Neuropathological abnormalities in schizophrenia: evidence from magnetization transfer imaging

Abstract

Post-mortem and structural brain imaging studies in schizophrenia have reported macroscopic changes such as global and regional cortical volume reductions, but it has been more difficult to characterize the histopathological changes that underlie these abnormalities. Magnetization transfer imaging (MTI), a novel MRI technique, more sensitive to subtle or early neuropathological changes than conventional MRI, provides a quantitative measure of macromolecular structural integrity represented by the magnetization transfer ratio (MTR). In this study, we used MTI to examine 25 patients with schizophrenia compared with 30 age-matched controls. A voxel-based analysis of the MTR maps revealed widespread MTR reductions in the cortex unrelated to volume reduction, predominantly in the frontal and temporal regions, in the schizophrenic patients when compared with controls. MTR reductions in bilateral parieto-occipital cortex and the genu of the corpus callosum were associated with the severity of negative symptoms in the schizophrenic patients. However, MTR changes were not related to other clinical variables of age, duration of illness and current dose of antipsychotic medication. This study demonstrates that MTR abnormalities in the cortex can be detected in chronic schizophrenia that may reflect subtle neuropathological changes involving neurones or neuronal processes. Longitudinal studies are needed to determine whether these abnormalities are related to disease progression or other disease manifestations such as cognitive changes.

Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia☆

“…Converging lines of evidence suggest that the processes governing myelination and/or the regulation of oligodendroglia are abnormal in schizophrenia (Reviewed in: ). Studies using magnetic resonance, magnetization transfer, and diffusion tensor imaging support the hypothesis that there are white matter abnormalities in this illness, and pathological examination by electron microscopy suggests a role for alterations of the myelin sheath (Buchsbaum et al, 1998;Lim et al, 1998;Lim et al, 1999;Pfefferbaum et al, 1999;Foong et al, 2000;Agartz et al, 2001;Foong et al, 2001;Sigmundsson et al, 2001;Steel et al, 2001;Uranova et al, 2001;Bagary et al, 2003;Sun et al, 2003;Hubl et al, 2004;Uranova et al, 2004;Wang et al, 2004;Szeszko et al, 2005). A subset of myelin-related genes has been consistently implicated in schizophrenia by genetic studies (Reviewed in: ), and subsequent microarray and QPCR analyses have found decreases in mRNA expression of myelin-related genes in prefrontal and temporal cortices (Hakak et al, 2001;Tkachev et al, 2003;Aston et al, 2004;Dracheva et al, 2005a;Haroutunian et al, 2005).…”

Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis

“…12,13,23,66,67 The second possibility is that the function of IWMN is to serve as modulators, either by monitoring (and perhaps affecting) impulse flow along passing fibres, or as regulators of the local vasculature. 67 If so, the IWMN findings in schizophrenia might be relevant to the altered patterns of blood flow 68 and white matter characteristics 69,70 seen in imaging studies, as well as to the emerging evidence for oligodendrocyte pathology. [71][72][73] A final point to note is that some controversy exists as to whether IWMNs are necessarily the adult remnants of subplate neurons.…”

Schizophrenia, neurodevelopment and corpus callosum

“…78 Also, decreased fractional anisotropy was found in the splenium of the CC using tensor diffusion imaging (TDI), 89,91 possibly involving axons that interconnect temporal and/or occipital areas. 98 A decreased magnetic transfer ratio was found in the genu, 92 possibly betraying abnormal connections between the prefrontal areas. 98 Relevant to the same issue is the preliminary finding of increased interhemispheric conduction time as estimated by the latency of the transcallosal inhibition of motor response of the first dorsal interossus muscle in 10 S patients.…”

“…135 Negative correlation between CC size and negative symptoms was found by Tibbo et al 81 The alterations in S patients with negative symptoms might relate to the anterior part of the CC, whose size appears to be reduced 80 and where abnormalities were localized with MTR. 92 In two separate studies 117,137 examining a total of 31 male, unmedicated patients, Merrin and collaborators reported a negative correlation between ICoh in the a band of the EEG and negative symptoms. 117,137 Other associations between CC markers and S have also been reported (Table 4), but await confirmation.…”