Progressive Brain Change in Schizophrenia: A Prospective Longitudinal Study of First-Episode Schizophrenia

Psychiatric Iowa Neuroimaging Consortium, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Biological psychiatry (Impact Factor: 10.26). 07/2011; 70(7):672-9. DOI: 10.1016/j.biopsych.2011.05.017
Source: PubMed


Schizophrenia has a characteristic onset during adolescence or young adulthood but also tends to persist throughout life. Structural magnetic resonance studies indicate that brain abnormalities are present at onset, but longitudinal studies to assess neuroprogression have been limited by small samples and short or infrequent follow-up intervals.
The Iowa Longitudinal Study is a prospective study of 542 first-episode patients who have been followed up to 18 years. In this report, we focus on those patients (n = 202) and control subjects (n = 125) for whom we have adequate structural magnetic resonance data (n = 952 scans) to provide a relatively definitive determination of whether progressive brain change occurs over a time interval of up to 15 years after intake.
A repeated-measures analysis showed significant age-by-group interaction main effects that represent a significant decrease in multiple gray matter regions (total cerebral, frontal, thalamus), multiple white matter regions (total cerebral, frontal, temporal, parietal), and a corresponding increase in cerebrospinal fluid (lateral ventricles and frontal, temporal, and parietal sulci). These changes were most severe during the early years after onset. They occur at severe levels only in a subset of patients. They are correlated with cognitive impairment but only weakly with other clinical measures.
Progressive brain change occurs in schizophrenia, affects both gray matter and white matter, is most severe during the early stages of the illness, and occurs only in a subset of patients. Measuring severity of progressive brain change offers a promising new avenue for phenotype definition in genetic studies of schizophrenia.

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    • "Schizophrenia is a devastating and disabling neuropsychiatric disorder. The neural mechanisms of this disorder have been attributed to structural and functional abnormalities of the brain [1] [2] [3] [4] [5]. Schizophrenia patients have exhibited functional changes in both task-evoked activation and spontaneous brain activity [6] [7]. "
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    ABSTRACT: Altered spontaneous brain activity as measured by ALFF, fALFF, and ReHo has been reported in schizophrenia, but no consensus has been reached on alternations of these indexes in the disorder. We aimed to clarify the regional alterations in ALFF, fALFF, and ReHo in schizophrenia using a meta-analysis and a large-sample validation. A meta-analysis of activation likelihood estimation was conducted based on the abnormal foci of ten studies. A large sample of 86 schizophrenia patients and 89 healthy controls was compared to verify the results of the meta-analysis. Meta-analysis demonstrated that the alternations in ALFF and ReHo had similar distribution in schizophrenia patients. The foci with decreased ALFF/fALFF and ReHo in schizophrenia were mainly located in the somatosensory cortex, posterior parietal cortex, and occipital cortex; however, foci with increased ALFF/fALFF and ReHo were mainly located in the bilateral striatum, medial temporal cortex, and medial prefrontal cortex. The large-sample study showed consistent findings with the meta-analysis. These findings may expound the pathophysiological hypothesis and guide future research.
    07/2015; 2015:1-11. DOI:10.1155/2015/204628
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    • "The change score of clinical assessments were calculated by subtracting the scores of clinical assessments at follow-up from the scores of clinical assessments at baseline. We also recorded time in hospital during the interscan interval as a measure of illness severity in patients with schizophrenia, reasoning that hospitalization time was a proxy measure of relapse duration, which has been associated with volume loss in schizophrenia (Andreasen et al., 2011). "
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    ABSTRACT: Progressive brain volume loss in schizophrenia has been reported in previous studies but its cause and regional distribution remains unclear. We investigated progressive regional brain reductions in schizophrenia and correlations with potential mediators. Participants were drawn from the Northern Finland Birth Cohort 1966. A total of 33 schizophrenia individuals and 71 controls were MRI scanned at baseline (mean age=34.7, SD=0.77) and at follow-up (mean age=43.4, SD=0.44). Regional brain change differences and associations with clinical mediators were examined using FSL voxelwise SIENA. Schizophrenia cases exhibited greater progressive brain reductions than controls, mainly in the frontal and temporal lobes. The degree of periventricular brain volume reductions were predicted by antipsychotic medication exposure at the fourth ventricular edge and by the number of days in hospital between the scans (a proxy measure of relapse duration) at the thalamic ventricular border. Decline in social and occupational functioning was associated with right supramarginal gyrus reduction. Our findings are consistent with the possibility that antipsychotic medication exposure and time spent in relapse partially explain progressive brain reductions in schizophrenia. However, residual confounding could also account for the findings and caution must be applied before drawing causal inferences from associations demonstrated in observational studies of modest size. Less progressive brain volume loss in schizophrenia may indicate better preserved social and occupational functions. Copyright © 2015. Published by Elsevier B.V.
    Schizophrenia Research 07/2015; 70. DOI:10.1016/j.schres.2015.06.016 · 3.92 Impact Factor
    • "The significance of neuroprogressive changes in the risk and progression of schizophrenia are being appreciated widely in recent times (Andreasen et al. 2011; Davis et al. 2014; Stein and Broome 2015). Several underlying mechanisms including neurotransmitter abnormality, immuno-inflammatory, oxidative and nitrosative stress (IO&NS) pathway, mitochondrial dysfunction, tryptophan catabolite (TRYCAT) pathway etc. contribute to neuroprogressive changes in schizophrenia (Anderson and Maes 2013; Venkatasubramanian and Debnath 2013; Debnath and Berk 2014; Rajasekaran et al. "
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    ABSTRACT: Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.
    Journal of Neuroimmune Pharmacology 07/2015; DOI:10.1007/s11481-015-9626-9 · 4.11 Impact Factor
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