Neuropsychological Impairment and Structural Brain Abnormalities among the Non-psychotic Relatives of Schizophrenic Patients

Abstract

Although family, twin and adoption studies show that genetic factors play a substantial role in the etiology of schizophrenia, molecular genetic studies have not yet identified susceptibility genes. Due to these difficulties, some authors have suggested that new strategies may be needed to detect linkage to schizophrenia and other etiologically complex disorders. One such strategy has been to define schizophrenia “spectrum” phenotypes that reflect the genetic liability to schizophrenia in non-schizophrenic subjects. This strategy focuses on one of the obstacles hindering linkage analyses of schizophrenia: our ability to measure the disorder and the variable expression of its susceptibility genes. In fact, if multiple genes cause schizophrenia, they might not be detectable without reducing measurement error and creating measures that more directly assess the genes and their consequences. In this presentation, we review data from our family studies of schizophrenia which show elevated rates of neuropsychological impairment and structural brain abnormalities among relatives of schizophrenic patients. The neuropsychological impairments were stable over a four year period. Moreover, the severity of the neuropsychological and structural brain abnormalities was greatest among relatives who had two (as opposed to only one) schizophrenic relative. Observed impairements were greatest for abstraction, auditory attention and verbal declarative memory. We also reported that gray matter subcortical volumes were significantly smaller in relatives of schizophrenic patients compared with controls. Significant effects were found for the left and right hippocampus, right amygdale, right putamen, left thalamus, and in the brain stem. Relatives also had significantly enlarged left and right inferior lateral ventricles. When we increased the sample size, we continued to find significant volume reductions in the amygdala-hippocampal region and thalamus. Marginal differences were seen for putamen, cerebellum and third and fourth ventricles. There was a linear trend indicating smaller hippocampal volumes in multiplex compared to simplex relatives and controls, consistent with the hypothesis that increased genetic loading for schizophrenia affects brain structure. This parallels our finding that verbal memory deficits are more severe in multiplex than simplex relatives. The positive association between verbal declarative memory deficits and smaller hippocampal volumes, particularly in multiplex relatives, suggests that smaller hippocampal volumes are meaningfully related to important cognitive functions. Our finding of specifically left hippocampal abnormalities, and reversed hippocampal asymmetry (in both simplex and multiplex relatives), provides novel support for the hypothesis that lateralized temporal lobe abnormalities observed in patients with schizophrenia actually reflect genetic, neurodevelopmental vulnerability to the illness. Taken together, the above studies of adults suggest that the genes which cause schizophrenia may also cause neuropsychological impairment and structural brain abnormalities. Thus, these methods may be useful in designing molecular genetic studies of schizophrenia.