Choroid plexus mis-splicing and altered cerebrospinal fluid composition in myotonic dystrophy type 1.

Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knock-in model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knock-in mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from neurologically unaffected (two females, three males; ages 50-70 years) and myotonic dystrophy type 1 (one female, three males; ages 50-70 years) donors. To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55 years) and non-myotonic dystrophy patients (three females, four males; ages 26-51 years), and western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knock-in mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knock-in mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.

Acceptability, usage, and efficacy of mindfulness apps for college student mental health: A systematic review and meta-analysis of RCTs.

BACKGROUND: Preventing anxiety and depression among college students is a pressing public health need. Recent meta-analyses have examined mobile mindfulness interventions in adult populations; however, college students are in a unique developmental stage and institutional setting. METHODS: We conducted a systematic literature review and meta-analysis of published and unpublished studies in English language on the acceptability, usage, and efficacy of mindfulness training apps on mental health among non-clinical samples of college students. Out of 167 reviewed studies, 47 were included in the narrative review. Additionally, we summarized effects from 19 stress, 12 anxiety, 13 depression, and 8 emotional well-being trials (total N = 2974) using robust variance estimation meta-regression and evaluated certainty of evidence with the GRADE approach. RESULTS: Apps were acceptable, with usage levels varying. They reduced stress by 0.435 standard deviation units, 95 % CI (-0.615,-0.255), and increased emotional well-being by 0.431 (0.162,0.7) approaching medium effect sizes. The apps had small effects on depression (B = -0.219 (-0.374, -0.065)) and anxiety (B = -0.218 (-0.42, -0.016)). Certainty of evidence was moderate for stress, depression, and well-being; and low-to-moderate for anxiety. Distressed participants had larger improvements in all outcomes except depression. LIMITATIONS: Small sample sizes in the original studies and small numbers of studies limit the precision of our effect estimates. The small number of studies with objective usage data impedes our ability to characterize the optimal dose. CONCLUSIONS: With moderate certainty of evidence, mindfulness training apps may improve student mental health with similar or larger effect sizes than in the general adult population. However, sustained usage may be a challenge, and more research is needed on the optimal implementation strategy, dose, and equity.