Time is ticking faster for long genes in aging

Recent studies of aging organisms have identified a systematic phenomenon, characterized by a negative correlation between gene length and their expression in various cell types, species, and diseases. We term this phenomenon gene-length-dependent transcription decline (GLTD) and suggest that it may represent a bottleneck in the transcription machinery and thereby significantly contribute to aging as an etiological factor. We review potential links between GLTD and key aging processes such as DNA damage and explore their potential in identifying disease modification targets. Notably, in Alzheimer's disease, GLTD spotlights extremely long synaptic genes at chromosomal fragile sites (CFSs) and their vulnerability to postmitotic DNA damage. We suggest that GLTD is an integral element of biological aging.</p

Time is ticking faster for long genes in aging

Recent studies of aging organisms have identified a systematic phenomenon, characterized by a negative correlation between gene length and their expression in various cell types, species, and diseases. We term this phenomenon gene-length-dependent transcription decline (GLTD) and suggest that it may represent a bottleneck in the transcription machinery and thereby significantly contribute to aging as an etiological factor. We review potential links between GLTD and key aging processes such as DNA damage and explore their potential in identifying disease modification targets. Notably, in Alzheimer's disease, GLTD spotlights extremely long synaptic genes at chromosomal fragile sites (CFSs) and their vulnerability to postmitotic DNA damage. We suggest that GLTD is an integral element of biological aging.</p

Structural and Functional Reorganization of the Brain in Migraine Without Aura

It remains unknown whether migraine headache has a progressive component in its pathophysiology. Quantitative MRI may provide valuable insight into abnormal changes in the migraine interictum and assist in identifying disrupted brain networks. We carried out a data-driven study of structural integrity and functional connectivity of the resting brain in migraine without aura. MRI scanning was performed in 36 patients suffering from episodic migraine without aura and 33 age-matched healthy subjects. Voxel-wise analysis of regional brain volume was performed by registration of the T1-weighted MRI scans into a common study brain template using the tensor-based morphometry (TBM) method. Changes in functional synchronicity of the brain networks were assessed using probabilistic independent component analysis (ICA). TBM revealed that migraine is associated with reduced volume of the medial prefrontal cortex (mPFC). Among 375 functional brain networks, resting-state connectivity was decreased between two components spanning the visual cortex, posterior insula, and parietal somatosensory cortex. Our study reveals structural and functional alterations of the brain in the migraine interictum that may stem from underlying disease risk factors and the “silent” aura phenomenon. Longitudinal studies will be needed to investigate whether interictal brain changes are progressive and associated with clinical disease trajectories

Imaging genetics of language network functional connectivity reveals links with language-related abilities, dyslexia and handedness

Published on 28 september 2024Language is supported by a distributed network of brain regions with a particular contribution from the left hemisphere. A multi-level understanding of this network requires studying its genetic architecture. We used resting-state imaging data from 29,681 participants (UK Biobank) to measure connectivity between 18 left-hemisphere regions involved in multimodal sentence-level processing, as well as their right-hemisphere homotopes, and interhemispheric connections. Multivariate genome-wide association analysis of this total network, based on genetic variants with population frequencies >1%, identified 14 genomic loci, of which three were also associated with asymmetry of intrahemispheric connectivity. Polygenic dispositions to lower language-related abilities, dyslexia and left-handedness were associated with generally reduced leftward asymmetry of functional connectivity. Exome-wide association analysis based on rare, protein-altering variants (frequencies <1%) suggested 7 additional genes. These findings shed new light on genetic contributions to language network organization and related behavioural traits.This research was funded by the Max Planck Society (Germany), together with grants from the Netherlands Organisation for Scientific Research (NWO) (grant number 054-15-101) and French National Research Agency (ANR, grant No. 15-HBPR-0001-03) as part of the FLAG-ERA consortium project “MULTI-LATERAL”, a Partner Project to the European Union’s Flagship Human Brain Project, and the Language in Interaction consortium (NWO Gravitation grant number 024-001-006). The study was conducted using the UK Biobank resource under application no. 16066 with C.F. as the principal applicant. Our study made use of quality-controlled brain images generated by an image-processing pipeline developed and run on behalf of the UK Biobank. The funders had no role in study design, data collection and analysis, and the decision to publish or preparation of the manuscript. The authors thank Else Eising, Giacomo Bignardi and Tristan Looden for their thoughts on the methodology. The authors thank Fabrice Crivello and Antonietta Pepe for their involvement in the inception of this project. The authors would like to thank the research participants and employees of 23andMe, Inc. for making this work possible

Longitudinal changes of ADHD symptoms in association with white matter microstructure: A tract-specific fixel-based analysis

Background: Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18 – 34 years), and using the more physiologically informative fixel-based analysis (FBA). Methods: Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined ADHD and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up. Results: Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax = 1.092, standardized effect[SE] = 0.044, pFWE = 0.016). Improvement in combined ADHD symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax = 3.775, SE = 0.051, pFWE = 0.019). Conclusions: Aberrant white matter development involves both lCST micro- and macrostructural alterations, and its path may be moderated by preceding symptom trajectory

Reduced fronto-striatal volume in attention-deficit/hyperactivity disorder in two cohorts across the lifespan

Attention-Deficit/Hyperactivity Disorder (ADHD) has been associated with altered brain anatomy in neuroimaging studies. However, small and heterogeneous study samples, and the use of region-of-interest and tissue-specific analyses have limited the consistency and replicability of these effects. We used a data-driven multivariate approach to investigate neuroanatomical features associated with ADHD in two independent cohorts: the Dutch NeuroIMAGE cohort (n = 890, 17.2 years) and the Brazilian IMpACT cohort (n = 180, 44.2 years). Using independent component analysis of whole-brain morphometry images, 375 neuroanatomical components were assessed for association with ADHD. In both discovery (corrected-p = 0.0085) and replication (p = 0.032) cohorts, ADHD was associated with reduced volume in frontal lobes, striatum, and their interconnecting white-matter. Current results provide further evidence for the role of the fronto-striatal circuit in ADHD in children, and for the first time show its relevance to ADHD in adults. The fact that the cohorts are from different continents and comprise different age ranges highlights the robustness of the findings

Exome-wide analysis implicates rare protein-altering variants in human handedness

Abstract Handedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examine whether left-handedness is also influenced by rare coding variants (frequencies ≤ 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals from the UK Biobank. The beta-tubulin gene TUBB4B shows exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers than right-handers. The TUBB4B variants are mostly heterozygous missense changes, but include two frameshifts found only in left-handers. Other TUBB4B variants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening, DSCAM and FOXP1 show evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study reveals a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes

Longitudinal changes of ADHD symptoms in association with white matter microstructure: A tract-specific fixel-based analysis

Background: Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18 – 34 years), and using the more physiologically informative fixel-based analysis (FBA). Methods: Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined ADHD and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up. Results: Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax = 1.092, standardized effect[SE] = 0.044, pFWE = 0.016). Improvement in combined ADHD symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax = 3.775, SE = 0.051, pFWE = 0.019). Conclusions: Aberrant white matter development involves both lCST micro- and macrostructural alterations, and its path may be moderated by preceding symptom trajectory