Cytokine and chemokine map of peripheral specific immune cell subsets in Parkinson's disease.

Peripheral immune cells play a vital role in the development of Parkinson's disease (PD). However, their cytokine and chemokine secretion functions remain unclear. Therefore, we aimed to explore the cytokine and chemokine secretion functions of specific immune cell subtypes in drug-naïve patients with PD at different ages of onset. We included 10 early-onset and 10 late-onset patients with PD and age-matched healthy controls (HCs). We used mass cytometry to select specific immune cell subsets and evaluate intracellular cytokine and chemokine expression. Statistical tests included t-tests, analysis of variance, bivariate correlation analysis, and linear regression analysis. Compared with HCs, patients with PD exhibited significantly decreased intracellular pro-inflammatory cytokines and chemokines in selected clusters (e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-1ß, and CC-chemokine ligand (CCL)17). Specific cytokines and cell clusters were associated with clinical symptoms. TNF-α played an important role in cognitive impairment. Intracellular TNF-α levels in the naïve CD8+ T-cell cluster C16 (CD57- naïve CD8+ T) and natural killer (NK) cell cluster C32 (CD57- CD28- NK) were negatively correlated with Montreal Cognitive Assessment scores. The C16 cluster affected cognitive function and motor symptoms. Increased TNF-α and decreased interferon-γ expression in C16 correlated with increased Unified Parkinson's Disease Rating Scale III scores in patients with PD. In summary, we developed a more detailed cytokine and chemokine map of peripheral specific CD8+ T cell and NK cell subsets, which revealed disrupted secretory function in patients with PD and provided unique clues for further mechanistic exploration.

Nigral Iron Deposition Influences Disease Severity by Modulating the Effect of Parkinson's Disease on Brain Networks.

BACKGROUND: In Parkinson's disease (PD), excessive iron deposition in the substantia nigra may exacerbate α-synuclein aggregation, facilitating the degeneration of dopaminergic neurons and their neural projection. OBJECTIVE: To investigate the interaction effect between nigral iron deposition and PD status on brain networks. METHODS: Eighty-five PD patients and 140 normal controls (NC) were included. Network function and nigral iron were measured using multi-modality magnetic resonance imaging. According to the median of nigral magnetic susceptibility of NC (0.095 ppm), PD and NC were respectively divided into high and low nigral iron group. The main and interaction effects were investigated by mixed effect analysis. RESULTS: The main effect of disease was observed in basal ganglia network (BGN) and visual network (VN). The interaction effect between nigral iron and PD status was observed in left inferior frontal gyrus and left insular lobe in BGN, as well as right middle occipital gyrus, right superior temporal gyrus, and bilateral cuneus in VN. Furthermore, multiple mediation analysis revealed that the functional connectivity of interaction effect clusters in BGN and medial VN partially mediated the relationship between nigral iron and Unified Parkinson's Disease Rating Scale II score. CONCLUSION: Our study demonstrates an interaction of nigral iron deposition and PD status on brain networks, that is, nigral iron deposition is associated with the change of brain network configuration exclusively when in PD. We identified a potential causal mediation pathway for iron to affect disease severity that was mediated by both BGN dysfunction and VN hyperfunction in PD.

Altered brain iron depositions from aging to Parkinson's disease and Alzheimer's disease: A quantitative susceptibility mapping study.

Brain iron deposition is a promising marker for human brain health, providing insightful information for understanding aging as well as neurodegenerations, e.g., Parkinson's disease (PD) and Alzheimer's disease (AD). To comprehensively evaluate brain iron deposition along with aging, PD-related neurodegeneration, from prodromal PD (pPD) to clinical PD (cPD), and AD-related neurodegeneration, from mild cognitive impairment (MCI) to AD, a total of 726 participants from July 2013 to December 2020, including 100 young adults, 189 old adults, 184 pPD, 171 cPD, 31 MCI and 51 AD patients, were included. Quantitative susceptibility mapping data were acquired and used to quantify regional magnetic susceptibility, and the resulting spatial standard deviations were recorded. A general linear model was applied to perform the inter-group comparison. As a result, relative to young adults, old adults showed significantly higher iron deposition with higher spatial variation in all of the subcortical nuclei (p < 0.01). pPD showed a high spatial variation of iron distribution in the subcortical nuclei except for substantia nigra (SN); and iron deposition in SN and red nucleus (RN) were progressively increased from pPD to cPD (p < 0.01). AD showed significantly higher iron deposition in caudate and putamen with higher spatial variation compared with old adults, pPD and cPD (p < 0.01), and significant iron deposition in SN compared with old adults (p < 0.01). Also, linear regression models had significances in predicting motor score in pPD and cPD (Rmean = 0.443, Ppermutation = 0.001) and cognition score in MCI and AD (Rmean = 0.243, Ppermutation = 0.037). In conclusion, progressive iron deposition in the SN and RN may characterize PD-related neurodegeneration, namely aging to cPD through pPD. On the other hand, extreme iron deposition in the caudate and putamen may characterize AD-related neurodegeneration.

Inflammatory markers of hemogram parameters as predictive factors for disease severity in anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: This study aimed to investigate the utility of inflammatory markers of hemogram parameters as objective indicators of disease severity in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: A total of 98 patients were retrospectively reviewed. Inflammatory markers of hemogram parameters, including neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio, were acquired within 24 h of admission. We then analyzed their utility as predictive factors for disease severity at different time points assessing with the modified Rankin Scale (mRS). RESULTS: There were 49 patients in the mild group (mRS ≤ 2) and 49 patients in the moderate-to-severe (mRS > 2) group at admission. The moderate-to-severe group presented more frequently with psychiatric symptoms and central hypoventilation, as well as a lower lymphocyte count, a higher neutrophil count, a higher NLR and a higher MLR (all p < 0.05) when compared with the mild group. NLR and MLR showed similar positive correlations with mRS scores (r = 0.40, r = 0.40, both p < 0.001). Further multivariate logistic regression analyses indicated that NLR > 4.232 was an independent risk factor for moderate-to-severe status at admission. Meanwhile, NLR and MLR were associated with disease severity at different stages of follow-up but showed no independent predictive value. CONCLUSION: Our findings suggested that NLR was an independent risk factor for moderate-to-severe status in the initial stage of anti-NMDAR encephalitis with a cut-off value of > 4.232.

cFos-ANAB: A cFos-based Web Tool for Exploring Activated Neurons and Associated Behaviors.

cFos is one of the most widely-studied genes in the field of neuroscience. Currently, there is no systematic database focusing on cFos in neuroscience. We developed a curated database-cFos-ANAB-a cFos-based web tool for exploring activated neurons and associated behaviors in rats and mice, comprising 398 brain nuclei and sub-nuclei, and five associated behaviors: pain, fear, feeding, aggression, and sexual behavior. Direct relationships among behaviors and nuclei (even cell types) under specific stimulating conditions were constructed based on cFos expression profiles extracted from original publications. Moreover, overlapping nuclei and sub-nuclei with potentially complex functions among different associated behaviors were emphasized, leading to results serving as important clues to the development of valid hypotheses for exploring as yet unknown circuits. Using the analysis function of cFos-ANAB, multi-layered pictures of networks and their relationships can quickly be explored depending on users' purposes. These features provide a useful tool and good reference for early exploration in neuroscience. The cFos-ANAB database is available at www.cfos-db.net .

Serum Ceruloplasmin Depletion is Associated With Magnetic Resonance Evidence of Widespread Accumulation of Brain Iron in Parkinson's Disease.

BACKGROUND: Excessive iron accumulation is one of the main pathogeneses of Parkinson's disease (PD). Ceruloplasmin plays an important role in keeping the iron homoeostasis. PURPOSE: To explore the association between serum ceruloplasmin depletion and subcortical iron distribution in PD. STUDY TYPE: Prospective. POPULATION: One hundred and twenty-one normal controls, 34 PD patients with low serum ceruloplasmin (PD-LC), and 28 patients with normal serum ceruloplasmin (PD-NC). SEQUENCE: Enhanced susceptibility-weighted angiography (ESWAN) on a 3 T scanner. ASSESSMENT: Quantitative susceptibility mapping was employed to quantify the regional iron content by using a semi-automatic method. Serum ceruloplasmin concentration was measured from peripheral blood sample. Clinical assessments were conducted by a neurologist. STATISTICAL TESTS: General linear model was used to compare the intergroup difference of region iron distribution among groups, and the statistics was adjusted by Bonferroni method (P < 0.01). Partial correlation analysis was used to detect the association between regional iron distribution and serum ceruloplasmin concentration (P < 0.05). RESULTS: Compared with normal controls, significant iron accumulation in substantia nigra, putamen, and red nucleus was observed in PD-LC, while the only region showing significant iron accumulation was SN in PD-NC. Between PD-NC and PD-LC, the iron accumulation in putamen remained significantly different, which had a negative correlation with serum ceruloplasmin in whole PD patients (r = -0.338, P = 0.008). DATA CONCLUSION: Nigral iron accumulation characterizes PD patients without significant association with serum ceruloplasmin. Differentially, when PD patients appear with reduced serum ceruloplasmin, more widespread iron accumulation would be expected with additionally involving putamen and red nucleus. All these findings provide insightful evidence for the abnormal iron metabolism behind the ceruloplasmin depletion in PD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: 2.

A Patient With Multiple Sclerosis and Coexisting Moyamoya Disease: Why and How.

Introduction: Multiple sclerosis (MS) and moyamoya (MM) are two separate diseases that rarely coexist. A special case with the two diseases coexisting was reported herein, and previously published articles were reviewed to investigate the clinical manifestations, management, outcomes, and underlying pathogenesis. Patient concerns: A 42-year-old male presented with gradual right limb weakness and slow response for 3 months. However, these symptoms abruptly progressed during his hospital stay. Diagnosis: This patient was diagnosed with coexisting MS and MM finally. The diagnosis of MS was made according to McDonald criteria of multiple lesions and multiple time episodes. Meanwhile, cerebral angiography indicated the diagnosis of MM. Interventions: This patient was treated with methylprednisolone and antiplatelet drug and received bilateral superficial temporal artery bypass surgery for the occulted artery. Outcomes: This patient's right limbs recovered to 4/5-grade muscle strength after 1 month of follow-up after hospital discharge, and his speech function improved after 3 months after hospital discharge. Conclusion: We reported a rare scenario in a patient with the coexistence of MS and MM. We suspect that MS might induce immune response that plays a role in the pathogenesis of MM, while MM might accelerate the demyelination of MS. However, the pathogenesis and therapeutics of MM and MS coexistence need further investigation.

Asymmetrical nigral iron accumulation in Parkinson's disease with motor asymmetry: an explorative, longitudinal and test-retest study.

Parkinson's disease (PD) is commonly characterized by asymmetrical motor impairment. This study aimed to clarify the iron distributions in PD patients with significant motor asymmetry and their longitudinal alterations. This study included 123 PD patients and 121 normal controls. Thirty-eight PD patients were revisited. PD patients with significant motor asymmetry were identified by using an objective criterion. Inter-group, inter-hemisphere and inter-visit differences of regional tissue susceptibility were analyzed. Iron accumulation in dominantly and non-dominantly affected substantia nigra (SN) were observed in PD patients with motor asymmetry compared with normal controls (p < 0.005, Bonferroni corrected). Iron accumulation in the dominantly affected SN was significantly higher than that in the non-dominantly affected SN (p < 0.01, Bonferroni corrected). After follow-up, time effect on the iron content in SN was observed, directing to decrease in PD patients with motor asymmetry without hemispherical difference (p < 0.05). In conclusion, asymmetrical iron accumulation in SN was associated with the motor asymmetry in PD at baseline, while along the disease evolution iron content in SN became longitudinally decreased. All these findings provide new evidence for PD pathogenesis that the abnormal iron metabolism in SN is complicated and not always unidirectional.

Rapidly progressive cognitive impairment: an unusual presentation of cerebral venous thrombosis caused by JAK2 V617F-positive primary myelofibrosis: A case report.

RATIONALE: Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition, which mainly manifests as headaches, seizures, and focal neurological deficits. JAK2 mutation in myeloproliferative diseases increases the risk of CVT. PATIENT CONCERNS: This 40-year-old woman suffered from rapidly progressive cognitive impairment and limb weakness. Her symptoms worsened while being treated with mannitol with the diagnose of cerebral hemorrhage. DIAGNOSIS: The patient was diagnosed with CVT and multiple intracranial hemorrhage caused by JAK2 V617F mutation-positive primary myelofibrosis by neuroimage and whole-exome sequencing. INTERVENTION: She received low-molecular-weight heparin sodium 3800 IU twice a day followed by oral anticoagulant therapy. OUTCOMES: The patient showed full recovery from limb weakness and in the follow-up period she noticed no change in her memory. LESSONS: Clinicians should be aware of the possibility of the JAK2 V617F mutation in CVT patients without known causes or risk factors.

TET1 Deficiency Impairs Morphogen-free Differentiation of Human Embryonic Stem Cells to Neuroectoderm.

The TET family of 5-methylcytosine (5mC) dioxygenases plays critical roles in development by modifying DNA methylation. Using CRISPR, we inactivated the TET1 gene in H9 human embryonic stem cells (hESCs). Mutant H9 hESCs remained pluripotent, even though the level of hydroxymethylcytosine (5hmC) decreased to 30% of that in wild-type cells. Neural differentiation induced by dual SMAD inhibitors was not significantly affected by loss of TET1 activity. However, in a morphogen-free condition, TET1 deficiency significantly reduced the generation of NESTIN+SOX1+ neuroectoderm cells from 70% in wild-type cells to 20% in mutant cells. This was accompanied by a 20-fold reduction in the expression level of PAX6 and a significant decrease in the amount of 5hmC on the PAX6 promoter. Overexpression of the TET1 catalytic domain in TET1-deficient hESCs significantly increased 5hmC levels and elevated PAX6 expression during differentiation. Consistent with these in vitro data, PAX6 expression was significantly decreased in teratomas formed by TET1-deficient hESCs. However, TET1 deficiency did not prevent the formation of neural tube-like structures in teratomas. Our results suggest that TET1 deficiency impairs the intrinsic ability of hESCs to differentiate to neuroectoderm, presumably by decreasing the expression of PAX6, a key regulator in the development of human neuroectoderm.

Genetic testing of FUS, HTRA2, and TENM4 genes in Chinese patients with essential tremor.

INTRODUCTION: Essential tremor (ET) is one of the most prevalent movement disorders. The genetic etiology of ET has not been well defined although a significant proportion (≥50%) are familial cases. Linkage analysis and genome-wide association studies (GWASs) have identified several risk variants. In recent years, whole-exome sequencing of ET has revealed several specific causal variants in FUS (p.Q290X), HTRA2 (p.G399S), and TENM4 (c.4324 G>A, c.4100C>A, and c.3412G>A) genes. OBJECTIVE: To investigate the genetic contribution of these three genes to ET, the protein-coding sequences of FUS, HTRA2, and TENM4 were analyzed in a total of 238 ET patients and 272 controls from eastern China using direct Sanger sequencing. RESULTS: We identified two synonymous coding single nucleotide polymorphisms (SNPs), rs741810 and rs1052352 in FUS, and three previously reported synonymous SNPs, rs11237621, rs689369, and rs2277277 in TENM4. No nonsynonymous exonic variants were identified in these subjects. We found that the frequency of the rs1052352C allele was significantly higher (P = .001) in the ET group than in the control group. CONCLUSION: Overall, our findings suggest that rs1052352 of FUS might contribute to ET risk in Chinese population.

Oscillation-specific nodal alterations in early to middle stages Parkinson's disease.

BACKGROUND: Different oscillations of brain networks could carry different dimensions of brain integration. We aimed to investigate oscillation-specific nodal alterations in patients with Parkinson's disease (PD) across early stage to middle stage by using graph theory-based analysis. METHODS: Eighty-eight PD patients including 39 PD patients in the early stage (EPD) and 49 patients in the middle stage (MPD) and 36 controls were recruited in the present study. Graph theory-based network analyses from three oscillation frequencies (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; slow-3: 0.073-0.198 Hz) were analyzed. Nodal metrics (e.g. nodal degree centrality, betweenness centrality and nodal efficiency) were calculated. RESULTS: Our results showed that (1) a divergent effect of oscillation frequencies on nodal metrics, especially on nodal degree centrality and nodal efficiency, that the anteroventral neocortex and subcortex had high nodal metrics within low oscillation frequencies while the posterolateral neocortex had high values within the relative high oscillation frequency was observed, which visually showed that network was perturbed in PD; (2) PD patients in early stage relatively preserved nodal properties while MPD patients showed widespread abnormalities, which was consistently detected within all three oscillation frequencies; (3) the involvement of basal ganglia could be specifically observed within slow-5 oscillation frequency in MPD patients; (4) logistic regression and receiver operating characteristic curve analyses demonstrated that some of those oscillation-specific nodal alterations had the ability to well discriminate PD patients from controls or MPD from EPD patients at the individual level; (5) occipital disruption within high frequency (slow-3) made a significant influence on motor impairment which was dominated by akinesia and rigidity. CONCLUSIONS: Coupling various oscillations could provide potentially useful information for large-scale network and progressive oscillation-specific nodal alterations were observed in PD patients across early to middle stages.

Presence of Multiple Autoimmune Antibodies Involved in Concurrent Myositis and Myocarditis and Myasthenia Gravis Without Thymoma: A Case Report.

Inflammatory myositis (IM) and myasthenia gravis (MG) are both immune disorders involving muscle. The concurrent presence of both conditions in the same patient is extremely rare and the diagnosis is important and challenging. Here, we report a case of concurrent myositis and myocarditis and MG without thymoma in a 69-year-old man with progressive proximal muscle weakness and dysphagia. As an atypical finding, the laboratory immunity assay showed the presence of multiple antibodies (acetylcholine receptor-Ab, titin-Ab, M7-Ab, smooth muscle alpha (SMA)-Ab, and citrate acid extract (CAE)-Ab). We predicted that thymoma-associated antibodies (titin-Ab, SMA-Ab, and CAE-Ab) and anti-M7 antibodies play an important role in the concurrent presence of MG and myositis and myocarditis. In this overlap case, immunotherapy was determined to be effective.

Plasmid-based generation of neural cells from human fibroblasts using non-integrating episomal vectors.

Differentiation of human fibroblasts into functional neurons depends on the introduction of viral-mediated transcription factors, which present risks of viral gene integration and tumorigenicity. In recent years, although some studies have been successful in directly inducing neurons through sustained expression of small molecule compounds, they have only been shown to be effective on mouse-derived cells. Thus, herein we delivered vectors containing Epstein-Barr virus-derived oriP/Epstein-Barr nuclear antigen 1 encoding the neuronal transcription factor, Ascl1, the neuron-specific microRNA, miR124, and a small hairpin directed against p53, into human fibroblasts. Cells were incubated in a neuron-inducing culture medium. Immunofluorescence staining was used to detect Tuj-1, microtubule-associated protein 2, neuron-specific nucleoprotein NeuN and nerve cell adhesion molecules in the induced cells. The proportion of Tuj1-positive cells was up to 36.7% after induction for 11 days. From day 21, these induced neurons showed neuron-specific expression patterns of microtubule-associated protein 2, NeuN and neural cell adhesion molecule. Our approach is a simple, plasmid-based process that enables direct reprogramming of human fibroblasts into neurons, and provides alternative avenues for disease modeling and neurodegenerative medicine.

Iron-related nigral degeneration influences functional topology mediated by striatal dysfunction in Parkinson's disease.

In Parkinson's disease (PD), iron accumulation in the substantia nigra (SN) exacerbates oxidative stress and α-synuclein aggregation, leading to neuronal death. However, the influence of iron-related nigral degeneration on the subcortical function and global network configuration in PD remains unknown. Ninety PD patients and 38 normal controls underwent clinical assessments and multimodality magnetic resonance imaging scans. Iron accumulation in the inferior SN and disrupted functional connectivity between the bilateral striatums were observed in PD, and negative correlation between them was found in the whole population. The binarized functional network exhibited enhanced global efficiency and reduced local efficiency while the weighted functional network exhibited reduction in both, and both changes were correlated with nigral iron accumulation in PD. Mediation analysis demonstrated that the functional connectivity between bilateral striatums was a mediator between the nigral iron accumulation and weighted functional network alterations. In conclusion, our findings reveal that iron-related nigral degeneration possibly influences the functional topology mediated by striatal dysfunction, which extends the scientific understanding of PD pathogenesis.

Genetic analysis of ATP13A2, PLA2G6 and FBXO7 in a cohort of Chinese patients with early-onset Parkinson's disease.

Several genes have already been certified as causative genes in patients with autosomal recessive early-onset Parkinson's syndrome with pyramidal tract signs, including ATP13A2, PLA2G6 and FBXO7. Variants in these three genes may also play roles in early-onset Parkinson's disease (EOPD). In order to investigate the contribution of genetic variants in these three genes to Chinese sporadic EOPD patients, we screened 101 Chinese sporadic EOPD patients and 83 age- and sex-matched healthy controls using direct sequencing. Interpretation of those detected variants was performed based on the guidelines developed by the American College of Medical Genetics and Genomics (ACMG). Two missense variants, p.G360E and p.T733M, with "uncertain significance" classification were identified in the ATP13A2 gene and five synonymous variants were significantly over-represented in EOPD patients. Two missense variants, p.R53C and p.T319M, were absent in both our control group and online databases, classified as "likely pathogenic" in the PLA2G6 gene. Only benign variants were identified in the FBXO7 gene. These results indicate that rare variants of PLA2G6 may contribute to PD susceptibility in Chinese population, the ATP13A2 might be associated with higher risk for sporadic EOPD, while the FBXO7 gene doesn't seem to be a risk factor to develop sporadic PD in Chinese population. Further biochemical and molecular biological studies needs to be conducted to support our main results in our future researches.

Recent Advances: Decoding Alzheimer's Disease With Stem Cells.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that destroys cognitive functions. Recently, a number of high-profile clinical trials based on the amyloid cascade hypothesis have encountered disappointing results. The failure of these trials indicates the necessity for novel therapeutic strategies and disease models. In this review, we will describe how recent advances in stem cell technology have shed light on a novel treatment strategy and revolutionized the mechanistic investigation of AD pathogenesis. Current advances in promoting endogenous neurogenesis and transplanting exogenous stem cells from both bench research and clinical translation perspectives will be thoroughly summarized. In addition, reprogramming technology-based disease modeling, which has shown improved efficacy in recapitulating pathological features in human patients, will be discussed.

Stable cell lines of human SH-SY5Y uniformly expressing wild-type or mutant-type FERM domain containing 7 gene.

It has been reported that FERM domain containing 7 (FRMD7) may cause X-linked idiopathic congenital nystagmus (ICN). A total of >40 mutations of the FRMD7 gene have been identified, however their pathogenic role remains unclear. In the present study, enhanced green fluorescent protein-tagged wild-type (WT) and mutant (MT) FRMD7 (c. C781>G) were expressed in stably expressing human neuroblastoma SH-SY5Y cells following viral transfection and antibiotic selection. Uniform expression of the FRMD7 fusion proteins was confirmed via fluorescence microscopy and western blotting. The expression profiles of neuron-specific proteins and Rho guanine triphosphatases (GTPases) differed significantly between the wild-type and mutant cell lines. Levels of Mtap2, NF-M, nestin, GAP43 and Rac1 mRNA were significantly increased in MT-FRMD7 cells compared with controls (P<0.01). However, the expression of Rac1 protein did not differ significantly among the two cell lines. Taken together, the results of the current study suggest that MT-FRMD7 influences the expression of neuron-specific genes and Rho GTPases, which may be involved in the pathogenesis of ICN. The FRMD7 stable expression cell line may facilitate future studies investigating the role of this protein in neuronal development.

Exosomes Secreted from HEK293-APP Swe/Ind Cells Impair the Hippocampal Neurogenesis.

This study aimed to investigate the neurotoxicity of exosomes to cultured neuroblastoma and neurons in vitro and to mature and newborn neurons in the hippocampus in vivo. Recent in vitro and in vivo studies have shown that exosomes, small membranous vesicles secreted from many cell types, contain pathogenic proteins including full-length amyloid precursor protein (flAPP) and amyloid precursor protein (APP) metabolites. However, the function of these exosomes in Alzheimer disease (AD) has not been much explored. In the present study, exosomes were harvested from the conditioned medium of HEK293-APP Swe/Ind cells and injected into the hippocampal dentate gyrus region via a stereotactic method to detect their effects on the neuronal survival in vivo. These exosomes containing pathogenic proteins showed high neurotoxicity and could impair neurogenesis in the hippocampus. The data demonstrated that exosomes secreted from sick cells might damage neurogenesis and promote disease progression in AD.

Hypersomnia as the first presentation in a patient with insulinoma: A case report and review of the literature.

Insulinoma is a rare neuroendocrine tumor. Hypersomnia as the first presentation in a patient with insulinoma is even more rare and may be easy to misdiagnose. We are herein reporting a case of insulinoma initially presenting with prolonged sleep time and extreme difficulty in waking. The abovementioned symptoms occurred every 2-3 months. Over the last 2 months, the attacks had become more frequent and severe. On computed tomography examination, a 12×9-mm cystic nodule was detected in the uncinate process of the pancreas, which was pathologically diagnosed as insulinoma. Since resection, the symptom of hypersomnia has not occurred again. The aim of the present report was to raise awareness among physicians to consider insulinoma in the differential diagnosis of hypersomnia in patients without other known diseases.