Cognitive impairment in sporadic cerebral small vessel disease: A systematic review and meta-analysis.

This paper is a proposal for an update on the characterization of cognitive impairments associated with sporadic cerebral small vessel disease (SVD). We pose a series of questions about the nature of SVD-related cognitive impairments and provide answers based on a comprehensive review and meta-analysis of published data from 69 studies. Although SVD is thought primarily to affect executive function and processing speed, we hypothesize that SVD affects all major domains of cognitive ability. We also identify low levels of education as a potentially modifiable risk factor for SVD-related cognitive impairment. Therefore, we propose the use of comprehensive cognitive assessments and the measurement of educational level both in clinics and research settings, and suggest several recommendations for future research.

Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons.

Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes. Intriguingly, bursts fired by FXS neurons co-cultured with control astrocytes are indistinguishable from control neurons. Conversely, control neurons exhibit aberrant firing in the presence of FXS astrocytes. Thus, the astrocyte genotype determines the neuronal firing phenotype. Strikingly, astrocytic-conditioned medium, and not the physical presence of astrocytes, is capable of determining the firing phenotype. The mechanistic basis of this effect indicates that the astroglial-derived protein, S100ß, restores normal firing by reversing the suppression of a persistent sodium current in FXS neurons.

Translational neuroscience: the state of the nation (a PhD student perspective).

Many brain disorders are currently untreatable. It has been suggested that taking a 'translational' approach to neuroscientific research might change this. We discuss what 'translational neuroscience' is and argue for the need to expand the traditional translational model if we are to make further advances in treating brain disorders.

White Matter Microstructure and Its Relation to Longitudinal Measures of Depressive Symptoms in Mid- and Late Life.

BACKGROUND: Studies of white matter microstructure in depression typically show alterations in individuals with depression, but they are frequently limited by small sample sizes and the absence of longitudinal measures of depressive symptoms. Depressive symptoms are dynamic, however, and understanding the neurobiology of different trajectories could have important clinical implications. METHODS: We examined associations between current and longitudinal measures of depressive symptoms and white matter microstructure (fractional anisotropy and mean diffusivity [MD]) in the UK Biobank Imaging Study. Depressive symptoms were assessed on two to four occasions over 5.9 to 10.7 years (n = 18,959 individuals on at least two occasions, n = 4444 on four occasions), from which we derived four measures of depressive symptomatology: cross-sectional measure at the time of scan and three longitudinal measures, namely trajectory and mean and intrasubject variance over time. RESULTS: Decreased white matter microstructure in the anterior thalamic radiation demonstrated significant associations across all four measures of depressive symptoms (MD: ßs = .020-.029, pcorr < .030). The greatest effect sizes were seen between white matter microstructure and longitudinal progression (MD: ßs = .030-.040, pcorr < .049). Cross-sectional symptom severity was particularly associated with decreased white matter integrity in association fibers and thalamic radiations (MD: ßs = .015-.039, pcorr < .041). Greater mean and within-subject variance were mainly associated with decreased white matter microstructure within projection fibers (MD: ßs = .019-.029, pcorr < .044). CONCLUSIONS: These findings indicate shared and differential neurobiological associations with severity, course, and intrasubject variability of depressive symptoms. This enriches our understanding of the neurobiology underlying dynamic features of the disorder.

Characterisation of Cdkl5 transcript isoforms in rat.

CDKL5 deficiency is a severe neurological disorder caused by mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5). The predominant human CDKL5 brain isoform is a 9.7kb transcript comprised of 18 exons with a large 6.6kb 3'-untranslated region (UTR). Mammalian models of CDKL5 disorder are currently limited to mouse, and little is known about Cdkl5 in other organisms used to model neurodevelopmental disorders, such as rat. In this study we characterise, both bioinformatically and experimentally, the rat Cdkl5 gene structure and its associated transcript isoforms. New exonic regions, splice sites and UTRs are described, confirming the presence of four distinct transcript isoforms. The predominant isoform in the brain, which we name rCdkl5_1, is orthologous to the human hCDKL5_1 and mouse mCdkl5_1 isoforms and is the most highly expressed isoform across all brain regions tested. This updated gene model of Cdkl5 in rat provides a framework for studies into its protein products and provides a reference for the development of molecular therapies for testing in rat models of CDKL5 disorder.