Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study.
ABSTRACT: Premorbid cognitive deficits in schizophrenia are well documented and have been interpreted as supporting a neurodevelopmental etiological model. The authors investigated the following three unresolved questions about premorbid cognitive deficits: What is their developmental course? Do all premorbid cognitive deficits follow the same course? Are premorbid cognitive deficits specific to schizophrenia or shared by other psychiatric disorders?Participants were members of a representative cohort of 1,037 males and females born between 1972 and 1973 in Dunedin, New Zealand. Cohort members underwent follow-up evaluations at specific intervals from age 3 to 32 years, with a 96% retention rate. Cognitive development was analyzed and compared in children who later developed schizophrenia or recurrent depression as well as in healthy comparison subjects.Children who developed adult schizophrenia exhibited developmental deficits (i.e., static cognitive impairments that emerge early and remain stable) on tests indexing verbal and visual knowledge acquisition, reasoning, and conceptualization. In addition, these children exhibited developmental lags (i.e., growth that is slower relative to healthy comparison subjects) on tests indexing processing speed, attention, visual-spatial problem solving ability, and working memory. These two premorbid cognitive patterns were not observed in children who later developed recurrent depression.These findings suggest that the origins of schizophrenia include two interrelated developmental processes evident from childhood to early adolescence (ages 7-13 years). Children who will grow up to develop adult schizophrenia enter primary school struggling with verbal reasoning and lag further behind their peers in working memory, attention, and processing speed as they get older.
Project description:Despite the widespread belief that neuropsychological decline is a cardinal feature of the progression from the premorbid stage to the chronic form of schizophrenia, few longitudinal studies have examined change in neuropsychological functioning from before to after illness onset. The authors examined whether neuropsychological decline is unique to schizophrenia, whether it is generalized or confined to particular mental functions, and whether individuals with schizophrenia also have cognitive problems in everyday life.Participants were members of a representative cohort of 1,037 individuals born in Dunedin, New Zealand, in 1972 and 1973 and followed prospectively to age 38, with 95% retention. Assessment of IQ and specific neuropsychological functions was conducted at ages 7, 9, 11, and 13, and again at age 38. Informants also reported on any cognitive problems at age 38.Individuals with schizophrenia exhibited declines in IQ and in a range of mental functions, particularly those tapping processing speed, learning, executive function, and motor function. There was little evidence of decline in verbal abilities or delayed memory, however, and the developmental progression of deficits in schizophrenia differed across mental functions. Processing speed deficits increased gradually from childhood to beyond the early teen years, whereas verbal deficits emerged early but remained static thereafter. Neuropsychological decline was specific to schizophrenia, as no evidence of decline was apparent among individuals with persistent depression, children with mild cognitive impairment, individuals matched on childhood risk factors for schizophrenia, and psychiatrically healthy individuals. Informants also noticed more cognitive problems in individuals with schizophrenia.There is substantial neuropsychological decline in schizophrenia from the premorbid to the postonset period, but the extent and developmental progression of decline varies across mental functions. Findings suggest that different pathophysiological mechanisms may underlie deficits in different mental functions.
Project description:Individuals with disorders that include psychotic symptoms (i.e. psychotic disorders) experience broad cognitive impairments in the chronic state, indicating a dimension of abnormality associated with the experience of psychosis. These impairments negatively impact functional outcome, contributing to the disabling nature of schizophrenia, bipolar disorder, and psychotic depression. The robust and reliable nature of cognitive deficits has led researchers to explore the timing and profile of impairments, as this may elucidate different neurodevelopmental patterns in individuals who experience psychosis. Here, we review the literature on cognitive deficits across the life span of individuals with psychotic disorder and psychotic-like experiences, highlighting the dimensional nature of both psychosis and cognitive ability. We identify premorbid generalized cognitive impairment in schizophrenia that worsens throughout development, and stabilizes by the first-episode of psychosis, suggesting a neurodevelopmental course. Research in affective psychosis is less clear, with mixed evidence regarding premorbid deficits, but a fairly reliable generalized deficit at first-episode, which appears to worsen into the chronic state. In general, cognitive impairments are most severe in schizophrenia, intermediate in bipolar disorder, and the least severe in psychotic depression. In all groups, cognitive deficits are associated with poorer functional outcome. Finally, while the generalized deficit is the clearest and most reliable signal, data suggests specific deficits in verbal memory across all groups, specific processing speed impairments in schizophrenia and executive functioning impairments in bipolar disorder. Cognitive deficits are a core feature of psychotic disorders that provide a window into understanding developmental course and risk for psychosis.
Project description:AIM:Previous research investigating outcomes after pediatric intracerebral hemorrhage (ICH) has generally been limited to global and sensorimotor outcomes. This study examined cognitive outcomes after spontaneous ICH in school-aged children with serial assessments over 2 years after stroke. METHOD:Seven children (age range 6-16y, median 13; six males, one female; 57% white, 43% black) presenting with spontaneous ICH (six arteriovenous malformations) were assessed at 3 months, 12 months, and 24 months after stroke. The Pediatric Stroke Outcome Measure (PSOM) quantified neurological outcome and Wechsler Intelligence Scales measured cognitive outcomes: verbal comprehension, perceptual reasoning, working memory, and processing speed. RESULTS:PSOM scales showed improved neurological function over the first 12 months, with mild to no sensorimotor deficits and moderate overall deficits at 1- and 2-year follow-ups (median 2-year sensorimotor PSOM=0.5, total PSOM=1.5). Changes in cognitive function indicated a different trajectory; verbal comprehension and perceptual reasoning improved over 24 months; low performance was sustained in processing speed and working memory. Age-normed centile scores decreased between 1- and 2-year follow-ups for working memory, suggesting emerging deficits compared with peers. INTERPRETATION:Early and serial cognitive testing in children with ICH is needed to assess cognitive functioning and support children in school as they age and cognitive deficits become more apparent and important for function. WHAT THIS PAPER ADDS:In children with intracerebral hemorrhage (ICH), motor function improved between 3 months and 24 months. Improvements in cognitive function were variable between 3 months and 24 months. Working memory centiles declined, suggesting emerging deficits compared with peers. Processing speed improved but remained significantly below the 50th centile. Cognitive impact of ICH may increase with age in children.
Project description:Schizophrenia neurocognitive domain profiles are predominantly based on paper-and-pencil batteries. This study presents the first schizophrenia domain profile based on the Computerized Multiphasic Interactive Neurocognitive System (CMINDS(®)). Neurocognitive domain z-scores were computed from computerized neuropsychological tests, similar to those in the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB), administered to 175 patients with schizophrenia and 169 demographically similar healthy volunteers. The schizophrenia domain profile order by effect size was Speed of Processing (d=-1.14), Attention/Vigilance (d=-1.04), Working Memory (d=-1.03), Verbal Learning (d=-1.02), Visual Learning (d=-0.91), and Reasoning/Problem Solving (d=-0.67). There were no significant group by sex interactions, but overall women, compared to men, showed advantages on Attention/Vigilance, Verbal Learning, and Visual Learning compared to Reasoning/Problem Solving on which men showed an advantage over women. The CMINDS can readily be employed in the assessment of cognitive deficits in neuropsychiatric disorders; particularly in large-scale studies that may benefit most from electronic data capture.
Project description:Importance:Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. Objective:To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Design, Setting, and Participants:Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n?=?79?757 [cases, 34?486; controls, 45?271]); verbal-numerical reasoning (n?=?36?035) and reaction time (n?=?111?483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n?=?53?949) and COGENT (Cognitive Genomics Consortium) (n?=?27?888). Main Outcomes and Measures:Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Results:Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P?=?5.53?×?10-7), general cognitive function (z score, -4.43; P?=?9.42?×?10-6), and verbal-numerical reasoning (z score, -5.43; P?=?5.64?×?10-8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. Conclusions and Relevance:The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.
Project description:OBJECTIVE:A premorbid IQ deficit supports a developmental dimension to schizophrenia and its cognitive aspects that are crucial to functional outcome. Better characterisation of the association between premorbid IQ and the disorder may provide further insight into its origin and etiology. We aimed to quantify premorbid cognitive function in schizophrenia through systematic review and meta-analysis of longitudinal, population-based studies, and to characterize the risk of schizophrenia across the entire range of premorbid IQ. METHOD:Electronic and manual searches identified general population-based cohort or nested case-control studies that measured intelligence before onset of schizophrenic psychosis using standard psychometric tests, and that defined cases using contemporaneous ICD or DSM. Meta-analyses explored dose-response relationships between premorbid cognitive deficit (using full-scale, verbal and performance IQ) and risk of schizophrenia. Meta-regression analyses explored relationships with age of illness onset, change in premorbid intelligence over time and gender differences. RESULTS:Meta-analysis of 4396 cases and over 745000 controls from 12 independent studies confirmed significant decrements in premorbid IQ (effect size -0.43) among future cases. Risk of schizophrenia operated as a consistent dose-response effect, increasing by 3.7% for every point decrease in IQ (p<0.0001). Verbal and nonverbal measures were equally affected. Greater premorbid IQ decrement was associated with earlier illness onset (p<0.0001). There was no evidence of a progressively increasing deficit during the premorbid period toward illness onset. CONCLUSIONS:Strong associations between premorbid IQ and risk for schizophrenia, and age of illness onset argue for a widespread neurodevelopmental contribution to schizophrenia that operates across the entire range of intellectual ability. This also suggests higher IQ may be protective in schizophrenia, perhaps by increasing active cognitive reserve.
Project description:Objective:To determine the cognitive profile of adult patients with mitochondrial disease, and the effect of disease severity on cognition. Methods:Using a prospective case-control design, we compared cognition of patients to normative data and to matched controls, assessed three times over 18 months. Forty-nine patients with m.3243A>G (N = 36) and m.8344A>G (N = 13) mtDNA mutations and 32 controls, matched by age (±5 years) and premorbid cognition (±10 WTAR FSIQ points), participated. Participants completed neuropsychological assessments of general cognition (WAIS-IV), executive function (D-KEFS), and memory (WMS-IV). Potential predictors of cognition were explored. Results:Patients show mild-to-moderate premorbid cognitive impairment, but substantial impairment in current general cognition and distinct domains, including verbal comprehension, perceptual reasoning, working memory, processing speed, and memory retrieval. Executive dysfunction may be caused by slower decision-making. Patients performed worse than controls, except on memory tasks, indicating intact memory, when premorbid cognition is controlled for. Premorbid cognition and disease severity were consistent predictors of cognition in patients; however, cognitive decline appears slow and is unlikely in the short-term, when other disease-specific factors remain stable. Interpretation:Patients should be monitored to facilitate early identification of a complex profile of cognitive deficits and individuals with higher disease burden should be followed up more closely. On development of cognitive difficulties, appropriate compensatory strategies should be determined through in-depth assessment. Using strategies such as slower presentation of information, multiple modes of presentation, active discussion to aid understanding and decision-making, and use of memory aids, may ameliorate difficulties.
Project description:Microduplication of chromosome 1q21.1 is observed in ~0.03% of adults. It has a highly variable, incompletely penetrant phenotype that can include intellectual disability, global developmental delay, specific learning disabilities, autism, schizophrenia, heart anomalies and dysmorphic features. We evaluated a 10-year-old-male with a 1q21.1 duplication by CGH microarray. He presented with major attention deficits, phonological dysphasia, poor fine motor skills, dysmorphia and mild autistic features, but not the typical macrocephaly. Neuropsychiatric evaluation demonstrated a novel phenotype: an unusually large discrepancy between non-verbal capacities (borderline-impaired WISC-IV index scores of 70 for Working Memory and 68 for Processing Speed) vs. strong verbal skills - scores of 126 for Verbal Comprehension (superior) and 111 for Perceptual Reasoning (normal). HYDIN2 has been hypothesized to underlie macrocephaly and perhaps cognitive deficits in this syndrome, but assessment of HYDIN2 copy number by microarray is difficult because of extensive segmental duplications. We performed whole-genome sequencing which supported HYDIN2 duplication (chr1:146,370,001-148,590,000, 2.22?Mb, hg38). To evaluate copy number more rigorously we developed droplet digital PCR assays of HYDIN2 (targeting unique 1?kb and 6?kb insertions) and its paralog HYDIN (targeting a unique 154?bp segment outside the HYDIN2 overlap). In an independent cohort, ddPCR was concordant with previous microarray data. Duplication of HYDIN2 was confirmed in the patient by ddPCR. This case demonstrates that a large discrepancy of verbal and non-verbal abilities can occur in 1q21.1 duplication syndrome, but it remains unclear whether this has a specific genomic basis. These ddPCR assays may be useful for future research on HYDIN2 copy number.
Project description:This study assessed genetic contributions to six cognitive domains, identified by the MATRICS Cognitive Consensus Battery as relevant for schizophrenia, cognition-enhancing, clinical trials. Psychiatric Genomics Consortium Schizophrenia polygenic risk scores showed significant negative correlations with each cognitive domain. Genome-wide association analyses identified loci associated with attention/vigilance (rs830786 within HNF4G), verbal memory (rs67017972 near NDUFS4), and reasoning/problem solving (rs76872642 within HDAC9). Gene set analysis identified unique and shared genes across cognitive domains. These findings suggest involvement of common and unique mechanisms across cognitive domains and may contribute to the discovery of new therapeutic targets to treat cognitive deficits in schizophrenia.
Project description:Autism Spectrum Disorder (ASD) and schizophrenia are neurodevelopmental disorders which show substantial cognitive heterogeneity in adulthood, yet it remains unclear whether cognitive profiles may overlap across these diagnoses. Thus, the aim of this review was to summarize comparisons between ASD and schizophrenia on nonsocial cognition in adulthood. To minimize between-study heterogeneity in a relatively small literature, subtest scaled scores from the Wechsler Adult Intelligence Scale were compared between ASD (N=190) and schizophrenia (N=260) in six studies comprising a total of 450 participants. Meta-analyses of 11 subtests indicated that participants with ASD demonstrated significantly better performance than schizophrenia for visuospatial perception and reasoning and problem solving (Hedge's g=0.636), as well as visual attention and organization (g=0.433-0.475). Participants with ASD also demonstrated better performance than those with schizophrenia for working memory (g=0.334) and language (g=0.275), and generally comparable performance on processing speed and verbal comprehension. These findings were largely stable across age, sex, intelligence quotient (IQ), intellectual disability, scale version, and age- and sex-matching. Overall, ASD and schizophrenia showed striking differences in visuospatial perception and reasoning and problem solving, small differences in working memory and language, and substantial overlap in processing speed and verbal comprehension. These cognitive profiles were generally stable from adolescence to middle adulthood. To our knowledge, this is the first review to summarize comparisons of nonsocial cognition in verbal adults with ASD or schizophrenia. These findings are consistent with and substantially extend prior meta-analyses of case-control studies for ASD and schizophrenia (8, 9), which also suggest that, in comparison to neurotypical controls, ASD demonstrates smaller cognitive impairments than schizophrenia across most cognitive domains, particularly working memory, visuospatial learning/memory, and language. Our findings therefore highlight the importance of comparing cognition transdiagnostically to inform the etiologies of these neurodevelopmental disorders and to refine shared and unique targets for remediating cognition.