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17ß-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo brain 18F-fluoroestradiol (18F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age, plasma estradiol and sex hormone binding globulin, and were highly consistent, correctly classifying all women as being postmenopausal or premenopausal. Higher ER density in target regions was associated with poorer memory performance for both postmenopausal and perimenopausal groups, and predicted presence of self-reported mood and cognitive symptoms after menopause. These findings provide novel insights on brain ER density modulation by female neuroendocrine aging, with clinical implications for women's health.
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Envejecimiento , Encéfalo , Cognición , Tomografía de Emisión de Positrones , Receptores de Estrógenos , Humanos , Femenino , Persona de Mediana Edad , Cognición/fisiología , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Envejecimiento/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Estradiol/sangre , Estradiol/metabolismo , Sistemas Neurosecretores/metabolismo , Menopausia/metabolismoRESUMEN
17ß-estradiol,the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo multi-modality neuroimaging study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age and plasma estradiol levels, and were highly consistent, correctly classifying all women as being post-menopausal or not. Higher ER density was generally associated with lower gray matter volume and blood flow, and with higher mitochondria ATP production, possibly reflecting compensatory mechanisms. Additionally, ER density predicted changes in thermoregulation, mood, cognition, and libido. Our data provide evidence that ER density impacts brainstructure, perfusion and energy production during female endocrine aging, with clinical implications for women's health.
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BACKGROUND: Alzheimer's disease (AD) diagnosis can be hindered by amyloid biomarkers discordances. OBJECTIVE: We aim to interpret discordances between amyloid positron emission tomography (Amy-PET) and cerebrospinal fluid (CSF) (Aß42 and Aß42/40), using Amy-PET semiquantitative analysis, [18F]fluorodeoxyglucose (FDG)-PET pattern, and CSF assays. METHOD: Thirty-six subjects with dementia or mild cognitive impairment, assessed by neuropsychological tests, structural and functional imaging, and CSF assays (Aß42, Aß42/40, p-tau, t-tau), were retrospectively examined. Amy-PET and FDG-PET scans were analyzed by visual assessment and voxel-based analysis. SUVR were calculated on Amy-PET scans. RESULTS: Groups were defined basing on the agreement among CSF Aß42 (A), CSF Aß42/40 Ratio (R), and Amy-PET (P) dichotomic results ( ±). In discordant groups, CSF assays, Amy-PET semiquantification, and FDG-PET patterns supported the diagnosis suggested by any two agreeing amyloid biomarkers. In groups with discordant CSF Aß42, the ratio always agrees with Amy-PET results, solving both false-negative and false-positive Aß42 results, with Aß42 levels close to the cut-off in A + R-P- subjects. The A + R + P- group presented high amyloid deposition in relevant areas, such as precuneus, posterior cingulate cortex (PCC) and dorsolateral frontal inferior cortex at semiquantitative analysis. CONCLUSION: The amyloid discordant cases could be overcome by combining CSF Aß42, CSF ratio, and Amy-PET results. The concordance of any 2 out of the 3 biomarkers seems to reveal the remaining one as a false result. A cut-off point review could avoid CSF Aß42 false-negative results. The regional semiquantitative Amy-PET analysis in AD areas, such as precuneus and PCC, could increase the accuracy in AD diagnosis.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico por imagen , Humanos , Fragmentos de Péptidos/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeoRESUMEN
OBJECTIVE: To investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates. METHODS: The same standardized picture naming test was administered to a consecutive sample of patients (n = 148) who had been studied with [18F] FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network. RESULTS: Semantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital-posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors. CONCLUSIONS: Naming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias.
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Conectoma , Demencia , Lenguaje , Enfermedades Neurodegenerativas , Lóbulo Occipital , Tomografía de Emisión de Positrones , Lóbulo Temporal , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Afasia Progresiva Primaria/diagnóstico por imagen , Afasia Progresiva Primaria/metabolismo , Afasia Progresiva Primaria/fisiopatología , Demencia/diagnóstico por imagen , Demencia/metabolismo , Demencia/fisiopatología , Femenino , Fluorodesoxiglucosa F18 , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/fisiopatología , Humanos , Masculino , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Lóbulo Occipital/diagnóstico por imagen , Lóbulo Occipital/metabolismo , Lóbulo Occipital/fisiopatología , Reconocimiento Visual de Modelos/fisiología , Estudios Retrospectivos , Semántica , Habla/fisiología , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/metabolismo , Parálisis Supranuclear Progresiva/fisiopatología , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/metabolismo , Lóbulo Temporal/fisiopatologíaRESUMEN
BACKGROUND: Discordance among amyloid biomarkers is a challenge to overcome in order to increase diagnostic accuracy in dementia. OBJECTIVES: 1) To verify that cerebrospinal fluid (CSF) Aß42/Aß40 ratio (AßR) better agrees with Amyloid PET (Amy-PET) results compared to CSF Aß42; 2) to detect differences among concordant positive, concordant negative, and discordant cases, basing the concordance definition on the agreement between CSF AßR and Amy-PET results; 3) to define the suspected underlying pathology of discordant cases using in vivo biomarkers. METHOD: We retrospectively enrolled 39 cognitively impaired participants in which neuropsychological tests, apolipoprotein E genotype determination, TC/MRI, FDG-PET, Amy-PET, and CSF analysis had been performed. In all cases, CSF analysis was repeated using the automated Lumipulse method. In discordant cases, FDG-PET scans were evaluated visually and using automated classifiers. RESULTS: CSF AßR better agreed with Amy-PET compared to CSF Aß42 (Cohen's K 0.431 versus 0.05). Comparisons among groups did not show any difference in clinical characteristics except for age at symptoms onset that was higher in the 6 discordant cases with abnormal CSF AßR values and negative Amy-PET (CSF AßR+/AmyPET-). FDG-PET and all CSF markers (Aß42, AßR, p-Tau, t-Tau) were suggestive of Alzheimer's disease (AD) in 5 of these 6 cases. CONCLUSION: 1) CSF AßR is the CSF amyloid marker that shows the better level of agreement with Amy-PET results; 2) The use of FDG-PET and CSF-Tau markers in CSFAßR+/Amy-PET-discordant cases can support AD diagnosis; 3) Disagreement between positive CSF AßR and negative Amy-PET in symptomatic aged AD patients could be due to the variability in plaques conformation and a negative Amy-PET scan cannot be always sufficient to rule out AD.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/líquido cefalorraquídeo , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/psicología , Biomarcadores/líquido cefalorraquídeo , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeoAsunto(s)
Encéfalo/fisiopatología , Electroencefalografía/métodos , Demencia Frontotemporal/diagnóstico por imagen , Encefalitis Límbica/diagnóstico por imagen , Trastornos de la Memoria/etiología , Pólipos Adenomatosos/diagnóstico por imagen , Anciano , Diagnóstico Diferencial , Humanos , Encefalitis Límbica/diagnóstico , Encefalitis Límbica/patología , Imagen por Resonancia Magnética , Masculino , Enfermedad de Pick , Tomografía de Emisión de PositronesRESUMEN
BACKGROUND AND PURPOSE: Stress-related catecholamines have a role in cancer and ß-adrenoceptors; specifically, ß2 -adrenoceptors have been identified as new targets in treating melanoma. Recently, ß3 -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which ß3 -adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis. Understanding the mechanisms of cancer immune-tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of ß3 -adrenoceptors in immune-tolerance regulation. EXPERIMENTAL APPROACH: A mouse model of melanoma in which syngeneic B16-F10 cells were injected in C57BL-6 mice was used to evaluate the effect of ß-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with ß-blockers (propranolol and SR59230A) and specific ß-adrenoceptor siRNAs targeting ß2 - or ß3 -adrenoceptors were used. KEY RESULTS: Only ß3 -, but not ß2 -adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. SR59230A and ß3 -adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub-populations in the tumour mass, blood, and spleen. SR59230A and ß3 -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes. CONCLUSIONS AND IMPLICATIONS: Our data suggest that ß3 -adrenoceptors are involved in immune-tolerance, which opens the way for new strategic therapies to overcome melanoma growth. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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Melanoma Experimental/inmunología , Receptores Adrenérgicos beta 3/inmunología , Neoplasias Cutáneas/inmunología , Antagonistas Adrenérgicos beta/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Receptores Adrenérgicos beta 3/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Células Tumorales CultivadasRESUMEN
Bilingualism is an independent component of cognitive reserve that permits to delay dementia onset up to 5 years. We describe a case of a bilingual Italian man affected by mild cognitive impairment with high cognitive reserve that, despite the presence of multiple risk factors (ApoE É4/É4 genotype, older age, untreated Obstructive Sleep Apnea Syndrome, AD-like biomarker alterations) did not convert to Alzheimer's disease up to 5 years follow-up. The present case confirms the role of bilingualism as a strong protective factor for dementia, even in the occurrence of multiple risk factors.
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Enfermedad de Alzheimer/psicología , Disfunción Cognitiva/psicología , Reserva Cognitiva/fisiología , Multilingüismo , Anciano , Progresión de la Enfermedad , Humanos , Italia , Masculino , Pruebas Neuropsicológicas , Factores ProtectoresRESUMEN
Primary bone lymphoma (PBL) is a rare disease. Little is reported about response evaluation procedures in these patients. Our aim was to evaluate response to therapy according to fluorodeoxyglucose-positron emission tomography (FDG-PET) results, and in particular to test the Deauville 5-point scale as compared to the visual evaluation of FDG-PET scans in PBL. In this single-center study, we diagnosed 31 consecutive patients with PBL, of which 24 were evaluated with end-of-treatment FDG-PET. Patients' ages ranged from 19 to 82 years. Six patients were treated with chemotherapy, 24 with chemotherapy and radiotherapy, and one patient with radiotherapy alone. Six patients were affected by a pathological fracture. Four patients died within the range of 3 to 36 months after diagnosis. The average follow-up of the remaining patients was 70 (24-173) months. Overall survival was 87% at 5 years. The only positive prognostic factor was complete remission after chemotherapy. According to visual criteria, end-of-treatment FDG-PET was evaluated in 24 patients and it was positive in 11 (46%) and negative in 13 patients. We organized a retrospective central-blinded revision of end-of-therapy FDG-PET scans using the 5-point Deauville Score (DS). We reviewed 17 out of 24 patients and obtained the following results: at the end of therapy, 12 patients with DS score 2, three patients with DS score 3, one patient with DS score 4, and none with DS score 5. Considering that all the 24 patients achieved complete remission after treatment, visual interpretation produced 11/24 false-positive results, and DS interpretation produced 1/17 false-positive results, thus significantly reducing the number of false positives. In PBL, the final evaluation at the end of therapy with FDG-PET should be evaluated using Deauville 5-point scale in order to significantly reduce the risk of false-positive scans.
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BACKGROUND: An early differentiation between Alzheimer's Disease (AD) and other dementias is crucial for an adequate patients' management, albeit it may result difficult for the occurrence of "atypical presentations." Current diagnostic criteria recognize the importance of biomarkers for AD diagnosis, but still an optimal diagnostic work-up isn't available. OBJECTIVE: Evaluate the utility and reproducibility of biomarkers and propose an "optimal" diagnostic work-up in atypical dementia. METHODS: (1) a retrospective selection of "atypical dementia cases"; (2) a repetition of diagnostic assessment by two neurologists following two different diagnostic work-ups, each consisting of multiple steps; (3) a comparison between diagnostic accuracy and confidence reached at each step by both neurologists and evaluation of the inter-rater agreement. RESULTS: In AD, regardless of the undertaken diagnostic work-up, a significant gain in accuracy was reached by both neurologists after the second step, whereas in frontotemporal dementia (FTD), adding subsequent steps was not always sufficient to increase significantly the baseline accuracy. A relevant increment in diagnostic confidence was detectable after studying pathophysiological markers in AD, and after assessing brain metabolism in FTD. The inter-rater agreement was higher at the second step for the AD group when the pathophysiological markers were available and for the FTD group when the results of FDG-PET were accessible. CONCLUSIONS: In atypical cases of dementia, biomarkers significantly raise diagnostic accuracy, confidence, and agreement. This study introduces a proof of diagnostic work-up that combines imaging and CSF biomarkers and suggests distinct ways to proceed on the basis of a greater diagnostic likelihood.
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Demencia/diagnóstico , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Demencia/metabolismo , Diagnóstico Diferencial , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Variaciones Dependientes del Observador , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosforilación , Tomografía de Emisión de Positrones , Radiofármacos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeoRESUMEN
OBJECTIVE: To examine in a 3-year brain imaging study the effects of higher vs lower adherence to a Mediterranean-style diet (MeDi) on Alzheimer disease (AD) biomarker changes (brain ß-amyloid load via 11C-Pittsburgh compound B [PiB] PET and neurodegeneration via 18F-fluorodeoxyglucose [FDG] PET and structural MRI) in midlife. METHODS: Seventy 30- to 60-year-old cognitively normal participants with clinical, neuropsychological, and dietary examinations and imaging biomarkers at least 2 years apart were examined. These included 34 participants with higher (MeDi+) and 36 with lower (MeDi-) MeDi adherence. Statistical parametric mapping and volumes of interest were used to compare AD biomarkers between groups at cross section and longitudinally. RESULTS: MeDi groups were comparable for clinical and neuropsychological measures. At baseline, compared to the MeDi+ group, the MeDi- group showed reduced FDG-PET glucose metabolism (CMRglc) and higher PiB-PET deposition in AD-affected regions (p < 0.001). Longitudinally, the MeDi--group showed CMRglc declines and PiB increases in these regions, which were greater than those in the MeDi+ group (pinteraction < 0.001). No effects were observed on MRI. Higher MeDi adherence was estimated to provide 1.5 to 3.5 years of protection against AD. CONCLUSION: Lower MeDi adherence was associated with progressive AD biomarker abnormalities in middle-aged adults. These data support further investigation of dietary interventions for protection against brain aging and AD.
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Enfermedad de Alzheimer/dietoterapia , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Dieta Mediterránea , Adulto , Enfermedad de Alzheimer/psicología , Encéfalo/diagnóstico por imagen , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Encuestas y CuestionariosRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0185926.].
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A new risk gene associated with amyotrophic lateral sclerosis (ALS) has recently been identified: the Tank-binding kinase 1 (TBK1) gene. Up to now, 90 TBK1 variants have been described in ALS patients with or without frontotemporal dementia (FTD), thus making TBK1 the third or fourth most frequent genetic cause of ALS and FTD. A point mutation analysis in a cohort of 69 Italian ALS patients was performed in order to analyze the frequency of TBK1 mutations and the correlation with clinical phenotypes. The analysis identified the novel variant p.Tyr424Asp in a patient with a rapid progression of the disease. Our data supports the implication of TBK1 in ALS pathogenesis in Italy.
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Esclerosis Amiotrófica Lateral/genética , Disfunción Cognitiva/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , Anciano , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Ácido Aspártico/genética , Proteína C9orf72/genética , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Análisis Mutacional de ADN , Femenino , Fluorodesoxiglucosa F18/metabolismo , Estudios de Asociación Genética , Humanos , Italia , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Tirosina/genéticaRESUMEN
After advanced age, female sex is the major risk factor for Alzheimer's disease (AD). The biological mechanisms underlying the increased AD risk in women remain largely undetermined. Preclinical studies identified the perimenopause to menopause transition, a neuroendocrine transition state unique to the female, as a sex-specific risk factor for AD. In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency which is sustained thereafter. This study bridges basic to clinical science to characterize brain bioenergetics in a cohort of forty-three, 40-60 year-old clinically and cognitively normal women at different endocrine transition stages including premenopause (controls, CNT, n = 15), perimenopause (PERI, n = 14) and postmenopause (MENO, n = 14). All participants received clinical, laboratory and neuropsychological examinations, 18F-fluoro-deoxyglucose (FDG)-Positron Emission Tomography (PET) FDG-PET scans to estimate CMRglc, and platelet mitochondrial cytochrome oxidase (COX) activity measures. Statistical parametric mapping and multiple regression models were used to examine clinical, CMRglc and COX data across groups. As expected, the MENO group was older than PERI and controls. Groups were otherwise comparable for clinical measures and distribution of APOE4 genotype. Both MENO and PERI groups exhibited reduced CMRglc in AD-vulnerable regions which was correlated with decline in mitochondrial COX activity compared to CNT (p's<0.001). A gradient in biomarker abnormalities was most pronounced in MENO, intermediate in PERI, and lowest in CNT (p<0.001). Biomarkers correlated with immediate and delayed memory scores (Pearson's 0.26≤r≤0.32, p≤0.05). These findings validate earlier preclinical findings and indicate emergence of bioenergetic deficits in perimenopausal and postmenopausal women, suggesting that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.
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Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Metabolismo Energético/fisiología , Perimenopausia/metabolismo , Posmenopausia/metabolismo , Adulto , Envejecimiento/patología , Envejecimiento/psicología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Plaquetas/metabolismo , Plaquetas/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Mapeo Encefálico , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Fluorodesoxiglucosa F18/administración & dosificación , Glucosa/metabolismo , Humanos , Memoria/fisiología , Persona de Mediana Edad , Mitocondrias/enzimología , Mitocondrias/patología , Pruebas Neuropsicológicas , Perimenopausia/psicología , Fenotipo , Tomografía de Emisión de Positrones , Posmenopausia/fisiología , Radiofármacos/administración & dosificaciónRESUMEN
OBJECTIVE: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. METHODS: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (ß-amyloid [Aß] deposition, a hallmark of AD pathology). RESULTS: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aß deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Aß deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001). CONCLUSIONS: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.
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Envejecimiento/metabolismo , Envejecimiento/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagen , Caracteres Sexuales , Adulto , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores/metabolismo , Encéfalo/metabolismo , Sistema Endocrino/metabolismo , Endofenotipos , Femenino , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Menopausia/metabolismo , Persona de Mediana Edad , Imagen Multimodal , Tamaño de los Órganos , Tomografía de Emisión de Positrones , Radiofármacos , RiesgoRESUMEN
Taking advantage of the structural similarity between aspartic proteases, small-molecule peptidomimetic inhibitors that already showed activity towards Secreted Aspartic Protease 2 as anti-Candida agents and HIV protease inhibitors were exploited as potential BACE1 inhibitors. A focused library of 6,8-dioxa-3-azabicyclo[3.2.1]-octane peptidomimetic scaffolds was synthesized and assayed towards BACE1 enzyme, resulting in the identification of a thiolactam-containing hit compound possessing IC50 in the low micromolar range, and confirming the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Peptidomiméticos/química , Peptidomiméticos/farmacología , Acetales/síntesis química , Acetales/química , Acetales/farmacología , Secuencia de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/química , Ácido Aspártico Endopeptidasas/metabolismo , Compuestos de Azabiciclo/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Humanos , Simulación del Acoplamiento Molecular , Peptidomiméticos/síntesis química , Alineación de SecuenciaRESUMEN
According to the literature, the APP Ala713Thr mutation is associated with Alzheimer's disease and cerebral amyloid angiopathy. We describe a case of dementia clinically compatible with frontotemporal dementia in an APP Ala713Thr mutation carrier in which both [18F]Florbetapir PET uptake and Aß1-42 cerebrospinal fluid levels were normal. Further evidences are required to establish if this association is only incidental.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/genética , Mutación/genética , Fragmentos de Péptidos/líquido cefalorraquídeo , Alanina/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Compuestos de Anilina/metabolismo , Encéfalo/diagnóstico por imagen , Glicoles de Etileno/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Treonina/genéticaRESUMEN
INTRODUCTION: Ischemia in hypertrophic cardiomyopathy (HCM) is caused by coronary microvascular dysfunction (CMD), which is detected by measuring myocardial blood flow (MBF) with PET. Whether CMD may be associated with ischemic left ventricular (LV) dysfunction is unclear. We therefore assessed LV ejection fraction (EF) reserve in HCM patients undergoing dipyridamole (Dip) PET. METHODS: Resting and stress 13NH3 dynamic as well as gated PET were performed in 34 HCM patients. Segmental MBF and transmural perfusion gradient (TPG = subendocardial / subepicardial MBF) were assessed. LVEF reserve was considered abnormal if Dip LVEF decreased more than 5 units as compared to rest. RESULTS: Eighteen patients had preserved (group A) and 16 abnormal LVEF reserve (group B; range -7 to -32). Group B patients had greater wall thickness than group A, but resting volumes, LVEF, resting and Dip MBF, and myocardial flow reserve were similar. Group B had slightly higher summed stress score and summed difference score in visual analysis than group A, and a significantly higher summed stress wall motion score. In group B, resting TPG was slightly lower (1.31 ± 0.29 vs. 1.37 ± 0.34, p <0.05), and further decreased after Dip, whilst in group A it increased (B = 1.20 ± 0.39, p < 0.0001 vs. rest and vs. A = 1.40 ± 0.43). The number of segments per patient with TPG <1 was higher than in group A (p < 0.001) and was a significant predictor of impaired LVEF reserve (OR 1.86, p < 0.02), together with wall thickness (OR 1.3, p < 0.02). CONCLUSION: Abnormal LVEF response is common in HCM patients following Dip, and is related to abnormal TPG, suggesting that subendocardial ischemia might occur under Dip and cause transient LV dysfunction. Although in vivo this effect may be hindered by the adrenergic drive associated with effort, these findings may have relevance in understanding exercise limitation and heart failure symptoms in HCM.
Asunto(s)
Compuestos de Amonio , Técnicas de Imagen Sincronizada Cardíacas , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/fisiopatología , Circulación Coronaria , Tomografía de Emisión de Positrones , Disfunción Ventricular Izquierda/diagnóstico por imagen , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radioisótopos de Nitrógeno , Volumen SistólicoRESUMEN
Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor ß1 (TGFß1) play a central role. When exposed to TGFß1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of αv integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFß1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with αvß3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFß1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFß1, and reduces both ALK5/TGFß1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing α-smooth muscle actin (α-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.