Cognitive correlates of gray matter abnormalities in adolescent siblings of patients with childhood-onset schizophrenia.

Patients with childhood onset schizophrenia (COS) display widespread gray matter (GM) structural brain abnormalities. Healthy siblings of COS patients share some of these structural abnormalities, suggesting that GM abnormalities are endophenotypes for schizophrenia. Another possible endophenotype for schizophrenia that has been relatively unexplored is corticostriatal dysfunction. The corticostriatal system plays an important role in skill learning. Our previous studies have demonstrated corticostriatal dysfunction in COS siblings with a profound skill learning deficit and abnormal pattern of brain activation during skill learning. This study investigated whether structural abnormalities measured using volumetric brain morphometry (VBM) were present in siblings of COS patients and whether these were related to deficits in cognitive skill learning. Results revealed smaller GM volume in COS siblings relative to controls in a number of regions, including occipital, parietal, and subcortical regions including the striatum, and greater GM volume relative to controls in several subcortical regions. Volume in the right superior frontal gyrus and cerebellum were related to performance differences between groups on the weather prediction task, a measure of cognitive skill learning. Our results support the idea that corticostriatal and cerebellar impairment in unaffected siblings of COS patients are behaviorally relevant and may reflect genetic risk for schizophrenia.

Divergent CSF τ alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy.

BACKGROUND: Elevated CSF τ is considered a biomarker of neuronal injury in newly developed Alzheimer's disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of τ species in other primary tauopathies. We assessed CSF τ protein abnormalities in AD, a tauopathy with prominent Aß pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterised by deposition of four microtubule-binding repeat (4R) τ with minimal Aß pathology. METHODS: 26 normal control (NC), 37 AD, and 24 patients with PSP participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aß, total τ, and ptau181. Additional, novel ELISAs targeting different N-terminal and central τ epitopes were developed to examine CSF τ components and to investigate interactions between diagnostic group, demographics and genetic variables. RESULTS: PSP had lower CSF N-terminal and C-terminal τ concentrations than NC and AD measured with the novel τ ELISAs and the standard AlzBio3 τ and ptau assays. AD had higher total τ and ptau levels than NC and PSP. There was a gender by diagnosis interaction in AD and PSP for most τ species, with lower concentrations for male compared to female patients. CONCLUSIONS: CSF τ fragment concentrations are different in PSP compared with AD despite the presence of severe τ pathology and neuronal injury in both disorders. CSF τ concentration likely reflects multiple factors in addition to the degree of neuronal injury.

Evidence for corticostriatal dysfunction during cognitive skill learning in adolescent siblings of patients with childhood-onset schizophrenia.

Patients with schizophrenia perform poorly on cognitive skill learning tasks. This study is the first to investigate the neural basis of impairment in cognitive skill learning in first-degree adolescent relatives of patients with schizophrenia. We used functional magnetic resonance imaging to compare activation in 16 adolescent siblings of patients with childhood-onset schizophrenia (COS) and 45 adolescent controls to determine whether impaired cognitive skill learning in individuals with genetic risk for schizophrenia was associated with specific patterns of neural activation. The siblings of patients with COS were severely impaired on the Weather Prediction Task (WPT) and showed a relative deactivation in frontal regions and in the striatum after extensive training on the WPT compared with controls. These differences were not accounted for by performance differences in the 2 groups. The results suggest that corticostriatal dysfunction may be part of the liability for schizophrenia.

Impaired automatization of a cognitive skill in first-degree relatives of patients with schizophrenia.

We studied healthy, first-degree relatives of patients with schizophrenia to test the hypothesis that deficits in cognitive skill learning are associated with genetic liability to schizophrenia. Using the Weather Prediction Task (WPT), 23 healthy controls and 10 adult first-degree Relatives Of Schizophrenia (ROS) patients were examined to determine the extent to which cognitive skill learning was automated using a dual-task paradigm to detect subtle impairments in skill learning. Automatization of a skill is the ability to execute a task without the demand for executive control and effortful behavior and is a skill in which schizophrenia patients possess a deficit. ROS patients did not differ from healthy controls in accuracy or reaction time on the WPT either during early or late training on the single-task trials. In contrast, the healthy control and ROS groups were differentially affected during the dual-task trials. Our results demonstrate that the ROS group did not automate the task as well as controls and continued to rely on controlled processing even after extensive practice. This suggests that adult ROS patients may engage in compensatory strategies to achieve normal levels of performance and support the hypothesis that impaired cognitive skill learning is associated with genetic risk for schizophrenia.

Deficits in probabilistic classification learning and liability for schizophrenia.

Patients with schizophrenia show deficits in skill learning. We tested the hypothesis that impaired skill learning is associated with liability for schizophrenia by determining if it is present in non-affected siblings of patients. This study examined cognitive skill learning in adolescent siblings of patients with childhood onset schizophrenia (COS), who are at high genetic risk for the disorder, and age-matched controls. A probabilistic classification task was used to assess cognitive skill learning, which has been shown to be impaired in patients with striatal dysfunction or schizophrenia. Differences between the groups emerged within the first 50 trials of training: the controls showed significant learning while the COS siblings did not. Furthermore, after extended training over 800 additional trials the siblings of COS probands reached a lower level of asymptotic performance than controls. These results suggest that a behavioral impairment in probabilistic classification learning in healthy, unaffected siblings mirrors the deficits seen in patients and thus may reflect genetic liability for the disease.