Biology subjects

Levitis, E.

Publications and source records attributed to Levitis, E..

3 recordsLinked to original sources

bioRxiv2022

The variegation of human brain vulnerability to rare genetic disorders and convergence with behaviorally defined disorders

Diverse gene dosage disorders (GDDs) increase risk for psychiatric impairment, but characterization of GDD effects on the human brain has so far been piecemeal and lacked simultaneous analysis of multiple brain features across different GDDs. Here, through multimodal neuroimaging of 3 aneuploidy syndromes (XXY, XYY, trisomy 21), we reveal considerable diversity in cortical changes across GDDs and imaging-derived phenotypes (IDPs). This variegation of IDP change underlines the limitations of studying GDD effects unimodally. Integration across all IDP maps reveals highly distinct architectures of cortical change in each GDD, along with partial coalescence onto a common spatial axis of cortical vulnerability. This common axis shows strong alignment with shared cortical changes in behaviorally defined psychiatric disorders, and is enriched for specific molecular and cellular signatures - offering a high-priority target for future translational research.

neuroscience↗

bioRxiv2022

A cross-species study of sex chromosome dosage effects on mammalian brain anatomy

All eutherian mammals show chromosomal sex determination with contrasting sex chromosome dosages (SCDs) between males (XY) and females (XX). Studies in transgenic mice and humans with sex chromosome trisomy (SCT) have revealed direct SCD effects on regional mammalian brain anatomy, but we lack a formal test for cross-species conservation of these effects. Here, we develop a harmonized framework for comparative structural neuroimaging and apply this to systematically profile SCD effects on regional brain anatomy in both humans and mice by contrasting groups with SCT (XXY and XYY) vs. XY controls. We show that total brain size is substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Controlling for global effects reveals robust and spatially convergent effects of XXY and XYY on regional brain volume in humans, but not mice. However, mice do show subtle effects of XXY and XYY on regional volume, although there is not a general spatial convergence in these effects within mice or between species. Notwithstanding this general lack of conservation in SCT effects, we detect several brain regions that show overlapping effects of XXY and XYY both within and between species (cerebellum, parietal, and orbitofrontal cortex) - thereby nominating high priority targets for future translational dissection of SCD effects on the mammalian brain. Our study introduces a generalizable framework for comparative neuroimaging in humans and mice and applies this to achieve a cross-species comparison of SCD effects on the mammalian brain through the lens of SCT. HighlightsO_LIParallel structural neuroimaging in humans and mice with sex chromosome trisomies C_LIO_LIDivergent X- and Y-chromosome effects on human brain size, but convergent effects on regional anatomy C_LIO_LIMuted impact of additional X or Y on mouse brain, but subtle regional effects evident C_LIO_LIEvidence for conserved cross-species impact of X and Y on fronto-parietal cortices and cerebellum C_LI

neuroscience↗

bioRxiv2021

Differentiating amyloid beta spread in autosomal dominant and sporadic Alzheimer's disease

Amyloid-beta (A{beta}) deposition is one of the hallmark pathologies in both sporadic Alzheimers disease (sAD) and autosomal dominant Alzheimers disease (ADAD), the latter of which is caused by mutations in genes involved in A{beta} processing. Despite A{beta} deposition being a centerpiece to both sAD and ADAD, some differences between these AD subtypes have been observed with respect to the spatial pattern of A{beta}. Previous work has shown that the spatial pattern of A{beta} in individuals spanning the sAD spectrum can be reproduced with high accuracy using an epidemic spreading model (ESM), which simulates the diffusion of A{beta} across neuronal connections and is constrained by individual rates of A{beta} production and clearance. However, it has not been investigated whether A{beta} deposition in the rarer ADAD can be modeled in the same way, and if so, how congruent the spreading patterns of A{beta} across sAD and ADAD are. We leverage the ESM as a data-driven approach to probe individual-level variation in the spreading patterns of A{beta} across three different large-scale imaging datasets (2 SAD, 1 ADAD). We applied the ESM separately to the Alzheimers Disease Neuroimaging initiative (N=737), the Open Access Series of Imaging Studies (N=510), and the Dominantly Inherited Alzheimers Network (N=249), the latter two of which were processed using an identical pipeline. We assessed inter- and intra-individual model performance in each dataset separately, and further identified the most likely epicenter of A{beta} spread for each individual. Using epicenters defined in previous work in sAD, the ESM provided moderate prediction of the regional pattern of A{beta} deposition across all three datasets. We further find that, while the most likely epicenter for most A{beta}-positive subjects overlaps with the default mode network, 13% of ADAD individuals were best characterized by a striatal origin of A{beta} spread. These subjects were also distinguished by being younger than ADAD subjects with a DMN A{beta} origin, despite having a similar estimated age of symptom onset. Together, our results suggest that most ADAD patients express A{beta} spreading patters similar to those of sAD, but that there may be a subset of ADAD patients with a separate, striatal phenotype.

neuroscience↗