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SUMMARY: Imagine if we could simultaneously predict spatial protein expression in tissues from their routine Hematoxylin and Eosin (H&E) stained images, and create tissue images given protein expression profiles thus enabling virtual simulations of how protein expression alterations impact histology in complex diseases like cancer. Such an approach could lead to more informed diagnostic and therapeutic decisions for precision medicine at lower costs and shorter turnaround times, more detailed insights into underlying disease pathology as well as improvement in predictive and generative performance. In this study, we investigate the intricate correlation between protein expressions obtained from Hyperion mass cytometry and histopathological microstructures in conventional H&E stained glioblastoma (GBM) samples, unveiling morphological patterns and cellular-level spatial alterations associated with protein expression changes. To model these complex relationships, we propose a novel generative-predictive framework called Ouroboros for producing H&E images from protein expressions and simultaneously predicting protein expressions from H&E images. Our comprehensive sample-independent validation over 9920 tissue spots from 4 GBM samples encompassing visual image analysis, quantitative analysis, subspace alignment and perturbation experiments shows that the proposed generative-predictive approach offers significant improvements in predicting protein expression from images in comparison to baseline methods as well as accurate generation of virtual GBM sample images. This proof of concept study can contribute to advancing our understanding of histological responses to protein expression perturbations and lays the foundations for further developments in this area. AVAILABILITY AND IMPLEMENTATION: Implementation and associated data for the proposed approach are available at the URL: https://github.com/Srijay/Ouroboros.
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Glioblastoma , Humanos , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Biologia Computacional/métodosRESUMO
OBJECTIVE: Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggests that whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages, leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at postmortem with clinical milestones. METHODS: In 269 MS brains, 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22, a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. RESULTS: ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increased prevalence and higher levels of PVI (both p < 0.0001). Shorter time from onset of progression to wheelchair use was associated with higher prevalence of ALs (odds ratio [OR] = 0.921, 95% confidence interval [CI] = 0.858-0.989, p = 0.0230) and higher level of PVI (OR = 0.932, 95% CI = 0.886-0.981, p = 0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. INTERPRETATION: ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. ANN NEUROL 2024;95:706-719.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla/patologia , Estudos de Coortes , Estudos Retrospectivos , Inflamação/complicações , Encéfalo/patologia , Esclerose Múltipla Crônica Progressiva/patologiaRESUMO
The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer's disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression.
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Atrofia de Múltiplos Sistemas , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/tratamento farmacológico , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/patologia , Imageamento por Ressonância Magnética , Reino UnidoRESUMO
Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/ß-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
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Neoplasias do Sistema Nervoso Central , Tumores Neuroectodérmicos Primitivos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Proteínas de Ciclo Celular/genética , Neoplasias do Sistema Nervoso Central/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Tumores Neuroectodérmicos Primitivos/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Via de Sinalização Wnt/genéticaRESUMO
We document a patient with colon adenocarcinoma who presented with rapidly worsening visual impairment. Staging computer tomography and subsequent magnetic resonance scans documented a sellar, suprasellar lesion compressing the optic chiasm. The patient underwent trans-sphenoidal surgery to relieve optic chiasm compression and obtain tissue for diagnosis. Histological examination revealed a metastatic mucinous adenocarcinoma in a gonadotroph pituitary neuroendocrine tumour (PitNET, formerly pituitary adenoma). The patient underwent adjuvant radiotherapy to the sella and chemotherapy but he died nine months after pituitary surgery. This report highlights the diagnostic and management challenges of metastases to PitNET.
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Adenocarcinoma , Adenoma , Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Hipofisárias , Masculino , Humanos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Imageamento por Ressonância MagnéticaRESUMO
The brain is protected by the endothelial blood-brain barrier (BBB) that limits the access of micro-organisms, tumour cells, immune cells and autoantibodies to the parenchyma. However, the classic model of disease spread across a disrupted BBB does not explain the focal distribution of lesions seen in a variety of neurological diseases and why lesions are frequently adjacent to the cerebrospinal fluid (CSF) spaces. We have critically reviewed the possible role of a blood-CSF-brain route as a disease entry pathway into the brain parenchyma. The initial step of this pathway is the transfer of pathogens or immune components from the blood into the CSF at the choroid plexuses, where the blood-CSF barrier (BCSFB) is located. The flow of CSF results in disease dissemination throughout the CSF spaces. Access to the brain parenchyma from the CSF can then occur across the ependymal layer at the ventricular surface or across the pial-glial barrier of the subarachnoid space and the Virchow-Robin spaces. We have reviewed the anatomy and physiology of the blood-CSF-brain pathway and the brain barriers controlling this process. We then summarised the evidence supporting this brain entry route in a cross-section of neurological diseases including neuromyelitis optica, multiple sclerosis, neurosarcoidosis, neuropsychiatric lupus, cryptococcal infection and both solid and haematological tumours. This summary highlights the conditions that share the blood-CSF-brain pathway as a pathogenetic mechanism. These include the characteristic proximity of lesions to CSF, evidence of disruption of the brain barriers and the identification of significant pathology within the CSF. An improved understanding of pathological transfer through the CSF and across all brain barriers will inform on more effective and targeted treatments of primary and secondary diseases of the central nervous system.
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Barreira Hematoencefálica , Encéfalo , Transporte Biológico/fisiologia , Encéfalo/metabolismo , Sistema Nervoso Central , Plexo CorióideoRESUMO
OBJECTIVES: Diagnosing the idiopathic inflammatory myopathies (IIMs) can be challenging as several conditions, including genetic myopathies such as limb girdle muscular dystrophy type R12 (LGMD 2 l, anoctaminopathy) mimic the presentation. Here we describe learning points identified from review of four patients with LGMD 2 l who were initially incorrectly diagnosed with IIM. Our aim is to provide clinicians working in adult rheumatology services with a toolkit to help identify non-inflammatory presentations of myopathy. METHODS: We performed retrospective review of medical notes, laboratory results, muscle imaging and histological findings of four patients with LGMD 2 l who were previously misdiagnosed with IIM. We focussed on clinical presentation and progression, therapeutic agents used and events leading to revision of the diagnosis. RESULTS: Three male patients and one female patient with a mean age of 51 years at presentation were reviewed. In each case, treatment with immunosuppressants, in one case for >15 years, was observed without a clear therapeutic response. All patients were negative for anti-nuclear antibodies and available myositis-associated/specific autoantibodies and associated connective tissue disease features were absent. Prominent fatty infiltration and selective muscle involvement on thigh MRI was found in common. CONCLUSIONS: Adult-onset genetic myopathies, particularly LGMD R12, can mimic IIM. Accurate diagnosis is crucial to avoid the use of potentially harmful immunosuppressive therapies, to allow appropriate genetic counselling and to facilitate involvement in research studies.
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Doenças Musculares , Distrofia Muscular do Cíngulo dos Membros , Miosite , Erros de Diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/genética , Miosite/diagnósticoRESUMO
INTRODUCTION: Magnetic resonance imaging (MRI) is the main modality to diagnose adenohypophyseal tumours, while biochemical assessment of pituitary hormones allows for their functional classification. In this retrospective exploratory cohort study, we investigated if quantitative differences in tumour MR signal intensity (SI) could be utilized to predict the function and histotype. METHODS: Clinically acquired pretreatment MRI images were retrospectively analysed in 67 clinically non-functioning gonadotropinomas (NFG), 38 somatotropinomas, and 16 medically treated giant macroprolactinomas. Mean T1- and T2-weighted SI values were determined for each tumour and normalized against either centrum semiovale white matter or CSF to derive relative T1W and T2W SI values and the relative tumour T2/T1 SI ratio. Inter-group differences in quantitative MR parameters were compared, and the power of each parameter to discriminate tumour type and subtype was assessed using the area under the receiver operator characteristic curve (AUROC). In resected somatotropinomas, the relationship between tumour granulation status, relative MR SI values, and biochemical data was also compared. RESULTS: Compared to somatotropinomas, NFG and macroprolactinomas displayed higher relative T2W SI (p < 0.001) and higher relative tumour T2/T1 SI ratio values (p < 0.001, ANOVA). Compared to intermediate/densely granulated tumours, sparsely granulated somatotropinomas were larger (p = 0.006, Mann-Whitney U test), had higher relative T2W SI (p ≤ 0.005), and higher relative tumour T2/T1 SI ratios (p ≤ 0.001, 2-tailed t test). Relative tumour T2W SI values and relative tumour T2/T1 ratio values demonstrated good discriminatory power in differentiating NFG from somatotropinoma (AUROC = 0.87-0.94) and predicting somatotropinoma subtypes (AUROC = 0.87-0.95). CONCLUSION: Quantitative SI-based MR parameters derived using clinical acquisition MRI protocols may help non-invasively discriminate the functional status of adenohypophyseal tumours and the histological subtype of somatotropinomas.
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Imageamento por Ressonância Magnética , Neoplasias , Biomarcadores , Estudos de Coortes , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Estudos RetrospectivosRESUMO
INTRODUCTION: Surgical remission for acromegaly is dependent on a number of factors including tumour size, invasiveness, and surgical expertise. We studied the value of early post-operative growth hormone (GH) level as a predictor of outcome and to guide early surgical re-exploration for residual disease in patients with acromegaly. METHODS: Patients with acromegaly undergoing first-time endoscopic transsphenoidal surgery between 2005 and 2015, in 2 regional neurosurgical centres, were studied. Insulin-like growth factor-1 (IGF-1), basal GH (i.e., sample before oral glucose), and GH nadir on oral glucose tolerance test (OGTT) were tested at various time points, including 2-5 days post-operatively. Definition of disease remission was according to the 2010 consensus statement (i.e., GH nadir <0.4 µg/L during an OGTT and normalized population-matched IGF-1). Forward stepwise logistic regression was used to determine factors associated with remission. RESULTS: We investigated 81 consecutive patients with acromegaly, 67 (83%) of which had macroadenomas and 22 (27%) were noted to be invasive at surgery. Mean follow-up was 44 ± 25 months. Overall, surgical remission was achieved in 55 (68%) patients at final follow-up. On univariate analysis, the remission rates at the end of the study period for patients with early post-operative GH nadir on OGTT of <0.4 (N = 43), between 0.4 and 1 (N = 28), and >1 µg/L (N = 8) were 88, 54, and 20%, respectively. Similar results were seen with basal GH on early post-operative OGTT. On multivariate regression analysis, pre-operative IGF-1 (odds ratio of 13.1) and early post-operative basal GH (odds ratio of 5.0) and GH nadir on OGTT (odds ratio of 6.8) were significant predictors of residual disease. Based on a raised early GH nadir and post-operative MR findings, 10 patients underwent early surgical re-exploration. There was reduction in post-operative GH levels in 9 cases, of which 5 (50%) achieved long-term remission. There was an increased risk of new pituitary hormone deficiencies in patients having surgical re-exploration compared to those having a single operation (60 vs. 14%). CONCLUSIONS: An early post-operative basal GH and GH nadir on OGTT are reliable predictors of long-term disease remission. It can be used to guide patients for early surgical re-exploration for residual disease, although there is increased risk of hypopituitarism.
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Acromegalia , Hormônio do Crescimento Humano , Acromegalia/cirurgia , Teste de Tolerância a Glucose , Hormônio do Crescimento , Humanos , Fator de Crescimento Insulin-Like I , Período Pós-Operatório , Resultado do TratamentoRESUMO
We report on a patient with atypical parkinsonism due to coexistent Lewy body disease (LBD) and diffuse anaplastic astrocytoma. The patient presented with a mixed cerebellar and parkinsonian syndrome, incomplete levodopa response, and autonomic failure. The clinical diagnosis was multiple system atrophy (MSA). Supportive features of MSA according to the consensus diagnostic criteria included postural instability and early falls, early dysphagia, pyramidal signs, and orofacial dystonia. Multiple exclusion criteria for a diagnosis of idiopathic Parkinson's disease (iPD) were present. Neuropathological examination of the left hemisphere and the whole midbrain and brainstem revealed LBD, neocortical-type consistent with iPD, hippocampal sclerosis, and widespread neoplastic infiltration by an anaplastic astrocytoma without evidence of a space occupying lesion. There were no pathological features of MSA. The classification of atypical parkinsonism was difficult in this patient. The clinical features and disease course were confounded by the coexistent tumor, leading to atypical presentation and a diagnosis of MSA. We suggest that the initial features were due to Lewy body pathology, while progression and ataxia, pyramidal signs, and falls were accelerated by the occurrence of the astrocytoma. Our case reflects the challenges of an accurate diagnosis of atypical parkinsonism, the potential for confounding co-pathology and the need for autopsy examination to reach a definitive diagnosis.
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Doença por Corpos de Lewy , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Doença por Corpos de Lewy/complicações , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnóstico , Atrofia de Múltiplos Sistemas/patologia , Doença de Parkinson/patologia , LevodopaRESUMO
We investigated the cerebral folate system in post-mortem brains and matched cerebrospinal fluid (CSF) samples from subjects with definite Alzheimer's disease (AD) (n = 21) and neuropathologically normal brains (n = 21) using immunohistochemistry, Western blot and dot blot. In AD the CSF showed a significant decrease in 10-formyl tetrahydrofolate dehydrogenase (FDH), a critical folate binding protein and enzyme in the CSF, as well as in the main folate transporter, folate receptor alpha (FRα) and folate. In tissue, we found a switch in the pathway of folate supply to the cerebral cortex in AD compared to neurologically normal brains. FRα switched from entry through FDH-positive astrocytes in normal, to entry through glial fibrillary acidic protein (GFAP)-positive astrocytes in the AD cortex. Moreover, this switch correlated with an apparent change in metabolic direction to hypermethylation of neurons in AD. Our data suggest that the reduction in FDH in CSF prohibits FRα-folate entry via FDH-positive astrocytes and promotes entry through the GFAP pathway directly to neurons for hypermethylation. This data may explain some of the cognitive decline not attributable to the loss of neurons alone and presents a target for potential treatment.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Estudos de Coortes , Encéfalo/metabolismo , Astrócitos/metabolismo , Ácido Fólico/metabolismo , Proteína Glial Fibrilar Ácida/metabolismoRESUMO
PURPOSE: A DCE-MRI technique that can provide both high spatiotemporal resolution and whole-brain coverage for quantitative microvascular analysis is highly desirable but currently challenging to achieve. In this study, we sought to develop and validate a novel dual-temporal resolution (DTR) DCE-MRI-based methodology for deriving accurate, whole-brain high-spatial resolution microvascular parameters. METHODS: Dual injection DTR DCE-MRI was performed and composite high-temporal and high-spatial resolution tissue gadolinium-based-contrast agent (GBCA) concentration curves were constructed. The high-temporal but low-spatial resolution first-pass GBCA concentration curves were then reconstructed pixel-by-pixel to higher spatial resolution using a process we call LEGATOS. The accuracy of kinetic parameters (Ktrans , vp , and ve ) derived using LEGATOS was evaluated through simulations and in vivo studies in 17 patients with vestibular schwannoma (VS) and 13 patients with glioblastoma (GBM). Tissue from 15 tumors (VS) was examined with markers for microvessels (CD31) and cell density (hematoxylin and eosin [H&E]). RESULTS: LEGATOS derived parameter maps offered superior spatial resolution and improved parameter accuracy compared to the use of high-temporal resolution data alone, provided superior discrimination of plasma volume and vascular leakage effects compared to other high-spatial resolution approaches, and correlated with tissue markers of vascularity (P ≤ 0.003) and cell density (P ≤ 0.006). CONCLUSION: The LEGATOS method can be used to generate accurate, high-spatial resolution microvascular parameter estimates from DCE-MRI.
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Meios de Contraste , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , HumanosRESUMO
Gliomas are highly dynamic and heterogeneous tumours of the central nervous system (CNS). They constitute the most common neoplasm of the CNS and the second most common cause of death from intracranial disease after stroke. The advances in detailing the genetic profile of paediatric and adult gliomas along with the progress in MRI and PET multimodal molecular imaging technologies have greatly improved prognostic stratification of patients with glioma and informed on treatment decisions. Amino acid PET has already gained broad clinical application in the study of gliomas. PET imaging targeting the translocator protein (TSPO) has recently been applied to decipher the heterogeneity and dynamics of the tumour microenvironment (TME) and its various cellular components especially in view of targeted immune therapies with the goal to delineate pro- and anti-glioma immune cell modulation. The current review provides a comprehensive overview on the historical developments of TSPO PET for gliomas and summarizes the most relevant experimental and clinical data with regard to the assessment and quantification of various cellular components with the TME of gliomas by in vivo TSPO PET imaging.
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Neoplasias Encefálicas , Glioma , Criança , Glioma/diagnóstico por imagem , Humanos , Tomografia por Emissão de Pósitrons , Receptores de GABA/genética , Microambiente TumoralRESUMO
OBJECTIVES: Early diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help to stratify those at highest risk of late-life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death. METHODS/DESIGN: Between 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD). RESULTS: Baseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology. CONCLUSIONS: GDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD-related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD.
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Doença de Alzheimer , Disfunção Cognitiva , Idoso , Cognição , Depressão , Humanos , Estudos LongitudinaisRESUMO
INTRODUCTION: The aged brain frequently exhibits multiple pathologies, rather than a single hallmark pathology (pure pathology [PurP]), ranging from low/intermediate levels of additional pathology (LowP) to mixed severe pathology (mixed SevP). We investigated the frequency of PurP, LowP, and mixed SevP, and the impact of additional LowP on cognition. METHODS: Data came from 670 cases from the Brains for Dementia research program. Cases were categorized into PurP, mixed SevP, or a main disease with additional LowP; 508 cases had a clinical dementia rating. RESULTS: 69.9% of cases had LowP, 22.7% had PurP, and 7.5% had mixed SevP. Additional LowP increased the likelihood of having mild dementia versus mild cognitive impairment (MCI) by almost 20-fold (odds ratio = 19.5). DISCUSSION: Most aged individuals have multiple brain pathologies. The presence of one additional LowP can significantly worsen cognitive decline, increasing the risk of transitioning from MCI to dementia 20-fold. Multimorbidity should be considered in dementia research and clinical studies.
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Autopsia , Encéfalo/patologia , Disfunção Cognitiva/patologia , Demência/patologia , Multimorbidade , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência/estatística & dados numéricos , Tauopatias/patologiaRESUMO
Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide expansion from 55 to 200 repeats in the non-coding region of the fragile X mental retardation 1 (FMR1) gene (FMR1). Clinical features include cognitive decline, progressive tremor, and gait ataxia. Neuropathologically, FXTAS shows white matter changes, hippocampal and cerebellar involvement, and p62-positive eosinophilic intranuclear inclusions in astrocytes and neurons. Here, we document the neuropathological findings from a subject who developed cognitive impairment but not tremor and was proved to have genetically confirmed FMR1 premutation. Microscopically, typical p62-postive intranuclear inclusions were present in all the regions examined. Neocortical regions demonstrated gliosis of layer I and mild degree of neuronal loss and atrophy across the other layers. The molecular, Purkinje's cell, and granule cell layers of the cerebellar folia demonstrated mild gliosis, and cerebellar white matter was mildly affected. Aside from p62-positive inclusions, the hippocampus was spared. Arteries in the deep white matter often showed changes consistent with moderate small vessel disease (SVD). Reactive gliosis and severe SVD were features of basal ganglia. Florid reactive astrocytosis was found in the white matter of all regions. Axonal loss and features of axonal damage were found in the white matter of the centrum semiovale. Microglial activation was widespread and evenly seen in both the white matter and grey matter, although the grey matter appeared more severely affected. Pathology associated with Alzheimer's disease was limited. Similarly, no abnormal accumulations of α-synuclein were present. We postulate that age at death and disease duration may play a role in the extent of the pathological features associated with FXTAS. The present results suggest that immunohistochemical staining for p62 can help with the diagnosis of cases with atypical phenotype. In addition, it is likely that the cognitive impairment observed was a result of white matter changes.
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Ataxia/patologia , Encéfalo/patologia , Síndrome do Cromossomo X Frágil/patologia , Tremor/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Substância Cinzenta/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Substância Branca/patologiaRESUMO
Primary salivary gland-like tumors of the sella are rare and often challenging to diagnose. They reportedly derive from serous and mucinous glands that remain trapped in the infundibulum during embryogenesis. We report a 68-year-old man who presented with partial left third cranial nerve palsy, visual loss in the left eye without visual field defects, headache, weight loss and reduced muscle bulk. Neuroimaging studies demonstrated a solid and cystic, avidly enhancing lesion expanding the pituitary fossa and extending to the left cavernous sinus. The patient underwent craniotomy and the tissue removed showed features of epithelial-myoepithelial carcinoma similar to the salivary gland, skin and breast counterpart. No primary tumor was found outside the sella. The lesion behaved aggressively despite radio-chemotherapy and the patient died 22 months from the onset. The tumor showed a novel TP53 in-frame deletion (Gly154del) while no variants were found in H-RAS hotspot regions (codons 12, 13 and 61). Our report expands the spectrum of salivary gland-like tumors primarily occurring in the sella and emphasizes the need for specialist review of rare, non-neuroendocrine tumors of the pituitary and sella regions.
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Carcinoma/patologia , Mioepitelioma/patologia , Neoplasias Hipofisárias/patologia , Idoso , Humanos , MasculinoRESUMO
BACKGROUND: Recent studies of cortical pathology in secondary progressive multiple sclerosis have shown that a more severe clinical course and the presence of extended subpial grey matter lesions with significant neuronal/glial loss and microglial activation are associated with meningeal inflammation, including the presence of lymphoid-like structures in the subarachnoid space in a proportion of cases. METHODS: To investigate the molecular consequences of pro-inflammatory and cytotoxic molecules diffusing from the meninges into the underlying grey matter, we carried out gene expression profiling analysis of the motor cortex from 20 post-mortem multiple sclerosis brains with and without substantial meningeal inflammation and 10 non-neurological controls. RESULTS: Gene expression profiling of grey matter lesions and normal appearing grey matter not only confirmed the substantial pathological cell changes, which were greatest in multiple sclerosis cases with increased meningeal inflammation, but also demonstrated the upregulation of multiple genes/pathways associated with the inflammatory response. In particular, genes involved in tumour necrosis factor (TNF) signalling were significantly deregulated in MS cases compared with controls. Increased meningeal inflammation was found to be associated with a shift in the balance of TNF signalling away from TNFR1/TNFR2 and NFkB-mediated anti-apoptotic pathways towards TNFR1- and RIPK3-mediated pro-apoptotic/pro-necroptotic signalling in the grey matter, which was confirmed by RT-PCR analysis. TNFR1 was found expressed preferentially on neurons and oligodendrocytes in MS cortical grey matter, whereas TNFR2 was predominantly expressed by astrocytes and microglia. CONCLUSIONS: We suggest that the inflammatory milieu generated in the subarachnoid space of the multiple sclerosis meninges by infiltrating immune cells leads to increased demyelinating and neurodegenerative pathology in the underlying grey matter due to changes in the balance of TNF signalling.
Assuntos
Córtex Cerebral/metabolismo , Substância Cinzenta/metabolismo , Meninges/metabolismo , Esclerose Múltipla/metabolismo , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Córtex Cerebral/patologia , Feminino , Substância Cinzenta/patologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Meninges/patologia , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Transcriptoma/fisiologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
Since the first studies of luminescent sensors based on metal organic frameworks (MOFs) about ten years ago, there has been an increased interest in the development of specific sensors towards cations, anions, explosives, small molecules, solvents, etc. However, the detection of toxic compounds related to agro-industry and nuclear activity is noticeably scarce or even non-existent. In this work, we report the synthesis and characterization of luminescent lanthanide-based MOFs (Ln-MOFs) with diverse crystalline architectures obtained by solvothermal methods. The luminescent properties of the lanthanides, and the hypersensitive transitions of Eu3+ (5D0â7F2) and Tb3+ (5D4â7F5) intrinsically found in the obtained MOFs in particular, were evaluated and employed as chemical sensors for agrochemical and cationic species. The limit of detection (LOD) of Tb-PSA MOFs (PSA = 2-phenylsuccinate) was 2.9 ppm for [UO22+] and 5.6 ppm for [Cu2+]. The variations of the 4fâ»4f spectral lines and the quenching/enhancement effects of the Ln-MOFs in the presence of the analytes were fully analyzed and discussed in terms of a combinatorial "hostâ»guest" vibrational and "in-silico" interaction studies.