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1.
Cureus ; 16(9): e69095, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39391419

RESUMO

Cavernous malformations, low-flow vascular lesions predominantly found in the brain and occasionally in the spinal cord, can be congenital or acquired, with acquired forms often being single and congenital ones multiple. While many patients remain asymptomatic, hemorrhage from these lesions can lead to significant neurological symptoms. This case report describes a 35-year-old female with a hemorrhagic lesion in the right precentral gyrus, initially challenging to diagnose due to atypical imaging findings. Advanced magnetic resonance imaging (MRI) techniques, including dynamic susceptibility contrast perfusion and advanced diffusion methods, were employed to distinguish the lesion from other hemorrhagic conditions and suggested that the lesion is benign in nature. Follow-up MRI revealed regression of the hemorrhage and typical characteristics of a cavernous malformation. The case underscores the utility of advanced diffusion MRI techniques in differentiating hemorrhagic cavernous malformations from other pathologies, particularly in complex cases where conventional imaging may fall short.

2.
Neuroradiology ; 2024 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-39305355

RESUMO

PURPOSE: This study investigates the morphometric changes in the brains of patients with frontal focal cortical dysplasia (FCD) Type II, distinguishing between right and left FCD, using voxel-based morphometry (VBM), surface-based morphometry (SBM), and subcortical shape analysis. METHODS: The study included 53 patients with frontal lobe FCD Type II (28 left-sided, 25 right-sided) and 66 age- and gender-matched healthy controls. VBM and SBM analyses were conducted using Computational Anatomy Toolbox 12.8 (CAT12.8) and Statistical Parametric Mapping 12 (SPM12). Subcortical structures were segmented using FSL-FIRST. Statistical analyses were performed using non-parametric tests, with a significance threshold of p < 0.05. RESULTS: VBM revealed increased gray matter volume in the bilateral ventral diencephalon, left putamen, and left thalamus in the left FCD group. SBM indicated reduced sulcal depth in the right precentral, postcentral, and caudal middle frontal gyrus in the right FCD group. Subcortical shape analysis showed internal deformation in the left hippocampus and external deformation in bilateral putamen in the left FCD group, and external deformation in the left caudate nucleus, left putamen, and right amygdala in the right FCD group. CONCLUSION: Morphometric changes in frontal FCD Type II patients vary depending on the hemisphere. Right FCD Type II is associated with sulcal shallowing and external deformation in contralateral subcortical structures, while left FCD Type II shows internal and external deformations in the hippocampus and putamen, respectively, along with increased gray matter volume in the basal ganglia. These findings highlight the need for hemisphere-specific analyses in epilepsy research.

3.
Diagn Interv Radiol ; 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39221653

RESUMO

PURPOSE: To evaluate the diagnostic efficacy of computed diffusion-weighted imaging (DWI) in pediatric posterior fossa tumors generated using high b-values. METHODS: We retrospectively performed our study on 32 pediatric patients who had undergone brain magnetic resonance imaging for a posterior fossa tumor between January 2016 and January 2022. The DWIs were evaluated for each patient by two blinded radiologists. The computed DWI (cDWI) was mathematically derived using a mono-exponential model from images with b = 0 and 1,000 s/mm2 and high b-values of 1,500, 2,000, 3,000, and 5,000 s/mm2. The posterior fossa tumors were divided into two groups, low grade and high grade, and the tumor/thalamus signal intensity (SI) ratios were compared. The Mann-Whitney U test and receiver operating characteristic (ROC) curves were used to compare the diagnostic performance of the acquired DWI (DWI1000), apparent diffusion coefficient (ADC)1000 maps, and cDWI (cDWI1500, cDWI2000, cDWI3000, and cDWI5000). RESULTS: The comparison of the two tumor groups revealed that the tumor/thalamus SI ratio on the DWI1000 and cDWI (cDWI1500, cDWI2000, cDWI3000, and cDWI5000) was statistically significantly higher in high-grade tumors (P < 0.001). In the ROC curve analysis, higher sensitivity and specificity were detected in the cDWI1500, cDWI2000, cDWI3000, and ADC1000 maps (100%, 90.90%) compared with the DWI1000 (80%, 81.80%). cDWI3000 had the highest area under the curve (AUC) value compared with other parameters (AUC: 0.976). CONCLUSION: cDWI generated using high b-values was successful in differentiating between low-grade and high-grade posterior fossa tumors without increasing imaging time. CLINICAL SIGNIFICANCE: cDWI created using high b-values can provide additional information about tumor grade in pediatric posterior fossa tumors without requiring additional imaging time.

4.
Br J Radiol ; 97(1162): 1645-1652, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39180418

RESUMO

OBJECTIVE: This study aims to assess the microstructural abnormalities in white matter (WM) among Behcet's disease (BD) patients, both with and without neurological involvement, utilising tract-based spatial statistics (TBSS) to elucidate the underlying causes of WM microstructural changes. METHODS: This prospective study comprised 43 BD patients without neurological involvement, 15 neuro-Behcet's disease (NBD) patients with normal conventional MRI, and 54 healthy controls matched for age and sex. TBSS was applied in this diffusion tensor imaging study to conduct a whole-brain voxel-wise analysis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of WM. RESULTS: Compared to the control group, BD patients exhibited decreased FA and increased MD and RD in nearly all WM tracts, along with increased AD in the left corticospinal tract (CST), left inferior longitudinal fasciculus (ILF), and left superior longitudinal fasciculus (SLF). NBD patients also showed a widespread decrease in FA and increased MD and RD, similar to BD patients without neurological involvement. Additionally, NBD patients had increased AD in the left CST, left ILF, left SLF, left inferior fronto-occipital fasciculus (IFOF), and right CST. Compared to BD patients without neurological involvement, NBD patients exhibited a greater reduction in FA and an increase in MD and RD in WM tracts, with no significant differences in AD. CONCLUSION: These results suggest that the main mechanism of microstructural changes in the WM of BD patients may be related to impaired fibre integrity, demyelination, and decreased myelin sheath integrity. ADVANCES IN KNOWLEDGE: This study demonstrated BD patients without neurological involvement and NBD patients a decrease in FA and an increase in MD and RD were observed in larger areas of major WM tracts, while an increase in AD values was observed in fewer tracts. Our findings may be useful in understanding the pathophysiology underlying subclinical parenchymal involvement and neurological dysfunction in BD patients and the management of BD patients.


Assuntos
Síndrome de Behçet , Imagem de Tensor de Difusão , Substância Branca , Humanos , Síndrome de Behçet/diagnóstico por imagem , Síndrome de Behçet/complicações , Síndrome de Behçet/patologia , Imagem de Tensor de Difusão/métodos , Masculino , Feminino , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto , Estudos Prospectivos , Estudos de Casos e Controles , Pessoa de Meia-Idade , Anisotropia
5.
Diagn Interv Radiol ; 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39158063

RESUMO

PURPOSE: We investigated the diagnostic accuracy of simplified intravoxel incoherent motion (IVIM) imaging for detecting synovial inflammation in the sacroiliac joint (SIJ) in a population with active sacroiliitis. METHODS: In accordance with the Assessment of Spondyloarthritis International Society criteria, 86 SIJs of 46 patients with active sacroiliitis were included in this retrospective study conducted between November 2020 and January 2022. Based on T1-weighted post-gadolinium images, the SIJs were divided into two groups: synovial inflammation positive (SIP) (n = 28) and synovial inflammation negative (SIN) (n = 58). Synovial areas in the SIJ space were independently and blindly reviewed for the presence of inflammation by two radiologists with differing levels of expertise in radiology. Using four b values, apparent diffusion coefficient (ADC)= ADC (0, 800) and the simplified 3T IVIM method parameters true diffusion coefficient (D1)= ADC (50, 800), D= ADC (400, 800), f1= f (0, 50, 800), f2= f (0, 400, 800), pseudodiffusion coefficient (D*)= D* (0, 50, 400, 800), ADClow = ADC (0, 50), and ADCdiff= ADClow - D were generated voxel by voxel for each patient. The IVIM and ADC parameters at the SIN and SIP joints were compared. RESULTS: The D parameter was significantly increased in SIP areas (1.23 ± 0.34 × 10-3 mm2/s) compared with SIN areas (1.02 ± 0.16 × 10-3 mm2/s) (P = 0.004). Conversely, the D* parameter was significantly decreased in SIP areas (21.78 ± 3.77 × 10-3 mm2/s) compared with SIN areas (16.19 ± 4.58 × 10-3 mm2/s) (P < 0.001). When the optimal cut-off value of 1.11 × 10-3 mm2/s was selected, the sensitivity for the D value was 71% and the specificity was 72% [area under the curve (AUC): 0.716)]. When the optimal cut-off value of 21.06 × 10-3 mm2/s was selected, the sensitivity for the D* value was 78.6%, and the specificity was 79.3% (AUC: 0.829). The interclass correlation coefficient was excellent for f1, f2 D*, D, and ADCdiff, good for ADClow and D1, but reasonable for ADC. CONCLUSION: The presence of synovial inflammation in the SIJ can be evaluated with high sensitivity and specificity using only four b values through the simplified IVIM method without the need for a contrast agent. CLINICAL SIGNIFICANCE: IVIM imaging is a technique that allows us to gain insights into tissue perfusion without the administration of contrast agents, utilizing diffusion-weighted images. In this study, for the first time, we demonstrated the potential of detecting synovial inflammation in the SIJ using IVIM, specifically through the pseudodiffusion (D*) parameter, without the need for contrast agents.

6.
Neuroradiology ; 66(10): 1721-1728, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38975995

RESUMO

PURPOSE: Transfusion-dependent thalassemia (TDT) is associated with iron accumulation in the body and an increased tendency for thrombosis. With the increased life expectancy in these patients, the detection of neurocognitive complications has gained importance. This study investigates the microstructural changes in TDT patients using advanced diffusion MRI techniques and their relationship with laboratory parameters. METHODS: The study included 14 TDT patients and 14 control subjects. Tract-based spatial statistics (TBSS) were used to examine differences in DTI parameters such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in thalassemia patients using multi-shell DWI images. The mean kurtosis (MK) difference was investigated using diffusion kurtosis imaging. Fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC) differences were examined using fixel-based analysis. In the patient group, correlative tractography was used to investigate the relationship between DTI parameters and platelet (PLT) and ferritin levels. RESULTS: Increase in RD and MD was observed, particularly in the white matter tracts of the corona radiata in patient group. Additionally, an increase in AD was detected in a limited area. Correlative tractography in thalasemia patients showed a positive correlation between increases in RD, MD, and AD with PLT and ferritin. Fixel-based analysis demonstrated a dispersed distribution in white matter fibers, with a more pronounced decrease in FD, FC, and FDC in the internal capsule. CONCLUSION: There is widespread involvement in the white matter and fiber tracts in thalassemia patients, which is highly correlated with thrombotic parameters.


Assuntos
Imagem de Tensor de Difusão , Talassemia , Humanos , Masculino , Feminino , Talassemia/diagnóstico por imagem , Talassemia/terapia , Talassemia/complicações , Adulto , Imagem de Tensor de Difusão/métodos , Estudos de Casos e Controles , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Anisotropia , Adolescente , Imagem de Difusão por Ressonância Magnética/métodos
7.
Diagn Interv Radiol ; 30(5): 328-334, 2024 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-38836466

RESUMO

PURPOSE: This study aimed to detect supratentorial cortical and subcortical morphological changes in pediatric patients with infratentorial tumors. METHODS: The study included 24 patients aged 4-18 years who were diagnosed with primary infratentorial tumors and 41 age- and gender-matched healthy controls. Synthetic magnetization-prepared rapid gradient echo images of brain magnetic resonance imaging were generated using deep learning algorithms applied to T2-axial images. The cortical thickness, surface area, volume, and local gyrification index (LGI), as well as subcortical gray matter volumes, were automatically calculated. Surface-based morphometry parameters for the patient and control groups were compared using the general linear model, and volumes between subcortical structures were compared using the t-test and Mann-Whitney U test. RESULTS: In the patient group, cortical thinning was observed in the left supramarginal, and cortical thickening was observed in the left caudal middle frontal (CMF), left fusiform, left lateral orbitofrontal, left lingual gyrus, right CMF, right posterior cingulate, and right superior frontal (P < 0.050). The patient group showed a volume reduction in the pars triangularis, paracentral, precentral, and supramarginal gyri of the left hemisphere (P < 0.05). A decreased surface area was observed in the bilateral superior frontal and cingulate gyri (P < 0.05). The patient group exhibited a decreased LGI in the right precentral and superior temporal gyri, left supramarginal, and posterior cingulate gyri and showed an increased volume in the bilateral caudate nucleus and hippocampus, while a volume reduction was observed in the bilateral putamen, pallidum, and amygdala (P < 0.05). The ventricular volume and tumor volume showed a positive correlation with the cortical thickness in the bilateral CMF while demonstrating a negative correlation with areas exhibiting a decreased LGI (P < 0.05). CONCLUSION: Posterior fossa tumors lead to widespread morphological changes in cortical structures, with the most prominent pattern being hypogyria. CLINICAL SIGNIFICANCE: This study illuminates the neurological impacts of infratentorial tumors in children, providing a foundation for future therapeutic strategies aimed at mitigating these adverse cortical and subcortical changes and improving patient outcomes.


Assuntos
Neoplasias Infratentoriais , Imageamento por Ressonância Magnética , Humanos , Criança , Masculino , Feminino , Pré-Escolar , Adolescente , Imageamento por Ressonância Magnética/métodos , Neoplasias Infratentoriais/diagnóstico por imagem , Neoplasias Infratentoriais/patologia , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia
8.
J Neuroendocrinol ; 36(3): e13369, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38326952

RESUMO

Thyroid hormones play a critical role in brain development, but paradoxically, patients with hyperthyroidism often exhibit cognitive decline and irritability. This study aims to explore the pattern of atrophy in hyperthyroid patients, changes in specific areas of the brain, including hypothalamic subfields and limbic structures, and their relationships with hormonal levels and psychometric tests. This prospective cross-sectional study involves 19 newly diagnosed, untreated hyperthyroid patients, and 15 age and gender-matched control subjects. The participants underwent psychometric and cognitive tests and volumetric MRI. The hypothalamic subfield (anterior-inferior, anterior-superior, superior-tubular, inferior-tubular, and posterior hypothalamus) and limbic structures (fornix, basal forebrain, nucleus accumbens, and septal nucleus) were segmented using voxel-based morphometry, surface-based morphometry, and deep learning algorithms. The groups were compared using the t-test, and correlation analyses were performed between clinical parameters and volumetric measurements. The correlation between hormonal parameters and volumetric measurements in patient and control groups was assessed with the Meng test. Hyperthyroid patients displayed widespread grey matter loss and sulcal shallowing in the left hemisphere. However, no local gyrification index changes or cortical thickness variations were detected. The limbic structures and hypothalamic subunits did not show any volume discrepancies. Free thyroxine in the patient group negatively correlated with bilateral anterior-inferior and right septal nucleus, but positively correlated with left anterior-inferior in the control group. Thyroid stimulating hormone in the patient group showed a positive correlation with bilateral fornix volume, a correlation absent in the control group. Disease duration negatively correlated with right anterior-inferior, right tubular inferior, and right septal nucleus. Changes in cognitive and psychometric test scores in the patient group correlated with the bilateral septal nucleus volume. Hyperthyroidism primarily leads to a reduction in grey matter volume and sulcal shallowing. Thyroid hormones have differing volumetric effects in limbic structures and hypothalamic subunits under physiological and hyperthyroid conditions.


Assuntos
Encéfalo , Hipertireoidismo , Humanos , Estudos Transversais , Estudos Prospectivos , Hormônios Tireóideos , Imageamento por Ressonância Magnética
9.
Childs Nerv Syst ; 40(1): 41-46, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37470834

RESUMO

BACKGROUND AND PURPOSE: Intracranial tumours in children can exhibit different characteristics compared to those in adults. Understanding the microstructural changes in the contralateral normal-appearing white matter (NAWM) in children with primary intracranial masses is essential for optimizing treatment strategies. This study aimed to investigate the apparent diffusion coefficient (ADC) changes in contralateral NAWM using fully automated methods and deep learning algorithms. METHODS: We included 22 paediatric patients with primary supratentorial intracranial masses (23% high-grade) in the study. ADC values of the contralateral NAWM in the patient group were compared to those of a control group. Deep learning algorithms were utilized to analyse diffusion changes in NAWM. RESULTS: The mean ADC values of contralateral NAWM in the patient group were 0.80 ± 0.03 × 10-3 mm2/s, while the control group had a mean ADC value of 0.81 ± 0.03 × 10-3 mm2/s. There was no statistically significant difference between the groups (p = 0.39). Our findings indicate that there are no significant diffusion changes in the contralateral white matter of children with supratentorial intracranial masses. CONCLUSION: Primary supratentorial intracranial masses in children do not cause microstructural changes in contralateral normal-appearing white matter. This could be attributed to the less infiltrative nature and different biochemical profile of these tumour groups in the paediatric population. Further studies using advanced imaging techniques could provide additional insights into the distinct characteristics of paediatric intracranial tumours and improve patient management.


Assuntos
Neoplasias Encefálicas , Neoplasias Supratentoriais , Substância Branca , Adulto , Humanos , Criança , Substância Branca/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Supratentoriais/diagnóstico por imagem , Neoplasias Supratentoriais/patologia
10.
Magn Reson Med Sci ; 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37532585

RESUMO

PURPOSE: Glioblastoma patients develop recurrence in the opposite hemisphere far from the primary tumor site even after complete resection. This is one of the main reasons for short disease survival. Our aim in this study is to detect microstructural changes in the contralateral hemisphere of glioblastoma patients using different diffusion models with the fully automated tract-based spatial statistics (TBSS) method. METHODS: Fourteen right-sided and eleven left-sided glioblastoma patients without any treatment and eighteen age- and gender-matched controls were included in the study. Multi-shell diffusion weighted images were created with a 3T MRI device. After various preprocessing steps, images of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), axial kurtosis (AK), mean kurtosis (MK), radial kurtosis (RK), intracellular volume fraction (ICVF), orientation dispersion index (ODI), and isotropic water fraction (ISO) were obtained. TBSS was used to compare diffusion tensor imaging, diffusion kurtosis imaging, and neurite orientation dispersion and density imaging parameters of right- and left-sided glioblastoma patients with the control group for the contralateral hemisphere. RESULTS: Both right-sided and left-sided glioblastoma patients have shown an increase in MD and ODI in the contralateral hemisphere. While right-sided glioblastoma patients showed an increase in RD, AD, and ISO in a more limited area in the contralateral hemisphere, left-sided glioblastoma patients showed an increase in MK and AK. FA, ICVF, and RK did not show any difference in both groups. CONCLUSION: There are microstructural changes in the contralateral hemisphere in glioblastoma patients, and these changes differ between right-sided and left-sided glioblastoma patients.

11.
Neuroradiology ; 65(9): 1405-1413, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37344675

RESUMO

PURPOSE: Multiple sclerosis (MS) is a disease that progresses not only with demyelination but also with neurodegeneration. One of the goals of drug treatment in MS is to prevent neurodegeneration. Cortical thickness (CT), sulcal depth (SD), and local gyrification index (LGI) are indicators related to neurodegeneration. The aim of this study is to investigate changes in CT, SD, and LGI in patients with relapsing-remitting MS (RRMS). METHODS: T1 images of 74 RRMS patients and 65 healthy controls were used. T1 hypointense areas in RRMS patients were corrected using fully automated methods. CT, SD, and LGI were calculated for each patient. RESULTS: RRMS patients showed widespread cortical thinning, especially in bilateral temporoparietal areas, decreased SD in bilateral supramarginal gyrus, superior temporal gyrus, postcentral gyrus, and transverse temporal gyrus, and decreased LGI, especially in the left posterior cingulate gyrus and insula. The decrease in cortical thickness was associated with the number of attacks and lesion volume. EDSS was related to CT in the right lingual, inferior temporal, and fusiform gyrus. The LGI was correlated with T2 lesion volume in bilateral insula, with EDSS in the right insula and transverse and superior temporal gyri, and with the number of attacks in the right paracentral gyrus and pre-cuneus. However, SD did not show any correlation with EDSS, T2 lesion volume, or the number of attacks. CONCLUSION: Our results demonstrate widespread cortical thinning, decreased sulcal depth in local areas, and decreased gyrification in folds in RRMS patients, which are related to clinical parameters.


Assuntos
Córtex Cerebral , Esclerose Múltipla , Humanos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Afinamento Cortical Cerebral/patologia , Imageamento por Ressonância Magnética/métodos , Lobo Frontal
12.
J Neuroimaging ; 33(4): 644-651, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37170070

RESUMO

BACKGROUND AND PURPOSE: Conventional MRI sequences in neuro-oncology are insufficient for glioma grading. However, newly developed diffusion-weighted imaging techniques have been shown to have a great potential for glioma grading. This study examined the diagnostic performance of diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), neurite orientation dispersion and density imaging (NODDI), and their combinations in glioma grading. METHODS: Multishell diffusion tensor images were obtained with 3T MRI in 38 glioma patients (22 high-grade glioma [HGG], 16 low-grade glioma [LGG]). DTI (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], radial diffusivity [RD]), DKI (Axial kurtosis [AK], mean kurtosis [MK], radial kurtosis [RK]), and NODDI (intracellular volume fraction [ICVF], orientation distribution index, isotropic water fraction [ISO]) images were obtained after preprocessing. The average value of these parameters was calculated in the solid components of the tumors. The receiver operating characteristic curve analyses were performed to investigate the diagnostic performance and the curves were compared with the Delong test. RESULTS: FA shows an increase in HGG, while MD, RD, and AD exhibit a decrease. AK, MK, and RK were higher in HGG than LGG. ICVF increased in HGG, while ISO decreased. AK demonstrated the best diagnostic performance among all parameters, and kurtosis outperformed NODDI but not DTI. Combining these parameters did not yield a statistically significant improvement in diagnostic performance. CONCLUSION: DTI, DKI, and NODDI approaches can differentiate between HGG and LGG; however, kurtosis parameters perform better and adding NODDI parameters does not improve diagnostic performance. Using multishell b-value has not led to an increase in diagnostic performance.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Imagem de Tensor de Difusão/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neuritos/patologia , Glioma/diagnóstico por imagem , Glioma/patologia , Imagem de Difusão por Ressonância Magnética/métodos
13.
Gene Ther ; 30(7-8): 560-574, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36823441

RESUMO

Recombinant adeno-associated virus (rAAV)-based gene therapies offer an immense opportunity for rare diseases, such as amyotrophic lateral sclerosis (ALS), which is defined by the loss of the upper and the lower motor neurons. Here, we describe generation, characterization, and utilization of a novel vector system, which enables expression of the active form of hepatocyte growth factor (HGF) under EF-1α promoter with bovine growth hormone (bGH) poly(A) sequence and is effective with intrathecal injections. HGF's role in promoting motor neuron survival had been vastly reported. Therefore, we investigated whether intrathecal delivery of HGF would have an impact on one of the most common pathologies of ALS: the TDP-43 pathology. Increased astrogliosis, microgliosis and progressive upper motor neuron loss are important consequences of ALS in the motor cortex with TDP-43 pathology. We find that cortex can be modulated via intrathecal injection, and that expression of HGF reduces astrogliosis, microgliosis in the motor cortex, and help restore ongoing UMN degeneration. Our findings not only introduce a novel viral vector for the treatment of ALS, but also demonstrate modulation of motor cortex by intrathecal viral delivery, and that HGF treatment is effective in reducing astrogliosis and microgliosis in the motor cortex of ALS with TDP-43 pathology.


Assuntos
Esclerose Lateral Amiotrófica , Córtex Motor , Animais , Bovinos , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/terapia , Proteínas de Ligação a DNA/genética , Gliose , Fator de Crescimento de Hepatócito/genética , Córtex Motor/patologia
14.
Neurobiol Dis ; 178: 106022, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36716828

RESUMO

Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most commonly observed proteinopathy. Disrupted inner mitochondrial membrane (IMM) reported in the upper motor neurons (UMNs) of ALS patients with TDP-43 pathology is recapitulated in the UMNs of well-characterized hTDP-43 mouse model of ALS. The construct validity, such as shared and common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate to patients. SBT-272 is a well-tolerated brain-penetrant small molecule that stabilizes cardiolipin, a phospholipid found in IMM, thereby restoring mitochondrial structure and respiratory function. We investigated whether SBT-272 can improve IMM structure and health in UMNs diseased with TDP-43 pathology in our well-characterized UMN reporter line for ALS. We found that SBT-272 significantly improved mitochondrial structural integrity and restored mitochondrial motility and function. This led to improved health of diseased UMNs in vitro. In comparison to edaravone and AMX0035, SBT-272 appeared more effective in restoring health of diseased UMNs. Chronic treatment of SBT-272 for sixty days starting at an early symptomatic stage of the disease in vivo led to a significant reduction in astrogliosis, microgliosis, and TDP-43 pathology in the ALS motor cortex. Our results underscore the therapeutic potential of SBT-272, especially within the context of TDP-43 pathology and mitochondrial dysfunction.


Assuntos
Esclerose Lateral Amiotrófica , Humanos , Camundongos , Animais , Esclerose Lateral Amiotrófica/metabolismo , Neurônios Motores/patologia , Mitocôndrias/patologia , Proteínas de Ligação a DNA/metabolismo
15.
Neuroradiology ; 65(5): 899-905, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36720749

RESUMO

PURPOSE: Studies on hypothalamic changes in patients with relapsing remitting multiple sclerosis (RRMS) are very scarce, despite the fact that the relationship with the hypothalamus is frequently reported. The aim of the study was to determine the volume of the hypothalamic subunits and the total hypothalamus and its relationship with the total demyelinating lesion volume (TLV) and expanded disability status scale (EDSS) in RRMS patients. METHODS: In this cross-sectional study, anterior-superior, superior tubular, posterior hypothalamus, anterior-inferior, inferior tubular subunits of hypothalamus, and total hypothalamus volume were calculated, with fully automatic analysis methods using volumetric T1 images of 65 relapsed RRMS patients and 68 healthy controls (HC). Volume changes in the hypothalamus and its subunits in RRMS patients were examined using multivariate analysis of covariance (MANCOVA). The relationship of these volumes with EDSS and TLV was investigated by partial correlation analysis. RESULTS: There is volume reduction in total hypothalamus (F = 13.87, p < 0.001), anterior-superior (F = 19.2, p < 0.001), superior tubular (F = 10.1, p = 0.002) subunits, and posterior hypothalamus (F = 19.2, p < 0.001) volume in RRMS patients. EDSS correlates negatively with anterior-superior (p = 0.017, r = - 0.333), superior tubular subunits (p = 0.023, r = - 0.439), posterior hypothalamus (p < 0.001, r = - 0.511), and whole hypothalamus volume (p = 0.001, r = - 0.439). TLV correlates negatively with anterior superior (p < 0.001, r = - 0.565), anterior inferior (p = 0.002, r = - 0.431), superior tubular subunits (p = 0.002, r = - 0.432), posterior hypothalamus (p < 0.001, r = - 0.703), and whole hypothalamus (p < 0.001, r = - 0.627) volumes. CONCLUSION: This study demonstrates a reduction in total hypothalamus volume, anterior-superior, superior tubular, and posterior hypothalamus in patients with RRMS. Anterior-superior and superior tubular subunit, posterior hypothalamus, and total hypothalamus volume were negatively correlated with TLV and EDSS scores.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , Estudos Transversais , Imageamento por Ressonância Magnética/métodos , Hipotálamo/diagnóstico por imagem , Hipotálamo/patologia
16.
Turk J Med Sci ; 53(6): 1840-1851, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38813507

RESUMO

Background/aim: The cause and treatment of electrical status epilepticus during sleep (ESES), one of the epileptic encephalopathies of childhood, is unclear. The aim of this study was to evaluate possible microstructural abnormalities in the brain using advanced magnetic resonance imaging (MRI) techniques in ESES patients with and without genetic mutations. Materials and methods: This research comprised 12 ESES patients without structural thalamic lesions (6 with genetic abnormalities and 6 without) and 12 healthy children. Whole-exome sequencing was used for the genetic mutation analysis. Brain MRI data were evaluated using tractus-based spatial statistics, voxel-based morphometry, a local gyrification index, subcortical shape analysis, FreeSurfer volume, and cortical thickness. The data of the groups were compared. Results: The mean age in the control group was 9.05 ± 1.85 years, whereas that in the ESES group was 9.45 ± 2.72 years. Compared to the control group, the ESES patients showed higher mean thalamus diffusivity (p < 0.05). ESES patients with genetic mutations had lower axial diffusivity in the superior longitudinal fasciculus and gray matter volume in the entorhinal region, accumbens area, caudate, putamen, cerebral white matter, and outer cerebellar areas. The superior and middle temporal cortical thickness increased in the ESES patients. Conclusion: This study is important in terms of presenting the microstructural evaluation of the brain in ESES patients with advanced MRI analysis methods as well as comparing patients with and without genetic mutations. These findings may be associated with corticostriatal transmission, ictogenesis, epileptogenesis, neuropsychiatric symptoms, cognitive impairment, and cerebellar involvement in ESES. Expanded case-group studies may help to understand the physiology of the corticothalamic circuitry in its etiopathogenesis and develop secondary therapeutic targets for ESES.


Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Estado Epiléptico , Humanos , Estado Epiléptico/diagnóstico por imagem , Estado Epiléptico/fisiopatologia , Masculino , Criança , Feminino , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Sono/fisiologia , Adolescente , Estudos de Casos e Controles , Tálamo/diagnóstico por imagem , Tálamo/patologia
17.
J Clin Neurosci ; 106: 128-134, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36302293

RESUMO

PURPOSE: To evaluate the spatial distribution of cortical damage in Behcet's Disease (BD) with or without neurological involvement using a cortical thickness measurement approach using three-dimensional T1-weighted imaging. MATERIAL AND METHODS: Fifty-eight BD patients without neurological involvement, twenty-two Parenchymal Neuro-Behçets disease (PNBD) patients, and fifty healthy controls were included in the prospective study. Anatomical 3D T1 images were obtained from all participants using 3T MRI. Using a computational anatomy toolbox (CAT12), we calculated and compared group differences in cortical thickness. RESULTS: Patients with BD without neurological involvement showed cortical thickness reduction in bilateral frontal, bilateral parietal, and right precuneus compared with the healthy controls (HCs) (p < 0.05 FWE corrected [FWEc]). PNBD patients showed frontoparietal cortical thickness reduction when compared with BD patients without neurological involvement (p < 0.05 FWEc). The PNBD patients showed widespread cortical thickness reduction compared with the HC patients (p < 0.05 FWEc). Disease duration was correlated with cortical thickness in the right pericalcarine (p = 0.012 false discovery rate [FDR], r = -0.40), left pericalcarine (p = 0.013 FDR, r = -0.44), and left transverse temporal (p = 0.007 FDR, r = -0.41) regions. CONCLUSION: There is a decrease in cortical thickness in BD patients without neurological involvement. Cortical thickness reduction is more prominent in parenchymal neurobehçet's patients. Cortical thickness shows a negative correlation with disease duration in some regions.


Assuntos
Síndrome de Behçet , Humanos , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico por imagem , Estudos Prospectivos , Imageamento por Ressonância Magnética
18.
Sci Rep ; 12(1): 5383, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35354901

RESUMO

Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro.


Assuntos
Esclerose Lateral Amiotrófica , Riluzol , Esclerose Lateral Amiotrófica/tratamento farmacológico , Animais , Edaravone/farmacologia , Humanos , Camundongos , Neurônios Motores , Riluzol/farmacologia , Riluzol/uso terapêutico , Superóxido Dismutase
19.
Gene Ther ; 29(3-4): 178-192, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34853443

RESUMO

There are no effective cures for upper motor neuron (UMN) diseases, such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and hereditary spastic paraplegia. Here, we show UMN loss occurs independent of spinal motor neuron degeneration and that UMNs are indeed effective cellular targets for gene therapy, which offers a potential solution especially for UMN disease patients. UCHL1 (ubiquitin C-terminal hydrolase-L1) is a deubiquitinating enzyme crucial for maintaining free ubiquitin levels. Corticospinal motor neurons (CSMN, a.k.a UMNs in mice) show early, selective, and profound degeneration in Uchl1nm3419 (UCHL1-/-) mice, which lack all UCHL1 function. When UCHL1 activity is ablated only from spinal motor neurons, CSMN remained intact. However, restoring UCHL1 specifically in CSMN of UCHL1-/- mice via directed gene delivery was sufficient to improve CSMN integrity to the healthy control levels. In addition, when UCHL1 gene was delivered selectively to CSMN that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology via AAV-mediated retrograde transduction, the disease causing misfolded SOD1 and mutant human TDP-43 were reduced in hSOD1G93A and prpTDP-43A315T models, respectively. Diseased CSMN retained their neuronal integrity and cytoarchitectural stability in two different mouse models that represent two distinct causes of neurodegeneration in ALS.


Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/terapia , Animais , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Terapia Genética , Humanos , Camundongos , Camundongos Transgênicos , Neurônios Motores/patologia , Superóxido Dismutase/genética , Superóxido Dismutase-1/genética , Ubiquitina Tiolesterase/genética
20.
Clin Transl Med ; 11(2): e336, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33634973

RESUMO

BACKGROUND: Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies. METHODS: Novel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP-43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU-9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses. RESULTS: Problems with mitochondria and ER are conserved in diseased UMNs among different species. NU-9 has drug-like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU-9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP-43 pathology, two distinct and important overarching causes of motor neuron degeneration. CONCLUSIONS: Mechanism-focused and cell-based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU-9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.


Assuntos
Retículo Endoplasmático/patologia , Mitocôndrias/patologia , Doença dos Neurônios Motores/patologia , Deficiências na Proteostase/patologia , Superóxido Dismutase-1/metabolismo , Proteinopatias TDP-43/patologia , Animais , Retículo Endoplasmático/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Doença dos Neurônios Motores/metabolismo , Deficiências na Proteostase/metabolismo , Teste de Desempenho do Rota-Rod , Proteinopatias TDP-43/metabolismo
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