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Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

ABSTRACT: Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P?

SUBMITTER: Versace A

PROVIDER: S-EPMC6135796 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Versace A A Ladouceur C D CD Graur S S Acuff H E HE Bonar L K LK Monk K K McCaffrey A A Yendiki A A Leemans A A Travis M J MJ Diwadkar V A VA Holland S K SK Sunshine J L JL Kowatch R A RA Horwitz S M SM Frazier T W TW Arnold L E LE Fristad M A MA Youngstrom E A EA Findling R L RL Goldstein B I BI Goldstein T T Axelson D D Birmaher B B Phillips M L ML

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20180504 11

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-prof ...[more]

PMID: 29795244

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Project description:BackgroundClinical neuroimaging studies often investigate group differences between patients and controls, yet multivariate imaging features may enable individual-level classification. This study aims to classify youth with bipolar disorder (BD) versus healthy youth using grey matter cerebral blood flow (CBF) data analyzed with logistic regressions.MethodsUsing a 3 Tesla magnetic resonance imaging (MRI) system, we collected pseudo-continuous, arterial spin-labelling, resting-state functional MRI (rfMRI) and T 1-weighted images from youth with BD and healthy controls. We used 3 logistic regression models to classify youth with BD versus controls, controlling for age and sex, using mean grey matter CBF as a single explanatory variable, quantitative CBF features based on principal component analysis (PCA) or relative (intensity-normalized) CBF features based on PCA. We also carried out a comparison analysis using rfMRI data.ResultsThe study included 46 patients with BD (mean age 17 yr, standard deviation [SD] 1 yr; 25 females) and 49 healthy controls (mean age 16 yr, SD 2 yr; 24 females). Global mean CBF and multivariate quantitative CBF offered similar classification performance that was above chance. The association between CBF images and the feature map was not significantly different between groups (p = 0.13); however, the multivariate classifier identified regions with lower CBF among patients with BD (ΔCBF = -2.94 mL/100 g/min; permutation test p = 0047). Classification performance decreased when considering rfMRI data.LimitationsWe cannot comment on which CBF principal component is most relevant to the classification. Participants may have had various mood states, comorbidities, demographics and medication records.ConclusionBrain CBF features can classify youth with BD versus healthy controls with above-chance accuracy using logistic regression. A global CBF feature may offer similar classification performance to distinct multivariate CBF features.

Project description:Bipolar disorder is a highly heritable illness that onsets in adolescence and young adulthood. We examined gene expression (mRNA) and protein levels of candidate immune and neurotrophic markers in well-characterized offspring of bipolar parents in order to identify reliable indicators of illness risk status and the early clinical stages of illness development. We measured mRNA expression and protein levels in candidate immune (TNF-?, IL-1?, IL-10, IFN-?) and neurotrophic (brain-derived neurotrophic factor (BDNF)) markers from plasma. High-risk offspring were identified from families in which one parent had confirmed bipolar disorder. Control offspring were identified from families in which neither parent met lifetime criteria for a major psychiatric disorder. All parental Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnoses were based on Schedule for Affective Disorders - Lifetime Version (SADS-L) interviews and blind consensus review. As part of an ongoing study, all offspring were prospectively assessed using KSADS-PL format interviews and diagnoses confirmed on blind consensus review. High-risk offspring had significantly increased IL-6 (p?=?0.050) and BDNF (p?=?0.006) protein levels compared to controls. Those high-risk offspring in earlier compared to later clinical stages of illness development had higher IL-6 (p?=?0.050) and BDNF (p?=?0.045) protein levels. After adjustments, only differences in BDNF protein levels remained significant. There was a moderating effect of the BDNF genotype on both gene expression and protein levels in high-risk compared to control offspring. The BDNF genotype also moderated the association between clinical stage and gene expression levels in high-risk offspring. These findings provide support for detectable differences in candidate immune and neurotrophic markers in individuals at high risk of developing bipolar disorder and for detectable changes over the clinical stages of illness development. These associations appear to be moderated by genetic variants.

Project description:ImportanceFunctional brain networks are associated with both behavior and genetic factors. To uncover clinically translatable mechanisms of psychopathology, it is critical to define how the spatial organization of these networks relates to genetic risk during development.ObjectiveTo determine the relationship between transdiagnostic polygenic risk scores (PRSs), personalized functional brain networks (PFNs), and overall psychopathology (p-factor) during early adolescence.DesignThe Adolescent Brain Cognitive Development (ABCD) Study is an ongoing longitudinal cohort study of 21 collection sites across the United States. Here, we conduct a cross-sectional analysis of ABCD baseline data, collected 2017-2018.SettingThe ABCD Study ® is a multi-site community-based study.ParticipantsThe sample is largely recruited through school systems. Exclusion criteria included severe sensory, intellectual, medical, or neurological issues that interfere with protocol and scanner contraindications. Split-half subsets were used for cross-validation, matched on age, ethnicity, family structure, handedness, parental education, site, sex, and anesthesia exposure.ExposuresPolygenic risk scores of transdiagnostic genetic factors F1 (PRS-F1) and F2 (PRS-F2) derived from adults in Psychiatric Genomic Consortium and UK Biobanks datasets. PRS-F1 indexes liability for common psychiatric symptoms and disorders related to mood disturbance; PRS-F2 indexes liability for rarer forms of mental illness characterized by mania and psychosis.Main outcomes and measures(1) P-factor derived from bifactor models of youth- and parent-reported mental health assessments. (2) Person-specific functional brain network topography derived from functional magnetic resonance imaging (fMRI) scans.ResultsTotal participants included 11,873 youths ages 9-10 years old; 5,678 (47.8%) were female, and the mean (SD) age was 9.92 (0.62) years. PFN topography was found to be heritable (N=7,459, 57.06% of vertices h 2 p FDR <0.05, mean h 2 =0.35). PRS-F1 was associated with p-factor (N=5,815, r=0.12, 95% CI [0.09-0.15], p<0.001). Interindividual differences in functional network topography were associated with p-factor (N=7,459, mean r=0.12), PRS-F1 (N=3,982, mean r=0.05), and PRS-F2 (N=3,982, mean r=0.08). Cortical maps of p-factor and PRS-F1 regression coefficients were highly correlated (r=0.7, p=0.003).Conclusions and relevancePolygenic risk for transdiagnostic adulthood psychopathology is associated with both p-factor and heritable PFN topography during early adolescence. These results advance our understanding of the developmental drivers of psychopathology.

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Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Publications

Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

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