Dataset Information

Association of Age at Onset and Longitudinal Course of Prefrontal Function in Youth With Schizophrenia.

ABSTRACT:

Importance

The extent of cognitive deterioration after schizophrenia (SZ) onset is poorly understood because prior longitudinal studies used small samples of older individuals with established illness.

Objective

To examine the association of age at onset and subsequent longitudinal course of prefrontal activity during the first 2 years of illness in youths with SZ and healthy control participants (HCs).

Design, setting, and participants

This naturalistic, longitudinal, functional magnetic resonance imaging (fMRI) study included patients with recent-onset SZ and HCs aged 12 to 25 years enrolled in an ongoing study of cognition in recent-onset psychosis in the Sacramento, California, area from October 13, 2004, through June 25, 2013. Participants completed clinical assessments and an established measure of cognitive control, the AX Continuous Performance Task (AX-CPT), during fMRI at baseline and at 6-, 12-, and 24-month follow-up. Whole-brain, voxelwise, and an a priori dorsolateral prefrontal cortex (DLPFC) region of interest analyses were performed. Group differences in developmental trajectories were examined by focusing on behavioral performance (d'-context) and cognitive control-associated brain activity. The association of antipsychotic medication and clinical factors were also examined. Data were analyzed from April 15, 2015, through August 29, 2017.

Main outcomes and measures

Primary outcomes included group differences (HC vs SZ) in behavioral performance (d'-context from AX-CPT) and brain activity for cue B-A trials of the AX-CPT in an a priori DLPFC region of interest at baseline and across the age span. Secondary analysis examined the influence of antipsychotics on behavioral performance and DLPFC activity.

Results

Among the sample of 180 participants (66.1% male; mean [SD] age at baseline, 19.2 [3.2] years), 87 patients with SZ (mean [SD] age, 19.6 [3.0] years) showed impaired performance compared with 93 HCs (mean [SD] age, 18.8 [3.4] years) across the age span (estimated difference [SE], -0.571 [0.12], d'-context; P?Conclusions and relevanceDuring the initial 1 to 2 years after illness onset, young individuals with SZ showed deficits in DLPFC activation and cognitive control, with developmental trajectories comparable to those of HCs. Younger age at onset was not associated with reduced cognition or activation. For individuals contributing to longitudinal analysis, results suggest that young patients do not show deterioration or disruption of ongoing brain development in the initial years after illness onset.

SUBMITTER: Niendam TA

PROVIDER: S-EPMC6583034 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Association of Age at Onset and Longitudinal Course of Prefrontal Function in Youth With Schizophrenia.

Niendam Tara A TA Ray Kimberly L KL Iosif Ana-Maria AM Lesh Tyler A TA Ashby Stefania R SR Patel Pooja K PK Smucny Jason J Ferrer Emilio E Solomon Marjorie M Ragland J Daniel JD Carter Cameron S CS

JAMA psychiatry 20181201 12

<h4>Importance</h4>The extent of cognitive deterioration after schizophrenia (SZ) onset is poorly understood because prior longitudinal studies used small samples of older individuals with established illness.<h4>Objective</h4>To examine the association of age at onset and subsequent longitudinal course of prefrontal activity during the first 2 years of illness in youths with SZ and healthy control participants (HCs).<h4>Design, setting, and participants</h4>This naturalistic, longitudinal, func ...[more]

PMID: 30285056

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Project description:BACKGROUND: Schizophrenia is a severe mental disorder with high heritability, and cognitive dysfunction is one of the core features. Growing evidence suggests the genetic risk of schizophrenia may contribute to cognitive impairments. The variant rs1635 (nucleotide sequence: c.455C>A; amino acid sequence: T152N) located on the (NFKB activating protein like) NKAPL gene confers risk for schizophrenia and might play a role in the neurodevelopmental process, which is particularly relevant to cognitive function. However, the relationship between rs1635 and cognitive function remains unclear. METHODS: A total of 130 patients with early-onset schizophrenia (EOS) and 300 patients with adult-onset schizophrenia (AOS) of Han Chinese were recruited and underwent neurocognitive tests by using the MATRICS Consensus Cognitive Battery (MCCB). The NKAPL rs1635 was genotyped by using DNA sequencing. The peripheral blood NKAPL mRNA expression level was examined in 152T or 152N carriers (n = 20) in EOS patients, by using the qRT-PCR. The phosphorylation level of NAKPL T152N polymorphism was detected by cell experiments. In utero electroporation of mouse embryos was examined to explore the effect of Nkapl on neuronal migration. RESULTS: Compared with rs1635 AA and AC carriers, CC (the CC genotype encodes the protein NKAPL-152T) carriers of EOS patients performed better in cognitive domain of speed of processing (t = 2.644, p = 0.009), trail making test (t = 2.221, p = 0.028) and category fluency (t = 2.578, p = 0.011). However, patients with AOS exhibited no significant differences in seven domains among the three genotype groups. There were no significant differences in cognitive performance between EOS and AOS. In EOS patients, NKAPL mRNA level in NKAPL-152N carriers is significantly lower than that of NKAPL-152T carriers. The phosphorylation level of NKAPL-152N is significantly decreased compared to NKAPL-152T. In utero electroporation showed that Nkapl deletion impairs the embryonic radial migration process. CONCLUSION: The present study found that NKAPL rs1635 was associated with cognitive impairments and peripheral blood mRNA expression level in EOS patients. The NKAPL full-length protein is required for embryonic cortical neuronal migration. The phosphorylation level of NKAPL-152N is significantly decreased. The NKAPL T152N may affect the NAKPL mRNA expression level and embryonic cortical neuronal migration by regulating the NAKPL protein phosphorylation. These data suggest that NKAPL rs1635 affects cognitive function by regulating early brain development in early-onset schizophrenia.

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Dataset Information

Association of Age at Onset and Longitudinal Course of Prefrontal Function in Youth With Schizophrenia.

Importance

Objective

Design, setting, and participants

Main outcomes and measures

Results

Publications

Association of Age at Onset and Longitudinal Course of Prefrontal Function in Youth With Schizophrenia.

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