Molecular medicine: a path towards a personalized medicine (original) (raw)
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2013
Imaging of the human brain has been an invaluable aid in understanding neuropsychopharmacology and, in particular, the role of dopamine in the striatum in mental illness. Here, we report a study in a genetic mouse model for major mental illness guided by results from human brain imaging: a systematic study using small animal positron emission tomography (PET), autoradiography, microdialysis and molecular biology in a putative dominant-negative mutant DISC1 transgenic model. This mouse model showed augmented binding of radioligands to the dopamine D2 receptor (D2R) in the striatum as well as neurochemical and behavioral changes to methamphetamine administration. Previously we reported that this model displayed deficits in the forced swim test, a representative indicator of antidepressant efficacy. By combining the results of our two studies, we propose a working hypothesis for future studies that this model might represent a mixed condition of depression and psychosis. We hope that this study will also help bridge a major gap in translational psychiatry between basic characterization of animal models and clinico-pharmacological assessment of patients mainly through PET imaging.
Molecular imaging for depressive disorders
AJNR. American journal of neuroradiology, 2014
Molecular imaging is the visualization, characterization, and measurement of biologic processes at the molecular and cellular levels in humans and other living systems. Molecular imaging techniques such as MR spectroscopy and PET have been used to explore the molecular pathophysiology of depression and assess treatment responses. MR spectroscopy is a noninvasive technique that assesses the levels of biochemical metabolites in the brain, while PET uses radioligands injected in the bloodstream that have high binding affinity for target molecules. MR spectroscopy findings suggest a role for glutamate/glutamine and gamma-aminobutyric acid in depression. PET has generally failed to find a correlation between radioligand binding potential and depression severity or treatment response, though it may offer promise in distinguishing responders and nonresponders to treatment. A major challenge for both modalities is that depression is a heterogeneous, multifactorial disorder, while MR spectro...
PET-based molecular imaging in neuroscience
European Journal of Nuclear Medicine and Molecular Imaging, 2003
Positron emission tomography (PET) allows non-invasive assessment of physiological, metabolic and molecular processes in humans and animals in vivo. Advances in detector technology have led to a considerable improvement in the spatial resolution of PET (1-2 mm), enabling for the first time investigations in small experimental animals such as mice. With the developments in radiochemistry and tracer technology, a variety of endogenously expressed and exogenously introduced genes can be analysed by PET. This opens up the exciting and rapidly evolving field of molecular imaging, aiming at the non-invasive localisation of a biological process of interest in normal and diseased cells in animal models and humans in vivo. The main and most intriguing advantage of molecular imaging is the kinetic analysis of a given molecular event in the same experimental subject over time. This will allow non-invasive characterisation and "phenotyping" of animal models of human disease at various disease stages, under certain pathophysiological stimuli and after therapeutic intervention. The potential broad applications of imaging molecular events in vivo lie in the study of cell biology, biochemistry, gene/protein function and regulation, signal transduction, transcriptional regulation and characterisation of transgenic animals. Most importantly, molecular imaging will have great implications for the identification of potential molecular therapeutic targets, in the development of new treatment strategies, and in their successful implementation into clinical application. Here, the potential impact of molecular imaging by PET in applications in neuroscience research with a special focus on neurodegeneration and neuro-oncology is reviewed.
Neuroimaging as a potential biomarker to optimize psychiatric research and treatment
International review of psychiatry (Abingdon, England), 2013
Complex, polygenic phenotypes in psychiatry hamper our understanding of the underlying molecular pathways and mechanisms of many diseases. The unknown aetiology, together with symptoms which often show a large variability both across individuals and over time and also tend to respond comparatively slowly to medication, can be a problem for patient treatment and drug development. We argue that neuroimaging has the potential to improve psychiatric treatment in two ways. First, by reducing phenotypic complexity, neuroimaging intermediate phenotypes can help to identify disease-related genes and can shed light into the biological mechanisms of known risk genes. Second, quantitative neuroimaging markers -refl ecting the spectrum of impairment on a brain-based level -can be used as a more sensitive, reliable and immediate treatment response biomarker. In the end, enhancing both our understanding of the pathophysiology of psychiatric disorders and the prediction of treatment success could eventually optimise current therapy plans.
Molecular Psychiatry, 2009
We have discovered two genes, RSRC1 and ARHGAP18, associated with schizophrenia and in an independent study provided additional support for this association. We have both discovered and verified the association of two genes, RSRC1 and ARHGAP18, with schizophrenia. We combined a genome-wide screening strategy with neuroimaging measures as the quantitative phenotype and identified the single nucleotide polymorphisms (SNPs) related to these genes as consistently associated with the phenotypic variation. To control for the risk of false positives, the empirical Pvalue for association significance was calculated using permutation testing. The quantitative phenotype was Blood-Oxygen-Level Dependent (BOLD) Contrast activation in the left dorsal lateral prefrontal cortex measured during a working memory task. The differential distribution of SNPs associated with these two genes in cases and controls was then corroborated in a larger, independent sample of patients with schizophrenia (n = 82) and healthy controls (n = 91), thus suggesting a putative etiological function for both genes in schizophrenia. Up until now these genes have not been linked to any neuropsychiatric illness, although both genes have a function in prenatal brain development. We introduce the use of functional magnetic resonance imaging activation as a quantitative phenotype in conjunction with genome-wide association as a gene discovery tool. . Author contributions: The fMRI task, imaging data from the discovery sample and imaging analyses for these results were programmed and implemented by Jessica Turner; the neuroanatomical and neuroscience expertize and genetic annotation was contributed by James Fallon; the genetic data analysis, PLINK and Eigenstrat analyses and genetic annotation were performed by Guia Guffanti and Fabio Macciardi; the in silico annotations were performed by Anita Lakatos; the visualization and gene viewer methods were developed by David Keator; the design and oversight of the experiments and analyses were the responsibility of Steven Potkin. Article preparation was a joint effort of all authors.
In vivo imaging of neurotransmitter systems in neuropsychiatry
Clinical Neuroscience Research, 2001
A wide variety of nuclear medical, radiological, ultrasound, electroencephalographic, and other neuroimaging techniques are available to assist clinicians in the characterization and treatment of neurological and psychiatric disorders by the visualization of the living human brain. In particular, radioligand neuroreceptor imaging can be accomplished by positron emission tomography (PET) and single photon emission computerized tomography (SPECT), nuclear medical procedures involving the administration of radioisotopes to the subject. While currently primarily a research tool, several practical clinical applications of radioligand neuroreceptor imaging are available today. Radioligand neuroreceptor imaging permits the determination of optimal dosages of traditional and novel psychoactive agents to produce maximal bene®cial effects but minimal adverse effects. Furthermore, radioligand neuroreceptor imaging allows the identi®cation of dysfunction in the release and transport of neurochemicals, such as second messenger systems, in the brains of individuals af¯icted with different biological subtypes of nervous and mental diseases to facilitate the application of effective interventions to correct the underlying abnormalities. Gene therapy is another application of imaging techniques that provides the means to correct abnormalities in victims of malignancies, such as brain cancers, and other diseases. Thus, the diagnosis and treatment of nervous and mental disorders is enhanced by the utilization of in vivo imaging of neurotransmitter systems. q
The intersection of pharmacology, imaging, and genetics in the development of personalized medicine
Dialogues in clinical neuroscience, 2009
We currently rely on large randomized controlled trials and meta-analyses to make clinical decisions; this places us at a risk of discarding subgroup or individually specific treatment options owing to their failure to prove efficacious across entire populations. There is a new era emerging in personalized medicine that will focus on individual differences that are not evident phenomenologically. Much research is directed towards identifying genes, endophenotypes, and biomarkers of disease that will facilitate diagnosis and predict treatment outcome. We are at the threshold of being able to predict treatment response, primarily through genetics and neuroimaging. In this review we discuss the most promising markers of treatment response and adverse effects emerging from the areas of pharmacogenetics and neuroimaging in depression and schizophrenia.
Integrative Biological Analysis For Neuropsychopharmacology
Neuropsychopharmacology, 2013
Although advances in psychotherapy have been made in recent years, drug discovery for brain diseases such as schizophrenia and mood disorders has stagnated. The need for new biomarkers and validated therapeutic targets in the field of neuropsychopharmacology is widely unmet. The brain is the most complex part of human anatomy from the standpoint of number and types of cells, their interconnections, and circuitry. To better meet patient needs, improved methods to approach brain studies by understanding functional networks that interact with the genome are being developed. The integrated biological approaches-proteomics, transcriptomics, metabolomics, and glycomics-have a strong record in several areas of biomedicine, including neurochemistry and neuro-oncology. Published applications of an integrated approach to projects of neurological, psychiatric, and pharmacological natures are still few but show promise to provide deep biological knowledge derived from cells, animal models, and clinical materials. Future studes that yield insights based on integrated analyses promise to deliver new therapeutic targets and biomarkers for personalized medicine.