HONOLULU— The extent to which neurocognitive impairments serve as indicators of liability to schizophrenia and/or attention-deficit/hyperactivity disorder (ADHD) is a burgeoning field of neuropsychiatric research. “This work has really been stimulated by the belief that one of the major bottlenecks to detecting susceptibility genes for schizophrenia is uncertainty over the boundaries for the schizophrenia phenotype,” said Robert F. Asarnow, PhD. “What’s very apparent is that liability to schizophrenia is expressed behaviorally in more than just schizophrenic psychosis. It includes certain personality disorders.” At the 31st Annual Meeting of the International Neuropsychological Society, Dr. Asarnow presented evidence suggesting that “liability to schizophrenia can be reflected in subtle neurocognitive impairments that are not ubiquitous in relatives of patients with psychiatric disorders.”

FAMILY BACKGROUND

The working assumptions behind Dr. Asarnow’s research are first, that there are genetic predispositions to schizophrenia and ADHD, and second, that these predispositions are reflected in subtle brain abnormalities, which may be reflected in certain types of behavioral and cognitive impairments.

Historically, said Dr. Asarnow, there have been two types of family design studies used to test such hypotheses. “One approach is to look at the aggregation of neurocognitive impairments of non-psychotic relatives of patients with schizophrenia. Liability to schizophrenia in the proband is reflected in impaired neurocognition in unaffected relatives. This is a fairly traditional family design.” Another approach, he continued, “is to look at the effect of familial liability on neurocognitive functioning in probands who themselves don’t have schizophrenia spectrum disorders. So these individuals don’t have schizophrenia themselves, but their relatives have schizophrenia, and in this design, you look for the effect of familial loading for schizophrenia on certain kinds of neurocognitive indicators.” Dr. Asarnow, Della Martin Professor of Psychiatry and Biobehavioral Sciences and Professor of Psychology at the University of California, Los Angeles (UCLA) School of Medicine, provided examples of both types of paradigms, demonstrating that they yield converging results.

THE UCLA FAMILY STUDY

Most of the data Dr. Asarnow presented came from the UCLA Family Study, a case-control family study of schizophrenia with two arms, focusing on relatives of patients with adult- and childhood-onset schizophrenia, respectively. In the childhood arm, the psychiatric comparison group is children with ADHD; in the adult arm, it is relatives of adults with bipolar disorder. Both arms had a community-control group consisting of relatives of individuals who had neither schizophrenia nor ADHD or bipolar disorder, but who could have had any other psychiatric disorder.

The first results Dr. Asarnow discussed were from the childhood onset arm. The key inclusion criterion is that the patient meets DSM-III criteria for schizophrenia by having hallucinations or delusions and by having an onset of psychosis prior to age 13. “We use a series of age-appropriate structured diagnostic interviews to assess DSM-III-R Axis I and Axis II psychopathology in both probands and their first-degree relatives. We take—typically from two informants—a family history of frank psychopathology among first- and second-degree relatives. We have separate diagnostic panels for probands and the relatives. The diagnoses used in our research are definite consensus diagnoses incorporating information from direct interview, family history, and medical records.” Three neurocognitive tasks are employed: the Trail Making Test, the Degraded Stimulus Continuous Performance Test, and the Partial Report Span of Apprehension task; in prior research, these tests demonstrated “the ability to detect subtle cognitive impairments in patients with schizophrenia and ADHD.”

A PAIR OF PARADIGMS

The first paradigm examined aggregation of neurocognitive impairments in the first-degree relatives of patients with schizophrenia. “This is an analysis of the combined data from the three neurocognitive tests,” Dr. Asarnow said. “We looked to see if the parents’ neurocognitive functioning predicts the diagnosis of the proband—and we found that about 20% of the parents of children with schizophrenia get scores on the combination of these three tests that are outside of the range of the normal controls.”

What’s interesting, he added, “is that even though these measures were selected because they detect impairments in patients with ADHD, they don’t detect impairments in relatives of patients with ADHD. A substantial proportion of mothers of childhood-onset schizophrenia probands reported outside of the range of mothers of ADHD probands and the same with fathers.” Parents of ADHD and community-control probands did not significantly differ on any of the three neurocognitive tests, Dr. Asarnow said. “Certain neurocognitive impairments are present in both the individuals with schizophrenia and their parents, and that suggests that these impairments can reflect liability to schizophrenia. In contrast, neurocognitive impairments are present in individuals with ADHD, but not their parents.”

In the second paradigm, Dr. Asarnow and colleagues looked at the data in the community controls, stratifying the group into those with and without a family loading for schizophrenia. “The prediction was that community-control probands with a family loading would do more poorly [on the neuropsychological tests] than those without. In this case, since the probands are children, we focused on standardized psychological tests where there are good age corrections,” such as measures of expressive and receptive vocabulary, general intelligence, visual-motor coordination, and verbal memory.

Vocabulary test data and psychiatric diagnoses were available from the parents, and family history diagnoses were available for the second-degree relatives. In this data set, family loading for schizophrenia came from second-degree relatives. Only one parent had a schizophrenia spectrum diagnosis. The community-control probands with a family history of schizophrenia performed significantly more poorly on measures of expressive and receptive vocabulary, general intelligence, and visual-motor coordination than the community controls without a family history of schizophrenia. In addition, the correlation between these measures in the probands and the vocabulary score of the parent was between 0.6 and 0.85 in families with a loading for schizophrenia, while it was less than half that in families without a loading for schizophrenia, Dr. Asarnow said. “What this data set suggests is that liability to schizophrenia is being transmitted across two generations through subtle neurocognitive impairments. These parents don’t have schizophrenia spectrum disorder, so the liability is coming from the second-degree relatives of the probands. This shows that you can account for a significant amount of the variance in the neurocognitive functioning of these community-control probands by knowing whether their second-degree relatives have a history of schizophrenia spectrum disorders,” he added.

ADDITIONAL ANALYSIS

Using the data from the adult and childhood samples, Keith Nuechterlein, PhD, Professor in the Department of Psychiatry and Biobehavioral Sciences at the UCLA School of Medicine, carried out a factor analysis of the three neurocognitive variables and symptoms of schizotypal personality disorder. “What he found was that the neurocognitive measures fall on a factor that includes only one symptom of schizotypy: odd or eccentric behavior,” Dr. Asarnow reported. “The other schizotypal symptoms fell on two factors: one called negative schizotypy and the other called positive schizotypy. This suggests that neurocognitive impairments and schizophrenia spectrum disorders are not coextensive. That they may be—in some instances—independent expressions of liability to schizophrenia.”

Collectively, these data encourage the belief that certain subtle neurocognitive impairments are part of the extended schizophrenia phenotype, Dr. Asarnow concluded. He and his colleagues are conducting a genetic linkage study, which, “when we have enough DNA and other data … may help determine whether there are separate susceptibility genes to schizophrenia psychosis versus these neurocognitive impairments which appear to be a critically important feature in schizophrenia disorders,” he said.

—C. Justin Romano

Suggested Reading
Asarnow RF, Nuechterlein KH, Subotnik KL, et al. Neurocognitive impairments in nonpsychotic parents of children with schizophrenia and attention-deficit/hyperactivity disorder: the University of California, Los Angeles Family Study. Arch Gen Psychiatry. 2002;59:1053-1060.

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