Background Elevated CSF tau 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 tau species in other primary tauopathies. We assessed CSF tau protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterized by deposition of four microtubule binding repeat (4R) tau with minimal Aβ pathology. Methods 26 normal control (NC), 37 AD, and 24 PSP patients 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 Aβ, total tau, and ptau181. Additional, novel ELISAs targeting different N-terminal and central tau epitopes were developed to examine CSF tau components and to investigate interactions between diagnostic group, demographics, and genetic variables. Results PSP had lower CSF N-terminal and C-terminal tau concentrations than NC and AD measured with both the novel tau ELISAs and the standard AlzBio3 tau and ptau assays. AD had higher total tau and ptau levels than NC and PSP. There was a gender by diagnosis interaction in both AD and PSP for most tau species, with lower concentrations for male compared to female patients. Conclusions CSF tau fragment concentrations are different in PSP compared with AD despite the presence of severe tau pathology and neuronal injury in both disorders. CSF tau concentration likely reflects multiple factors in addition to the degree of neuronal injury.
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
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.
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.
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