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Objective: To identify imaging subtypes of the cortico-basal syndrome (CBS) based solely on a data-driven assessment of MRI atrophy patterns, and investigate whether these subtypes provide information on the underlying pathology. Methods: We applied Subtype and Stage Inference (SuStaIn), a machine learning algorithm that identifies groups of individuals with distinct biomarker progression patterns, to a large cohort of 135 CBS cases (52 had a pathological or biomarker defined diagnosis) and 252 controls. The model was fit using volumetric features extracted from baseline T1-weighted MRI scans and validated using follow-up MRI. We compared the clinical phenotypes of each subtype and investigated whether there were differences in associated pathology between the subtypes. Results: SuStaIn identified two subtypes with distinct sequences of atrophy progression; four-repeat-tauopathy confirmed cases were most commonly assigned to the Subcortical subtype (83% of CBS-PSP and 75% of CBS-CBD), while CBS-AD was most commonly assigned to the Fronto-parieto-occipital subtype (81% of CBS-AD). Subtype assignment was stable at follow-up (98% of cases), and individuals consistently progressed to higher stages (100% stayed at the same stage or progressed), supporting the model's ability to stage progression. Interpretation: By jointly modelling disease stage and subtype, we provide data-driven evidence for at least two distinct and longitudinally stable spatiotemporal subtypes of atrophy in CBS that are associated with different underlying pathologies. In the absence of sensitive and specific biomarkers, accurately subtyping and staging individuals with CBS at baseline has important implications for screening on entry into clinical trials, as well as for tracking disease progression.
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There was consensus that both amyloid and tau pathologies should be targeted in Alzheimer's disease, as well as additional pathophysiological mechanisms such as neuroinflammation. The selection of one or both of these targets may depend upon a personalized approach that takes into account the genetic and acquired factors that cause AD in any given person as well as their stage of disease as reflected in a biomarker profile. The validation of this therapeutic approach will be made possible by new methodologies for subdividing into predominant pathology, by efficient methods for identifying people in the earliest stages of disease, and by combination studies.
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Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Biomarcadores , Consenso , Humanos , Proteínas tauRESUMO
The most common clinical phenotype of progressive supranuclear palsy is Richardson syndrome, characterized by levodopa unresponsive symmetric parkinsonism, with a vertical supranuclear gaze palsy, early falls and cognitive impairment. There is currently no detailed understanding of the full sequence of disease pathophysiology in progressive supranuclear palsy. Determining the sequence of brain atrophy in progressive supranuclear palsy could provide important insights into the mechanisms of disease progression, as well as guide patient stratification and monitoring for clinical trials. We used a probabilistic event-based model applied to cross-sectional structural MRI scans in a large international cohort, to determine the sequence of brain atrophy in clinically diagnosed progressive supranuclear palsy Richardson syndrome. A total of 341 people with Richardson syndrome (of whom 255 had 12-month follow-up imaging) and 260 controls were included in the study. We used a combination of 12-month follow-up MRI scans, and a validated clinical rating score (progressive supranuclear palsy rating scale) to demonstrate the longitudinal consistency and utility of the event-based model's staging system. The event-based model estimated that the earliest atrophy occurs in the brainstem and subcortical regions followed by progression caudally into the superior cerebellar peduncle and deep cerebellar nuclei, and rostrally to the cortex. The sequence of cortical atrophy progresses in an anterior to posterior direction, beginning in the insula and then the frontal lobe before spreading to the temporal, parietal and finally the occipital lobe. This in vivo ordering accords with the post-mortem neuropathological staging of progressive supranuclear palsy and was robust under cross-validation. Using longitudinal information from 12-month follow-up scans, we demonstrate that subjects consistently move to later stages over this time interval, supporting the validity of the model. In addition, both clinical severity (progressive supranuclear palsy rating scale) and disease duration were significantly correlated with the predicted subject event-based model stage (P < 0.01). Our results provide new insights into the sequence of atrophy progression in progressive supranuclear palsy and offer potential utility to stratify people with this disease on entry into clinical trials based on disease stage, as well as track disease progression.
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INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.
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Cognição/fisiologia , Exercício Físico , Degeneração Lobar Frontotemporal , Atividades de Lazer , Testes Neuropsicológicos/estatística & dados numéricos , Idoso , Atrofia/patologia , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: We aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration. METHODS: 337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures. RESULTS: DRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity. CONCLUSIONS: We conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD.
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Encéfalo/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Receptores de Dopamina D4/genética , Receptores de Dopamina D4/fisiologia , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Atrofia , Feminino , Demência Frontotemporal/psicologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Polimorfismo Genético , SíndromeRESUMO
Frontotemporal dementias (FTDs) are clinically, genetically and pathologically heterogeneous neurodegenerative disorders that affect the frontal and anterior temporal lobes of the brain. They are relatively common causes of young-onset dementia and usually present with behavioural disturbance (behavioural variant FTD) or language impairment (primary progressive aphasia), but there is also overlap with motor neurone disease and the atypical parkinsonian disorders, corticobasal syndrome and progressive supranuclear palsy. At post mortem, neuronal inclusions containing tau, TDP-43 or infrequently FUS protein are seen in most cases. However, a poor correlation between clinical syndrome and underlying pathology means that it is difficult to diagnose the underlying molecular basis using clinical criteria. At this point, biomarkers for the underlying pathology come into play. This paper provides a brief update on fluid biomarkers for FTDs that may be useful to dissect the underlying molecular changes in patients presenting with signs of frontal and/or temporal lobe dysfunction. The hope is that such biomarkers, together with genetics and imaging, would be useful in clinical trials of novel drug candidates directed against specific pathologies and, in the long run, helpful in clinical practice to select the most appropriate treatment at the right dose for individual patients.
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Biomarcadores/metabolismo , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/metabolismo , HumanosRESUMO
BACKGROUND: Quantification of biofluid cytokines is a rapidly growing area of translational research. However, comparability across the expanding number of available assay platforms for detection of the same proteins remains to be determined. We aimed to directly compare a panel of commonly measured cytokines in plasma of typically aging adults across two high sensitivity quantification platforms, Meso Scale Discovery high performance electrochemiluminiscence (HPE) and single-molecule immunosorbent assays (Simoa) by Quanterix. METHODS: 57 community-dwelling older adults completed a blood draw, neuropsychological assessment, and brain MRI as part of a healthy brain aging study. Plasma samples from the same draw dates were analyzed for IL-10, IP-10, IL-6, TNFα, and IL-1ß on HPE and Simoa, separately. Reliable detectability (coefficient of variance (CV)â¯<â¯20% and outliers 3 interquartiles above the median removed), intra-assay precision, absolute concentrations, reproducibility across platforms, and concurrent associations with external variables of interest (e.g., demographics, peripheral markers of vascular health, and brain health) were examined. RESULTS: The proportion of cytokines reliably measured on HPE (87.7-93.0%) and Simoa (75.4-93.0%) did not differ (psâ¯>â¯0.32), with the exception of IL-1ß which was only reliably measured using Simoa (68.4%). On average, CVs were acceptable at <8% across both platforms. Absolute measured concentrations were higher using Simoa for IL-10, IL-6, and TNFα (psâ¯<â¯0.05). HPE and Simoa shared only small-to-moderate proportions of variance with one another on the same cytokine proteins (range: râ¯=â¯0.26 for IL-10 to râ¯=â¯0.64 for IL-6), though platform agreement did not dependent on cytokine concentrations. Cytokine ratios within each platform demonstrated similar relative patterns of up- and down-regulation across HPE and Simoa, though still significantly differed (psâ¯<â¯0.001). Supporting concurrent validity, all 95% confidence intervals of the correlations between cytokines and external variables overlapped between the two platforms. Moreover, most associations were in expected directions and consistently so across platforms (e.g., IL-6 and TNFα), though with several notable exceptions for IP-10 and IL-10. CONCLUSIONS: HPE and Simoa showed comparable detectability and intra-assay precision measuring a panel of commonly examined cytokine proteins, with the exception of IL-1ß which was not reliably detected on HPE. However, Simoa demonstrated overall higher concentrations and the two platforms did not show agreement when directly compared against one another. Relative cytokine ratios and associations demonstrated similar patterns across platforms. Absolute cytokine concentrations may not be directly comparable across platforms, may be analyte dependent, and interpretation may be best limited to discussion of relative associations.
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Biomarcadores/sangue , Biomarcadores/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoensaio/métodos , Interleucina-10/sangue , Interleucina-10/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Successful therapeutic trials require well-targeted populations to demonstrate the effectiveness of a drug candidate. Most trials in the field of Alzheimer's disease (AD) have been conducted in patients with mild to moderate dementia. However, the advent of amyloid PET imaging has demonstrated that a significant proportion of individuals enrolled in such studies do not have evidence of brain amyloidosis and may in fact not have Alzheimer's disease. Further, dementia represents an advanced stage of neurodegeneration, perhaps too late for significant benefits of disease-modifying interventions. The successful development of effective disease-slowing therapies requires a study population selected in accordance with the mechanism of the specific intervention. An international task force of investigators from academia, industry, non-profit foundations, and regulatory agencies met in San Diego, California, USA, on November 13, 2013, to address issues related to screening and identification of clinical trial participants, and the ramifications of decisions made in this regard for drug development in AD and other dementias.
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OBJECTIVE: We sought to determine whether the Val(158)Met polymorphism in the catechol-O-methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions. METHODS: A total of 252 subjects, including healthy controls and patients with Alzheimer disease, behavioral variant frontotemporal dementia, and semantic dementia, underwent COMT genotyping and structural MRI. RESULTS: Whole-brain voxel-wise regression analyses revealed that COMT Val(158)Met Val allele dosage, known to produce a dose-dependent decrease in synaptic dopamine (DA) availability, correlated with decreased gray matter in the region of the ventral tegmental area (VTA), ventromedial prefrontal cortex, bilateral dorsal midinsula, left dorsolateral prefrontal cortex, and right ventral striatum. Unexpectedly, patients carrying a Met allele showed greater VTA volumes than age-matched controls. Gray matter intensities within COMT-related brain regions correlated with cognitive and behavioral deficits. CONCLUSIONS: The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions.
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Catecol O-Metiltransferase/genética , Córtex Cerebral/patologia , Demência/patologia , Dopamina/fisiologia , Idoso , Alelos , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Córtex Cerebral/metabolismo , Demência/etiologia , Dopamina/genética , Feminino , Demência Frontotemporal/etiologia , Demência Frontotemporal/patologia , Degeneração Lobar Frontotemporal/etiologia , Degeneração Lobar Frontotemporal/patologia , Genótipo , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Metionina/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Valina/genéticaRESUMO
OBJECTIVE: To create and validate a simple, standardized version of the antisaccade (AS) task that requires no specialized equipment for use as a measure of executive function in multicenter clinical studies. METHODS: The bedside AS (BAS) task consisted of 40 pseudorandomized AS trials presented on a laptop computer. BAS performance was compared with AS performance measured using an infrared eye tracker in normal elders (NE) and individuals with mild cognitive impairment (MCI) or dementia (n = 33). The neuropsychological domain specificity of the BAS was then determined in a cohort of NE, MCI, and dementia (n = 103) at UCSF, and the BAS was validated as a measure of executive function in a 6-center cohort (n = 397) of normal adults and patients with a variety of brain diseases. RESULTS: Performance on the BAS and laboratory AS task was strongly correlated and BAS performance was most strongly associated with neuropsychological measures of executive function. Even after controlling for disease severity and processing speed, BAS performance was associated with multiple assessments of executive function, most strongly the informant-based Frontal Systems Behavior Scale. CONCLUSIONS: The BAS is a simple, valid measure of executive function in aging and neurologic disease.
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Encefalopatias/fisiopatologia , Função Executiva/fisiologia , Testes Neuropsicológicos/normas , Movimentos Sacádicos/fisiologia , Idoso , Envelhecimento/fisiologia , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Demência/fisiopatologia , Medições dos Movimentos Oculares , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To derive an algorithm for genetic testing of patients with frontotemporal lobar degeneration (FTLD). METHODS: A literature search was performed to review the clinical and pathologic phenotypes and family history associated with each FTLD gene. RESULTS: Based on the literature review, an algorithm was developed to allow clinicians to use the clinical and neuroimaging phenotypes of the patient and the family history and autopsy information to decide whether or not genetic testing is warranted, and if so, the order for appropriate tests. CONCLUSIONS: Recent findings in genetics, pathology, and imaging allow clinicians to use the clinical presentation of the patient with FTLD to inform genetic testing decisions.
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Algoritmos , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Testes Genéticos/normas , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normas , Árvores de Decisões , Diagnóstico Diferencial , Feminino , Degeneração Lobar Frontotemporal/fisiopatologia , Testes Genéticos/economia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , FenótipoRESUMO
OBJECTIVE: To compare the in vivo uptake of two amyloid-binding PET agents, PIB and FDDNP, in human subjects with a prion protein (PrP) gene (PRNP) mutation that produces a clinical syndrome similar to Alzheimer disease (AD). BACKGROUND: Amyloid imaging with specific PET ligands offers great promise for early detection and differential diagnosis of AD. Genetic forms of prion disease can present with clinical features that resemble AD, and at autopsy may show deposition of mutant PrP-amyloid. FDDNP binds to PrP-amyloid in postmortem human specimens, but has not been reported in vivo in prion disease. The ability of PIB to bind PrP-amyloid is not known. METHODS: Two brothers with a 6 octapeptide repeat insertion mutation (6-OPRI) in the PRNP gene underwent clinical, structural MRI, and FDG-PET evaluations. One brother received a PIB-PET evaluation, while the other received an FDDNP-PET scan. PET results were compared with five normal subjects and five individuals with AD scanned with either agent. RESULTS: PIB uptake was similar to controls in one brother, while FDDNP uptake was intermediate between AD and controls in the other brother. CONCLUSIONS: Different amyloid-binding agents may have differential sensitivity to prion-related brain pathology. A combination of amyloid imaging agents may be useful in the diagnosis of early-onset dementia.
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Doença de Alzheimer/diagnóstico por imagem , Amiloide/análise , Tomografia por Emissão de Pósitrons/métodos , Doenças Priônicas/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Mutação , Doenças Priônicas/diagnóstico , Doenças Priônicas/genéticaRESUMO
The neurocognitive features of juvenile-onset Huntington disease (HD) are not well understood. We present three patients with onset of HD symptoms before age 10 years in whom speech delay was the first symptom. Speech delay predated motor symptoms by at least 2 years, and language function was consistently impaired on formal testing. Screening for speech delay is particularly important in children with a family history of HD.
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Doença de Huntington/complicações , Doença de Huntington/diagnóstico , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , PrognósticoRESUMO
Pedigrees from 269 patients with frontotemporal lobar degeneration (FTLD), including frontotemporal dementia (FTD), FTD with ALS (FTD/ALS), progressive nonfluent aphasia, semantic dementia (SD), corticobasal degeneration, and progressive supranuclear palsy were analyzed to determine the degree of heritability of these disorders. FTD/ALS was the most and SD the least heritable subtype. FTLD syndromes appear to have different etiologies and recurrence risks.
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Demência/genética , Predisposição Genética para Doença/genética , Padrões de Herança/genética , Tauopatias/genética , Adulto , Idoso , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/genética , Afasia Primária Progressiva/genética , Transtornos Cromossômicos/genética , Estudos de Coortes , Saúde da Família , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Estudos Retrospectivos , Paralisia Supranuclear Progressiva/genética , Proteínas tau/genéticaRESUMO
An elevated serum homocysteine level is a risk factor for the development of cognitive impairment. Reported is a late-onset case of hyperhomocystinemia due to a vitamin B12 metabolic deficit (cobalamin C) with cognitive impairment, primarily in frontal/executive function. After homocysteine-lowering therapy, the patient's functional and neuropsychological status improved in conjunction with a decrease in leukoariosis on his MRI scan. These findings suggest that homocysteine-related cognitive impairment may be partially reversible.
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Transtornos Cognitivos/etiologia , Confusão/etiologia , Homocisteína/sangue , Hiper-Homocisteinemia/complicações , Leucoaraiose/etiologia , Convulsões/etiologia , Adulto , Anticoagulantes/uso terapêutico , Betaína/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Confusão/tratamento farmacológico , Confusão/metabolismo , Progressão da Doença , Quimioterapia Combinada , Ácido Fólico/uso terapêutico , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Homocisteína/antagonistas & inibidores , Humanos , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/fisiopatologia , Leucoaraiose/diagnóstico , Leucoaraiose/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Ácido Metilmalônico/sangue , Ácido Metilmalônico/metabolismo , Indução de Remissão , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Resultado do Tratamento , Vitamina B 12/metabolismo , Vitamina B 12/uso terapêutico , Vitamina B 6/uso terapêuticoRESUMO
Laryngeal carcinoma is one of the commonest primary head and neck malignancy and the need for early identification is very important for successful treatment. Outpatient fibreoptic examination of the larynx is unreliable in differentiating benign, pre-malignant and malignant lesions, and therefore surgeons have to rely on biopsies for a definitive diagnosis. This is an invasive procedure requiring general anaesthesia and may have a detrimental effect on the patient's voice. Conventional imaging modalities (ultrasound, computed tomography and magnetic resonance imaging) have a limited resolution and hence cannot give sufficient information on the extent or nature of laryngeal lesions. The aim of our study is to investigate the feasibility of optical coherence tomography (OCT) in imaging the normal larynx, to lay the foundations for an investigation of its ability to differentiate between benign and malignant disease. Ten tissue specimens from normal larynges were imaged with an 850 nm OCT system that was capable of providing both B-scan (longitudinal or cross-section) images as well as C-scan (en-face or images at constant depth). The en-face OCT mode allowed us to reconstruct 3-D OCT images of the tissue examined. Imaged specimens were processed with standard histopathological techniques and sectioned in the plane of the B-scan OCT images. Haematoxylin-eosin stained specimens were compared with the OCT images thus collected. Preliminary results showed good correlation between OCT images and histology sections in normal tissue.
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Imageamento Tridimensional/instrumentação , Mucosa Laríngea/patologia , Tomografia de Coerência Óptica/instrumentação , Humanos , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/cirurgia , Laringectomia , Imageamento por Ressonância Magnética , Invasividade NeoplásicaRESUMO
OBJECTIVE: To explore the structural neuroimaging correlates of visual constructive impairment in patients with mild to moderate Alzheimer disease (AD). BACKGROUND: There is considerable heterogeneity in the non-memory cognitive deficits associated with AD. Structural neuroimaging with MRI is an important diagnostic tool that is gaining acceptance as a surrogate measure of brain pathology in AD treatment trials. Most MRI measurements have focused on medial temporal lobe or global cortical atrophy, which may not reflect some important clinical features of AD. METHODS: Thirty-two patients with probable AD were stratified into two groups based on their relative performance on a visual constructive task, the copy of a modified Rey-Osterrieth figure (Rey). The two groups did not differ in basic demographic features or in neuropsychological performance, other than on the visual constructive task. MRI measurements of hippocampal volume, cortical gray matter volume, and focal cortical gray matter loss were performed in the patients and a group of 71 age-matched, normal controls. RESULTS: Both groups showed significant, bilateral hippocampal as well as cortical gray matter volume loss relative to controls. The more spatially impaired AD group (SAD) had more right than left cortical gray matter loss, whereas the opposite was true in the less spatially impaired group (NSAD). The SAD group had significantly less gray matter in the right inferior temporal gyrus relative to the NSAD group. Atrophy of this region was correlated with performance on the Rey task in all patients with AD. CONCLUSIONS: Right inferotemporal atrophy may serve as a neuroimaging marker of visual constructive impairment in mild to moderate AD. Heterogeneous cortical atrophy is a common feature of AD.
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Doença de Alzheimer/patologia , Lobo Temporal/patologia , Transtornos da Visão/patologia , Idoso , Doença de Alzheimer/diagnóstico , Atrofia , Córtex Cerebral/patologia , Feminino , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos da Visão/diagnósticoRESUMO
Peptide growth factors such as the neurotrophins and fibroblast growth factors have potent effects on synaptic transmission, development, and cell survival. We report that chronic (hours) treatment with basic fibroblast growth factor (FGF-2) potentiates Ca(2+)-dependent N-methyl-D-aspartate (NMDA) receptor inactivation in cultured hippocampal neurons. This effect is specific for the NMDA-subtype of ionotropic glutamate receptor and FGF-2. The potentiated inactivation requires ongoing protein synthesis during growth factor treatment and the activity of protein phosphatase 2B (PP2B or calcineurin) during agonist application. These results suggest a mechanism by which FGF-2 receptor signaling may regulate neuronal survival and synaptic plasticity.
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Cálcio/fisiologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Actinina/fisiologia , Animais , Calcineurina/metabolismo , Canais de Cálcio/fisiologia , Células Cultivadas , Estimulação Elétrica , Eletrofisiologia , Hipocampo/citologia , Imuno-Histoquímica , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Técnicas de Patch-Clamp , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: To explore the medical issues, attitudes, concerns, and choices that parents have about their children born with the use of assisted reproductive technology (ART). DESIGN: Retrospective and prospective survey. SETTING: An academic medical center and a private practice. PATIENT(S): Participants who conceived and were delivered of infants in two ART programs. INTERVENTION(S): A total of 373 patients were mailed an anonymous survey, a consent form, and the Parent Child Relationship Inventory. The rate of response was approximately 49% for clinic A and 33% for clinic B. MAIN OUTCOME MEASURE(S): Pregnancy outcomes and attitudes about parenting. RESULT(S): Respondents' major concerns during pregnancy revolved around miscarriage and the infant's health; complications occurred in 38.9% of first pregnancies. Parents believed that their children were more appreciated, that their children were not emotionally different, that ART did not create ongoing medical or emotional problems, and they were not overprotective as parents. Gender differences were statistically significant on attitudinal variables. CONCLUSION(S): Parents had concerns about pregnancy. Overall, men and women felt positive about ART and their parenting. The ART experience is associated with complex choices, attitudes, and emotions.
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Atitude , Fertilização in vitro , Relações Pais-Filho , Criança , Demografia , Feminino , Transferência Intrafalopiana de Gameta , Humanos , Lactente , Masculino , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Psicometria , Estudos RetrospectivosRESUMO
There remains a great deal to be accomplished in freeing many millions of gays and lesbian from the tyranny of fear of discovery, of actual and potential economic disenfranchisement, of the burden of ridicule, shame, and scorn, and of penalties for alleged criminal behavior. Nevertheless, the recognized status, for example, of openly gay and lesbian psychologists ... is light years away from their inferior and almost certainly closed status of 1954. They are not only free now of the criminal penalties and of the stigma of mental illness, but are in positions of trust, respect, and power.