Systematic proteomics in Autosomal dominant Alzheimer's disease reveals decades-early changes of CSF proteins in neuronal death, and immune pathways.

Background: To date, there is no high throughput proteomic study in the context of Autosomal Dominant Alzheimer's disease (ADAD). Here, we aimed to characterize early CSF proteome changes in ADAD and leverage them as potential biomarkers for disease monitoring and therapeutic strategies. Methods: We utilized Somascan® 7K assay to quantify protein levels in the CSF from 291 mutation carriers (MCs) and 185 non-carriers (NCs). We employed a multi-layer regression model to identify proteins with different pseudo-trajectories between MCs and NCs. We replicated the results using publicly available ADAD datasets as well as proteomic data from sporadic Alzheimer's disease (sAD). To biologically contextualize the results, we performed network and pathway enrichment analyses. Machine learning was applied to create and validate predictive models. Findings: We identified 125 proteins with significantly different pseudo-trajectories between MCs and NCs. Twelve proteins showed changes even before the traditional AD biomarkers (Aß42, tau, ptau). These 125 proteins belong to three different modules that are associated with age at onset: 1) early stage module associated with stress response, glutamate metabolism, and mitochondria damage; 2) the middle stage module, enriched in neuronal death and apoptosis; and 3) the presymptomatic stage module was characterized by changes in microglia, and cell-to-cell communication processes, indicating an attempt of rebuilding and establishing new connections to maintain functionality. Machine learning identified a subset of nine proteins that can differentiate MCs from NCs better than traditional AD biomarkers (AUC>0.89). Interpretation: Our findings comprehensively described early proteomic changes associated with ADAD and captured specific biological processes that happen in the early phases of the disease, fifteen to five years before clinical onset. We identified a small subset of proteins with the potentials to become therapy-monitoring biomarkers of ADAD MCs. Funding: Proteomic data generation was supported by NIH: RF1AG044546.

Blood Pressure Variability May Be a New Predictor for the Occurrence and Prognosis of Ischemic Stroke.

Despite declines in morbidity and mortality in recent years, ischemic stroke (IS) remains one of the leading causes of death and disability from cerebrovascular diseases. Addressing the controllable risk factors underpins the successful clinical management of IS. Hypertension is one of the most common treatable risk factors for IS and is associated with poor outcomes. Ambulatory blood pressure monitoring has revealed that patients with hypertension have a higher incidence of blood pressure variability (BPV) than those without hypertension. Meanwhile, increased BPV has been identified as a risk factor for IS. The risk of IS is higher and the prognosis after infarction is worse with higher BPV, no matter in the acute or subacute phase. BPV is multifactorial, with alterations reflecting individual physiological and pathological changes. This article reviews the current research advances in the relationship between BPV and IS, with an attempt to raise awareness of BPV among clinicians and IS patients, explore the increased BPV as a controllable risk factor for IS, and encourage hypertensive patients to control not only average blood pressure but also BPV and implement personalized blood pressure management.

Corrigendum: Case report and literature analysis: Autoimmune cerebellar ataxia associated with homer-3 antibodies.

[This corrects the article DOI: 10.3389/fneur.2022.951659.].

Case report and literature analysis: Autoimmune cerebellar ataxia associated with homer-3 antibodies.

Objective: We present a case of autoimmune cerebellar ataxia (ACA) associated with Homer protein homolog 3 (Homer-3) antibodies. Then, a review of the literature was conducted to summarize its clinical spectrum to improve clinicians' understanding of this rare entity. Case presentation: A 25-year-old man suffered from the subacute onset of cerebellar ataxia and psychiatric symptoms with abnormalities in the cerebellum on initial brain MRI and Homer-3 antibodies titers of 1:100 in the serum. His neurological symptoms did not improve after intravenous methylprednisolone but significantly improved following plasma exchange with a modified Rankin Scale (mRS) score of 1. However, 5 months later, he experienced relapse during oral prednisone tapering with enhanced cerebellar lesions and obvious cerebellar atrophy on repeated MRI. Various immunomodulatory approaches, including corticosteroids and plasma exchange, were utilized with no improvement. Then rituximab was given for the first time to treat Homer-3 autoimmunity with partial improvement of symptoms. However, the patient remained profoundly disabled with an mRS score of 4. Conclusion: ACA associated with Homer-3 antibodies may have a suboptimal response to corticosteroid therapy. More intense immunotherapy such as rituximab may contribute to the improvement of cerebellar syndrome. Relapsing courses and presentation of cerebellar atrophy may suggest a poor prognosis in this entity.

Elevated repulsive guidance molecule-a mRNA in peripheral blood mononuclear cells are associated with impaired leptomeningeal collaterals in patients with middle cerebral artery occlusions.

BACKGROUND: In the event of middle cerebral artery occlusion (MCAO), leptomeningeal collaterals (LMCs) play a crucial role in determining the survival of brain tissue distal to occlusion. Previous findings indicated that genes controlling arteriogenesis can impact the extent of LMCs. Therefore, probe for potential genetic parameters correlating of arteriogenesis may be clinically useful in predicting LMCs status in MCAO. During the screening process, we focused on repulsive guidance molecule a (RGMa), which has been reported to play a negative role in angiogenesis after stroke by decreasing the proliferation, migration, and tube formation of endothelial cells (ECs) in vivo and in vitro. Indeed, endothelial function plays a main role in arteriogenesis and is essential in determining the LMCs status. Therefore, in present study, we aimed to testify the hypothesis that RGMa might be associated with LMCs status in MCAO. METHODS: We prospectively enrolled patients with acute M1 MCA +/- intracranial internal carotid artery (ICA) occlusions (n=96) and healthy controls (n=33). Status of LMCs was evaluated according to computed tomographic angiography (CTA) on admission. Baseline RGMa mRNA expression was quantified by using quantitative real-time PCR. RESULTS: Patients with poor LMCs showed significantly higher RGMa mRNA levels than patients with good LMCs status (P=0.001) as well as healthy controls (P=0.002), respectively; whereas good LMCs group showed similar baseline RGMa levels than controls (P=1.000). RGMa mRNA level and baseline NIHSS score were independent predictors for impaired LMCs. CONCLUSIONS: In MCAO patients, elevated PBMCs RGMa mRNA levels were associated with impaired LMCs status, indicating that measurement of RGMa mRNA expression in the early phase of stroke, together with other clinical approaches, was logically expected to be useful for predicting LMCs status. Moreover, a role for RGMa in leptomeningeal arteriogenesis following ischemic stroke can be hypothesized.

Altered expression of long noncoding RNAs in peripheral blood mononuclear cells in patients with impaired leptomeningeal collaterals after acute anterior large vessel occlusions.

BACKGROUND: In the event of acute ischemic stroke (AIS) due to anterior large vessel occlusion (aLVO), leptomeningeal collaterals (LMCs) status is a key factor to define the severity and functional prognosis of this disease. However, the extent of LMCs exhibits substantial variability among the patients, which is genetic determined. Long non-coding RNAs (lncRNAs) expression profiles in human peripheral blood have been found to be altered after AIS. But whether there are specific lncRNAs correlated with LMC status in aLVO has not yet been investigated. METHODS: Differential lncRNA expression panels in peripheral blood mononuclear cells (PBMCs) were assessed by microarray analysis and individual quantitative real-time polymerase chain reaction (RT-PCR) in three independent sets consist of 134 patients with aLVO and 73 healthy controls (HCs). LMCs Status in those patients was assessed based on baseline computed tomographic angiography (CTA). RESULTS: Microarray analysis showed 23 differentially expressed lncRNAs in patients with poor LMCs status. After independent validations by RT-PCR, lncRNA ENST00000422956 was found to be significantly downregulated in patients with poor LMCs status. Receiver-operating characteristic (ROC) analysis revealed the area under the ROC curve (AUC) for ENST00000422956 to predict poor LMCs status was 0.749. Moreover, ENST00000422956 expression level and baseline National Institutes of Health Stroke Scale (NIHSS) score were identified as independent predictors for impaired LMCs, and a significantly positive correlation was observed between ENST00000422956 expression level and LMCs status. Via cis-regulatory analysis, paired box 8 (Pax8) was identified as the target gene for ENST00000422956. CONCLUSIONS: The dysregulated lncRNA ENST00000422956 in PBMCs was associated with impairment of LMCs in patients with aLVO, suggesting that measurement of circulatory lncRNAs might be included as possible biomarkers for evaluation of LMCs status in AIS. More importantly, this might be the foundation for understand the potential roles of lncRNAs in LMCs formation after ischemic stroke.

Efficacy and Safety of Endovascular Thrombectomy for Ischemic Stroke in Nonagenarians.

INTRODUCTION: Increased life expectancy results in a rapid increase of nonagenarian patients presenting with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). We conducted this study to assess the efficacy and safety of endovascular thrombectomy (ET) in this age group with use of imaging-based selection. METHODS: We retrospectively analyzed clinical and imaging data from 2 different comprehensive stroke centers and compared the outcomes of ET versus intravenous thrombolysis (IVT) alone among eligible nonagenarians with LVO in anterior circulation and evidence of salvageable tissue on brain magnetic resonance imaging (MRI). RESULTS: A total of 617 patients of AIS had been treated with IVT or ET, including 23 eligible nonagenarians. Among these, 9 patients were treated with IVT alone (IVT group) and 14 patients received ET group. Notably, the symptomatic intracranial hemorrhage rates were significantly lower after ET than after IVT (European-Australasian Acute Stroke Study II criteria, 0 vs. 33.3%; p = 0.047; National Institute of Neurological Disorders and Stroke criteria, 7.1 vs. 66.7%; p = 0.005). Moreover, although there were no statistically significant differences between the 2 groups on efficacy, ET tended to lead to greater early neurologic recovery at discharge (71.4 vs. 33.3%, p = 0.102) and improve functional outcome at 90 days (71.4 vs. 44.4%, p = 0.383), respectively. CONCLUSION: By using MRI-based selection, ET in nonagenarians with AIS caused by LVO within anterior circulation was safe and may lead to improve early neurologic recovery and functional independence at 90 days, as compared with IVT alone. Randomized trial in larger sample size testing efficacy of ET using diffusion-weighted imaging-fluid attenuated inversion recovery mismatch selection in this age group appears feasible.

Heterogeneity of radiological spectrum in tacrolimus-associated encephalopathy after lung transplantation.

BACKGROUND: Tacrolimus-associated encephalopathy (TAC-E) is usually described under the term of posterior reversible encephalopathy syndrome (PRES). However, a large amount of data has suggested that TAC-E is not a homogenous entity: indeed, TAC-E which is often presented with atypical and potentially misleading imaging characteristics does not always correspond to PRES. OBJECTIVE: We aimed to identify the spectrum of brain MR imaging of TAC-E and discuss the underlying pathophysiological features. METHODS: From September 2008 to October 2010, the neurological statuses of 45 patients, who underwent lung transplantation with TAC as posttransplantation immunosuppressive therapy, were regularly assessed in a prospective study. MRI was repeatedly performed, until recovery, in patients who developed central neurological symptoms. RESULTS: Symptoms suggestive of encephalopathy occurred in five out of 45 patients (11.1%). According to our MRI study, two patients presented with reversible bilateral and relatively symmetric subcortical white matter edema with proximal vasospasms on MRA; however, three other patients were characterized by coexistence of two different lesions including laminar cortical infarcts with hemorrhagic transformation not typically found in PRES and reversible deep white matter edema, associated with distal vasospasms on MRA. CONCLUSIONS: It is considered that the mechanism of TAC-E would be more heterogenous than commonly perceived.

Up-regulated methyl CpG binding protein-2 in intractable temporal lobe epilepsy patients and a rat model.

Methyl CpG binding protein-2 (MeCP2) is a multifunctional nuclear protein, and regulates dendritic morphology, synaptic transmission, spontaneous neurotransmission, and short-term synaptic plasticity in the central nervous system. This study was designed to investigate the expression of MeCP2 mRNA and protein in intractable temporal lobe epilepsy (TLE) patients and an experimental animal model. MeCP2 expression was detected in 35 temporal neocortex tissue samples from patients with intractable TLE and 14 histologically normal temporal lobe tissue samples from trauma patients without epilepsy by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry and double-label immunofluorescence. In addition, the timing of MeCP2 expression was evaluated in the hippocampus and adjacent cortex of lithium chloride/pilocarpine-induced TLE rats and uninduced controls. MeCP2 was found to be expressed mainly in the nuclei of neurons, and not expressed in astrocytes. MeCP2 expression was significantly higher in the TLE patients and rats than in the control groups. Following seizures in the rat model, MeCP2 expression gradually increased in the hippocampus and adjacent cortex during the acute period (days 1 and 2) and the latent period (days 7 and 14), but decreased during the chronic period (days 30 and 60). Up-regulated expression of MeCP2 in intractable TLE patients and experimental animals suggested that MeCP2 may be involved in the pathogenesis of TLE.

Subarachnoid hemorrhage associated with epidemic hemorrhagic fever: a rare case report.

Nervous system injuries associated with epidemic hemorrhagic fever (EHF) are not rarely seen. However, cerebrovascular disease arising from EHF is rarely reported in the literature. A 50-year-old male patient suffered from subarachnoid hemorrhage (SAH). No abnormal condition was found in intracranial vascular digital subtraction angiography (DSA). But, this patient presented with positive hantavirus-IgM and IgG, with typical clinical process, which lead to the diagnosis of EHF followed by SAH. To our knowledge, SAH associated with EHF has not been previously reported. A meticulous assessment of EHF patients with a serious condition had one or more central nervous system (CNS) abnormalities, such as sudden headache, vomiting, confusion, meningismus, and convulsions, which is necessary for diagnosing and giving timely treatment to improve the prognosis.

shRNA targeting PLCε inhibits bladder cancer cell growth in vitro and in vivo.

OBJECTIVES: To investigate the role of phospholipase Cε (PLCε) by silencing PLCε with short hairpin RNA (shRNA) in human bladder cancer cells BIU-87 in vitro and in vivo. METHODS: A PLCε shRNA expression vector was transfected into BIU-87 cells, and the expression of PLCε protein was detected by Western blotting. Cell proliferation was determined using the MTT assay, and the cell cycle was detected using flow cytometry. A tumor xenograft experiment was established to evaluate the tumor growth under the condition of PLCε knockdown, and the expression of PLCε, proliferating cell nuclear antigen, and cyclin D1 were detected by Western blotting or immunohistrochemistry. RESULTS: PLCε shRNA reduced the protein level of PLCε, leading to marked proliferation inhibition and significant cell cycle arrest. Furthermore, PLCε shRNA reduced the tumor xenograft growth implanted with BIU-87 cells. The protein expression of PLCε, proliferating cell nuclear antigen, and cyclin D1 were downregulated in the bladder tumor xenograft. CONCLUSIONS: The knockdown of PLCε by shRNA could inhibit bladder tumor growth and might be an alternative approach for human bladder cancer therapy.

Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation.

Tacrolimus (TAC) is an immunosuppressant drug discovered in 1984 by Fujisawa Pharmaceutical Co., Ltd. This drug belongs to the group of calcineurin inhibitors, which has been proven highly effective in preventing acute rejection after transplantation of solid organs. However, neurotoxicity and nephrotoxicity are its major adverse effects. Posterior reversible encephalopathy syndrome (PRES) is the most severe and dramatic consequence of calcineurin inhibitor neurotoxicity. It was initially described by Hinchey et al. in 1996 [N Engl J Med 1996;334:494-450]. Patients typically present with altered mental status, headache, focal neurological deficits, visual disturbances, and seizures. Magnetic resonance imaging is the most sensitive imaging test to detect this. With the more deep-going studies done recently, we have learnt more about this entity. It was noted that this syndrome is frequently reversible, rarely limited to the posterior regions of the brain, and often located in gray matter and cortex as well as in white matter. Therefore, in this review, the focus is on the current understanding of clinical recognition, pathogenesis, neuroimaging and management of TAC-associated PRES after solid organ transplantation.