Can PET/CT imaging advance our understanding of the neurobiology of schizophrenia?

Schizophrenia is a severe psychiatric disorder affecting approximately 1% of the population worldwide. The disorder is ranked among the top 10 causes of disability worldwide. New drugs and therapeutic interventions are therefore warranted to reduce symptomatology, delay onset, or potentially cure this devastating disorder. This would greatly help individuals in the early stages of schizophrenia. Although schizophrenia has a strong genetic basis (80%), owing to the nature of the neurobiological and genetic heterogeneity of the disorder, its a etiology has remained elusive. Schizophrenia is characterized by psychotic symptoms, emotional disturbances, and cognitive dysfunction. These symptoms may be the result of dopamine dysregulation in individuals with schizophrenia [1]. Advances in anatomical and functional imaging have provided useful insights into the neurobiological mechanisms of schizophrenia, enabling brain function to be studied at a molecular level. Recent imaging investigations using computed tomography (CT) and magnetic resonance imaging (MRI) have reported grey matter reduction and ventricular enlargement in schizophrenia [2], and functional MRI studies have reported abnormalities in the frontotemporal and frontoparietal function regions. Diffusion tensor imaging is used to provide an insight into white matter tract integrity and regional cerebral connectivity. Recent studies show abnormalities in frontoparietal and left cerebellar white matter tract integrity in schizophrenia [3]. Positron emission tomography (PET) is an effective functional imaging technique that uses radioactive tracers to help identify regions associated with brain function. It has been used to detect levels of dopaminergic activity in individuals with major psychiatric disorders. The most consistent findings from adult-onset schizophrenia studies are differences in dopaminergic content in the prefrontal cortex (PFC), anterior cingulate gyrus, and hippocampus between normal controls and patients with schizophrenia. Several PET tracers have been used to identify brain abnormalities, including 11C-PET [4], 15O-H2O [5,6], 18F-fallypride [7], and 18F-FDOPA [8–10]. Compartmental modeling has been used to determine tracer binding kinetics in cases and controls. Multimodality imaging has been used to investigate the level of dopamine receptor binding in healthy volunteers to establish a baseline. One such study used 18F-fallypride PET coregistered with T1-weighted structural MRI [4], reporting an elevated D2/D3 receptor binding ratio in the putamen and caudate. This study was based on data collected on six healthy controls. A decrease of more than 10% in 18F-fallypride binding per decade in all brain regions was suggested, which may be explained by damage to cells and loss of proteins with age. The tracer 18F-FDOPA provides a map of presynaptic dopamine metabolism in neuropsychiatric disorders. Studies using statistical parametric mapping and region-of-interest analysis to obtain uptake rates in different brain regions have reported increased uptake in the striatum, with no reduction in the prefrontal cortical uptake, in schizophrenia [9]. Some studies, however, assume that the trapping of metabolites in the brain is irreversible [9], underestimating the true value of tracer studies in the brain. Kumakura et al. [8] used steady-state 18F-FDOPA kinetics to estimate the time–activity curves of brain regions in unmedicated schizophrenia patients. They reported that (i) the fractional rate constant for the catabolism and elimination of 18F-FDOPA was increased by nearly two-fold in the striatum and that (ii) 18F-FOPA storage was reduced by one-third in the caudate and amygdala. This increase in the turnover of striatal dopamine function may be associated with prodromal symptoms of schizophrenia, and can be correlated with severity of symptoms and neurocognitive dysfunction [10]. Heightened dopamine function is generally associated with increased likelihood of psychosis as opposed to the development of psychotic symptoms in schizophrenia alone. PET imaging can be used to measure both cerebral blood flow (using 15O-water) and glucose metabolism (using 18F-FDG, fluorodeoxyglucose) during neuropsychological testing by mapping brain regions selectively activated during performance on cognitive tasks. Cognitive deficits are a core feature of schizophrenia. These deficits have been associated with functional decline and influence psychosocial functioning [11]. Several PET studies have reported cognitive deficits in memory [12], verbal learning and recognition [13], attention [12,14], problem solving ability [15], episodic memory [15], and executive function [13,16,17]. This has led to cognitive deficits being considered a biological trait marker for schizophrenia. An early 133Xesingle photon emission computed tomography study showed reduced activation in the PFC while performing the Tower of London task in patients with schizophrenia compared with normal controls [15]. Reduced hippocampal activation during performance of an episodic memory task has also been reported [18]. Crespo-Facorro et al. [6] investigated cognitive dysmetria in medication-free patients and controls by examining verbal learning and recognition. Consistent with an earlier study [5], the authors reported no activation in the cortical–cerebellar–thalamic–cortical circuitry in patients with schizophrenia during the recall of a list of words [6]. Abi-Dargham et al. [19] reported a relationship between D1 receptor density in the PFC and performance during a working memory task, in which increased prefrontal cortical D1 receptor binding was associated with impairments in the Wisconsin card sorting test (WCST). In support of these findings, Meyer-Lindenberg et al. [16] reported a positive correlation between WCST perseverative errors and striatal 18F-FDOPA in patients with schizophrenia (but not healthy volunteers), whereby poor performance on the WCST was associated with heightened striatal 18F-FDOPA uptake. Similar findings have been reported in Parkinson disease, in which reduced 18F-FDOPA uptake in the frontal cortex positively correlated with cognitive function, particularly in attention and working memory [14]. Using time-dependent kinetic modeling, Christian et al. [12] found a strong correlation between performance during a spatial-attention task and measured dopamine release in the extrastriatal region of the thalamus in healthy volunteers. However, there have been inconsistent findings. For example, Vernaleken et al. [20] used net blood–brain clearance of 18F-FDOPA to investigate the correlation between cognitive performance and utilization of 18F-FDOPA during these tasks in healthy volunteers. Although they reported no correlation between WCST perseverative errors and 18F-FDOPA, inconsistent with earlier findings [16], they did report a positive association between performance on the Stroop test, the continuous performance test, and the Trail Making Test and heightened 18F-FDOPA influx in the putamen, caudate nucleus, and midbrain. These findings suggest that patients with schizophrenia show a relatively strong relationship between prefrontal activity and striatal dopamine, whereas studies on healthy individuals suggest a different influence of striatal dopaminergic transmission on cognition. It is well established that genes play a role in elucidating the pathogenesis of schizophrenia, although the mode of inheritance is unclear. The general consensus on the genetic architecture of this illness is that additive actions of several common alleles (small to large effect sizes), some rare alleles (much larger effect sizes), and environmental influences (e.g. adverse life events, drug abuse, migration, etc.) may lead to the development of schizophrenia. The most promising candidate genes for schizophrenia include neuregulin-1 (NRG1), dysbindin (DTNBP1), and D-amino acid oxidase inhibitor (DAOA). These have provided useful insights into putative disease mechanisms of schizophrenia. The gene encoding for catechol-O-methyltransferase (COMT) plays a vital role in the degradation pathways of cortical dopamine. It contains a functional polymorphism at codon 158/108 causing substitution of methionine (Met158) with valine (Val158). Using PET imaging in adult-onset schizophrenia, a recent study reported that Val158 homozygote patients showed higher frontal lobe activation than Met158 homozygotes during the n-back task [17]. However, as with other genes, COMT confers a very small increase in susceptibility to this multifactorial neuropsychiatric disorder. A novel trend in genetics is to focus on copy number variants (CNVs), which are moderately large duplications or deletions in the human genome. Recent evidence suggests an excess burden of CNVs in schizophrenia. However, there is great variability in the magnitude of the reported effect sizes. The exploration of larger sample sizes and the minimization of the impact of population stratification in genetic association studies are required. In the early days of these discoveries, identifying large CNVs and understanding the precise neurochemical mechanisms of these genes is vital to gain insights and potentially drive the discovery process. In summary, schizophrenia is a complex disorder with heterogeneous clinical manifestations. PET/CT imaging provides high-resolution morphological imaging with functional information. Further research will provide better insights into whether the disorder is a state-related phenomenon reflected by heightened activation of subcortical dopamine, or whether the presentation is a reflection of complex underlying genetic mechanisms. Brain imaging investigations will study the role of molecular genetics, neurochemistry, and structural and functional relationships in relation to cognitive networks.