Biology subjects

Koob, M.

Publications and source records attributed to Koob, M..

9 recordsLinked to original sources

bioRxiv2026

Characterization of Fetal Cortical Development Using Spectral Analysis of Gyrification (SPANGY)

The prenatal period of human brain development is critical for mental health and cognition across the entire lifespan. During this period, the cortex undergoes a dramatic transformation from a smooth lissencephalic surface into an elaborately folded structure, a process whose precise characterization is essential for understanding neurodevelopmental trajectories. This study represents the first application of Spectral Analysis of Gyrification (SPANGY) to a large multi-centric fetal brain MRI dataset (635 subjects, 20-38 weeks gestational age). SPANGY characterizes geometric variations on a surface based on the wavelength of folds, hence, providing a quantitative local description of gyrification at the individual level. Using rigorous normative modeling (GAMLSS) and statistical harmonization (ComBat-GAM), we established age-specific reference trajectories for multi-scale gyrification features (spectral frequency bands). We provide the first ever quantification of the temporally-ordered emergence of cortical folding in successive waves: the earliest-emerging low frequency, deep fissures are progressively superseded by the accelerating expansion of higher frequency folds. The normative curves provide the first step in taking prenatal neurodevelopmental assessment from qualitative inspection into a rigorous statistical inference, creating an objective reference against which deviations from healthy brain growth can be caught earlier, and with greater precision.

neuroscience↗

bioRxiv2026

Mutant ATXN1 impacts human and mouse microglia and contributes to cognitive, mood, and motor deficits in SCA1 mice

Microglia, resident immune cells of the brain, are important players in neurodegeneration. While microglial activation is a hallmark of many neurodegenerative diseases, the specific role of microglia intrinsic factors in microglial activation and disease pathogenesis remains unknown. Spinocerebellar ataxia type-1 (SCA1) is an inherited autosomal dominant neurodegenerative disease characterized by severe neuronal loss and early microglial activation in the cerebellum. SCA1 is caused by CAG repeat expansion in the ubiquitously expressed ATAXIN1 (ATXN1) gene. Using human microglia differentiated from SCA1 patient derived iPSCs, we found that mutant ATXN1 is sufficient to alter morphology, gene and protein expression in human microglia in a cell-autonomous manner. Moreover, compared to controls, human SCA1 microglia exhibited increased phagocytosis and pro-inflammatory cytokine production, indicating an immune priming. To determine the extent to which mutant ATXN1 in microglia contributes to SCA1 pathogenesis and behavioral symptoms, we removed mutant ATXN1 from microglia and macrophages in a novel conditional SCA1 mouse model, f-ATXN1146Q/2Q mice. Microglial mutant ATXN1 reduction led to a marked correction in microglia phenotype, in particular in the transcriptomic signature of interferon type 1 mediated immune response, reduced microglial density and resulted in smaller microglia with reduced branching in the cerebellum. Pathology of Purkinje neurons and cerebellar astrogliosis were also ameliorated. Utilizing a battery of behavioral tests, we found that microglia and macrophage mutant ATXN1 reduction ameliorated cognitive, mood, and motor deficits in SCA1 mice. Together, these results indicate that mutant ATXN1 directly impacts microglial phenotype in SCA1, contributing to SCA1 pathology and behavioral deficits.

neuroscience↗

bioRxiv2026

Data quality biases normative models derived from fetal brain MRI

Normative modeling is increasingly used to characterize typical growth trajectories and identify atypical neurodevelopment, including early brain development using magnetic resonance imaging (MRI) acquired before birth. Recent work has emphasized the importance of large sample sizes for accurate and robust centile estimation. In this study, we investigate how image quality influences fetal brain normative models, a critical factor in this context where MRI is acquired on a moving fetus in utero. Using a multi-centric cohort of 635 fetal MRI scans, we applied a standardized visual quality control (QC) protocol with continuous quality ratings. We fit normative models for multiple brain structures under progressively relaxed QC stringency, and quantified the deviations in centile estimates relative to a high-quality reference subgroup. Our results showed that including lower-quality data systematically biased normative centiles, with the strongest effects observed in the outer centiles, particularly the lower tail (1st-10th). Bias increased progressively as QC stringency was relaxed and could not be attributed solely to the number of subjects used to fit the models. Quality-induced bias was structure-dependent, and often not visually apparent at the segmentation level. These findings highlight that image quality is an important source of bias in normative fetal brain modeling, and that increasing sample size at the expense of quality may systematically affect centile estimates, potentially jeopardizing the utility of the model.

neuroscience↗

bioRxiv2025

MAPT Splicing Modulators as a Therapeutic Strategy for Tauopathies

Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation of microtubule-associated protein tau (MAPT) in the brain. These disorders, like frontotemporal dementia (FTD-Tau), currently lack effective therapies and can occur sporadically or be inherited when associated with MAPT gene mutations. The MAPT gene region encompassing exon 10 and adjacent introns is a hotspot for pathogenic variants, including splicing mutations that enhance exon 10 inclusion and increase 4R tau expression, and gain-of-function mutations that generate aggregation-prone mutant 4R tau protein. For these 4R-specific tauopathies, a targeted mRNA splicing approach that promotes exon 10 exclusion may offer therapeutic benefit. In this study, we discovered novel splicing modulator compounds (SMCs) that promote MAPT exon 10 exclusion, and demonstrated their efficacy in FTD patient-derived neuronal models carrying the tau-P301L gain-of-function mutation or the tau-S305N splicing mutation. Treatment with SMC reduced 4R tau expression and decreased the accumulation of hyperphosphorylated tau (pTau), oligomeric and insoluble tau, thereby rescuing tau-associated neuronal toxicity. Importantly, our lead SMC corrected the 3R/4R splice ratio in vivo and significantly reduced pTau in the brain of a gene- replacement (GR) mouse model expressing the human tau-N279K splicing mutation. These findings support the therapeutic potential of this class of small molecules and establish MAPT pre- mRNA splicing modulation as a promising strategy for the treatment of 4R tauopathies. One Sentence SummaryDiscovery of SMCs that correct MAPT splicing, reduce 4R tau, and rescue pathology in patient- derived neuronal and in vivo models of 4R tauopathies.

neuroscience↗

bioRxiv2024

Cerebellar contribution to cognitive deficits and prefrontal cortex dysfunction in Spinocerebellar Ataxia Type 1 (SCA1)

The cerebellums role in cognition and its functional bi-directional connectivity with prefrontal cortex (PFC) is now recognized. However, how chronic cerebellar dysfunction affects PFC function and cognition remains less understood. Spinocerebellar ataxia type 1 (SCA1), is an inherited, fatal neurodegenerative disease caused by an abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1) and characterized by severe loss of Purkinje cells (PCs) in the cerebellum. Patients with SCA1 suffer from movement and balance deficits, cognitive decline and premature lethality. Cognitive deficits significantly impact patients quality of life, yet how exactly cerebellar degeneration contributes to cognitive deficits and PFC dysfunction in SCA1 is unknown. We have previously demonstrated that expression of mutant ATXN1 only in cerebellar Purkinje cells (PCs) is sufficient to cause cognitive deficits in a transgenic ATXN1[82Q] mouse line. To understand how cerebellar dysfunction impacts the PFC, we examined neuronal activity, synaptic density, and gene expression changes in the PFC of ATXN1[82Q] mice. Remarkably, we found decreased neuronal activity, reduced synaptic density, and altered expression of immediate early genes and pathways involved in glucose metabolism, inflammation and amphetamine in the PFC of ATXN1[82Q] mice. Furthermore, we characterized cellular and molecular PFC dysfunction in a novel conditional knock-in SCA1 line, f-ATXN1146Q mice, expressing floxed human expanded ATXN1 throughout the brain. Intriguingly, we found an increased number of neurons, increased synaptic density and large gene expression alterations in the PFC of f-ATXN1146Q mice. Finally, to precisely determine the role of cerebellar dysfunction in cognitive deficits and PFC dysfunction in SCA1, we crossed f-ATXN1146Q mice with Pcp2-Cre mice expressing Cre recombinase in PCs to delete expanded ATXN1 only in PCs. Surprisingly, we have found that deleting expanded ATXN1 in PCs exacerbated cognitive deficits and PFC dysfunction in these mice. Our findings demonstrate that circumscribed cerebellar dysfunction is sufficient to impact PFC activity and synaptic connectivity impairing cognition. However, when multiple brain regions are impacted in disease, cerebellar dysfunction may ameliorate PFC pathology and cognitive performance.

neuroscience↗

bioRxiv2024

Assessing data quality on fetal brain MRI reconstruction: a multi-site and multi-rater study

Quality assessment (QA) has long been considered essential to guarantee the reliability of neuroimaging studies. It is particularly important for fetal brain MRI, where unpredictable fetal motion can lead to substantial artifacts in the acquired images. Multiple images are then combined into a single volume through super-resolution reconstruction (SRR) pipelines, a step that can also introduce additional artifacts. While multiple studies designed automated quality control pipelines, no work evaluated the reproducibility of the manual quality ratings used to train these pipelines. In this work, our objective is twofold. First, we assess the inter- and intra-rater variability of the quality scoring performed by three experts on over 100 SRR images reconstructed using three different SRR pipelines. The raters were asked to assess the quality of images following 8 specific criteria like blurring or tissue contrast, providing a multi-dimensional view on image quality. We show that, using a protocol and training sessions, artifacts like bias field and blur level still have a low agreement (ICC below 0.5), while global quality scores show very high agreement (ICC = 0.9) across raters. We also observe that the SRR methods are influenced differently by factors like gestational age, input data quality and number of stacks used by reconstruction. Finally, our quality scores allow us to unveil systematic weaknesses of the different pipelines, indicating how further development could lead to more robust, well rounded SRR methods. Our rating protocol is made available at https://doi.org/10.5281/zenodo.15696638.

neuroscience↗

bioRxiv2024

Maturation-informed synthetic Magnetic Resonance Images of the Developing Human Fetal Brain

Magnetic resonance imaging is a powerful modality to investigate abnormal developmental patterns in utero. However, since it is not the first-line diagnostic tool in this sensitive population, data remain scarce and heterogeneous between scanners and centers. In addressing the data scarcity issue while generating data representative of real fetal brain MRI, we proposed FaBiAN, a Fetal Brain magnetic resonance Acquisition Numerical phantom. Here, we present a novel synthetic dataset of 594 two-dimensional, low-resolution series of T2-weighted images corresponding to 78 developing human fetal brains between 20.0 and 34.8 weeks of gestational age. Data are generated with substantive improvements from the original FaBiAN to account for local heterogeneities within white matter tissues throughout maturation. These synthetic-yet-highly-realistic images cover both healthy and pathological development trajectories simulated with standard clinical settings and anatomically informed by the Fetal Tissue Annotations (FeTA) dataset. Two independent radiologists qualitatively assessed the realism of the simulated images. We also quantitatively demonstrate the simulated datas increased fidelity to real data compared to the previous FaBiAN version. The reuse potential of the proposed dataset was also evaluated in the context of automated fetal brain tissue segmentation. Besides, our dataset that combines images generated from various clinical scenarios has been made publicly available to support the continuous endeavor of the community to develop advanced post-processing methods aswell as cutting-edge artificial intelligence models.

bioinformatics↗

bioRxiv2023

A common Alu element insertion in the 3'UTR of TMEM106B is associated with an increased risk of dementia

Sequence variants in TMEM106B have been associated with an increased risk of developing several different types of dementia. As part of our efforts to generate a set of mouse lines in which we replaced the mouse Tmem106b gene with a human TMEM106B gene comprised of either a risk or protective haplotype, we conducted an in-depth sequence analysis of these alleles. We identified an AluYb8 insertion in the 3 untranslated region (3UTR) of the TMEM106B risk haplotype. We analyzed transcribed TMEM106B sequences using RNA-seq data available through the AD Knowledge portal and full genome sequences from the 1000Genomes databases and found that every risk allele analyzed shares this same AluYb8 insertion. The allele frequency of the risk haplotype ranges from 26% to 60% in the populations examined, and the balance of the alleles in each population is the protective haplotype. The primary sequence features of both haplotypes are distinct from the variants found in other primates. We conclude that the risk haplotype arose early in human development with a single Alu-insertion event within a unique haplotype context. Together these two non-ancestral allele variant types now appear to constitute the vast majority of the TMEM106B alleles but neither has come to fully predominate in any modern human population.

genetics↗

bioRxiv2021

Through-plane super-resolution with autoencoders in diffusion magnetic resonance imaging of the developing human brain

Fetal brain diffusion magnetic resonance images are often acquired with a lower through-plane than in-plane resolution. This anisotropy is often overcome by classical upsampling methods such as linear or cubic interpolation. In this work, we employ an unsupervised learning algorithm using an autoencoder neural network to enhance the through-plane resolution by leveraging a large amount of data. Our framework, which can also be used for slice outliers replacement, overperformed conventional interpolations quantitatively and qualitatively on pre-term newborns of the developing Human Connectome Project. The evaluation was performed on both the original diffusion-weighted signal and on the estimated diffusion tensor maps. A byproduct of our autoencoder was its ability to act as a denoiser. The network was able to generalize to fetal data with different levels of motion and we qualitatively showed its consistency, hence supporting the relevance of pre-term datasets to improve the processing of fetal brain images.

bioinformatics↗