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BACKGROUND: Cerebral blood flow (CBF) and dopamine transporter (DAT) images are clinically used for the differential diagnosis of parkinsonian disorders. OBJECTIVES: This study aimed to examine the correlation of CBF with striatal DAT in patients with Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) and evaluate the diagnostic power of DAT-correlated CBF in PD through machine learning with each imaging modality alone or in combination. METHODS: Fifty-eight patients with PD and 71 with APS (24 with multiple system atrophy, 21 with progressive supranuclear palsy, and 26 with corticobasal syndrome) underwent 123 I-IMP and 123 I-FP-CIT single-photon emission computed tomography. Multiple regression analyses for CBF and striatal DAT binding were conducted on each group. PD probability was predicted by machine learning and receiver operating characteristic curves. RESULTS: The PD group showed more affected striatal DAT binding positively correlated with the ipsilateral prefrontal perfusion and negatively with the bilateral cerebellar perfusion. In corticobasal syndrome, striatal DAT binding positively correlated with the ipsilateral prefrontal perfusion and negatively with the contralateral precentral perfusion. In Richardson's syndrome, striatal DAT binding positively correlated with perfusion in the ipsilateral precentral cortex and basal ganglia. Machine learning showed that the combination of CBF and DAT was better for delineating PD from APS (area under the curve [AUC] = 0.87) than either CBF (0.67) or DAT (0.50) alone. CONCLUSIONS: In PD and four-repeat tauopathy, prefrontal perfusion was related to ipsilateral nigrostriatal dopaminergic function. This dual-tracer frontostriatal relationship may be effectively used as a diagnostic tool for delineating PD from APS. © 2022 International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Trastornos Parkinsonianos , Circulación Cerebrovascular , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
BACKGROUND: Individuals with early-onset Alzheimer disease (EOAD) differ from those with late-onset Alzheimer disease (LOAD) not only in genetics and age at onset but also in their clinical symptoms. OBJECTIVE: To differentiate the neuropathological and neurocognitive features of EOAD and LOAD by comparing the pattern of regional gray matter volume (GMV) reduction and its symptomatic correlates. METHOD: Three-dimensional T1-weighted MRIs and Mini-Mental State Examination (MMSE) scores were obtained from 12 individuals with EOAD, 65 with LOAD, and 49 healthy controls (HC). Regional GMV reduction between the three groups was assessed using voxel-based morphometry. Multiple regression analyses were conducted with MMSE total score as an independent variable. RESULTS: Compared to the HC, both AD groups showed a significant GMV reduction in the bilateral hippocampus and the left temporoparietal junction; in addition, the LOAD group showed one in the bilateral anterior temporal lobes. Multiple regression analyses revealed a positive correlation between MMSE total score and GMV in the left anterior temporal lobe in both AD groups; that is, lower scores were associated with reduced GMV. Interestingly, a positive correlation in hippocampal GMV was revealed only in the LOAD group. CONCLUSION: MMSE total score is associated with the anterior temporal lobe volume in individuals with AD. Hippocampal volume and its relationship with MMSE total score are associated with LOAD pathophysiology but not EOAD pathophysiology. The hippocampal volume reduction and low MMSE scores are hallmarks of LOAD but are less specific to EOAD, which may cause a delay in diagnosis.
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Enfermedad de Alzheimer/fisiopatología , Sustancia Gris/patología , Imagen por Resonancia Magnética/métodos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal syndrome for Parkinson's disease (PD) and related α-synucleinopathies. We conducted a longitudinal imaging study of network changes in iRBD and their relationship to phenoconversion. Expression levels for the PD-related motor and cognitive networks (PDRP and PDCP) were measured at baseline, 2 and 4 years, along with dopamine transporter (DAT) binding. PDRP and PDCP expression increased over time, with higher values in the former network. While abnormal functional connections were identified initially within the PDRP, others bridging the two networks appeared later. A model based on the rates of PDRP progression and putamen dopamine loss predicted phenoconversion within 1.2 years in individuals with iRBD. In aggregate, the data suggest that maladaptive reorganization of brain networks takes place in iRBD years before phenoconversion. Network expression and DAT binding measures can be used together to assess phenoconversion risk in these individuals.
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INTRODUCTION: Corticobasal degeneration (CBD) is the most common neuropathological substrate for clinically diagnosed corticobasal syndrome (CBS), while identifying CBD pathology in living individuals has been challenging. This study aimed to examine the capability of positron emission tomography (PET) to detect CBD-type tau depositions and neuropathological classification of CBS. METHODS: Sixteen CBS cases diagnosed by Cambridge's criteria and 12 cognitively healthy controls (HCs) underwent PET scans with 11C-PiB, 11C-PBB3, and 18F-FDG, along with T1-weighted magnetic resonance imaging. Amyloid positivity was assessed by visual inspection of 11C-PiB retentions. Tau positivity was judged by quantitative comparisons of 11C-PBB3 binding to HCs. RESULTS: Sixteen CBS cases consisted of two cases (13%) with amyloid and tau positivities indicative of Alzheimer's disease (AD) pathologies, 11 cases (69%) with amyloid negativity and tau positivity, and three cases (19%) with amyloid and tau negativities. Amyloid(-), tau(+) CBS cases showed increased retentions of 11C-PBB3 in the frontoparietal areas, basal ganglia, and midbrain, and reduced metabolism in the precentral gyrus and thalamus relative to HCs. The enhanced tau probe retentions in the frontal gray and white matters partially overlapped with metabolic deficits and atrophy and correlated with Clinical Dementia Rating scores. CONCLUSIONS: PET-based classification of CBS was in accordance with previous neuropathological reports on the prevalences of AD, non-AD tauopathies, and others in CBS. The current work suggests that 11C-PBB3-PET may assist the biological classification of CBS and understanding of links between CBD-type tau depositions and neuronal deteriorations leading to cognitive declines.
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Enfermedad de Alzheimer , Degeneración Corticobasal , Enfermedad de Alzheimer/metabolismo , Fluorodesoxiglucosa F18 , Humanos , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Diastolic retrograde flow in the descending aorta (DAo) may occur in the presence of atherosclerosis and may be overlooked as a mechanism of retrograde embolization in patients with stroke. We performed thoracic endovascular aortic repair (TEVAR) in a patient with recurrent cerebral infarctions for treatment of aortic aneurysm with atheromatic plaque, which was considered as the source of embolism. CASE PRESENTATION: A 56-year-old man with a history of idiopathic thrombocytopenia and hypertension was referred to our hospital with paralysis of the right upper and lower limbs. Multiple cerebral infarctions were found and treated; however, 1 month later, another cerebral infarction developed. A small saccular aortic aneurysm with plaque was found beyond the left subclavian artery, and this site was deemed as the source of embolism. We performed TEVAR to prevent further recurrence of cerebral infarctions. No cerebral infarctions were observed 6 months post-operation. CONCLUSIONS: TEVAR is a useful treatment for not only aortic aneurysm and dissection, but also cerebral infarctions caused by an embolic source proximal to the DAo due to retrograde aortic blood flow.
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Hiccups, nausea and vomiting are known as the clinical manifestations of neuromyelitis optica spectrum disorder (NMOSD) linked to lesions of the area postraema in the medullary tegmentum. Here, we describe a 74-year-old male patient with NMOSD who presented with recurrent syncope due to severe orthostatic hypotension (OH) following symptoms of hiccups, nausea and vomiting. Brain magnetic resonance imaging revealed the lesion of the area postraema and it could be responsible for the symptom of OH. Considering the numerous related reports, we suspect that the prevalence of OH is underreported in the patients with NMOSD. OH may transition into more serious conditions, so it should be evaluated carefully in all patients with NMOSD, particularly when there is a lesion of the area postraema.
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Background: Language dysfunction is a feature of cognitive impairment in amyotrophic lateral sclerosis (ALS) that may compromise communication. Objective: To elucidate language dysfunction in patients with ALS and its relationship with other neuropsychological tests and to identify the brain regions associated with this dysfunction using perfusion image. Methods: Overall, 37 patients with ALS were included in this study. Their neuropsychological function was investigated using the Western Aphasia Battery (WAB), Frontal Assessment Battery and Behavioral Assessment of the Dysexecutive Syndrome. N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography was used to examine regional cerebral blood flow and its relationship with WAB scores was investigated using multiple regression analyses, controlled for age, sex and years of education. Results: Frequency of language abnormality in ALS was 8.5% for spontaneous speech, 25.7% for auditory verbal comprehension, 8.8% for repetition, 14.7% for naming, 17.6% for reading and 51.4% for writing. The writing error was mainly omission and substitution of kana letters. Executive tests were correlated with naming (r > 0.5, p < 0.001) and reading (r > 0.4, p < 0.01) scores. With respect to the writing sub-test, positive perfusional relationship was only detected in the left angular gyrus. Conclusions: The left angular gyrus is the region associated with the writing errors observed in ALS.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Encéfalo , Humanos , Pruebas Neuropsicológicas , Lóbulo Parietal , EscrituraRESUMEN
BACKGROUND: Neuropsychological tests, structural neuroimaging, and functional neuroimaging are employed as diagnostic and monitoring biomarkers of patients with Alzheimer's disease (AD)Objective:We aimed to elucidate the similarities and differences in neuropsychological tests and neuroimaging with the use of the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog), structural magnetic resonance image (MRI), and perfusion single photon emission computed tomography (SPECT), and parametric image analyses to understand its role in AD. METHODS: Clinically-diagnosed AD patients (nâ=â155) were scanned with three-dimensional T1-weighted MRI and N-isopropyl-p-[123I] iodoamphetamine SPECT. Statistical parametric mapping 12 was used for preprocessing images, statistical analyses, and voxel-based morphometry for gray matter volume analyses. Group comparison (AD versus healthy controls), multiple regression analyses with MMSE, ADAS-cog total score, and ADAS-cog subscores as variables, were performed. RESULTS: The AD group showed bilateral hippocampal volume reduction and hypoperfusion in the bilateral temporo-parietal lobe and posterior midline structures. Worse MMSE and ADAS-cog total score were associated with bilateral temporo-parietal volume loss and hypoperfusion. MMSE, but not ADAS-cog, was associated with the posterior midline structures. The ADAS-cog subscores were associated with the temporal volume, while perfusion analyses were linked to the left temporo-parietal region with the language function and right analogous region with the constructional praxis subscore. CONCLUSION: MMSE and ADAS-cog are associated with temporo-parietal regions, both in volume and perfusion. The MMSE score is associated with posterior midline structures and linked to an abnormal diagnostic AD pattern. Perfusion image analyses better represents the cognitive function in AD patients.
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Enfermedad de Alzheimer/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Sustancia Gris/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Encéfalo/irrigación sanguínea , Encéfalo/patología , Estudios de Casos y Controles , Femenino , Sustancia Gris/irrigación sanguínea , Sustancia Gris/patología , Hipocampo/irrigación sanguínea , Hipocampo/patología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tamaño de los Órganos , Lóbulo Parietal/irrigación sanguínea , Lóbulo Parietal/diagnóstico por imagen , Lóbulo Parietal/patología , Imagen de Perfusión , Lóbulo Temporal/irrigación sanguínea , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/patología , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for alleviating motor symptoms in advanced Parkinson's disease (PD) patients; however, a postoperative decline in cognitive and speech function has become problematic although its mechanism remains unclear. The aim of the present study was to elucidate the properties of language and drawing ability and cerebral perfusion in PD patients after bilateral STN DBS surgery. METHODS: Western aphasia battery, including drawing as a subcategory, and perfusion (N-isopropyl-p-[123I] iodoamphetamine) SPECT scan was conducted in 21 consecutive PD patients, before, and three to six months after, bilateral STN DBS surgery while on stimulation. Perfusion images were compared with those of 17 age- and gender-matched healthy volunteers. In the parametric image analysis, the statistical peak threshold was set at P < 0.001 uncorrected with a cluster threshold set at P < 0.05 uncorrected. RESULTS: Although motor symptoms were improved and general cognition was preserved in the patient group, 11 patients (52.4%) showed a decline in the drawing subcategory after surgery, which showed a reduction in Frontal Assessment Battery score in this group of patients. Statistical parametric analysis of the brain perfusion images showed a decrease of cerebral blood flow in the prefrontal and cingulate cortex after surgery. Patients whose drawing ability declined showed decreased perfusion in the middle cingulate cortex comparing before and after surgery. CONCLUSION: Present results show that some PD patients show a decline in drawing ability after bilateral STN DBS which may attributable by dysfunction in the cingulate network.
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Circulación Cerebrovascular/fisiología , Estimulación Encefálica Profunda/efectos adversos , Giro del Cíngulo/fisiopatología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Corteza Prefrontal/fisiopatología , Desempeño Psicomotor/fisiología , Núcleo Subtalámico , Anciano , Femenino , Estudios de Seguimiento , Giro del Cíngulo/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagen , Núcleo Subtalámico/cirugía , Tomografía Computarizada de Emisión de Fotón Único , Resultado del TratamientoRESUMEN
Both cognitive function and striatal dopamine function decline by normal aging. However, the relationship among these three factors remains unclear. The aim of this study was to elucidate the association among age-related changes in the striatal dopamine transporter (DAT) and cognitive function in healthy subjects. The 30 healthy volunteers were enrolled in this research, the age ranged from 41 to 82 (64.5 ± 11.5, mean ± SD). All subjects were scanned with both T1-weighted magnetic resonance imaging (MRI) and 123I-FP-CIT single-photon emission computed tomography (SPECT) images. The Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) was used to evaluate cognitive function. Six spherical regions of interest (ROI) using 10 mm in diameter on the caudate nucleus, anterior putamen and posterior putamen were manually drawn on MRI image which was applied onto SPECT image. The relationship between striatal occipital ratio (SOR) values and WAIS-III subscore were analyzed by multiple regression analysis. Subscores which was significant were further analyzed by path analyses. Full intelligence quotient (IQ), verbal IQ, verbal comprehension were all positively correlated with age-adjusted striatal DAT binding (P < 0.01). Multiple regression analyses revealed that the coding digit symbol correlated with all striatal regions except for the left caudate (P < 0.04). Picture completion and right caudate, similarities and left caudate also showed a positive correlation (P < 0.04). Path analysis found that the right caudate and picture completion; the left caudate and similarities were correlated independently from age, whereas the models of coding digit symbol were not significant. These results suggest that age-based individual diversity of striatal DAT binding was associated with verbal function, and the caudate nucleus plays an important role in this association.
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BACKGROUND AND PURPOSE: New immature neurons appear out of the germinative zone, in cortical Layers V to VI, after induced spreading depression in the adult rat brain. Because neural progenitors have been isolated in the cortex, we set out to determine whether a subgroup of mature cells in the adult cortex has the potential to divide and generate neural precursors. METHODS: We examined the expression of endogenous markers of mitotic activity, proliferating cell nuclear antigen, and vimentin as a marker for neuronal progenitor cells, if any, in the adult rat cortex after spreading depression stimulation. Immunohistochemical analysis was also performed using antibodies for proliferating cell nuclear antigen, for vimentin, and for nestin. Nestin is a marker for activity dividing neural precursors. RESULTS: At the end of spreading depression (Day 0), glial fibrillary acidic protein-positive cells in the subpial zone and cortical Layer I demonstrated increased mitotic activity, expressing vimentin and nestin. On Day 1, nestin(+) cells were found spreading in deeper cortical layers. On Day 3, vimentin(-)/nestin(+), neural precursor-like cells appeared in cortical Layers V to VI. On Day 6, new immature neurons appeared in cortical Layers V to VI. Induced spreading depression evokes cell division of astrocytes residing in the subpial zone, generating neural precursor-like cells. CONCLUSIONS: Although neural precursor-like cells found in cortical Layers V to VI might have been transferred from the germinative zone rather than the cortical subpial zone, astrocytic cells in the subpial zone may be potent neural progenitors that can help to reconstruct impaired central nervous system tissue. Special caution is required when observing or treating spreading depression waves accompanying pathological conditions in the brain.
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Astrocitos/citología , División Celular/fisiología , Corteza Cerebral/citología , Depresión de Propagación Cortical/fisiología , Neuronas/citología , Células Madre/citología , Factores de Edad , Animales , Astrocitos/fisiología , Corteza Cerebral/fisiología , Masculino , Neurogénesis/fisiología , Neuronas/fisiología , Piamadre/citología , Piamadre/fisiología , Ratas , Ratas Sprague-Dawley , Células Madre/fisiologíaRESUMEN
Excitatory neurons are preferentially impaired in early Alzheimer's disease but the pathways contributing to their relative vulnerability remain largely unknown. Here we report that pathological tau accumulation takes place predominantly in excitatory neurons compared to inhibitory neurons, not only in the entorhinal cortex, a brain region affected in early Alzheimer's disease, but also in areas affected later by the disease. By analyzing RNA transcripts from single-nucleus RNA datasets, we identified a specific tau homeostasis signature of genes differentially expressed in excitatory compared to inhibitory neurons. One of the genes, BCL2-associated athanogene 3 (BAG3), a facilitator of autophagy, was identified as a hub, or master regulator, gene. We verified that reducing BAG3 levels in primary neurons exacerbated pathological tau accumulation, whereas BAG3 overexpression attenuated it. These results define a tau homeostasis signature that underlies the cellular and regional vulnerability of excitatory neurons to tau pathology.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Homeostasis/fisiología , Neuronas/metabolismo , Proteínas tau/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Encéfalo/patología , Humanos , Ratones , Ratones Transgénicos , Neuronas/patología , Proteínas tau/genéticaRESUMEN
Development of a safe method to increase brain-derived neurotrophic factor (BDNF) in the brain is expected to have utility in enhancing learning and memory, in protecting the brain, and in suppressing appetite. We investigated the effects of whole-body exposure to high voltage electric potential (HELP), which generates an electric field and current density in the body, on BDNF levels in the brain, spatial learning, or resistance to cerebral infarction development after focal ischemia. Adult mice (C57BL/6J) were exposed to 3.5 kV, or 5.8 kV for 5 h a day, making indirect contact with the ground via room air, over 1, 3, 6 or 12 consecutive weeks. After treatment, BDNF levels, performances in the Morris water maze task (MWM), or development of infarct lesion after focal ischemia was analyzed. Treatment with 3.5 kV for 1, 3, 6 or 12 weeks, or with 5.8 kV for 1, 3 or 12 weeks increased BDNF levels in the cortex (P<0.05, one-way ANOVA). Every HELP treatment differentially improved escape latency in the MWM, compared with the corresponding untreated controls (P<0.05, one-way ANOVA). Treatment with 3.5 kV for 6 or 12 weeks, but not with 5.8 kV protected the brain suppressing cerebral infarction development (P<0.05). The HELP treatment with 3.5 kV for 6 or 12 weeks improves spatial learning, gently suppressing body weight gain, and protects the brain against cerebral infarction.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Encéfalo/fisiología , Encéfalo/efectos de la radiación , Infarto Cerebral/prevención & control , Campos Electromagnéticos/efectos adversos , Aprendizaje/efectos de la radiación , Conducta Espacial/efectos de la radiación , Análisis de Varianza , Animales , Presión Sanguínea/efectos de la radiación , Infarto Cerebral/etiología , Circulación Cerebrovascular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Frecuencia Cardíaca/efectos de la radiación , Isquemia/complicaciones , Masculino , Aprendizaje por Laberinto/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Natación , Factores de TiempoRESUMEN
BACKGROUND AND PURPOSE: Status epilepticus and cerebral ischemia stimulate persistent neurogenesis in the adult brain, but both conditions cause neuronal damage. We determined whether spreading depression, a common epiphenomenon of these conditions, stimulates persistent neurogenesis. METHODS: We analyzed the effect of KCl-induced spreading depression on persistent neurogenesis and the spatio-temporal distribution of cells exhibiting immunohistochemical markers for divided and early committed neurons (new neurons) in the adult rat brain. RESULTS: After induction of spreading depression for 48 hours, the density of mitotic cells, divided cells, and new neurons in the subventricular zone increased at days 1 to 3, days 3 to 6, and day 6, respectively (P<0.05). The divided cell density in the rostral migratory stream and the stream size increased at day 12 (P<0.001). Vehicle (saline) infusion or induction of spreading depression for 4 hours only did not increase the divided cell density, but the latter increased new neuron density in the subventricular zone (P<0.001). Double-labeled new neuron-like cells also appeared in the caudate putamen or cortex in ectopic fashion at day 3, with dramatic increases at days 6 and 12. Administration of the NMDA receptor antagonist, MK-801, which inhibits the propagation of spreading depression, abolished the increase in new neurons in the subventricular zone and the appearance of ectopic new neuron-like cells after 48-hour KCl infusion. There was no neuronal damage, as evidenced by mature neuron density, neurite density, and apoptotic cell appearance after spreading depression for 48 hours. CONCLUSIONS: Spreading depression has the potential to stimulate persistent neurogenesis or to produce ectopic new neuron-like cells.
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Biomarcadores/química , Corteza Cerebral/metabolismo , Depresión de Propagación Cortical , Neuronas/patología , Putamen/metabolismo , Animales , Antimetabolitos/farmacología , Apoptosis , Encéfalo/metabolismo , Isquemia Encefálica/patología , Bromodesoxiuridina/farmacología , Diferenciación Celular , División Celular , Sistema Nervioso Central/patología , Maleato de Dizocilpina/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Potenciales de la Membrana , Microscopía Confocal , Neuronas/metabolismo , Cloruro de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Estado Epiléptico/patología , Células Madre/metabolismo , Factores de TiempoRESUMEN
Preconditioning the rat brain with spreading depression for 48 h induces potent ischemic tolerance (infarct tolerance) after an interval of 12-15 days, consequently reducing the infarcted lesion size in the acute phase following focal cerebral ischemia. However, persistence of the morphological and functional neuroprotection has not yet been proven. We tested whether tolerance-derived neuroprotection against focal cerebral ischemia persists or merely delays the progress of cerebral infarction. Prolonged spreading depression was induced in mice by placing a depolarized focus with intracerebral microinfusion of KCl for 24 h; after intervals of 3, 6, 9 or 12 days, temporary focal ischemia was imposed. In the analysis of the infarcted lesion volume 24 h after ischemia, groups with 6 or 9 day interval demonstrated significantly smaller lesion volume compared to time-matched vehicle control group (P=0.002). Significant reduction in cerebral infarction was also observed at the chronic phase, namely 14 days after ischemia (33% reduction) (P=0.021) accompanied with less severe neurological deficits (38% reduction) (P=0.020). Using this technique, we also investigated if the mice with targeted disruption of a single BDNF allele (heterozygous BDNF-deficient mice) can gain the same potency of tolerance as the wild mice. In the result on infarcted lesion volumes following temporary focal ischemia, potent tolerance developed in the wild type (35% reduction) (P=0.007) but not in the heterozygous BDNF-deficient mice (<19% reduction) (P=0.155), indicating that BDNF expression level following spreading depression is contributing to infarct tolerance development.
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Infarto Encefálico/genética , Infarto Encefálico/patología , Factor Neurotrófico Derivado del Encéfalo/deficiencia , Factor Neurotrófico Derivado del Encéfalo/genética , Depresión de Propagación Cortical/genética , Animales , Infarto Encefálico/prevención & control , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Femenino , Ataque Isquémico Transitorio/genética , Ataque Isquémico Transitorio/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de TiempoRESUMEN
Brain-derived neurotrophic factor (BDNF), a neurotrophin, is known to promote neuronal differentiation stimulating neurite outgrowth in the developing CNS, and is also known to modulate synaptic plasticity, thereby contributing to learning and memory in the mature brain. Here, we investigated the role of increased levels of intracerebral BDNF in learning and memory function. Using genetically engineered transgenic BDNF overexpressing mice (RTG-BDNF), young adult, homozygous (+/+), heterozygous (+/-), or wild-type (-/-) littermates, we analyzed escape latency to a hidden-platform and swimming velocity in the Morris Water Maze test (MWM) with modifications for the mice. The MWM comprised 4 trials per day over 5 consecutive days (sessions) without prior or subsequent training. In a separate set of animals, BDNF protein levels in the cortex, thalamostriatum and the hippocampus were measured quantitatively using ELISA. In the BDNF (+/-) mice, the BDNF levels in the cortex, the thalamostriatum and the hippocampus were significantly high, compared to the wild-type littermates; 238%, 158%, and 171%, respectively (P<0.01, one-way ANOVA and a post-hoc test in each region). The BDNF levels in the BDNF (+/+) mice were not elevated. The BDNF (+/-), but not the (+/+) mice, demonstrated significantly shorter escape latency, shorter total path length in the MWM, and more frequent arrivals at the location where the platform had been placed previously in the probe trial, compared with the wild-type littermates (P<0.05, at each time pint). Because the maximum swimming velocity was not affected in the BDNF-transgenic mice, increased BDNF levels in the brain were found to enhance spatial learning and memory function. Although it has been postulated that excessive BDNF is deteriorating for neuronal survival or neurite outgrowth, further investigations are needed to clarify the mechanism of paradoxical lack of increase in BDNF levels in the (+/+) mouse brain.
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Química Encefálica/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Encéfalo/metabolismo , Aprendizaje/fisiología , Memoria/fisiología , Animales , Conducta Animal/fisiología , Encéfalo/anatomía & histología , Diferenciación Celular/genética , Supervivencia Celular/genética , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Noqueados , Ratones Transgénicos , Plasticidad Neuronal/genética , Pruebas Neuropsicológicas , Prosencéfalo/anatomía & histología , Prosencéfalo/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Mammalian metaphase II (mII) exit and embryogenesis are induced at fertilisation by a signal thought to come from the sperm protein, phospholipase C-zeta (PLCZ1). Meiotic progression can also be triggered without sperm, as in parthenogenesis, although the classic mouse in vivo parthenogenetic model, LT/Sv, fails in meiosis I owing to an unknown molecular etiology. Here, we dissect PLCZ1 specificity and function in vivo and address its ability to interfere with maternal meiotic exit. Wild-type mouse Plcz1 expression was restricted to post-pubertal testes and the brains of both sexes, with region-specifying elements mapping to a 4.1 kb Plcz1 promoter fragment. When broad ectopic PLCZ1 expression was forced in independent transgenic lines, they initially appeared healthy. Their oocytes underwent unperturbed meiotic maturation to mII but subsequently exhibited autonomous intracellular free calcium oscillations, second polar body extrusion, pronucleus formation and parthenogenetic development. Transfer of transgenic cumulus cell nuclei into wild-type oocytes induced activation and development, demonstrating a direct effect of PLCZ1 analogous to fertilisation. Whereas Plcz1 transgenic males remained largely asymptomatic, females developed abdominal swellings caused by benign ovarian teratomas that were under-represented for paternally- and placentally-expressed transcripts. Plcz1 was not overexpressed in the ovaries of LT/Sv or in human germline ovarian tumours. The narrow spectrum of PLCZ1 activity indicates that it is modulated by tissue-restricted accessory factors. This work characterises a novel model in which parthenogenesis and tumourigenesis follow full meiotic maturation and are linked to fertilisation by PLCZ1.
Asunto(s)
Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Partenogénesis , Fosfoinositido Fosfolipasa C/metabolismo , Espermatozoides/metabolismo , Animales , Secuencia de Bases , Transformación Celular Neoplásica , Células Cultivadas , Femenino , Regulación de la Expresión Génica , N-Metiltransferasa de Histona-Lisina , Humanos , Masculino , Meiosis , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Oocitos/citología , Oocitos/metabolismo , Neoplasias Ováricas/genética , Fosfoinositido Fosfolipasa C/química , Fosfoinositido Fosfolipasa C/genética , Sensibilidad y EspecificidadRESUMEN
Fertilizable mammalian oocytes are arrested at the second meiotic metaphase (mII) by the cyclinB-Cdc2 heterodimer, maturation promoting factor (MPF). MPF is stabilized via the activity of an unidentified cytostatic factor (CSF), thereby suspending meiotic progression until fertilization. We here present evidence that a conserved 71 kDa mammalian orthologue of Xenopus XErp1/Emi2, which we term endogenous meiotic inhibitor 2 (Emi2) is an essential CSF component. Depletion in situ of Emi2 by RNA interference elicited precocious meiotic exit in maturing mouse oocytes. Reduction of Emi2 released mature mII oocytes from cytostatic arrest, frequently inducing cytodegeneration. Mos levels autonomously declined to undetectable levels in mII oocytes. Recombinant Emi2 reduced the propensity of mII oocytes to exit meiosis in response to activating stimuli. Emi2 and Cdc20 proteins mutually interact and Cdc20 ablation negated the ability of Emi2 removal to induce metaphase release. Consistent with this, Cdc20 removal prevented parthenogenetic or sperm-induced meiotic exit. These studies show in intact oocytes that the interaction of Emi2 with Cdc20 links activating stimuli to meiotic resumption at fertilization and during parthenogenesis in mammals.