Brain white matter metabolite abnormalities are shown in elderly patients with schizophrenia; specifically, we observed overall decreased NA and MI, elevated GLX, and a trend for elevation of CHO in schizophrenic subjects compared to healthy volunteers. Decreased NA suggests decreased neuronal content or neuronal dysfunction, while decreased MI suggests decreased glial content or function, and elevated GLX may reflect a hyperglutamatergic state in the white matter regions of these patients.
The decreases in the frontal and temporal white matter NA (12–18%) in these elderly schizophrenic patients are similar to or greater than those typically observed in the frontal gray matter (6.4% on average across 27 studies) or frontal white matter (6.4% matter across 17 studies) (13
). The longer disease duration in our elderly schizophrenics might have contributed to the greater decreases in NA, as reported previously (24
). Although neuropathology of schizophrenic brains consistently found increased, but maldistributed, neuronal density in the white matter (27
), many also found decreased soma size (28
), decreased dendritic arborization (29
), and hence fewer synaptic contacts and decreased brain volumes (31
). Therefore, the decreased NA in the white matter likely reflects decreased neuronal content associated with decreased synapses and neuronal cell volumes (including the axons that traverse the white matter).
Imaging and neurocytochemical studies also showed white matter abnormalities in schizophrenic patients. For instance, MRI demonstrated decreased global and regional white matter volumes (32
), decreased magnetization transfer ratios (36
), as well as decreased anisotropy on diffusion tensor imaging (DTI) (38
) in various white matter brain regions of schizophrenic patients, all of which point to possible myelin or white matter abnormalities. Unlike acute inflammatory demyelinating disorders, such as multiple sclerosis (43
) or active progressive multifocal leukoencephalopathy (PML) (44
), we only observed a trend for increased CHO in the white matter of our elderly schizophrenic patients. The lack of significance might be due to the small effect size relative to the sample size.
However, unlike many acute inflammatory demyelinating brain disorders that show concomitant elevation of MI and CHO, our schizophrenic participants showed decreased MI in most brain regions studied. Since MI is a glial marker (45
), it is typically elevated during glial activation or glial hypertrophy associated with active inflammation or demyelination, such as in the white matter of patients with HIV (46
), multiple sclerosis (43
), or PML (44
). The lack of elevated MI in patients with schizophrenia is also different from degenerative brain disorders, such as Alzheimer’s and frontotemporal dementia, which show increased MI along with decreased NA (48
). In these degenerative dementias, elevated MI probably reflects a glial response to the neuronal injury. Conversely, the decreased MI in our schizophrenic patients suggests decreased or dysfunctional glial response despite abnormal neuronal function (decreased NA). The decreased glial marker MI is also consistent with recent postmortem finding of reduced glial fibrillary acidic protein-reactive astroglia in the dorsal lateral prefrontal cortex of schizophrenic patients (50
In addition, our schizophrenia subjects had elevations of white matter GLX. This finding is consistent with two previous studies that found elevated glutamate or GLX/CR in the frontal white matter of both medication-naïve and treated schizophrenic patients (12
). In contrast, another MRS study reported lower glutamate and glutamine levels in the anterior cingulate, but increased glutamine in the thalamus, of medicated schizophrenia patients (52
). We found an average of 25.8% elevated GLX across brain regions, including the occipital regions, which tended to show normal levels for the other metabolites. The elevated GLX signal may reflect elevated glutamate, which could be due to a hyper-glutamatergic state of white matter in schizophrenia. Alternately, increased GLX may reflect a compensatory response to reduced glutamatergic transmission or binding to the receptors. Both possibilities, however, imply a pronounced dysfunction in the glutamate-glutamine homeostasis.
Since one important function of glia, especially astroglia, is re-uptake of glutamate from the extracellular space after neurotransmission, astroglial dysfunction might prevent this reuptake and lead to excess extracellular glutamate. Therefore, excess neuronal glutamate release coupled with dysfunctional glial reuptake could lead to the elevated extracelluar glutamate concentration. Among glial cells, oligodendroglia are particularly vulnerable to glutamate-mediated glial cell damage, via overactivation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate receptors (53
). Interestingly, patients with multiple sclerosis also showed elevated glutamate on MRS in acute demyelinating lesions (43
). Since multiple sclerosis is associated with pathology in the oligodendroglia, and hence demyelination, similar mechanism of astroglial dysfunction may contribute to the disease.
One limitation of the current study is that with a standard short-echo time MRS sequence (TE=30 ms), the spectral peaks of glutamate, glutamine and GABA were overlapping and difficult to separate even on the 4 Tesla scanner. Therefore, while GLX was fitted only from glutamate and glutamine concentrations, it is possible that some of the GABA signal was attributed to “GLX”, despite the separate fitting of GABA in the basis function. However, the contribution of GABA to the GLX would be minimal, since typical GABA concentrations are substantially (10–20 times) lower than those in the GLX peak. In addition, macromolecules might contribute to the GLX peak, as observed from degradation products in acute multiple sclerosis lesions (54
). However, our LC Model analyses indicated little or no effect on the GLX levels from the macromolecule resonances. A novel technique, echo-time (TE)-averaged PRESS, can measure glutamate with minimal contamination of the glutamine and macromolecule peaks (55
) which may be useful for future studies of schizophrenic patients. A second potential confound may be the effect of subtle differences in the partial volume of gray matter in the voxels between participant groups on metabolite concentrations. However, the relatively large changes in metabolite concentrations measured are much larger than the small concentration difference due to the different proportion of gray-white composition within the voxels. Thirdly, the potential effects of chronic medications on brain metabolite levels should be considered. Specifically, valproic acid and lithium both can stimulate glutamate release; however, the 9 schizophrenic participants who received divalproex and one that additionally received lithium did not show group difference in GLX any of the brain regions. Our finding is consistent with a recent MRS study that valproic acid had no effect on GLX in patients with bipolar disorder (56
). Lastly, since chronic D2 blockade may lead to both structural and metabolic changes in the brains of schizophrenic patients (57
), decreased NA also may be related to the effects of antipsychotics. A recent study in rats treated long-term with haloperidol, however, showed no effect on brain NA or glutamate levels (59
). Therefore, the metabolite changes observed in the current study are probably not due to medication effects; however, a larger sample size is needed to further validate these findings.
Schizophrenic subjects with cognitive decline had greater decreases in white matter NA than those without cognitive decline. In contrast to the greater than normal age-related decline of NA in younger participants with schizophrenia (24
), elderly schizophrenic patients showed a similar slope but lower NA across the age span compared to controls. The prior study (24
), however, did not correct for the partial volume effect from CSF in the voxels, which may be larger due to greater brain atrophy in the aging schizophrenic subjects. Postmortem studies indeed suggest schizophrenia does not involve ongoing neuronal degeneration (28
). Although glutamatergic dysfunction is thought to be related to cognitive impairment in schizophrenia, both subjects with or without cognitive decline showed elevated GLX. Further correlation with cognitive testing and longitudinal studies are needed to assess the relationship between glutamate and cognitive function.
Assuming that age-related decline in CHO is associated with loss of myelin, the age by disease status interaction effects on CHO in the frontal white matter would support the hypothesis that elderly patients with schizophrenia may develop greater age-related myelin loss. CR also decreased with age in the schizophrenic subjects, which would suggest lower energy requirement and lack of age-related glial proliferation in the normal aging process, and age-associated elevation of CR and MI (60
). These changes could lead to slower neuronal conduction and decline in frontal lobe function (e.g. executive function or working memory), as had been reported in elderly patients with schizophrenia (63
). Since glutamate reuptake is also important for shaping of excitatory post-synaptic currents (65
), dysfunctional or decreased glutamate reuptake by glia may also interfere with neuronal function. Further evaluation of the relationships between MRS abnormalities to cognitive function in these patients is needed.