Renee Testa

Age of Onset of Schizophrenia: Perspectives From Structural Neuroimaging Studies

Many of the major neuropsychiatric illnesses, including schizophrenia, have a typical age of onset in late adolescence. Late adolescence may reflect a critical period in brain development making it particularly vulnerable for the onset of psychopathology. Neuroimaging studies that focus on this age range may provide unique insights into the onset and course of psychosis. In this review, we examine the evidence from 2 unique longitudinal cohorts that span the ages from early childhood through young adulthood; a study of childhood-onset schizophrenia where patients and siblings are followed from ages 6 through to their early twenties, and an ultra-high risk study where subjects (mean age of 19 years) are studied before and after the onset of psychosis. From the available evidence, we make an argument that subtle, regionally specific, and genetically influenced alterations during developmental age windows influence the course of psychosis and the resultant brain phenotype. The importance of examining trajectories of development and the need for future combined approaches, using multimodal imaging together with molecular studies is discussed.

Neurobiological Markers of Illness Onset in Psychosis and Schizophrenia: The Search for a Moving Target

In this review, we describe neuropsychological and brain imaging findings in the early stages of psychosis and schizophrenia. We focus on recent clinical high-risk studies and consider whether the evidence supports these as ‘endophenotypes’ of a vulnerability to the illness or as ‘biomarkers’ of illness onset and transition. The findings suggest that there are a number of processes at psychosis onset that may represent biomarkers of incipient illness. These neurobiological indices particularly implicate the integrity of frontal and temporal cortices, which may or may not be related to the genetics of psychosis (i.e. potential ‘endophenotypes’). However, these brain regions are dynamically changing during normal maturation, meaning that any putative neurobiological markers identified at the earliest stages of illness may be relatively unstable. We suggest that, while such measures may be readily identified as potential neurobiological markers of established illness, they are inconsistent at (or around) the time of illness onset when assessed cross-sectionally. Instead, identification of more valid risk markers may require longitudinal assessment to ascertain normal or abnormal trajectories of neurodevelopment. Accordingly, we assert that the current conceptualisations of potential biomarkers and/or ‘endophenotypes’ for schizophrenia may need to be reconsidered in the context of normal and abnormal brain maturational processes at the time of onset of psychotic disorders.

Predicting the diagnosis of autism spectrum disorder using gene pathway analysis

Autism spectrum disorder (ASD) depends on a clinical interview with no biomarkers to aid diagnosis. The current investigation interrogated single-nucleotide polymorphisms (SNPs) of individuals with ASD from the Autism Genetic Resource Exchange (AGRE) database. SNPs were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived pathways to identify affected cellular processes and develop a diagnostic test. This test was then applied to two independent samples from the Simons Foundation Autism Research Initiative (SFARI) and Wellcome Trust 1958 normal birth cohort (WTBC) for validation. Using AGRE SNP data from a Central European (CEU) cohort, we created a genetic diagnostic classifier consisting of 237 SNPs in 146 genes that correctly predicted ASD diagnosis in 85.6% of CEU cases. This classifier also predicted 84.3% of cases in an ethnically related Tuscan cohort; however, prediction was less accurate (56.4%) in a genetically dissimilar Han Chinese cohort (HAN). Eight SNPs in three genes (KCNMB4, GNAO1, GRM5) had the largest effect in the classifier with some acting as vulnerability SNPs, whereas others were protective. Prediction accuracy diminished as the number of SNPs analyzed in the model was decreased. Our diagnostic classifier correctly predicted ASD diagnosis with an accuracy of 71.7% in CEU individuals from the SFARI (ASD) and WTBC (controls) validation data sets. In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD. While SNPs differ across ethnic groups, our pathway approach identified cellular processes common to ASD across ethnicities. Our results have wide implications for detection, intervention and prevention of ASD.

The Ecological and Construct Validity of a Newly Developed Measure of Executive Function: The Virtual Library Task

Virtual reality (VR) assessment paradigms have the potential to address the limited ecological validity of pen and paper measures of executive function (EF) and the pragmatic and reliability issues associated with functional measures. To investigate the ecological validity and construct validity of a newly developed VR measure of EF, the Virtual Library Task (VLT); a real life analogous task--the Real Library Task (RLT); and five neuropsychological measures of EF were administered to 30 patients with traumatic brain injury (TBI) and 30 healthy Controls. Significant others for each participant also completed the Dysexecutive Questionnaire (DEX), which is a behavioral rating scale of everyday EF. Performances on the VLT and the RLT were significantly positively correlated indicating that VR performance is similar to real world performance. The TBI group performed significantly worse than the Control group on the VLT and the Modified Six Elements Test (MSET) but the other four neuropsychological measures of EF failed to differentiate the groups. Both the MSET and the VLT significantly predicted everyday EF suggesting that they are both ecologically valid tools for the assessment of EF. The VLT has the advantage over the MSET of providing objective measurement of individual components of EF.

Grey and white matter abnormalities are associated with impaired spatial working memory ability in first-episode schizophrenia

Spatial working memory (SWM) dysfunction has been suggested as a trait marker of schizophrenia and implicates a diffuse network involving prefrontal, temporal and parietal cortices. However, structural abnormalities in both grey and white matter in relation to SWM deficits are largely unexplored. The current magnetic resonance imaging (MRI) study examined this relationship in a sample of young first-episode schizophrenia (FES) patients using a whole-brain voxel-based method. SWM ability of 21 FES patients and 41 comparable controls was assessed by the CANTAB SWM task. Using an automated morphometric analysis of brain MRI scans, we assessed the relationship between SWM abilities and both grey matter volume and white matter density in both groups. Our findings demonstrated the different directionality of the association between SWM errors and grey matter volume in left frontal regions and white matter tracts connecting these regions with temporal and occipital areas between FES patients and controls. This suggests that the substrate underpinning the normal variability in SWM function in healthy individuals may be abnormal in FES, and that the normal neurodevelopmental processes that drive the development of SWM networks are disrupted in schizophrenia.

The Abilities Associated with Verbal Fluency Performance in a Young, Healthy Population Are Multifactorial and Differ Across Fluency Variants

Numerous variants of verbal fluency tasks exist within clinical and research domains that purport to measure “executive function.” However, to date, there has been a paucity of research examining what specific abilities are measured by these tasks. In this study, the relationships between a select group of cognitive constructs and phonemic, semantic, alternating, and excluded-letter verbal fluency tests were examined in 93 young healthy individuals (aged 18 to 35 years old). Forward-selection multiple regression analyses were performed for each fluency task. Phonemic fluency was associated with verbal intellectual function and processing speed; semantic fluency was associated with working memory and semantic word retrieval; excluded-letter fluency was associated with processing speed; and alternating fluency was associated with semantic word retrieval. These results highlight verbal intellectual function, processing speed, and semantic word-retrieval contributions to verbal fluency performances. The main conclusion from this study is that the abilities associated with verbal fluency performance in a young healthy population are multifactorial and differ across fluency variants. These findings progress our theoretical understanding of what is measured by different verbal fluency tasks and will assist interpretation of performance.

Hoarding Behaviors in Children With Learning Disabilities

Our objective was to describe the prevalence, comorbidity, and neuropsychological profiles of children with hoarding and learning disabilities. From 61 children with learning disabilities, 16.4% exhibited hoarding as a major clinical issue. Although children with learning disabilities and hoarding displayed greater rates of obsessive-compulsive disorder (30%) as compared to those with learning disabilities without hoarding (5.9%), the majority of patients belonging to the former group did not display obsessive-compulsive disorder diagnosis. When learning disability patients with hoarding were compared to age-, sex-, and IQ-matched learning disability subjects without hoarding, hoarders exhibited a slower learning curve on word list-learning task. In conclusion, salient hoarding behaviors were found to be relatively common in a sample of children with learning disabilities and not necessarily associated with obsessive-compulsive disorder, supporting its nosological independence. It is unclear whether underlying cognitive features may play a major role in the development of hoarding behaviors in children with learning disabilities.

Muscarinic M1 receptor sequence: Preliminary studies on its effects on cognition and expression

It has been reported that people with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism of the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test than those who are heterozygous. We investigated whether CHRM1 sequence is associated with impaired executive function, a common problem in schizophrenia. We sequenced the CHRM1 using peripheral DNA from 97 people with schizophrenia who completed the Wisconsin Card Sorting Test, a verbal fluency test and the National Adult Reading Test. Clinical severity was assessed using the Positive and Negative Syndrome Scale. To determine whether CHRM1 sequence affected receptor expression, we used post-mortem data, from another cohort, to investigate associations between CHRM1 sequence and mRNA levels. On the Wisconsin Card Sorting Test, 267C/C participants with schizophrenia made more perseverative errors (p<0.05) and perseverative responses (p<0.05) than 267C/A participants. Genotype had no effect on verbal fluency (p=0.8) or National Adult Reading test (p=0.62). Cortical CHRM1 mRNA levels did not vary with gene sequence (p=0.409). The clinical study supports the proposal that CHRM1 sequence is associated with alterations in some aspects of executive function. However, the post-mortem study indicates this is not simply due to altered expression at the level of mRNA, suggesting this sequence alteration may affect the functionality of the CHRM1.

Convergent evidence for mGluR5 in synaptic and neuroinflammatory pathways implicated in ASD

The pathogenesis of Autism Spectrum Disorder (ASD), a serious neurodevelopmental disorder, is poorly understood. We review evidence for alterations in glutamatergic signalling in the aetiology of ASD, with a focus on the metabotropic glutamate receptor-5 (mGluR5). mGluR5 signalling is important for synapse formation, neuroplasticity and long term potentiation as well as neuroprotection and has been shown to have a regulatory role in neuroinflammation. Evidence for neuroinflammation in ASD is supported by increase in pro-inflammatory cytokines in the blood and cerebrospinal fluid (CSF) and increased number and activation of microglia in postmortem dorsolateral prefrontal cortex (DLPFC). mGlur5 signalling has also been shown to downregulate microglial activation. Therefore, we focus on mGluR5 as a potential unifying explanation for synapse alteration and neuroinflammation seen in ASD. Data from mGluR5 knockout mouse models, and syndromic and non syndromic forms of ASD are discussed in relation to how alterations in mGluR5 are associated with ASD symptoms. This review supports altered mGluR5 functioning as a convergent point in ASD pathogenesis and indicates more research is warranted into mGluR5 as a potential therapeutic target.

Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications

Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, whilst activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n=30) and ASD (n=27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p=0.018) as well as downstream elements SHANK3 (p=0.005) and PLCB1 (p=0.009) but that the pro-inflammatory marker NOS2 was increased (p=0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p=0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p=0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning.