Fossella_cdt-cnsnd

Current Drug Targets - CNS & Neurological Disorders, 2003, 2, 357-362
Exploring Genetic Influences on Cognition: Emerging Strategies for Target
Validation and Treatment Optimization
John A. Fossella*, Sonia Bishop and B.J. Casey The Sackler Institute for Developmental Psychobiology, Weill Medical College Cornell University, 1300 York Ave,New York, NY 10021, USA Abstract: Genomic research has produced an abundance of new candidate targets that remain to be validated as
potential treatments for neuropsychiatric disorders. Functional neuroimaging, meanwhile, has provided
detailed new insights into the neural circuits involved in emotional and cognitive control. At the growing
interface between these independent lines of progress, new efforts are underway to unify our understanding of
regional brain function with that of genetic and biochemical influences on behavior. Such a unified
understanding of the mechanisms involved in cognitive and emotional control may open up new avenues for
therapeutic intervention at the pharmacological and behavioral levels. In line with this, a new initiative
sponsored by the National Institutes of Mental Health (NIMH) aims to bridge gaps between clinical
diagnostics and the molecular processes that influence susceptibility to psychiatric disorders [1]. A major
goal of this initiative is to identify the neural and neurochemical substrates of basic cognitive processes that
are disrupted in psychiatric disorders and to examine the influence of genetic factors at the cognitive level.
This review describes some well-known findings that are at the forefront of this interface. The progress already
made indicates that the goals of the new initiative are well founded and achievable.
Keywords: Genetics; Attention; Cognition; Neuroimaging; Pharmacogenetics; Psychopathology
INTRODUCTION
measures of cognitive and neural function that may serve asendpoints and surrogate outcome measures in clinical trials.
The neural and neuroendocrine circuits that underlie These measures must meet three important criteria: i) they normal and abnormal behavior are widely distributed must reflect a process disruption of which is central to the throughout the brain and body. The distributed nature of given disorder (ii) the process must be thought to have a these circuits and their complex modulation of neural strong genetic compenent and (iii) the measures must show function presents obstacles to the development of drug good test-retest reliability. The goal of this article is to therapies aimed at remediating specific aspects of cognitive summarize some of the notable progress associated with this or emotional regulation. To further complicate new therapy initiative and point out the future potential and limitations development, the diagnostic criteria and clinically relevant of the integration of these methods in basic and clinical treatment goals for psychiatric disorders are often vague, heterogeneous and not easily correlated with any specificbiochemical marker or measure of neural activity. The To illustrate how cognitive methods can bridge the gap integration of cognitive paradigms with neuro-imaging between the clinical setting and molecular biology, consider through PET and fMRI has however begun to suggest a the case of Schizophrenia. According to DSM IV, for a number of candidate neural circuits that may be disrupted in diagnosis of Schizophrenia to be reached an individual needs disorders such as Schizophrenia [2-4], depression [5,6], to show two or more of the following symptoms:- obsessive-compulsive disorder [7-10], anxiety disorders [11], delusions, hallucinations, disorganised speech, disorganized attention deficit hyperactivity disorder (ADHD) [12-15] and or catatonic behavior and ‘negative’ symptoms (a reduction autism [16]. At the same time, long standing evidence or loss in normal functions such as language or goal-directed shows that these psychiatric disorders are heavily influenced behavior). It is immediately apparent that this leaves room by genetic factors [17-19]. Despite the large genetic for a huge degree of heterogeneity amongst patients meeting contribution, it has been difficult to identify individual these diagnostic criteria. Indeed, it hardly seems surprising genes that contribute to the risk of illness. This may reflect that genetic markers for ‘Schizophrenia’ per se have not been problems with the current symptom-based measures of forthcoming. Furthermore, it raises the question of what we disorder. As an alternative to symptom-based diagnostic should expect such genetic markers to predict. Do we expect criteria, a more successful approach may be to perform a gene for ‘hallucinations’ or a gene for ‘disorganized genetic studies using cognitive and neurophysiological behavior’? Surely these vague concepts relate to underlying ‘endophenotypes’ [20]. This approach has recently gained processes, and it is these processes which are more directly momentum and forms the basis of a new initiative influenced by genetic factors. One candidate process (or sponsored by the NIMH [1]. The initiative aims to identify arguably class of closely-related processes) is that of‘attentional control’ or ‘executive processing’.
Attentional difficulties have been repeatedly linked to *Address correspondence to this author at the Sackler Institute forDevelopmental Psychobiology, Weill Medical College Cornell University, Schizophrenia (see [21] for a review). Attentional deficits 1300 York Ave, New York, NY 10021, USA; Tel.: +212-746-5830; E- have been objectively quantified using sensorimotor gating [22], smooth pursuit eye-tracking [23], set-shifting [24], 1568-007X/03 $41.00+.00
2003 Bentham Science Publishers Ltd.
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inhibition [25] and working memory tasks [26].
relative cost make it attractive to the research and clinical Furthermore, performance on attentional tasks has been communities. Many studies have found differences in brain shown to be influenced by genetic factors. For example, the anatomy and activity for a variety of brain disorders d' signal detection component of performance on the including Schizophrenia [3], depression [6], anxiety Continuous Performance Task (CPT) has a heritability disorders [11] and ADHD [14]. MRI-based measures of brain among normal subjects of 0.49 (suggesting about one half of anatomy are of interest since studies in rodents, nonhuman the overall population variability is due to genetic variation) primates and humans have established that genes are major [27]. The P/N ratio of the Spontaneous Selective Attention determinants of overall brain size [43-44]. Whole brain Task (SSAT) has also been shown to have an heritability volume in monozygotic and dizygotic twin populations among normal subjects of 0.41 [28]. Beyond this, twin show that individual variation in cortical structure is highly studies using normal control twins show that spatial heritable (h2 = 0.9) [45-46]. Functional magnetic resonance working memory, divided attention, choice reaction time imaging (fMRI) goes beyond the structural level to quantify and selective attention [29], attentional set-shifting [30], activity of brain networks during discrete time intervals.
sensorimotor gating [31], smooth pursuit eye tracking [32] Structural (MRI) and functional (fMRI) approaches can and executive attention [33] are all underlain by inherited complement the genetic and cognitive endophenotype aims factors. In addition, neuroimaging studies have both revealed of the new NIMH initiative. In the context of a fMRI study, frontal cortical abnormalities in Schizophrenia [34] and Egan and colleagues [36] showed that a methionine/valine indicated that the prefrontal cortex is part of the neural polymorphism in the catechol-O-methyl transferase gene substrate of attentional control [35]. Taken together, these (COMT) correlated with both performance on a working results clearly suggest that it could be beneficial to examine memory task and associated levels of regional neural the influence of genetic factors in Schizophrenia in relation activity. Specifically, those subjects with the valine allele to their impact on measures of attention/executive processing showed worse performance and higher levels of brain and on associated prefrontal cortical function. An example of activation in the prefrontal cortex. The same valine allele this is provided by the work of Egan et al. [36] which is also accounts for a portion of the genetic risk towards Schizophrenia. Thus, by assaying a cognitive processthought to be impaired in Schizophenia, insights linkinggenetic susceptibility to both functional neural anatomy and Target Validation: at the Interface of Genomics and
psychiatric diagnostic status were possible. Clinical Functional Neuroimaging
development of compounds selective for the COMT enzyme A number of lines of research have begun to exploit the are underway and it is hoped that ‘cognitive endpoints’ will advantages of an integrated cognitive, genetic and prove useful in this process [47]. In addition, the neuroimaging approach. Positron emission tomography relationship between the met/val polymorphism in the (PET) is a well-established method for measuring specific COMT gene and PFC activity during working memory biochemical processes in the body over time and in 3- performance may take us a step forward to understanding any dimensions. Individual differences in radioligand binding are impact of a COMT-based treatment upon clinical outcome often observed. Two genes, the dopamine transporter (DAT) and the dopamine D2 receptor (DRD2) contain genetic Replications of such multi-tiered genetic and imaging polymorphisms that have been associated with psychiatric studies are poised to expand as the focus of interest in fMRI illness [37-39]. DRD2 and DAT levels also can be probed studies, population genetic association studies and clinical using specific PET radioligands suitable for quantitative treatment studies increasingly start to overlap. For example, measures of ligand binding. The dopamine transporter carries genetic polymorphisms in the serotonin transporter gene that a polymorphic 40-basepair repeat that varies in length across have been associated with emotional dimensions of human populations. The ability of radioligand to bind to the psychopathology such as anxiety [48], have also been the transporter seems to be influenced by the number of repeats.
focus of fMRI studies [49]. Similarly, polymorphisms in For example, subjects homozygous for the 10-repeat allele the BDNF gene have been examined in clinically diagnosed showed significantly lower dopamine transporter binding Schizophrenia [50], with performance on cognitive tasks than carriers of the 9-repeat allele [40]. These results may involving episodic memory and with hippocampal activation relate to the mechanisms of alcohol addiction since DAT assessed via fMRI during a working memory task [51].
polymorphisms have been associated with the severity ofwithdrawl [41]. Similarly, PET and genetic studies show Electroencephalographic (EEG) and event related that genetic polymorphisms in the DRD2 gene are associated potential (ERP) measurements have also long been used to with differences in DRD2 receptor levels [42]. Since these probe psychological, cognitive and neurophysiological polymorphisms have been found to contribute to the risk of processes in studies of mental illness and genetics. The Schizophrenia and alcoholism [39], it is possible that extensive literature, temporal specificity, ease and low cost receptor levels are key mediators of disease risk and perhaps make this approach ideal for validation strategies that exploit valid targets for clinical development and diagnosis. It cognitive endophenotypes. Although fewer single gene would be desirable to extend such PET studies to all genes association studies have been reported than for MRI-based that have been implicated in mental illness, however, it is studies, the basis for EEG and ERP endophenotypic assays difficult to obtain safe and selective radioligands that bind to is well substantiated. For example, in alcoholism, a the ever-increasing numbers of candidate targets.
reduction in the P300 amplitude in patients and in firstdegree relatives has been studied [52]. Additional family and Magnetic resonance imaging (MRI) is a method whose twin studies show that individual differences in the P300 are safety, high spatial and good temporal resolution and at least moderately heritable [53,54]. Another ERP Exploring Genetic Influences on Cognition
Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 6 359
component, the P50, has been used to study early sensory tantalisingly suggestive about how genetic factors, processing of paired stimuli in Schizophrenia [22].
impairments in cognitive mechanisms and altered Impairment in the P50 is a reliable marker for Schizophrenia neurochemical modulation of the prefrontal cortex may tie and has been shown to be heritable [31]. Polymorphisms in together to explain at least one part of the puzzle that the alpha 7-nicotinic cholinergic receptor were shown to Schizophenia provides. They also indicate how functional contribute to the susceptibility of the disorder and a neuroimaging and genomics may be used in conjunction to advance our understanding and treatment of psychiatricdisorders.
Treatment Optimization: at the Interface of
Turning briefly to the issue of adverse side effects, a Pharmacology, Functional Neuroimaging and Genomics
good example of the potential role of functional genomicshere is provided by research into tardive dyskinesia. This is Integrating knowledge from molecular, functional an involuntary movement disorder of the face and body, that anatomic and clinical levels may not only provide insight occurs in approximately 30% of patients treated with into the mechanisms of psychopathology, but also yield antipsychotic medications. Pharmacogenetic analysis of the information that can be used to optimize treatment outcome.
DRD3 gene which encodes a dopamine receptor expressed Experience with pharmacological therapies shows that there abundantly motor control regions including the basal ganglia is tremendous variation in how individual patients respond and ventral putamen, show that a serine to glycine to medication. Schizophrenia, for example, is one of the substitution at amino acid 9 contributes to the overall risk of most well-studied brain disorders and there is an extensive tardive dyskinesia [67-69]. The risk is further compounded literature on its pharmacologic treatment. One of the by polymorphisms in the metabolic CYP1A2 gene. Patients difficulties in the pharmacologic treatment of Schizophrenia who carried the high risk alleles at both DRD3 and CYP1A2 is the consistent finding that approximately 20% of patients showed the highest levels of tardive dyskinesia while those do not respond to initial therapy, an additional 30% do not with the low risk alleles showed the lowest levels of tardive sustain a response to therapy and some 20% of patients dyskinesia. These findings on adverse effects were further experience adverse side effects that prevent further treatment augmented by FDG-PET studies that found that patients [56]. While there are many possible reasons for this finding, with the high risk alleles of DRD3 showed elevated levels of including diagnostic and environmental heterogeneity, one glucose metabolism. Together, these studies have deliniated possible reason for the individual differences in the response a sub-group of patients for whom antipsychotic medication to medication may be genetic differences among patients.
Pharmacogenetic studies seek to identify specific types ofgenetic variation influencing the response that individual Just as pharmacogenetics has opened up new avenues for patients have to a particular medication. Many processes treatment optimization, many groups have explored the such as drug absorption, distribution and metabolism are possibility that neuroimaging might provide information to known to influence drug response and genes that correspond optimize treatment response. Differences in brain structure to these processes such as receptors, transporters and and function between healthy controls and patients have been metabolic enzyme have been explored in candidate gene documented in disorders such as Schizophrenia [2, 4, 51] studies. Surprisingly, the predisposition to respond or not depression [6], ADHD [70] and anxiety [11,71]. Subsequent respond can be accounted for by variation in relatively few studies have examined whether these structural and genes. So-called ‘extensive metabolizers’ and ‘poor functional differences are normalized in response to metabolizers’ of at least 40 drugs can be distinguished by pharmacologic treatment. For example, in Schizophrenia, polymorphisms in the cytochrome P450 enzyme CYP2D6 there are many findings of structural abnormalities such as [57-58]. Other P450 genes such as CYP2C19, CYP2C9, reduced grey matter, reduced thalamus volume and increased CYP2E1 and CYP2A6 as well as the glutathione S- ventricle size, as well as functional abnormalities such as low blood flow in the frontal cortex [34]. Investigations of acetyltransferase gene NAT2 have been shown to influence whether any of these abnormalities can be reversed or the metabolism of various medications. Variations in partially reversed after treatment with antipsychotic CYP2D6, for example, influence the toxicity of tricyclic medication consistently find is an increase in blood flow in antidepressants [59] and the breakdown of haloperidol [60].
the basal ganglia [72-75]. The basal ganglia shows a The molecular genetic influences on metabolism are structural response to treatment that is dependent on the supported by twin and family investigations of the class of antipsychotic medication given. Treatment with heritability of medication response [61-63]. As an example, typical antipsychotics such as haloperidol (DRD2 consider that only 30-60% of patients who are resistant to antagonist) may increase the volume of the caudate nucleus typical antipsychotics show a response to clozapine. Genetic while atypical antipsychotics such as clozapine (mixed polymorphisms in the serotonin system may mediate DRD2, 5HT2A antagonist) show either no change or a clozapine response [64]. PET studies have shown that reversal of the previous volume increase [4,76]. In addition, polymorphisms in the dopamine D1 receptor (DRD1) gene the atypical medication risperidone did not affect blood flow influence baseline metabolic activity in the dorsolateral in the basal ganglia, while the typical medication led to frontal cortex in response to clozapine treatment [65, 66].
increased blood flow in the basal ganglia [77]. These These polymorphisms showed significant associations with structural and functional differences may be related to changes in attention and working memory; two cognitive differences in improvement in positive and negative functions that are disrupted in Schizophrenia [56] and which symptoms and cognitive impairments [78,79] thus are thought to, at least in part, be dependent upon prefrontal providing a basis for the optimization of treatment using cortical function. Taken together, these findings are neuroimaging. Ideally, these studies need to be 360 Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 6
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complemented by additional work integrating Still many regulatory and economic challenges, beyond pschyopharmacological techniques with fMRI studies using the scope of this review, remain. The vast economic cognitive paradigms focusing on different aspects of resources expended in meeting regulatory standards for safety attentional control / executive function. Through integration and efficacy pose a barrier to the widespread implementation of genetic analysis, psychopharmacological studies, and both of more advanced cognitive and genomic approaches. The structural and functional neuroimaging techniques, together large sample sizes needed for genetic studies and the with careful specification of outcome endpoints in terms of accompanying investment in genotyping and neuroimaging symptom subsets and/or specific cognitive functions, we can technology will be costly. The increased specificity of hope to make greater progress in both understanding and medicines that are custom tailored by genotype and brain treating such heterogenous diagnostic entities as structure/activity will fragment patient markets and conflict with the current ‘one size fits all’ or ‘blockbuster’ drug There is also a high degree of heterogenity within groups development model. Even if small, genetically defined of individuals meeting diagnostic criteria for ADHD. This clinical trials gain FDA approval, it is not clear whether the condition provides a second example of the attempt to cost of development, though cheaper, will be offset by sales improve treatment with the aid of genetics and neuro- to a smaller, anatomically and genetically defined patient imaging studies. Structural MRI studies on ADHD populations. These worries however, may be overstated. The consistently show reduced caudate nucleus volumes Orphan Drug Act, passed by Congress in 1983 offers many [12,13,70]. In addition, performance on cognitive tasks financial incentives for medication development for diseases designed to measure inhibitory control and activate the that affect less than 200,000 people [90]. Incentives for frontal cortex and basal ganglia have shown that caudate treatments that affect small, genetically fragmented volume can be an accurate predictor of performance [25,80].
populations have been proposed [91]. The most successful Furthermore, this structural MRI phenotype also predicts example of a personalized medicine is Herceptin a response to treatment. Filipek et al., [81] found that subjects treatment designed against a specific form of breast cancer.
with smaller and more symmetrical caudate nuclei showed a This treatment was designed based on the finding that about more favorable response to treatment with stimulant 25% of breast cancer patients overexpress HER-2, a cell medication. The Multimodality Treatment of ADHD (MTA) surface marker involved in tumor growth [92]. Genetech Inc.
project [82] carries out cognitive, genetic, structural and first developed a diagnostic test to determine that HER-2 functional imaging work in various treatment groups in an status among patients and then carried out clinical trial effort to better understand the underlying mechanisms of among women preselected for their HER-2 status. These ADHD and to develop improved methods for treatment studies, carried out from 1994 -1996 demonstrated the optimization. Swanson et al., [83] has suggested that at clinical efficacy of the treatment in a population of patients least two treatment groups exist in ADHD, one characterized [92]. Much like the current NIMH initiative hopes to ensure, by genetic abnormalities and the other characterized by brain FDA approval of Herceptin was based on newly approved structure abnormalities that might respond differentially to surrogate endpoints related to tumor shrinkage that set a behavioral vs. medication therapy. The development of more specific threshold of efficacy. Currently, annual sales additional projects along these lines targeted at other of Herceptin have vastly surpassed initial expectations and psychiatric illnesses may well lead to similar advances in validated the 'genetically-based' personalized medicine our understanding of Depression, Generalised Anxiety and strategy. The development of this compound was supported other vitally important, common, and debilitating but yet by personalized diagnostic tests and continues to be remarkably poorly understood conditions.
developed through the use of functional imaging studies[93].
FUTURE PERSPECTIVES
In summary, genomic research has produced an abundance of new target molecules for the treatment of brain The confluence of information relating behavior with disorders in parallel with functional neuroimaging studies functional anatomy, physiology and molecular biology has providing insights into neural circuits involved in behavior.
contributed to a more comprehensive understanding the With this progress, new efforts are underway to unify the pathogenesis of brain disorders. Many factors bode well for understanding of functional brain anatomy with future progress in treatment development. Firstly, physiological, cellular and molecular processes that influence pharmacogenetics has already been used to optimize behavior. In this way, cognitive neuroscience is being treatment regimens for chemotherapy [84], peptic ulcer viewed as an important intermediate step between bridging treatment [85], hypertension [86], asthma [87] and anti- cellular neurophysiology and clinical psychiatry. This review retroviral therapy for HIV [88] and should be easily adapted has described some well-known findings that bridge this gap to psychopharmacology. Secondly, the NIMH has based on cognitive neuroscience, functional neuroimaging recognized that cognitive neuroscience can be used to fill knowledge gaps between drug mechanisms and clinicaloutcome. By incorporating cognitive measures as surrogateendpoints in clinical trials, it is hoped that the so-called ACKNOWLEDGEMENTS
‘translational bottleneck’ can be bridged. The ‘brain imaginginitiative’, a $100 million effort sponsored by the National We wish to thank the members of the Sackler Institute Institute for Drug Abuse (NIDA) aims to collect both brain for helpful discussions. J.F. acknowledges support from imaging and genetic data on thousands of human subjects NIMH (#1 F32 MH64360-01A1) and a Young Investigator over the next ten years and will provide more extensive Exploring Genetic Influences on Cognition
Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 6 361
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