Corpus callosum area in patients with bipolar disorder with and without psychotic features: an international multicentre study.

BACKGROUND: Previous studies have reported MRI abnormalities of the corpus callosum (CC) in patients with bipolar disorder (BD), although only a few studies have directly compared callosal areas in psychotic versus nonpsychotic patients with this disorder. We sought to compare regional callosal areas in a large international multicentre sample of patients with BD and healthy controls. METHODS: We analyzed anatomic T1 MRI data of patients with BD-I and healthy controls recruited from 4 sites (France, Germany, Ireland and the United States). We obtained the mid-sagittal areas of 7 CC subregions using an automatic CC delineation. Differences in regional callosal areas between patients and controls were compared using linear mixed models (adjusting for age, sex, handedness, brain volume, history of alcohol abuse/dependence, lithium or antipsychotic medication status, symptomatic status and site) and multiple comparisons correction. We also compared regional areas of the CC between patients with BD with and without a history of psychotic features. RESULTS: We included 172 patients and 146 controls in our study. Patients with BD had smaller adjusted mid-sagittal CC areas than controls along the posterior body, the isthmus and the splenium of the CC. Patients with a positive history of psychotic features had greater adjusted area of the rostral CC region than those without a history of psychotic features. LIMITATIONS: We found small to medium effect sizes, and there was no calibration technique among the sites. CONCLUSION: Our results suggest that BD with psychosis is associated with a different pattern of interhemispheric connectivity than BD without psychosis and could be considered a relevant neuroimaging subtype of BD.

A multicenter tractography study of deep white matter tracts in bipolar I disorder: psychotic features and interhemispheric disconnectivity.

IMPORTANCE: Tractography studies investigating white matter (WM) abnormalities in patients with bipolar disorder have yielded heterogeneous results owing to small sample sizes. The small size limits their generalizability, a critical issue for neuroimaging studies of biomarkers of bipolar I disorder (BPI). OBJECTIVES: To study WM abnormalities using whole-brain tractography in a large international multicenter sample of BPI patients and to compare these alterations between patients with or without a history of psychotic features during mood episodes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, multicenter, international, Q-ball imaging tractography study comparing 118 BPI patients and 86 healthy control individuals. In addition, among the patient group, we compared those with and without a history of psychotic features. University hospitals in France, Germany, and the United States contributed participants. INTERVENTIONS: Participants underwent assessment using the Diagnostic Interview for Genetic Studies at the French sites or the Structured Clinical Interview for DSM-IV at the German and US sites. Diffusion-weighted magnetic resonance images were acquired using the same acquisition parameters and scanning hardware at each site. We reconstructed 22 known deep WM tracts using Q-ball imaging tractography and an automatized segmentation technique. MAIN OUTCOMES AND MEASURES: Generalized fractional anisotropy values along each reconstructed WM tract. RESULTS: Compared with controls, BPI patients had significant reductions in mean generalized fractional anisotropy values along the body and the splenium of the corpus callosum, the left cingulum, and the anterior part of the left arcuate fasciculus when controlling for age, sex, and acquisition site (corrected for multiple testing). Patients with a history of psychotic features had a lower mean generalized fractional anisotropy value than those without along the body of the corpus callosum (corrected for multiple testing). CONCLUSIONS AND RELEVANCE: In this multicenter sample, BPI patients had reduced WM integrity in interhemispheric, limbic, and arcuate WM tracts. Interhemispheric pathways are more disrupted in patients with than in those without psychotic symptoms. Together these results highlight the existence of an anatomic disconnectivity in BPI and further underscore a role for interhemispheric disconnectivity in the pathophysiological features of psychosis in BPI.

Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder.

Patients affected by bipolar disorder (BD) frequently report abnormalities in sleep/wake cycles. In addition, they showed abnormal oscillating melatonin secretion, a key regulator of circadian rhythms and sleep patterns. The acetylserotonin O-methyltransferase (ASMT) is a key enzyme of the melatonin biosynthesis and has recently been associated with psychiatric disorders such as autism spectrum disorders and depression. In this paper, we analysed rare and common variants of ASMT in patients with BD and unaffected control subjects and performed functional analysis of these variants by assaying the ASMT activity in their B-lymphoblastoid cell lines. We sequenced the coding and the regulatory regions of the gene in a discovery sample of 345 patients with BD and 220 controls. We performed an association study on this discovery sample using common variants located in the promoter region and showed that rs4446909 was significantly associated with BD (P= 0.01) and associated with a lower mRNA level (P< 10(-4)) and a lower enzymatic activity (P< 0.05) of ASMT. A replication study and a meta-analysis using 480 independent patients with BD and 672 controls confirmed the significant association between rs4446909 and BD (P= 0.002). These results correlate with the general lower ASMT enzymatic activity observed in patients with BD (P= 0.001) compared with controls. Finally, several deleterious ASMT mutations identified in patients were associated with low ASMT activity (P= 0.01). In this study, we determined how rare and common variations in ASMT might play a role in BD vulnerability and suggest a general role of melatonin as susceptibility factor for BD.

Diastolic blood pressure and mortality in the elderly with cardiovascular disease.

Isolated systolic hypertension is predominantly observed in the elderly because of increased arterial stiffness. Aggressive treatment leads to excessive lowering of diastolic blood pressure and favors the presence of a J-shaped curve association with mortality. We investigated whether, in the elderly, this pattern of association is a simple epiphenomenon of increased arterial stiffness and impaired cardiac function. In a cohort of 331 hospitalized subjects >70 years old (mean age+/-SD: 85+/-7 years), aortic pulse wave velocity and pressure wave reflections, by pulse wave analysis, and cardiac function, by ultrasound, were assessed. During a 2-year follow-up period, 110 subjects died. No association of prognosis with systolic pressure, pulse pressure, or pulse wave velocity was observed. A J-shaped association between diastolic pressure and overall and cardiovascular mortality was observed. Unadjusted Cox regression analysis showed that patients in the first tertile of diastolic pressure (< or =60 mm Hg) had higher mortality. In Cox regression analysis, diastolic pressure < or =60 mm Hg was a predictor of mortality independently from cardiac-vascular properties, cardiovascular risk factors, and drug treatment. Multivariate regression analysis showed that increased age and low total peripheral resistance, but not left ventricular function, were the cardinal determinants of low diastolic pressure. An "optimal" diastolic pressure of 70 mm Hg in subjects with isolated systolic hypertension was found. We showed that, in the frail elderly, a value of diastolic blood pressure < or =60 mm Hg is associated with reduced survival, independent from large artery stiffness and left ventricular function, suggesting that more rational antihypertensive therapy, not only based on systolic pressure level, is needed.