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PubMed2003

Looking backward to move forward: early detection of neurodegenerative disorders.

Early detection of neurodegenerative disorders would provide clues to the underlying pathobiology of these diseases and would enable more effective diagnosis and treatment of patients. Recent advances in molecular neuroscience have begun to provide the tools to detect diseases like Alzheimer's disease, Parkinson's disease, and others early in their course and potentially even before the development of clinical manifestations of disease. These genetic, imaging, clinical, and biochemical tools are being validated in a number of studies. Early detection of these slowly progressive diseases offers the promise of presymptomatic diagnosis and, ultimately, of disease-modifying medications for use early in disease and during the presymptomatic period.

Aging↗
PubMed1997

[Genes and chromosomes: imaging in genetics].

FISH methodologies have made spectacular progress and found wide applications in several areas of clinical studies and research. These techniques are successfully used for visualisation of specific DNA sequences in metaphase chromosomes and interphase cells making this approach, with appropriately chosen probes, a useful adjuvant to conventional cytogenetics in the study of chromosome abnormalities. Improvements have been made in probe generation, developments of new fluorochromes, combinatorial and ratio labelling for multicolor signals and novel hybridization targets as extended DNA. By varying the probe and the target in fluorescence hybridization, numerous applications are being implemented in many fields of human genetics, from clinical cytogenetics to the identification and study of genes involved in monogenic disorders and oncogenic rearrangements.

Chromosome Aberrations↗
PubMed2006

A hybrid vector for ligand-directed tumor targeting and molecular imaging.

Merging tumor targeting and molecular-genetic imaging into an integrated platform is limited by lack of strategies to enable systemic yet ligand-directed delivery and imaging of specific transgenes. Many eukaryotic viruses serve for transgene delivery but require elimination of native tropism for mammalian cells; in contrast, prokaryotic viruses can be adapted to bind to mammalian receptors but are otherwise poor vehicles. Here we introduce a system containing cis-elements from adeno-associated virus (AAV) and single-stranded bacteriophage. Our AAV/phage (AAVP) prototype targets an integrin. We show that AAVP provides superior tumor transduction over phage and that incorporation of inverted terminal repeats is associated with improved fate of the delivered transgene. Moreover, we show that the temporal dynamics and spatial heterogeneity of gene expression mediated by targeted AAVP can be monitored by positron emission tomography. This new class of targeted hybrid viral particles will enable a wide range of applications in biology and medicine.

Animals↗
PubMed2006

Combination of multimodal imaging and molecular genetic information to investigate complex psychiatric disorders.

Multimodal imaging, the combination of several brain imaging techniques in one subject, provides a wealth of parameters and favours the interpretation of complex models in schizophrenia research. Moreover, new imaging tools allow the investigation of distinct neurotransmitter systems and their modulation by pharmacological intervention. An important feature of multimodal imaging is the possibility to characterize the activation dependencies of different neurotransmitters and provide the experimental tool to test system models of brain function and dysfunction. The combination of measurement techniques with high temporal resolution (e. g. MEG, EEG) and high spatial resolution (e. g. fMRI) facilitate the understanding of local and global systems as well as time characteristics. Moreover, the association of imaging parameters with genetic variations of neurotransmitter systems allows the investigation of neurotransmitter activity and its role in the pathophysiology of schizophrenia. To overcome the limitations of standard statistical methods, new approaches in machine learning have to be adapted to handle multiple parameters obtained from brain imaging and genetic measurements.

Brain↗
PubMed2006

Intermediate phenotypes and genetic mechanisms of psychiatric disorders.

Genes are major contributors to many psychiatric diseases, but their mechanisms of action have long seemed elusive. The intermediate phenotype concept represents a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative, mechanistic aspects of brain function implicated in psychiatric disease. Using imaging genetics as an example, we illustrate recent advances, challenges and implications of linking genes to structural and functional variation in brain systems related to cognition and emotion.

Animals↗
PubMed2005

Genetic-based fuzzy image filter and its application to image processing.

In this paper, we propose a Genetic-based Fuzzy Image Filter (GFIF) to remove additive identical independent distribution (i.i.d.) impulse noise from highly corrupted images. The proposed filter consists of a fuzzy number construction process, a fuzz filtering process, a genetic learning process, and an image knowledge base. First, the fuzzy number construction process receives sample images or the noise-free image and then constructs an image knowledge base for the fuzzy filtering process. Second, the fuzzy filtering process contains a parallel fuzzy inference mechanism, a fuzzy mean process, and a fuzzy decision process to perform the task of noise removal. Finally, based on the genetic algorithm, the genetic learning process adjusts the parameters of the image knowledge base. By the experimental results, GFIF achieves a better performance than the state-of-the-art filters based on the criteria of Peak-Signal-to-Noise-Ratio (PSNR), Mean-Square-Error (MSE), and Mean-Absolute-Error (MAE). On the subjective evaluation of those filtered images, GFIF also results in a higher quality of global restoration.

Algorithms↗
PubMed2003

Neuroimaging and mechanisms of drug abuse: interface of molecular imaging and molecular genetics.

Whereas ligand studies can inform the end-products of dysregulation of genetic expression, reporter gene imaging can provide the means to understand the genetic origin of these end-products. As with radioligand studies, in vivo direct measurement of gene expression will allow genetic processes to be monitored over time in the same subject, use of a subject as his/her own control in intervention studies (i.e., measurement before and after an intervention), and monitoring the spatial distribution of molecular events in the whole brain. Furthermore, reporter gene imaging, by advancing knowledge of the biologic mechanisms of disease states, has important clinical implications, particularly in the development and monitoring of treatments. We expect PET to play a prominent role in the elucidation of substance abuse mechanisms and contribute significantly to the development of innovative treatment strategies.

Brain↗
PubMed2006

Fetal magnetic resonance imaging and human genetics.

The use of fetal magnetic resonance imaging (MRI), in addition to prenatal genetic testing and sonography, has the potential to improve prenatal diagnosis of genetic disorders. MRI plays an important role in the evaluation of fetal abnormalities and malformations. Fetal MRI often enables a differential diagnosis, a determination of the extent of the disorder, the prognosis, and an improvement in therapeutic management. For counseling of parents, as well as to basically understand how genetic aberrations affect fetal development, it is of great importance to correlate different genotypes with fetal MRI data.

Biomarkers↗
PubMed2003

[Image reconstruction in electrical impedance tomography based on genetic algorithm].

Image reconstruction in electrical impedance tomography (EIT) is a highly ill-posed, non-linear inverse problem. The modified Newton-Raphson (MNR) iteration algorithm is deduced from the strictest theoretic analysis. It is an optimization algorithm based on minimizing the object function. The MNR algorithm with regularization technique is usually not stable, due to the serious image reconstruction model error and measurement noise. So the reconstruction precision is not high when used in static EIT. A new static image reconstruction method for EIT based on genetic algorithm (GA-EIT) is proposed in this paper. The experimental results indicate that the performance (including stability, the precision and space resolution in reconstructing the static EIT image) of the GA-EIT algorithm is better than that of the MNR algorithm.

Algorithms↗
PubMed2006

In vitro evaluation of herpes simplex virus type 1 thymidine kinase reporter system in dynamic studies of transcriptional gene regulation.

The herpes simplex virus type 1 thymidine kinase (HSV1-TK) reporter system is being used to directly and indirectly monitor therapeutic gene expression, immune cell trafficking and protein-protein interactions in various living animals. However, the issues of HSV1-TK enzyme stability in living cells and whether this reporter system is optimal for dynamic studies of gene expression events in genetic imaging have not be addressed. The purpose of the present study was to evaluate the application of this reporter system in dynamic studies of transcriptional gene regulation. To achieve this purpose, we established two tetracycline-inducible murine sarcoma cell lines, tetracycline-turn-off HSV1-tk-expressing cell line (NG4TL4/tet-off-HSV1-tk) and tetracycline-turn-off Luc-expressing cell line (NG4TL4/tet-off-Luc), to create an artificially regulated gene expression model in vitro. The dynamic transcriptional events mediating a series of doxycycline (Dox) inductions were monitored by HSV1-TK or by the firefly luciferase reporter gene using HSV1-TK enzyme activity assay and luciferase assay, respectively. The results of dynamic gene expression studies showed that the luciferase gene is an optimal reporter gene for monitoring short-timescale, dynamic transcriptional events mediating a series of Dox inductions, whereas the HSV1-tk is not optimal to achieve this purpose. Furthermore, the enzyme half-life of HSV1-TK in NG4TL4 cells is about 35 h after cycloheximide-induced protein inhibition. On the other hand, the results of an efflux assay of [(131)I] FIAU and [(3)H] GCV revealed that the molecular probe phosphorylated by HSV1-TK can be trapped long term within HSV1-TK stably transformed cells. Therefore, a long half-life radionuclide is not suitable for dynamic gene expression studies. Based on these results, we suggest that the HSV1-TK reporter system is not optimal for monitoring short-timescale dynamic processes such as kinetic gene expression controlled by inducible promoters or a less stable protein with a more rapid turnover due to the limitations of the half-life of the HSV1-TK enzyme and the cellular retention time of their phosphorylated molecular probes.

Arabinofuranosyluracil↗
PubMedDate not supplied

[Correlation of neurodevelopmental disorders in schizophrenia].

Contemporary aetiopathogenetic considerations, based on neuro-imaging, genetic and developmental neurobiology studies, suggest neurodevelopmental origin of schizophrenia. Several lines of evidence including structural abnormalities on in vivo brain imaging, the excess of prenatal and obstetric complications and the association of congenital and minor physical anomalies with schizophrenia, strongly indicate the neurodevelopmental pathogenesis of schizophrenia. On the other hand, controversial concept of psychotic continuum suggests schizophrenia and depression sharing the same genetic contribution to the pathogenesis. If this would be the case, depression could also be considered as neurodevelopmental disorder. The aims of the study were to investigate the association between: a) pregnancy and birth complications (PBC), and b) minor physical anomalies (MPA) and schizophrenia or depression. Experimental groups consisted of 60 schizophrenic, 28 major depression patients and 30 healthy controls. All patients were diagnosed according to DSM-IV. Schizophrenic group was divided with regard to PANSS score into positive (n = 32) and negative form (n = 28) subgroups. PBC informations were gathered from maternal recall while MPA were examined by using Waldrop scale for adults. The results showed that negative and positive schizophrenic subgroups had significantly more PBC than depressive group (p < 0.05), as well than controls (p < 0.001; p < 0.05; respectively). There was nonsignificant trend for more PBC in negative than in positive subgroup. All schizophrenic patients had higher rates of MPA than depressives (p < 0.05). This trend for more MPA was not significant in comparison with healthy controls. These findings suggest that schizophrenia, especially its negative forms, could be considered as a member of the spectrum of neurodevelopmental disorders, which does not seem to be the case with depression. PBC and MPA could also be valuable in evaluation of risks for schizophrenia and possible predictive indicators of its development.

Adult↗
PubMed2006

Intrafamilial variability of noncompaction of the ventricular myocardium.

BACKGROUND: Noncompaction of the ventricular myocardium (NVM) is a relatively uncommon form of cardiomyopathy characterized by a highly trabeculated myocardium. This report describes the clinical and genetic evaluation of a 3-generation kindred. METHODS: Family members were initially evaluated by 2-dimensional echocardiography. Most family members with signs of NVM were further evaluated by magnetic resonance imaging. Genetic analyses included mutational screening of the taffazin (TAZ) and alpha-dystrobrevin (DTNA) genes. RESULTS: Eight family members had signs of NVM. Considerable interindividual variation was noted in terms of spatial distribution and severity of affected regions and ventricular dysfunction. Depending on which of 2 previously proposed quantitative diagnostic criteria were used and where ventricular myocardial measurements were taken, between 4 and 7 of these individuals had findings that were considered diagnostic. Magnetic resonance imaging served as a useful adjunct for confirming or establishing diagnoses in all 8 individuals. No mutation was found in TAZ or DTNA. CONCLUSIONS: This kindred demonstrates the remarkably wide phenotypic spectrum that can be seen in familial cases of NVM, ranging from prenatal/neonatal lethality to a complete lack of symptoms. The fact that all 8 affected individuals either have shown improvement in ventricular function or symptoms during childhood or have been asymptomatic indicates that NVM can have a relatively benign course. The degree and nature of cardiac involvement are also quite varied, and there is a weak correlation with ventricular function and symptoms. Evaluation of families with NVM requires careful assessment that uses a combination of imaging techniques and diagnostic criteria.

Adolescent↗
PubMed2005

Magnetic resonance imaging of the kinked fetal brain stem: a sign of severe dysgenesis.

OBJECTIVE: Magnetic resonance imaging (MRI) allows visualization of the fetal brain stem in a manner not previously possible. A "kinked" brain stem is a sign of severe neurodysgenesis. The purpose of this series was to describe cases of a kinked brain stem detected on prenatal MRI and to discuss the possible genetic and syndromic etiologies. METHODS: Seven cases of a kinked brain stem on fetal MRI (gestational age range, 18-34 weeks) were reviewed and correlated with other clinical, genetic, imaging, and autopsy findings. RESULTS: In all cases, there was associated cerebellar hypogenesis. Additional findings were ventriculomegaly (4 cases), cerebral hypogenesis (3 cases), microcephaly (4 cases), schizencephaly (1 case), cephalocele (1 case), hypogenesis of the corpus callosum (1 case), and hydrocephalus (1 case). In 2 cases, prenatal sonography misidentified the kinked brain stem as the cerebellum. CONCLUSIONS: A kinked brain stem is an indicator of severe neurodysgenesis arising early in gestation. Magnetic resonance imaging provides the necessary resolution to detect this sign and delineate any associated anomalies in utero to assist with further genetic evaluation, management, and counseling.

Adolescent↗
PubMed2000

Magnetic resonance imaging screening in women at genetic risk of breast cancer: imaging and analysis protocol for the UK multicentre study. UK MRI Breast Screening Study Advisory Group.

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation.

Adult↗
PubMedDate not supplied

Neuroimaging-genetic paradigms: a new approach to investigate the pathophysiology and treatment of cognitive deficits in schizophrenia.

Cognitive impairment is a prominent and debilitating feature of schizophrenia. Genetic predisposition likely accounts for a large proportion of these cognitive deficits. Direct associations between candidate genes and cognitive dysfunction have been difficult to establish, however, largely due to the subtle effects of these genes on observable behavior. Neuroimaging techniques can provide a sensitive means to bridge the neurobiology of genes and behavior. Here we illustrate the use of neuroimaging-genetics paradigms to elaborate the relationship between genes and cognitive dysfunction in schizophrenia. After reviewing principles important for the selection of genes, neuroimaging techniques, and subjects, we describe how imaging-genetics investigations have helped clarify the contribution of five candidate genes (COMT, GRM3, G72, DISC1, and BDNF) to cognitive deficits in schizophrenia. The potential of this approach for improving patient care will depend on its ability to predict outcomes with greater accuracy and sensitivity than current clinical measures.

Brain↗
PubMed2001

Advances in biomedical imaging.

In the 21st century, diseases will be diagnosed and treated using increasingly less invasive, more sophisticated imaging and image-guided procedures. During the past 100 years, the field of biomedical imaging has developed from Roentgen's original discovery of the x-ray to the imaging tools of today, such as magnetic resonance imaging, computed tomography, positron emission tomography, and ultrasonography. The benefits of using these sophisticated noninvasive imaging tools are already evident: more accurate and timely diagnosis of disease has translated into improved patient care. Recent advances in imaging research have shown the potential to change many aspects of clinical medicine within the next decade. Major new areas of research focus on development of the molecular, functional, cellular, and genetic imaging tools of the future, aided by new information technology and image fusion/integration capabilities. Image-guided therapy is growing rapidly, with advances in computer science, technology, and noninvasive treatment methods, such as focused ultrasonography. Undoubtedly, these and other new imaging techniques will enhance the ability to accurately diagnose and recognize disease and allow understanding of the molecular mechanisms of diseases and their respective responses to therapy. Given this explosion in new technologies, the next 25 years promise to result in dramatic changes in diagnostic imaging, particularly with respect to detection and recognition of disease.

Computational Biology↗
PubMed2005

Clinical, imaging and pathological correlates of a hereditary deficit in verb and action processing.

Selective verb and noun deficits have been observed in a number of neurological conditions and their occurrence has been interpreted as evidence for different neural networks underlying the processing of specific word categories. We describe the first case of a familial occurrence of a selective deficit of verb processing. Father (Individual I) and son (Individual II) developed a movement disorder resembling progressive supranuclear palsy (PSP) and associated with dementia. A second child of Individual II remained symptom-free on consecutive examinations. The dissociation between the processing of nouns and verbs in Individuals I and II was confirmed with different methods, including a longitudinal assessment of naming, comprehension, picture and word association, as well as a lexical decision task. The difference remained stable on follow-up testing despite overall deterioration. It was associated with left-sided frontal hypometabolism on FDG-PET imaging (Individual II) and with ubiquitin-positive inclusions on post-mortem examination (Individual I). The association of a selective verb deficit with a familial movement disorder raises the question whether related genetic factors might influence both movements and their abstract conceptual representations in the form of action verbs. By demonstrating a link between pathology, genetics, imaging and abstract cognitive impairments this study advances our understanding of degenerative brain disease with implications for both neuroscience and clinical practice.

Adult↗
PubMed2001

99mTc-labeled divalent and tetravalent CC49 single-chain Fv's: novel imaging agents for rapid in vivo localization of human colon carcinoma.

UNLABELLED: Radioimmunopharmaceutical agents enabling rapid high-resolution imaging, high tumor-to-background ratios, and minimal immunogenicity are being sought for cancer diagnosis and imaging. Genetic engineering techniques have allowed the design of single-chain Fv's (scFv's) of monoclonal antibodies (mAbs) recognizing tumor-associated antigens. These scFv's show good tumor targeting and biodistribution properties in vivo, indicating their potential as imaging agents when labeled with a suitable radionuclide. METHODS: Divalent (sc(Fv)(2)) and tetravalent ([sc(Fv)(2)](2)) scFv's of mAb CC49 were evaluated for radioimmunolocalization of LS-174T colon carcinoma xenografts in athymic mice. scFv's were radiolabeled with (99m)Tc by way of the bifunctional chelator succinimidyl-6-hydrazinonicotinate hydrochloride using tricine as the transchelator. The immunoreactivity and in vitro stability of the scFv's were analyzed after radiolabeling. Biodistribution and pharmacokinetic studies were performed to determine the tumor-targeting potential of the radiolabeled scFv's. Whole-mouse autoradiography illustrated the possible application of these (99m)Tc-labeled multivalent scFv's for imaging. RESULTS: The radiolabeling procedure gave > or =95% radiometal incorporation, with a specific activity of >74 MBq/mg scFv. In solid-phase radioimmunoassay, both sc(Fv)(2) and [sc(Fv)(2)](2) exhibited 75%-85% immunoreactivity, with nonspecific binding between 0.8% and 1.2%. Size-exclusion high-performance liquid chromatography showed sc(Fv)(2) as a 60-kDa protein and [sc(Fv)(2)](2) as a 120-kDa protein. Blood clearance studies showed the elimination half-life of (99m)Tc-labeled sc(Fv)(2) as 144 min and that of [sc(Fv)(2)](2) as 307 min. Whole-body clearance studies confirmed the rapid elimination of scFv's, with half-lives of 184 +/- 19 min for sc(Fv)(2) and 265 +/- 39 min for [sc(Fv)(2)](2) (P < 0.001). At 6 h after administration, the tumor localization was 7.2 +/- 0.7 percentage injected dose per gram of tumor (%ID/g) for (99m)Tc-sc(Fv)(2). (99m)Tc-[sc(Fv)(2)](2) showed a tumor uptake of 19.1 +/- 1.1 %ID/g at the same time; the amount of radioactivity in the tumors was 4-fold higher than in the spleen and kidneys and 2-fold higher than in the liver. Macroautoradiography performed at 6 and 16 h after administration clearly detected the tumor with both scFv's. CONCLUSION: (99m)Tc-labeled multivalent scFv's show good tumor-targeting characteristics and high radiolocalization indices (tumor-to-background ratio). These reagents, therefore, have the potential for use in clinical imaging studies of cancer in the field of nuclear medicine.

Animals↗