Subtypes of cognitive dysfunction

Cognitive deficits in schizophrenia are heterogeneous, ranging from pervasive generalized dysfunction through patchy focal disorders to mild focal deficits or nearly normal performance.^{282, 283, 284, 285, 286, 287, 288} Yet amidst seemingly extensive heterogeneity, converging evidence points to specific deficits in verbal declarative memory and working memory (mainly in the early encoding stage) as major sources of variance.^{289, 290} This observation has prompted attempts at delineating particular profiles or subtypes. While conventional cluster analyses tend to simply distribute patients into groups of severely compromised, intermediate and mildly affected performance,^{291, 292} 'classical' fine-grain neuropsychological analyses (case studies of individual profiles rather than group means; delineation of generalized/differential deficits; search for 'double dissociations') have identified patterns of dysfunction that parallel the amnestic syndromes in coarse brain disease, such as Huntington's (HD), PD, or AD.

In a series of 175 schizophrenia patients, compared with 229 normal controls on the performance of the California Verbal Learning Test (CVLT), Paulsen et al.²³⁶ elicited from 50% of the patients a subcortical (striatal, HD/PD-type) memory profile combining prominent retrieval deficit (poor free-format recall of word lists, improving substantially on presentation of cues) with absence of storage deficits (lack of rapid forgetting). Another 15% had a cortical (hippocampal-thalamic, AD-type) profile (primary encoding and storage impairment, with an excess of irrelevant word intrusions on free and cued recall), while the profiles of the remaining 35% did not deviate significantly from those of the controls. These findings were replicated by Turetsky et al.²³⁷ and supported by neuroimaging data suggesting ventricular enlargement with preserved temporal lobe grey matter and no significant metabolic abnormalities in the subcortical group. In contrast, the cortical group was characterized by a left-hemisphere temporal and frontal volume reduction, and metabolic abnormalities in the superior temporal gyrus, hippocampus, and thalamus. Using a different statistical approach, Dickinson et al.²⁴¹ estimated that over 30% of the variance in cognitive test performance by schizophrenia patients could be explained by a large-effect 'g' factor, affecting fundamental processes that integrate multiple intermodal brain functions into 'core' cognitive operations such as concept formation and reasoning skills. Further variance, however, can be explained by a number of independent, small-effect variables selectively affecting specific functions, such as processing speed and visual memory. Table 4 provides an overview of proposed cognitive subtypes associated with schizophrenia.

Promising as they are, these approaches to 'splitting schizophrenia'²⁹³ are limited by sample size, as well as by insufficient efforts to integrate multidomain data (e.g. neuroimaging and neurophysiological measurements) that might increase their capacity to parse the deficits characterizing schizophrenia.

Cognitive phenotypes have rarely been tested as phenotypes in molecular genetic studies. In one such study, Egan et al.²⁹⁴ used working memory/executive function (assessed by the Wisconsin Card Sorting test, WCST) as the phenotype in a functional investigation of the val158/108met polymorphism in the catechol-o-methyltransferase (COMT) gene. Allele dosage effect of worsening WCST performance and reduced fMRI activation response in the prefrontal cortex was found for the val/met and val/val genotypes, likely due to a more rapid inactivation of synaptic dopamine by the COMT-val variant. No effect on sustained attention was detected.²³⁸ In another study, using a more inclusive neurocognitive battery, Bilder et al.²⁹⁵ found greater impact of the val158/108met genotype on processing speed and attention than on executive function, suggesting that the effect of the COMT polymorphism on cognition may not be exclusively mediated by prefrontal dopamine. Considering that the COMT-val allele has shown an association with schizophrenia in some reports,^{296, 297, 298} although not in others,^{299, 300, 301} the possibility that this polymorphism might contribute to the risk of schizophrenia requires further study.

In a study of 168 Finnish families with schizophrenia, Paunio et al.³⁰² applied a variance component analysis (SOLAR) to genome scan data, using 11 neuropsychological test battery scores obtained from probands and relatives as quantitative trait phenotypes before linkage analysis. Compared with diagnosis only as the phenotype, use of quantitative traits resulted in a stronger signal and evidence of linkage for verbal learning and memory over a 30 cM region on 4q13–25 (Zmp=3.84), as well as suggestive evidence for visual working memory on 2q36 (Zmp=2.08), visual attention on 15q22 and executive function on 9p22. Although the advantages of using quantitative traits are demonstrated by this study, the interpretation of specific linkage findings for subcomponent cognitive processes will be tenuous until replication or convergent evidence from endophenotyping studies become available.

Date: 2016-04-22; view: 909