RESUMO
In Huntington disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying the HTT protein, we aim to reduce proteolytic cleavage and ameliorate the consequences of mutant HTT without lowering total HTT levels. To that end, we use an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces partial skipping of exon 12, which contains the critical caspase-6 cleavage site. Here, we show that AON-treatment can partially restore the phenotype of YAC128 mice, a mouse model expressing the full-length human HTT gene including 128 CAG-repeats. Wild-type and YAC128 mice were treated intracerebroventricularly with AON12.1, scrambled AON or vehicle starting at 6 months of age and followed up to 12 months of age, when MRI was performed and mice were sacrificed. AON12.1 treatment induced around 40% exon skip and protein modification. The phenotype on body weight and activity, but not rotarod, was restored by AON treatment. Genes differentially expressed in YAC128 striatum changed toward wild-type levels and striatal volume was preserved upon AON12.1 treatment. However, scrambled AON also showed a restorative effect on gene expression and appeared to generally increase brain volume.
Assuntos
Doença de Huntington , Animais , Humanos , Camundongos , Caspase 6/genética , Caspase 6/metabolismo , Corpo Estriado/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Oligonucleotídeos Antissenso/farmacologia , FenótipoRESUMO
Pathogenesis of the inherited neurodegenerative disorder Huntington's disease (HD) is progressive with a long presymptomatic phase in which subtle changes occur up to 15 years before the onset of symptoms. Thus, there is a need for early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. Recent studies have shown that white matter may be affected early in mutant HTT gene carriers. A previous study performed on 12 months old Ki140CAG mice showed reduced glutamate level measured by Chemical Exchange Saturation Transfer of glutamate (gluCEST), especially in the corpus callosum. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, diffusion tensor imaging, gluCEST and magnetization transfer imaging, in order to assess white matter integrity over the life of this mouse model characterized by slow progression of symptoms. Our results show early defects of diffusion properties in the anterior part of the corpus callosum at 5 months of age, preceding gluCEST defects in the same region at 8 and 12 months that spread to adjacent regions. At 12 months, frontal and piriform cortices showed reduced gluCEST, as well as the pallidum. MT imaging showed reduced signal in the septum at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the potential role of white matter in the brain dysfunction that characterizes HD and the pertinence of gluCEST and DTI as biomarkers in HD.
Assuntos
Doença de Huntington , Substância Branca , Animais , Camundongos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/genética , Doença de Huntington/patologia , Substância Branca/patologia , Imagem de Tensor de Difusão/métodos , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Modelos Animais de Doenças , Ácido GlutâmicoRESUMO
Huntington's disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntington's disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntington's disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntington's disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntington's disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntington's disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.
Assuntos
Doença de Huntington , Doenças Neurodegenerativas , Animais , Camundongos , Doença de Huntington/genética , Astrócitos/metabolismo , Proteostase , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismoRESUMO
BACKGROUND: Older patients are increasingly showing multi-comorbidities, including advanced chronic diseases. When admitted to the emergency department (ED), the decision to pursue life-prolonging treatments or to initiate a palliative care approach is a challenge for clinicians. We test for the first time the diagnostic accuracy of the Supportive and Palliative Care Indicators Tool (SPICT) in the ED to identify older patients at risk of deteriorating and dying, and timely address palliative care needs. METHODS: We conducted a prospective bicentric cohort study on 352 older patients (≥ 75 years) admitted to two EDs in Belgium between December 2019 and March 2020 and between August and November 2020. SPICT (French version, 2019) variables were collected during the patients' admission to the ED, along with socio-demographic, medical and functional data. The palliative profile was defined as a positive SPICT assessment. Survival, symptoms and health degradation (≥ 1 point in ADL Katz score or institutionalisation and death) were followed at 12 months by phone. Main accuracy measures were sensitivity, specificity and likelihood ratios (LR) as well as cox regression, survival analysis using the Kaplan Meier method, and ordinal regression. RESULTS: Out of 352 patients included in the study (mean age 83 ± 5.5 years, 43% male), 167 patients (47%) had a positive SPICT profile. At one year follow up, SPICT positive patients presented significantly more health degradation (72%) compared with SPICT negative patients (35%, p < 0.001). SPICT positivity was correlated with 1-year health degradation (OR 4.9; p < 0.001). The sensitivity and specificity of SPICT to predict health degradation were 0.65 (95%CI, 0.57-0.73) and 0.72 (95%CI, 0.64-0.80) respectively, with a negative LR of 0.48 (95%CI, 0.38-0.60) and a positive LR of 2.37 (1.78-3.16). The survival time was shorter in SPICT positive patients than in SPICT negative ones (p < 0.001), the former having a higher 1-year mortality rate (HR = 4.21; p < 0.001). CONCLUSIONS: SPICT successfully identifies older patients at high risk of health degradation and death. It can support emergency clinicians to identify older patients with a palliative profile and subsequently initiate a palliative care approach with a discussion on goals of care.
Assuntos
Serviço Hospitalar de Emergência , Cuidados Paliativos , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos de Coortes , Estudos Prospectivos , BélgicaRESUMO
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination because of progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-SCA3, SCA6, and SCA17; however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7140Q/5Q, we analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphologic alterations, pacemaker dysfunction, and motor incoordination. Strikingly, most PC genes downregulated in SCA7 have also decreased expression in SCA1 and SCA2 mice, revealing converging pathomechanisms and a common disease signature involving cGMP-PKG and phosphatidylinositol signaling pathways and LTD. Our study thus points out molecular targets for therapeutic development, which may prove beneficial for several SCAs. Furthermore, we show that SCA7140Q/5Q males and females exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology, and photoreceptor dystrophy, which account for progressive impairment of behavior, motor, and visual functions. SCA7140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis.SIGNIFICANCE STATEMENT Spinocerebellar ataxia 7 (SCA7) is one of the several forms of inherited SCAs characterized by cerebellar degeneration because of polyglutamine expansion in specific proteins. The ATXN7 involved in SCA7 is a subunit of SAGA transcriptional coactivator complex. To understand the pathomechanisms of SCA7, we determined the cell type-specific gene deregulation in SCA7 mouse cerebellum. We found that the Purkinje cells are the most affected cerebellar cell type and show downregulation of a large subset of neuronal identity genes, critical for their spontaneous firing and synaptic functions. Strikingly, the same Purkinje cell genes are downregulated in mouse models of two other SCAs. Thus, our work reveals a disease signature shared among several SCAs and uncovers potential molecular targets for their treatment.
Assuntos
Cerebelo/patologia , Células de Purkinje/patologia , Ataxias Espinocerebelares/patologia , Animais , Regulação para Baixo , Feminino , Técnicas de Introdução de Genes , Masculino , Camundongos , TranscriptomaRESUMO
Glutamate is the amino acid with the highest cerebral concentration. It plays a central role in brain metabolism. It is also the principal excitatory neurotransmitter in the brain and is involved in multiple cognitive functions. Alterations of the glutamatergic system may contribute to the pathophysiology of many neurological disorders. For example, changes of glutamate availability are reported in rodents and humans during Alzheimer's and Huntington's diseases, epilepsy as well as during aging. Most studies evaluating cerebral glutamate have used invasive or spectroscopy approaches focusing on specific brain areas. Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) is a recently developed imaging technique that can be used to study relative changes in glutamate distribution in the entire brain with higher sensitivity and at higher resolution than previous techniques. It thus has strong potential clinical applications to assess glutamate changes in the brain. High field is a key condition to perform gluCEST images with a meaningful signal to noise ratio. Thus, even if some studies started to evaluate gluCEST in humans, most studies focused on rodent models that can be imaged at high magnetic field. In particular, systematic characterization of gluCEST contrast distribution throughout the whole brain has never been performed in humans or non-human primates. Here, we characterized for the first time the distribution of the gluCEST contrast in the whole brain and in large-scale networks of mouse lemur primates at 11.7 Tesla. Because of its small size, this primate can be imaged in high magnetic field systems. It is widely studied as a model of cerebral aging or Alzheimer's disease. We observed high gluCEST contrast in cerebral regions such as the nucleus accumbens, septum, basal forebrain, cortical areas 24 and 25. Age-related alterations of this biomarker were detected in the nucleus accumbens, septum, basal forebrain, globus pallidus, hypophysis, cortical areas 24, 21, 6 and in olfactory bulbs. An age-related gluCEST contrast decrease was also detected in specific neuronal networks, such as fronto-temporal and evaluative limbic networks. These results outline regional differences of gluCEST contrast and strengthen its potential to provide new biomarkers of cerebral function in primates.
Assuntos
Ácido Glutâmico , Imageamento por Ressonância Magnética , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Mapeamento Encefálico , Ácido Glutâmico/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , PrimatasRESUMO
OBJECTIVE: During the deconfinement period after the coronavirus disease-2019 (COVID-19) pandemic, the number and characteristics of psychiatric visits changed in our emergency department (ED). We aimed to assess changes in the number of visits and characterize the profiles of these patients. METHODS: In this retrospective observational study, we examined the number of psychiatric ED visits and their proportion among the total number of ED visits. We also evaluated psychiatric visits characteristics during a one-month period after the declaration of deconfinement, and we compared those characteristics to characteristics observed during the same month over the previous 4 years. RESULTS: The number of psychiatric visits to our emergency department during deconfinement was similar to the number observed in the same month of previous years. However, the proportion of psychiatric visits to our emergency department among all visits to the ED rose during deconfinement to a level never before observed. The mean proportion of psychiatric admissions to all ED admissions rose from 3.5% in past years to 5.3% during deconfinement (p = 0.013). Moreover, during deconfinement, more visits (80%) were without an acute intoxication compared to past years (58.5%; p = 0.031). Also, in the deconfinement period, more visits lacked a follow-up consultation organized at discharge (40%) compared to the historical period (25%, p = 0.036). CONCLUSIONS: The deconfinement period after the first wave COVID-19 changed the number and type of psychiatric emergency medicine consultations at our hospital, suggesting a psychiatric impact of confinement during this pandemic. These findings will be of interest to practitioners and politicians in the coming months.
Assuntos
Ansiedade/epidemiologia , COVID-19 , Controle de Doenças Transmissíveis , Depressão/epidemiologia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Transtornos Mentais/epidemiologia , Política Pública , Tentativa de Suicídio/estatística & dados numéricos , Adulto , Assistência ao Convalescente , Intoxicação Alcoólica/epidemiologia , Bélgica/epidemiologia , Emergências , Feminino , Humanos , Masculino , Transtornos da Personalidade/epidemiologia , Estudos Retrospectivos , SARS-CoV-2 , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
Identification of relevant biomarkers is fundamental to understand biological processes of neurodegenerative diseases and to evaluate therapeutic efficacy. Atrophy of brain structures has been proposed as a biomarker, but it provides little information about biochemical events related to the disease. Here, we propose to identify early and relevant biomarkers by combining biological specificity provided by 1 H-MRS and high spatial resolution offered by gluCEST imaging. For this, two different genetic mouse models of Huntington's disease (HD)-the Ki140CAG model, characterized by a slow progression of the disease, and the R6/1 model, which mimics the juvenile form of HD-were used. Animals were scanned at 11.7 T using a protocol combining 1 H-MRS and gluCEST imaging. We measured a significant decrease in levels of N-acetyl-aspartate, a metabolite mainly located in the neuronal compartment, in HD animals, and the decrease seemed to be correlated with disease severity. In addition, variations of tNAA levels were correlated with striatal volumes in both models. Significant variations of glutamate levels were also observed in Ki140CAG but not in R6/1 mice. Thanks to its high resolution, gluCEST provided complementary insights, and we highlighted alterations in small brain regions such as the corpus callosum in Ki140CAG mice, whereas the glutamate level was unchanged in the whole brain of R6/1 mice. In this study, we showed that 1 H-MRS can provide key information about biological processes occurring in vivo but was limited by the spatial resolution. On the other hand, gluCEST may finely point to alterations in unexpected brain regions, but it can also be blind to disease processes when glutamate levels are preserved. This highlights in a practical context the complementarity of the two methods to study animal models of neurodegenerative diseases and to identify relevant biomarkers.
Assuntos
Ácido Glutâmico/metabolismo , Doença de Huntington/diagnóstico por imagem , Espectroscopia de Prótons por Ressonância Magnética , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Atrofia , Modelos Animais de Doenças , Humanos , Camundongos Transgênicos , Neostriado/diagnóstico por imagem , Neostriado/patologiaRESUMO
Reactive astrocytes exhibit hypertrophic morphology and altered metabolism. Deciphering astrocytic status would be of great importance to understand their role and dysregulation in pathologies, but most analytical methods remain highly invasive or destructive. The diffusion of brain metabolites, as non-invasively measured using diffusion-weighted magnetic resonance spectroscopy (DW-MRS) in vivo, depends on the structure of their micro-environment. Here we perform advanced DW-MRS in a mouse model of reactive astrocytes to determine how cellular compartments confining metabolite diffusion are changing. This reveals myo-inositol as a specific intra-astrocytic marker whose diffusion closely reflects astrocytic morphology, enabling non-invasive detection of astrocyte hypertrophy (subsequently confirmed by confocal microscopy ex vivo). Furthermore, we measure massive variations of lactate diffusion properties, suggesting that intracellular lactate is predominantly astrocytic under control conditions, but predominantly neuronal in case of astrocyte reactivity. This indicates massive remodeling of lactate metabolism, as lactate compartmentation is tightly linked to the astrocyte-to-neuron lactate shuttle mechanism.
Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Inositol/análise , Espectroscopia de Ressonância Magnética/métodos , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Imagem de Difusão por Ressonância Magnética , Inositol/metabolismo , Ácido Láctico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Autoantibodies against myelin oligodendrocyte glycoprotein (anti-MOG-Abs) occur in a majority of children with acquired demyelinating syndromes (ADS) and physiopathology is still under investigation. As cynomolgus macaques immunized with rhMOG, all develop an experimental autoimmune encephalomyelitis (EAE), we assessed relatedness between anti-MOG-Abs associated diseases in both species. METHODS: The study includes 27 children followed for ADS and nine macaques with rhMOG-induced EAE. MRI lesions, cytokines in blood, and CSF at onset of ADS or EAE, as well as histopathological features of brain lesions were compared. RESULTS: Twelve children with anti-MOG-Abs ADS (ADS MOG+) and nine macaques with EAE, presented increased IL-6 and G-CSF in the CSF, whereas no such signature was found in 15 ADS MOG-. Furthermore, IgG and C1q were associated to myelin and phagocytic cells in brains with EAE (n = 8) and in biopsies of ADS MOG+ (n = 2) but not ADS MOG- children (n = 1). Macaque brains also revealed prephagocytic lesions with IgG and C1q depositions but no leukocyte infiltration. CONCLUSIONS: Children with ADS MOG+ and macaques with EAE induced with rhMOG, present a similar cytokine signature in the CSF and a comparable aspect of brain lesions indicating analogous pathophysiological processes. In EAE, prephagocytic lesions points at IgG as an initial effector of myelin attack. These results support the pertinence of modeling ADS MOG+ in non-human primates to apprehend the natural development of anti-MOG-associated disease, find markers of evolution, and above all explore the efficacy of targeted therapies to test primate-restricted molecules.
Assuntos
Autoanticorpos/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico por imagem , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito/sangue , Adolescente , Animais , Autoanticorpos/líquido cefalorraquidiano , Criança , Pré-Escolar , Doenças Desmielinizantes/líquido cefalorraquidiano , Encefalomielite Autoimune Experimental/líquido cefalorraquidiano , Feminino , Humanos , Macaca , Masculino , Glicoproteína Mielina-Oligodendrócito/líquido cefalorraquidianoRESUMO
The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington's disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodelling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington's disease could render the striatum highly vulnerable to neurodegeneration.
Assuntos
Corpo Estriado/enzimologia , Proteína Huntingtina/genética , Doença de Huntington/terapia , Mutação/genética , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Quinases Semelhantes a Duplacortina , Regulação para Baixo/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Força da Mão/fisiologia , Doença de Huntington/genética , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora , Neurônios/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The brain is one of the most complex organs, and tools are lacking to assess its cellular morphology in vivo. Here we combine original diffusion-weighted magnetic resonance (MR) spectroscopy acquisition and novel modeling strategies to explore the possibility of quantifying brain cell morphology noninvasively. First, the diffusion of cell-specific metabolites is measured at ultra-long diffusion times in the rodent and primate brain in vivo to observe how cell long-range morphology constrains metabolite diffusion. Massive simulations of particles diffusing in synthetic cells parameterized by morphometric statistics are then iterated to fit experimental data. This method yields synthetic cells (tentatively neurons and astrocytes) that exhibit striking qualitative and quantitative similarities with histology (e.g., using Sholl analysis). With our approach, we measure major interspecies difference regarding astrocytes, whereas dendritic organization appears better conserved throughout species. This work suggests that the time dependence of metabolite diffusion coefficient allows distinguishing and quantitatively characterizing brain cell morphologies noninvasively.
Assuntos
Astrócitos/citologia , Encéfalo , Imagem de Difusão por Ressonância Magnética/métodos , Neurônios/citologia , Animais , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Macaca fascicularis , Masculino , CamundongosRESUMO
BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is a devastating form of stroke with neurological outcomes dependent on the occurrence of delayed cerebral ischemia. It has been shown in rodents that some of the mechanisms leading to delayed cerebral ischemia are related to a decreased circulation of the cerebrospinal fluid (CSF) within the brain parenchyma. Here, we evaluated the cerebral circulation of the CSF in a nonhuman primate in physiological condition and after SAH. METHODS: We first evaluated in physiological condition the circulation of the brain CSF in Macacafacicularis, using magnetic resonance imaging of the temporal DOTA-Gd distribution after its injection into the CSF. Then, animals were subjected to a minimally invasive SAH before an MRI evaluation of the impact of SAH on the brain parenchymal CSF circulation. RESULTS: We first demonstrate that the CSF actively penetrates the brain parenchyma. Two hours after injection, almost the entire brain is labeled by DOTA-Gd. We also show that our model of SAH in nonhuman primate displays the characteristics of SAH in humans and leads to a dramatic impairment of the brain parenchymal circulation of the CSF. CONCLUSIONS: The CSF actively penetrates within the brain parenchyma in the gyrencephalic brain, as described for the glymphatic system in rodent. This parenchymal CSF circulation is severely impaired by SAH.
Assuntos
Encéfalo/metabolismo , Circulação Cerebrovascular/fisiologia , Tecido Parenquimatoso/metabolismo , Índice de Gravidade de Doença , Hemorragia Subaracnóidea/líquido cefalorraquidiano , Animais , Encéfalo/diagnóstico por imagem , Macaca fascicularis , Masculino , Tecido Parenquimatoso/diagnóstico por imagem , Primatas , Hemorragia Subaracnóidea/diagnóstico por imagemRESUMO
Because they bridge the genetic gap between rodents and humans, non-human primates (NHPs) play a major role in therapy development and evaluation for neurological disorders. However, translational research success from NHPs to patients requires an accurate phenotyping of the models. In patients, magnetic resonance imaging (MRI) combined with automated segmentation methods has offered the unique opportunity to assess in vivo brain morphological changes. Meanwhile, specific challenges caused by brain size and high field contrasts make existing algorithms hard to use routinely in NHPs. To tackle this issue, we propose a complete pipeline, Primatologist, for multi-region segmentation. Tissue segmentation is based on a modular statistical model that includes random field regularization, bias correction and denoising and is optimized by expectation-maximization. To deal with the broad variety of structures with different relaxing times at 7 T, images are segmented into 17 anatomical classes, including subcortical regions. Pre-processing steps insure a good initialization of the parameters and thus the robustness of the pipeline. It is validated on 10 T2-weighted MRIs of healthy macaque brains. Classification scores are compared with those of a non-linear atlas registration, and the impact of each module on classification scores is thoroughly evaluated.
Assuntos
Algoritmos , Encéfalo/anatomia & histologia , Macaca/anatomia & histologia , Neuroimagem/métodos , Software , Animais , Atlas como Assunto , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional/métodos , Imageamento por Ressonância MagnéticaRESUMO
Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early atrophy of the striatum. While the disease progresses, other brain structures also degenerate, including the cerebral cortex. Changes are also seen outside the brain, in particular weight loss/cachexia despite high dietary intake. The disease is caused by an abnormal expansion of a CAG repeat in the gene encoding the huntingtin protein (Htt). This mutation leads to the expression of a poly-glutamine stretch that changes the biological functions of mutant Htt (mHtt). The mechanisms underlying neurodegeneration in HD are not totally elucidated. Here, we discuss recent results obtained in patients, animal and cellular models suggesting that early disturbance in energy metabolism at least in part associated with mitochondrial defects may play a central role, even though all data are not congruent, possibly because most findings were obtained in cell culture systems or using biochemical analyses of post mortem tissues from rodent models. Thus, we put a particular focus on brain imaging studies that could identify biomarkers of energy defects in vivo and would be of prime interest in preclinical and clinical trials testing the efficacy of new therapies targeting energy metabolism in HD.
Assuntos
Metabolismo Energético , Doença de Huntington/metabolismo , Animais , Cálcio/metabolismo , Corpo Estriado/metabolismo , Humanos , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismoRESUMO
Huntington's disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive and psychiatric symptoms. Atrophy of the striatum has been proposed for several years as a biomarker to assess disease progression in HD gene carriers. However, it does not provide any information about the biological mechanisms linked to HD pathogenesis. Changes in brain metabolites have been also consistently seen in HD patients and animal models using Magnetic Resonance Spectroscopy (MRS), but metabolite measurements are generally limited to a single voxel. In this study, we used Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) in order to map glutamate distribution in the brain of a knock-in mouse model (Ki140CAG) with a precise anatomical resolution. We demonstrated that both heterozygous and homozygous mice with pathological CAG repeat expansion in gene encoding huntingtin exhibited an atrophy of the striatum and a significant alteration of their metabolic profile in the striatum as compared to wild type littermate controls. The striatal decrease was then confirmed by gluCEST imaging. Surprisingly, CEST imaging also revealed that the corpus callosum was the most affected structure in both genotype groups, suggesting that this structure could be highly vulnerable in HD. We evaluated for the first time gluCEST imaging as a potential biomarker of HD and demonstrated its potential for characterizing metabolic defects in neurodegenerative diseases in specific regions.
Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Ácido Glutâmico/metabolismo , Doença de Huntington/metabolismo , Imagem Molecular/métodos , Espectroscopia de Prótons por Ressonância Magnética/métodos , Animais , Regulação para Baixo , Feminino , Técnicas de Introdução de Genes , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurotransmissores/metabolismoRESUMO
BACKGROUND: Paracetamol is a widely used analgesic and antipyretic. Paracetamol-induced hepatotoxicity is well known, but nephrotoxicity without hepatotoxicity is rarely seen. CASE PRESENTATION: We present a case of acute kidney injury without hepatotoxicity in paracetamol overdose. A 15-year-old girl was admitted 48 h after she had taken 10 g of paracetamol. She was complaining of abdominal pain and vomiting. Her blood level of creatinine was 1.20 mg/dL on admission, with a peak at 3.67 mg/dL 3 days later. The liver blood tests and blood paracetamol level were negative. She did not receive N-acetyl cysteine and was treated with intravenous fluid (crystalloid). The ultrasonography of the kidneys was normal. Her renal function returned almost to baseline 7 days after admission. It was concluded that the diagnosis was an acute kidney injury caused by acute tubular necrosis due to paracetamol overdose. CONCLUSION: This case shows that nephrotoxicity can occur without hepatotoxicity in paracetamol overdose.
RESUMO
Huntington's disease is an inherited disorder characterized by psychiatric, cognitive, and motor symptoms due to degeneration of medium spiny neurons in the striatum. A prodromal phase precedes the onset, lasting decades. Current biomarkers include clinical score and striatal atrophy using Magnetic Resonance Imaging (MRI). These markers lack sensitivity for subtle cellular changes during the prodromal phase. MRI and MR spectroscopy offer different contrasts for assessing metabolic, microstructural, functional, or vascular alterations in the disease. They have been used in patients and mouse models. Mouse models can be of great interest to study a specific mechanism of the degenerative process, allow better understanding of the pathogenesis from the prodromal to the symptomatic phase, and to evaluate therapeutic efficacy. Mouse models can be divided into three different constructions: transgenic mice expressing exon-1 of human huntingtin (HTT), mice with an artificial chromosome expressing full-length human HTT, and knock-in mouse models with CAG expansion inserted in the murine htt gene. Several studies have used MRI/S to characterized these models. However, the multiplicity of modalities and mouse models available complicates the understanding of this rich corpus. The present review aims at giving an overview of results obtained using MRI/S for each mouse model of HD, to provide a useful resource for the conception of neuroimaging studies using mouse models of HD. Finally, despite difficulties in translating preclinical protocols to clinical applications, many biomarkers identified in preclinical models have already been evaluated in patients. This review also aims to cover this aspect to demonstrate the importance of MRI/S for studying HD.
RESUMO
SpinoCerebellar Ataxia type 7 (SCA7) is an inherited disorder caused by CAG triplet repeats encoding polyglutamine expansion in the ATXN7 protein, which is part of the transcriptional coactivator complex SAGA. The mutation primarily causes neurodegeneration in the cerebellum and retina, as well as several forebrain structures. The SCA7140Q/5Q knock-in mouse model recapitulates key disease features, including loss of vision and motor performance. To characterize the temporal progression of brain degeneration of this model, we performed a longitudinal study spanning from early to late symptomatic stages using high-resolution magnetic resonance imaging (MRI) and in vivo 1H-magnetic resonance spectroscopy (1H-MRS). Compared to wild-type mouse littermates, MRI analysis of SCA7 mice shows progressive atrophy of defined brain structures, with the striatum, thalamus and cortex being the first and most severely affected. The volume loss of these structures coincided with increased motor impairments in SCA7 mice, suggesting an alteration of the sensory-motor network, as observed in SCA7 patients. MRI also reveals atrophy of the hippocampus and anterior commissure at mid-symptomatic stage and the midbrain and brain stem at late stage. 1H-MRS of hippocampus, a brain region previously shown to be dysfunctional in patients, reveals early and progressive metabolic alterations in SCA7 mice. Interestingly, abnormal glutamine accumulation precedes the hippocampal atrophy and the reduction in myo-inositol and total N-acetyl-aspartate concentrations, two markers of glial and neuronal damage, respectively. Together, our results indicate that non-cerebellar alterations and glial and neuronal metabolic impairments may play a crucial role in the development of SCA7 mouse pathology, particularly at early stages of the disease. Degenerative features of forebrain structures in SCA7 mice correspond to current observations made in patients. Our study thus provides potential biomarkers that could be used for the evaluation of future therapeutic trials using the SCA7140Q/5Q model.
Assuntos
Ataxias Espinocerebelares , Humanos , Camundongos , Animais , Estudos Longitudinais , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Ataxina-7/genética , Imageamento por Ressonância Magnética , Prosencéfalo/metabolismo , Espectroscopia de Ressonância Magnética , Atrofia/patologiaRESUMO
LipoCEST are liposome-encapsulating paramagnetic contrast agents (CA) based on chemical exchange saturation transfer with applications in biomolecular MRI. Their attractive features include biocompatibility, subnanomolar sensitivity, and amenability to functionalization for targeting biomarkers. We demonstrate MR imaging using a targeted lipoCEST, injected intravenously. A lipoCEST carrying Tm(III)-complexes was conjugated to RGD tripeptide (RGD-lipoCEST), to target integrin α(ν)ß(3) receptors involved in tumor angiogenesis and was compared with an unconjugated lipoCEST. Brain tumors were induced in athymic nude mice by intracerebral injection of U87MG cells and were imaged at 7 T after intravenous injection of either of the two contrast agents (n = 12 for each group). Chemical exchange saturation transfer-MSME sequence was applied over 2 h with an average acquisition time interval of 13.5 min. The chemical exchange saturation transfer signal was â¼1% in the tumor and controlateral regions, and decreased to â¼0.3% after 2 h; while RGD-lipoCEST signal was â¼1.4% in the tumor region and persisted for up to 2 h. Immunohistochemical staining revealed a persistent colocalization of RGD-lipoCEST with α(ν)ß(3) receptors in the tumor region. These results constitute an encouraging step toward in vivo MRI imaging of tumor angiogenesis using intravenously injected lipoCEST.