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1.
Neurobiol Dis ; 200: 106631, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39111701

RESUMO

Friedreich ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in the FXN gene. This deficiency causes progressive degeneration of specific neuronal populations in the cerebellum and the consequent loss of movement coordination and equilibrium, which are some of the main symptoms observed in affected individuals. Like in other neurodegenerative diseases, previous studies suggest that glial cells could be involved in the neurodegenerative process and disease progression in patients with Friedreich ataxia. In this work, we followed and characterized the progression of changes in the cerebellar cortex in the latest version of Friedreich ataxia humanized mouse model, YG8-800 (Fxnnull:YG8s(GAA)>800), which carries a human FXN transgene containing >800 GAA repeats. Comparative analyses of behavioral, histopathological, and biochemical parameters were conducted between the control strain Y47R and YG8-800 mice at different time points. Our findings revealed that YG8-800 mice exhibit an ataxic phenotype characterized by poor motor coordination, decreased body weight, cerebellar atrophy, neuronal loss, and changes in synaptic proteins. Additionally, early activation of glial cells, predominantly astrocytes and microglia, was observed preceding neuronal degeneration, as was increased expression of key proinflammatory cytokines and downregulation of neurotrophic factors. Together, our results show that the YG8-800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in humans. Accordingly, this humanized model could represent a valuable tool for studying Friedreich ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.


Assuntos
Córtex Cerebelar , Modelos Animais de Doenças , Frataxina , Ataxia de Friedreich , Camundongos Transgênicos , Neuroglia , Ataxia de Friedreich/patologia , Ataxia de Friedreich/metabolismo , Ataxia de Friedreich/genética , Animais , Neuroglia/metabolismo , Neuroglia/patologia , Córtex Cerebelar/metabolismo , Córtex Cerebelar/patologia , Camundongos , Proteínas de Ligação ao Ferro/genética , Proteínas de Ligação ao Ferro/metabolismo , Humanos , Degeneração Neural/patologia , Degeneração Neural/metabolismo , Masculino
2.
BMC Vet Res ; 20(1): 263, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38890680

RESUMO

BACKGROUND: Neurological inherited disorders are rare in domestic animals. Cerebellar cortical degeneration remains amongst the most common of these disorders. The condition is defined as the premature loss of fully differentiated cerebellar components due to genetic or metabolic defects. It has been studied in dogs and cats, and various genetic defects and diagnostic tests (including magnetic resonance imaging (MRI)) have been refined in these species. Cases in cats remain rare and mostly individual, and few diagnostic criteria, other than post-mortem exam, have been evaluated in reports with multiple cases. Here, we report three feline cases of cerebellar cortical degeneration with detailed clinical, diagnostic imaging and post-mortem findings. CASE PRESENTATION: The three cases were directly (siblings, case #1 and #2) or indirectly related (same farm, case #3) and showed early-onset of the disease, with clinical signs including cerebellar ataxia and tremors. Brain MRI was highly suggestive of cerebellar cortical degeneration on all three cases. The relative cerebrospinal fluid (CSF) space, relative cerebellum size, brainstem: cerebellum area ratio, and cerebellum: total brain area ratio, were measured and compared to a control group of cats and reference cut-offs for dogs in the literature. For the relative cerebellum size and cerebellum: total brain area ratio, all affected cases had a lower value than the control group. For the relative CSF space and brainstem: cerebellum area ratio, the more affected cases (#2 and #3) had higher values than the control group, while the least affected case (#3) had values within the ranges of the control group, but a progression was visible over time. Post-mortem examination confirmed the diagnosis of cerebellar cortical degeneration, with marked to complete loss of Purkinje cells and associated granular layer depletion and proliferation of Bergmann glia. One case also had Wallerian-like degeneration in the spinal cord, suggestive of spinocerebellar degeneration. CONCLUSION: Our report further supports a potential genetic component for the disease in cats. For the MRI examination, the relative cerebellum size and cerebellum: total brain area ratio seem promising, but further studies are needed to establish specific feline cut-offs. Post-mortem evaluation of the cerebellum remains the gold standard for the final diagnosis.


Assuntos
Doenças do Gato , Imageamento por Ressonância Magnética , Animais , Gatos , Doenças do Gato/patologia , Doenças do Gato/diagnóstico por imagem , Córtex Cerebelar/patologia , Córtex Cerebelar/diagnóstico por imagem , Cerebelo/patologia , Cerebelo/diagnóstico por imagem , Imageamento por Ressonância Magnética/veterinária
3.
Ultrastruct Pathol ; 48(4): 247-260, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38850541

RESUMO

Levetiracetam (LEV) is being used by women with reproductive-age epilepsy at a significantly higher rate. The purpose of the study was to assess how levetiracetam treatment during pregnancy affected the offspring's weight and cerebellum. Forty pregnant rats were divided into two groups (I, II). Two smaller groups (A, B) were created from each group. The rats in group I were gavaged with approximately 1.5 mL/day of distilled water either continuously during pregnancy (for subgroup IA) or continuously during pregnancy and 14 days postpartum (for subgroup IB). The rats in group II were gavaged with about 1.5 mL/day of distilled water (containing 36 mg levetiracetam) either continuously during pregnancy (for subgroup IA) or continuously during pregnancy and 14 days postpartum (for subgroup IB). After the work was completed, the body weight of the pups in each group was recorded, and their cerebella were analyzed histologically and morphometrically. Following levetiracetam treatment, the offspring showed decreased body weight and their cerebella displayed delayed development and pathological alterations. These alterations manifested as, differences in the thicknesses of the layers of cerebellar cortex as compared to the control groups; additionally, their cells displayed cytoplasmic vacuolation, nuclear alterations, fragmented rough endoplasmic reticulum and lost mitochondrial cristae. Giving levetiracetam to pregnant and lactating female rats had a negative impact on the body weight and cerebella of the offspring. Levetiracetam should be given with caution during pregnancy and lactation.


Assuntos
Anticonvulsivantes , Córtex Cerebelar , Levetiracetam , Animais , Levetiracetam/farmacologia , Feminino , Gravidez , Ratos , Anticonvulsivantes/toxicidade , Anticonvulsivantes/farmacologia , Córtex Cerebelar/efeitos dos fármacos , Córtex Cerebelar/patologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Piracetam/análogos & derivados , Piracetam/farmacologia , Ratos Wistar
4.
Int J Dev Neurosci ; 84(5): 406-422, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38773676

RESUMO

The cerebellum has a long, protracted developmental period that spans from the embryonic to postnatal periods; as a result, it is more sensitive to intrauterine and postnatal insults like nutritional deficiencies. Folate is crucial for foetal and early postnatal brain development; however, its effects on cerebellar growth and development are unknown. The aim of this study was to examine the effects of maternal folate intake on the histomorphology and cell density of the developing cerebellum. Twelve adult female rats (rattus norvegicus) were randomly assigned to one of four premixed diet groups: standard (2 mg/kg), folate-deficient (0 mg/kg), folate-supplemented (8 mg/kg) or folate supra-supplemented (40 mg/kg). The rats started their diets 14 days before mating and consumed them throughout pregnancy and lactation. On postnatal days 1, 7, 21 and 35, five pups from each group were sacrificed, and their brains were processed for light microscopic analysis. Histomorphology and cell density of the external granule, molecular, Purkinje and internal granule layers were obtained. The folate-deficient diet group had smaller, dysmorphic cells and significantly lower densities of external granule, molecular, Purkinje and internal granule cells. Although the folate-enriched groups had greater cell densities than the controls, the folate-supplemented group had considerably higher cell densities than the supra-supplemented group. The folate supra-supplemented group had ectopic Purkinje cells in the internal granule cell layer. These findings imply that a folate-deficient diet impairs cellular growth and reduces cell density in the cerebellar cortex. On the other hand, folate supplementation increases cell densities, but there appears to be an optimal dose of supplementation since excessive folate levels may be detrimental.


Assuntos
Animais Recém-Nascidos , Córtex Cerebelar , Ácido Fólico , Animais , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/farmacologia , Ratos , Gravidez , Contagem de Células , Córtex Cerebelar/efeitos dos fármacos , Córtex Cerebelar/crescimento & desenvolvimento , Córtex Cerebelar/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Suplementos Nutricionais , Deficiência de Ácido Fólico/patologia , Ratos Sprague-Dawley , Dieta , Masculino , Fatores Etários , Neurônios/efeitos dos fármacos , Neurônios/patologia
5.
Ann Clin Transl Neurol ; 11(6): 1514-1525, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38644741

RESUMO

OBJECTIVE: Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs. METHODS: Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples. RESULTS: Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web-based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis. INTERPRETATION: These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem.


Assuntos
Cerebelo , Tremor Essencial , Humanos , Tremor Essencial/diagnóstico , Idoso , Feminino , Masculino , Cerebelo/patologia , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Algoritmos , Córtex Cerebelar/patologia
6.
J Vet Intern Med ; 38(4): 2368-2372, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38662636

RESUMO

Granuloprival degeneration is an uncommon form of cerebellar cortical degeneration (CCD). A 3-month-old Yorkshire Terrier and a 7-month-old Lagotto Romagnolo dog were presented with a history of progressive cerebellar dysfunction including wide-based stance, cerebellar ataxia, intention tremors, and loss of menace response despite normal vision. Magnetic resonance imaging of the brain identified marked diffuse decrease of the cerebellum size. Euthanasia was performed in both cases because of progression of clinical signs. Histopathological examination identified marked diffuse thinning of the granular cell layer with almost complete loss of the granular cell neurons, providing a definitive diagnosis of granuloprival CCD. Granuloprival CCD should be considered as a differential diagnosis in Yorkshire Terrier and Lagotto Romagnolo dogs with post-natal progressive clinical signs of cerebellar dysfunction.


Assuntos
Doenças do Cão , Animais , Cães , Doenças do Cão/patologia , Doenças do Cão/diagnóstico , Doenças do Cão/diagnóstico por imagem , Imageamento por Ressonância Magnética/veterinária , Masculino , Córtex Cerebelar/patologia , Feminino
7.
Cerebellum ; 23(5): 1942-1949, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38607531

RESUMO

This was a study of 12 cerebellar cortical dysplasias (CCDs) fetuses, these cases were characterized by a disorder of cerebellar fissures. Historically, CCD diagnosis was primarily performed using postnatal imaging. Unique to this study was the case series of CCD for prenatal diagnosis using prenatal ultrasound, as well as we found that AXIN1 and FOXC1 mutations may be related to CCD.


Assuntos
Diagnóstico Pré-Natal , Humanos , Feminino , Gravidez , Diagnóstico Pré-Natal/métodos , Ultrassonografia Pré-Natal , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/genética , Adulto , Fatores de Transcrição Forkhead/genética , Proteína Axina/genética , Córtex Cerebelar/diagnóstico por imagem , Córtex Cerebelar/anormalidades , Córtex Cerebelar/patologia , Mutação
8.
Neuroimage ; 270: 119950, 2023 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-36822250

RESUMO

Understanding cerebellar alterations due to healthy aging provides a reference point against which pathological findings in late-onset disease, for example spinocerebellar ataxia type 6 (SCA6), can be contrasted. In the present study, we investigated the impact of aging on the cerebellar nuclei and cerebellar cortex in 109 healthy controls (age range: 16 - 78 years) using 3 Tesla magnetic resonance imaging (MRI). Findings were compared with 25 SCA6 patients (age range: 38 - 78 years). A subset of 16 SCA6 (included: 14) patients and 50 controls (included: 45) received an additional MRI scan at 7 Tesla and were re-scanned after one year. MRI included T1-weighted, T2-weighted FLAIR, and multi-echo T2*-weighted imaging. The T2*-weighted phase images were converted to quantitative susceptibility maps (QSM). Since the cerebellar nuclei are characterized by elevated iron content with respect to their surroundings, two independent raters manually outlined them on the susceptibility maps. T1-weighted images acquired at 3T were utilized to automatically identify the cerebellar gray matter (GM) volume. Linear correlations revealed significant atrophy of the cerebellum due to tissue loss of cerebellar cortical GM in healthy controls with increasing age. Reduction of the cerebellar GM was substantially stronger in SCA6 patients. The volume of the dentate nuclei did not exhibit a significant relationship with age, at least in the age range between 18 and 78 years, whereas mean susceptibilities of the dentate nuclei increased with age. As previously shown, the dentate nuclei volumes were smaller and magnetic susceptibilities were lower in SCA6 patients compared to age- and sex-matched controls. The significant dentate volume loss in SCA6 patients could also be confirmed with 7T MRI. Linear mixed effects models and individual paired t-tests accounting for multiple comparisons revealed no statistical significant change in volume and susceptibility of the dentate nuclei after one year in neither patients nor controls. Importantly, dentate volumes were more sensitive to differentiate between SCA6 (Cohen's d = 3.02) and matched controls than the cerebellar cortex volume (d = 2.04). In addition to age-related decline of the cerebellar cortex and atrophy in SCA6 patients, age-related increase of susceptibility of the dentate nuclei was found in controls, whereas dentate volume and susceptibility was significantly decreased in SCA6 patients. Because no significant changes of any of these parameters was found at follow-up, these measures do not allow to monitor disease progression at short intervals.


Assuntos
Ataxias Espinocerebelares , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/patologia , Cerebelo/patologia , Córtex Cerebelar/diagnóstico por imagem , Córtex Cerebelar/patologia , Núcleos Cerebelares/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Atrofia/patologia
9.
Acta Neuropathol ; 145(3): 265-283, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36607423

RESUMO

In recent years, numerous morphologic changes have been identified in the essential tremor (ET) cerebellar cortex, distinguishing ET from control brains. These findings have not been fully contextualized within a broader degenerative disease spectrum, thus limiting their interpretability. Building off our prior study and now doubling the sample size, we conducted comparative analyses in a postmortem series of 320 brains on the severity and patterning of cerebellar cortex degenerative changes in ET (n = 100), other neurodegenerative disorders of the cerebellum [spinocerebellar ataxias (SCAs, n = 47, including 13 SCA3 and 34 SCA1, 2, 6, 7, 8, 14); Friedreich's ataxia (FA, n = 13); multiple system atrophy (MSA), n = 29], and other disorders that may involve the cerebellum [Parkinson's disease (PD), n = 62; dystonia, n = 19] versus controls (n = 50). We generated data on 37 quantitative morphologic metrics, grouped into 8 broad categories: Purkinje cell (PC) loss, heterotopic PCs, PC dendritic changes, PC axonal changes (torpedoes), PC axonal changes (other than torpedoes), PC axonal changes (torpedo-associated), basket cell axonal hypertrophy, and climbing fiber-PC synaptic changes. Principal component analysis of z scored raw data across all diagnoses (11,651 data items) revealed that diagnostic groups were not uniform with respect to pathology. Dystonia and PD each differed from controls in only 4/37 and 5/37 metrics, respectively, whereas ET differed in 21, FA in 10, SCA3 in 10, MSA in 21, and SCA1/2/6/7/8/14 in 27. Pathological changes were generally on the milder end of the degenerative spectrum in ET, FA and SCA3, and on the more severe end of that spectrum in SCA1/2/6/7/8/14. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. In summary, we present a robust and reproducible method that identifies somewhat distinctive signatures of degenerative changes in the cerebellar cortex that mark each of these disorders.


Assuntos
Distonia , Distúrbios Distônicos , Tremor Essencial , Transtornos Motores , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Ataxias Espinocerebelares , Humanos , Córtex Cerebelar/patologia , Cerebelo/patologia , Distonia/patologia , Distúrbios Distônicos/patologia , Tremor Essencial/metabolismo , Atrofia de Múltiplos Sistemas/patologia , Doença de Parkinson/patologia , Células de Purkinje/patologia , Ataxias Espinocerebelares/patologia
10.
Cerebellum ; 22(2): 249-260, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35286708

RESUMO

The cerebellum is ontogenetically one of the first structures to develop in the central nervous system; nevertheless, it has been only recently reconsidered for its significant neurobiological, functional, and clinical relevance in humans. Thus, it has been a relatively under-studied compared to the cerebrum. Currently, non-invasive imaging modalities can barely reach the necessary resolution to unfold its entire, convoluted surface, while only histological analyses can reveal local information at the micrometer scale. Herein, we used the BigBrain dataset to generate area and point-wise thickness measurements for all layers of the cerebellar cortex and for each lobule in particular. We found that the overall surface area of the cerebellar granular layer (including Purkinje cells) was 1,732 cm2 and the molecular layer was 1,945 cm2. The average thickness of the granular layer is 0.88 mm (± 0.83) and that of the molecular layer is 0.32 mm (± 0.08). The cerebellum (both granular and molecular layers) is thicker at the depth of the sulci and thinner at the crowns of the gyri. Globally, the granular layer is thicker in the lateral-posterior-inferior region than the medial-superior regions. The characterization of individual layers in the cerebellum achieved herein represents a stepping-stone for investigations interrelating structural and functional connectivity with cerebellar architectonics using neuroimaging, which is a matter of considerable relevance in basic and clinical neuroscience. Furthermore, these data provide templates for the construction of cerebellar topographic maps and the precise localization of structural and functional alterations in diseases affecting the cerebellum.


Assuntos
Córtex Cerebelar , Cerebelo , Humanos , Córtex Cerebelar/patologia , Cerebelo/fisiologia , Células de Purkinje
11.
J Integr Neurosci ; 21(1): 13, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164449

RESUMO

The hallmark of Multiple Sclerosis (MS) pathophysiology is the damage to the myelin sheath around axons. The cerebellum is a predilection site for demyelination with a well-recognized role in motor and a rather understudied contribution to cognitive functions. The aim of this study is to investigate patterns of cerebellar grey and white matter pathology, expressed as reduced volume, as well as cortical thickness and their potential contribution to cognitive performance and disability status of patients with MS. 24 patients with MS underwent extensive neuropsychological assessment using paper and pencil tests and the Brain Health Assessment (BHA) tablet-based battery. Cerebellar lobular volumes and thickness were calculated using a volumetric analysis with automated segmentation of the cerebellum and its lobules. The main findings are a reduction of cerebellar grey matter (CGMV) and white matter volumes (CWMV) in lobule X and a widespread cerebellar cortical thinning in patients. Overall disease severity and neurological disability, assessed with the Expanded Disability Status Severity Scale, was correlated with fatigue and information processing speed tasks, but not with CGMV and CWMV. CWMV and CGMV of lobule I-II was negatively correlated with information processing speed, as well as visuospatial memory tests and, finally, inverse cortical thinning associations were noted between the whole cerebellum, lobule I-II, lobule III, lobule VI, Crus I, lobule VIIIA and information processing speed and verbal fluency tasks. The inverse associations observed may represent a compensatory mechanism activated in MS engaging additional high-level cortical areas functionally interconnected with the damaged cerebellum, in order to cope with the cognitive demands of a task.


Assuntos
Cerebelo/patologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Substância Cinzenta/patologia , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Substância Branca/patologia , Adulto , Córtex Cerebelar/diagnóstico por imagem , Córtex Cerebelar/patologia , Cerebelo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
12.
J Affect Disord ; 302: 50-57, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35074460

RESUMO

BACKGROUND: Bipolar disorder (BP) is a common psychiatric disorder characterized by extreme fluctuations in mood. Recent studies have indicated the involvement of cerebellum in the pathogenesis of BP. However, no study has focused on the precise role of cerebellum exclusively in patients with bipolar I disorder (BP-I). METHODS: Forty-five patients with BP-I and 40 healthy controls were recruited. All subjects underwent clinical evaluation and Magnetic Resonance diffusion Tension Imaging scans. For structural images, we used a spatially unbiased infratentorial template toolbox to isolate the cerebellum and then preformed voxel-based morphometry (VBM) analyses to assess the difference in cerebellar gray matter volume (GMV) between the two groups. For the functional images, we chose the clusters that survived from VBM analysis as seeds and performed functional connectivity (FC) analysis. Between-group differences were assessed using the independent Students t test or the nonparametric Mann-Whitney U Test. For multiple comparisons, the results were further corrected with Gaussian random field (GRF) approach (voxel-level P < 0.001, cluster-level P < 0.05). RESULTS: Compared with healthy controls, BP-I patients showed significantly decreased GMV in left lobule V and left lobule VI (P < 0.05, GRF corrected). The FC of cerebellum with bilateral superior temporal gyrus, bilateral insula, bilateral rolandic operculum, right putamen, and left precentral gyrus was disrupted in BP-I patients (P < 0.05, GRF corrected). CONCLUSIONS: BP-I patients showed decreased cerebellar GMV and disrupted cerebellar-cortex resting-state FC. This suggests that cerebellar abnormalities may play an important role in the pathogenesis of BP-I.


Assuntos
Transtorno Bipolar , Córtex Cerebelar , Substância Cinzenta , Transtorno Bipolar/patologia , Transtorno Bipolar/fisiopatologia , Córtex Cerebelar/patologia , Córtex Cerebelar/fisiopatologia , Substância Cinzenta/patologia , Substância Cinzenta/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos
13.
Tissue Cell ; 73: 101624, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34419739

RESUMO

Metanil yellow is a food dye that has harmful impacts on different body systems. Scutellarin has antioxidant, antiapoptotic, and anti-inflammatory activities. The aim of the current research was to study the effect of chronic administration of metanil yellow on the cerebellar cortex of rats and to evaluate the protective effect of scutellarin. Forty adult male rats were allocated into four groups: group I acted as control, group II was administrated scutellarin (100 mg/kg/day), group III was administrated metanil yellow (200 mg/kg/day), and group IV was administrated scutellarin and metanil yellow as in group II and group III. The agents were administered via oral gavage for 8 weeks. Metanil yellow induced a significant rise in the malondialdehyde coupled with a significant reduction in the superoxide dismutase and glutathione peroxidase. The Purkinje cells were irregular and shrunken with condensed nuclei. A significant elevation in glial fibrillary acidic protein (GFAP) and cleaved caspase-3 as well as a significant reduction of synaptophysin expression were revealed in comparison with the control group. Interestingly, few changes were noticed in rats given metanil yellow concomitant with scutellarin. In conclusion, scutellarin could protect against metanil yellow-induced alterations in the cerebellar cortex by reducing oxidative stress and minimizing gliosis.


Assuntos
Apigenina/farmacologia , Apoptose , Compostos Azo/toxicidade , Córtex Cerebelar/patologia , Gliose/patologia , Glucuronatos/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Acetilcolinesterase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Glutationa/metabolismo , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Masculino , Malondialdeído/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804256

RESUMO

Lysosomal acid phosphatase 2 (Acp2) mutant mice (naked-ataxia, nax) have a severe cerebellar cortex defect with a striking reduction in the number of granule cells. Using a combination of in vivo and in vitro immunohistochemistry, Western blotting, BrdU assays, and RT-qPCR, we show downregulation of MYCN and dysregulation of the SHH signaling pathway in the nax cerebellum. MYCN protein expression is significantly reduced at P10, but not at the peak of proliferation at around P6 when the number of granule cells is strikingly reduced in the nax cerebellum. Despite the significant role of the SHH-MycN pathway in granule cell proliferation, our study suggests that a broader molecular pathway and additional mechanisms regulating granule cell development during the clonal expansion period are impaired in the nax cerebellum. In particular, our results indicate that downregulation of the protein synthesis machinery may contribute to the reduced number of granule cells in the nax cerebellum.


Assuntos
Fosfatase Ácida/genética , Ataxia Cerebelar/genética , Córtex Cerebelar/metabolismo , Proteínas Hedgehog/genética , Proteína Proto-Oncogênica N-Myc/genética , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/patologia , Córtex Cerebelar/anormalidades , Córtex Cerebelar/patologia , Grânulos Citoplasmáticos/genética , Grânulos Citoplasmáticos/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lisossomos/genética , Lisossomos/patologia , Camundongos , Mutação , Neurônios/metabolismo , Neurônios/patologia , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Transdução de Sinais/genética
15.
Cerebellum ; 20(6): 904-912, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33768479

RESUMO

Essential tremor (ET) is among the most prevalent movement disorders, and by some accounts, the most common form of cerebellar degeneration. Over the past 15 years, we have carefully documented a large number of postmortem changes within the cerebellum; these cerebellar changes differ significantly between ET and controls. A recent Consensus Classification of tremor proposed that ET patients with other neurological signs aside from action tremor (e.g., parkinsonism, ataxia, cognitive changes, dystonia) should be segregated off as "ET-plus". This diagnostic concept has raised considerable controversy and its validity is not yet established. Indeed, "ET-plus" has not been distinguished from ET based on differences in genetics, pathology or prognosis. Here we determine whether ET cases differ from "ET-plus" cases in underlying pathological changes in the postmortem brain. We examined postmortem brains from 50 ET cases (24 ET and 26 ET-plus), using a set of 14 quantitative metrics of cerebellar pathology determined by histologic and immunohistochemical methods. These metrics reflect changes across the Purkinje cell (PC) body (PC counts, empty baskets, heterotopias), PC dendrites (swellings), PC axon (torpedoes and associated axonal changes), basket cell axonal hypertrophy and climbing fiber-PC dendrite synaptic changes. ET and ET-plus were similar with respect to 13 of 14 cerebellar pathologic metrics (p > 0.05). Only one metric, the linear density of thickened PC axon profiles, differed between these groups (ET = 0.529 ± 0.397, ET-plus = 0.777 ± 0.477, p = 0.013), although after correcting for multiple comparisons, there were no differences. If ET-plus were indeed a different entity, then the underlying pathological basis should be distinct from that of ET. This study demonstrated there were no pathological differences in cerebellar cortex between ET versus ET-plus cases. These data do not support the notion that ET and ET-plus represent distinct clinical-pathological entities.


Assuntos
Cerebelo , Tremor Essencial , Córtex Cerebelar/patologia , Cerebelo/patologia , Tremor Essencial/patologia , Humanos , Células de Purkinje/patologia , Tremor/patologia
16.
J Neurophysiol ; 125(5): 1735-1745, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33760649

RESUMO

Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of gait, posture, speech, fine motor, and oculomotor function. Yet, little is known how the cerebro-cerebellar network compensates for the loss in cerebellar cortical neurons. To address this knowledge gap, we examined 30 people with cerebellar cortical degeneration and a group of 30 healthy controls. We assessed visuomotor performance during a forearm-pointing task to 10°, 25°, and 50° targets. In addition, using MRI imaging, we determined neurodegenerative-induced changes in gray matter volume (GMV) in the cerebro-cerebellar network and correlated them to markers of motor performance. The main results are as follows: first, the relative joint position error (RJPE) during pointing was significantly greater in the ataxia group for all targets confirming the expected motor control deficit. Second, in the ataxia group, GMV was significantly reduced in cerebellar cortex but increased in the deep cerebellar nuclei. Motor error (RJPE) correlated negatively with decreased cerebellar GMV but positively with increased GMV in supplementary motor area (SMA) and premotor cortex. GMV of the deep cerebellar nuclei did not correlate significantly with markers of motor performance. We discuss whether the GMV changes in the cerebellar output nuclei and the extracerebellar efferent targets in secondary motor cortex can be understood as a central compensatory response to the neurodegeneration of the cerebellar cortex.NEW & NOTEWORTHY Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of movement. We here show that the neurodegenerative process not only leads to cells loss in cerebellar cortex but also induces neurostructural changes in the form of increased gray matter in the efferent targets of the cerebellar cortex, namely, the cerebellar output nuclei, the SMA, and premotor cortex.


Assuntos
Ataxia Cerebelar , Córtex Cerebelar , Núcleos Cerebelares , Substância Cinzenta , Atividade Motora/fisiologia , Córtex Motor/fisiopatologia , Desempenho Psicomotor/fisiologia , Adulto , Idoso , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/patologia , Ataxia Cerebelar/fisiopatologia , Córtex Cerebelar/diagnóstico por imagem , Córtex Cerebelar/patologia , Córtex Cerebelar/fisiopatologia , Núcleos Cerebelares/diagnóstico por imagem , Núcleos Cerebelares/patologia , Núcleos Cerebelares/fisiopatologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Substância Cinzenta/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
17.
J Mol Endocrinol ; 66(4): 259-272, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33729996

RESUMO

Earlier, it was shown that reversing the downregulation of neuritin expression in the brain improves central neuropathy in diabetic rats. We investigated the protective mechanism of neuritin in diabetic cognitive dysfunction via astrocytes. Further, the impact of the overexpression of neuritin in the cortex and the hippocampus on diabetic cognitive dysfunction and astrogliosis in type 2 diabetic (db/db) mice was assessed. Antagonists were used to inhibit the JAK2/STAT3 signaling pathway in U-118MG, an astrocyte cell line. Immunofluorescence, Western blotting, and real-time PCR were performed. Neuritin overexpression in the hippocampus of db/db mice significantly ameliorated cognitive dysfunction, hippocampal neuronal impairment, and synaptic plasticity deterioration, and inhibited astrogliosis and the JAK2/STAT3 signaling pathway in the hippocampus. Neuritin suppressed the JAK2/STAT3 signaling pathway to inhibit lipopolysaccharide-induced gliosis in U-118MG cells. It was observed that neuritin regulates the JAK2/STAT3 signaling pathway in astrocytes to inhibit astrogliosis and improve diabetic cognitive dysfunction.


Assuntos
Disfunção Cognitiva/genética , Gliose/genética , Janus Quinase 2/genética , Neuropeptídeos/genética , Fator de Transcrição STAT3/genética , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Córtex Cerebelar/metabolismo , Córtex Cerebelar/patologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Complicações do Diabetes/complicações , Complicações do Diabetes/genética , Complicações do Diabetes/patologia , Complicações do Diabetes/terapia , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/patologia , Neuropatias Diabéticas/terapia , Modelos Animais de Doenças , Proteínas Ligadas por GPI/genética , Regulação da Expressão Gênica/genética , Gliose/induzido quimicamente , Gliose/patologia , Gliose/terapia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Lipopolissacarídeos/toxicidade , Camundongos , Plasticidade Neuronal/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos
18.
Hum Mol Genet ; 30(1): 103-118, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33555315

RESUMO

Oligodendrocytes exist in a heterogenous state and are implicated in multiple neuropsychiatric diseases including dementia. Cortical oligodendrocytes are a glial population uniquely positioned to play a key role in neurodegeneration by synchronizing circuit connectivity but molecular pathways specific to this role are lacking. We utilized oligodendrocyte-specific translating ribosome affinity purification and RNA-seq (TRAP-seq) to transcriptionally profile adult mature oligodendrocytes from different regions of the central nervous system. Weighted gene co-expression network analysis reveals distinct region-specific gene networks. Two of these mature myelinating oligodendrocyte gene networks uniquely define cortical oligodendrocytes and differentially regulate cortical myelination (M8) and synaptic signaling (M4). These two cortical oligodendrocyte gene networks are enriched for genes associated with dementia including MAPT and include multiple gene targets of the regulatory microRNA, miR-142-3p. Using a combination of TRAP-qPCR, miR-142-3p overexpression in vitro, and miR-142-null mice, we show that miR-142-3p negatively regulates cortical myelination. In rTg4510 tau-overexpressing mice, cortical myelination is compromised, and tau-mediated neurodegeneration is associated with gene co-expression networks that recapitulate both the M8 and M4 cortical oligodendrocyte gene networks identified from normal cortex. We further demonstrate overlapping gene networks in mature oligodendrocytes present in normal cortex, rTg4510 and miR-142-null mice, and existing datasets from human tauopathies to provide evidence for a critical role of miR-142-3p-regulated cortical myelination and oligodendrocyte-mediated synaptic signaling in neurodegeneration.


Assuntos
MicroRNAs/genética , Tauopatias/genética , Proteínas tau/genética , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Córtex Cerebelar/metabolismo , Córtex Cerebelar/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , Camundongos , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Oligodendroglia/metabolismo , RNA-Seq , Tauopatias/metabolismo , Tauopatias/patologia
19.
J Alzheimers Dis ; 80(1): 113-132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33523050

RESUMO

BACKGROUND: It has been proposed that amyloid-ß (Aß) plays a causal role in Alzheimer's disease (AD) by triggering a series of pathologic events-possibly including neuroinflammation-which culminate in progressive brain atrophy. However, the interplay between the two pathological molecular events and how both are associated with neurodegeneration is still unclear. OBJECTIVE: We aimed to estimate the spatial inter-relationship between neurodegeneration, neuroinflammation and Aß deposition in a cohort of 20 mild AD patients and 17 healthy controls (HC). METHODS: We resorted to magnetic resonance imaging to measure cortical atrophy, using the radiotracer 11C-PK11195 PET to measure neuroinflammation levels and 11C-PiB PET to assess Aß levels. Between-group comparisons were computed to explore AD-related changes in the three types of markers. To examine the effects of each one of the molecular pathologic mechanisms on neurodegeneration we computed: 1) ANCOVAs with the anatomic data, controlling for radiotracer uptake differences between groups and 2) voxel-based multiple regression analysis between-modalities. In addition, associations in anatomically defined regions of interests were also investigated. RESULTS: We found significant differences between AD and controls in the levels of atrophy, neuroinflammation, and Aß deposition. Associations between Aß aggregation and brain atrophy were detected in AD in a widely distributed pattern, whereas associations between microglia activation and structural measures of neurodegeneration were restricted to few anatomically regions. CONCLUSION: In summary, Aß deposition, as opposed to neuroinflammation, was more associated with cortical atrophy, suggesting a prominent role of Aß in neurodegeneration at a mild stage of the AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encefalite/metabolismo , Substância Cinzenta/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Atrofia , Córtex Cerebelar/diagnóstico por imagem , Córtex Cerebelar/metabolismo , Córtex Cerebelar/patologia , Estudos de Coortes , Manual Diagnóstico e Estatístico de Transtornos Mentais , Encefalite/diagnóstico por imagem , Encefalite/patologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Voluntários Saudáveis , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Tomografia por Emissão de Pósitrons
20.
Medicine (Baltimore) ; 100(4): e24190, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33530210

RESUMO

ABSTRACT: Using voxel-based morphometry (VBM), we studied cortical gray matter volume changes in patients with cervical spondylotic myelopathy (CSM) before and after cervical cord surgical decompression. We then discussed the structural damage mechanisms and the neural plasticity mechanisms involved in postsurgical CSM.Forty-five presurgical CSM patients, 41 of the same group followed-up 6 months after decompression surgery and 45 normal controls (NC) matched for age, sex and level of education underwent high-resolution 3-dimensional T1-weighted scans by 3.0 T MR. Then, VBM measurements were compared and cortical gray matter volume alterations were assessed among pre- or postsurgical CSM patients and NC, as well as correlations with clinical indexes by Pearson correlation.Compared with NC, presurgical CSM patients showed reduced gray matter volume in the left caudate nucleus and the right thalamus. After 6 months, postsurgical CSM patients had lower gray matter volume in the bilateral cerebellar posterior lobes but had higher gray matter volume in the brain-stem than did presurgical CSM patients. Postsurgical CSM patients had significantly lower gray matter volume in the left caudate nucleus but greater regional gray matter volume in the right inferior temporal gyrus, the right middle orbitofrontal cortex (OFC) and the bilateral lingual gyrus / precuneus /posterior cingulate cortex than did NC. Abnormal areas gray volume in presurgical CSM and postsurgical CSM patients showed no significant correlation with clinical data (P > .05).Myelopathy in the cervical cord may cause chronic cerebral structural damage before and after the decompression stage, markedly in outlier brain regions involving motor execution/control, vision processing and the default mode network and in areas associated with brain compensatory plasticity to reverse downstream spinal cord compression and respond to spinal cord surgical decompression.


Assuntos
Córtex Cerebelar/patologia , Vértebras Cervicais/cirurgia , Descompressão Cirúrgica/métodos , Substância Cinzenta/patologia , Plasticidade Neuronal/fisiologia , Espondilose/cirurgia , Adulto , Córtex Cerebelar/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
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