RESUMEN
Parkinson's disease and other Lewy body spectrum diseases (LBDs) are associated with a specific risk for clinical depression. In the present clinicopathological study with 73 patients with LBD, we observed that the substantia nigra pars compacta dopamine neuron density was markedly lower in patients who had comorbid depression antemortem than in nondepressed patients (1.52 vs 2.32 n/mm2 , p = 0.004). There were no differences in cognition, motor disease severity, antiparkinsonian medications, or disease duration between groups. The results implicate the substantia nigra as an important psychomotor modulatory area of mood in patients with Lewy body disorders. ANN NEUROL 2021;;89:1046-1050.
Asunto(s)
Depresión/psicología , Neuronas Dopaminérgicas/patología , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/psicología , Sustancia Negra/patología , Anciano , Anciano de 80 o más Años , Autopsia , Recuento de Células , Depresión/etiología , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/complicaciones , Masculino , Pruebas de Estado Mental y Demencia , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: The dopaminergic system modulates growth hormone secretion and previous results have suggested a link between short stature and an increased risk of Parkinson's disease (PD). METHODS: In 36 Lewy body spectrum disease (LBD) cases (PD = 22) and 19 controls, nigral TH-positive neuron densities were measured postmortem from midbrain sections and corrected with the Abercrombie method. Body measurements were collected from autopsies or patient records. Our aim was to investigate the possible relationship between height and the density of neurons in the substantia nigra pars compacta (SNc). RESULTS: SNc neuron density (n/mm2) had an inverse association with height, (R2 = 0.317, p < 0.0001) in patients. The association was not explained by weight, age, sex, brain weight, medication, or disease motor severity. The association was also separately observed in patients with PD (n = 22), but not in subjects who died without diagnosed neurological diseases. CONCLUSIONS: Individual adult height may be connected to nigral neuron numbers in patients with LBDs, including PD.
Asunto(s)
Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Adulto , Dopamina , Humanos , Mesencéfalo , Neuronas , Sustancia NegraRESUMEN
BACKGROUND: Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-ß (FR-ß), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (68Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-ß is expressed in the brain of patients with MS. METHODS: Focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). 68Ga-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-ß expression in postmortem brain samples from 5 patients with MS and 5 healthy controls. RESULTS: Immunofluorescence and histological analyses revealed significant reductions in FR-ß expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected 68Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-ß positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples. CONCLUSIONS: EC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-ß-positive cells in chronically active plaques, which suggests that these results may have translational relevance.
Asunto(s)
Aminopterina/farmacología , Encefalomielitis Autoinmune Experimental/patología , Receptor 2 de Folato/metabolismo , Antagonistas del Ácido Fólico/farmacología , Ácido Fólico/farmacología , Animales , Humanos , Esclerosis Múltiple/metabolismo , Ratas , Ratas Endogámicas LewRESUMEN
BACKGROUND: The prognosis of glioblastoma remains poor, related to its diffuse spread within the brain. There is an ongoing search for molecular regulators of this particularly invasive behavior. One approach is to look for actin regulating proteins that might be targeted by future anti-cancer therapy. The formin family of proteins orchestrates rearrangement of the actin cytoskeleton in multiple cellular processes. Recently, the formin proteins mDia1 and mDia2 were shown to be expressed in glioblastoma in vitro, and their function could be modified by small molecule agonists. This finding implies that the formins could be future therapeutic targets in glioblastoma. METHODS: In cell studies, we investigated the changes in expression of the 15 human formins in primary glioblastoma cells and commercially available glioblastoma cell lines during differentiation from spheroids to migrating cells using transcriptomic analysis and qRT-PCR. siRNA mediated knockdown of selected formins was performed to investigate whether their expression affects glioblastoma migration. Using immunohistochemistry, we studied the expression of two formins, FHOD1 and INF2, in tissue samples from 93 IDH-wildtype glioblastomas. Associated clinicopathological parameters and follow-up data were utilized to test whether formin expression correlates with survival or has prognostic value. RESULTS: We found that multiple formins were upregulated during migration. Knockdown of individual formins mDia1, mDia2, FHOD1 and INF2 significantly reduced migration in most studied cell lines. Among the studied formins, knockdown of INF2 generated the greatest reduction in motility in vitro. Using immunohistochemistry, we demonstrated expression of formin proteins FHOD1 and INF2 in glioblastoma tissues. Importantly, we found that moderate/high expression of INF2 was associated with significantly impaired prognosis. CONCLUSIONS: Formins FHOD1 and INF2 participate in glioblastoma cell migration. Moderate/high expression of INF2 in glioblastoma tissue is associated with worse outcome. Taken together, our in vitro and tissue studies suggest a pivotal role for INF2 in glioblastoma. When specific inhibiting compounds become available, INF2 could be a target in the search for novel glioblastoma therapies.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Movimiento Celular , Proteínas Fetales/metabolismo , Forminas/metabolismo , Glioblastoma/metabolismo , Actinas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proteínas Fetales/genética , Forminas/genética , Técnicas de Silenciamiento del Gen , Glioblastoma/patología , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Regulación hacia ArribaRESUMEN
Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening among a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two-thirds of the cases (63%). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33%). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by highly recurrent combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease.
Asunto(s)
Neoplasias Encefálicas/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Glioma/genética , Neurofibromina 1/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Adolescente , Adulto , Anciano , Niño , Metilación de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neuronas/patología , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Brain dopamine transporter binding has been considered a possible biomarker for nigrostriatal degeneration in PD. OBJECTIVE: To investigate whether dopamine transporter binding is associated with the number of dopaminergic neurites in the putamen. METHODS: Tyrosine hydroxylase-positive nerve fibers were counted from postmortem putamen sections taken from 14 parkinsonism patients who had been scanned with dopamine transporter single-photon emission computed tomography antemortem. Fiber counts were correlated with putamen dopamine transporter binding and SN neuron counts. RESULTS: The putamen dopamine transporter specific binding ratio did not correlate with the putamen tyrosine hydroxylase-positive axon counts (r = 0.00; P = 1.0; PD patients: r = 0.07; P = 0.86). The nigra neuron counts had a positive correlation with the putamen tyrosine hydroxylase-positive axon counts. CONCLUSIONS: Striatal dopamine transporter imaging does not associate with axonal nor somal loss of the nigrostriatal neurons in PD. It may reflect dopaminergic activity rather than number of surviving neurons or their striatal projection axons. © 2019 International Parkinson and Movement Disorder Society.
Asunto(s)
Axones/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Enfermedad de Parkinson/metabolismo , Anciano , Anciano de 80 o más Años , Cuerpo Estriado/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas/metabolismo , Enfermedad de Parkinson/complicaciones , Putamen/metabolismo , Sustancia Negra/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
PURPOSE: To quantitate gadolinium deposits in gliomas and adjacent normal brain specimens, and to evaluate their association with tumor contrast enhancement and the type of gadolinium-based contrast agent (GBCA) used. METHODS: A total of 69 patients with primary glioma who underwent contrast-enhanced magnetic resonance imaging (MRI) prior to surgery were included in this retrospective study. Gadolinium was measured from histologically viable tumor, normal brain, and necrosis within the sample, when available, using inductively coupled plasma mass spectrometry (ICP-MS). Tumor contrast enhancement was categorized as none, minimal, or noticeable. Differences in gadolinium deposits by contrast enhancement and GBCA type were assessed. RESULTS: Seven patients received linear GBCA and 62 macrocyclic, respectively. At the time of surgery, gadolinium deposits were detected in 39 out of 69 (57%) tumor samples, 8 out of 13 (62%) normal brain, and 12 out of 14 (86%) necrotic specimens. Gadolinium was detected in both enhancing and non-enhancing tumors, but was greatest in gliomas with noticeable enhancement (p = 0.02). Administration of linear agents gadodiamide and gadopentetate dimeglumine resulted in significantly higher tumor gadolinium relative to macrocyclic gadoterate meglumine (p < 0.01 and p < 0.05, respectively). Normal brain and necrosis also showed higher gadolinium after exposure to linear gadodiamide (both p < 0.05). In multivariate regression, GBCA type (linear/macrocyclic) was the most powerful predictor of tumor gadolinium retention (p < 0.001). CONCLUSION: Gadolinium can be detected in both enhancing and non-enhancing gliomas, neighboring normal brain, and necrosis. Gadolinium retention is higher after exposure to linear GBCAs compared with the macrocyclic gadoterate meglumine.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Medios de Contraste/farmacocinética , Glioma/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Femenino , Gadolinio DTPA/farmacocinética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Meglumina/farmacocinética , Persona de Mediana Edad , Compuestos Organometálicos/farmacocinética , Estudios RetrospectivosRESUMEN
BACKGROUND: 68Ga-DOTANOC PET/CT is routinely used to image neuroendocrine tumors (NETs). A case of lymphoma initially thought to be NET based on a positive 68Ga-DOTANOC PET/CT was recently seen at our institution. This prompted us to determine prospectively somatostatin receptor (SSTR) status in patients with lymphoma by immunohistochemical analysis of SSTR subtypes 2, 3 and 5 (SSTR2,3,5) and 68Ga-DOTANOC PET/CT imaging. MATERIAL AND METHODS: Twenty-one patients with newly diagnosed lymphoma were referred to 68Ga-DOTANOC and FDG PET/CT prior to any treatment. Tracer uptake was evaluated visually by two nuclear medicine specialists. Maximum standardized uptake values (SUVmax) were determined from 14 nodal and two extranodal regions with highest uptake in each patient. Lesions were then graded with Deauville score (1-5) on FDG PET/CT and modified Krenning score (0-4) on 68Ga-DOTANOC PET/CT, respectively. SSTR2,3,5 status was analyzed from routine biopsies of lymphomatous tissue and matched to corresponding PET/CT findings. RESULTS: About 20/21 patients had FDG-positive lymphoma (Deauville score ≥3). Uptake of 68Ga-DOTANOC was regarded as positive if Krenning score was ≥2 and resulted in 13/21 (62%) patients having 68Ga-DOTANOC-positive lymphomas. The highest uptake of 68Ga-DOTANOC was seen in Hodgkin's lymphoma of nodular sclerosis subtype and in diffuse large B-cell lymphoma (SUVmax median 9.8 and 9.7, respectively). Both cases showed strong SSTR2 immunopositivity in tumor cells. Some patients had SSTR2 immunopositivity predominantly in endothelial and dendritic cells and follicular centers of lymph nodes contributing to a positive PET/CT with probably low tumor-specific uptake. SSTR3 and SSTR5 were negative in most lymphoma subtypes. CONCLUSIONS: According to this pilot study, 68Ga-DOTANOC PET/CT is positive in some lymphoma subtypes which express SSTRs. These tumors present a potential risk of being misinterpreted as NETs if a representative tumor sample is not available. Lymphomas with high expression of SSTRs may be amenable to treatments targeting these receptors.
Asunto(s)
Biomarcadores de Tumor/análisis , Linfoma/diagnóstico por imagen , Tumores Neuroendocrinos/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Receptores de Somatostatina/análisis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Persona de Mediana Edad , Compuestos Organometálicos , Proyectos Piloto , Adulto JovenRESUMEN
The functional properties of actin-regulating formin proteins are diverse and in many cases cell-type specific. FHOD1, a formin expressed predominantly in cells of mesenchymal lineage, bundles actin filaments and participates in maintenance of cell shape, migration and cellular protrusions. FHOD1 participates in cancer-associated epithelial to mesenchymal transition (EMT) in oral squamous cell carcinoma and breast cancer. The role of FHOD1 in melanomas has not been characterized. Here, we show that FHOD1 expression is typically strong in cutaneous melanomas and cultured melanoma cells while the expression is low or absent in benign nevi. By using shRNA to knockdown FHOD1 in melanoma cells, we discovered that FHOD1 depleted cells are larger, rounder and have smaller focal adhesions and inferior migratory capacity as compared to control cells. Importantly, we found FHOD1 depleted cells to have reduced colony-forming capacity and attenuated tumor growth in vivo, a finding best explained by the reduced proliferation rate caused by cell cycle arrest. Unexpectedly, FHOD1 depletion did not prevent invasive growth at the tumor margins. These results suggest that FHOD1 participates in key cellular processes that are dysregulated in malignancy, but may not be essential for melanoma cell invasion.
Asunto(s)
Citoesqueleto de Actina/metabolismo , Proteínas Fetales/metabolismo , Melanoma/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Cutáneas/metabolismo , Fibras de Estrés/metabolismo , Actinas/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal/fisiología , Forminas , Humanos , Ratones , Activación Transcripcional/fisiología , Regulación hacia Arriba , Melanoma Cutáneo MalignoRESUMEN
Our aim was to study the association of two potential serum biomarkers glial fibrillary acidic protein (GFAP) and epidermal growth factor receptor (EGFR) with prognostic markers such as IDH1 mutation, tumor burden, and survival in patients with high-grade gliomas (HGG). Additionally, our objective was to evaluate the potential of serum EGFR as a surrogate marker for EGFR status in the tumor. Pre-operative serum samples were prospectively collected from patients with primary (n = 17) or recurrent (n = 10) HGG. Serum GFAP and EGFR levels were determined by ELISA and studied for correlation with molecular markers including EGFR amplification, tumor volume in contrast-enhanced T1-weighted MRI, and progression-free survival (PFS). Pre-operative serum GFAP level of ≥0.014 ng/ml was 86 % sensitive and 85 % specific for the diagnosis of glioblastoma. High GFAP was related to the lack of IDH1 mutation (P = 0.016), high Ki67 proliferation index (P < 0.001), and poor PFS (HR 5.9, CI 1.2-29.9, P = 0.032). Serum GFAP correlated with enhancing tumor volume in primary (r = 0.64 P = 0.005), but also in recurrent HGGs (r = 0.76 P = 0.011). In contrast, serum EGFR levels did not differ between HGG patients and 13 healthy controls, and were not related to EGFR status in the tumor. We conclude that high serum GFAP associates with IDH1 mutation-negative HGG, and poor PFS. Correlation with tumor burden in recurrent HGG implicates the potential of serum GFAP for detection of tumor recurrence. Our results suggest that circulating EGFR is not derived from glioma cells and cannot be used as a marker for EGFR status in the tumor.
Asunto(s)
Neoplasias Encefálicas/fisiopatología , Receptores ErbB/sangre , Proteína Ácida Fibrilar de la Glía/sangre , Glioma/patología , Glioma/fisiopatología , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Supervivencia sin Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Glioma/diagnóstico , Glioma/cirugía , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/fisiopatología , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Estudios Prospectivos , Carga TumoralRESUMEN
Recent neuropathologically confirmed clinical data suggest that the midbrain-to-pons ratio, as calculated from conventional brain MRI, has high specificity and sensitivity for the diagnosis of progressive supranuclear palsy (PSP). Here, we aimed to replicate these findings in an independent autopsy-confirmed cohort of 6 PSP patients and 23 non-PSP patients. Patients with confirmed PSP had clearly lower midbrain-to-pons ratios compared to non-PSP patients (p < 0.0001). All non-PSP patients had midbrain-to-pons ratios higher than 0.50, whereas all but one PSP patient had a ratio lower than 0.50. The positive predictive value (PPV) of the ratio (<0.50) was 100% and the negative predictive value (NPV) was 95.8 %. The results of this second autopsy-confirmed sample confirm that midbrain-to-brain ratios constitute reliable and clinically useful estimates of diagnostic midbrain atrophy in relation to PSP pathology.
Asunto(s)
Mesencéfalo/patología , Puente/patología , Parálisis Supranuclear Progresiva/diagnóstico , Anciano , Anciano de 80 o más Años , Autopsia , Estudios de Cohortes , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
INTRODUCTION: The incidence of Creutzfeldt-Jakob disease (CJD) in Finland in 1974-1989 was reported to be 0.6/1 000 000. Our aim was to compare the current incidence of CJD in Finland with the earlier incidence and also study the diagnostics of the disease. METHODS: Register study of the Finnish CJD cases from 1997 to 2012 and the clinical data of CJD patients within the Hospital District of Southwest Finland from 2007 to 2013. RESULTS: There were 119 cases. The average yearly incidence was 1.36-1.44/1 000 000. CONCLUSIONS: Compared with the previous study, the incidence in Finland appears to have increased. The change is propably due to increased awareness and improved diagnostic methods.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/epidemiología , Femenino , Finlandia/epidemiología , Humanos , Incidencia , Masculino , FenotipoAsunto(s)
Muerte , Neuronas Dopaminérgicas/metabolismo , Enfermedad de Parkinson/metabolismo , Fotoperiodo , Estaciones del Año , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Finlandia , Humanos , Masculino , Sustancia Negra/patologíaRESUMEN
UNLABELLED: Somatostatin receptor subtype 2 (sstr2) is regarded as a potential target in malignant gliomas for new therapeutic approaches. Therefore, visualizing and quantifying tumor sstr2 expression in vivo would be highly relevant for the future development of sstr2-targeted therapies. The purpose of this study was to evaluate sstr2 status in experimental BT4C malignant gliomas. METHODS: Rat BT4C malignant glioma cells were injected into BDIX rat brain or subcutaneously into nude mice. Tumor uptake of [(68)Ga]DOTA-(Tyr(3))-Octreotide ([(68)Ga]DOTATOC), a somatostatin analog binding to sstr2, was studied by positron emission tomography/computed tomography (PET/CT). Additionally, subcutaneous tumor-bearing mice underwent PET imaging with 5-deoxy-5-[(18)F]fluororibose-NOC ([(18)F]FDR-NOC), a novel glycosylated peptide tracer also targeting sstr2. Ex vivo tissue radioactivity measurements, autoradiography and immunohistochemistry were performed to study sstr2 expression. RESULTS: Increased tumor uptake of [(68)Ga]DOTATOC was detected at autoradiography with mean tumor-to-brain ratio of 68 ± 30 and tumor-to-muscle ratio of 9.2 ± 3.8 for rat glioma. High tumor-to-muscle ratios were also observed in subcutaneous tumor-bearing mice after injection with [(68)Ga]DOTATOC and [(18)F]FDR-NOC with both autoradiography (6.7 ± 1.5 and 4.3 ± 0.8, respectively) and tissue radioactivity measurements (6.5 ± 0.8 and 4.8 ± 0.6, respectively). Furthermore, sstr2 immunohistochemistry showed positive staining in both tumor models. However, surprisingly low tumor signal compromised PET imaging. Mean SUVmax for rat gliomas was 0.64 ± 0.28 from 30 to 60 min after [(68)Ga]DOTATOC injection. The majority of subcutaneous tumors were not visualized by [(68)Ga]DOTATOC or [(18)F]FDR-NOC PET. CONCLUSIONS: Experimental BT4C gliomas show high expression of sstr2. Weak signal in PET imaging, however, suggests only limited benefit of [(68)Ga]DOTATOC or [(18)F]FDR-NOC PET/CT in this tumor model for in vivo imaging of sstr2 status.
Asunto(s)
Glioma/metabolismo , Proteínas de Neoplasias/metabolismo , Octreótido/análogos & derivados , Compuestos Organometálicos/farmacocinética , Receptores de Somatostatina/metabolismo , Animales , Autorradiografía , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Línea Celular Tumoral , Fluorodesoxiglucosa F18/farmacocinética , Glioma/diagnóstico por imagen , Masculino , Ratones , Ratones Desnudos , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Trasplante de Neoplasias/métodos , Octreótido/farmacocinética , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Ratas , Tomografía Computarizada por Rayos X/métodosRESUMEN
The C9ORF72 hexanucleotide expansion is a major pathological expansion pattern found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (C9FTD/ALS). We describe a patient in whom early clinical evaluation, MRI and fluorodeoxyglucose (FDG) positron emission tomography (PET) findings failed to definitively differentiate between FTD and Alzheimer's disease (AD), whereas (11)C-Pittsburgh compound B (PiB) PET was negative for amyloid pathology. He later developed ALS symptoms, and post mortem neuropathological findings were diagnostic of FTD-ALS, while no findings suggested AD. His sister was diagnosed with FTD, and the C9ORF72 expansion was detected in both siblings. We conclude that ¹¹C-PiB PET imaging may help the early differential diagnosis between AD and FTD, including C9FTD/ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Demencia Frontotemporal/diagnóstico por imagen , Tomografía de Emisión de Positrones , Proteínas/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Compuestos de Anilina , Encéfalo/patología , Proteína C9orf72 , Expansión de las Repeticiones de ADN , Diagnóstico Diferencial , Femenino , Fluorodesoxiglucosa F18 , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Humanos , Masculino , Persona de Mediana Edad , Neuronas/patología , Hermanos , TiazolesRESUMEN
INTRODUCTION: Positron emission tomography (PET) imaging can be used to evaluate arterial wall inflammation in extracranial vascular diseases. However, the application of PET imaging in unruptured intracranial aneurysms (UIA) remains unexplored. Our objective is to investigate feasibility of PET imaging using 18F-FDG and 68Ga-DOTANOC tracers to evaluate arterial wall inflammation in UIA. METHODS AND ANALYSIS: This PET imaging feasibility study will enrol patients scheduled for surgical treatment of UIA. The study subjects will undergo PET imaging of the intracranial arteries within 1 month before planned surgery. The imaging protocol includes 18F-FDG PET MRI, MRA with gadolinium enhancement, and 68Ga-DOTANOC PET CT. The study will also involve preoperative blood samples, intraoperative cerebrospinal fluid (CSF) samples, and aneurysm sac biopsy. Planned sample size is at least 18 patients. Primary outcome is uptake of 18F-FDG or 68Ga-DOTANOC in intracranial arterial aneurysms compared with contralateral normal vessel as maximum standardised uptake value or target-to-blood pool ratio and correlation of uptake of 18F-FDG or 68Ga-DOTANOC to aneurysm histological findings. Secondary outcomes include estimating the correlations between uptake of 18F-FDG or 68Ga-DOTANOC and histological findings with blood and CSF miRNA-levels, arterial wall enhancement in gadolinium enhanced MRA, aneurysm size and shape, smoking, hypertension, and location of the aneurysm. ETHICS AND DISSEMINATION: This study is approved by the Human Research Ethics Committee of the Hospital District of Southwest Finland, Finnish Medicines Agency Fimea, and Turku University Hospital. Findings will be disseminated through peer-reviewed journal articles and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04715503.
Asunto(s)
Fluorodesoxiglucosa F18 , Aneurisma Intracraneal , Compuestos Organometálicos , Humanos , Medios de Contraste , Estudios de Factibilidad , Gadolinio , Inflamación/diagnóstico por imagen , Aneurisma Intracraneal/diagnóstico por imagen , Tomografía de Emisión de PositronesRESUMEN
In pre-clinical models of brain gliomas, Relaxation Along a Fictitious Field in second rotating frame (TRAFF2), continues wave T1rho (T1ρcw), adiabatic T1rho (T1ρadiab), and adiabatic T2rho (T2ρadiab) relaxation time mappings have demonstrated potential to non-invasively characterize brain gliomas. Our aim was to evaluate the feasibility and potential of 4 different spin lock methods at 3T to characterize primary brain glioma. 22 patients (26-72 years) with suspected primary glioma. T1ρcw was performed using pulse peak amplitude of 500Hz and pulse train durations of 40 and 80 ms while the corresponding values for T1ρadiab, T2ρadiab, TRAFF2 were 500/500/500Hz and 48 and 96, 64 and 112, 45 and 90 ms, respectively. The parametric maps were calculated using a monoexponential model. Molecular profiles were evaluated from tissue specimens obtained during the resection. The lesion regions-of-interest were segmented from high intensity FLAIR using automatic segmentation with manual refinement. Statistical descriptors from the voxel intensity values inside each lesion and radiomic features (Pyrad MRC package) were calculated. From extracted radiomics, mRMRe R package version 2.1.0 was used to select 3 features in each modality for statistical comparisons. Of the 22 patients, 10 were found to have IDH-mutant gliomas and of those 5 patients had 1p/19q codeletion group comparisons. Following correction for effects of age and gender, at least one statistical descriptor was able to differentiate between IDH and 1p/19q codeletion status for all the parametric maps. In the radiomic analysis, corner-edge detector features with Harris-Stephens filtered signal showed significant group differences in IDH and 1p/19q codeletion groups. Spin lock imaging at 3T of human glioma was feasible and various qualitative parameters derived from the parametric maps were found to have potential to differentiate IDH and 1p19q codeletion status. Future larger prospective clinical trials are warranted to evaluate these methods further.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Estudios de Factibilidad , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Estudios Prospectivos , Imagen por Resonancia Magnética/métodos , Mutación , Glioma/diagnóstico por imagen , Glioma/patología , Aberraciones Cromosómicas , Isocitrato Deshidrogenasa/genética , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19RESUMEN
The EWSR1::CREM fusion gene, caused by a chromosomal translocation t(10;22)(p11;q12), has been discovered in divergent malignancies, ranging from low-grade to highly malignant cancers. The translocation gives rise to a chimeric protein, EWSR1::CREM. The molecular mechanisms behind the oncogenic properties of the EWSR1::CREM protein have not previously been systematically characterized. In this study, we performed transcriptional profiling of the melanoma cell line CHL-1, with depletion of endogenous EWSR1::CREM protein using siRNA mediated knockdown. We found that the expression of 712 genes was altered (Log2 fold-change ≥ 2). We performed pathway analysis to identify EWSR1::CREM mediated pathways and cell studies to examine functional differences brought upon by the knockdown. Altered pathways involved cell cycle and proliferation, this was further validated by the cell studies where cell migration was affected as well. Among the target genes with the greatest downregulation, we discovered ODC1-a well-established oncogenic enzyme that can be pharmacologically inhibited and is essential for polyamine synthesis. We found that the main effects seen upon EWSR1::CREM knockdown can be reproduced by directly silencing ODC1 expression. These findings provide novel insights into pathogenesis of tumors harboring a EWSR1::CREM fusion gene, hopefully facilitating the development of novel therapeutic strategies.