RESUMEN
Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.
Asunto(s)
Cerebro/patología , Proteína 4 Similar a ELAV/genética , Ácido Glutámico/metabolismo , Mutación/genética , Neuronas/patología , Organoides/metabolismo , Empalme del ARN/genética , Proteínas tau/genética , Autofagia/efectos de los fármacos , Autofagia/genética , Biomarcadores/metabolismo , Tipificación del Cuerpo/efectos de los fármacos , Tipificación del Cuerpo/genética , Muerte Celular/efectos de los fármacos , Línea Celular , Humanos , Hidrazonas/farmacología , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Morfolinas/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Organoides/efectos de los fármacos , Organoides/ultraestructura , Fosforilación/efectos de los fármacos , Pirimidinas/farmacología , Empalme del ARN/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Gránulos de Estrés/efectos de los fármacos , Gránulos de Estrés/metabolismo , Sinapsis/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.
Asunto(s)
Enfermedades del Sistema Nervioso Central/genética , Mutación Missense , Proteínas Nucleares/metabolismo , Enfermedades del Sistema Nervioso Periférico/genética , Fosfotransferasas/metabolismo , ARN de Transferencia/metabolismo , Factores de Transcripción/metabolismo , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Animales , Enfermedades del Sistema Nervioso Central/patología , Cerebro/patología , Preescolar , Endorribonucleasas/metabolismo , Femenino , Fibroblastos/metabolismo , Humanos , Lactante , Masculino , Ratones , Ratones Endogámicos CBA , Microcefalia/genética , Enfermedades del Sistema Nervioso Periférico/patología , ARN de Transferencia/genética , Proteínas de Unión al ARNRESUMEN
OBJECTIVE: To investigate the relationship between neurocognitive deficits and structural changes on brain magnetic resonance imaging in people living with HIV (PLWH) with good virological control on combination antiretroviral therapy, compared with socioeconomically matched control participants recruited from the same communities. METHODS: Brain magnetic resonance imaging scans, and clinical and neuropsychological data were obtained from virologically controlled PLWH (viral load of <50 c/mL and at least 1 year of combination antiretroviral therapy) and socioeconomically matched control participants. Magnetic resonance imaging was carried out on 3 T scanner with 8-channel head coils and segmented using Classification using Derivative-based Features. Multiple regression analysis was performed to examine the association between brain volume and various clinical and neuropsychiatric parameters adjusting for age, race, and sex. To evaluate longitudinal changes in brain volumes, a random coefficient model was used to evaluate the changes over time (age) adjusting for sex and race. RESULTS: The cross-sectional study included 164 PLWH and 51 controls, and the longitudinal study included 68 PLWH and 20 controls with 2 or more visits (mean 2.2 years, range 0.8-5.1 years). Gray matter (GM) atrophy rate was significantly higher in PLWH compared with control participants, and importantly, the GM and global atrophy was associated with the various neuropsychological domain scores. Higher volume of white matter hyperintensities were associated with increased atherosclerotic cardiovascular disease risk score, and decreased executive functioning and memory domain scores in PLWH. INTERPRETATION: These findings suggest ongoing neurological damage even in virologically controlled participants, with significant implications for clinical management of PLWH. ANN NEUROL 2024;95:941-950.
Asunto(s)
Sustancia Gris , Infecciones por VIH , Trastornos Neurocognitivos , Sustancia Blanca , Humanos , Estudios Transversales , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico por imagen , Infecciones por VIH/patología , Infecciones por VIH/terapia , Trastornos Neurocognitivos/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Adulto , Persona de Mediana Edad , Masculino , Femenino , Cerebro/diagnóstico por imagen , Cerebro/patología , Estudios LongitudinalesRESUMEN
PURPOSE: Cerebellum modulates the amplitude of resting tremor in Parkinson's disease (PD) via cerebello-thalamo-cortical (CTC) circuit. Tremor-related white matter alterations have been identified in PD patients by pathological studies, but in vivo evidence is limited; the influence of such cerebellar white matter alterations on tremor-related brain network, including CTC circuit, is also unclear. In this study, we investigated the cerebral and cerebellar white matter alterations in PD patients with resting tremor using diffusion tensor imaging (DTI). METHODS: In this study, 30 PD patients with resting tremor (PDWR), 26 PD patients without resting tremor (PDNR), and 30 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort were included. Tract-based spatial statistics (TBSS) and region of interest-based analyses were conducted to determine white matter difference. Correlation analysis between DTI measures and clinical characteristics was also performed. RESULTS: In the whole brain, TBSS and region of interest-based analyses identified higher fractional anisotropy (FA) value, lower mean diffusivity (MD) value, and lower radial diffusivity (RD) in multiple fibers. In the cerebellum, TBSS analysis revealed significantly higher FA value, decreased RD value as well as MD value in multiple cerebellar tracts including the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) when comparing the PDWR with HC, and higher FA value in the MCP when compared with PDNR. CONCLUSION: We identified better white matter integrity in the cerebrum and cerebellum in PDWR indicating a potential association between the cerebral and cerebellar white matter and resting tremor in PD.
Asunto(s)
Cerebro , Enfermedad de Parkinson , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Temblor/diagnóstico por imagen , Temblor/patología , Imagen de Difusión Tensora , Encéfalo/patología , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Cerebro/patologíaRESUMEN
Astroblastomas are considered extremely rare tumors and have not been formally graded. While gene mutations are used to diagnose these tumors, further research is needed for proper diagnosis and classification. This report presents a case of astroblastoma in a 44-year-old woman. A tumor was found to have histology consistent with astroblastoma, with no MN1 gene changes. Several mutations were present, and fusion of the EWSR1 and EZHIP genes was noted, which has never been reported before in the literature. Fusions of the EWSR1 gene could be characteristics of astroblastomas, in addition to MN1 alterations, and identification of these mutations could help in the diagnosis of these rare tumors.
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Neoplasias Encefálicas , Cerebro , Neoplasias Neuroepiteliales , Femenino , Humanos , Adulto , Transactivadores/genética , Neoplasias Neuroepiteliales/patología , Factores de Transcripción/genética , Diagnóstico Diferencial , Cerebro/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Fusión Génica , Proteína EWS de Unión a ARN/genéticaRESUMEN
Introduction: Cerebral radiation necrosis is rarely encountered in pediatric patients. This case report describes a child with cerebral radiation necrosis who was successfully treated using corticosteroids, bevacizumab, and hyperbaric oxygenation. Case report: A 3-year-old boy developed progressive extremity weakness six months after the completion of radiation therapy for the treatment of a neuroepithelial malignancy. Treatment with corticosteroids and bevacizumab was initiated, but his symptoms did not improve, and he was then referred for hyperbaric oxygen therapy. After completing 60 hyperbaric treatments, he experienced significant improvements in mobility, which remained stable over the next year. Discussion: Cerebral radiation necrosis typically presents in children with symptoms of ataxia or headache. Corticosteroids and bevacizumab are common treatments, but hyperbaric oxygen therapy has also been studied as a therapeutic modality for this condition. When considering the use of hyperbaric oxygenation in pediatric patients, careful attention to treatment planning and patient safety can reduce the risks of adverse events such as middle ear barotrauma and confinement anxiety. Conclusion: In addition to other available pharmacologic therapies, hyperbaric oxygenation should be considered for the treatment of pediatric patients with cerebral radiation necrosis.
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Lesiones Encefálicas , Cerebro , Oxigenoterapia Hiperbárica , Traumatismos por Radiación , Preescolar , Humanos , Masculino , Barotrauma/etiología , Barotrauma/prevención & control , Bevacizumab/uso terapéutico , Oxigenoterapia Hiperbárica/efectos adversos , Oxigenoterapia Hiperbárica/métodos , Necrosis/etiología , Necrosis/terapia , Cerebro/patología , Cerebro/efectos de la radiación , Lesiones Encefálicas/etiología , Lesiones Encefálicas/patología , Lesiones Encefálicas/terapia , Traumatismos por Radiación/etiología , Traumatismos por Radiación/patología , Traumatismos por Radiación/terapia , Neoplasias Neuroepiteliales/radioterapiaRESUMEN
Alzheimer's disease (AD) is the most common age-associated dementia with complex pathological hallmarks. Mitochondrion, synaptosome, and myelin sheath appear to be vulnerable and play a key role in the pathogenesis of AD. To clarify the early mechanism associated with AD, followed by subcellular components separation, we performed iTRAQ (isobaric tags for relative and absolute quantification)-based proteomics analysis to simultaneously investigate the differentially expressed proteins (DEPs) within the mitochondria, synaptosome, and myelin sheath in the cerebrum of the 6-month-old triple transgenic AD (3 × Tg-AD) and 6-month-old wild-type (WT) mice. A large number of DEPs between the AD and WT mice were identified. Most of them are related to mitochondria and synaptic dysfunction and cytoskeletal protein change. Differential expressions of Lrpprc, Nefl, and Sirpa were verified by Western blot analysis. The results suggest that decreased energy metabolism, impaired amino acid metabolism and neurotransmitter synthesis, increase compensatory fatty acid metabolism, up-regulated cytoskeletal protein expression, and oxidative stress are the early events of AD. Among these, mitochondrial damage, synaptic dysfunction, decreased energy metabolism, and abnormal amino acid metabolism are the most significant events. The results indicate that it is feasible to separate and simultaneously perform proteomics analysis on the three subcellular components.
Asunto(s)
Enfermedad de Alzheimer , Cerebro , Enfermedad de Alzheimer/patología , Aminoácidos/metabolismo , Animales , Cerebro/metabolismo , Cerebro/patología , Proteínas del Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Mitocondrias/metabolismo , Vaina de Mielina/metabolismo , Proteómica/métodos , Sinaptosomas/metabolismoRESUMEN
BACKGROUND: Adult patients with moyamoya disease (MMD) occasionally exhibit cerebral hyperperfusion after arterial bypass surgery, leading to persistent cognitive decline. The present supplementary analysis of a prospective 5-year cohort study aimed to determine whether cerebral hyperperfusion after arterial bypass surgery for adult patients with misery perfusion due to ischemic MMD causes cerebral atrophy, and whether the development of cerebral atrophy is related to persistent cognitive decline. METHODS: In total, 31 patients who underwent arterial bypass surgery also underwent fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and neuropsychological testing before surgery and at the end of a 5-year follow-up. The development of cerebral hyperperfusion and hyperperfusion syndrome after surgery was defined based on brain perfusion single-photon emission computed tomography (SPECT) findings and clinical symptoms. Univariate and multivariate logistic regression analyses of factors related to the development of cerebral atrophy on FLAIR MRI or cognitive decline on neuropsychological testing at the end of the 5-year follow-up were performed. RESULTS: Eleven patients (35%) developed cerebral atrophy in the frontal lobe where the superficial temporal artery was anastomosed. Cerebral hyperperfusion on brain perfusion SPECT (odds ratio [OR], 50.6; p = 0.0008) or cerebral hyperperfusion syndrome (OR, 41.8; p = 0.0026) was independently associated with the development of cerebral atrophy, and cerebral atrophy development was significantly associated with cognitive decline (OR, 47.7; p = 0.0010). CONCLUSIONS: Cerebral hyperperfusion after arterial bypass surgery for adult patients with misery perfusion due to ischemic MMD can cause cerebral atrophy related to persistent cognitive decline.
Asunto(s)
Revascularización Cerebral , Enfermedad de Moyamoya , Adulto , Atrofia/etiología , Revascularización Cerebral/efectos adversos , Revascularización Cerebral/métodos , Circulación Cerebrovascular , Cerebro/patología , Estudios de Cohortes , Humanos , Arteria Cerebral Media/cirugía , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/cirugía , Complicaciones Posoperatorias/diagnóstico por imagen , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Objective: To investigate clinicopathological features of multinodular and vacuolar neurodegenerative tumor (MVNT) of the cerebrum, and to investigate its immunophenotype, molecular characteristics and prognosis. Methods: Four cases were collected at the General Hospital of Southern Theater Command, Guangzhou, China and one case was collected at the First People's Hospital of Huizhou, China from 2013 to 2021. Clinical, histological, immunohistochemical and molecular characteristics of these five cases were analyzed. Follow-up was carried out to evaluate their prognoses. Results: There were four females and one male, with an average age of 42 years (range, 17 to 51 years). Four patients presented with seizures, while one presented with discomfort on the head. Pre-operative imaging demonstrated non-enhancing, T2-hyperintense multinodular lesions in the deep cortex and superficial white matter of the frontal (n=1) or temporal lobes (n=4). Microscopically, the tumor cells were mostly arranged in discrete and coalescent nodules primarily within the deep cortical ribbon and superficial subcortical white matter. The tumors were composed of large cells with ganglionic morphology, vesicular nuclei, prominent nucleoli and amphophilic or lightly basophilic cytoplasm. They exhibited varying degrees of matrix vacuolization. Vacuolated tumor cells did not show overt cellular atypia or any mitotic activities. Immunohistochemically, tumor cells exhibited widespread nuclear staining for the HuC/HuD neuronal antigens, SOX10 and Olig2. Expression of other neuronal markers, including synaptophysin, neurofilament and MAP2, was patchy to absent. The tumor cells were negative for NeuN, GFAP, p53, H3K27M, IDH1 R132H, ATRX, BRG1, INI1 and BRAF V600E. No aberrant molecular changes were identified in case 3 and case 5 using next-generation sequencing (including 131 genes related to diagnosis and prognosis of central nervous system tumors). All patients underwent complete or substantial tumor excision without adjuvant chemoradiotherapy. Post-operative follow-up information over intervals of 6 months to 8 years was available for five patients. All patients were free of recurrence. Conclusions: MVNT is an indolent tumor, mostly affecting adults, which supports classifying MVNT as WHO grade 1. There is no tumor recurrence even in the patients treated with subtotal surgical excision. MVNTs may be considered for observation or non-surgical treatments if they are asymptomatic.
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Neoplasias Encefálicas , Cerebro , Adulto , Femenino , Humanos , Masculino , Neoplasias Encefálicas/patología , Cerebro/metabolismo , Cerebro/patología , Neuronas/metabolismo , Convulsiones , Lóbulo Temporal/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
Individual-based morphological brain networks built from T1-weighted magnetic resonance imaging (MRI) reflect synchronous maturation intensities between anatomical regions at the individual level. Autism spectrum disorder (ASD) is a socio-cognitive and neurodevelopmental disorder with high neuroanatomical heterogeneity, but the specific patterns of morphological networks in ASD remain largely unexplored at the individual level. In this study, individual-based morphological networks were constructed by using high-resolution structural MRI data from 40 young children with ASD (age range: 2-8 years) and 38 age-, gender-, and handedness-matched typically developing children (TDC). Measurements were recorded as threefold. Results showed that compared with TDC, young children with ASD exhibited lower values of small-worldness (i.e., σ) of individual-level morphological brain networks, increased morphological connectivity in cortico-striatum-thalamic-cortical (CSTC) circuitry, and decreased morphological connectivity in the cortico-cortical network. In addition, morphological connectivity abnormalities can predict the severity of social communication deficits in young children with ASD, thus confirming an associational impact at the behavioral level. These findings suggest that the morphological brain network in the autistic developmental brain is inefficient in segregating and distributing information. The results also highlight the crucial role of abnormal morphological connectivity patterns in the socio-cognitive deficits of ASD and support the possible use of the aberrant developmental patterns of morphological brain networks in revealing new clinically-relevant biomarkers for ASD.
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Trastorno del Espectro Autista/patología , Trastorno del Espectro Autista/fisiopatología , Cerebro/patología , Red Nerviosa/patología , Tálamo/patología , Trastorno del Espectro Autista/diagnóstico por imagen , Cerebro/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/diagnóstico por imagen , Tálamo/diagnóstico por imagenRESUMEN
Glucocorticoids (GCs) regulate astrocyte function, while glutamine synthetase (GS), an enzyme highly expressed in astrocytes, is one of the most remarkable GCs-induced genes. GCs mediate their effects through their cognate glucocorticoid receptor (GRα and GRß isoforms); however, the mechanism via which these isoforms regulate GS activity in astrocytes remains unknown. We used dexamethasone (DEX), a classical GRα/GRß agonist, RU486, which is a specific GRß ligand, and Compound A, a known "dissociated" ligand, to delineate the mechanism via which GR modulates GS activity. Aged Mouse Cerebral Hemisphere astrocytes were treated with DEX (1 µM), RU486 (1 nM-1 µM) or compound A (10 µM), alone or in combination with DEX. GS activity and expression, GR isoforms (mRNA and protein levels), and GRα subcellular trafficking were measured. DEX increased GS activity in parallel with GRα nuclear translocation. RU486 increased GS activity in absence of GRα nuclear translocation implicating thus a role of GRß-mediated mechanism compound A had no effect on GS activity implicating a GRα-GRE-mediated mechanism. None of the compounds affected whole-cell GRα protein content. DEX reduced GRα and GRß mRNA levels, while RU486 increased GRß gene expression. We provide evidence that GS activity, in astrocytes, is regulated via GRα- and GRß-mediated pathways with important implications in pathological conditions in which astrocytes are involved.
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Astrocitos/metabolismo , Cerebro/metabolismo , Glutamato-Amoníaco Ligasa/metabolismo , Receptores de Glucocorticoides/metabolismo , Acetatos/farmacología , Factores de Edad , Animales , Antiinflamatorios/farmacología , Antiinflamatorios no Esteroideos/farmacología , Astrocitos/efectos de los fármacos , Células Cultivadas , Cerebro/efectos de los fármacos , Cerebro/patología , Dexametasona/farmacología , Antagonistas de Hormonas/farmacología , Ratones , Mifepristona/farmacología , Tiramina/análogos & derivados , Tiramina/farmacologíaRESUMEN
BACKGROUND: The impact of pediatric chronic kidney disease (pCKD) on the brain remains poorly defined. The objective of this study was to compare brain morphometry between children with early-stage pCKD and typically developing peers using structural magnetic resonance imaging (MRI). METHODS: The sample age range was 6-16 years. A total of 18 children with a diagnosis of pCKD (CKD stages 1-3) due to congenital anomalies of the kidney and urinary tract and 24 typically developing peers were included. Volumetric data from MRI and neurocognitive testing were compared using linear models including pCKD status, age, maternal education level, and socioeconomic status. RESULTS: Cerebellar gray matter volume was significantly smaller in pCKD, t(38) = -2.71, p = 0.01. In contrast, cerebral gray matter volume was increased in pCKD, t(38) = 2.08, p = 0.04. Reduced cerebellum gray matter volume was associated with disease severity, operationalized as estimated glomerular filtration rate (eGFR), t(14) = 2.21, p = 0.04 and predicted lower verbal fluency scores in the pCKD sample. Enlarged cerebral gray matter in the pCKD sample predicted lower scores on mathematics assessment. CONCLUSIONS: This study provides preliminary evidence for a morphometric underpinning to the cognitive deficits observed in pCKD. IMPACT: The impact of pediatric chronic kidney disease (CKD) on the brain remains poorly defined, with no data linking brain morphometry and observed cognitive deficits noted in this population. We explored the relationship between brain morphometry (using structural magnetic resonance imaging), cognition, and markers of CKD. Cerebellar and cerebral gray matter volumes are different in early CKD. Volumetric decreases in cerebellar gray matter are predicted by lower eGFR, suggesting a link between disease and brain morphometry. Reduced cerebellar gray matter predicted lower verbal fluency for those with pCKD. Enlarged cerebral gray matter in the pCKD sample predicted lower mathematics performance.
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Sustancia Gris/patología , Trastornos Neurocognitivos/etiología , Insuficiencia Renal Crónica/patología , Adolescente , Cerebelo/patología , Cerebro/patología , Niño , Escolaridad , Femenino , Tasa de Filtración Glomerular , Sustancia Gris/diagnóstico por imagen , Humanos , Riñón/anomalías , Imagen por Resonancia Magnética , Masculino , Matemática , Madres/educación , Trastornos Neurocognitivos/diagnóstico por imagen , Neuroimagen , Tamaño de los Órganos , Proyectos Piloto , Insuficiencia Renal Crónica/complicaciones , Clase Social , Trastornos del Habla/diagnóstico por imagen , Trastornos del Habla/etiología , Sistema Urinario/anomalíasRESUMEN
Neurodevelopmental abnormalities are the most common noncardiac complications in patients with congenital heart disease (CHD). Prenatal brain abnormalities may be due to reduced oxygenation, genetic factors, or less commonly, teratogens. Understanding the contribution of these factors is essential to improve outcomes. Because primary sulcal patterns are prenatally determined and under strong genetic control, we hypothesized that they are influenced by genetic variants in CHD. In this study, we reveal significant alterations in sulcal patterns among subjects with single ventricle CHD (n = 115, 14.7 ± 2.9 years [mean ± standard deviation]) compared with controls (n = 45, 15.5 ± 2.4 years) using a graph-based pattern-analysis technique. Among patients with CHD, the left hemisphere demonstrated decreased sulcal pattern similarity to controls in the left temporal and parietal lobes, as well as the bilateral frontal lobes. Temporal and parietal lobes demonstrated an abnormally asymmetric left-right pattern of sulcal basin area in CHD subjects. Sulcal pattern similarity to control was positively correlated with working memory, processing speed, and executive function. Exome analysis identified damaging de novo variants only in CHD subjects with more atypical sulcal patterns. Together, these findings suggest that sulcal pattern analysis may be useful in characterizing genetically influenced, atypical early brain development and neurodevelopmental risk in subjects with CHD.
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Cerebro/patología , Cardiopatías Congénitas/complicaciones , Trastornos del Neurodesarrollo/etiología , Adolescente , Cerebro/diagnóstico por imagen , Femenino , Cardiopatías Congénitas/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos del Neurodesarrollo/patología , Trastornos del Neurodesarrollo/psicología , Pruebas NeuropsicológicasRESUMEN
Genetic Creutzfeldt-Jakob disease (gCJD) with a methionine to arginine substitution at codon 232 of the prion protein gene (gCJD-M232R) is rare and has only been reported in Japan. We report an autopsy case of gCJD-M232R showing alleles of codon 129 that were homozygous for methionine and the presence of multiple strains of the protease-resistant, abnormal isoform of prion protein (PrPSc ), M1 + M2C + M2T. The patient, a 54-year-old Japanese man, died after a clinical course of 21 months characterized by slowly progressive dementia and sleep disturbance. At autopsy, the neuropil of the cerebral neocortex showed a widespread and severe spongiform change. Grape-like clusters of large confluent vacuoles were admixed with fine vacuoles. Neuronal loss was moderate, but reactive astrocytosis was mild. The dorsomedial nucleus of the thalamus and the inferior olivary nucleus showed moderate and severe neuronal loss, respectively. Many amyloid plaques were present in the cerebellar molecular layer. PrPSc deposition pattern was predominantly the synaptic type in the cerebrum and corresponded to the plaques in the cerebellum. Perivacuolar deposition was also seen. Western blot analysis of PrPSc revealed the predominance of type 2. Moreover, by employing Western blot analysis in combination with the protein misfolding cyclic amplification (PMCA) method, which selectively amplifies the minor M2T prion strain, we demonstrated the presence of M2T, in addition to M1 and M2C strains, in the brain of the patient. PMCA was a powerful method for demonstrating the presence of the M2T strain, although the amount is often small and the transmission is difficult.
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Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patología , Metionina/genética , Proteínas PrPSc/genética , Atrofia/genética , Atrofia/patología , Autopsia , Western Blotting , Cerebelo/patología , Cerebro/patología , Humanos , Japón , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Miocardio/patología , Tálamo/patologíaRESUMEN
Pathologic inflammation in response to injury, infection, or oxidative stress is a proposed mechanism relating cognitive decline to dementia. The kynurenine pathway and thioredoxin-interacting protein (TXNIP) activity regulate inflammation and neurotoxicity in Alzheimer disease (AD). We examined cognitive deficits, kynurenine pathway mediators, TXNIP, and oxidative damage in the cerebrum and spleen, including inflammatory cytokine production by stimulated splenocytes, from female triple transgenic (3xTg-AD) mice in early and late stages of disease progression, and characterized tissue-specific epigenetic regulation of Txnip gene expression. We show that cognitive deficits in 7-month-old 3xTg-AD mice are associated with a stable increase in cerebrum and spleen tryptophan metabolites, with a concomitant increase in amyloid ß 40 (Aß40)/Aß42 and tau/hyperphosphorylated tau pathologies and a coordinated reduction in spleen proinflammatory cytokine production in 17-month-old mice. The enhanced cerebrum TXNIP expression is associated with increased histone acetylation, transcription factor [Aß42 or CCCTC-binding factor (CTCF)] binding, and Txnip promoter hypomethylation, whereas the attenuated spleen TXNIP expression is associated with increased histone methylation, reduced CTCF binding, and Txnip promoter hypermethylation. These results suggest a causal relationship among epigenomic state, TXNIP expression, cerebral-spleen tryptophan metabolism, inflammatory cytokine production, and cognitive decline; and they provide a potential mechanism for Txnip gene regulation in normal and pathologic conditions, suggesting TXNIP levels may be a useful predictive or diagnostic biomarker for Aß40/Aß42 targeted AD therapies.
Asunto(s)
Enfermedad de Alzheimer , Cerebro , Disfunción Cognitiva , Estrés Oxidativo , Bazo , Triptófano , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Cerebro/metabolismo , Cerebro/patología , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Bazo/metabolismo , Bazo/patología , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Triptófano/genética , Triptófano/metabolismoRESUMEN
BACKGROUND: Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome. METHODS: In this prospective cohort study an MRI protocol was developed to evaluate gray matter (GM) and white matter (WM) volume of the cerebrum and cerebellum, WM hyperintensity volume, WM microstructure and myelin content with the use of conventional MRI techniques, diffusion tensor imaging (DTI) and quantitative T1 mapping. The association between several neuroimaging parameters and both neurological and intellectual outcome was investigated. RESULTS: Twenty-one patients with CG (median age 22 years, range 8-47) and 24 controls (median age 30, range 16-52) were included. Compared to controls, the WM of CG patients was lower in volume and the microstructure of WM was impaired both in the whole brain and corticospinal tract (CST) and the lower R1 values of WM, GM and the CST were indicative of less myelin. The volume of WM lesions were comparable between patients and controls. The 9/16 patients with a poor neurological outcome (defined as the presence of a tremor and/or dystonia), demonstrated a lower WM volume, an impaired WM microstructure and lower R1 values of the WM indicative of less myelin content compared to 7/16 patients without movement disorders. In 15/21 patients with a poor intellectual outcome (defined as an IQ < 85) both GM and WM were affected with a lower cerebral and cerebellar WM and GM volume compared to 6/21 patients with an IQ ≥ 85. Both the severity of the tremor (as indicated by the Tremor Rating Scale) and IQ (as continuous measure) were associated with several neuroimaging parameters such as GM volume, WM volume, CSF volume, WM microstructure parameters and R1 values of GM and WM. CONCLUSION: In this explorative study performed in patients with Classical Galactosemia, not only WM but also GM pathology was found, with more severe brain abnormalities on MRI in patients with a poor neurological and intellectual outcome. The finding that structural changes of the brain were associated with the severity of long-term complications indicates that quantitative MRI techniques could be of use to explain neurological and cognitive dysfunction as part of the disease spectrum. Based on the clinical outcome of patients, the absence of widespread WM lesions and the finding that both GM and WM are affected, CG could be primarily a GM disease with secondary damage to the WM as a result of neuronal degeneration. To investigate this further the course of GM and WM should be evaluated in longitudinal research, which could also clarify if CG is a neurodegenerative disease.
Asunto(s)
Galactosemias/metabolismo , Sustancia Gris/metabolismo , UTP-Hexosa-1-Fosfato Uridililtransferasa/genética , Sustancia Blanca/metabolismo , Adolescente , Adulto , Cerebelo/diagnóstico por imagen , Cerebelo/metabolismo , Cerebelo/patología , Cerebro/diagnóstico por imagen , Cerebro/metabolismo , Cerebro/patología , Femenino , Galactosemias/diagnóstico por imagen , Galactosemias/genética , Galactosemias/patología , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Degeneración Nerviosa/diagnóstico por imagen , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuroimagen/métodos , UTP-Hexosa-1-Fosfato Uridililtransferasa/metabolismo , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
Pseudorabies virus (PRV) is known to cause severe encephalitis in juvenile pigs and various non-native hosts; recent evidences suggest that PRV might cause encephalitis in humans. In a multicenter cohort study in China, next-generation sequencing of cerebrospinal fluid (CSF) was performed to detect pathogens in all patients with clinically suspected central nervous system infections. This study involved all the patients whose CSF samples were positive for PRV-DNA; their clinical features were evaluated, and species-specific PCR and serological tests were sequentially applied for validation. Among the 472 patients tested from June 1, 2016, to December 1, 2018, six were positive for PRV-DNA, which were partially validated by PCR and serological tests. Additionally, we retrospectively examined another case with similar clinical and neuroimaging appearance and detected the presence of PRV-DNA. These patients had similar clinical manifestations, including a rapid progression of panencephalitis, and similar neuroimaging features of symmetric lesions in the basal ganglia and bilateral hemispheres. Six of the patients were engaged in occupations connected with swine production. PRV infection should be suspected in patients with rapidly progressive panencephalitis and characteristic neuroimaging features, especially with exposure to swine.
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Ganglios Basales/patología , Cerebro/patología , ADN Viral/genética , Encefalitis Viral/patología , Herpesvirus Suido 1/genética , Carne/virología , Seudorrabia/patología , Adulto , Animales , Anticuerpos Antivirales/líquido cefalorraquídeo , Ganglios Basales/diagnóstico por imagen , Ganglios Basales/virología , Cerebro/diagnóstico por imagen , Cerebro/virología , China , ADN Viral/líquido cefalorraquídeo , Encefalitis Viral/líquido cefalorraquídeo , Encefalitis Viral/diagnóstico , Encefalitis Viral/virología , Femenino , Herpesvirus Suido 1/crecimiento & desarrollo , Herpesvirus Suido 1/patogenicidad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Seudorrabia/líquido cefalorraquídeo , Seudorrabia/diagnóstico , Seudorrabia/virología , PorcinosRESUMEN
BACKGROUND: The adolescent and young adult (AYA) age group lacks targeted epidemiologic studies that assess the prevalence and outcome of tumors. We aim to provide deep analysis of the epidemiology of central nervous system (CNS) tumors in AYA in Jordan. METHODOLOGY: This is a retrospective study for all CNS tumors in the AYA group patients diagnosed and managed at King Hussein Cancer Center in 2007-2016. A patient list was retrieved from the Center's Cancer Registry, and clinicopathologic data were reviewed individually from the patients' records. RESULTS: A total of 370 cases of primary CNS tumors were retrieved, with a median age of 28.5 years. Males outnumbered females; 57.6 and 42.4%, respectively. Most tumors occurred in the cerebrum (62.2%, n = 230), the frontal lobe was the most commonly affected (29%). Glioma was the most common histologic category (58.9%, n = 218), with high-grade tumors, including glioblastoma and anaplastic astrocytoma, prevailing. Embryonal tumors comprised the second most common group (16.8%, n = 62). Medulloblastoma was the prototype of embryonal tumors (91.9%; n = 57). Glioma tended to affect the older age group than embryonal tumors (p value = 0.002). On last available follow-up, 29.5% were lost to follow-up, 36% were alive, and 34.6% were deceased. The median overall survival (OS) for all tumors was 47.6 months. Embryonal tumors had a better outcome than glioma (median OS 76.3 vs. 30.3 months, respectively; p value = 0.001). CONCLUSIONS: High-grade glioma affecting the cerebrum was the most common tumor among AYA age group and was associated with a less favorable outcome compared to embryonal tumors. More research is needed to address this special age group.
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Neoplasias del Sistema Nervioso Central/epidemiología , Cerebro , Glioma/epidemiología , Neoplasias de Células Germinales y Embrionarias/epidemiología , Sistema de Registros/estadística & datos numéricos , Adolescente , Adulto , Cerebro/patología , Humanos , Jordania/epidemiología , Estudios Retrospectivos , Factores Sexuales , Adulto JovenRESUMEN
OBJECTIVE: In healthy individuals, the visuospatial attentional network consists of frontoparietal bundles; however, the anatomical organization of this network in persons with schizophrenia remains largely unknown. Using diffusion tensor imaging-based tractography, the authors investigated the white matter integrity and volume of frontoparietal and frontotemporo-occipital bundles in the right and left hemispheres and studied their structural asymmetry in persons with schizophrenia and in healthy individuals. METHODS: This study included 34 participants with schizophrenia and 69 healthy individuals. Integrity parameters and volume were calculated in the three branches of the superior longitudinal fasciculus (SLF I, II, and III), the inferior longitudinal fasciculus, and the inferior fronto-occipital fasciculus in both hemispheres. RESULTS: In the SLF II and SLF III of the right hemisphere, healthy individuals showed greater integrity, compared with participants with schizophrenia. Both groups presented increased integrity in the SLF III of the right hemisphere, compared with the SLF III of the left hemisphere, but only healthy individuals had this pattern regarding the SLF II. Bundle volumes did not differ between groups. CONCLUSIONS: This study is the first to describe the structural hemispheric lateralization and organization of the visuospatial attentional network in persons with schizophrenia. The main findings indicate loss of integrity in the SLF II, associated with loss of asymmetry in participants with schizophrenia, compared with healthy individuals, suggesting a potential substrate of attentional deficits.
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Atención , Cerebro/patología , Lateralidad Funcional , Red Nerviosa/patología , Trastornos Psicóticos/patología , Esquizofrenia/patología , Percepción Espacial , Percepción Visual , Sustancia Blanca/patología , Adulto , Cerebro/diagnóstico por imagen , Imagen de Difusión Tensora , Femenino , Humanos , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/patología , Trastornos Psicóticos/diagnóstico por imagen , Esquizofrenia/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Adulto JovenRESUMEN
Subarachnoid hemorrhage (SAH) is a serious neurological event associated with high morbidity and mortality. Computed tomography of the cerebrum (CTC) is the diagnostic method of choice, but in case of negative CTC but strong suspicion of SAH, lumbar puncture with spectrophotometric analysis of cerebrospinal fluid (CSF) for xanthochromia is performed. We wanted to examine the diagnostic properties of CSF spectrophotometry for xanthochromia testing. We performed a retrospective study of the diagnostic properties of CSF analysis for xanthochromia using spectrophotometry in the diagnosis of SAH. A total of 489 CSF samples were analyzed for xanthochromia, according to international guidelines, from 2009 until 2014 and for 411 of these the patient files were retrieved and examined for final clinical diagnosis and result of CTC. One patient with SAH did not have a positive spectrophotometry report and another patient with SAH had an equivocal report. In four patients did initial CTC not correctly identify SAH. For patients with a negative CTC within six hours of symptom onset spectrophotometry for xanthochromia in the CSF had a diagnostic sensitivity of 100% and a diagnostic specificity of 98.5%. The positive predictive value was 16.7% and the negative predictive value 100%. We conclude that spectrophotometry of CSF for xanthochromia is a sensitive and specific test for diagnosing SAH. However, it seems that an initial CTC identifies almost all patients with SAH. This suggests that in our and similar diagnostic settings, lumbar puncture and testing for xanthochromia might only be relevant in very few cases, if not obsolete.