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1.
J Thorac Cardiovasc Surg ; 160(2): e55-e66, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689704

RESUMO

OBJECTIVES: This study aims to evaluate the protective effects of progesterone on white matter injury and brain immaturity in neonatal rats with chronic hypoxia. METHODS: Three-day old Sprague-Dawley rats were randomly divided into 3 groups: (1) control (n = 48), rats were exposed to normoxia (fraction of inspired oxygen: 21% ± 0%); (2) chronic hypoxia (n = 48), rats were exposed to hypoxia (fraction of inspired oxygen: 10.5% ± 1.0%); and (3) progesterone (n = 48), rats were exposed to hypoxia and administrated with progesterone (8 mg/kg/d). Hematoxylin-eosin staining, immunohistochemistry, real-time quantitative polymerase chain reaction, and Western blot analyses were compared on postnatal day 14 in different groups. Motor skill and coordination abilities of rats were assessed via rotation experiments. RESULTS: Increased brain weights (P < .05), narrowed ventricular sizes (P < .01), and rotarod experiment scores (P < .01) were better in the progesterone group than in the chronic hypoxia group. The number of mature oligodendrocytes and myelin basic protein expression increased in the progesterone group compared with the chronic hypoxia group (P < .01). The polarization of M1 microglia cells in the corpus callosum of chronic hypoxia-induced hypomyelination rats was significantly increased, whereas there were fewer M2 microglia cells. Conversely, progesterone therapy had an opposite effect and caused an increase in M2 microglia polarization versus a reduction in M1 microglia cells. CONCLUSIONS: Progesterone could prevent white matter injury and improve brain maturation in a neonatal hypoxic rat model; this may be associated with inducing a switch from M1 to M2 in microglia.


Assuntos
Encéfalo/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Leucoencefalopatias/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Substância Branca/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Plasticidade Celular/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Feminino , Hipóxia/metabolismo , Hipóxia/patologia , Hipóxia/fisiopatologia , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos Sprague-Dawley , Substância Branca/metabolismo , Substância Branca/patologia , Substância Branca/fisiopatologia
2.
Neurology ; 95(3): e291-e298, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32576636

RESUMO

OBJECTIVE: To determine whether deep white matter and periventricular hyperintensities affect the motor symptoms of Parkinson disease (PD) differently, we analyzed MRI and dopamine transporter imaging. METHODS: We analyzed the medical records of patients with de novo PD who underwent dopamine transporter PET scanning and MRI at their first visit. Deep white matter and periventricular hyperintensities were scored with a visual rating scale, and motor symptoms were assessed by Unified Parkinson's Disease Rating Scale motor score and tremor, rigidity, bradykinesia, and axial symptom subscores. The influence of white matter hyperintensity on motor symptoms was explored using multivariable linear regression models. RESULTS: A total of 93 patients (mean age, 67.2 ± 9.9 years; 44 male) were included and the mean motor score was 25.0 ± 10.8. Subscores for bradykinesia and axial symptoms were correlated with both deep white matter and periventricular hyperintensities scores. Multivariable linear regression models revealed that deep white matter hyperintensities score was significantly associated with subscore for bradykinesia and periventricular hyperintensities score was associated with subscores for bradykinesia and axial symptoms after adjusting for putaminal dopamine transporter availability and clinical factors. CONCLUSIONS: These results demonstrate that deep white matter hyperintensities are associated with bradykinesia and periventricular hyperintensities are associated with bradykinesia and axial symptoms in patients with PD independently of the severity of dopaminergic depletion.


Assuntos
Transtornos das Habilidades Motoras/diagnóstico por imagem , Transtornos das Habilidades Motoras/metabolismo , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Idoso , Feminino , Humanos , Imagem por Ressonância Magnética/tendências , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/tendências
3.
PLoS One ; 15(5): e0224912, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407311

RESUMO

Myotonic dystrophy type 1 (DM1) is a multi-system disorder caused by CTG repeats in the myotonic dystrophy protein kinase (DMPK) gene. This leads to the sequestration of splicing factors such as muscleblind-like 1/2 (MBNL1/2) and aberrant splicing in the central nervous system. We investigated the splicing patterns of MBNL1/2 and genes controlled by MBNL2 in several regions of the brain and between the grey matter (GM) and white matter (WM) in DM1 patients using RT-PCR. Compared with amyotrophic lateral sclerosis (ALS, as disease controls), the percentage of spliced-in parameter (PSI) for most of the examined exons were significantly altered in most of the brain regions of DM1 patients, except for the cerebellum. The splicing of many genes was differently regulated between the GM and WM in both DM1 and ALS. In 7 out of the 15 examined splicing events, the level of PSI change between DM1 and ALS was significantly higher in the GM than in the WM. The differences in alternative splicing between the GM and WM may be related to the effect of DM1 on the WM of the brain.


Assuntos
Processamento Alternativo , Substância Cinzenta/metabolismo , Distrofia Miotônica/genética , Proteínas de Ligação a RNA/genética , Substância Branca/metabolismo , Adulto , Feminino , Humanos , Masculino , Proteínas de Ligação a RNA/metabolismo , Adulto Jovem
4.
Neurobiol Aging ; 91: 5-14, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32305782

RESUMO

This study investigated the relationship between white matter hyperintensities (WMH) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Subjects included 180 controls, 107 individuals with a significant memory concern, 320 individuals with early mild cognitive impairment, 171 individuals with late mild cognitive impairment, and 151 individuals with AD, with 3T MRI and CSF Aß1-42, total tau (t-tau), and phosphorylated tau (p-tau) data. Multiple linear regression models assessed the relationship between WMH and CSF Aß1-42, t-tau, and p-tau. Directionally, a higher WMH burden was associated with lower CSF Aß1-42 within each diagnostic group, with no evidence for a difference in the slope of the association across diagnostic groups (p = 0.4). Pooling all participants, this association was statistically significant after adjustment for t-tau, p-tau, age, diagnostic group, and APOE-ε4 status (p < 0.001). Age was the strongest predictor of WMH (partial R2~16%) compared with CSF Aß1-42 (partial R2~5%). There was no evidence for an association with WMH and either t-tau or p-tau. These data are supportive of a link between amyloid burden and presumed vascular pathology.


Assuntos
Envelhecimento/líquido cefalorraquidiano , Envelhecimento/patologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Substância Branca/metabolismo , Substância Branca/patologia , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/líquido cefalorraquidiano , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/patologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Substância Branca/diagnóstico por imagem
5.
Cogn Behav Neurol ; 33(1): 67-75, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32132405

RESUMO

Humans are highly social animals whose survival and well-being depend on their capacity to cooperate in complex social settings. Advances in anthropology and psychology have demonstrated the importance of cooperation for enhancing social cohesion and minimizing conflict. The understanding of social behavior is informed by the notion of social cognition, a set of mental operations including emotion perception, mentalizing, and empathy. The social brain hypothesis posits that the mammalian brain has enlarged over evolution to meet the challenges of social life, culminating in a large human brain well adapted for social cognition. The structures subserving social cognition are mainly located in the frontal and temporal lobes, and although gray matter is critical, social cognition also requires white matter. Whereas the social brain hypothesis assumes that brain enlargement has been driven by neocortical expansion, cerebral white matter has expanded even more robustly than the neocortex, coinciding with the emergence of social cognition. White matter expansion is most evident in the frontal and temporal lobes, where it enhances connectivity between regions critical for social cognition. Myelination has, in turn, conferred adaptive social advantages by enabling prompt empathic concern for offspring and by strengthening networks that support cooperation and the related capacities of altruism and morality. Social cognition deficits related to myelinated tract involvement occur in many disorders, including stroke, Binswanger disease, traumatic brain injury, multiple sclerosis, glioma, and behavioral variant frontotemporal dementia. The contribution of white matter to social cognition can be conceptualized as the enhancement of cooperation through brain connectivity.


Assuntos
Encéfalo/patologia , Cognição/fisiologia , Comportamento Social , Substância Branca/metabolismo , Substância Branca/fisiopatologia , Feminino , Humanos , Masculino
6.
Neurobiol Aging ; 89: 118-128, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32111392

RESUMO

Beta amyloid (Aß) accumulation is the earliest pathological marker of Alzheimer's disease (AD), but early AD pathology also affects white matter (WM) integrity. We performed a cross-sectional study including 44 subjects (23 healthy controls and 21 mild cognitive impairment or early AD patients) who underwent simultaneous PET-MR using 18F-Florbetapir, and were categorized into 3 groups based on Aß burden: Aß- [mean mSUVr ≤1.00], Aßi [1.00 < mSUVr <1.17], Aß+ [mSUVr ≥1.17]. Intergroup comparisons of diffusion MRI metrics revealed significant differences across multiple WM tracts. Aßi group displayed more restricted diffusion (higher fractional anisotropy, radial kurtosis, axonal water fraction, and lower radial diffusivity) than both Aß- and Aß+ groups. This nonmonotonic trend was confirmed by significant continuous correlations between mSUVr and diffusion metrics going in opposite direction for 2 cohorts: pooled Aß-/Aßi and pooled Aßi/Aß+. The transient period of increased diffusion restriction may be due to inflammation that accompanies rising Aß burden. In the later stages of Aß accumulation, neurodegeneration is the predominant factor affecting diffusion.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Imagem de Tensor de Difusão , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Idoso , Doença de Alzheimer/metabolismo , Biomarcadores/metabolismo , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Substância Branca/metabolismo
7.
Sci Adv ; 6(11): eaax6328, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32195337

RESUMO

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen-free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function.


Assuntos
Carnitina , Clostridiales/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal , Substância Branca/metabolismo , Animais , Carnitina/análogos & derivados , Carnitina/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos
8.
J Neuropathol Exp Neurol ; 79(4): 419-429, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32167542

RESUMO

Gerstmann-Sträussler-Scheinker (GSS) disease with P102L mutation and familial Creutzfeldt-Jakob disease (CJD) with V180I mutation are 2 major hereditary prion diseases in Japan. GSS and some familial CJD [V180I] exhibit characteristic prion protein (PrP) plaques. Overexpression of the astrocytic water channel proteins aquaporin (AQP) 1 and AQP4 was recently reported in sporadic CJD. To clarify the pathological characteristics of AQP1 and AQP4 in prion disease patient brains with plaque-type deposition, we investigated 5 patients with GSS, 2 patients with CJD [V180I], and 2 age-matched control cases without neurological diseases using immunohistochemistry and double immunofluorescence methods. We demonstrated that there is the intense expression of AQP1 and AQP4 around prion plaques, especially in distal astrocytic processes deep inside these plaques. Similar results have been reported in the senile plaques and ghost tangles of Alzheimer disease brains and a protective role of AQP4 in which AQP4 is redistributed toward the plaques and works as a barrier against the deleterious effects of these plaques has been suggested. Our results, which show a similar clustering of AQPs around PrP plaques, therefore support the possibility that AQPs also have a protective role in plaque formation in prion diseases.


Assuntos
Aquaporina 1/metabolismo , Aquaporina 4/metabolismo , Astrócitos/patologia , Encéfalo/patologia , Síndrome de Creutzfeldt-Jakob/patologia , Doença de Gerstmann-Straussler-Scheinker/patologia , Proteínas Priônicas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Astrócitos/metabolismo , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Feminino , Doença de Gerstmann-Straussler-Scheinker/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Substância Branca/metabolismo , Substância Branca/patologia
9.
Neurology ; 94(16): e1716-e1725, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32209649

RESUMO

OBJECTIVE: To test the hypothesis that neuroinflammation is a key process in adult Niemann-Pick type C (NPC) disease, we undertook PET scanning utilizing a ligand binding activated microglia on 9 patients and 9 age- and sex-matched controls. METHOD: We scanned all participants with the PET radioligand 11C-(R)-PK-11195 and undertook structural MRI to measure gray matter volume and white matter fractional anisotropy (FA). RESULTS: We found increased binding of 11C-(R)-PK-11195 in total white matter compared to controls (p < 0.01), but not in gray matter regions, and this did not correlate with illness severity or duration. Gray matter was reduced in the thalamus (p < 0.0001) in patients, who also showed widespread reductions in FA across the brain compared to controls (p < 0.001). A significant correlation between 11C-(R)-PK11195 binding and FA was shown (p = 0.002), driven by the NPC patient group. CONCLUSIONS: Our findings suggest that neuroinflammation-particularly in white matter-may underpin some structural and degenerative changes in patients with NPC.


Assuntos
Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Inflamação/diagnóstico por imagem , Doença de Niemann-Pick Tipo C/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto , Anisotropia , Encéfalo/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Substância Cinzenta/metabolismo , Substância Cinzenta/patologia , Humanos , Inflamação/metabolismo , Isoquinolinas , Imagem por Ressonância Magnética , Masculino , Doença de Niemann-Pick Tipo C/metabolismo , Tamanho do Órgão , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Substância Branca/metabolismo , Adulto Jovem
10.
Neurobiol Aging ; 88: 108-118, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035845

RESUMO

Given the worldwide increasing socioeconomic burden of aging-associated brain diseases, there is pressing need to gain in-depth knowledge about the neurobiology of brain anatomy changes across the life span. Advances in quantitative magnetic resonance imaging sensitive to brain's myelin, iron, and free water content allow for a detailed in vivo investigation of aging-related changes while reducing spurious morphometry differences. Main aim of our study is to link previous morphometry findings in aging to microstructural tissue properties in a large-scale cohort (n = 966, age range 46-86 y). Addressing previous controversies in the field, we present results obtained with different approaches to adjust local findings for global effects. Beyond the confirmation of age-related atrophy, myelin, and free water decreases, we report proportionally steeper volume, iron, and myelin decline in sensorimotor and subcortical areas paralleled by free water increase. We demonstrate aging-related white matter volume, myelin, and iron loss in frontostriatal projections. Our findings provide robust evidence for spatial overlap between volume and tissue property differences in aging that affect predominantly motor and executive networks.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Tamanho do Órgão , Substância Branca/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Atrofia , Água Corporal/metabolismo , Estudos de Coortes , Feminino , Humanos , Ferro/metabolismo , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Bainha de Mielina/metabolismo , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo
11.
Nat Commun ; 11(1): 964, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075970

RESUMO

Hypoxic damage to the developing brain due to preterm birth causes many anatomical changes, including damage to the periventricular white matter. This results in the loss of glial cells, significant disruptions in myelination, and thereby cognitive and behavioral disabilities seen throughout life. Encouragingly, these neurological morbidities can be improved by environmental factors; however, the underlying cellular mechanisms remain unknown. We found that early and continuous environmental enrichment selectively enhances endogenous repair of the developing white matter by promoting oligodendroglial maturation, myelination, and functional recovery after perinatal brain injury. These effects require increased exposure to socialization, physical activity, and cognitive enhancement of surroundings-a complete enriched environment. Using RNA-sequencing, we identified oligodendroglial-specific responses to hypoxic brain injury, and uncovered molecular mechanisms involved in enrichment-induced recovery. Together, these results indicate that myelin plasticity induced by modulation of the neonatal environment can be targeted as a therapeutic strategy for preterm birth.


Assuntos
Lesões Encefálicas/reabilitação , Meio Ambiente , Neuroproteção , Substância Branca/fisiologia , Animais , Animais Recém-Nascidos , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Modelos Animais de Doenças , Hipóxia/patologia , Hipóxia/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Bainha de Mielina/fisiologia , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Oligodendroglia/fisiologia , RNA-Seq , Recuperação de Função Fisiológica , Substância Branca/citologia , Substância Branca/lesões , Substância Branca/metabolismo
12.
Radiology ; 295(1): 181-189, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32068505

RESUMO

Background Altered metabolism is a characteristic of cancer. Because of a shift in glucose metabolism from oxidative phosphorylation to lactate production for energy generation, malignant tumors are characterized by increased glycolysis followed by lactic acid fermentation, even in the presence of abundant oxygen (the Warburg effect). Purpose To quantitatively investigate dynamic oxygen 17 (17O) MRI in healthy participants and participants with untreated glioma to understand altered cerebral oxygen metabolism in glioma. Materials and Methods In this prospective study conducted from September 2016 to June 2018, individuals with newly diagnosed previously untreated glioma (World Health Organization grade II-IV) and healthy volunteers were included. Dynamic 17O MRI was performed with a 7.0-T whole-body system. 17O2 gas inhalation enabled dynamic measurement of the cerebral metabolic rate of oxygen (CMRO2) consumption. In healthy volunteers and participants with glioma, CMRO2 values in gray matter and white matter volumes were compared by using Wilcoxon signed rank tests. In participants with glioma, the tumor volume and tumor subcompartments were compared with normal-appearing gray matter and white matter by using Friedman test followed by Holm-Sidak post hoc tests. Results Ten participants (mean age, 42 years ± 18 [standard deviation]; nine men) with glioma and three healthy volunteers (mean age, 44 years ± 21; all men) were evaluated. CMRO2 was higher in normal-appearing gray matter compared with white matter in both participants with glioma (2.36 µmol/g/min ± 0.22 vs 0.75 µmol/g/min ± 0.10, respectively) and healthy volunteers (2.38 µmol/g/min ± 0.15 vs 0.63 µmol/g/min ± 0.05, respectively) (P < .001 and P = .03, respectively). In the tumor region, CMRO2 was reduced (high-grade tumor CMRO2, 0.23 µmol/g/min ± 0.07; low-grade tumor CMRO2, 0.39 µmol/g/min ± 0.16; overall CMRO2, 0.34 µmol/g/min ± 0.16) compared with normal-appearing gray matter (P < .001) and normal-appearing white matter (P < .001) in accordance with the Warburg theorem. Conclusion Dynamic oxygen 17 MRI method at 7.0 T as a direct metabolic imaging technique in glioma enabled quantitative visualization of the Warburg effect. A general reduction in oxidative glycolysis was observed in accordance with the Warburg theorem. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Rapalino in this issue.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Imagem por Ressonância Magnética/métodos , Consumo de Oxigênio , Isótopos de Oxigênio , Oxigênio/metabolismo , Adulto , Idoso , Feminino , Substância Cinzenta/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Substância Branca/metabolismo , Adulto Jovem
13.
Molecules ; 25(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979414

RESUMO

Myelin is the main component of the white matter of the central nervous system (CNS), allowing the proper electrical function of the neurons by ensheathing and insulating the axons. The extensive use of magnetic resonance imaging has highlighted the white matter alterations in Alzheimer's dementia (AD) and other neurodegenerative diseases, alterations which are early, extended, and regionally selective. Given that the white matter turnover is considerable in the adulthood, and that myelin repair is currently recognized as being the only true reparative capability of the mature CNS, oligodendrocyte precursor cells (OPCs), the cells that differentiate in oligodendrocyte, responsible for myelin formation and repair, are regarded as a potential target for neuroprotection. In this review, several aspects of the OPC biology are reviewed. The histology and functional role of OPCs in the neurovascular-neuroglial unit as described in preclinical and clinical studies on AD is discussed, such as the OPC vulnerability to hypoxia-ischemia, neuroinflammation, and amyloid deposition. Finally, the position of OPCs in drug discovery strategies for dementia is discussed.


Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Células-Tronco/metabolismo , Substância Branca/metabolismo , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Animais , Diferenciação Celular , Células Cultivadas , Descoberta de Drogas , Humanos , Bainha de Mielina/patologia , Neurônios/metabolismo , Neuroproteção/fisiologia , Células-Tronco/citologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
14.
Exp Neurol ; 327: 113207, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31962129

RESUMO

One of the consistent pathologies associated with both clinical and experimental traumatic brain injury is axonal injury, especially following mild traumatic brain injury (or concussive injury). Several lines of experimental evidence have demonstrated a role for NAD+ metabolism in axonal degeneration. One of the enzymes that metabolizes NAD+ in axons is Sarm1 (Sterile Alpha and TIR Motif Containing 1), and its activity is thought to play a key role in axonal degeneration. Using a Sarm1 knock-out mouse, we examined if loss of Sarm1 offers axonal injury protection and improves cognitive outcome after repeated mild closed head injury (rmCHI). Our results indicate that rmCHI caused white matter damage that can be observed in the corpus callosum, cingulum bundle, alveus of the hippocampus, and fimbria of the fornix of wild-type mice. These pathological changes were markedly reduced in injured Sarm1-/- mice. Interestingly, the activation of astrocytes and microglia was also attenuated in the areas with white matter damage, suggesting reduced inflammation. Associated with these improved pathological outcomes, injured Sarm1-/- mice performed significantly better in both motor and cognitive tasks. Taken together, our results suggest that strategies aimed at inhibiting Sarm1 and/or restoring NAD+ levels in injured axons may have therapeutic utility.


Assuntos
Proteínas do Domínio Armadillo/genética , Axônios/metabolismo , Encéfalo/metabolismo , Cognição/fisiologia , Proteínas do Citoesqueleto/genética , Traumatismos Cranianos Fechados/genética , Substância Branca/metabolismo , Animais , Proteínas do Domínio Armadillo/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Axônios/patologia , Encéfalo/patologia , Proteínas do Citoesqueleto/metabolismo , Traumatismos Cranianos Fechados/metabolismo , Traumatismos Cranianos Fechados/patologia , Masculino , Camundongos , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Atividade Motora/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Reconhecimento Psicológico/fisiologia , Substância Branca/patologia
15.
Oxid Med Cell Longev ; 2020: 8285065, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998445

RESUMO

White matter injury (WMI) is an important cause of high disability after intracerebral haemorrhage (ICH). It is widely accepted that reactive oxygen species (ROS) contributes to WMI, but there is still no evidence-based treatment. Here, mitoquinone (MitoQ), a newly developed selective mitochondrial ROS scavenger, was used to test its neuroprotective potential. The data showed that MitoQ attenuated motor function deficits and motor-evoked potential (MEP) latency prolongation. Further research found that MitoQ blunted the loss of oligodendrocytes and oligodendrocyte precursor cells, therefore reduced demyelination and axon swelling after ICH. In the in vitro experiments, MitoQ, but not the nonselective antioxidant, almost completely attenuated the iron-induced membrane potential decrease and cell death. Mechanistically, MitoQ blocked the ATP deletion and mitochondrial ROS overproduction. The present study demonstrates that the selective mitochondrial ROS scavenger MitoQ may improve the efficacy of antioxidant treatment of ICH by white matter injury alleviation.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Mitocôndrias/metabolismo , Compostos Organofosforados/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Ubiquinona/análogos & derivados , Substância Branca/metabolismo , Animais , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Camundongos , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/farmacologia , Substância Branca/patologia
16.
Neurol Res ; 42(2): 126-132, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31900093

RESUMO

Objective: This study aimed to establish whether there is a relationship between the Monocyte to High-Density Lipoprotein Cholesterol (HDL-C) ratio (MHR) white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI), and whether it can be used as a new marker for predicting disability and severity of attack.Materials and methods: This case-control study included 201 migraine patients (114 without WMHs and 87 with WMHs) and 150 healthy control subjects. Intensity of pain was determined by Visual Analogue Scale (VAS) and disability rates were determined by Migraine Disability Assessment Scale (MIDAS). Blood samples were taken for hematological and biochemical measurements. MHR ratios were calculated and compared statistically with the control group.Results: The mean MHR rate was established to be 15.04 ± 5.63 in migraine patients and 9.3 ± 2.95 in control group. This difference was statistically significant (p <0.001). The cut-off value of MHR was 12.9 in patients with migraine compared to the control group. There was a statically significant positive correlation between MHR ratio and VAS score and MIDAS stage (r: 0.424, r: 0.356 respectively), (p <0.001). Furthermore, MHR was higher in migraine patients with WMHs than those without WMH (p <0.001).Conclusion: In this study, especially in patients with episodic migraine with WMHs, MHR was found to be statistically significant as a marker for endothelial dysfunction. This finding contributes to the pathogenesis of migraine and may be used as an independent marker for predicting disability and WMHs. However, large-scale studies are needed to produce clearer results.


Assuntos
HDL-Colesterol/sangue , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/diagnóstico por imagem , Monócitos/metabolismo , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino
17.
Brain Struct Funct ; 225(1): 427-439, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31894407

RESUMO

Imaging biomarkers for immune activation may be valuable for early-stage detection, therapeutic testing, and research on neurodegenerative conditions. In the present study, we determined whether diffusion magnetic resonance imaging-derived free water signal is a sensitive marker for neuroinflammatory effects of interferon-gamma (Ifn-γ). Neonatal wild-type mice were injected in the cerebral ventricles with recombinant adeno-associated viruses expressing the inflammatory cytokine Ifn-γ. Groups of mice expressing Ifn-γ and age-matched controls were imaged at 1, 5 and 8 months. Mice deficient in Ifngr1-/- and Stat1-/- were scanned at 5 months as controls for the signaling cascades activated by Ifn-γ. The results indicate that Ifn-γ affected fractional anisotropy (FA), mean diffusivity (MD), and free water (FW) in white matter structures, midline cortical areas, and medial thalamic areas. In these structures, FA and MD decreased progressively from 1 to 8 months of age, while FW increased significantly. The observed reductions in FA and MD and increased FW with elevated brain Ifn-γ was not observed in Ifngr1-/- or Stat1-/- mice. These results suggest that the observed microstructure changes involve the Ifn-gr1 and Stat1 signaling. Interestingly, increases in FW were observed in midbrain of Ifngr1-/- mice, which suggests alternative Ifn-γ signaling in midbrain. Although initial evidence is offered in relation to the sensitivity of the FW signal to neurodegenerative and/or inflammatory patterns specific to Ifn-γ, further research is needed to determine applicability and specificity across animal models of neuroinflammatory and degenerative disorders.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Encefalite/diagnóstico por imagem , Encefalite/patologia , Interferon gama/metabolismo , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Animais , Anisotropia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encefalite/induzido quimicamente , Feminino , Interferon gama/administração & dosagem , Interferon gama/genética , Masculino , Camundongos Knockout , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Água/análise , Substância Branca/efeitos dos fármacos , Substância Branca/metabolismo
18.
Neuroimage ; 204: 116202, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557546

RESUMO

Lactate is now recognized as an important intermediate in brain metabolism, but its role is still under investigation. In this work we mapped the distribution of lactate and bicarbonate produced from intravenously injected 13C-pyruvate over the whole brain using a new imaging method, hyperpolarized 13C MRI (N = 14, ages 23 to 77). Segmenting the 13C-lactate images into brain atlas regions revealed a pattern of lactate that was preserved across individuals. Higher lactate signal was observed in cortical grey matter compared to white matter and was highest in the precuneus, cuneus and lingual gyrus. Bicarbonate signal, indicating flux of [1-13C]pyruvate into the TCA cycle, also displayed consistent spatial distribution. One-way ANOVA to test for significant differences in lactate among atlas regions gave F = 87.6 and p < 10-6. This report of a "lactate topography" in the human brain and its consistent pattern is evidence of region-specific lactate biology that is preserved across individuals.


Assuntos
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Córtex Cerebral/metabolismo , Substância Cinzenta/metabolismo , Ácido Láctico/metabolismo , Substância Branca/metabolismo , Adulto , Idoso , Atlas como Assunto , Bicarbonatos/metabolismo , Córtex Cerebral/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Pirúvico/farmacocinética , Substância Branca/diagnóstico por imagem , Adulto Jovem
19.
World Neurosurg ; 137: e9-e17, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31518742

RESUMO

BACKGROUND: With little information available on axonal and myelin damage surrounding the contusion, the study of spinal cord injury (SCI) so far has focused on neuronal death. In this study, we investigated the role of iron overload in long-term oligodendroglia death and progressive white matter damage to rats after SCI using the iron chelator, deferoxamine (DFX). METHODS: Female Sprague-Dawley rats received either a contusion at T10 or sham-surgery. The rats were treated with DFX or vehicle. All rats were evaluated in behavioral assessments and then euthanized at different time points. Spinal cords were analyzed by diaminobenzidine-enhanced Perls' staining, non-heme iron measurements, Western blotting, immunohistochemistry, and transmission electron microscopy. RESULTS: Iron accumulation after SCI resulted in the upregulation of transferrin receptor and divalent metal transporter 1, which exacerbated the intracellular iron overload. DFX treatment reduced iron overload-induced delayed oligodendrocyte death (e.g., 21 days: 47.12 ± 10.5 vs. 20.02 ± 9.4 x 103/mm2 in the vehicle-treated group, n = 4, P < 0.05). After SCI, the markers of axonal damage and demyelination were increased in white matter in the vehicle-treated group compared with the DFX-treated group (P < 0.05). CONCLUSIONS: Iron overload plays an important role in progressive white matter damage after SCI. DFX may be an effective treatment for white matter damage after SCI.


Assuntos
Desferroxamina/uso terapêutico , Oligodendroglia/efeitos dos fármacos , Sideróforos/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Substância Branca/efeitos dos fármacos , Animais , Desferroxamina/farmacologia , Modelos Animais de Doenças , Feminino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos , Ratos Sprague-Dawley , Receptores da Transferrina/metabolismo , Sideróforos/farmacologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Substância Branca/metabolismo , Substância Branca/patologia
20.
Glia ; 68(2): 393-406, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31633850

RESUMO

Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell-dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.


Assuntos
Substância Cinzenta/metabolismo , Células-Tronco Neurais/citologia , Oligodendroglia/metabolismo , Substância Branca/metabolismo , Células-Tronco Adultas/metabolismo , Animais , Astrócitos/metabolismo , Diferenciação Celular/fisiologia , Linhagem da Célula/fisiologia , Camundongos Endogâmicos C57BL , Neuroglia/metabolismo , Ratos
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