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Understanding the normal function of the Huntingtin (HTT) protein is of significance in the design and implementation of therapeutic strategies for Huntington's disease (HD). Expansion of the CAG repeat in the HTT gene, encoding an expanded polyglutamine (polyQ) repeat within the HTT protein, causes HD and may compromise HTT's normal activity contributing to HD pathology. Here, we investigated the previously defined role of HTT in autophagy specifically through studying HTT's association with ubiquitin. We find that HTT interacts directly with ubiquitin in vitro. Tandem affinity purification was used to identify ubiquitinated and ubiquitin-associated proteins that copurify with a HTT N-terminal fragment under basal conditions. Copurification is enhanced by HTT polyQ expansion and reduced by mimicking HTT serine 421 phosphorylation. The identified HTT-interacting proteins include RNA-binding proteins (RBPs) involved in mRNA translation, proteins enriched in stress granules, the nuclear proteome, the defective ribosomal products (DRiPs) proteome and the brain-derived autophagosomal proteome. To determine whether the proteins interacting with HTT are autophagic targets, HTT knockout (KO) cells and immunoprecipitation of lysosomes were used to investigate autophagy in the absence of HTT. HTT KO was associated with reduced abundance of mitochondrial proteins in the lysosome, indicating a potential compromise in basal mitophagy, and increased lysosomal abundance of RBPs which may result from compensatory up-regulation of starvation-induced macroautophagy. We suggest HTT is critical for appropriate basal clearance of mitochondrial proteins and RBPs, hence reduced HTT proteostatic function with mutation may contribute to the neuropathology of HD.
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Proteína Huntingtina , Lisossomos , Mitocôndrias , Proteínas de Ligação a RNA , Ubiquitina , Proteína Huntingtina/metabolismo , Proteína Huntingtina/genética , Lisossomos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Humanos , Ubiquitina/metabolismo , Mitocôndrias/metabolismo , Autofagia , Animais , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Camundongos , Ligação Proteica , Doença de Huntington/metabolismo , Doença de Huntington/genética , Doença de Huntington/patologia , Peptídeos/metabolismoRESUMO
The human apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found, by examining cells stably expressing each APOE isoform, that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-Golgi compartment is degraded through autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells, and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and internalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that might contribute to AD pathogenesis. This article has an associated First Person interview with the first author of the paper.
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Doença de Alzheimer , Proteômica , Doença de Alzheimer/genética , Animais , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Autofagia , Lisossomos , Camundongos , Isoformas de Proteínas/genéticaRESUMO
BACKGROUND: Given the sparse nature of acute mania or psychosis in primary adrenal insufficiency (PAI), physicians may not be aware of the association of these two entities. OBJECTIVE: To conduct a systematic review of the literature for the purpose of identifying all studies reporting mania and/or psychosis in individuals with PAI. METHOD: We conducted a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the PubMed, Embase, and Web of Science databases from June 22, 1970 to June 22, 2021, for the purpose of identifying all studies reporting instances of mania or psychosis associated with PAI. RESULTS: We identified nine case reports featuring nine patients (M age = 43.3 years, male = 44.4%) over eight countries that fit our inclusion/exclusion criteria. Eight (89%) of the patients had experienced psychosis. Manic and/or psychotic symptom resolution was achieved in 100% of the cases, of which steroid replacement therapy was efficacious in seven (78%) cases and was sufficient in six (67%). CONCLUSION: Acute mania and psychosis in the context of PAI is a very rare presentation of an already uncommon disease. Resolution of acute psychiatric change is reliably achieved with the correction of underlying adrenal insufficiency.
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Doença de Addison , Transtornos Psicóticos , Humanos , Masculino , Adulto , Mania , Transtornos Psicóticos/complicaçõesRESUMO
Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKß, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington's disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKß on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKß phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKß to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKß knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKß in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKß knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKß is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKß is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKß may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.
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Doença de Huntington , Quinase I-kappa B , Animais , Autofagia/genética , Corpo Estriado/citologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Progressão da Doença , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microglia/citologia , Microglia/patologia , Fosforilação/genéticaRESUMO
This study sought to describe head impact exposure in women's collegiate club lacrosse. Eleven women's collegiate club lacrosse players wore head impact sensors during eight intercollegiate competitions. Video recordings of competitions were used to verify impact data. Athletes completed questionnaires detailing their concussion history and perceived head impact exposure. During the monitored games, no diagnosed concussions were sustained. Three athletes reported sustaining head impacts (median = 0; range: 0-3 impacts per game). Six impacts registered by the sensors were verified on video across a total of 81 athlete-game exposures. Verified impacts had a median peak linear acceleration of 21.0 g (range: 18.3 g - 48.3 g) and peak rotational acceleration of 1.1 krad/s2 (range: 0.7 krad/s2 - 5.7 krad/s2). Women competing in collegiate club lacrosse are at a low risk of sustaining head impacts, comparable to previous reports of the high school and collegiate varsity levels of play.
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Traumatismos em Atletas , Concussão Encefálica , Esportes com Raquete , Aceleração , Atletas , Traumatismos em Atletas/epidemiologia , Feminino , Humanos , UniversidadesRESUMO
OBJECTIVE: Minimally invasive anterior lumbar interbody fusion surgery (MIS ALIF) is a technique that restores disc height and lumbar lordosis through a smaller exposure and less soft-tissue trauma compared to open approaches. The mini-open and laparoscopic assistance techniques are two main forms of MIS ALIF. The authors conducted a systematic review that sought to critically summarize the literature on back pain following MIS ALIF. METHODS: In March 2020, the authors searched the PubMed, Web of Science, and Cochrane Library databases for studies describing back pain visual analog scale (VAS) outcomes after MIS ALIF. The following exclusion criteria were applied to studies evaluated in full text: 1) the study included fewer than 20 patients, 2) the mean follow-up duration was shorter than 12 months, 3) the study did not report back pain VAS score as an outcome measure, and 4) MIS ALIF was not studied specifically. The methodology for the included studies were evaluated for potential biases and assigned a level of evidence. RESULTS: There were a total of 552 patients included from 13 studies. The most common biases were selection and interviewer bias. The majority of studies were retrospective. The mean sample size was 42.3 patients. The mean follow-up duration was approximately 41.8 months. The mean postoperative VAS reduction was 5.1 points. The mean VAS reduction for standalone grafts was 5.9 points, and 5.0 points for those augmented with posterior fixation. The most common complications included bladder or urinary dysfunction, infection, and hardware-related complications. CONCLUSIONS: This was a systematic review of back pain outcomes following MIS ALIF. Back pain VAS score was reduced postoperatively across all studies. The complication rates were low overall. MIS ALIF is safe and effective at reducing back pain in appropriate patient populations.
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Dor nas Costas/cirurgia , Vértebras Lombares/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Medição da Dor/métodos , Fusão Vertebral/métodos , Dor nas Costas/diagnóstico por imagem , Humanos , Vértebras Lombares/diagnóstico por imagem , Procedimentos Cirúrgicos Minimamente Invasivos/tendências , Medição da Dor/tendências , Estudos Retrospectivos , Fusão Vertebral/tendências , Resultado do TratamentoRESUMO
The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in ß-amyloid (Aß) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aß clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive-innate immunity cross talk and accelerated disease progression.
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Adaptação Fisiológica , Doença de Alzheimer/fisiopatologia , Microglia/patologia , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Imunoglobulina G/sangue , Camundongos , FagocitoseRESUMO
Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety- and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety- and depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety- and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.
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Ansiedade/psicologia , Neurônios Colinérgicos/metabolismo , Depressão/psicologia , Hipocampo/metabolismo , Resiliência Psicológica , Transdução de Sinais , Estresse Psicológico/metabolismo , Acetilcolinesterase/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Antagonistas Colinérgicos/farmacologia , Antagonistas Colinérgicos/uso terapêutico , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/patologia , Dependovirus/metabolismo , Depressão/complicações , Depressão/tratamento farmacológico , Depressão/metabolismo , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Técnicas de Silenciamento de Genes , Elevação dos Membros Posteriores , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Fisostigmina , RNA Interferente Pequeno/metabolismo , Receptores Colinérgicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Fatores de TempoRESUMO
BACKGROUND: In the management of multi-drug-resistant focal epilepsies, intracranial electrode implantation is used for precise localization of the ictal onset zone. In select patients, subdural grid electrode implantation is utilized. Subdural grid placement traditionally requires large craniotomies to visualize the cortex prior to mapping. However, smaller craniotomies may enable shorter operations and reduced risks. We aimed to compare surgical outcomes between patients undergoing traditional large craniotomies with those undergoing tailored "mini" craniotomies (the "mail-slot" technique) for subdural grid placement. METHODS: This retrospective cohort study included 23 patients who underwent subdural electrode implantation for epilepsy monitoring between 2014 and 2020. Patients were categorized into mini-craniotomies (n = 9) and traditional large craniotomies (n = 14) groups. Demographics, operative details, and outcomes were reviewed. Craniotomy size and number of electrodes were determined via post hoc radiographs. RESULTS: Of the 23 patients studied, the mini group had smaller craniotomy sizes (mean: 22.71 cm2 vs. 65.17 cm2, P < 0.001) and higher electrode-to-size ratios (mean: 4.25 vs. 1.71, P < 0.0001). The mini group had slightly fewer total electrodes (mean: 88.67 vs. 107.43, P = 0.047). No significant differences were found in operative duration, blood loss, invasive electroencephalography duration, complications, or Engel scores between the groups. One patient per group required further invasive epilepsy monitoring for localization; all patients underwent therapeutic surgery. CONCLUSIONS: Our findings suggest that mini-craniotomies for subdural grid placement in epilepsy monitoring offer significant advantages, including smaller craniotomy sizes and shorter operation durations, without compromising safety or efficacy. These results support the trend towards minimally invasive, patient-tailored surgical approaches in epilepsy treatment.
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Craniotomia , Epilepsia Resistente a Medicamentos , Eletrodos Implantados , Espaço Subdural , Humanos , Masculino , Feminino , Estudos Retrospectivos , Adulto , Craniotomia/métodos , Espaço Subdural/cirurgia , Epilepsia Resistente a Medicamentos/cirurgia , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Procedimentos Cirúrgicos Minimamente Invasivos/instrumentação , Adulto Jovem , Estudos de Coortes , Eletroencefalografia/métodos , Adolescente , Resultado do Tratamento , Epilepsias Parciais/cirurgia , Mapeamento Encefálico/métodosRESUMO
BACKGROUND AND OBJECTIVES: We present an illustrative case of spontaneous intracranial hypotension (SIH) in the setting of a suspected C1-2 cerebrospinal fluid (CSF) leak that was successfully treated with muscle, collagen, and epidural blood patch. We examined the literature to identify similar cases reporting Cl-2 retrospinal fluid collections identified on imaging in the setting of SIH and quantified the success of targeted treatment to this area despite previous reports that caution about a "C1-2 false localizing sign." METHODS: A systematic search was performed identifying cases of SIH resulting from CSF leak with C1-2 fluid collection observed on imaging. PubMed, Google Scholar, and Web of Science were queried, and articles were screened for possible inclusion by 2 authors and supervised by the senior author. RESULTS: In total, 28 studies were included with a total of 32 patients. The number of patients in each study with C1-2 fluid collections, number of patients with fluid collections at multiple levels, specific intervention used, and outcomes of each intervention were recorded, with a focus on whether treatment occurred at the levels exhibiting fluid signal. CONCLUSION: Although the C1-2 fluid signal in SIH has previously been described as a "false localizing sign," our study indicates that treating this level as the source of CSF leak results in successful and durable outcomes. Most SIH cases with signal at C1-2 did not have a fluid signal at any other level and were treated successfully and most commonly through epidural blood patch at the C1-2 level. Symptom resolution was also reported after direct repair of C1-2 CSF leaks through primary closure, Gelfoam patch, and muscle fragment with fibrin. In patients with SIH, C1-2 fluid signal, and no other source of CSF leak identified on imaging, surgical intervention at the C1-2 level seemed to have a high success rate.
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We describe a case of a young patient with a recurrent pleomorphic xanthoastrocytoma (PXA) showing unusual cell-in-cell (CiC) phenomena. We observed mostly viable but also necrotic neutrophils engulfed within tumor cells. The recurrent tumor was immunopositive for BRAFV600E mutant protein and showed CDKN2 homozygous deletions typical of PXA. Both genetic alterations were also reported in the original primary tumor. Unlike the original tumor that was GFAP and Olig-2 immunopositive, the recurrent neoplasm was largely negative for GFAP and Olig-2 suggesting dedifferentiation. The large malignant cells that contained the neutrophils were negative for histiocytic and lymphohematopoietic markers. Whereas CDKN2 homozygous deletion is common in PXA, its presence is rare in histiocytic neoplasms. Both reactive astrocytes and glial neoplasms very rarely may engulf neutrophils in a process resembling emperipolesis or cellular cannibalism. Future work may clarify which type of CiC pathway is involved.
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Mesial temporal lobe epilepsy (MTLE) is a common cause of seizures, and hippocampal sclerosis (HS) is the predominant subtype. BRAFV600E mutations in MTLE-HS have only been reported infrequently. Herein, we illustrate the neurologic, radiological, and histopathological details of a patient with MTLE-HS and BRAFV600E mutant neurons. A 31-year-old male with medically refractory epilepsy presented with magnetic resonance imaging (MRI) and electroencephalography (EEG) findings typical of mesial temporal sclerosis without a mass lesion. The surgical specimens showed ILAE Type 1 HS with neurons immunopositive for BRAFV600E mutant protein distributed along the Cornu Ammonis (CA) curvature. Instead of the normal mostly perpendicular orientation of pyramidal neurons relative to the hippocampal surface, the BRAF mutant neurons were often oriented in a parallel manner. On CD34 immunostaining, sparse clusters or nodules of CD34+ stellate cells and single immunopositive stellate cells were identified. BRAFV600E or CD34 immunopositive cells were less than 1 % of total cells. The patient responded well to surgery with no further seizures after 2 years and occasional auras. Hippocampal BRAF mutant non-expansive lesion (HBNL) has been used to describe such lesions with preserved cytoarchitecture and without overt tumor mass. Others may argue for the dual pathology of HS with early ganglioglioma. Whether pre-neoplastic lesions or early tumors, these cases are important for understanding early glioneuronal tumorigenesis and suggest that BRAFV600E studies should be routinely performed on MTLE-HS cases in the setting of clinical trials. With next-generation sequencing, a FANCL deletion was detected in almost half of the alleles in our case, suggesting that many of the histologically normal-appearing cells of the hippocampus contain this alteration. FANCL mutations can result in cytogenetic anomalies and defective DNA repair and therefore may underlie the development of a low frequency BRAF alteration.
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BACKGROUND: Nonfunctional pituitary neuroendocrine tumors (PitNETs) exhibit wide variability in growth pattern based on subtype. Silent corticotroph adenomas (SCAs) demonstrate aggressive growth compared with other nonfunctional pituitary adenomas (NFPAs), especially into the cavernous sinus. In this study, we sought to characterize other growth patterns of SCAs compared with NFPAs. METHODS: We performed a retrospective analysis of all patients with nonfunctional PitNETs treated with surgical resection via endoscopic endonasal approach at a single institution from August 1, 2018, to May 11, 2024. Preoperative computed tomography and magnetic resonance imaging were reviewed to determine extension into the suprasellar space, sphenoid sinus, cavernous sinus, and clivus. RESULTS: The study comprised 91 patients, including 20 SCAs and 71 NFPAs. SCAs demonstrated significantly greater rates of growth into the sphenoid sinus (55.0% vs. 23.94%, P = 0.013), clivus (65.0% vs. 16.9%, P < 0.0001), and cavernous sinus (defined as Knosp grade 3 or 4; 55.0% vs. 23.35%, P = 0.016). Other NFPAs were more likely to grow into the suprasellar space (92.96% vs. 75.0%, P = 0.038). Tumor volume was similar between groups (11.93 cm3 vs. 9.06 cm3, P = 0.2). CONCLUSIONS: Silent corticotroph PitNETs demonstrate predilection for invasion of bony structures, with higher rates of growing through the sellar floor into the sphenoid sinus, growing posteroinferiorly into the clivus and laterally into the cavernous sinuses. Other nonfunctional PitNETs tended to follow the path of least resistance, growing superiorly into the suprasellar space. These differences in growth patterns may account for some of the clinical challenges of treating silent corticotroph PitNETs.
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We describe a rare case of acute mania in the setting of autoimmune adrenalitis. A 41-year-old male with no previous psychiatric diagnoses presented with impulsivity, grandiosity, delusions of telepathy, and hyperreligiosity following a previous hospitalization for an acute adrenal crisis and 2 subsequent days of low-dose corticosteroid treatment. Workups for encephalopathy and lupus cerebritis were negative, raising concern that this presentation might represent steroid-induced psychosis. However, discontinuation of corticosteroids for 5 days did not resolve the patient's manic episode, suggesting that his clinical presentation was more likely new onset of a primary mood disorder or a psychiatric manifestation of adrenal insufficiency itself. The decision was made to restart corticosteroid treatment for the patient's primary adrenal insufficiency (formerly known as Addison disease), coupled with administration of both risperidone and valproate for mania and psychosis. Over the following 2 weeks, the patient's manic symptoms resolved, and he was discharged home. His final diagnosis was acute mania secondary to autoimmune adrenalitis. Although acute mania in adrenal insufficiency is quite rare, clinicians should be aware of the range of psychiatric manifestations associated with Addison disease so that they can pursue the optimal course of both medical and psychiatric treatment for these patients.
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Doença de Addison , Insuficiência Adrenal , Masculino , Humanos , Adulto , Doença de Addison/complicações , Doença de Addison/diagnóstico , Doença de Addison/tratamento farmacológico , Mania/complicações , Risperidona/uso terapêutico , Corticosteroides/uso terapêutico , Insuficiência Adrenal/complicações , Insuficiência Adrenal/diagnósticoRESUMO
Human APOE4 (apolipoprotein E4 isoform) is a powerful genetic risk factor for late-onset Alzheimer disease (AD). Many groups have investigated the effect of APOE4 on the degradation of amyloid ß (Aß), the main component of plaques found in the brains of AD patients. However, few studies have focused on the degradation of APOE itself. We investigated the lysosomal trafficking of APOE in cells and found that APOE from the post-Golgi compartment is degraded through an autophagic process requiring the lysosomal membrane protein LAMP2A. We found that APOE4 accumulates in enlarged lysosomes, alters autophagic flux, and changes the proteomic contents of lysosomes following internalization. This dysregulated lysosomal trafficking may represent one of the mechanisms that contributes to AD pathogenesis.
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Intracranial artery calcifications (IAC), a common and easily identifiable finding on computed tomorgraphy angiography (CTA), has gained recognition as a possible risk factor for ischemic stroke. While atherosclerosis of intracranial arteries is believed to be a mechanism that commonly contributes to ischemic stroke, and coronary artery calcification is well-established as a predictor of both myocardial infarction (MI) and ischemic stroke risk, IAC is not currently used as a prognostic tool for stroke risk or recurrence. This review examines the pathophysiology and prevalence of IAC, and current evidence suggesting that IAC may be a useful tool for prediction of stroke incidence, recurrence, and response to acute ischemic stroke therapy.
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BACKGROUND: In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington's disease (HD) progression. OBJECTIVE: The goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes. METHODS: Primary adult astrocytes were derived from two HD mouse models; the fast-progressing R6/2 and slower progressing Q175. With the use of laser nanosurgery, a single astrocyte was lysed within an astrocyte network. The phagocytic response of astrocytes was observed with phase contrast and by fluorescence microscopy for GFP-LC3 transiently transfected cells. RESULTS: Astrocyte phagocytosis was significantly diminished in primary astrocytes, consistent with the progression of HD in R6/2 and Q175 mouse models. This was defined by the number of astrocytes responding via phagocytosis and by the average number of vesicles formed per cell. GFP-LC3 was found to increasingly localize to phagocytic vesicles over a 20-min imaging period, but not in HD mice, suggesting the involvement of LC3 in astrocyte phagocytosis. CONCLUSION: We demonstrate a progressive decrease in LC3-associated phagocytosis in HD mouse striatal astrocytes.
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Doença de Huntington , Animais , Astrócitos/patologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , FagocitoseRESUMO
Ependymomas have rarely been described to contain pigment other than melanin, neuromelanin, lipofuscin or a combination. In this case report, we present a pigmented ependymoma in the fourth ventricle of an adult patient and review 16 additional cases of pigmented ependymoma from the literature. A 46-year-old female showed up with hearing loss, headaches, and nausea. Magnetic resonance imaging revealed a 2.5 cm contrast-enhancing cystic mass in the fourth ventricle, which was resected. Intraoperatively, the tumor appeared grey-brown, cystic, and was adherent to the brainstem. Routine histology revealed a tumor with true rosettes, perivascular pseudorosettes and ependymal canals consistent with ependymoma, but also showed chronic inflammation and abundant distended pigmented tumor cells that mimicked macrophages in frozen and permanent sections. The pigmented cells were positive for GFAP and negative for CD163 consonant with glial tumor cells. The pigment was negative for Fontana-Masson, positive for Periodic-acid Schiff and autofluorescent, which coincide with characteristics of lipofuscin. Proliferation indices were low and H3K27me3 showed partial loss. H3K27me 3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates the tri-methylation of lysine 27 on histone H3 protein. This methylation classification was compatible with a posterior fossa group B ependymoma (EPN_PFB). The patient was clinically well without recurrence at three-month post-operative follow-up appointment. Our analysis of all 17 cases, including the one presented, shows that pigmented ependymomas are most common in the middle-aged with a median age of 42 years and most have a favorable outcome. However, one patient that also developed secondary leptomeningeal melanin accumulations died. Most (58.8%) arise in the 4th ventricle, while spinal cord (17.6%) and supratentorial locations (17.6%) were less common. The age of presentation and generally good prognosis raise the question of whether most other posterior fossa pigmented ependymomas may also fall into the EPN_PFB group, but additional study is required to address that question.
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BACKGROUND: Altered plasma levels of sphingolipids, including sphingomyelins (SM), have been found in mouse models of Alzheimer's disease (AD) and in AD patient plasma samples. OBJECTIVE: This study assesses fourteen plasma SM species in a late-onset AD (LOAD) patient cohort (nâ=â138). METHODS: Specimens from control, preclinical, and symptomatic subjects were analyzed using targeted mass-spectrometry-based metabolomic methods. RESULTS: Total plasma SM levels were not significantly affected by age or cognitive status. However, one metabolite that has been elevated in manifest AD in several recent studies, SM OHC14:1, was reduced significantly in pre-clinical AD and MCI relative to normal controls. CONCLUSION: We recommend additional comprehensive plasma lipidomics in experimental and clinical biospecimens related to LOAD that might advance the utility of plasma sphingomyelin levels in molecular phenotyping and interpretations of pathobiological mechanisms.
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Doença de Alzheimer/sangue , Doenças Assintomáticas , Metabolômica , Esfingolipídeos/sangue , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Espectrometria de MassasRESUMO
Cellular adhesive connections directed by the extracellular matrix (ECM) and maintenance of cellular homeostasis by autophagy are seemingly disparate functions that are molecularly intertwined, each regulating the other. This is an emerging field in the brain where the interplay between adhesion and autophagy functions at the intersection of neuroprotection and neurodegeneration. The ECM and adhesion proteins regulate autophagic responses to direct protein clearance and guide regenerative programs that go awry in brain disorders. Concomitantly, autophagic flux acts to regulate adhesion dynamics to mediate neurite outgrowth and synaptic plasticity with functional disruption contributed by neurodegenerative disease. This review highlights the cooperative exchange between cellular adhesion and autophagy in the brain during health and disease. As the mechanistic alliance between adhesion and autophagy has been leveraged therapeutically for metastatic disease, understanding overlapping molecular functions that direct the interplay between adhesion and autophagy might uncover therapeutic strategies to correct or compensate for neurodegeneration.