Genetic risk for white matter abnormalities in bipolar disorder

White matter deficits have been demonstrated in people with bipolar disorder, schizophrenia and their unaffected relatives. These deficits are supported by evidence from post-mortem studies, including microarray investigations which have repeatedly implicated abnormal myelin-associated gene expression. Furthermore, several risk-associated genes have now been identified that encode for proteins which have effects on white matter integrity. These genes include neuregulin-1 (NRG1) polymorphisms of which have been associated with risk to bipolar disorder. NRG1 has been shown to have effects on axonal migration, myelination and oligodendrocyte function. We and others have also shown that 5' risk-associated genetic variants in NRG1 are associated with reductions in both white matter density and integrity in regions associated with prefrontal connectivity. These findings are discussed in the context of the current literature, along with possible future research directions

Progressive gray matter loss in patients with bipolar disorder

BACKGROUND: Structural brain abnormalities of the medial temporal lobe have been found in people with bipolar disorder (BPD). It is not known whether these abnormalities progress over the course of the illness or how they relate to neuropsychologic functioning. We sought to address these uncertainties in a prospective cohort study of people with bipolar I disorder. METHODS: Twenty patients with bipolar I disorder and 21 control subjects were recruited from the community. Participants were group matched for age, sex, and premorbid IQ. Longitudinal change in gray matter density was assessed using magnetic resonance imaging and evaluated using the technique of tensor-based morphometry with SPM2 software. Changes in gray and white matter density were estimated and compared with changes in cognitive function and clinical outcome. RESULTS: Patients with BPD showed a larger decline in hippocampal, fusiform, and cerebellar gray matter density over 4 years than control subjects. No significant changes in white matter density were found. Reductions in temporal lobe gray matter correlated with decline in intellectual function and with the number of intervening mood episodes over the follow-up period. CONCLUSIONS: Patients with BPD lose hippocampal, fusiform and cerebellar gray matter at an accelerated rate compared with healthy control subjects. This tissue loss is associated with deterioration in cognitive function and illness course

Changes in gyrification over 4 years in bipolar disorder and their association with the brain-derived neurotrophic factor valine66 methionine variant

BACKGROUND: Evidence suggests that structural brain changes occur over time in bipolar disorder but few studies have examined this longitudinally. Additional work implicates brain-derived neurotrophic factor (BDNF) valine (val)(66)methionine (met) variant in these changes. The present study examined longitudinal trends in prefrontal gyrification index (GI) in bipolar disorder and the effect of BDNF genotype. METHODS: Eighteen patients with bipolar I disorder and 18 control subjects underwent magnetic resonance imaging at study entry and after 4 years. Prefrontal GI was computed as the ratio of folded inner contour to exposed outer contour. RESULTS: Ventral and dorsal GI decreased significantly with time in both cohorts; the rate did not differ for bipolar patients. Within the bipolar cohort, individuals with one or more BDNF met alleles showed greater losses in GI, an effect that correlated with gray matter loss in the left hemisphere. CONCLUSIONS: Gyrification index may be sensitive to atrophy, as well as being a neurodevelopmental measure. While the loss of prefrontal gyrification over time is not accelerated in bipolar disorder, a greater rate of loss is associated with the possession of one or more BDNF met alleles

White matter tractography in bipolar disorder and schizophrenia

BACKGROUND: Abnormalities of white matter integrity have been repeatedly demonstrated in both schizophrenia and bipolar disorder with voxel based methods. Because these methods are limited in their ability to localize deficits to specific tracts, we sought to investigate alterations in fractional anisotropy (FA) in the uncinate fasciculus and anterior thalamic radiation with probabilistic tractography. METHODS: Individuals with schizophrenia (n = 25) or bipolar disorder (n = 40) were recruited from families with two or more affected members and age-matched to a control group (n = 49). All participants underwent diffusion tensor magnetic resonance imaging that was subsequently analyzed with probabilistic tractography. Mean FA was calculated bilaterally for the uncinate and anterior thalamic radiation and compared between groups with repeated measures analysis of variance. RESULTS: Patients with schizophrenia or bipolar disorder showed common reductions in the uncinate fasciculus and anterior thalamic radiation. These reductions were unrelated to age, duration of illness, current medication, or current psychiatric symptoms in all patients or the lifetime presence of psychotic symptoms in bipolar subjects. CONCLUSIONS: Patients with schizophrenia or bipolar disorder show common abnormalities in the uncinate fasciculus and anterior thalamic radiation that fail to respect traditional diagnostic boundaries. These deficits might be related to shared risk factors and disease mechanisms common to both disorders