Altered White-Matter Functional Network in Children with Idiopathic Generalized Epilepsy.

RATIONALE AND OBJECTIVES: The white matter (WM) functional network changes offers insights into the potential pathological mechanisms of certain diseases, the alterations of WM functional network in idiopathic generalized epilepsy (IGE) remain unclear. We aimed to explore the topological characteristics changes of WM functional network in childhood IGE using resting-state functional Magnetic resonance imaging (MRI) and T1-weighted images. METHODS: A total of 84 children (42 IGE and 42 matched healthy controls) were included in this study. Functional and structural MRI data were acquired to construct a WM functional network. Group differences in the global and regional topological characteristics were assessed by graph theory and the correlations with clinical and neuropsychological scores were analyzed. A support vector machine algorithm model was employed to classify individuals with IGE using WM functional connectivity as features, and the model's accuracy was evaluated using leave-one-out cross-validation. RESULTS: In IGE group, at the network level, the WM functional network exhibited increased assortativity; at the nodal level, 17 nodes presented nodal disturbances in WM functional network, and nodal disturbances of 11 nodes were correlated with cognitive performance scores, disease duration and age of onset. The classification model achieved the 72.6% accuracy, 0.746 area under the curve, 69.1% sensitivity, 76.2% specificity. CONCLUSION: Our study demonstrated that the WM functional network topological properties changes in childhood IGE, which were associated with cognitive function, and WM functional network may help clinical classification for childhood IGE. These findings provide novel information for understanding the pathogenesis of IGE and suggest that the WM function network might be qualified as potential biomarkers.

N-homocysteinylation of DJ-1 promotes neurodegeneration in Parkinson's disease.

DJ-1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ-1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ-1 on the lysine 182 (K182) residue in an age-dependent manner. The N-homocysteinylation (N-hcy) of DJ-1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N-hcy of DJ-1 restores its protective effect. These results indicate that the N-hcy of DJ-1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N-hcy of DJ-1 may exert neuroprotective effect against PD.

Bridging integrator 1 fragment accelerates tau aggregation and propagation by enhancing clathrin-mediated endocytosis in mice.

The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1-277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1-277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1-277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD.

The yeast prion protein Sup35 initiates α-synuclein pathology in mouse models of Parkinson's disease.

Parkinson's disease (PD) is characterized by the pathologic aggregation and prion-like propagation of α-synuclein (α-syn). Emerging evidence shows that fungal infections increase the incidence of PD. However, the molecular mechanisms by which fungi promote the onset of PD are poorly understood. Here, we show that nasal infection with Saccharomyces cerevisiae (S. cerevisiae) in α-syn A53T transgenic mice accelerates the aggregation of α-syn. Furthermore, we found that Sup35, a prion protein from S. cerevisiae, is the key factor initiating α-syn pathology induced by S. cerevisiae. Sup35 interacts with α-syn and accelerates its aggregation in vitro. Notably, injection of Sup35 fibrils into the striatum of wild-type mice led to α-syn pathology and PD-like motor impairment. The Sup35-seeded α-syn fibrils showed enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Together, these observations indicate that the yeast prion protein Sup35 initiates α-syn pathology in PD.

The yeast protein Ure2p triggers Tau pathology in a mouse model of tauopathy.

The molecular mechanisms that trigger Tau aggregation in Alzheimer's disease (AD) remain elusive. Fungi, especially Saccharomyces cerevisiae (S. cerevisiae), can be found in brain samples from patients with AD. Here, we show that the yeast protein Ure2p from S. cerevisiae interacts with Tau and facilitates its aggregation. The Ure2p-seeded Tau fibrils are more potent in seeding Tau and causing neurotoxicity in vitro. When injected into the hippocampus of Tau P301S transgenic mice, the Ure2p-seeded Tau fibrils show enhanced seeding activity compared with pure Tau fibrils. Strikingly, intracranial injection of Ure2p fibrils promotes the aggregation of Tau and cognitive impairment in Tau P301S mice. Furthermore, intranasal infection of S. cerevisiae in the nasal cavity of Tau P301S mice accelerates the aggregation of Tau. Together, these observations indicate that the yeast protein Ure2p initiates Tau pathology. Our results provide a conceptual advance that non-mammalian prions may cross-seed mammalian prion-like proteins.

Rare cavitary lymphoepithelioma-like carcinoma of lung: clinical experience and literature review.

BACKGROUND: Lymphoepithelioma-like carcinoma of the lung is a rare primary malignancy of the lung, accounting for only 0.9% of primary malignancies of the lung. Those associated with cavities are even rarer, with fewer than five cases reported in the English literature. Concurrently, the imaging findings of tumors are usually non-specific, resulting in insufficient understanding of the disease by clinicians, thus leading to misdiagnosis and delayed treatment. CASE PRESENTATION: A 42-year-old female presented with a right lower lung mass with cavities. First identified on chest computed tomography (CT) in 2021, the mass persisted for 1 year and subsequently enlarged on chemotherapy and routine follow-up CT. Right lower lobectomy was then performed. Postoperative pathology confirmed primary pulmonary lymphoepithelioma-like carcinoma. After 10 months of follow-up, the patient was still alive and no recurrence was observed. CONCLUSIONS: This article aims to describe a rare case of cavitary lymphoepithelioma-like carcinoma of the lung and review it clinical and imaging characteristics reported in previous cases, which will be helpful for clinicians and imaging physicians in diagnosing this disease.

Undifferentiated carcinoma with osteoclast­like giant cells of the pancreas: A case report.

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas (UCOGCP) is a rare pancreatic tumor that accounts for <1% of all primary pancreatic malignant tumors. Although the tumor is considered a variant of pancreatic ductal adenocarcinoma, there are substantial differences in the clinicopathological characteristics between UCOGCP and pancreatic ductal adenocarcinoma. Imaging examinations are useful in making a correct diagnosis, and providing a reasonable and effective surgical treatment regimen; however, the imaging characteristics of UCOGCP require further investigation. The present report describes a rare case of UCOGCP with rapid progression and poor prognosis. The patient could not undergo surgery and received chemotherapy drugs only. Chemotherapy did not markedly improve the outcome, and a follow-up 6 months after discharge showed that the patient had died. The present report describes this case and summarizes the available imaging findings to increase awareness, and to improve early diagnosis of this rare disease and therapeutic outcomes.

Islet amyloid polypeptide triggers α-synuclein pathology in Parkinson's disease.

Pathologic aggregation and prion-like propagation of α-synuclein (α-syn) are the hallmarks of Parkinson's disease (PD). Emerging evidence shows that type 2 diabetes mellitus (T2DM) is a risk factor for PD. Interestingly, T2DM is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. Although T2DM and PD share pathological similarities, the underlying molecular mechanisms bridging these two diseases remain unknown. Here, we report that IAPP co-deposits with α-syn in the brains of PD patients. IAPP interacts with α-syn and accelerates its aggregation. In addition, the IAPP-seeded α-syn fibrils show enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Strikingly, intravenous injection of IAPP fibrils into α-syn A53T transgenic mice or human SNCA transgenic mice accelerated the aggregation of α-syn and PD-like motor deficits. Taken together, these findings support that IAPP acts as a trigger of α-syn pathology in PD, and provide a mechanistic explanation for the increased risk and faster progression of PD in patients with T2DM.

C/EBPß/AEP is age-dependently activated in Parkinson's disease and mediates α-synuclein in the gut and brain.

Parkinson's disease (PD) is the most common neurodegenerative motor disorder, and its pathologic hallmarks include extensive dopaminergic neuronal degeneration in the Substantia nigra associated with Lewy bodies, predominantly consisting of phosphorylated and truncated α-Synuclein (α-Syn). Asparagine endopeptidase (AEP) cleaves human α-Syn at N103 residue and promotes its aggregation, contributing to PD pathogenesis. However, how AEP mediates Lewy body pathologies during aging and elicits PD onset remains incompletely understood. Knockout of AEP or C/EBPß from α-SNCA mice, and their chronic rotenone exposure models were used, and the mechanism of α-Syn from the gut that spread to the brain was observed. Here we report that C/EBPß/AEP pathway, aggravated by oxidative stress, is age-dependently activated and cleaves α-Syn N103 and regulates Lewy body-like pathologies spreading from the gut into the brain in human α-SNCA transgenic mice. Deletion of C/EBPß or AEP substantially diminished the oxidative stress, neuro-inflammation, and PD pathologies, attenuating motor dysfunctions in aged α-SNCA mice. Noticeably, PD pathologies initiate in the gut and progressively spread into the brain. Chronic gastric exposure to a low dose of rotenone initiates Lewy body-like pathologies in the gut that propagate into the brain in a C/EBPß/AEP-dependent manner. Hence, our studies demonstrate that C/EBPß/AEP pathway is critical for mediating Lewy body pathology progression in PD.

Reducing the water residence time is inadequate to limit the algal proliferation in eutrophic lakes.

The eutrophication problem now threatens many lakes and reservoirs. To avoid the occurrence of algal blooms, some cities try to increase the flow rate or directly choose lakes or reservoirs with a short water residence time (WRT) as drinking water sources. However, up to now, whether such a strategy can achieve its goal is still unclear. In this study, a newly restored lake with a WRT of approximately 3 days was chosen to investigate algal growth potential as well as its responses to external nitrogen (N) and phosphorus (P) inputs. The results suggested that although the water quality of the lake could generally meet the environmental quality standards for surface water, dissolved inorganic nitrogen reached a high level with an average value of 1.58 mg/L. Meanwhile, a considerable increase in Chl-a concentration was observed across the flow direction. Especially, in July, Chl-a concentration at the site near the outlet was 8.1 times higher than that at the inlet, and cyanobacteria became the dominant species accounting for 83% of the total cell density. Nutrient enrichment experiments showed that algae could grow rapidly within 3 days with average specific growth rates (µ) of 0.36-0.42 d-1. The addition of N and P furtherly promoted the algal growth, and µ values of the treatments with P addition were the highest at 0.67-0.83 d-1. These results indicated that even if the WRT was reduced to 3 days, the risk of the occurrence of algal blooms still exists, and this undesirable trend would be enhanced by the short-term external nutrient input. Our findings indicated that the hydrodynamic control measures may not be entirely successful in protecting the drinking water source from algal blooms, especially when its influent has already been under eutrophication.

N-homocysteinylation of α-synuclein promotes its aggregation and neurotoxicity.

The aggregation of α-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Epidemiological evidence indicates that high level of homocysteine (Hcy) is associated with an increased risk of PD. However, the molecular mechanisms remain elusive. Here, we report that homocysteine thiolactone (HTL), a reactive thioester of Hcy, covalently modifies α-synuclein on the K80 residue. The levels of α-synuclein K80Hcy in the brain are increased in an age-dependent manner in the TgA53T mice, correlating with elevated levels of Hcy and HTL in the brain during aging. The N-homocysteinylation of α-synuclein stimulates its aggregation and forms fibrils with enhanced seeding activity and neurotoxicity. Intrastriatal injection of homocysteinylated α-synuclein fibrils induces more severe α-synuclein pathology and motor deficits when compared with unmodified α-synuclein fibrils. Increasing the levels of Hcy aggravates α-synuclein neuropathology in a mouse model of PD. In contrast, blocking the N-homocysteinylation of α-synuclein ameliorates α-synuclein pathology and degeneration of dopaminergic neurons. These findings suggest that the covalent modification of α-synuclein by HTL promotes its aggregation. Targeting the N-homocysteinylation of α-synuclein could be a novel therapeutic strategy against PD.

Altered neurovascular coupling in children with idiopathic generalized epilepsy.

AIMS: Alterations in neuronal activity and cerebral hemodynamics have been reported in idiopathic generalized epilepsy (IGE) patients, possibly resulting in neurovascular decoupling; however, no neuroimaging evidence confirmed this disruption. This study aimed to investigate the possible presence of neurovascular decoupling and its clinical implications in childhood IGE using resting-state fMRI and arterial spin labeling imaging. METHODS: IGE patients and healthy participants underwent resting-state fMRI and arterial spin labeling imaging to calculate degree centrality (DC) and cerebral blood flow (CBF), respectively. Across-voxel CBF-DC correlations were analyzed to evaluate the neurovascular coupling within the whole gray matter, and the regional coupling of brain region was assessed with the CBF/DC ratio. RESULTS: The study included 26 children with IGE and 35 sex- and age-matched healthy controls (HCs). Compared with the HCs, the IGE group presented lower across-voxel CBF-DC correlations, higher CBF/DC ratio in the right posterior cingulate cortex/precuneus, middle frontal gyrus, and medial frontal gyrus (MFG), and lower ratio in the left inferior frontal gyrus. The increased CBF/DC ratio in the right MFG was correlated with lower performance intelligence quotient scores in the IGE group. CONCLUSION: Children with IGE present altered neurovascular coupling, associated with lower performance intelligence quotient scores. The study shed a new insight into the pathophysiology of epilepsy and provided potential imaging biomarkers of cognitive performances in children with IGE.

Corrigendum: Alterations of cerebral perfusion and functional connectivity in children with idiopathic generalized epilepsy.

[This corrects the article DOI: 10.3389/fnins.2022.918513.].

Alterations of Cerebral Perfusion and Functional Connectivity in Children With Idiopathic Generalized Epilepsy.

Background: Studies have demonstrated that adults with idiopathic generalized epilepsy (IGE) have functional abnormalities; however, the neuropathological pathogenesis differs between adults and children. This study aimed to explore alterations in the cerebral blood flow (CBF) and functional connectivity (FC) to comprehensively elucidate the neuropathological mechanisms of IGE in children. Methods: We obtained arterial spin labeling (ASL) and resting state functional magnetic resonance imaging data of 28 children with IGE and 35 matched controls. We used ASL to determine differential CBF regions in children with IGE. A seed-based whole-brain FC analysis was performed for regions with significant CBF changes. The mean CBF and FC of brain areas with significant group differences was extracted, then its correlation with clinical variables in IGE group was analyzed by using Pearson correlation analysis. Results: Compared to controls, children with IGE had CBF abnormalities that were mainly observed in the right middle temporal gyrus, right middle occipital gyrus (MOG), right superior frontal gyrus (SFG), left inferior frontal gyrus (IFG), and triangular part of the left IFG (IFGtriang). We observed that the FC between the left IFGtriang and calcarine fissure (CAL) and that between the right MOG and bilateral CAL were decreased in children with IGE. The CBF in the right SFG was correlated with the age at IGE onset. FC in the left IFGtriang and left CAL was correlated with the IGE duration. Conclusion: This study found that CBF and FC were altered simultaneously in the left IFGtriang and right MOG of children with IGE. The combination of CBF and FC may provide additional information and insight regarding the pathophysiology of IGE from neuronal and vascular integration perspectives.

Tau accelerates α-synuclein aggregation and spreading in Parkinson's disease.

The aggregation and prion-like propagation of α-synuclein are involved in the pathogenesis of Parkinson's disease. However, the underlying mechanisms regulating the assembly and spreading of α-synuclein fibrils remain poorly understood. Tau co-deposits with α-synuclein in the brains of Parkinson's disease patients, suggesting a pathological interplay between them. Here we show that tau interacts with α-synuclein and accelerates its aggregation. Compared with pure α-synuclein fibrils, the tau-modified α-synuclein fibrils show enhanced seeding activity, inducing mitochondrial dysfunction, synaptic impairment and neurotoxicity in vitro. Injection of the tau-modified α-synuclein fibrils into the striatum of mice induces more severe α-synuclein pathology, motor dysfunction and cognitive impairment when compared with the mice injected with pure α-synuclein fibrils. Knockout of tau attenuates the propagation of α-synuclein pathology and Parkinson's disease-like symptoms both in mice injected with α-syn fibrils and α-syn A53T transgenic mice. In conclusion, tau facilitates α-synuclein aggregation and propagation in Parkinson's disease.

C/EBPß/AEP signaling couples atherosclerosis to the pathogenesis of Alzheimer's disease.

Atherosclerosis (ATH) and Alzheimer's disease (AD) are both age-dependent inflammatory diseases, associated with infiltrated macrophages and vascular pathology and overlapping molecules. C/EBPß, an Aß or inflammatory cytokine-activated transcription factor, and AEP (asparagine endopeptidase) are intimately implicated in both ATH and AD; however, whether C/EBPß/AEP signaling couples ATH to AD pathogenesis remains incompletely understood. Here we show that C/EBPß/AEP pathway mediates ATH pathology and couples ATH to AD. Deletion of C/EBPß or AEP from primary macrophages diminishes cholesterol load, and inactivation of this pathway reduces foam cell formation and lesions in aorta in ApoE-/- mice, fed with HFD (high-fat-diet). Knockout of ApoE from 3xTg AD mouse model augments serum LDL and increases lesion areas in the aorta. Depletion of C/EBPß or AEP from 3xTg/ApoE-/- mice substantially attenuates these effects and elevates cerebral blood flow and vessel length, improving cognitive functions. Strikingly, knockdown of ApoE from the hippocampus of 3xTg mice decreases the cerebral blood flow and vessel length and aggravates AD pathologies, leading to cognitive deficits. Inactivation of C/EBPß/AEP pathway alleviates these events and restores cognitive functions. Hence, our findings demonstrate that C/EBPß/AEP signaling couples ATH to AD via mediating vascular pathology.

A synapsin â cleavage fragment contributes to synaptic dysfunction in Alzheimer's disease.

Synaptic dysfunction is a key feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying synaptic dysfunction remain unclear. Here, we show that synapsin Ⅰ, one of the most important synaptic proteins, is fragmented by the cysteine proteinase asparagine endopeptidase (AEP). AEP cleaves synapsin at N82 in the brains of AD patients and generates the C-terminal synapsin Ⅰ (83-705) fragment. This fragment is abnormally distributed in neurons and induces synaptic dysfunction. Overexpression of AEP in the hippocampus of wild-type mice results in the production of the synapsin Ⅰ (83-705) fragment and induces synaptic dysfunction and cognitive deficits. Moreover, overexpression of the AEP-generated synapsin Ⅰ (83-705) fragment in the hippocampus of tau P301S transgenic mice and wild-type mice promotes synaptic dysfunction and cognitive deficits. These findings suggest a novel mechanism of synaptic dysfunction in AD.

Case Report: Biatrial Myxoma With Pulmonary Embolism and Cerebral Embolism: Clinical Experience and Literature Review.

Cardiac myxoma is a common benign primary intracardiac tumor in the general population, and it is generally characterized as a benign tumor, and the morbidity of biatrial myxoma is low. Cases of biatrial myxoma in young patients are extremely rare. Furthermore, severe complications of cardiac myxoma, such as cerebral embolism, can have fatal consequences. Imaging can effectively assist in making a correct diagnosis and a safe and efficient surgical treatment plan. In this case report, we describe a unique case of a young woman who presented with biatrial myxoma accompanied by pulmonary embolism and cerebral embolism. Computed tomography pulmonary angiography (CTPA) detected multiple filling defects in the bilateral cardiac and bilateral inferior pulmonary artery basal branches. Transthoracic echocardiography (TTE) revealed irregular isoechoic masses in the bilateral atrium. Postoperative histopathology confirmed a biatrial myxoma. The patient was discharged on the ninth day after surgery.

Islet amyloid polypeptide cross-seeds tau and drives the neurofibrillary pathology in Alzheimer's disease.

BACKGROUND: The pathologic accumulation and aggregation of tau is a hallmark of tauopathies including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau aggregation in AD remain elusive. The incidence of AD is increased in patients with type 2 diabetes (T2DM), which is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. However, the molecular mechanisms bridging AD and T2DM remain unknown. METHODS: We first examined the presence of IAPP in the neurofibrillary tangles of AD patients. Then we tested the effect of IAPP on tau aggregation. The biochemical and biological characteristics of the IAPP-tau fibrils were tested in vitro. The seeding activity and neurotoxicity of the IAPP-tau fibrils were confirmed in cultured neurons. Lastly, the effect of IAPP on tau pathology and cognitive impairments was determined by injecting the IAPP-tau fibrils and IAPP fibrils into the hippocampus of tau P301S mice. RESULTS: We found that IAPP interacts with tau and accelerates the formation of a more toxic strain, which shows distinct morphology with enhanced seeding activity and neurotoxicity in vitro. Intrahippocampal injection of the IAPP-tau strain into the tau P301S transgenic mice substantially promoted the spreading of tau pathology and induced more severe synapse loss and cognitive deficits, when compared with tau fibrils. Furthermore, intracerebral injection of synthetic IAPP fibrils initiated tauopathy in the brain of tau P301S transgenic mice. CONCLUSIONS: These observations indicate that IAPP acts as a crucial mediator of tau pathology in AD, and provide a mechanistic explanation for the higher risk of AD in individuals with T2DM.

UNC5C Receptor Proteolytic Cleavage by Active AEP Promotes Dopaminergic Neuronal Degeneration in Parkinson's Disease.

Netrin-1 is a chemotropic cue mediating axon growth and neural migration in neuronal development, and its receptors deletion in colorectal cancer and UNC5s act as dependence receptors regulating neuronal apoptosis. Asparagine endopeptidase (AEP) is an age-dependent protease that cuts human alpha-synuclein (α-Syn) at N103 and triggers its aggregation and neurotoxicity. In the current study, it is reported that UNC5C receptor is cleaved by AEP in Parkinson's disease (PD) and facilitates dopaminergic neuronal loss. UNC5C is truncated by active AEP in human α-SNCA transgenic mice in an age-dependent manner or induced by neurotoxin rotenone. Moreover, UNC5C is fragmented by AEP in PD brains, inversely correlated with reduced netrin-1 levels. Netrin-1 deprivation in primary cultures induces AEP and caspase-3 activation, triggering UNC5C proteolytic fragmentation and enhancing neuronal loss. Noticeably, blocking UNC5C cleavage by AEP attenuates netrin-1 deprivation-elicited neuronal death and motor disorders in netrin flox/flox mice. Overexpression of AEP-truncated UNC5C intracellular fragment strongly elicits α-Syn aggregation and dopaminergic loss, locomotor deficits in α-SNCA transgenic mice. Hence, the findings demonstrate that netrin-1 reduction and UNC5C truncation by AEP contribute to PD pathogenesis.