Spatial Working Memory as a Cognitive Endophenotype of Schizophrenia: Assessing Risk for Pathophysiological Dysfunction

Abstract

Research suggests that first-degree relatives and individuals with schizophrenia spectrum personality disorders (SSPD) may represent nonpenetrant carriers of the genetic diathesis for schizophrenia. This study examined visuospatial working memory (SWM) as a cognitive endophenotype of schizophrenia by expanding the concept of risk for pathophysiological dysfunction beyond overt psychosis. Risk was thus defined by familial status and the presence or absence of SSPD. SWM was assessed in the following groups, in order of decreasing likelihood of genetic vulnerability: 23 patients with schizophrenia, 17 SSPD relatives of patients with schizophrenia, 23 non-SSPD relatives of patients with schizophrenia, 14 SSPD community members with no family history of psychosis, and 36 non-SSPD community members. SWM performance during a computer task was quantified by A-Prime. Relative risk ratios for SWM deficits were compared among the groups. Compared with community non-SSPD volunteers, relative risk (RR) of SWM deficits was significantly elevated in patients with schizophrenia (RR = 3.76, p = .002) and SSPD family members (RR = 2.97, p = .027), but not in the family non-SSPD (RR = 1.88, p = .241) or community SSPD (RR = 1.03, p = .971) groups. The pattern of SWM performance deficits reflected the proposed model of latent genetic liability, upholding SWM as a viable cognitive endophenotype. The results underscore the importance of including both familial liability and the schizophrenia spectrum when considering risk for schizophrenia and schizophrenia-related traits. This is particularly relevant for research efforts to identify pathophysiological components of the disease.

The NTSR1 gene modulates the association between hippocampal structure and working memory performance

“…In humans, a previous study showed an association between NTSR1 gene polymorphisms and schizophrenia (Lee et al, 1999). This result indirectly supports a connection between the NTSR1 gene and WM because impaired WM has been found to be an important endophenotype of schizophrenia (Glahn et al, 2003;Saperstein et al, 2006). Several lines of evidence have shown an important role of the hippocampus in WM.…”

Abnormal effective connectivity and psychopathological symptoms in the psychosis high-risk state

“…Although previous n-back studies in ARMS samples found no difference in task performance relative to controls or only a statistical trend in terms of accuracy and reaction time, 11,12 behavioural studies in larger samples have indicated clear neuropsychological deficits in high-risk populations, 45,46 including individuals at genetic risk for schizophrenia, 47 confirming that these deficits may be a cognitive marker of increased vulnerability to disease. This is in line with previous studies reporting working memory deficits in the early course of the illness 6 and with a recent metaanalysis demonstrating that the psychosis high-risk state is characterized by prominent impairments in working memory.…”

Verbal working memory impairments in individuals with schizophrenia and their first-degree relatives: Findings from the Consortium on the Genetics of Schizophrenia

“…Prior studies of the relationship between WM and schizotypal features among unaffected relatives of schizophrenia probands have shown generally mixed results (e.g., (Conklin et al 2005;Delawalla 2006;Johnson et al 2003;Saperstein et al 2006), possibly reflecting differences in the schizotypy assessment instruments and WM tasks employed across studies. The current results suggest that the LNS Reordered impairments in the relatives reflect vulnerability to schizophrenia rather than the clinical or subclinical features of schizophrenia spectrum disorders assessed in this study.…”