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1.
Brain ; 146(11): 4766-4783, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37437211

RESUMO

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.


Assuntos
Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Animais , Camundongos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Encéfalo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Cognição , Proteínas dos Microfilamentos/genética
2.
Behav Brain Funct ; 19(1): 19, 2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37932782

RESUMO

Compulsivity is considered a transdiagnostic dimension in obsessive-compulsive and related disorders, characterized by heterogeneous cognitive and behavioral phenotypes associated with abnormalities in cortico-striatal-thalamic-cortical circuitry. The present study investigated the structural morphology of white and gray matter in rats selected for low- (LD) and high- (HD) compulsive drinking behavior on a schedule-induced polydipsia (SIP) task. Regional brain morphology was assessed using ex-vivo high-resolution magnetic resonance imaging (MRI). Voxel-based morphometry of segmented MRI images revealed larger white matter volumes in anterior commissure and corpus callosum of HD rats compared with LD rats. HD rats also showed significantly larger regional volumes of dorsolateral orbitofrontal cortex, striatum, amygdala, hippocampus, midbrain, sub-thalamic nucleus, and cerebellum. By contrast, the medial prefrontal cortex was significantly smaller in HD rats compared with LD rats with no significant group differences in whole brain, ventricular, or cerebrospinal fluid volumes. These findings show that limbic cortico-basal ganglia structures implicated in impulse control disorders are distinct in rats that are vulnerable to develop compulsive behavior. Such abnormalities may be relevant to the etiology of compulsive disorders in humans.


Assuntos
Encéfalo , Comportamento Compulsivo , Humanos , Ratos , Masculino , Animais , Encéfalo/patologia , Comportamento Compulsivo/psicologia , Tonsila do Cerebelo/patologia , Gânglios da Base , Fenótipo , Imageamento por Ressonância Magnética , Mapeamento Encefálico
3.
Cereb Cortex ; 32(18): 4128-4140, 2022 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-35029670

RESUMO

Substantial progress has been made studying morphological changes in brain regions during adolescence, but less is known of network-level changes in their relationship. Here, we compare covariance networks constructed from the correlation of morphometric volumes across 135 brain regions of marmoset monkeys in early adolescence and adulthood. Substantial shifts are identified in the topology of structural covariance networks in the prefrontal cortex (PFC) and temporal lobe. PFC regions become more structurally differentiated and segregated within their own local network, hypothesized to reflect increased specialization after maturation. In contrast, temporal regions show increased inter-hemispheric covariances that may underlie the establishment of distributed networks. Regionally selective coupling of structural and maturational covariance is revealed, with relatively weak coupling in transmodal association areas. The latter may be a consequence of continued maturation within adulthood, but also environmental factors, for example, family size, affecting brain morphology. Advancing our understanding of how morphological relationships within higher-order brain areas mature in adolescence deepens our knowledge of the developing brain's organizing principles.


Assuntos
Callithrix , Imageamento por Ressonância Magnética , Animais , Encéfalo/anatomia & histologia , Córtex Pré-Frontal , Lobo Temporal
4.
Am J Hum Genet ; 99(2): 253-74, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27453576

RESUMO

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.


Assuntos
Proteínas de Transporte/genética , Haploinsuficiência/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Transcrição Gênica , Animais , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Córtex Cerebral/metabolismo , Montagem e Desmontagem da Cromatina/genética , Códon sem Sentido/genética , Transtornos Cognitivos/genética , Mutação da Fase de Leitura/genética , Hipocampo/metabolismo , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/psicologia , Masculino , Camundongos , Microcefalia/genética , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Fenótipo , Proteínas Repressoras , Comportamento Social , Síndrome , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Transcriptoma
5.
Circulation ; 135(12): 1160-1173, 2017 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-28137936

RESUMO

BACKGROUND: Elabela/toddler (ELA) is a critical cardiac developmental peptide that acts through the G-protein-coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern, and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is downregulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model. METHODS: In silico docking analysis, competition binding experiments, and downstream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using real-time quantitative polymerase chain reaction, dual-labeling immunofluorescent staining, and immunoassays. Acute cardiac effects of ELA-32 and [Pyr1]apelin-13 were assessed by MRI and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline- and Sugen/hypoxia-exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the monocrotaline rat model. RESULTS: ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. ELA activated G-protein- and ß-arrestin-dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, and cardiac output and elicited vasodilatation in rat in vivo. ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in monocrotaline-exposed rats. CONCLUSIONS: These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, and is downregulated in human disease and rodent PAH models, and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in humans.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Hormônios Peptídicos/uso terapêutico , Sequência de Aminoácidos , Animais , Apelina , Sítios de Ligação , Cateterismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Humanos , Hipertensão Pulmonar/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/agonistas , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Masculino , Simulação de Dinâmica Molecular , Hormônios Peptídicos/química , Hormônios Peptídicos/metabolismo , Hormônios Peptídicos/farmacologia , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley
6.
J Neurosci ; 36(31): 8238-49, 2016 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-27488642

RESUMO

UNLABELLED: Sheep have large brains with human-like anatomy, making them a useful species for studying brain function. Sleep homeostasis has not been studied in sheep. Here, we establish correlates of sleep homeostasis in sheep through a sleep deprivation experiment. We then use these correlates to elucidate the nature of sleep deficits in a naturally occurring ovine model of neuronal ceroid lipofuscinosis (NCL, Batten disease) caused by a mutation in CLN5 In humans, mutations in this gene lead to cortical atrophy and blindness, as well as sleep abnormalities. We recorded electroencephalograms (EEGs) from unaffected and early stage CLN5(-/-) (homozygous, affected) sheep over 3 consecutive days, the second day being the sleep deprivation day. In unaffected sheep, sleep deprivation led to increased EEG delta (0.5-4 Hz) power during non-rapid eye movement (NREM) sleep, increased time spent in the NREM sleep state, and increased NREM sleep bout length. CLN5(-/-) sheep showed comparable increases in time spent in NREM sleep and NREM sleep bout duration, verifying the presence of increased sleep pressure in both groups. Importantly, CLN5(-/-) sheep did not show the increase in NREM sleep delta power seen in unaffected sheep. This divergent delta power response is consistent with the known cortical degeneration in CLN5(-/-) sheep. We conclude that, whereas sleep homeostasis is present in CLN5(-/-) sheep, underlying CLN5(-/-) disease processes prevent its full expression, even at early stages. Such deficits may contribute to early abnormalities seen in sheep and patients and warrant further study. SIGNIFICANCE STATEMENT: Sleep abnormalities pervade most neurological diseases, including the neuronal ceroid lipofuscinoses (NCLs). Here, we show that, in an ovine model of a variant late-infantile NCL, there is abnormal expression of sleep homeostasis. Whereas some sleep pressure correlates respond to sleep deprivation, the strongest electroencephalogram (EEG) correlate of sleep pressure, non-REM delta power, failed to increase. This highlights the relevance of sleep deficits in this disease, in which the drive for sleep exists but the underlying disease prevents its full expression. Sleep abnormalities could contribute to early disease symptoms such as behavioral disorder and cognitive decline. Our study also shows sleep homeostatic EEG correlates in sheep, opening up new opportunities for studying sleep in a large social mammal with complex human-like brain neuroanatomy.


Assuntos
Encéfalo/fisiopatologia , Modelos Animais de Doenças , Homeostase , Proteínas de Membrana/metabolismo , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Privação do Sono/fisiopatologia , Fases do Sono , Animais , Eletroencefalografia , Masculino , Valores de Referência , Ovinos
7.
Neuroimage ; 163: 197-205, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28923275

RESUMO

Behaviorally relevant sex differences are often associated with structural differences in the brain and many diseases are sexually dimorphic in prevalence and progression. Characterizing sex differences is imperative to gaining a complete understanding of behavior and disease which will, in turn, allow for a balanced approach to scientific research and the development of therapies. In this study, we generated novel tissue probability maps (TPMs) based on 30 male and 30 female in vivo C57BL/6 mouse brain magnetic resonance images and used voxel-based morphometry (VBM) to analyze sex differences. Females displayed larger anterior hippocampus, basolateral amygdala, and lateral cerebellar cortex volumes, while males exhibited larger cerebral cortex, medial amygdala, and medial cerebellar cortex volumes. Atlas-based morphometry (ABM) revealed a statistically significant sex difference in cortical volume and no difference in whole cerebellar volume. This validated our VBM findings that showed a larger cerebral cortex in male mice and a pattern of dimorphism in the cerebellum where the lateral portion was larger in females and the medial portion was larger in males. These results are consonant with previous ex vivo studies examining sex differences, but also suggest further regions of interest.


Assuntos
Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Caracteres Sexuais , Animais , Feminino , Processamento de Imagem Assistida por Computador , Masculino , Camundongos Endogâmicos C57BL
8.
Brain Behav Immun ; 63: 50-59, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27940258

RESUMO

Genetic and environmental risk factors for psychiatric disorders are suggested to disrupt the trajectory of brain maturation during adolescence, leading to the development of psychopathology in adulthood. Rodent models are powerful tools to dissect the specific effects of such risk factors on brain maturational profiles, particularly when combined with Magnetic Resonance Imaging (MRI; clinically comparable technology). We therefore investigated the effect of maternal immune activation (MIA), an epidemiological risk factor for adult-onset psychiatric disorders, on rat brain maturation using atlas and tensor-based morphometry analysis of longitudinal in vivo MR images. Exposure to MIA resulted in decreases in the volume of several cortical regions, the hippocampus, amygdala, striatum, nucleus accumbens and unexpectedly, the lateral ventricles, relative to controls. In contrast, the volumes of the thalamus, ventral mesencephalon, brain stem and major white matter tracts were larger, relative to controls. These volumetric changes were maximal between post-natal day 50 and 100 with no differences between the groups thereafter. These data are consistent with and extend prior studies of brain structure in MIA-exposed rodents. Apart from the ventricular findings, these data have robust face validity to clinical imaging findings reported in studies of individuals at high clinical risk for a psychiatric disorder. Further work is now required to address the relationship of these MRI changes to behavioral dysfunction and to establish thier cellular correlates.


Assuntos
Encéfalo/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Tonsila do Cerebelo/patologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Hipocampo/patologia , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Masculino , Transtornos Mentais/patologia , Poli I-C/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley
9.
Brain ; 139(Pt 3): 751-64, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26767570

RESUMO

'True' transient ischaemic attacks are characterized not only clinically, but also radiologically by a lack of corresponding changes on magnetic resonance imaging. During a transient ischaemic attack it is assumed that the affected tissue is penumbral but rescued by early spontaneous reperfusion. There is, however, evidence from rodent studies that even brief focal ischaemia not resulting in tissue infarction can cause extensive selective neuronal loss associated with long-lasting sensorimotor impairment but normal magnetic resonance imaging. Selective neuronal loss might therefore contribute to the increasingly recognized cognitive impairment occurring in patients with transient ischaemic attacks. It is therefore relevant to consider treatments to reduce brain damage occurring with transient ischaemic attacks. As penumbral neurons are threatened by markedly constrained oxygen delivery, improving the latter by increasing arterial O2 content would seem logical. Despite only small increases in arterial O2 content, normobaric oxygen therapy experimentally induces significant increases in penumbral O2 pressure and by such may maintain the penumbra alive until reperfusion. Nevertheless, the effects of normobaric oxygen therapy on infarct volume in rodent models have been conflicting, although duration of occlusion appeared an important factor. Likewise, in the single randomized trial published to date, early-administered normobaric oxygen therapy had no significant effect on clinical outcome despite reduced diffusion-weighted imaging lesion growth during therapy. Here we tested the hypothesis that normobaric oxygen therapy prevents both selective neuronal loss and sensorimotor deficits in a rodent model mimicking true transient ischaemic attack. Normobaric oxygen therapy was applied from the onset and until completion of 15 min distal middle cerebral artery occlusion in spontaneously hypertensive rats, a strain representative of the transient ischaemic attack-prone population. Whereas normoxic controls showed normal magnetic resonance imaging but extensive cortical selective neuronal loss associated with microglial activation (present both at Day 14 in vivo and at Day 28 post-mortem) and marked and long-lasting sensorimotor deficits, normobaric oxygen therapy completely prevented sensorimotor deficit (P < 0.02) and near-completely Day 28 selective neuronal loss (P < 0.005). Microglial activation was substantially reduced at Day 14 and completely prevented at Day 28 (P = 0.002). Our findings document that normobaric oxygen therapy administered during ischaemia nearly completely prevents the neuronal death, microglial inflammation and sensorimotor impairment that characterize this rodent true transient ischaemic attack model. Taken together with the available literature, normobaric oxygen therapy appears a promising therapy for short-lasting ischaemia, and is attractive clinically as it could be started at home in at-risk patients or in the ambulance in subjects suspected of transient ischaemic attack/early stroke. It may also be a straightforward adjunct to reperfusion therapies, and help prevent subtle brain damage potentially contributing to long-term cognitive and sensorimotor impairment in at-risk populations.


Assuntos
Lesões Encefálicas/prevenção & controle , Isquemia Encefálica/terapia , Transtornos Neurológicos da Marcha/prevenção & controle , Oxigenoterapia Hiperbárica/métodos , Animais , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Transtornos Neurológicos da Marcha/metabolismo , Transtornos Neurológicos da Marcha/patologia , Hiperóxia/metabolismo , Hiperóxia/patologia , Masculino , Ratos , Ratos Endogâmicos SHR
10.
J Neurosci ; 35(9): 3747-55, 2015 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-25740505

RESUMO

We have previously shown that impulsivity in rats is linked to decreased dopamine D2/3 receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D2/3 receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [(18)F]fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [(18)F]fallypride PET scan. Before MPH treatment, we found that D2/3 receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D2/3 receptor availability through independent mechanisms.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Metilfenidato/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , Masculino , Metilfenidato/análogos & derivados , Tomografia por Emissão de Pósitrons , Ratos
11.
Neuroimage ; 124(Pt B): 1260-1262, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25941090

RESUMO

We describe the Cambridge animal brain magnetic resonance imaging repository comprising 400 datasets to date from mouse models of Huntington disease. The data include raw images as well as segmented grey and white matter images with maps of cortical thickness. All images and phenotypic data for each subject are freely-available without restriction from (http://www.dspace.cam.ac.uk/handle/1810/243361/). Software and anatomical population templates optimised for animal brain analysis with MRI are also available from this site.


Assuntos
Bases de Dados Factuais , Modelos Animais de Doenças , Doença de Huntington/patologia , Imageamento por Ressonância Magnética/estatística & dados numéricos , Animais , Córtex Cerebral/patologia , Substância Cinzenta/patologia , Humanos , Processamento de Imagem Assistida por Computador , Camundongos , Substância Branca/patologia
12.
Hum Mol Genet ; 23(13): 3375-83, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24488771

RESUMO

Insidious changes in behaviour herald the onset of progressive neurodegenerative disorders such as Huntington's disease (HD), sometimes years before overt symptoms are seen. Sleep and circadian disturbances are particularly disruptive symptoms in patients with neurological disorders, but they are difficult to measure in humans. Here we studied circadian behaviour in transgenic HD sheep expressing the full-length human huntingtin protein with an expanded CAG repeat mutation in the juvenile range. Young HD sheep with no other symptoms exhibited circadian behavioural abnormalities that worsened with age. The most obvious change was a disturbed evening behaviour reminiscent of 'sundowning' that is seen in some patients with dementia. There were no structural abnormalities seen with magnetic resonance imaging, even in 5-year-old HD sheep. Interestingly, detection of the circadian abnormalities depended upon their social grouping. Abnormalities emerged in sheep kept in an 'HD-only' flock, whereas the behaviour of HD sheep kept mixed with normal sheep was relatively normal. Sleep-wake abnormalities in HD patients are also likely to be hidden, and may precede overt symptoms by many years. Sleep disruption has deleterious effects, even in normal people. The knock-on effects of sleep-wake disturbance may exacerbate, or even cause symptoms such as irritability and depression that are common in early stage HD patients. HD sheep will be useful models for probing the mechanisms underlying circadian behavioural disorder in HD.


Assuntos
Ritmo Circadiano/fisiologia , Doença de Huntington/fisiopatologia , Meio Social , Animais , Ovinos
13.
Magn Reson Med ; 76(4): 1127-35, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26509746

RESUMO

PURPOSE: MR fingerprinting (MRF) can be used for quantitative estimation of physical parameters in MRI. Here, we extend the method to incorporate B1 estimation. METHODS: The acquisition is based on steady state free precession MR fingerprinting with a Cartesian trajectory. To increase the sensitivity to the B1 profile, abrupt changes in flip angle were introduced in the sequence. Slice profile and B1 effects were included in the dictionary and the results from two- and three-dimensional (3D) acquisitions were compared. Acceleration was demonstrated using retrospective undersampling in the phase encode directions of 3D data exploiting redundancy between MRF frames at the edges of k-space. RESULTS: Without B1 estimation, T2 and B1 were inaccurate by more than 20%. Abrupt changes in flip angle improved B1 maps. T1 and T2 values obtained with the new MRF methods agree with classical spin echo measurements and are independent of the B1 field profile. When using view sharing reconstruction, results remained accurate (error <10%) when sampling under 10% of k-space from the 3D data. CONCLUSION: The methods demonstrated here can successfully measure T1, T2, and B1. Errors due to slice profile can be substantially reduced by including its effect in the dictionary or acquiring data in 3D. Magn Reson Med 76:1127-1135, 2016. © 2015 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.


Assuntos
Algoritmos , Encéfalo/anatomia & histologia , Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Reconhecimento Automatizado de Padrão/métodos , Processamento de Sinais Assistido por Computador , Animais , Aumento da Imagem/métodos , Técnicas In Vitro , Ratos , Sensibilidade e Especificidade
14.
Magn Reson Med ; 76(3): 913-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26418189

RESUMO

PURPOSE: While MRI is enhancing our knowledge about the structure and function of the human brain, subject motion remains a problem in many clinical applications. Recently, the use of wireless radiofrequency markers with three one-dimensional (1D) navigators for prospective correction was demonstrated. This method is restricted in the range of motion that can be corrected, however, because of limited information in the 1D readouts. METHODS: Here, the limitation of techniques for disambiguating marker locations was investigated. It was shown that including more sampling directions extends the tracking range for head rotations. The efficiency of trading readout resolution for speed was explored. RESULTS: Tracking of head rotations was demonstrated from -19.2 to 34.4°, -2.7 to 10.0°, and -60.9 to 70.9° in the x-, y-, and z-directions, respectively. In the presence of excessive head motion, the deviation of marker estimates from SPM8 was reduced by 17.1% over existing three-projection methods. This was achieved by using an additional seven directions, extending the time needed for readouts by a factor of 3.3. Much of this increase may be circumvented by reducing resolution, without compromising accuracy. CONCLUSION: Including additional sampling directions extends the range in which markers can be used, for patients who move a lot. Magn Reson Med 76:913-918, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


Assuntos
Artefatos , Encéfalo/diagnóstico por imagem , Aumento da Imagem/instrumentação , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , Tecnologia sem Fio/instrumentação , Algoritmos , Desenho de Equipamento , Análise de Falha de Equipamento , Marcadores Fiduciais , Movimentos da Cabeça , Humanos , Aumento da Imagem/métodos , Ondas de Rádio , Reprodutibilidade dos Testes , Tamanho da Amostra , Sensibilidade e Especificidade , Transdutores
15.
Ann Neurol ; 78(2): 160-77, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25866151

RESUMO

OBJECTIVE: Although the underlying cause of Huntington's disease (HD) is well established, the actual pathophysiological processes involved remain to be fully elucidated. In other proteinopathies such as Alzheimer's and Parkinson's diseases, there is evidence for impairments of the cerebral vasculature as well as the blood-brain barrier (BBB), which have been suggested to contribute to their pathophysiology. We investigated whether similar changes are also present in HD. METHODS: We used 3- and 7-Tesla magnetic resonance imaging as well as postmortem tissue analyses to assess blood vessel impairments in HD patients. Our findings were further investigated in the R6/2 mouse model using in situ cerebral perfusion, histological analysis, Western blotting, as well as transmission and scanning electron microscopy. RESULTS: We found mutant huntingtin protein (mHtt) aggregates to be present in all major components of the neurovascular unit of both R6/2 mice and HD patients. This was accompanied by an increase in blood vessel density, a reduction in blood vessel diameter, as well as BBB leakage in the striatum of R6/2 mice, which correlated with a reduced expression of tight junction-associated proteins and increased numbers of transcytotic vesicles, which occasionally contained mHtt aggregates. We confirmed the existence of similar vascular and BBB changes in HD patients. INTERPRETATION: Taken together, our results provide evidence for alterations in the cerebral vasculature in HD leading to BBB leakage, both in the R6/2 mouse model and in HD patients, a phenomenon that may, in turn, have important pathophysiological implications.


Assuntos
Vasos Sanguíneos/patologia , Barreira Hematoencefálica/patologia , Doença de Huntington/patologia , Neostriado/irrigação sanguínea , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Adulto , Idoso , Animais , Vasos Sanguíneos/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Encéfalo/patologia , Circulação Cerebrovascular/genética , Modelos Animais de Doenças , Feminino , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/metabolismo , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Imunoeletrônica , Pessoa de Meia-Idade , Neostriado/metabolismo , Neostriado/patologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Tamanho do Órgão , Imagem de Perfusão , Proteínas de Junções Íntimas/metabolismo , Transcitose/genética
16.
J Magn Reson Imaging ; 43(6): 1308-12, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26633759

RESUMO

PURPOSE: To evaluate the feasibility of spectral editing for quantification of γ-aminobutyric acid (GABA) in the rat brain and to determine whether altered GABA concentration in the ventral striatum is a neural endophenotype associated with trait-like impulsive behavior. MATERIALS AND METHODS: Spectra were acquired at 4.7T for 23 male Lister-hooded rats that had been previously screened for extremely low and high impulsivity phenotypes on an automated behavioral task (n = 11 low-impulsive; n = 12 high-impulsive). Voxels of 3 × 7 × 4 mm(3) (84 µL) centered bilaterally across the ventral striatum were used to evaluate GABA concentration ratios. RESULTS: Quantifiable GABA signals in the ventral striatum were obtained for all rats. Mean-edited GABA to n-acetyl aspartate (NAA) ratios in the ventral striatum were 0.22 (95% confidence interval [CI] [0.18, 0.25]). Mean GABA/NAA ratios in this region were significantly decreased by 28% in high-impulsive rats compared to low-impulsive rats (P = 0.02; 95% CI [-53%, -2%]). CONCLUSION: These findings demonstrate that spectral editing at 4.7T is a feasible method to assess in vivo GABA concentrations in the rat brain. The results show that diminished GABA content in the ventral striatum may be a neural endophenotype associated with impulsivity. J. Magn. Reson. Imaging 2016;43:1308-1312.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Imagem Molecular/métodos , Ácido gama-Aminobutírico/metabolismo , Animais , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
Stroke ; 46(4): 1084-92, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25669312

RESUMO

BACKGROUND AND PURPOSE: New-definition transient ischemic attacks (TIAs) are frequent but difficult to diagnose because magnetic resonance imaging (MRI)-negative by definition. However, hidden underlying cell damage might be present and account for the reported long-lasting cognitive impairment after TIAs. Most prior rodent models of true TIA targeted the striatum or have not been fully characterized. Here we present the MRI, behavioral, and quantitative cell changes characterizing a new rodent model of true TIA targeting the more behaviorally relevant cerebral cortex. METHODS: Fifteen-minute distal middle cerebral artery occlusion was performed in 29 spontaneously hypertensive rats allowed to survive for 7 to 60 days. Behavior was assessed serially using both global neurological and fine sensorimotor tests. Diffusion- and T2-weighted MRI was obtained 20 min postreperfusion and again 7 to 60 days later, and then changes in neurons and microglia were quantified across the middle cerebral artery territory using immunohistochemistry. RESULTS: No MRI changes or pan-necrosis were observed at any time point, but patchy cortical selective neuronal loss affected 28/29 rats, regardless of survival interval, together with topographically congruent microglial activation that gradually declined over time. The Neuroscore was unchanged, but there was marked contralateral sensorimotor impairment, still recovering by day 28. CONCLUSIONS: Our new rodent model mimicking true cortical TIA is characterized by normal MRI, but consistent cortical selective neuronal loss and microglial activation and long-lasting sensorimotor deficits. By causing selective neuronal loss, TIAs and silent microemboli might affect neuronal reserve, thereby increasing long-term cognitive impairment risk. Selective neuronal loss and microglial activation might represent novel therapeutic targets that could be detectable in vivo after TIAs using appropriate imaging tracers.


Assuntos
Comportamento Animal/fisiologia , Córtex Cerebral , Ataque Isquêmico Transitório , Neurônios/patologia , Animais , Córtex Cerebral/citologia , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Ataque Isquêmico Transitório/patologia , Ataque Isquêmico Transitório/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Microglia/metabolismo , Ratos , Ratos Endogâmicos SHR
18.
IEEE Trans Nucl Sci ; 62(3 Pt 1): 628-633, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26213413

RESUMO

Accurate kinetic modelling using dynamic PET requires knowledge of the tracer concentration in plasma, known as the arterial input function (AIF). AIFs are usually determined by invasive blood sampling, but this is prohibitive in murine studies due to low total blood volumes. As a result of the low spatial resolution of PET, image-derived input functions (IDIFs) must be extracted from left ventricular blood pool (LVBP) ROIs of the mouse heart. This is challenging because of partial volume and spillover effects between the LVBP and myocardium, contaminating IDIFs with tissue signal. We have applied the geometric transfer matrix (GTM) method of partial volume correction (PVC) to 12 mice injected with 18F-FDG affected by a Myocardial Infarction (MI), of which 6 were treated with a drug which reduced infarction size [1]. We utilised high resolution MRI to assist in segmenting mouse hearts into 5 classes: LVBP, infarcted myocardium, healthy myocardium, lungs/body and background. The signal contribution from these 5 classes was convolved with the point spread function (PSF) of the Cambridge split magnet PET scanner and a non-linear fit was performed on the 5 measured signal components. The corrected IDIF was taken as the fitted LVBP component. It was found that the GTM PVC method could recover an IDIF with less contamination from spillover than an IDIF extracted from PET data alone. More realistic values of Ki were achieved using GTM IDIFs, which were shown to be significantly different (p<0.05) between the treated and untreated groups.

19.
NMR Biomed ; 27(6): 733-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24737267

RESUMO

In vivo assessment of heart function in mice is important for basic and translational research in cardiology. MRI is an accurate tool for the investigation of the anatomy and function in the preclinical setting; however, the long scan duration limits its usage. We aimed to reduce the acquisition time of cine MRI to 1 min. We employed spatiotemporal compressed sensing and parallel imaging to accelerate retrospectively gated cine MRI. We compared the functional parameters derived from full and undersampled data in Cartesian and radial MRI by means of Bland-Altman plots. We found that the scan time for the whole heart could be reduced to 2 min with Cartesian sampling and to 1 min with radial sampling. Despite a reduction in the signal-to-noise ratio, the accuracy in the estimation of left and right ventricular volumes was preserved for all tested subjects. This method can be used to perform accurate functional MRI examinations in mice for high-throughput phenotyping or translational studies.


Assuntos
Coração/fisiologia , Imageamento por Ressonância Magnética/métodos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Componente Principal , Razão Sinal-Ruído
20.
Int J Neuropsychopharmacol ; 18(2)2014 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-25552430

RESUMO

BACKGROUND: N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology of schizophrenia. Accordingly, NMDAR antagonists such as phencyclidine (PCP) are used widely in experimental animals to model cognitive impairment associated with this disorder. However, it is unclear whether PCP disrupts the structural integrity of brain areas relevant to the profile of cognitive impairment in schizophrenia. METHODS: Here we used high-resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats. RESULTS: Sub-chronic exposure of rats to PCP (5mg/kg twice daily for 7 days) impaired sustained visual attention on a 5-choice serial reaction time task, notably when the attentional load was increased. In contrast, sub-chronic PCP had no significant effect on the attentional filtering of a pre-pulse auditory stimulus in an acoustic startle paradigm. Voxel-based morphometry revealed significantly reduced grey matter density bilaterally in the hippocampus, anterior cingulate cortex, ventral striatum, and amygdala. PCP-treated rats also exhibited reduced cortical thickness in the insular cortex. CONCLUSIONS: These findings demonstrate that sub-chronic NMDA receptor antagonism is sufficient to produce highly-localized morphological abnormalities in brain areas implicated in the pathogenesis of schizophrenia. Furthermore, PCP exposure resulted in dissociable impairments in attentional function.


Assuntos
Atenção , Encéfalo/patologia , Esquizofrenia/patologia , Psicologia do Esquizofrênico , Percepção Visual , Animais , Percepção Auditiva , Modelos Animais de Doenças , Substância Cinzenta/patologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Fenciclidina , Inibição Pré-Pulso , Ratos , Reflexo de Sobressalto
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