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1.
Nat Commun ; 13(1): 4932, 2022 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-35995800

RESUMO

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.


Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Epigenoma , Lobo Frontal/patologia , Humanos , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/genética , Metilação , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
2.
J Neuropathol Exp Neurol ; 81(10): 773-780, 2022 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-35903039

RESUMO

Millions of individuals are exposed to repetitive head impacts (RHI) each year through contact sports, military blast, and interpersonal violence. RHI is the major risk factor for developing chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy. Recent consensus criteria defined the pathognomonic lesion in CTE as perivascular, hyperphosphorylated tau (p-tau) in neuronal aggregates. Astroglial p-tau is an inconsistent supporting feature and not in itself diagnostic of CTE. This study quantitated the spatial and cellular distribution of p-tau pathology in postmortem dorsolateral frontal cortex of 150 individuals with CTE, from ages 21 to 80 years old, without comorbid pathology. p-Tau-immunoreactive cells were quantitated in the gray matter sulcus, crest, subpial region, and within pathognomonic CTE lesions. Significantly more neuronal p-tau than astrocytic p-tau was found across all cortical regions (p < 0.0001). Sulcal astrocytic p-tau was primarily (75%, p < 0.0001) localized to subpial regions as thorn-shaped astrocytes, a form of age-related tau astrogliopathy. Neuronal p-tau was significantly associated with age, years of RHI exposure, and CTE severity; astrocytic p-tau pathology was only significantly associated with age. These findings strongly support neuronal degeneration as a driving feature of CTE and will help inform future research and the development of fluid biomarkers for the detection of neuronal degeneration in CTE.


Assuntos
Encefalopatia Traumática Crônica , Tauopatias , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrócitos/patologia , Encefalopatia Traumática Crônica/patologia , Lobo Frontal/patologia , Humanos , Pessoa de Meia-Idade , Neurônios/patologia , Tauopatias/patologia , Adulto Jovem
3.
Neurol India ; 70(3): 1226-1229, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35864673

RESUMO

Although the importance of bilateral cortical innervation in the control of swallowing is well known, neurogenic dysphagia caused by unilateral hemispheric ischemic lesion has been also reported. Our patient is a 41-year-old male who developed difficulty swallowing liquids, oral apraxia, and motor dysphasia, followed by right-hand ataxia. Brain magnetic resonance imaging (MRI) showed subcortical tumefactive conglomerate of cystic lesions in the left frontal, precentral region, which were sharp edged, with perilesional edema, concordant with lesions in Marburg's variant of multiple sclerosis. Steroid treatment and plasma exchange therapy led to disappearance of neurological symptoms. Treatment with interferon ß-1a 40 mcg sc was initiated. During a 3-year follow-up, clinical/brain MRI scan showed no new neurological manifestations, a significant regression of lesion size, and no new brain lesions. To the best of our knowledge, this is a first case of dysphagia caused by unilateral hemispheric lesion in a multiple sclerosis patient.


Assuntos
Transtornos de Deglutição , Esclerose Múltipla , Adulto , Encéfalo/patologia , Deglutição , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Seguimentos , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/diagnóstico , Fala
4.
Acta Neuropathol Commun ; 10(1): 86, 2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35676735

RESUMO

Although Down syndrome (DS), the most common developmental genetic cause of intellectual disability, displays proliferation and migration deficits in the prenatal frontal cortex (FC), a knowledge gap exists on the effects of trisomy 21 upon postnatal cortical development. Here, we examined cortical neurogenesis and differentiation in the FC supragranular (SG, II/III) and infragranular (IG, V/VI) layers applying antibodies to doublecortin (DCX), non-phosphorylated heavy-molecular neurofilament protein (NHF, SMI-32), calbindin D-28K (Calb), calretinin (Calr), and parvalbumin (Parv), as well as ß-amyloid (APP/Aß and Aß1-42) and phospho-tau (CP13 and PHF-1) in autopsy tissue from age-matched DS and neurotypical (NTD) subjects ranging from 28-weeks (wk)-gestation to 3 years of age. Thionin, which stains Nissl substance, revealed disorganized cortical cellular lamination including a delayed appearance of pyramidal cells until 44 wk of age in DS compared to 28 wk in NTD. SG and IG DCX-immunoreactive (-ir) cells were only visualized in the youngest cases until 83 wk in NTD and 57 wk DS. Strong SMI-32 immunoreactivity was observed in layers III and V pyramidal cells in the oldest NTD and DS cases with few appearing as early as 28 wk of age in layer V in NTD. Small Calb-ir interneurons were seen in younger NTD and DS cases compared to Calb-ir pyramidal cells in older subjects. Overall, a greater number of Calb-ir cells were detected in NTD, however, the number of Calr-ir cells were comparable between groups. Diffuse APP/Aß immunoreactivity was found at all ages in both groups. Few young cases from both groups presented non-neuronal granular CP13 immunoreactivity in layer I. Stronger correlations between brain weight, age, thionin, DCX, and SMI-32 counts were found in NTD. These findings suggest that trisomy 21 affects postnatal FC lamination, neuronal migration/neurogenesis and differentiation of projection neurons and interneurons that likely contribute to cognitive impairment in DS.


Assuntos
Síndrome de Down , Lobo Frontal , Neurogênese , Calbindinas/metabolismo , Pré-Escolar , Síndrome de Down/patologia , Lobo Frontal/citologia , Lobo Frontal/patologia , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Proteínas de Neurofilamentos/metabolismo , Parvalbuminas/metabolismo , Tioninas/metabolismo
5.
Neuroimage Clin ; 35: 103079, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35700600

RESUMO

Disinhibition is a core symptom of many neurodegenerative diseases, particularly frontotemporal dementia, and is a major cause of stress for caregivers. While a distinction between behavioural and cognitive disinhibition is common, an operational definition of behavioural disinhibition is still missing. Furthermore, conventional assessment of behavioural disinhibition, based on questionnaires completed by the caregivers, often lacks ecological validity. Therefore, their neuroanatomical correlates are non-univocal. In the present work, we used an original behavioural approach in a semi-ecological situation to assess two specific dimensions of behavioural disinhibition: compulsivity and social disinhibition. First, we investigated disinhibition profile in patients compared to controls. Then, to validate our approach, compulsivity and social disinhibition scores were correlated with classic cognitive tests measuring disinhibition (Hayling Test) and social cognition (mini-Social cognition & Emotional Assessment). Finally, we disentangled the anatomical networks underlying these two subtypes of behavioural disinhibition, taking in account the grey (voxel-based morphometry) and white matter (diffusion tensor imaging tractography). We included 17 behavioural variant frontotemporal dementia patients and 18 healthy controls. We identified patients as more compulsive and socially disinhibited than controls. We found that behavioural metrics in the semi-ecological task were related to cognitive performance: compulsivity correlated with the Hayling test and both compulsivity and social disinhibition were associated with the emotion recognition test. Based on voxel-based morphometry and tractography, compulsivity correlated with atrophy in the bilateral orbitofrontal cortex, the right temporal region and subcortical structures, as well as with alterations of the bilateral cingulum and uncinate fasciculus, the right inferior longitudinal fasciculus and the right arcuate fasciculus. Thus, the network of regions related to compulsivity matched the "semantic appraisal" network. Social disinhibition was associated with bilateral frontal atrophy and impairments in the forceps minor, the bilateral cingulum and the left uncinate fasciculus, regions corresponding to the frontal component of the "salience" network. Summarizing, this study validates our semi-ecological approach, through the identification of two subtypes of behavioural disinhibition, and highlights different neural networks underlying compulsivity and social disinhibition. Taken together, these findings are promising for clinical practice by providing a better characterisation of inhibition disorders, promoting their detection and consequently a more adapted management of patients.


Assuntos
Demência Frontotemporal , Atrofia/patologia , Imagem de Tensor de Difusão , Lobo Frontal/patologia , Demência Frontotemporal/patologia , Humanos , Testes Neuropsicológicos
6.
J Psychiatry Neurosci ; 47(3): E176-E185, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35508328

RESUMO

BACKGROUND: Abnormalities of cortical morphology have been consistently reported in major depressive disorder (MDD), with widespread focal alterations in cortical thickness, surface area and gyrification. However, it is unclear whether these distributed focal changes disrupt the system-level architecture (topology) of brain morphology in MDD. If present, such a topological disruption might explain the mechanisms that underlie altered cortical morphology in MDD. METHODS: Seventy-six patients with first-episode MDD (33 male, 43 female) and 66 healthy controls (32 male, 34 female) underwent structural MRI scans. We calculated cortical indices, including cortical thickness, surface area and local gyrification index, using FreeSurfer. We constructed morphological covariance networks using the 3 cortical indices separately, and we analyzed the topological properties of these group-level morphological covariance networks using graph theoretical approaches. RESULTS: Topological differences between patients with first-episode MDD and healthy controls were restricted to the thickness-based network. We found a significant decrease in global efficiency but an increase in local efficiency of the left superior frontal gyrus and the right paracentral lobule in patients with first-episode MDD. When we simulated targeted lesions affecting the most highly connected nodes, the thickness-based networks in patients with first-episode MDD disintegrated more rapidly than those in healthy controls. LIMITATIONS: Our sample of patients with first-episode MDD has limited generalizability to patients with chronic and recurrent MDD. CONCLUSION: A systems-level disruption in cortical thickness (but not surface area or gyrification) occurs in patients with first-episode MDD.


Assuntos
Transtorno Depressivo Maior , Encéfalo/patologia , Córtex Cerebral/patologia , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/patologia , Feminino , Lobo Frontal/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Córtex Pré-Frontal/patologia
7.
J Alzheimers Dis ; 88(1): 141-154, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35570485

RESUMO

BACKGROUND: Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer's disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-ß (Aß) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence Aß deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice. OBJECTIVE: In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 (PSD-95) palmitoylation, Aß pathologies, and expression of synaptic-associated proteins in APP/PS1 mice. METHODS: Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6 mL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections. RESULTS: CEGI treatment in APP/PS1 mice significantly reduced Aß deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between Aß expression and PSD-95 palmitoylation in APP/PS1 mice. CONCLUSION: Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/patologia , Bovinos , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Lobo Frontal/patologia , Glicosídeos , Lipoilação , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Presenilina-1/metabolismo
8.
Neuromuscul Disord ; 32(6): 477-485, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35396091

RESUMO

This study aimed to clarify the characteristics and progressive changes of brain image abnormalities in Duchenne muscular dystrophy (DMD). Brain images of 39 adult patients (median age, 24 years) were retrospectively reviewed, along with intellectual and/or neurodevelopmental test results. On magnetic resonance imaging (n = 13), atrophy of the frontal lobe, pars opercularis (without other frontal atrophy), and cerebellum was observed in 6, 1, and 1 patients, respectively. On computed tomography (n = 32), atrophy of the frontal lobe, pars opercularis, temporal lobe, and occipital lobe was observed in 20, 1, 1, and 1 patients, respectively. Re-imaging of 12 patients revealed progression of cerebral atrophy in 6. All 18 patients who underwent single photon emission computed tomography had reduced total and/or focal blood flow. Reduced total cerebral blood flow was observed significantly more frequently in patients with deleterious Dp140 mutations compared to those without. Re-examination 4 years later revealed worsening of reduced blood flow in the frontotemporal lobe in 1 patient. Abnormalities were detected by at least one imaging modality in 32 of 39 patients. No significant relationship was observed between imaging abnormalities and developmental disorders or intelligence quotient. In conclusion, DMD patients frequently exhibit frontal lobe-dominant cerebral blood flow reduction and atrophy, and may be at risk of progressive cerebral atrophy and reduced cerebral blood flow. MRI, CT, and/or brain single photon emission CT are useful for detecting brain abnormalities in adult DMD patients.


Assuntos
Distrofia Muscular de Duchenne , Adulto , Atrofia , Encéfalo/patologia , Circulação Cerebrovascular/fisiologia , Lobo Frontal/patologia , Humanos , Imageamento por Ressonância Magnética , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/diagnóstico por imagem , Distrofia Muscular de Duchenne/genética , Estudos Retrospectivos , Adulto Jovem
10.
Epilepsy Res ; 181: 106892, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35220206

RESUMO

Frontal lobe epilepsy (FLE) is the second most frequent type of epilepsy and the surgical outcome depends on the etiology. For instance, patients with posttraumatic FLE (PTE) have a worse surgical outcome compared to patients with FLE related to a tumoral lesion (TL). The present study focuses to determine if the FLE etiology is associated with the P-glycoprotein (P-gp) expression, a condition associated with drug resistance. P-gp expression and cellular localization were determined by Western Blot and immunohistochemical experiments in cortical brain samples obtained from patients with PTE (n = 5), TL (n = 5), and autopsies (n = 5). The neuronal count was estimated by Nissl and stereology procedure. Results showed that the autopsies tissue showed a neuronal count of 3514 ± 304.2 neurons per mm3. The P-gp expression ratio was 0.33 ± 0.02. Its expression was found in endothelial cells. Negligible P-gp expression was detected in neurons and astrocytes. Compared to the autopsies group, the TL group showed no changes in the neuronal count but, there was a decreased P-gp expression ratio (46%, p < 0.05). P-gp was located mainly in neurons, slight in astroglial, and endothelial cells. The PTE group showed a similar P-gp expression ratio compared to the autopsies group. P-gp was expressed in neurons, astrocytes, and endothelial cells in these samples. However, experiments revealed a high P-gp expression in a lower neuronal count (38%, p < 0.05 vs autopsy group). The present study reveals that patients with PTE present neuronal P-gp overexpression. This finding could underlie their worst surgical outcome.


Assuntos
Epilepsia do Lobo Frontal , Neocórtex , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epilepsia do Lobo Frontal/cirurgia , Lobo Frontal/patologia , Humanos , Neocórtex/metabolismo , Neurônios/metabolismo
11.
Sci Rep ; 12(1): 688, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35027599

RESUMO

Even after appropriate treatment, a proportion of Lyme disease patients suffer from a constellation of symptoms, collectively called Post-Treatment Lyme Disease Syndrome (PTLDS). Brain PET scan of patients with PTLDS have demonstrated likely glial activation indicating persistent neuroinflammatory processes. It is possible that unresolved bacterial remnants can continue to cause neuroinflammation. In previous studies, we have shown that non-viable Borrelia burgdorferi can induce neuroinflammation and apoptosis in an oligodendrocyte cell line. In this follow-up study, we analyze the effect of sonicated remnants of B. burgdorferi on primary rhesus frontal cortex (FC) and dorsal root ganglion (DRG) explants. Five FC and three DRG tissue fragments from rhesus macaques were exposed to sonicated B. burgdorferi and analyzed for 26 inflammatory mediators. Live bacteria and medium alone served as positive and negative control, respectively. Tissues were also analyzed for cell types mediating inflammation and overall apoptotic changes. Non-viable B. burgdorferi induced significant levels of several inflammatory mediators in both FC and DRG, similar to live bacteria. However, the levels induced by non-viable B. burgdorferi was often (several fold) higher than those induced by live ones, especially for IL-6, CXCL8 and CCL2. This effect was also more profound in the FC than in the DRG. Although the levels often differed, both live and dead fragments induced the same mediators, with significant overlap between FC and DRG. In the FC, immunohistochemical staining for several inflammatory mediators showed the presence of multiple mediators in astrocytes, followed by microglia and oligodendrocytes, in response to bacterial remnants. Staining was also seen in endothelial cells. In the DRG, chemokine/cytokine staining was predominantly seen in S100 positive (glial) cells. B. burgdorferi remnants also induced significant levels of apoptosis in both the FC and DRG. Apoptosis was confined to S100 + cells in the DRG while distinct neuronal apoptosis was also detected in most FC tissues in response to sonicated bacteria. Non-viable B. burgdorferi can continue to be neuropathogenic to both CNS and PNS tissues with effects likely more profound in the former. Persistence of remnant-induced neuroinflammatory processes can lead to long term health consequences.


Assuntos
Borrelia burgdorferi/patogenicidade , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/microbiologia , Animais , Apoptose , Quimiocina CCL2/metabolismo , Feminino , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Doença de Lyme/metabolismo , Doença de Lyme/patologia , Macaca mulatta , Masculino
12.
World Neurosurg ; 158: 156-157, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34798340

RESUMO

Medial orbitofrontal area arteriovenous malformations (AVMs) are located in the noneloquent cortex and typically drain superficially into Sylvian veins or the superior sagittal sinus, making them favorable for surgical treatment. However, while typically supplied by pial/cortical branches of the anterior cerebral artery (ACA), they can incorporate the recurrent artery of Heubner and other ACA perforators on their way to the anterior perforated substance located just posterior. We present a case of a 30-year-old female admitted with sudden collapse and intraventricular hemorrhage from a ruptured medial orbitofrontal area AVM. She was admitted to the intensive care unit and an external ventricular drain was placed to treat acute hydrocephalus. Catheter angiography demonstrated an AVM located just anteromedial to the termination of the internal carotid artery with a compact nidus and an associated intranidal flow aneurysm. Arterial supply originated from the orbitofrontal artery off the ACA, with medial lenticulostriates seen coursing past the nidus. Additional supply from the recurrent artery of Heubner could not be excluded. However, a hypodensity in the inferior frontal lobe seen on the presentation computed tomography scan was suggestive of a prior orbitofrontal infarct and thus cortical, rather than perforator, supply. In our practice, treatment of ruptured AVMs is dictated by the patients' clinical recovery and associated high-risk features (e.g., flow aneurysms). In this case, despite the presence of a flow aneurysm, treatment was delayed 18 days due to slow neurologic recovery and family preference. The patient remained in the intensive care unit under close neurologic observation. She was extubated on day 10, and the external ventricular drain was removed on day 12 after confirming resolution of intraventricular hemorrhage. Preoperatively the patient recovered to a Glasgow Coma Scale score of 15. Risks of treatment were discussed, and informed consent was obtained. The patient was treated using a standard pterional craniotomy. We describe the anatomic location of the lesion in the medial orbitofrontal area, the relationship to the olfactory tract and olfactory stria. We demonstrate olfactory tract dissection from its arachnoid cistern between the orbitofrontal lobe and gyrus rectus in order to access the lesion. Indocyanine green angiography is used to help surgical dissection and for quality control at the end of the procedure. We do not perform intraoperative angiography routinely; however, it can be a useful adjunct in deep and/or eloquent locations, which are difficult to image using videoangiography. Nevertheless, in the absence of intraoperative angiography close dissection directly over the nidus on the eloquent side ensures preservation of functional brain. We describe the microsurgical techniques of surgical treatment of AVMs, in particular the "cone" dissection technique of the AVM in order to allow identification of all feeding vessels and tracing "en passant" vessels from proximal to distal, as well as the use of intraoperative videoangiography to elucidate the nidus morphology and immediate postoperative quality control (Video 1, available at https://drive.google.com/file/d/1IXuLg84MwyMek1_Z1f1n7qssLThimvdx/view?usp=sharing).


Assuntos
Malformações Arteriovenosas Intracranianas , Adulto , Artéria Cerebral Anterior/diagnóstico por imagem , Artéria Cerebral Anterior/patologia , Artéria Cerebral Anterior/cirurgia , Angiografia Cerebral/métodos , Hemorragia Cerebral/complicações , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Lobo Frontal/cirurgia , Humanos , Malformações Arteriovenosas Intracranianas/complicações , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/cirurgia , Bulbo Olfatório/patologia
13.
Neuroradiol J ; 35(2): 226-232, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34423669

RESUMO

PURPOSE: To create a voxel-based map of the inter-arterial watershed derived from children who have sustained a hypoxic-ischemic injury involving this region at term. MATERIALS AND METHODS: Patients 0-18 years of age diagnosed with a hypoxic-ischemic injury of the watershed on magnetic resonance imaging (MRI) were included. Two pediatric neuroradiologists segmented the lesions as visualized on the T2-weighted sequence. All lesion maps were normalized to a brain template and overlapped to create a frequency map in order to highlight the frequency of involvement of portions of the cortical watershed. RESULTS: A total of 47 patients (35 boys) were included in the final sample. Their mean age was 7.6 ± 3.6 years. The cortical watershed was successfully mapped. Three watershed regions were defined: the anterior, peri-Sylvian, and posterior watershed zones. The anterior and peri-Sylvian watershed zones are connected through the involvement of the middle frontal gyrus. The peri-Sylvian and the posterior watershed zones are connected through the involvement of the inferior parietal lobule, the posterior aspect of the superior temporal gyrus, and the angular gyrus with the occipital lobe. The temporal lobe and orbital part of the frontal lobe are largely spared in all patients. CONCLUSION: A voxel-based lesion map of children with watershed hypoxic ischemic injury at term was created and three inter-arterial watershed zones defined: anterior, peri-Sylvian, and posterior watersheds.


Assuntos
Mapeamento Encefálico , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Criança , Pré-Escolar , Lobo Frontal/patologia , Humanos , Masculino , Lobo Parietal
14.
J Neurosurg ; 136(1): 45-55, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34243150

RESUMO

OBJECTIVE: The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity. Standards are lacking for surgical decision-making, and previous studies indicate treatment variations. These shortcomings reflect the need to evaluate larger populations from different care teams. In this study, the authors used probability maps to quantify and compare surgical decision-making throughout the brain by 12 neurosurgical teams for patients with glioblastoma. METHODS: The study included all adult patients who underwent first-time glioblastoma surgery in 2012-2013 and were treated by 1 of the 12 participating neurosurgical teams. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to identify and compare patient treatment variations. Brain regions with different biopsy and resection results between teams were identified and analyzed for patient functional outcome and survival. RESULTS: The study cohort consisted of 1087 patients, of whom 363 underwent a biopsy and 724 a resection. Biopsy and resection decisions were generally comparable between teams, providing benchmarks for probability maps of resections and biopsies for glioblastoma. Differences in biopsy rates were identified for the right superior frontal gyrus and indicated variation in biopsy decisions. Differences in resection rates were identified for the left superior parietal lobule, indicating variations in resection decisions. CONCLUSIONS: Probability maps of glioblastoma surgery enabled capture of clinical practice decisions and indicated that teams generally agreed on which region to biopsy or to resect. However, treatment variations reflecting clinical dilemmas were observed and pinpointed by using the probability maps, which could therefore be useful for quality-of-care discussions between surgical teams for patients with glioblastoma.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Neurocirurgiões , Procedimentos Neurocirúrgicos/métodos , Adulto , Idoso , Biópsia , Mapeamento Encefálico , Tomada de Decisão Clínica , Estudos de Coortes , Feminino , Lobo Frontal/patologia , Lobo Frontal/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Parietal/patologia , Lobo Parietal/cirurgia , Probabilidade , Análise de Sobrevida , Resultado do Tratamento
15.
Nature ; 601(7891): 139-143, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34880495

RESUMO

The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD)1,2. It is also common in other diseases, including Alzheimer's and Parkinson's. No disease-modifying therapies exist for these conditions and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. Here we used cryo-electron microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual who had ALS with FTLD and from the frontal cortex of a second individual with the same diagnosis. An identical amyloid-like filament structure comprising a single protofilament was found in both brain regions and individuals. The ordered filament core spans residues 282-360 in the TDP-43 low-complexity domain and adopts a previously undescribed double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro3,4. An abundance of glycine and neutral polar residues facilitates numerous turns and restricts ß-strand length, which results in an absence of ß-sheet stacking that is associated with cross-ß amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces that face external densities and suggest possible ligand-binding sites. This work enhances our understanding of the molecular pathogenesis of ALS and FTLD and informs the development of diagnostic and therapeutic agents that target aggregated TDP-43.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Microscopia Crioeletrônica , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/ultraestrutura , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Sequência de Aminoácidos , Peptídeos beta-Amiloides/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Lobo Frontal/ultraestrutura , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/metabolismo , Córtex Motor/patologia , Córtex Motor/ultraestrutura , Mutação
16.
Am J Dermatopathol ; 44(1): 1-6, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34889810

RESUMO

ABSTRACT: Neuronal intranuclear inclusion disease is a rare, progressive neurodegenerative disease whose hallmark histopathologic finding is the presence of ubiquitin-positive hyaline intranuclear inclusions in neuronal and non-neuronal cells. We present a case of neuronal intranuclear inclusion disease in a 61-year-old Asian man with a history of repeated episodes of altered mental status, long-standing bladder dysfunction, and cerebrovascular accidents. The patient had characteristic magnetic imaging findings of high signal along the cortico-medullary junction on diffusion-weighted sequences and symmetric T2 hyperintensity in the paravermal area of the cerebellum. Skin biopsies showed characteristic histopathologic findings of ubiquitin-positive intranuclear inclusions that ultrastructurally composed of filamentous material without limiting membrane within eccrine epithelium and dermal fibroblasts. Our case highlights the utility of readily accessible skin biopsy in the diagnosis of this rare neurodegenerative disease.


Assuntos
Doenças Neurodegenerativas/patologia , Pele/patologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Humanos , Corpos de Inclusão Intranuclear/patologia , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico
17.
Int J Mol Sci ; 22(24)2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34948340

RESUMO

Two classical surgical approaches for intraluminal filament middle cerebral artery occlusion (MCAO), the Longa et al. (LM) and Koizumi et al. methods (KM), are used as alternatives in preclinical studies to induce stroke in rodents. Comparisons of these MCAO models in mice showed critical differences between them along with similarities (Smith et al. 2015; Morris et al. 2016). In this study, a direct comparison of MCAO-KM and MCAO-LM in rats was performed. Three days after MCAO, infarct volume, mortality rate, neurological deficit, and weight loss were similar in these models. MCAO-LM rats showed an increase in ACTH levels, while MCAO-KM rats demonstrated elevated corticosterone and interleukin-1ß in blood serum. Corticosterone accumulation was detected in the frontal cortex (FC) and the hippocampus of the MCAO-KM group. IL1ß beta increased in the ipsilateral hippocampus in the MCAO-KM group and decreased in the contralateral FC of MCAO-LM rats. Differences revealed between MCAO-KM and MCAO-LM suggest that corticosterone and interleukin-1ß release as well as hippocampal accumulation is more expressed in MCAO-KM rats, predisposing them to corticosterone-dependent distant neuroinflammatory hippocampal damage. The differences between two models, particularly, malfunction of the hypothalamic-pituitary-adrenal axis, should be considered in the interpretation, comparison, and translation of pre-clinical experimental results.


Assuntos
Corticosterona/metabolismo , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Infarto da Artéria Cerebral Média/complicações , Inflamação , Acidente Vascular Cerebral/etiologia , Animais , Lobo Frontal/patologia , Hipocampo/patologia , Masculino , Ratos , Ratos Wistar , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
18.
Eur J Histochem ; 65(s1)2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814650

RESUMO

Evidence suggests that transient receptor potential (TRP) ion channels dysfunction significantly contributes to the physiopathology of metabolic and neurological disorders. Dysregulation in functions and expression in genes encoding the TRP channels cause several inherited diseases in humans (the so-called 'TRP channelopathies'), which affect the cardiovascular, renal, skeletal, and nervous systems. This study aimed to evaluate the expression of ion channels in the forebrain of rats with diet-induced obesity (DIO). DIO rats were studied after 17 weeks under a hypercaloric diet (high-fat diet, HFD) and were compared to the control rats with a standard diet (CHOW). To determine the systemic effects of HFD exposure, we examined food intake, fat mass content, fasting glycemia, insulin levels, cholesterol, and triglycerides. qRT-PCR, Western blot, and immunochemistry analysis were performed in the frontal cortex (FC) and hippocampus (HIP). After 17 weeks of HFD, DIO rats increased their body weight significantly compared to the CHOW rats. In DIO rats, TRPC1 and TRPC6 were upregulated in the HIP, while they were downregulated in the FC. In the case of TRPM2 expression, instead was increased both in the HIP and in the FC. These could be related to the increase of proteins and nucleic acid oxidation. TRPV1 and TRPV2 gene expression showed no differences both in the FC and HIP. In general, qRT-PCR analyses were confirmed by Western blot analysis. Immunohistochemical procedures highlighted the expression of the channels in the cell body of neurons and axons, particularly for the TRPC1 and TRPC6. The alterations of TRP channel expression could be related to the activation of glial cells or the neurodegenerative process presented in the brain of the DIO rat highlighted with post synaptic protein (PSD 95) alterations. The availability of suitable animal models may be useful for studying possible pharmacological treatments to counter obesity-induced brain injury. The identified changes in DIO rats may represent the first insight to characterize the neuronal alterations occurring in obesity. Further investigations are necessary to characterize the role of TRP channels in the regulation of synaptic plasticity and obesity-related cognitive decline.


Assuntos
Lobo Frontal/metabolismo , Hipocampo/metabolismo , Obesidade/fisiopatologia , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Axônios/metabolismo , Dieta Hiperlipídica , Regulação para Baixo/fisiologia , Lobo Frontal/patologia , Expressão Gênica/fisiologia , Hipocampo/patologia , Masculino , Obesidade/patologia , Estresse Oxidativo/fisiologia , Ratos Wistar , Regulação para Cima/fisiologia
19.
Proc Natl Acad Sci U S A ; 118(45)2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34725161

RESUMO

Although amyloid plaques composed of fibrillar amyloid-ß (Aß) assemblies are a diagnostic hallmark of Alzheimer's disease (AD), quantities of amyloid similar to those in AD patients are observed in brain tissue of some nondemented elderly individuals. The relationship between amyloid deposition and neurodegeneration in AD has, therefore, been unclear. Here, we use solid-state NMR to investigate whether molecular structures of Aß fibrils from brain tissue of nondemented elderly individuals with high amyloid loads differ from structures of Aß fibrils from AD tissue. Two-dimensional solid-state NMR spectra of isotopically labeled Aß fibrils, prepared by seeded growth from frontal lobe tissue extracts, are similar in the two cases but with statistically significant differences in intensity distributions of cross-peak signals. Differences in solid-state NMR data are greater for 42-residue amyloid-ß (Aß42) fibrils than for 40-residue amyloid-ß (Aß40) fibrils. These data suggest that similar sets of fibril polymorphs develop in nondemented elderly individuals and AD patients but with different relative populations on average.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Lobo Frontal/patologia , Placa Amiloide/patologia , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Placa Amiloide/química
20.
Int J Mol Sci ; 22(22)2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34830402

RESUMO

Lipids are closely associated with brain structure and function. However, the potential changes in the lipidome induced by aging remain to be elucidated. In this study, we used chromatographic techniques and a mass spectrometry-based approach to evaluate age-associated changes in the lipidome of the frontal cortex and cerebellum obtained from adult male Wistar rats (8 months), aged male Wistar rats (26 months), and aged male Wistar rats submitted to a methionine restriction diet (MetR)-as an anti-aging intervention-for 8 weeks. The outcomes revealed that only small changes (about 10%) were observed in the lipidome profile in the cerebellum and frontal cortex during aging, and these changes differed, in some cases, between regions. Furthermore, a MetR diet partially reversed the effects of the aging process. Remarkably, the most affected lipid classes were ether-triacylglycerols, diacylglycerols, phosphatidylethanolamine N-methylated, plasmalogens, ceramides, and cholesterol esters. When the fatty acid profile was analyzed, we observed that the frontal cortex is highly preserved during aging and maintained under MetR, whereas in the cerebellum minor changes (increased monounsaturated and decreased polyunsaturated contents) were observed and not reversed by MetR. We conclude that the rat cerebellum and frontal cortex have efficient mechanisms to preserve the lipid profile of their cell membranes throughout their adult lifespan in order to maintain brain structure and function. A part of the small changes that take place during aging can be reversed with a MetR diet applied in old age.


Assuntos
Envelhecimento/genética , Lobo Frontal/metabolismo , Lipídeos/genética , Metionina/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Cromatografia , Lobo Frontal/patologia , Humanos , Lipidômica/normas , Espectrometria de Massas , Estresse Oxidativo/genética , Ratos , Espécies Reativas de Oxigênio/metabolismo
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