Biology subjects

Vaher, K.

Publications and source records attributed to Vaher, K..

4 recordsLinked to original sources

bioRxiv2022

Feature similarity gradients detect alterations in the neonatal cortex associated with preterm birth

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multi-modal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt-Bailey index to provide a fine-grained description of regional homogeneities and sharp variations in cortical microstructure based on feature gradients, and we investigate the impact of being born preterm on cortical development. Preterm infants have a homogeneous microstructure in temporal and occipital lobes, and the medial parietal, cingulate, and frontal cortices, compared with term infants. These observations replicated across two independent datasets and were robust to differences that remain in the data after matching samples and alignment of processing and quality control strategies. We conclude that cortical microstructural architecture is altered in preterm infants in a spatially distributed rather than localised fashion.

neuroscience↗

bioRxiv2021

General factors of white matter microstructure from DTI and NODDI in the developing brain

Preterm birth is closely associated with diffuse white matter dysmaturation inferred from diffusion MRI and neurocognitive impairment in childhood. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) are distinct dMRI modalities, yet metrics derived from these two methods share variance across tracts. This raises the hypothesis that dimensionality reduction approaches may provide efficient whole-brain estimates of white matter microstructure that capture (dys)maturational processes. To investigate the optimal model for accurate classification of generalised white matter dysmaturation in preterm infants we assessed variation in DTI and NODDI metrics across 16 major white matter tracts using principal component analysis and structural equation modelling, in 79 term and 141 preterm infants at term equivalent age. We used logistic regression models to evaluate performances of single-metric and multimodality general factor frameworks for efficient classification of preterm infants based on variation in white matter microstructure. Single-metric general factors from DTI and NODDI capture substantial shared variance (41.8-72.5%) across 16 white matter tracts, and two multimodality factors captured 93.9% of variance shared between DTI and NODDI metrics themselves. General factors associate with preterm birth and a single model that includes all seven DTI and NODDI metrics provides the most accurate prediction of microstructural variations associated with preterm birth. This suggests that despite global covariance of dMRI metrics in neonates, each metric represents information about specific (and additive) aspects of the underlying microstructure that differ in preterm compared to term subjects. HighlightsO_LIWe measured variation of 7 DTI and NODDI metrics across 16 major tracts C_LIO_LIGeneral factors for DTI and NODDI capture substantial shared variance across tracts C_LIO_LIGeneral factors also capture substantial shared variance between DTI and NODDI C_LIO_LISingle-metric and multimodality factors associate with gestational age at birth C_LIO_LIThe best preterm prediction model contains all 7 single-metric g-factors C_LI

neuroscience↗

bioRxiv2021

Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters

Growing evidence supports a role for deficient Wnt signalling in Alzheimer's disease (AD). First, the Wnt antagonist DKK1 is elevated in AD brains and is required for amyloid-{beta}-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of interest due to their role in synapse formation/plasticity. Our analyses showed reduced FZD1 and FZD7 mRNA levels in the hippocampus of human early AD stages and in the hAPPNLGF/NLGF mouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 at Fzd1 and Fzd7 promoters in AD. In vitro and in vivo inhibition of Sirt2 rescued Fzd1 and Fzd7 mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment to Fzd1 and Fzd7 promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of Sirt2 inhibitory phosphorylation in nuclear samples from human early AD stages with a concomitant increased in the Sirt2 phosphatase PP2C. This results in hyperactive nuclear Sirt2 and favours Fzd1 and Fzd7 repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated Sirt2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose Sirt2 as an attractive target to ameliorate AD pathology.

neuroscience↗

bioRxiv2019

Assessment of DNA methylation differences between carriers of APOE ε4 and APOE ε2

BACKGROUNDThe Apolipoprotein E (APOE) {varepsilon}4 allele is the strongest genetic risk factor for late onset Alzheimers disease, while the {varepsilon}2 allele confers protection. Previous studies report differential DNA methylation of APOE between {varepsilon}4 and {varepsilon}2 carriers, but associations with epigenome-wide methylation have not previously been characterised. METHODSUsing the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimers disease-free APOE {varepsilon}4 (n=2469) and {varepsilon}2 (n=1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses. RESULTSWe obtained replicated evidence for DNA methylation differences in a ~169kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 x 10-100[≤]P[≤]2.44 x 10-8) and DMRs were identified in SREBF2 and LDLR (1.63 x 10-4[≤]P[≤]3.01 x 10-2). Pathway and meQTL analyses implicated lipid-related processes and high density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24. CONCLUSIONSAPOE {varepsilon}4 vs. {varepsilon}2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.

genetics↗