Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models. Glia abnormalities drive the progression of demyelinating diseases. Here, the authors show that reactivated astrocytes secrete clusterin to impede remyelination by blocking astrocytic removal of myelin debris and oligodendrocyte precursor cell differentiation in mouse models of demyelination.

Objectives: Clinicians often face the challenge of differentially diagnosing febrile patients who are suspected of infectious diseases, since the clinical manifestations of infection and cancer may overlap. A single test that can detect both pathogens and tumor could provide timely and accurate diagnostic clues to aid the treatment and management of these patients. Methods: We enrolled eight patients to evaluate the utility of metagenomic Next-Generation Sequencing for simultaneously detecting pathogens and neoplasms using body fluids and tissue samples. Patients were selected by the following criteria: 1) Tumor was not considered upon hospitalization, but mNGS testing indicated neoplasm; 2) Tumor was not excluded, but microbial infection was primarily suspected according to initial clinical assessment. Results: We detected potential pathogens in five patients, three of whom had progressed into critical infections. Moreover, abnormal chromosomal copy numbers were identified in all patients that indicated presence of neoplasms, which were pathologically confirmed. Conclusions: Although copy number variations do not render a definitive cancer diagnosis, it can prompt clinicians to conduct more focused diagnostic testing for cancer, potentially saving time and cost. As a result, integrating copy number analysis with pathogen detection in mNGS may help establish rapid and accurate diagnosis for febrile patients.

Introduction: It is important to note that complete myelination and formation of myelinated fibers are essential for functional nerve regeneration after peripheral nerve injury (PNI). However, suboptimal myelin regeneration is common and can hinder ideal nerve regeneration. Therefore, it is important to closely monitor and support myelin regeneration in patients with PNI to achieve optimal outcomes. Methods: This study analyzed the effects of three extracellular matrix (ECM) proteins on Schwann cells (SCs) in the nerve regeneration environment, including their adhesion, proliferation, and migration. The study also explored the use of composite sodium alginate hydrogel neural scaffolds with ECM components and investigated the effects of ECM proteins on remyelination following peripheral nerve injury. Results: The results showed that laminin (LN), fibronectin (FN), and collagen Ⅳ (type IV Col) promoted the early adhesion of SCs in 2-dimensional culture but the ratios of early cell adhesion were quite different and the maintenance of cells' morphology by different ECM proteins were significantly different. In transwell experiment, the ability of LN and FN to induce the migration of SCs was obviously higher than that of type IV Col. An vitro co-culture model of SCs and dorsal root ganglia (DRG) neurons showed that LN promoted the transition of SCs to a myelinated state and the maturation of the myelin sheath, and increased the thickness of neurofilaments. Animal experiments showed that LN had superior effects in promoting myelin sheath formation, axon repair, and reaching an ideal G-ratio after injury compared to FN and Col IV. The situation of gastrocnemius atrophy was significantly better in the LN group. Notably, the thickness of the regenerated myelin sheaths in the type IV Col group was the thickest. Conclusion: In this experiment, we analyzed and compared the effects of LN, FN, and type IV Col on the biological behavior of SCs and their effects on remyelination after PNI and further clarified their unique roles in the process of remyelination. Further research is necessary to explore the underlying mechanisms.

Background: Microbial infection and malignant tumor may present with overlapping symptoms and clinicians often face the challenge in differential diagnosis of febrile patients suspected of infectious diseases. However, timely diagnosis is crucial for rational use of antibiotics, and a tool that can simultaneously detect tumor and infection may greatly improve the efficiency of clinical diagnosis. This study investigated the utility of metagenomic Next-Generation Sequencing, which is usually used for pathogen detection, in differential diagnosis.Methods: We enrolled eleven patients from Nov. 2020 to May 2022. Two participants had been diagnosed with cancer prior to hospitalization and the rest of cases were thought to have microbial infections during initial examinations. Specimens including body fluids and biopsy were acquired and sent for conventional microbiological tests, metagenomic Next-Generation Sequencing and pathological examinations.Findings: Neoplasms were identified via copy number analysis in all patients and tumor was pathologically confirmed. The types of tumors included solid tumors (i.e. lung adenocarcinoma, brain tumor) and hematological malignancies (i.e. lymphoma, leukemia). Moreover, metagenomic sequencing detected pathogens in seven of the patients, and three of the patients got severe infectious disease.Interpretation: For febrile patients suspected of infections, mNGS can serve as a useful tool to provide timely differential diagnosis by incorporating host chromosomal CNV analysis for the detection of both neoplasms and pathogens in a single test. Funding Information: The study was supported by the National Natural Science Foundation of China [grant numbers 82072380, 81871734, 82002236]; research foundation for advanced talents of Guangdong Provincial People’s Hospital [grant number KJ012021097].Declaration of Interests: None of the authors has any conflict of interest to disclose.Ethics Approval Statement: We received approval by the board of Ethics at the Lingnan Hospital, Branch of the Third Affiliated Hospital of Sun Yat-sen University and Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences.

Lumbar cerebrospinal fluid (CSF) parameters are widely studied and have wide clinical applications, but ventricular CSF has rarely been studied since it is relatively difficult to obtain. To determine whether there are differences between ventricular and lumbar CSF parameters and whether the differences have clinical significance, we retrospectively reviewed 77 patients with Cryptococcal meningitis who received a ventriculoperitoneal shunt. We analyzed the following parameters: white blood cell count, total protein concentration, CSF/blood glucose ratio, chloride ion concentration, and Cryptococcal count. All parameters between lumbar and ventricular CSF were remarkably different (all p < 0.001). White blood cell count, total protein level and Cryptococcal count were lower in ventricular CSF than in lumbar CSF, while CSF/blood glucose ratio and chloride ion concentration were higher. Compared to patients without ventriculomegaly, patients with ventriculomegaly had a significantly higher total protein concentration in ventricular CSF ( p = 0.047). Compared to patients without surgical complications, patients with complications had a significantly lower CSF/blood glucose ratio in ventricular CSF ( p = 0.032). The lumbar CSF parameters had no significant differences between these groups. The changes in lumbar CSF indices over time after shunt placement were also analyzed. After shunt placement, total protein concentration was transiently increased, white blood cell count, CSF/blood glucose ratio and chloride ion concentration were continued at the preoperative level until two months after shunting surgery. These findings suggest that the composition of ventricular CSF differs from that of lumbar CSF, and different CSF parameters have disparate rostro-caudal gradients in patients with Cryptococcal meningitis. Furthermore, ventricular and lumbar CSF parameters may have different clinical implications. Transient deterioration of lumbar CSF parameters after ventriculoperitoneal shunt placement may not be due to disease progression, but to change in CSF flow rate by CSF shunts.

BACKGROUND AND PURPOSE:Central nervous system (CNS) B-cell lymphoma-mimicking demyelinating diseases creates a diagnostic dilemma. This study aimed to determine the specific magnetic resonance imaging (MRI) features of CNS B-cell lymphoma to facilitate the early identification of the disease.METHODS:We retrospectively reviewed the brain MRI of biopsy-confirmed CNS B-cell lymphoma patients. They were initially diagnosed with CNS demyelination, and these images were compared with those of actual patients with demyelinating diseases.RESULTS:A total of 20 patients with CNS B-cell lymphoma and 12 patients with demyelination were included in this study. Cohesive enhancement with satellite enhancing foci surrounded by prominent non-enhancing areas of oedema is the major contrast-enhancing pattern of lymphoma patients, accounting for 81% (13) of patients with primary diffuse large B-cell lymphoma (DLBCL). This imaging pattern revealed a sensitivity of 81% and a specificity of 75% for lymphoma in the differential diagnosis between primary DLBCL and demyelinating disease in our cohort. Among these lesions, most of the nodules were located deeply, which yielded a specificity of 100% and a sensitivity of 69% for primary DLBCL. Enhancement in a single pattern (mainly ring-like, patchy or punctate; 57%) and no enhancement (30%) were commonly observed in demyelinating lesions, distinct from primary DLBCL (p &lt; 0.05).CONCLUSIONS:Lesions with cohesive enhancement and satellite foci on T1 contrast-enhanced imaging could be a specific hallmark of CNS B-cell lymphoma, suggesting the need to withdraw steroidal therapy and biopsy confirmation.

Ischemic stroke (IS) is a severe neurological disease that is difficult to recovery. Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) is a promising therapeutic approach, while the exact therapy mechanisms of rTMS in improving neural functional recovery remain unclear. Furthermore, the inflammatory environment may influence the rehabilitation efficacy. Our study shows that long-term rTMS stimulation will significantly promote neurogenesis, inhibit apoptosis, and control inflammation. rTMS inhibits the activation of transcription factors nuclear factor kappa b (NF-κB) and signal transducer and activator of transcription 6 (STAT6) and promotes the anti-inflammatory polarization of microglia. Obvious promotion of anti-inflammatory cytokines production is observed both in vitro and in vivo through rTMS stimulation on microglia. In addition, neural stem cells (NSCs) cultured in conditioned medium (CM) from microglia treated with rTMS showed downregulation of apoptosis and upregulation of neuronal differentiation. Overall, our results illustrate that rTMS can modulate microglia with anti-inflammatory polarization variation, promote neurogenesis, and improve neural function recovery.

Objectives: We aimed to analyze the effect of cold ischemia time (CIT) on post-transplant graft function through mixed-effect model analysis to reduce the bias caused by paired mate kidneys. Methods: We reviewed all kidney transplantation records from 2015 to 2019 at our center. After applying the exclusion criteria, 561 cases were included for analysis. All donor characteristics, preservation and matching information, and recipient characteristics were collected. Transplant outcomes included delayed graft function (DGF) and estimated glomerular filtration rate (eGFR). Generalized linear mixed models were applied for analysis. We also explored potential effect modifiers, namely, donor death category, expanded criteria donors, and donor death causes. Results: Among the 561 cases, 79 DGF recipients developed DGF, and 15 recipients who died after surgery were excluded from the eGFR estimation. The median stable eGFR of the 546 recipients was 60.39 (47.63, 76.97) ml/min/1.73 m2. After adjusting for confounding covariates, CIT had a negative impact on DGF incidence [odds ratio = 1.149 (1.006, 1.313), P = 0.041]. In the evaluation of the impact on eGFR, the regression showed that CIT had no significant correlation with eGFR [β = −0.287 (−0.625, 0.051), P = 0.096]. When exploring potential effect modifiers, only the death category showed a significant interaction with CIT in the effect on eGFR (Pinteraction = 0.027). In the donation after brain death (DBD) group, CIT had no significant effect on eGFR [β = 0.135 (−0.433, 0.702), P = 0.642]. In the donation after circulatory death/donation after brain death followed by circulatory death (DCD/DBCD) group, CIT had a significantly negative effect on eGFR [β= −0.700 (−1.196, −0.204), P = 0.006]. Compared to a CIT of 0–6 h, a CIT of 6–8 or 8–12 h did not decrease the post-transplant eGFR. CIT over 12 h (12–16 h or over 16 h) significantly decreased eGFR. With the increase in CIT, the regenerated eGFR worsened (Ptrend = 0.011). Conclusion: Considering the effect of paired mate kidneys, the risk of DGF increased with prolonged CIT. The donor death category was an effect modifier between CIT and eGFR. Prolonged CIT did not reduce the eGFR level in recipients from DBDs but significantly decreased the eGFR in recipients from DCDs/DBCDs. This result indicates the potential biological interaction between CIT and donor death category.

Stereotactic biopsies for lesions in the brainstem and deep brain are rare. This study aimed to summarize our 6-year experience in the accurate diagnosis of lesions in the brain stem and deep brain and to discuss the technical note and strategies. From December 2011 to January 2018, 72 cases of intracranial lesions in the brainstem or deep in the lobes undergoing stereotactic biopsy were retrospectively reviewed. An individualized puncture path was designed based on the lesion's location and the image characteristics. The most common biopsy targets were deep in the lobes (43 cases, 59.7%), including frontal lobe (33 cases, 45.8%), temporal lobe (4 cases, 5.6%), parietal lobe (3 cases, 4.2%), and occipital lobe (3 cases, 4.2 %). There were 12 cases (16.7%) of the brainstem, including 8 cases (11.1%) of midbrain, and 4 cases (5.6%) of pons or brachium pontis. Other targets included internal capsule (2 cases, 2.8%), thalamus (3 cases, 4.2%), and basal ganglion (12 cases, 16.7%). As for complications, one patient developed acute intracerebral hemorrhage in the biopsy area at 2 h post-operation, and one patient had delayed intracerebral hemorrhage at 7 days post-operation. The remaining patients recovered well after surgery. There was no surgery-related death. The CT-MRI-guided stereotactic biopsy of lesions in the brainstem or deep in the brain has the advantages of high safety, accurate diagnosis, and low incidence of complications. It plays a crucial role in the diagnosis of atypical, microscopic, diffuse, multiple, and refractory lesions.

Miliary dissemination is common in tuberculosis, but is an extremely rare form of brain metastasis. It is mainly found in patients with primary lung cancer (small cell and adenocarcinoma). Here, we presented a case of miliary metastases of lung adenocarcinoma to the brain without lesion enhancement on MRI after administration of contrast. A 38-year-old Chinese male was diagnosed with lung adenocarcinoma and received chemotherapy monthly for 6 months. At one month after completion of chemotherapy, the patient presented with headache, dizziness, and vomiting. Brain MRI revealed numerous, disseminated, tiny, rounded cystic high-signal intensity lesions on T2-weighted images, and low-signal intensity lesions on T1-weighted images, with no enhancement. In addition, a high signal on T2-weighted images and uneven enhancement with contrast in the hypophysis were noted. A right frontal lobe biopsy revealed miliary metastases originating from primary lung adenocarcinoma, which was consistent with the pathological finding of a bronchial biopsy. However, the patient and his family requested supportive treatments only, and he died 3 months after the diagnosis. In summary, this case indicates that when imaging findings are not consistent with the most likely cause of miliary brain metastasis, a biopsy is necessary to make a definitive diagnosis.

BACKGROUND:The early diagnosis of basal ganglia and thalamus germinomas is often difficult due to the absence of elevated tumor markers, and atypical clinical symptoms and neuroimaging features.CASE SUMMARY:Four male children aged 8 to 15 years were diagnosed with germinomas in the basal ganglia and thalamus by stereotactic biopsy from 2017 to 2019. All patients developed hemiplegia except patient 4 who also had cognitive decline, speech disturbance, nocturnal enuresis, polydipsia, polyuria, precocious puberty and abnormalities of thermoregulation. All four cases were alpha-fetoprotein and beta-human chorionic gonadotrophin (β-HCG) negative except patient 3 who had slightly elevated β-HCG in cerebrospinal fluid (CSF). No malignant cells were detected in the patients' CSF. Brain magnetic resonance imaging findings were diverse in these patients with the exception of the unique and common characteristics of ipsilateral hemisphere atrophy, especially in the cerebral peduncle. All patients were diagnosed with germinomas of the basal ganglia and thalamus by stereotactic brain biopsy.CONCLUSION:Stereotactic brain biopsy is necessary to confirm the diagnosis of ectopic germinomas. Serial neuroimaging studies can not only differentiate disease but also determine the biopsy site.

Introduction Autonomic neuropathy is common in Parkinson's disease (PD). We evaluated whether SUDOSCAN, a novel electrophysiological device that provides a simple and quantitative assessment of sudomotor function, was able to detect PD-related autonomic neuropathy. We also used the device to examine potential risk factors for PD-related autonomic neuropathy. Methods Forty-three hospitalized patients in the later stages of PD underwent assessments including a clinical history, the Unified Parkinson's Disease Rating Scale (UPDRS), the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOPA-AUT), and measurement of homocysteine (HCY) and vitamin B12 levels. Sudomotor function was assessed by measuring electrochemical skin conductance (ESC) using SUDOSCAN. Forty-two healthy participants served as controls. Results ESC of the limbs, and especially the hands, was significantly lower in PD patients than in controls and was significantly correlated with SCOPA-AUT results. ESC was strongly negatively correlated with PD duration. The results also indicated that levodopa exposure and a higher HCY level may be risk factors for PD-related autonomic neuropathy. Conclusions SUDOSCAN was able to effectively identify autonomic neuropathy in PD patients. ESC was decreased in PD patients and was correlated with PD-related autonomic symptoms. These findings suggest that SUDOSCAN could be a promising new method for assessing PD-related autonomic neuropathy.

Bacicground: Sitagliptin is an anti-diabetic drug and its effects on Alzheimer's disease (AD) remain controversial. This study aimed to investigate the protective effect of sitagliptin on the cognition in AD and its underlying molecular mechanism. Methods: The APP/PS1 (a model of AD) mice received daily gastric gavage administration of sitagliptin (20 mg/kg) for 8 weeks. Then animals were subjected to behavioral experiment or sacrificed to histological staining and protein level analysis. Results: The MWM test showed that sitagliptin treatment significantly reduced the escape latency times in APP/ PS1 mice in the learning phase (day 3-5) and elongated the time spent in the target quadrant in the probe test. Sitagliptin significantly reduced amyloid plaque deposition and elevated the spine density and the protein levels of synaptoneurosome GluA1- and GluA2-containing AMPA receptor (GluA1R and GluA2R) in the brain of the APP/PS1 mice. Sitagliptin treatment significantly up-regulated the brain BNDF protein and phosphorylation of tyrosine receptor kinase B (TrkB). Furthermore, exendin-(9-39) (a glucagon-like peptide-1 [GLP-1] receptor antagonist) and K252a (a Trk tyrosine kinase inhibitor) treatment significantly abolished the cognitive protective effect of sitagliptin in the MWM test. Conclusion: Sitagliptin treatment effectively protected the cognition function of the AD mice by regulating synaptic plasticity, at least partially, through activating GLP-1 and BDNF-TrkB signalings.

Objective: To investigate the value of stereotactic biopsy in the accurate diagnosis of lesions in the brain stem and deep brain. Methods: A total of 29 consecutive patients who underwent stereotactic biopsy of brainstem and deep brain lesions between May 2012 and January 2018 were retrospectively reviewed. The Cosman-Roberts-Wells (CRW) stereotactic frame was installed under local anesthesia. Thin-layer CT and MRI scanning were performed. Target coordinates were calculated by inputting CT-MRI data into the radionics surgical planning system. The individualized puncture path was designed according to the location of the lesions and the characteristics of the image. Target distributions were as follows: 12 cases of midbrain or pons, 2 cases of internal capsule, 3 cases of thalamus, 12 cases of basal ganglia. The biopsy samples were used for further pathological and/or genetic diagnosis. Results: Twenty-eight of the 29 cases (96.6%) were diagnosed accurately by histopathology and genomic examination following stereotactic biopsy. Pathological results were as follows: 8 cases of lymphoma, 7 cases of glioma, 4 cases of demyelination, 2 cases of germ cell tumor, 2 cases of metastatic tumor, 1 cases of cerebral sparganosis, 1 case of tuberculous granuloma, 1 case of hereditary prion disease, 1 case of glial hyperplasia, 1 case of leukemia. The accurate diagnosis of one case required a combination of histopathology and genomic examination. Undefined diagnosis was still made in 1 cases (3.45%) after biopsy. After biopsy, there were 2 cases (6.9%) with symptomatic slight hemorrhage, 1 case (3.45%) with symptomatic severe hemorrhage, and 1 cass (3.45%) with permanent neurological dysfunction. No one died because of surgery or surgical complications. Conclusions: Stereotactic biopsy is fast, safe and minimally invasive. It is an ideal strategy for accurate diagnosis of lesions in brain stem and deep brain.

Background: Fatal familial insomnia (FFI) is a rare autosomal dominant disease caused by the PRNP D178N/129 M mutation. Routine brain CT and MRI usually reveal non-specific features. We report a patient with FFI presenting with diffuse abnormal signals on MRI, later confirmed as combined with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).Case presentation: The patient was a 58-year-old female, whose main clinical manifestations were insomnia, movement disorders, autonomic hyperactivity and mental deterioration. The patient also suffered a typical episode of transient global amnesia. MRI indicated a diffuse white matter abnormality and microbleeding on the susceptibility-weighted imaging. On biopsy, the brain tissue sections showed spongiform changes with gliosis, neuronal degeneration, and prion protein deposition in a portion of the neurons. In addition, arteriosclerosis was prominent. Transmission electron microscopy showed osmiophilic particle deposition in the matrix of medial smooth muscle cells. Gene sequencing confirmed a diagnosis of FFI with CADASIL.Conclusions: This case is a compelling example that even with evidence of leukoencephalopathy, prion disease should be an important differential diagnosis of rapidly progressive dementia and related diseases. In cases of genetic diseases with atypical manifestations, the coexistence of two or even more diseases should be considered as a possible explanation.