White matter density in patients with schizophrenia, bipolar disorder and their unaffected relatives.
ABSTRACT This study sought to assess white matter density in patients and relatives with histories of bipolar disorder and/or schizophrenia.
Subjects included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives of the three patient groups were also recruited. Subjects underwent an MRI brain scan which was analyzed using a white-matter optimized technique.
Subjects with schizophrenia and bipolar disorder showed reduced white matter density in the anterior limb of the internal capsule which was not found in unaffected relatives. Reductions were found in frontal subgyral white matter density in affected subjects with a family history of schizophrenia only.
Abnormal anterior internal capsule white matter may provide a structural substrate for both disorders.
SourceAvailable from: Francesco Benedetti[Show abstract] [Hide abstract]
ABSTRACT: Background. Bipolar disorder (BD) is associated with adverse childhood experiences (ACE), which worsen the lifetime course of illness, and with signs of widespread disruption of white matter (WM) integrity in adult life. ACE are associated with changes in WM microstructure in healthy humans. Method. We tested the effects of ACE on diffusion-tensor imaging (DTI) measures of WM integrity in 80 in-patients affected by a major depressive episode in the course of BD. We used whole-brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial, radial and mean diffusivity, and fractional anisotropy. Results. ACE hastened the onset of illness. We observed an inverse correlation between the severity of ACE and DTI measures of axial diffusivity in several WM fibre tracts contributing to the functional integrity of the brain and including the corona radiata, thalamic radiations, corpus callosum, cingulum bundle, superior longitudinal fasciculus, inferior fronto-occipital fasciculus and uncinate fasciculus. Conclusions. Axial diffusivity reflects the integrity of axons and myelin sheaths, and correlates with functional connectivity and with higher-order abilities such as reasoning and experience of emotions. In patients with BD axial diffusivity is increased by lithium treatment. ACE might contribute to BD pathophysiology by hampering structural connectivity in critical cortico-limbic networks.Psychological Medicine 03/2014; 44(14):1-14. DOI:10.1017/S0033291714000506 · 5.43 Impact Factor
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ABSTRACT: Objectives Genetic markers in the genes encoding ankyrin 3 (ANK3) and the α-calcium channel subunit (CACNA1C) are associated with bipolar disorder (BP). The associated variants in the CACNA1C gene are mainly within intron 3 of the gene. ANK3 BP-associated variants are in two distinct clusters at the ends of the gene, indicating disease allele heterogeneity.Methods In order to screen both coding and non-coding regions to identify potential aetiological variants, we used whole-genome sequencing in 99 BP cases. Variants with markedly different allele frequencies in the BP samples and the 1,000 genomes project European data were genotyped in 1,510 BP cases and 1,095 controls.ResultsWe found that the CACNA1C intron 3 variant, rs79398153, potentially affecting an ENCyclopedia of DNA Elements (ENCODE)-defined region, showed an association with BP (p = 0.015). We also found the ANK3 BP-associated variant rs139972937, responsible for an asparagine to serine change (p = 0.042). However, a previous study had not found support for an association between rs139972937 and BP. The variants at ANK3 and CACNA1C previously known to be associated with BP were not in linkage disequilibrium with either of the two variants that we identified and these are therefore independent of the previous haplotypes implicated by genome-wide association.Conclusions Sequencing in additional BP samples is needed to find the molecular pathology that explains the previous association findings. If changes similar to those we have found can be shown to have an effect on the expression and function of ANK3 and CACNA1C, they might help to explain the so-called ‘missing heritability’ of BP.Bipolar Disorders 04/2014; 16(6). DOI:10.1111/bdi.12203 · 4.89 Impact Factor
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ABSTRACT: White matter (WM) abnormalities are one of the most widely and consistently reported findings in schizophrenia (SZ) and bipolar disorder (BD). If these abnormalities are inherited determinants of illness, suitable to be classified as an endophenotype, relatives of patients must also have them at higher rate compared to the general population. In this review, we evaluate published diffusion tensor imaging (DTI) studies comparing first degree relatives of SZ and BD patients and healthy control subjects. We searched PubMed, Embase and PsychInfo for DTI studies which included an unaffected relative and a healthy comparison group. 22 studies fulfilled the inclusion criteria. WM abnormalities were found in many diverse regions in relatives of SZ patients. Although the findings were not completely consistent across studies, the most implicated areas were the frontal and temporal WM regions and the corpus callosum. Studies in relatives of BD patients were fewer in number with less consistent findings reported across studies. Our review supports the concept of WM abnormalities as an endophenotype in SZ, with somewhat weaker evidence in BD, but larger and higher quality studies are needed to make a definitive comment. Copyright © 2014 Elsevier B.V. All rights reserved.Schizophrenia Research 12/2014; 161(2-3). DOI:10.1016/j.schres.2014.12.008 · 4.43 Impact Factor