This year our focus was aimed at refining cognitive intermediate phenotypes. Our clinical sample consisted of a population of psychiatrically healthy siblings of patients with schizophrenia. We had previously shown that phenotypes related to abnormal executive cognition and cognitive control are associated with genetic risk for illness, suggesting that susceptibility genes impact on the neural processing of this type of information as an intermediate phenotype. Our studies were based on standard clinical neuropsychological tests. We have begun a new series of studies with the aim of characterizing the component processes in 1) executive cognition and cognitive control;2) in episodic memory, to refine our understanding of the cognitive phenotypes related to genetic risk;and 3) to differentiate those related to clinical state. We believe that a more refined cognitive analysis will lead to clearer understanding of the neural mechanisms involved and lead to potential clinical targets to better monitor the effects of treatment. To accomplish this, we have revised the standard battery of neuropsychological tests used for genetic association with cognition. This is important for reducing the redundancy of the cognitive data and for limiting the number of associated tests performed. The revised factor solution is based on 1824 subjects and yields six robust factors representing domains of cognitive performance (e.g, verbal memory, processing speed), and a single global cognitive composite which together capture most of the information available in the cognitive dataset. Verbal and visual memory deficits are prominent trait markers for schizophrenia, with impairments also observed in first degree relatives. It has not been clear, whether the deficits reside in encoding or retention, which implicate different neural systems, and which are heritable deficits. To determine which features of memory performance are impaired in both patients and their healthy siblings, we tested episodic memory using Logical Memory and Visual Reproduction tasks of the Wechsler Memory Scale in 162 patients with schizophrenia, 146 of their non-psychotic siblings, and 205 controls. We assessed immediate, 30 minute delay, and 24 hour delayed recall as well as retention scores for the short term (immediate to 30 minute) and long term (30 minute to 24 hour) intervals. We found marked verbal recall deficits in both patients and siblings compared to controls for all stages. However, short-term verbal and visual retention deficits as well as long-term verbal deficits were found only in patients with schizophrenia. These results confirm shared impairment in verbal learning, but not memory, for both patients and siblings, therefore refining potential schizophrenia-associated intermediate phenotype related to episodic memory. The results implicate neural systems involved in immediate encoding and stabilization of memory representations in those having a genetic risk for schizophrenia, providing an important, verifiable neurocognitive system for targeting studies of specific genes. In contrast, visual recall and retention impairments appear to be illness-related. In collaboration with the University of Maryland, we are exploring new tests to target this specific memory function in our studies of the effects of schizophrenia associated genes. Perhaps these tools can be used to help monitor drug treatment affects in patients with schizophrenia.
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