This is Part 2 of a two-part series. See also Part 1.
July 9, 2013.
Genetics of cognition
Two speakers at the April 21 University of Miami Cognition Meeting examined the role that genetics play in the cognitive impairments of schizophrenia. Anil Malhotra of the Zucker Hillside Hospital in Glen Oaks, New York, reviewed the evidence for shared overlap between genes for cognitive function and risk for schizophrenia. He then described the recent efforts of the Cognitive Genomics Consortium (COGENT). A meta-analysis did not find any single nucleotide polymorphisms (SNPs) that reached genomewide significance; however, he reported that in a polygene analysis (which focused on a set of many alleles rather than just one), genes associated with poorer cognitive functioning were also associated with risk for schizophrenia. These findings suggest a polygenetic component for general cognitive ability that overlaps with risk for schizophrenia.
Dwight Dickinson of the National Institute of Mental Health in Bethesda, Maryland, discussed his group’s recent finding of an association of an SNP in SCN2A, a sodium channel gene involved in action potential generation, with general cognitive ability in subjects with schizophrenia. In fact, the SNP accounted for 10 percent of the variance in “g,” a composite measure of cognition. It was also associated with “g” in unaffected siblings and in several additional independent samples of schizophrenia subjects.
Three presenters showed data generated from rodent models of schizophrenia. Herbert Meltzer of Northwestern University in Chicago, Illinois, first reviewed data on the effects of antipsychotics on cognition in schizophrenia, describing the early reports suggesting a beneficial effect and the more recent data indicating they have little effect (Keefe and Harvey, 2012). He then discussed rodent studies, concluding that efforts to develop new treatments for cognitive impairments in schizophrenia should not involve restoring glutamatergic, dopaminergic, or cholinergic function. Finally, he emphasized the importance of studying specific domains of cognition rather than summated cognitive measures.
Maarten van den Buuse of Australia’s University of Melbourne discussed his work using brain-derived neurotrophic factor (BDNF) heterozygous mice treated with methamphetamine. Males, but not females, showed disrupted performance on a social novelty preference task without a change in overall sociability or in spatial memory. Van den Buuse suggested that this two-hit model may be useful to investigate the neurobiology of social dysfunction in schizophrenia.
Jared Young of the University of California, San Diego, discussed mouse behavioral data that model the probabilistic learning deficits observed in schizophrenia. His data suggest that dopamine influences probabilistic learning by affecting responses to reward and punishment. Acute hyperdopaminergia (via amphetamine administration) improved learning by enhancing reward associations. In contrast, both chronically elevated dopamine (achieved through a reduction of dopamine transporter levels) and suppression of striatal D1 receptors diminished learning by impairing reward associations.
Mixed bag of topics
The remaining presentations were scattered across a wide range of subjects. Dana Wagshal of the University of California, San Francisco, assessed whether the skill learning deficits of schizophrenia are present in patients’ unaffected siblings, finding evidence of both learning deficits and corticostriatal dysfunction. Wagshal administered a probabilistic classification learning task to the adolescent siblings of subjects with childhood-onset schizophrenia and controls, finding that the siblings showed early learning deficits that persisted after extended practice (Wagshal et al., 2012). In a new study using fMRI, she has now also demonstrated that after extensive training on the task, siblings exhibit a deactivation of frontal and striatal brain areas relative to controls.
Recognizing that there are both similarities and dissimilarities between schizophrenia and bipolar disorder, Antonella Trotta of King's College London performed a meta-analysis of 27 studies comparing premorbid and post-onset intellectual function between the two illnesses. She found that schizophrenia was associated with significant premorbid deficits as well as severe post-onset impairments, while bipolar disorder was characterized by a lack of premorbid deficits and less severe post-onset performance deficits. Trotta noted that her findings support the hypothesis that schizophrenia is associated with neurodevelopmental abnormalities.
Bjørn Rund of Norway’s University of Oslo described his efforts to determine whether psychosis, as indexed by the duration of untreated psychosis, is toxic to the brain. He found that the majority of neurocognitive studies (14 out of 19) were not supportive of this hypothesis, while the data from morphological studies were less clear, with eight studies in favor and five against. Rund concluded that there may be limited evidence to suggest a relationship between the duration of untreated psychosis and changes in neurocognitive functioning or brain structures, but noted that definite conclusions cannot be drawn due to methodological limitations.
Keith Wesnes of Bracket Global in Goring-on-Thames, U.K., showed data, using a picture recognition paradigm, to suggest that there is compromised dentate gyrus neurogenesis in schizophrenia, which may at least partially explain the memory deficits observed. Because atypical antipsychotics, along with some newer ones, promote neurogenesis, he concluded that this brief cognitive task may be an important screening tool and outcome measure for testing this mechanism.
Henry Nasrallah of Ohio’s University of Cincinnati described the intersection of two major problems in schizophrenia: neurocognitive impairments that produce significant functional disability and metabolic dysfunction that can result in early mortality. Using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, Nasrallah found that, whereas some metabolic parameters (such as high BMI and hypertension) were associated with worse cognition, others (higher cholesterol and triglycerides) were associated with an improvement.—Allison A. Curley.