Neurite outgrowth deficits caused by rare PLXNB1 mutation in pediatric bipolar disorder.

Pediatric bipolar disorder (PBD) is a severe mood dysregulation condition that affects 0.5-1% of children and teens in the United States. It is associated with recurrent episodes of mania and depression and an increased risk of suicidality. However, the genetics and neuropathology of PBD are largely unknown. Here, we used a combinatorial family-based approach to characterize cellular, molecular, genetic, and network-level deficits associated with PBD. We recruited a PBD patient and three unaffected family members from a family with a history of psychiatric illnesses. Using resting-state functional magnetic resonance imaging (rs-fMRI), we detected altered resting-state functional connectivity in the patient as compared to an unaffected sibling. Using transcriptomic profiling of patient and control induced pluripotent stem cell (iPSC)-derived telencephalic organoids, we found aberrant signaling in the molecular pathways related to neurite outgrowth. We corroborated the presence of neurite outgrowth deficits in patient iPSC-derived cortical neurons and identified a rare homozygous loss-of-function PLXNB1 variant (c.1360C>C; p.Ser454Arg) responsible for the deficits in the patient. Expression of wild-type PLXNB1, but not the variant, rescued neurite outgrowth in patient neurons, and expression of the variant caused the neurite outgrowth deficits in cortical neurons from PlxnB1 knockout mice. These results indicate that dysregulated PLXNB1 signaling may contribute to an increased risk of PBD and other mood dysregulation-related disorders by disrupting neurite outgrowth and functional brain connectivity. Overall, this study established and validated a novel family-based combinatorial approach for studying cellular and molecular deficits in psychiatric disorders and identified dysfunctional PLXNB1 signaling and neurite outgrowth as potential risk factors for PBD.

Intergenerational transmission of lifetime stressor exposure in adolescent girls at differential maternal risk for depression.

OBJECTIVE: Adolescent girls who grow up with mothers who are depressed are themselves highly vulnerable to developing depression (i.e., "intergenerational transmission of depression"). Stressor exposure is a strong risk factor for depression, and the transmission of depression risk from mothers to daughters is partly due to mothers experiencing more stressors, increasing daughters' stressor burden. However, research in this area has only assessed recent stressors, making the role of cumulative lifetime stressors unclear. METHOD: To address this issue, we recruited 52 dyads of mothers and adolescent daughters, of which 22 daughters were at high maternal risk for depression. Participants completed diagnostic interviews, and daughters additionally self-reported their depressive symptoms. Participants also completed the Stress and Adversity Inventory, a new-generation instrument for assessing cumulative lifetime history of acute and chronic stressors based on the contextual threat approach. We tested moderated mediation models evaluating the conditional indirect effects of mothers' lifetime stressors on high- versus low-risk daughters' depressive symptoms through daughters' lifetime stressors. RESULTS: As hypothesized, mothers of high-risk (but not low-risk) adolescent daughters who reported more lifetime acute stressors had daughters who reported more lifetime acute stressors and current depressive symptoms. Moreover, this finding was driven specifically by mothers' stressors occurring after their daughters' births. There was also tentative evidence that high-risk daughters' lifetime chronic stressors potentiated the impact of daughters' acute stressors on their depressive symptoms. CONCLUSION: These findings provide new insights into how stressful contexts are transmitted intergenerationally.

Regional brain volumes relate to Alzheimer's disease cerebrospinal fluid biomarkers and neuropsychometry: A cross-sectional, observational study.

We hypothesized that automated assessment of brain volumes on MRI can predict presence of cerebrospinal fluid abnormal ß-amyloid42 and Tau protein levels and thus serve as a useful screening test for possible Alzheimer's disease. 113 participants ranging from cognitively healthy to Alzheimer's disease underwent MRI exams to obtain measurements of hippocampus, prefrontal cortex, precuneus, parietal cortex, and occipital lobe volumes. A non-exclusive subset (n = 107) consented to lumbar punctures to obtain cerebrospinal fluid for ß-amyloid42 and Tau protein assessment including cognitively health (n = 75), mild cognitively impaired (n = 22), and Alzheimer's disease (n = 10). After adjustment for false discovery rate, ß-amyloid42 was significantly associated with volumes in the hippocampus (p = 0.043), prefrontal cortex (p = 0.010), precuneus (p = 0.024), and the posterior cingulate (p = 0.002). No association between Tau levels and regional brain volume survived multiple test correction. Secondary analysis was performed to determine associations between MRI brain volumes and CSF protein levels to neuropsychological impairment. A non-exclusive subset (n = 96) including cognitively healthy (n = 72), mild cognitively impaired (n = 21), and Alzheimer's disease (n = 3) participants underwent Stroop Interference and Boston Naming neuropsychological testing. A higher score on the Boston Naming Test was optimally predicted in a selective regression model by greater hippocampus volume (p = 0.002), a higher ratio of ß-amyloid42 to Tau protein levels (p < 0.001), greater posterior cingulate volume (p = 0.0193), age (p = 0.0271), and a higher education level (p = 0.002). A better performance on the Stroop Interference Test was optimally predicted by greater hippocampus volume (p = 0.0003) and a higher education level (p < 0.001). Lastly, impaired cognitive status (mild cognitive impairment and Alzheimer's Disease) was optimally predicted in a selective regression model by a worse performance on the Stroop Interference Test (p < 0.001), a worse performance on the Boston Naming Test (p < 0.001), along with lower prefrontal cortex volume (p = 0.002) and lower hippocampus volume (p = 0.007).

The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children.

Antipsychotic medications are critical to child and adolescent psychiatry, from the stabilization of psychotic disorders like schizophrenia, bipolar disorder, and psychotic depression to behavioral treatment of autism spectrum disorder, tic disorders, and pediatric aggression. While effective, these medications carry serious risk of adverse events-most commonly, weight gain and cardiometabolic abnormalities. Negative metabolic consequences affect up to 60% of patients and present a major obstacle to long-term treatment. Since antipsychotics are often chronically prescribed beginning in childhood, cardiometabolic risk accumulates. An increased susceptibility to antipsychotic-induced weight gain (AIWG) has been repeatedly documented in children, particularly rapid weight gain. Associated cardiometabolic abnormalities include central obesity, insulin resistance, dyslipidemia, and systemic inflammation. Lifestyle interventions and medications such as metformin have been proposed to reduce risk but remain limited in efficacy. Furthermore, antipsychotic medications touted to be weight-neutral in adults can cause substantial weight gain in children. A better understanding of the biological underpinnings of AIWG could inform targeted and potentially more fruitful treatments; however, little is known about the underlying mechanism. As yet, modest genetic studies have nominated a few risk genes that explain only a small percentage of the risk. Recent investigations have begun to explore novel potential mechanisms of AIWG, including a role for gut microbiota and microbial metabolites. This article reviews the problem of AIWG and AP metabolic side effects in pediatric populations, proposed mechanisms underlying this serious side effect, and strategies to mitigate adverse impact. We suggest future directions for research efforts that may advance the field and lead to improved clinical interventions.

Teratomas of the cranial vault: a systematic analysis of clinical outcomes stratified by histopathological subtypes.

BACKGROUND: Teratomas of the cranial vault are divided into histopathological subtypes and grouped by prognoses: mature (good prognosis), mixed/malignant and immature teratomas (intermediate prognosis). This schema also includes non-teratomatous tumors. The authors of this study sought to elucidate histologically dependent predictors of survival and further clarify the classification system of intracranial teratomas. METHODS: We performed a systematic analysis of the published literature to identify studies describing patients with intracranial teratomas diagnosed with magnetic resonance imaging (MRI) and presenting definite information on histologies, therapies, and outcomes at a minimum follow-up of 2 years. Disease-free (DFS) and overall survival (OS) were evaluated. RESULTS: A total of 18 articles comprised of 134 patients were included. On univariate analysis, male sex and gross-total resection (GTR) were associated with high mean DFS (p = 0.0362 and p < 0.0001, respectively). On multivariate analysis, mature teratomas located in the pineal, and those having undergone subtotal resection (STR) demonstrated high mean OS (p = 0.0023 and p = 0.0044, respectively). Mature and mixed/malignant suprasellar teratomas had equally higher mean OS versus immature suprasellar teratomas (p < 0.0001). Mature and immature teratomas treated with adjuvant therapy had significantly higher mean OS compared to those managed with surgery alone (p = 0.0421 and p = 0.0423, respectively). Males with immature teratomas had the highest mean OS (p < 0.0001). Immature teratomas managed with surgery alone had higher mean DFS, but lower mean OS, compared to those treated with adjuvant therapy (p = 0.0176 and p = 0.0423, respectively). CONCLUSIONS: Our data highlight the divergent nature of the different histopathological subtypes of teratomas, and suggest that survival outcomes are multifactorial. Specifically, male sex, pineal, suprasellar, GTR, and STR were dependent predictors of OS, while histopathology was an independent predictor of OS.