RESUMO
BACKGROUND Ischemic stroke is usually accompanied by white matter damage. The effect of electroacupuncture (EA) on ameliorating white matter damage is still unclear. The purpose of this study was to explore the precise mechanism of EA in treating ischemic white matter. MATERIAL AND METHODS In this study, 40 Sprague-Dawley rats were randomly divided into 4 groups: normal group, the sham-operated group, model group, and EA group. The stroke model was established by right middle cerebral artery occlusion, and EA was performed 24 h after the operation for 30 min per day. After 14 days of treatment, brain tissue samples were collected. Hematoxylin and eosin and Luxol fast blue staining were used to observe the changes of white matter damage in the internal capsule (IC). The expression levels of myelin basic protein (MBP), Nogo-A, and Nogo-A receptor (NgR) were detected by immunohistochemistry and western blot. RESULTS Compared with the sham-operated group, the model group had decreased expression of MBP and significantly increased expression of Nogo-A and NgR (P<0.05). Compared with the model group, the IC damage was alleviated in the EA group. Immunohistochemistry and western blot analysis showed that EA significantly increased the expression of MBP in white matter (P<0.05) and downregulated the expression levels of Nogo-A and NgR (P<0.05). CONCLUSIONS The results of this study indicate that EA can inhibit the expression of Nogo-A/NgR and promote myelin sheath regeneration.
Assuntos
Isquemia Encefálica , Eletroacupuntura , Cápsula Interna/metabolismo , Bainha de Mielina/metabolismo , Proteínas Nogo/metabolismo , Animais , Infarto Cerebral , Proteínas da Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Paranodal axoglial junctions are essential for rapid nerve conduction and the organization of axonal domains in myelinated axons. Neurofascin155 (Nfasc155) is a glial cell adhesion molecule that is also required for the assembly of these domains. Previous studies have demonstrated that general ablation of Nfasc155 disorganizes these domains, reduces conduction velocity, and disrupts motor behaviors. Multiple sclerosis (MS), a typical disorder of demyelination in the central nervous system, is reported to have autoantibody to Nfasc. However, the impact of focal loss of Nfasc155, which may occur in MS patients, remains unclear. Here, we examined whether restricted focal loss of Nfasc155 affects the electrophysiological properties of the motor system in vivo. Adeno-associated virus type5 (AAV5) harboring EGFP-2A-Cre was injected into the glial-enriched internal capsule of floxed-Neurofascin (NfascFlox/Flox) mice to focally disrupt paranodal junctions in the cortico-fugal fibers from the motor cortex to the spinal cord. Electromyograms (EMGs) of the triceps brachii muscles in response to electrical stimulation of the motor cortex were successively examined in these awake mice. EMG analysis showed significant delay in the onset and peak latencies after AAV injection compared to control (Nfasc+/+) mice. Moreover, EMG half-widths were increased, and EMG amplitudes were gradually decreased by 13 weeks. Similar EMG changes have been reported in MS patients. These findings provide physiological evidence that motor outputs are obstructed by focal ablation of paranodal junctions in myelinated axons. Our findings may open a new path toward development of a novel biomarker for an early phase of human MS, as Nfasc155 detects microstructural changes in the paranodal junction.
Assuntos
Moléculas de Adesão Celular/metabolismo , Córtex Cerebral/metabolismo , Cápsula Interna/metabolismo , Músculos/fisiologia , Fatores de Crescimento Neural/metabolismo , Animais , Dependovirus/metabolismo , Eletromiografia , Integrases/metabolismo , CamundongosRESUMO
Diffusion-weighted magnetic resonance imaging (dMRI) enables the microstructural characterization and reconstruction of white matter pathways in vivo non-invasively. However, dMRI only provides information on the orientation of potential fibers but not on their anatomical plausibility. To that end, recent methodological advances facilitate the effective use of anatomical priors in the process of fiber reconstruction, thus improving the accuracy of the results. Here, we investigated the potential of anatomically constrained tracking (ACT), a modular addition to the tractography software package MRtrix3, to accurately reconstruct the optic radiation, a commonly affected pathway in multiple sclerosis (MS). Diffusion MRI data were acquired from 28 MS patients and 22 age- and sex-matched healthy controls. For each participant, the optic radiation was segmented based on the fiber reconstruction obtained using ACT. When implementing ACT in MS, it proved essential to incorporate lesion maps to avoid incorrect reconstructions due to tissue-type misclassifications in lesional areas. The ACT-based results were compared with those obtained using two commonly used probabilistic fiber tracking procedures, based on FSL (FMRIB Software Library) and MRtrix3 without ACT. All three procedures enabled a reliable localization of the optic radiation in both MS patients and controls. However, for FSL and MRtrix3 without ACT it was necessary to place an additional waypoint halfway between the lateral geniculate nucleus and the primary visual cortex to filter out anatomically implausible tracks. In the case of ACT, the results with and without an additional waypoint were virtually identical, presumably because the employed anatomical constraints already prevented the occurrence of the most implausible tracks. Irrespective of the employed tractography procedure, increased diffusivity and decreased anisotropy were found in the optic radiation of the MS patients compared to the controls.
Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Imagem de Tensor de Difusão/métodos , Esclerose Múltipla/diagnóstico por imagem , Córtex Visual/diagnóstico por imagem , Vias Visuais/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Cápsula Interna/diagnóstico por imagem , Cápsula Interna/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Córtex Visual/metabolismo , Vias Visuais/metabolismo , Substância Branca/metabolismo , Adulto JovemRESUMO
Posterior limb of the internal capsule lesions (PLICL) are one of the MRI features of neuromyelitis optica spectrum disorder (NMOSD). However, there is no evidence that such lesions are pathogenically related to NMOSD. We retrospectively analyzed features of PLICL in NMOSD, and other central nervous system inflammatory disorders, in 561 patients. We also examined the pathological samples of six patients. Of the 561 patients investigated, PLICL were found in 65 patients (11.6%). Lesions were bilateral in 26 cases (40%) and unilateral in 39 cases (60%). Unilateral lesions were mainly located on the left side (74.3%, 29/39). Of the 65 patients with PLICL, 46 patients had NMOSD (70.8%) and were positive for anti-aquaporin (AQP4-IgG), four had NMOSD (6.2%) and were AQP4-IgG negative, 10 patients had multiple sclerosis (MS), three patients had NMDAR encephalitis, and two had autoimmune meningoencephalitis. Of the six patients whose pathological samples were evaluated, all had PLICL and were negative for AQP4-IgG, and none had pathological NMOSD lesion features. These cases included three patients with multiple sclerosis, one with anti-N-methyl-D-aspartate receptor encephalitis, and two with autoimmune meningoencephalitis. In conclusion, PLICL are found not only in patients with NMOSD, but also in MS and other disorders.
Assuntos
Cápsula Interna/patologia , Neuromielite Óptica/patologia , Adulto , Idoso , Anticorpos/sangue , Anticorpos/líquido cefalorraquidiano , Antígenos CD/metabolismo , Aquaporina 4/imunologia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Cápsula Interna/diagnóstico por imagem , Cápsula Interna/metabolismo , Imageamento por Ressonância Magnética , Masculino , Neuromielite Óptica/sangue , Neuromielite Óptica/líquido cefalorraquidiano , Neuromielite Óptica/diagnóstico por imagem , Receptores de N-Metil-D-Aspartato/imunologia , Estudos Retrospectivos , Adulto JovemRESUMO
Blast-related traumatic brain injury (bTBI) resulting from improvised explosive devices is the hallmark injury of recent wars, and affects many returning veterans who experienced either direct or indirect exposure. Many of these veterans have long-term neurocognitive symptoms. However, there is very little evidence to show whether blast-induced acceleration alone, in the absence of secondary impacts, can cause mild TBI. In this study, we examine the effect of under-vehicle blast-induced hyperacceleration (uBIH) of â¼1700 g on the biochemical and microstrucutral changes in the brain using diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). Two groups of adult male Sprague-Dawley (SD) rats were subjected to a sham procedure and uBIH, respectively. Axonal and neurochemical alterations were assessed using in vivo DTI and MRS at 2 h, 24 h, and 7 days after uBIH. Significant reduction in mean diffusivity, axial diffusivity, and radial diffusivity were observed in the hippocampus, thalamus, internal capsule, and corpus callosum as early as 2 h, and sustained up to 7 days post-uBIH. Total creatine (Cr) and glutamine (Gln) were reduced in the internal capsule at 24 h post-uBIH. The reductions in DTI parameters, Cr and Gln in vivo suggest potential activation of astrocytes and diffuse axonal injury following a single underbody blast, confirming previous histology reports.
Assuntos
Aceleração/efeitos adversos , Traumatismos por Explosões/diagnóstico por imagem , Imagem de Tensor de Difusão/tendências , Hipocampo/diagnóstico por imagem , Cápsula Interna/diagnóstico por imagem , Espectroscopia de Ressonância Magnética , Animais , Traumatismos por Explosões/metabolismo , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/metabolismo , Imagem de Tensor de Difusão/métodos , Hipocampo/metabolismo , Cápsula Interna/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Hypoglycemia may cause acute hemiplegia. The most common diffusion-weighted MR imaging finding in patients with hypoglycemic hemiplegia is the hyperintense lesion involving the internal capsule, mimicking acute ischemic stroke. Thus, in patients with acute onset hemiplegia, it is important to differentiate hypoglycemia on arrival by immediate blood glucose measurement. It has recently been shown that hypoglycemic brain injury start in large white matter tracts such as internal capsule and spread throughout the whole brain, including the gray matter. However, it is still unclear why focal signs such as hemiplegia develope in metabolic disorders affecting the whole brain.
Assuntos
Encéfalo/patologia , Hemiplegia/tratamento farmacológico , Hemiplegia/metabolismo , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Cápsula Interna/metabolismo , Hemiplegia/diagnóstico , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/metabolismo , Processamento de Imagem Assistida por Computador/métodosRESUMO
OBJECTIVE: The white matter injury caused by intracerebral hemorrhage (ICH) includes demyelination and axonal injury. Oligodendrocyte apoptosis is reported to be involved in triggering demyelination. Experimental observations indicate that both endoplasmic reticulum and mitochondrial pathways could mediate cell apoptosis. The purpose of this study was to investigate the demyelination and the possible mechanisms in an autologous blood-injected rat model of internal capsule hemorrhage. METHODS: Transmission electron microscope was applied to examine the pathological changes of myelinated nerve fibers in internal capsule. Western blotting was used to detect the myelin basic protein (MBP) which was an important component of myelin sheath. Double immunofluorescence and Western blotting were used to determine the apoptosis and apoptotic pathways. The levels of caspase-12 (a representative protein of endoplasmic reticulum stress) and cytochrome c (an apoptosis factor released from mitochondria) were assessed in this study. RESULTS: Demyelination occurred on day 1, 3, and 7 after ICH onset. Myelin sheaths of internal capsule nerve fibers were swollen and broken down in ICH groups. MBP expression showed a downregulation after ICH with its minimum value occurred on day 7 post-ICH. Besides, neuron and oligodendrocyte apoptosis were observed at different time intervals post-ICH accompanied with an upregulated caspase-12 expression and enhanced cytochrome c release. CONCLUSIONS: These results suggested that oligodendrocyte and neuron apoptosis may contribute to the demyelination induced by internal capsule hemorrhage and oligodendrocyte apoptosis is positively mediated through both endoplasmic reticulum and mitochondrial pathways.
Assuntos
Apoptose , Hemorragia Cerebral/metabolismo , Retículo Endoplasmático/metabolismo , Cápsula Interna/metabolismo , Mitocôndrias/metabolismo , Oligodendroglia/metabolismo , Animais , Hemorragia Cerebral/patologia , Cápsula Interna/ultraestrutura , Masculino , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Oligodendroglia/ultraestrutura , Ratos , Ratos Sprague-DawleyRESUMO
Specific features of diffusion in the cerebral corticospinal tract of patients with early stages of schizophrenia were studied using methods of diffusion tensor magnetic-resonance imaging and magnetic resonance spectroscopy. A decrease in the coefficient of fractional anisotropy in the posterior limb of the internal capsule and an increase in diffusion coefficient in the radiate crown and motor cortex were observed. The results reflect different mechanisms of changes in water diffusion in various areas of the corticospinal tract: changes in nerve fiber microstructure in the internal capsule of the left hemisphere and a decrease in their density in the motor cortex and radiate crown.
Assuntos
Imagem de Tensor de Difusão , Tratos Piramidais/metabolismo , Esquizofrenia/metabolismo , Adolescente , Adulto , Anisotropia , Água Corporal , Pedúnculo Cerebral/metabolismo , Pedúnculo Cerebral/patologia , Difusão , Humanos , Cápsula Interna/metabolismo , Cápsula Interna/patologia , Masculino , Bulbo/metabolismo , Bulbo/patologia , Córtex Motor/metabolismo , Córtex Motor/patologia , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Tratos Piramidais/patologia , Esquizofrenia/patologia , Substância Branca/metabolismo , Substância Branca/patologia , Adulto JovemRESUMO
Dividing schizophrenia into its deficit (SZD) and nondeficit (SZND) subtypes may help to identify specific and more homogeneous pathophysiological characteristics. Our aim was to define a whole brain voxelwise map specifically characterizing white matter tracts of schizophrenia patients with and without the deficit syndrome. We compared microstructural diffusion-related parameters as measured by diffusion tensor imaging in 21 SZD patients, 21 SZND patients, and 21 healthy controls, age- and gender-matched. Results showed that fractional anisotropy was reduced in the right precentral area in SZND patients, and in the left corona radiata of the schizophrenia group as a whole. Axial diffusivity was reduced in the left postcentral area of SZD patients and in the left cerebellum of the whole schizophrenia group. Radial diffusivity was increased in the left forceps minor of SZD patients, in the left internal capsule of SZND patients, and in the right inferior fronto-occipital fasciculus in the whole schizophrenia group. Mean diffusivity was increased from healthy controls to SZD patients to SZND patients in the right occipital lobe. In conclusion, SZD patients are not simply at the extreme end of a severity continuum of white matter disruption. Rather, the SZD and SZND subtypes are associated with distinct and specific brain microstructural anomalies that are consistent with their peculiar psychopathological dimensions.
Assuntos
Esquizofrenia/classificação , Esquizofrenia/diagnóstico , Substância Branca/patologia , Adulto , Anisotropia , Mapeamento Encefálico/métodos , Cerebelo/metabolismo , Cerebelo/patologia , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Imagem de Tensor de Difusão/métodos , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Humanos , Cápsula Interna/metabolismo , Cápsula Interna/patologia , Masculino , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Lobo Occipital/metabolismo , Lobo Occipital/patologia , Esquizofrenia/metabolismo , Substância Branca/metabolismo , Adulto JovemRESUMO
Strokes attributable to subcortical infarcts have been increasing recently in elderly patients. To gain insight how this lesion influences the motor outcome and responds to rehabilitative training, we used circumscribed photothrombotic capsular infarct models on 36 Sprague-Dawley rats (24 experimental and 12 sham-operated). We used 2-deoxy-2-[(18)F]-fluoro-D-glucose-micro positron emission tomography (FDG-microPET) to assess longitudinal changes in resting-state brain activity (rs-BA) and daily single-pellet reaching task (SPRT) trainings to evaluate motor recovery. Longitudinal FDG-microPET results showed that capsular infarct resulted in a persistent decrease in rs-BA in bilateral sensory and auditory cortices, and ipsilesional motor cortex, thalamus, and inferior colliculus (P<0.0025, false discovery rate (FDR) q<0.05). The decreased rs-BA is compatible with diaschisis and contributes to manifest the malfunctions of lesion-specific functional connectivity. In contrast, capsular infarct resulted in increase of rs-BA in the ipsilesional internal capsule, and contralesional red nucleus and ventral hippocampus in recovery group (P<0.0025, FDR q<0.05), implying that remaining subcortical structures have an important role in conducting the recovery process in capsular infarct. The SPRT training facilitated motor recovery only in rats with an incomplete destruction of the posterior limb of the internal capsule (PLIC) (Pearson's correlation, P<0.05). Alternative therapeutic interventions are required to enhance the potential for recovery in capsular infarct with complete destruction of PLIC.
Assuntos
Comportamento Animal/fisiologia , Infarto Encefálico/patologia , Cápsula Interna/patologia , Recuperação de Função Fisiológica/fisiologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/metabolismo , Infarto Encefálico/fisiopatologia , Interpretação Estatística de Dados , Modelos Animais de Doenças , Fluordesoxiglucose F18 , Glucose/metabolismo , Processamento de Imagem Assistida por Computador , Cápsula Interna/diagnóstico por imagem , Cápsula Interna/metabolismo , Cápsula Interna/fisiopatologia , Atividade Motora/fisiologia , Tomografia por Emissão de Pósitrons , Ratos Sprague-Dawley , Fatores de TempoRESUMO
During the development of forebrain connectivity, ascending thalamocortical and descending corticofugal axons first intermingle at the pallial-subpallial boundary to form the internal capsule (IC). However, the identity of molecular cues that guide these axons remains largely unknown. Here, we show that the transmembrane protein Linx is robustly expressed in the prethalamus and lateral ganglionic eminence-derived corridor and on corticofugal axons, but not on thalamocortical axons, and that mice with a null mutation of Linx exhibit a complete absence of the IC. Moreover, regional inactivation of Linx either in the prethalamus and LGE or in the neocortex leads to a failure of IC formation. Furthermore, Linx binds to thalamocortical projections, and it promotes outgrowth of thalamic axons. Thus, Linx guides the extension of thalamocortical axons in the ventral forebrain, and subsequently, it mediates reciprocal interactions between thalamocortical and corticofugal axons to form the IC.
Assuntos
Axônios/metabolismo , Cápsula Interna/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Prosencéfalo/fisiologia , Tálamo/fisiologia , Animais , Axônios/fisiologia , Cápsula Interna/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Vias Neurais/fisiologia , Técnicas de Cultura de Órgãos , Ligação Proteica/fisiologiaRESUMO
Hydrocephalus can develop secondarily to a disturbance in production, flow and/or absorption of cerebrospinal fluid. Experimental models of hydrocephalus, especially subacute and chronic hydrocephalus, are few and limited, and the effects of hydrocephalus on the subventricular zone are unclear. The aim of this study was to analyze the effects of long-term obstructive hydrocephalus on the subventricular zone, which is the neurogenic niche lining the lateral ventricles. We developed a new method to induce hydrocephalus by obstructing the aqueduct of Sylvius in the mouse brain, thus simulating aqueductal stenosis in humans. In 120-day-old rodents (n=18 per group), the degree of ventricular dilatation and cellular composition of the subventricular zone were studied by immunofluorescence and transmission electron microscopy. In adult patients (age>18years), the sizes of the subventricular zone, corpus callosum, and internal capsule were analyzed by magnetic resonance images obtained from patients with and without aqueductal stenosis (n=25 per group). Mice with 60-day hydrocephalus had a reduced number of Ki67+ and doublecortin+cells on immunofluorescence, as well as decreased number of neural progenitors and neuroblasts in the subventricular zone on electron microscopy analysis as compared to non-hydrocephalic mice. Remarkably, a number of extracellular matrix structures (fractones) contacting the ventricular lumen and blood vessels were also observed around the subventricular zone in mice with hydrocephalus. In humans, the widths of the subventricular zone, corpus callosum, and internal capsule in patients with aqueductal stenosis were significantly smaller than age and gender-matched patients without aqueductal stenosis. In summary, supratentorial hydrocephalus reduces the proliferation rate of neural progenitors and modifies the cytoarchitecture and extracellular matrix compounds of the subventricular zone. In humans, this similar process reduces the subventricular niche as well as the width of corpus callosum and internal capsule.
Assuntos
Hidrocefalia/patologia , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Adulto , Animais , Estudos de Coortes , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Feminino , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Hidrocefalia/fisiopatologia , Cápsula Interna/metabolismo , Cápsula Interna/patologia , Antígeno Ki-67/metabolismo , Ventrículos Laterais/ultraestrutura , Imageamento por Ressonância Magnética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo , Fatores de Tempo , Adulto JovemRESUMO
We present a new method for inducing a circumscribed subcortical capsular infarct (SCI), which imposes a persistent motor impairment in rats. Photothrombotic destruction of the internal capsule (IC) was conducted in Sprague Dawley rats (male; n=38). The motor performance of all animals was assessed using forelimb placing, forelimb use asymmetry, and the single pellet reaching test. On the basis of the degree of motor recovery, rats were subdivided into either the poor recovery group (PRG) or the moderate recovery group (MRG). Imaging assessment of the impact of SCI on brain metabolism was performed using 2-deoxy-2-[(18)F]-fluoro-D-glucose ([(18)F]-FDG) microPET (positron emission tomography). Photothrombotic lesioning using low light energy selectively disrupted circumscribed capsular fibers. The MRG showed recovery of motor performance after 1 week, but the PRG showed a persistent motor impairment for >3 weeks. Damage to the posterior limb of the IC (PLIC) is more effective for producing a severe motor deficit. Analysis of PET data revealed decreased regional glucose metabolism in the ipsilesional motor and bilateral sensory cortex and increased metabolism in the contralesional motor cortex and bilateral hippocampus during the early recovery period after SCI. Behavioral, histologic, and functional imaging findings support the usefulness of this novel SCI rat model for investigating motor recovery.
Assuntos
Comportamento Animal/fisiologia , Infarto Encefálico/complicações , Cápsula Interna/patologia , Trombose Intracraniana/complicações , Transtornos dos Movimentos/etiologia , Recuperação de Função Fisiológica/fisiologia , Animais , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/patologia , Infarto Encefálico/fisiopatologia , Modelos Animais de Doenças , Fluordesoxiglucose F18 , Glucose/metabolismo , Cápsula Interna/diagnóstico por imagem , Cápsula Interna/metabolismo , Cápsula Interna/fisiopatologia , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/patologia , Trombose Intracraniana/fisiopatologia , Masculino , Atividade Motora/fisiologia , Transtornos dos Movimentos/diagnóstico por imagem , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/fisiopatologia , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-DawleyRESUMO
Canine models have many advantages for evaluating therapy of human central nervous system (CNS) diseases. In contrast to nonhuman primate models, naturally occurring canine CNS diseases are common. In contrast to murine models, the dog's lifespan is long, its brain is large and the diseases affecting it commonly have the same molecular, pathological and clinical phenotype as the human diseases. We compared the ability of four intracerebrally injected adeno-associated virus vector (AAV) serotypes to transduce the dog brain with green fluorescent protein as the first step in using these vectors to evaluate both delivery and efficacy in naturally occurring canine homologs of human diseases. Quantitative measures of transduction, maximum diameter and area, identified both AAV2/9 and AAV2/rh10 as significantly more efficient than either AAV2/1 or AAV2/5 at transducing cerebral cortex, caudate nucleus, thalamus and internal capsule. Fluorescence co-labeling with cell-type-specific antibodies demonstrated that AAV2/9 and AAV2/rh10 were capable of primarily transducing neurons, although glial transduction was also identified and found to be more efficient with the AAV2/9 vector. These data are a prerequisite to evaluating the efficacy of recombinant AAV vectors carrying disease-modifying transgenes to treat naturally occurring canine models in preclinical studies of human CNS disease therapy.
Assuntos
Encéfalo/metabolismo , Dependovirus/genética , Vetores Genéticos , Transdução Genética , Animais , Encéfalo/virologia , Núcleo Caudado/metabolismo , Núcleo Caudado/virologia , Córtex Cerebral/metabolismo , Córtex Cerebral/virologia , Dependovirus/classificação , Dependovirus/fisiologia , Modelos Animais de Doenças , Cães , Proteínas de Fluorescência Verde/genética , Humanos , Cápsula Interna/metabolismo , Cápsula Interna/virologia , Sorotipagem , Tálamo/metabolismo , Tálamo/virologia , TransgenesRESUMO
Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin's activity-dependent release. We used diffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Encéfalo/fisiologia , Metionina/genética , Valina/genética , Adolescente , Adulto , Algoritmos , Alelos , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Mapeamento Encefálico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Caloso/anatomia & histologia , Corpo Caloso/metabolismo , Corpo Caloso/fisiologia , Feminino , Frequência do Gene , Genótipo , Humanos , Cápsula Interna/anatomia & histologia , Cápsula Interna/metabolismo , Cápsula Interna/fisiologia , Desequilíbrio de Ligação , Imageamento por Ressonância Magnética/métodos , Masculino , Modelos Neurológicos , Fibras Nervosas/metabolismo , Fibras Nervosas/fisiologia , Rede Nervosa/anatomia & histologia , Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
The therapeutic benefits of bilateral capsulotomy for the treatment of refractory obsessive compulsive disorder (OCD) are probably attributed to interruption of the cortico-striato-thalamo-cortical circuitry. We evaluated resting brain metabolism and treatment response in OCD patients using positron emission tomography (PET) imaging. [(18)F]-fluoro-deoxy-glucose PET was performed in eight OCD patients precapsulotomy and postcapsulotomy. We determined metabolic differences between preoperative images in patients and those in eight age-matched healthy volunteers, and postoperative changes and clinical correlations in the patients. The OCD patients showed widespread metabolic increases in normalized glucose metabolism in the bilateral orbitofrontal cortex and inferior frontal gyrus, cingulate gyrus, and bilateral pons/cerebellum, and metabolic decreases bilaterally in the precentral and lingual gyri. Bilateral capsulotomy resulted in significant metabolic decreases bilaterally in the prefrontal cortical regions, especially in the dorsal anterior cingulate cortex (ACC) and in the medial dorsal thalamus and caudate nucleus. In contrast, metabolism increased bilaterally in the precentral and lingual gyri. Clinical improvement in patients correlated with metabolic changes in the bilateral dorsal ACC and in the right middle occipital gyrus after capsulotomy. This study underscores the importance of the internal capsule in modulating ventral prefrontal and dorsal anterior cingulate neuronal activity in the neurosurgical management of OCD patients.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Fluordesoxiglucose F18 , Cápsula Interna/cirurgia , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/cirurgia , Adolescente , Adulto , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Glucose/metabolismo , Giro do Cíngulo/irrigação sanguínea , Giro do Cíngulo/metabolismo , Giro do Cíngulo/patologia , Giro do Cíngulo/cirurgia , Humanos , Cápsula Interna/diagnóstico por imagem , Cápsula Interna/metabolismo , Cápsula Interna/patologia , Masculino , Transtorno Obsessivo-Compulsivo/metabolismo , Transtorno Obsessivo-Compulsivo/patologia , Tomografia por Emissão de Pósitrons/métodos , Estudos Retrospectivos , Adulto JovemRESUMO
A number of studies have shown an association between diabetes and depression. However, the underlying mechanisms are still unclear. Previous findings indicate a role for the prefrontal cortex and subcortical gray matter regions in type 2 diabetes and major depressive disorder (MDD). The purpose of this study was to examine the white matter integrity in the fibers that are part of the anterior limb of internal capsule (ALIC) in MDD and diabetic subjects using diffusion tensor imaging tractography. We studied 4 groups of subjects including 1) 42 healthy controls (HC), 2) 28 MDD subjects (MD), 3) 24 patients diagnosed with type 2 diabetes without depression (DC), and 4) 22 patients diagnosed with diabetes and depression (DD). Results revealed significantly decreased fractional anisotropy (FA; P=.021) and a trend towards significant increase in radial diffusivity (RD; P=.078) of the right ALIC in depressed subjects (MD+DD) compared to non-depressed subjects (HC+DC). While there were no significant diabetes effects or interactions between depression and diabetes, subjects with high depression ratings and high hemoglobin A1c levels had the lowest mean FA values in the right ALIC. In addition, we found a significant negative correlation between FA of the left ALIC with hemoglobin A1c in diabetic subjects (DC+DD; P=.016). Our study demonstrated novel findings of white matter abnormalities of the ALIC in depression and diabetes. These findings have implications for clinical manifestations of depression and diabetes as well as their pathophysiology.
Assuntos
Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/patologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Cápsula Interna/patologia , Fibras Nervosas Mielinizadas/patologia , Adulto , Idoso , Transtorno Depressivo Maior/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Cápsula Interna/metabolismo , Masculino , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/metabolismoRESUMO
Variations in the signalling NRG1-ErbB4 pathway have been associated with genetic susceptibility for both bipolar disorder and schizophrenia, although the underlying neural mechanisms are still uncertain. Reduced integrity of the anterior limb of the internal capsule (ALIC) has been found in association with risk-associated genetic variation in the 5' region of the NRG1 gene. We hypothesised that variation in the gene encoding the NRG1 receptor, ErbB4, would also be associated with reduced ALIC integrity and with cognitive impairments characteristic of individuals with bipolar disorder and schizophrenia. Using diffusion tensor imaging (DTI), we examined the white matter integrity associations of the ErbB4 polymorphism rs4673628, which resides within intron 12 of the gene encoding ErbB4, in 36 healthy individuals. We also sought to clarify the cognitive effects of any findings. We found that genetic variation at the rs4673628 locus in the ErbB4 gene was significantly associated with ALIC white matter integrity which was also significantly and positively associated with mnemonic function. These findings provide further evidence to support a key role of NRG1-ErbB4 signalling in the pathophysiology of major mental disorders.
Assuntos
Receptores ErbB/genética , Predisposição Genética para Doença/genética , Cápsula Interna/anatomia & histologia , Fibras Nervosas Mielinizadas , Polimorfismo de Nucleotídeo Único/genética , Adulto , Análise de Variância , Anisotropia , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Lateralidade Funcional , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Cápsula Interna/metabolismo , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/metabolismo , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Receptor ErbB-4RESUMO
PURPOSE: To study the features of proton magnetic resonance spectroscopy ((1)H-MRS) on amyotrophic lateral sclerosis (ALS) and its relation with clinical scale. MATERIALS AND METHODS: Fifteen patients with definite or probable ALS and 15 age- and gender-matched normal controls were enrolled. (1)H-MRS was performed on a 3.0 Tesla GE imaging system (GE Healthcare, Milwaukee, WI). TE-averaged Point Resolved Selective Spectroscopy was used. N-acetylaspartate (NAA), creatine (Cr), Glu, and Glx (glutamate + glutamine) values of the motor cortex and posterior limb of internal capsule were acquired. The t-test was used to compare differences between groups, and the correlations between the above values and clinical scale were analyzed. RESULTS: The motor area and posterior limb of the internal capsule of ALS patients had lower NAA/Cr (1.91 +/- 0.34, 1.53 +/- 0.17) compared with normal subjects (2.23 +/- 0.33, 1.66 +/- 0.07), and the differences between groups were statistically significant (P < 0.01, 0.01). ALS patients had higher Glu/Cr (0.34 +/- 0.05, 0.29 +/- 0.06) and Glx/Cr (0.40 +/- 0.04, 0.33 +/- 0.06) compared with normal subjects (0.30 +/- 0.03, 0.25 +/- 0.04) and (0.32 +/- 0.05, 0.26 +/- 0.03), and the differences between groups were statistically significant (P < 0.01, 0.01). The Norris scale was negatively correlated with Glx/Cr of primary motor cortex by lineal correlation analysis (r = -0.75), and this correlation had statistical significance (F = 16.60; P = 0.001). CONCLUSION: Neuronal loss and Glu+Gln increase can be detected by using proton MRS in ALS patients. (1)H-MRS is an useful tool in reflecting the characteristic changes of metabolite in ALS.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/metabolismo , Biomarcadores/análise , Cápsula Interna/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Córtex Motor/metabolismo , Reconhecimento Automatizado de Padrão/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prótons , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Our objective was to characterize the structural and metabolic changes of the corticospinal tract (CST) in ALS patients using combined diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI). Fourteen patients (male:female, 6:8; mean age, 54 years) and 14 controls (male:female, 8:6; mean age, 53 years) underwent imaging. Four regions of the CST were evaluated: precentral gyrus, corona radiata, posterior limb of the internal capsule, and cerebral peduncle. DTI and MRSI indices tested included fractional anisotropy (FA), apparent diffusion coefficient (ADC), and the ratio of N-acetylaspartate to choline (NAA/Cho) and creatine (NAA/Cr). In the precentral gyrus, NAA/Cho was reduced 18% (p<0.001), NAA/Cr was reduced 9% (p=0.01), and FA was reduced 3% (p=0.02). NAA/Cho and NAA/Cr were reduced in the corona radiata (p<0.001). Reduced NAA/Cho in the precentral gyrus correlated with shorter symptom duration (r=0.66, p=0.02) and faster disease progression (r=-0.65, p=0.008). Increased spasticity correlated with higher ADC in the precentral gyrus (R=0.52, p=0.005). In conclusion, both MRSI and DTI provided in vivo evidence of intracranial degeneration of the CST in ALS that was most prominent rostrally in the precentral gyrus.