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1.
Brain Behav Immun ; 80: 644-656, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31063847

RESUMO

Individuals with intact cognition and neuropathology consistent with Alzheimer's disease (AD) are referred to as asymptomatic AD (AsymAD). These individuals are highly likely to develop AD, yet transcriptomic changes in the brain which might reveal mechanisms for their AD vulnerability are currently unknown. Entorhinal cortex, frontal cortex, temporal cortex and cerebellum tissue from 27 control, 33 AsymAD and 52 AD human brains were microarray expression profiled. Differential expression analysis identified a significant increase of transcriptomic activity in the frontal cortex of AsymAD subjects, suggesting fundamental changes in AD may initially begin within the frontal cortex region prior to AD diagnosis. Co-expression analysis identified an overactivation of the brain "glutamate-glutamine cycle", and disturbances in the brain energy pathways in both AsymAD and AD subjects, while the connectivity of key hub genes in this network indicates a shift from an already increased cell proliferation in AsymAD subjects to stress response and removal of amyloidogenic proteins in AD subjects. This study provides new insight into the earliest biological changes occurring in the brain prior to the manifestation of clinical AD symptoms and provides new potential therapeutic targets for early disease intervention.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Redes Reguladoras de Genes/genética , Idoso , Idoso de 80 Anos ou mais , Astrócitos/metabolismo , Encéfalo/metabolismo , Cognição/fisiologia , Progressão da Doença , Feminino , Lobo Frontal/metabolismo , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Mitocôndrias/genética , Análise Serial de Tecidos/métodos , Transcriptoma/genética
2.
Transl Psychiatry ; 9(1): 150, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123309

RESUMO

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (rg ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h2SNP) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h2SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/estatística & dados numéricos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Adulto , Criança , Humanos
3.
Schizophr Res ; 209: 88-97, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31113746

RESUMO

BACKGROUND: Psychosis is a condition influenced by an interaction of environmental and genetic factors. Gene expression studies can capture these interactions; however, studies are usually performed in patients who are in remission. This study uses blood of first episode psychosis patients, in order to characterise deregulated pathways associated with psychosis symptom dimensions. METHODS: Peripheral blood from 149 healthy controls and 131 first episode psychosis patients was profiled using Illumina HT-12 microarrays. A case/control differential expression analysis was performed, followed by correlation of gene expression with positive and negative syndrome scale (PANSS) scores. Enrichment analyses were performed on the associated gene lists. We test for pathway differences between first episode psychosis patients who qualify for a Schizophrenia diagnosis against those who do not. RESULTS: A total of 978 genes were differentially expressed and enriched for pathways associated to immune function and the mitochondria. Using PANSS scores we found that positive symptom severity was correlated with immune function, while negative symptoms correlated with mitochondrial pathways. CONCLUSIONS: Our results identified gene expression changes correlated with symptom severity and showed that key pathways are modulated by positive and negative symptom dimensions.


Assuntos
Transtornos Psicóticos/genética , Esquizofrenia/genética , Transcriptoma , Adolescente , Adulto , Transtornos Psicóticos Afetivos/genética , Transtornos Psicóticos Afetivos/psicologia , Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Transtorno Depressivo/genética , Transtorno Depressivo/psicologia , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Transtornos Psicóticos/psicologia , RNA/sangue , Psicologia do Esquizofrênico , Índice de Gravidade de Doença , Adulto Jovem
4.
Nat Commun ; 10(1): 1150, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850646

RESUMO

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.


Assuntos
Alopecia/congênito , Loci Gênicos , Predisposição Genética para Doença , Antígeno HLA-B7/genética , Transcriptoma/imunologia , Imunidade Adaptativa , Alopecia/diagnóstico , Alopecia/genética , Alopecia/fisiopatologia , Estudos de Casos e Controles , Estudos de Coortes , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/imunologia , Feminino , Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Antígeno HLA-B7/imunologia , Humanos , Imunidade Inata , Polimorfismo de Nucleotídeo Único
5.
J Allergy Clin Immunol ; 143(6): 2120-2130, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30578879

RESUMO

BACKGROUND: Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness. OBJECTIVE: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti-TNF-α) and ustekinumab (anti-IL-12/23). METHODS: This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables. RESULTS: HLA-C*06:02-negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio [OR], 2.95; P = 5.85 × 10-7), and the difference was greater in HLA-C*06:02-negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10-5). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10-4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1. CONCLUSION: This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.


Assuntos
Adalimumab/uso terapêutico , Terapia Biológica/métodos , Biomarcadores Farmacológicos , Genótipo , Antígenos HLA-C/genética , Psoríase/genética , Ustekinumab/uso terapêutico , Adulto , Alelos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Valor Preditivo dos Testes , Prognóstico , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
6.
Nat Commun ; 9(1): 5075, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30542056

RESUMO

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne.


Assuntos
Acne Vulgar/genética , Acne Vulgar/patologia , Predisposição Genética para Doença/genética , Folículo Piloso/crescimento & desenvolvimento , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla , Infecções por Bactérias Gram-Positivas/microbiologia , Infecções por Bactérias Gram-Positivas/patologia , Humanos , Laminina/biossíntese , Laminina/genética , Masculino , Proteínas de Membrana/metabolismo , Propionibacterium acnes/crescimento & desenvolvimento , Semaforinas/genética , Pele/patologia , Proteínas Wnt/genética
7.
Transl Psychiatry ; 8(1): 174, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-30171181

RESUMO

In this study, we aimed to test if the schizophrenia (SCZ) polygenic risk score (PRS) was associated with clinical symptoms in (a) the first episode of psychosis pre-treatment (FEP), (b) at nine weeks after initiation of risperidone treatment (FEP-9W) and (c) with the response to risperidone. We performed a detailed clinical assessment of 60 FEP patients who were antipsychotic-naive and, again, after nine weeks of standardized treatment with risperidone. After blood collection and DNA isolation, the samples were genotyped using the Illumina PsychArrayChip and then imputed. To calculate PRS, we used the latest available GWAS summary statistics from the Psychiatric Genomics Consortium wave-2 SCZ group as a training set. We used Poisson regression to test association between PRS and clinical measurements correcting for the four principal components (genotyping). We considered a p-value < 0.0014 (Bonferroni correction) as significant. First, we verified that the schizophrenia PRS was also able to distinguish cases from controls in this south-eastern Brazilian sample, with a similar variance explained to that seen in Northern European populations. In addition, within-cases analyses, we found that PRS is significantly correlated with baseline (pre-treatment) symptoms, as measured by lower clinical global assessment of functioning (-GAF), higher depressive symptoms and higher scores on a derived excitement factor. After standardized treatment for nine weeks, the correlation with GAF and the excitement factor disappeared while depressive symptoms became negatively associated with PRS. We conclude that drug (and other treatments) may confound attempts to understand the aetiological influence on symptomatology of polygenic risk scores. These results highlight the importance of studying schizophrenia, and other disorders, pre-treatment to understand the relationship between polygenic risk and phenotypic features.


Assuntos
Antipsicóticos/uso terapêutico , Predisposição Genética para Doença , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Adolescente , Adulto , Brasil , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Medição de Risco , Risperidona/uso terapêutico , Adulto Jovem
8.
Sci Rep ; 7(1): 14738, 2017 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-29116126

RESUMO

Many antipsychotics promote weight gain, which can lead to non-compliance and relapse of psychosis. By developing models that accurately identify individuals at greater risk of weight gain, clinicians can make informed treatment decisions and target intervention measures. We examined clinical, genetic and expression data for 284 individuals with psychosis derived from a previously published randomised controlled trial (IMPACT). These data were used to develop regression and classification models predicting change in Body Mass Index (BMI) over one year. Clinical predictors included demographics, anthropometrics, cardiac and blood measures, diet and exercise, physical and mental health, medication and BMI outcome measures. We included genetic polygenic risk scores (PRS) for schizophrenia, bipolar disorder, BMI, waist-hip-ratio, insulin resistance and height, as well as gene co-expression modules generated by Weighted Gene Co-expression Network Analysis (WGCNA). The best performing predictive models for BMI and BMI gain after one year used clinical data only, which suggests expression and genetic data do not improve prediction in this cohort.


Assuntos
Antipsicóticos/uso terapêutico , Índice de Massa Corporal , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologia , Ganho de Peso/efeitos dos fármacos , Adulto , Antipsicóticos/efeitos adversos , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/genética , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Hum Mol Genet ; 26(21): 4301-4313, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973304

RESUMO

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.


Assuntos
Psoríase/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Exoma , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética , Psoríase/fisiopatologia , Fatores de Risco , TYK2 Quinase/genética , TYK2 Quinase/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Sequenciamento Completo do Exoma
10.
Am J Med Genet B Neuropsychiatr Genet ; 174(4): 427-434, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28394502

RESUMO

Antidepressant-induced hippocampal neurogenesis (AHN) is hypothesized to contribute to increases in hippocampal volume among major depressive disorder patients after long-term treatment. Furthermore, rodent studies suggest AHN may be the cellular mechanism mediating the therapeutic benefits of antidepressants. Here, we perform the first investigation of genome-wide expression changes associated with AHN in human cells. We identify gene expression networks significantly activated during AHN, and we perform gene set analyses to probe the molecular relationship between AHN, hippocampal volume, and antidepressant response. The latter were achieved using genome-wide association summary data collected from 30,717 individuals as part of the ENIGMA Consortium (genetic predictors of hippocampal volume dataset), and data collected from 1,222 major depressed patients as part of the NEWMEDS Project (genetic predictors of response to antidepressants dataset). Our results showed that the selective serotonin reuptake inhibitor, escitalopram evoked AHN in human cells; dose-dependently increasing the differentiation of cells into neuroblasts, as well as increasing gliogenesis. Activated genome-wide expression networks relate to axon and microtubule formation, and ribosomal biogenesis. Gene set analysis revealed that gene expression changes associated with AHN were nominally enriched for genes predictive of hippocampal volume, but not for genes predictive of therapeutic response.


Assuntos
Citalopram/farmacologia , Transtorno Depressivo Maior/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genoma Humano , Estudo de Associação Genômica Ampla , Hipocampo/metabolismo , Neurogênese/genética , Antidepressivos de Segunda Geração/farmacologia , Células Cultivadas , Transtorno Depressivo Maior/tratamento farmacológico , Redes Reguladoras de Genes/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
11.
World J Biol Psychiatry ; 18(3): 215-226, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27376411

RESUMO

OBJECTIVES: Exposure-based cognitive behavioural therapy (eCBT) is an effective treatment for anxiety disorders. Response varies between individuals. Gene expression integrates genetic and environmental influences. We analysed the effect of gene expression and genetic markers separately and together on treatment response. METHODS: Adult participants (n ≤ 181) diagnosed with panic disorder or a specific phobia underwent eCBT as part of standard care. Percentage decrease in the Clinical Global Impression severity rating was assessed across treatment, and between baseline and a 6-month follow-up. Associations with treatment response were assessed using expression data from 3,233 probes, and expression profiles clustered in a data- and literature-driven manner. A total of 3,343,497 genetic variants were used to predict treatment response alone and combined in polygenic risk scores. Genotype and expression data were combined in expression quantitative trait loci (eQTL) analyses. RESULTS: Expression levels were not associated with either treatment phenotype in any analysis. A total of 1,492 eQTLs were identified with q < 0.05, but interactions between genetic variants and treatment response did not affect expression levels significantly. Genetic variants did not significantly predict treatment response alone or in polygenic risk scores. CONCLUSIONS: We assessed gene expression alone and alongside genetic variants. No associations with treatment outcome were identified. Future studies require larger sample sizes to discover associations.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Terapia Implosiva/métodos , Transtorno de Pânico/genética , Transtorno de Pânico/terapia , Transtornos Fóbicos/genética , Transtornos Fóbicos/terapia , Adulto , Feminino , Expressão Gênica , Marcadores Genéticos , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Alemanha , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fenótipo , Resultado do Tratamento
12.
Psychiatr Genet ; 26(5): 211-7, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27315048

RESUMO

OBJECTIVES: Clozapine is an atypical antipsychotic primarily prescribed for treatment-resistant schizophrenia. We tested the specific effect of clozapine versus other drug treatments on whole-blood gene expression in a sample of patients with psychosis from the UK. METHODS: A total of 186 baseline whole-blood samples from individuals receiving treatment for established psychosis were analysed for gene expression on Illumina HumanHT-12.v4 BeadChips. After standard quality-control procedures, 152 samples remained, including 55 from individuals receiving clozapine. In a within-case study design, weighted gene correlation network analysis was used to identify modules of coexpressed genes. The influence of mood stabilizers, lithium carbonate/lithium citrate and sodium valproate was studied to identify their possible roles as confounders. RESULTS: Individuals receiving clozapine as their only antipsychotic (clozapine monotherapy) had a nominal association with one gene-expression module, whereas no significant change in gene expression was found for other drugs. CONCLUSION: Overall, this study does not provide evidence that clozapine treatment induces medium to large different gene-expression patterns in human whole blood versus other antipsychotic treatments. This does not rule out the possibility of smaller effects as observed for other common antipsychotic treatments.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Adulto , Antipsicóticos/sangue , Clozapina/sangue , Feminino , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Risperidona/uso terapêutico , Esquizofrenia/sangue
13.
Biomed Opt Express ; 6(6): 2191-210, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26114038

RESUMO

Adaptive optics scanning laser ophthalmoscopy (AO-SLO) has recently been used to achieve exquisite subcellular resolution imaging of the mouse retina. Wavefront sensing-based AO typically restricts the field of view to a few degrees of visual angle. As a consequence the relationship between AO-SLO data and larger scale retinal structures and cellular patterns can be difficult to assess. The retinal vasculature affords a large-scale 3D map on which cells and structures can be located during in vivo imaging. Phase-variance OCT (pv-OCT) can efficiently image the vasculature with near-infrared light in a label-free manner, allowing 3D vascular reconstruction with high precision. We combined widefield pv-OCT and SLO imaging with AO-SLO reflection and fluorescence imaging to localize two types of fluorescent cells within the retinal layers: GFP-expressing microglia, the resident macrophages of the retina, and GFP-expressing cone photoreceptor cells. We describe in detail a reflective afocal AO-SLO retinal imaging system designed for high resolution retinal imaging in mice. The optical performance of this instrument is compared to other state-of-the-art AO-based mouse retinal imaging systems. The spatial and temporal resolution of the new AO instrumentation was characterized with angiography of retinal capillaries, including blood-flow velocity analysis. Depth-resolved AO-SLO fluorescent images of microglia and cone photoreceptors are visualized in parallel with 469 nm and 663 nm reflectance images of the microvasculature and other structures. Additional applications of the new instrumentation are discussed.

15.
Invest Ophthalmol Vis Sci ; 55(12): 7904-18, 2014 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-25324288

RESUMO

PURPOSE: To test the recently proposed hypothesis that the second outer retinal band, observed in clinical OCT images, originates from the inner segment ellipsoid, by measuring: (1) the thickness of this band within single cone photoreceptors, and (2) its respective distance from the putative external limiting membrane (band 1) and cone outer segment tips (band 3). METHODS: Adaptive optics-optical coherence tomography images were acquired from four subjects without known retinal disease. Images were obtained at foveal (2°) and perifoveal (5°) locations. Cone photoreceptors (n = 9593) were identified and segmented in three dimensions using custom software. Features corresponding to bands 1, 2, and 3 were automatically identified. The thickness of band 2 was assessed in each cell by fitting the longitudinal reflectance profile of the band with a Gaussian function. Distances between bands 1 and 2, and between 2 and 3, respectively, were also measured in each cell. Two independent calibration techniques were employed to determine the depth scale (physical length per pixel) of the imaging system. RESULTS: When resolved within single cells, the thickness of band 2 is a factor of three to four times narrower than in corresponding clinical OCT images. The distribution of band 2 thickness across subjects and eccentricities had a modal value of 4.7 µm, with 48% of the cones falling between 4.1 and 5.2 µm. No significant differences were found between cells in the fovea and perifovea. The distance separating bands 1 and 2 was found to be larger than the distance between bands 2 and 3, across subjects and eccentricities, with a significantly larger difference at 5° than 2°. CONCLUSIONS: On the basis of these findings, we suggest that ascription of the outer retinal band 2 to the inner segment ellipsoid is unjustified, because the ellipsoid is both too thick and proximally located to produce the band.


Assuntos
Técnicas de Diagnóstico Oftalmológico , Retina/anatomia & histologia , Tomografia de Coerência Óptica , Membrana Basal/anatomia & histologia , Humanos , Modelos Anatômicos , Células Fotorreceptoras Retinianas Cones/citologia , Segmento Interno das Células Fotorreceptoras da Retina , Segmento Externo das Células Fotorreceptoras da Retina , Tomografia de Coerência Óptica/métodos
16.
Neurobiol Aging ; 35(2): 279-90, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24064185

RESUMO

An increased risk of developing Alzheimer's disease (AD) has previously been found to be associated with variants at the MS4A6A locus. We sought to identify which genes and transcripts in this region have altered expression in AD and mild cognitive impairment (MCI) and are influenced by the AD risk variant(s), as a first step to understanding the molecular basis of AD susceptibility at this locus. Common variants located within highly expressed MS4A6A transcripts were significantly associated with AD and MS4A6A expression levels in blood from MCI and AD subjects (p < 0.05, rs610932, rs7232, rs583791). More copies of the protective (minor) allele were associated with lower MS4A6A expression of each transcript (e.g., p = 0.019; rs610932-total MS4A6A). Furthermore, in heterozygous AD subjects, relative expression of the protective allele of V4-MS4A6A transcripts was lower (p < 0.008). Irrespective of genotype, MS4A6A transcripts were increased in blood from people with AD (p < 0.003), whereas lower expression of full length V1-MS4A6A (p = 0.002) and higher expression of V4-MS4A6A (p = 1.8 × 10(-4)) were observed in MCI, relative to elderly controls. The association between genotype and expression was less consistent in brain, although BA9 did have a similar genotype association with V4-MS4A6A transcripts as in blood. MS4A6A transcripts were widely expressed in tissues and cells, with the exception of V4-MS4A6A, which was not expressed in neuronal cells. Together these results suggest that high levels of MS4A6A in emerging AD pathology are detrimental. Persons with MCI may lower MS4A6A expression to minimize detrimental disease associated MS4A6A activity. However, those with the susceptibility allele appear unable to decrease expression sufficiently, which may explain their increased risk for developing AD. Inhibiting MS4A6A may therefore promote a more neuroprotective phenotype, although further work is needed to establish whether this is the case.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Expressão Gênica , Predisposição Genética para Doença/genética , Variação Genética/genética , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/sangue , Disfunção Cognitiva/genética , DNA , Genótipo , Humanos , Masculino , RNA , Reação em Cadeia da Polimerase em Tempo Real , Risco , Transcrição Genética/genética
17.
Biomed Opt Express ; 4(11): 2508-17, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24298411

RESUMO

We present an aberration cancelling optical design for a reflective adaptive optics - optical coherence tomography (AO-OCT) retinal imaging system. The optical performance of this instrument is compared to our previous multimodal AO-OCT/AO-SLO retinal imaging system. The feasibility of new instrumentation for improved visualization of microscopic retinal structures is discussed. Examples of images acquired with this new AO-OCT instrument are presented.

18.
Opt Express ; 19(13): 12053-65, 2011 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-21716441

RESUMO

We introduce an image upscaling method that reduces bit errors caused by Nyquist apertures. Nyquist apertures used for higher storage densities generate optical aberrations and degrade the quality of the image that is recorded on the medium. Here, to correct the bit errors caused by the Nyquist aperture, an image upscaling method is used to restore the degraded image in the enhanced spatial frequency domain using its point spread function (PSF) as a restoration filter. The proposed method reduces the bit error rate (BER) significantly and hence allows higher storage densities.


Assuntos
Holografia/instrumentação , Holografia/métodos , Processamento de Imagem Assistida por Computador/instrumentação , Processamento de Imagem Assistida por Computador/métodos , Simulação por Computador , Desenho de Equipamento , Modelos Teóricos
19.
J Opt Soc Am A Opt Image Sci Vis ; 27(10): 2304-12, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20922021

RESUMO

We propose an image-resolution upscaling method for compact imaging systems. The image resolution is calculated using the resolving power of the optics and the pixel size of a digital image sensor. The resolution limit of the compact imaging system comes from its size and the number of allowed lenses. To upscale the image resolution but maintain the small size, we apply wavefront coding and image restoration. Conventional image restoration could not enhance the image resolution of the sensor. Here, we use the upscaled image of a wavefront-coded optical system and apply an image-restoration algorithm using a more precisely calculated point-spread function (PSF) as the deconvolution filter. An example of a wavefront-coded optical system with a 5-megapixel image sensor is given. The final image had a resolution equivalent to that of a 10-megapixel image using only four plastic lenses. Moreover, image degradation caused by hand motion could also be reduced using the proposed method.

20.
J Opt Soc Am A Opt Image Sci Vis ; 25(11): 2764-6, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18978854

RESUMO

Diffractive optical elements (DOEs) are often used to improve the performance of optical systems. However, when a blazed DOE is machined, shape errors can be generated in the discontinuity region of the DOE due to the finite radius of the processing tool. We simulated the effects of this shape error on the optical path and modulation transfer function (MTF) in a hybrid lens for a compact camera module. The decrease rate of the MTF was larger in the low-spatial-frequency domain and when the light entered at a low incident angle.

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