Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype.

BACKGROUND: Shared neurobiological characteristics of patients with schizophrenia and their siblings may represent "intermediate phenotypes" that may more closely reflect the genetic susceptibility underlying this illness. We sought evidence of such phenotypes using magnetic resonance spectroscopy based on previously described regional abnormalities in levels of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampal area and dorsolateral prefrontal cortex of patients with schizophrenia. METHODS: We studied 47 schizophrenics, 60 unaffected siblings, and 66 healthy control subjects with long echo time multislice proton magnetic resonance spectroscopic imaging, primarily measuring NAA, creatine plus phosphocreatine (CRE), and choline-containing compounds. RESULTS: Both patients and their unaffected siblings had significant reductions in hippocampal area NAA/CRE as compared with control subjects. As exploratory analyses, estimates of heritability were performed. Although quantitative correlation of hippocampal NAA between patients and sibs was low (likely reflecting measurement noise), qualitatively defined "low hippocampal NAA/CRE phenotypes" yielded relative risk estimates (lambda s) of between 3.8 and 8.8, suggesting this characteristic is heritable. CONCLUSIONS: Our finding adds to the evidence that hippocampal abnormalities are associated with schizophrenia and may represent a novel biological phenotype for genetic studies of schizophrenia.

Selective relationship between prefrontal N-acetylaspartate measures and negative symptoms in schizophrenia.

OBJECTIVE: Certain cognitive, behavioral, and emotional deficits (so-called negative symptoms) in patients with schizophrenia have often been attributed to prefrontal cortical pathology, but direct evidence for a relationship between prefrontal neuronal pathology and negative symptoms has been lacking. The authors hypothesized that an in vivo measure of prefrontal neuronal pathology (N:-acetylaspartate [NAA] levels) in patients with schizophrenia would predict negative symptoms. METHOD: Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and rating scales for negative and positive symptoms were used to study 36 patients with schizophrenia. Magnetic resonance spectra were analyzed as metabolite ratios, and parametric correlations were performed. RESULTS: A regionally selective negative correlation was found between prefrontal NAA-creatine ratio and negative symptom ratings in this group of patients with schizophrenia. CONCLUSIONS: Lower prefrontal NAA-and by inference greater neuronal pathology-predicted more severe negative symptoms in patients with schizophrenia. These data demonstrate a relationship between an intraneuronal measure of dorsolateral prefrontal cortex integrity and negative symptoms in vivo and represent further evidence for the involvement of the dorsolateral prefrontal cortex in negative symptoms associated with schizophrenia.

Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited.

Evidence implicates subtle neuronal pathology of the prefrontal cortex (PFC) in schizophrenia, but how this pathology is reflected in physiological neuroimaging experiments remains controversial. We investigated PFC function in schizophrenia using functional magnetic resonance imaging (fMRI) and a parametric version of the n-back working memory (WM) task. In a group of patients who performed relatively well on this task, there were three fundamental deviations from the 'healthy' pattern of PFC fMRI activation to varying WM difficulty. The first characteristic was a greater magnitude of PFC fMRI activation in the context of slightly impaired WM performance (i.e. physiological inefficiency). The second was that the significant correlations between behavioral WM performance and dorsal PFC fMRI activation were in opposite directions in the two groups. Third, the magnitude of the abnormal dorsal PFC fMRI response was predicted by an assay of N-acetylaspartate concentrations (NAA) in dorsal PFC, a measure of neuronal pathology obtained using proton magnetic resonance spectroscopy. Patients had significantly lower dorsal PFC NAA than controls and dorsal PFC NAA inversely predicted the fMRI response in dorsal PFC (areas 9, 46) to varying WM difficulty - supporting the assumption that abnormal PFC responses arose from abnormal PFC neurons. These data suggest that under certain conditions the physiological ramifications of dorsal PFC neuronal pathology in schizophrenia includes exaggerated and inefficient cortical activity, especially of dorsal PFC.