disease (KD) is a rare neurodegenerative disease, and adult-onset GLD is more even neglected by clinicians. This review provides detailed discussions of the serum enzymes, genes, clinical manifestations, neuroimaging features, and therapies of GLD, with particular emphasis on the characteristics of adult-onset GLD, in an attempt to provide clinicians with in-depth insights into this disease.

Detection of Japanese Encephalitis by Metagenomic Next-Generation Sequencing of Cerebrospinal Fluid: A Case Report and Literature Review.

Japanese encephalitis (JE) is an acute viral central nervous system disease, although less than 1% of patients infected with Japanese encephalitis virus (JEV) result in JE, which has an extremely poor prognosis. The Routine detection methods for JEV are time-consuming or limited by hospital conditions, therefore, need the quicker and sensitive techniques to detect JEV. Here, we reported a 14-year-old female who was admitted to our hospital with a severe fever, progressively headache and unconsciousness. Based on the clinical presentation, Preliminary diagnosis on admission indicated central nervous system infection of suspected viral meningoencephalitis or autoimmune encephalitis. The patient's symptoms were unrelieved after being treated with empiric antiviral therapy. Magnetic resonance imaging (MRI) showed that the lesions were located in the bilateral thalamus, head of caudate nucleus, and right lenticular nucleus, so we had to consider the possibility of Flaviviruses infection. We sent the cerebrospinal fluid (CSF) for metagenomic next-generation sequencing (mNGS) immediately, subsequent result suggested the infection caused by JEV. Two days later the results of the serum agglutination test confirmed that virus immunoglobulin M antibody positive. After a week treatment with intravenous immunoglobulin (IVIG), meanwhile, the lumbar puncture was used to check the pressure and various indicators of the CSF again to evaluate the treatment effect, An decrease in the number of WBC indicates, protein and unique RNA reads that the previous experimental treatment was effective, accompany by temperature and consciousness of the patient was normalized. Two weeks after admission, the patient was transferred to the rehabilitation hospital, MR showed the lesions had disappeared completely after 2 months of follow-up. We believed that mNGS may be an effective method for rapid identification of JE.

Spinal Muscular Atrophy Type IIIb Complicated by Moyamoya Syndrome: A Case Report and Literature Review.

Spinal muscular atrophy (SMA) is an inherited disorder characterized by degeneration of motor neurons and symmetrical muscle weakness and atrophy. Moyamoya syndrome (MMS) or moyamoya disease (MMD) is radiologically defined by chronic cerebrovascular occlusion with abnormal vascular network formation in the skull base. We report herein a 21-year-old female patient with limb weakness and muscular atrophy for 17 years. Electromyography revealed extensive motor neuron damage. Cranial MRA showed occlusion of bilateral anterior and middle cerebral arteries, with increased peripheral blood vessels and collateral circulation. She was diagnosed as SMA type IIIb combined with MMS following genetic testing, in which homozygous deletion of exons 7 and 8 of survival motor neuron (SMN)1 gene and 3 copies of exons 7 and 8 of SMN2 gene were detected. After treatment, the patient's symptoms improved. Our study found that the rare SMA and MMS co-exist. We speculated that the moyamoya phenomenon may be related to the abnormal regulation of intracranial vascular endothelial cells and smooth muscle cells in proliferation and differentiation caused by functional defects of SMN protein. The relationship between the two diseases needs to be further elucidated in future clinical work.

Impact of H-Type Hypertension on Intraplaque Neovascularization Assessed by Contrast-Enhanced Ultrasound.

AIM: H-type hypertension is connected with carotid atherosclerotic plaques and stroke, whereas neovascularization is a dominant contributor to plaque vulnerability. However, the correlation between H-type hypertension and plaque vulnerability remains unclear. This study aims to explore the influence of H-type hypertension on intraplaque neovascularization (IPN). METHODS: We enrolled 235 patients with carotid plaques into the investigation and classified them into four groups: H-type hypertension group, simple hypertension group, isolated hyperhomocysteinemia group, and control group. Contrast-enhanced ultrasound (CEUS) was performed on them and IPN was evaluated using semi-quantitative visual grading: grade 1 (no microbubbles or microbubbles limited to the adventitial side and/or shoulder of plaque) and, grade 2 (diffused microbubbles within plaque or microbubbles enter plaque core). To analyze the correlation between H-type hypertension and the degree of plaque enhancement, logistic regression was used. RESULTS: Compared with those with CEUS grade 1 plaques, those with CEUS grade 2 plaques had higher frequency of ischemic stroke (29.0% vs. 45.1%, P＜0.05), hypertension (41.0% vs. 56.3%, P＜0.05), and H-type hypertension (18.0% vs. 29.6%, P＜0.05). No significant differences existed in plaque morphology, plaque echogenicity, and the severity of carotid artery stenosis between the degree of plaque enhancement (all P＞0.05). H-type hypertension (multivariate-adjusted OR: 3.036, 95% CI: 1.258-7.329) was independently connected with the degree of plaque enhancement even after adjusting for other covariates. CONCLUSION: H-type hypertension is expressly connected with the degree of plaque enhancement and may facilitate plaque vulnerability. Our findings may offer a new insight for treating vulnerable plaque, lowering blood pressure, and lowering homocysteine equally crucial.

Relationship of Neutrophil-to-Lymphocyte Ratio with Carotid Plaque Vulnerability and Occurrence of Vulnerable Carotid Plaque in Patients with Acute Ischemic Stroke.

BACKGROUND: Carotid plaque is an undefined risk factor in ischemic stroke and is driven by inflammation. Mounting evidence suggests that neutrophil-to-lymphocyte ratio (NLR) is crucial not only for cerebrovascular events but also in atherosclerosis progression. Here, we aimed to explore the association between the admission NLR and carotid plaque vulnerability as well as the occurrence of vulnerable carotid plaque detected by carotid ultrasonography in patients with acute ischemic stroke (AIS) among Chinese. METHODS: We conducted a retrospective study composed of 588 patients with AIS and 309 healthy controls free of carotid plaque in the Department of Neurology in The Second Hospital of Lanzhou University from March 2014 to February 2015. All patients were classified as nonplaque, stable plaque, and vulnerable plaque groups on the basis of carotid ultrasonography results. The baseline information was collected and compared among the four different groups. The correlation between variables and carotid plaque vulnerability was tested by Spearman linear correlation analysis. To identify the independent predictors for vulnerable carotid plaque, univariate and multivariate logistic regression analysis was performed. RESULTS: The comparisons of age, sex proportion, history of hypertension, diabetes, and smoking, the levels of HDL-C, Lp(a), BMI, SBP, DBP, Fib, CRP, leukocyte, and NLR among the four groups showed a statistically significant difference (P < 0.05); in particular, the NLR was significantly higher in the vulnerable plaque group as compared to the control (P = 0.043), nonplaque (P = 0.022), and stable plaque groups (P = 0.015). The Spearman correlation analysis presented a positive correlation between carotid plaque vulnerability and age (r = 0.302; P < 0.001), SBP (r = 0.163; P < 0.001), and NLR (r = 0.087; P = 0.034), while the lymphocyte was negatively related to the carotid plaque vulnerability (r = -0.089; P = 0.030). The multivariate logistic regression analysis adjusted for confounding factors revealed that age (odds ratio [OR], 1.042; 95% confidence interval [CI], 1.025-1.060; P < 0.001), male gender (OR, 2.005; 95% CI, 1.394-2.884; P < 0.001), diabetes (OR, 1.481; 95% CI, 1.021-2.149; P = 0.039), SBP (OR, 1.012; 95% CI, 1.003-1.021; P = 0.010), and NLR (OR, 1.098; 95% CI, 1.018-1.184; P = 0.015) are independent predictors of vulnerable carotid plaque in patients with AIS. CONCLUSION: The admission NLR is a novel and meaningful biomarker that can be used in predicting carotid plaque vulnerability and the presence of vulnerable carotid plaque assessed by carotid ultrasonography in patients with AIS among Chinese.

Multiple reversible encephalitic attacks: a rare manifestation of neuronal intranuclear inclusion disease.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative condition characterized by the loss of neurons and the presence of eosinophilic nuclear inclusions in the central and peripheral nervous system, skin and visceral organs. In this paper, we present a case of NIID with recurrent encephalitic attacks that remained stable and nonprogressive for seven years; no such case has previously been reported. CASE PRESENTATION: A 63-year-old female was hospitalized due to light-headedness, vomiting, unstable gait and cognitive impairment. Seven years prior, she had experienced an episode of light-headedness, central facial paralysis, unstable gait, aphasia, nausea, vomiting and loss of consciousness. She regained consciousness within 12 h, and her other symptoms were completely resolved within one week. During the present hospitalization, a brain magnetic resonance imaging (MRI) examination detected high signal intensity on diffusion-weighted imaging (DWI) of the bilateral frontal grey matter-white matter junction. We reviewed the patient's previous MRI results and found that she had also had high signal intensity on DWI of the bilateral frontal grey matter-white matter junction seven years prior. In the intervening seven years, the high signal intensity in the frontal lobes had spread along the grey matter-white matter junction, but the deep white matter remained unaffected. Skin biopsy was performed, and intranuclear inclusions were found in adipocytes, fibroblasts and sweat gland cells. GGC repeat expansions in the NOTCH2NLC (Notch 2 N-terminal like C) gene confirmed the diagnosis of NIID. She received supportive treatment such as nutrition support therapy and vitamin B and C supplementation, as well as symptomatic treatment during hospitalization. The patient's symptoms were completely relieved within one week. CONCLUSION: This is a detailed report of a case of NIID with multiple reversible encephalitic attacks, diagnosed by clinical symptoms, intranuclear inclusions, characteristic DWI signals, and genetic tests.

microRNA-592 blockade inhibits oxidative stress injury in Alzheimer's disease astrocytes via the KIAA0319-mediated Keap1/Nrf2/ARE signaling pathway.

MicroRNA-592 (miR-592) has been reported to play a significant role in mediating neuronal activity, but its possible link with Alzheimer's disease (AD) remains unclear. We aimed to explore the mechanism of miR-592 in oxidative stress (OS) injury of astrocytes (ASTs) from AD rat models induced by D-galactose or Aß25-35 injection. Bioinformatics website and dual-luciferase reporter gene assay clarified the binding affinity between miR-592 and KIAA0319. KIAA0319 was identified as a target gene of miR-592. The mechanism of miR-592, KIAA0319 and the Keap1/Nrf2/ARE signaling pathway in AD was examined after transducing miR-592 mimic, miR-592 inhibitor and siRNA-KIAA0319 into ASTs to query cell viability, OS injury and reactive oxygen species (ROS). The rat models of AD Exhibited highly expressed miR-592 and poorly expressed KIAA0319. Furthermore, inhibition of miR-592 diminished C-Keap1 expression and enhanced N-Nrf2 and NQO1 expression, thus promoting cell viability and reducing OS injury of ASTs. Taken together, these findings suggested that the downregulation of miR-592 inhibited OS injury of ASTs in rat models of AD by up-regulating KIAA0319 through the activation of the Keap1/Nrf2/ARE signaling pathway.

PIR promotes tumorigenesis of breast cancer by upregulating cell cycle activator E2F1.

Pirin (PIR) protein belongs to the superfamily of cupin and is highly conserved between eukaryotic and prokaryotic organisms. It has been reported that PIR is upregulated in various tumors and involved in tumorigenesis. However, its biological functions particularly in promoting tumorigenesis are, to date, poorly characterized. Here we report that knockdown of PIR in MCF7 and MDA-MB-231 cell lines causes a dramatic decrease in cell proliferation and xenograft tumor growth in mice. Mechanistically, the cell cycle activator E2F1 and its target genes cdk4, cdk6, cycE, cycD and DDR1 are remarkably downregulated in PIR depleted cells, leading to G1/S phase arrest. Luciferase reporter assay and chromatin immunoprecipitation assay indicate that PIR can activate E2F1 transcription by binding to its promoter region. Consistent with the observation in PIR knockdown cells, PIR inhibitors markedly inhibit the proliferation of both cell lines. Furthermore, knockdown of PIR significantly decreases the abilities of MCF7 cells for mobility and invasion in vitro and their metastasis in mice, which may be attributed to the decrease of DDR1. In conclusion, PIR stimulates tumorigenesis and progression by activating E2F1 and its target genes. Our finding thus suggests PIR as a potential druggable target for the therapy of cancers with high expression level of PIR.