Qamar, B. | Search bioRxiv

bioRxiv2023

Multi-Site Statistical Mapping of Along-Tract Microstructural Abnormalities in Bipolar Disorder with Diffusion MRI Tractometry

Investigating alterations in brain circuitry associated with bipolar disorder (BD) may offer a valuable approach to discover brain biomarkers for genetic and interventional studies of the disorder and related mental illnesses. Some diffusion MRI studies report evidence of microstructural abnormalities in white matter regions of interest, but we lack a fine-scale spatial mapping of brain microstructural differences along tracts in BD. We also lack large-scale studies that integrate tractometry data from multiple sites, as larger datasets can greatly enhance power to detect subtle effects and assess whether effects replicate across larger international datasets. In this multisite diffusion MRI study, we used BUndle ANalytics (BUAN, Chandio 2020), a recently developed analytic approach for tractography, to extract, map, and visualize profiles of microstructural abnormalities on 3D models of fiber tracts in 148 participants with BD and 259 healthy controls from 6 independent scan sites. Modeling site differences as random effects, we investigated along-tract white matter (WM) microstructural differences between diagnostic groups. QQ plots showed that group differences were gradually enhanced as more sites were added. Using the BUAN pipeline, BD was associated with lower mean fractional anisotropy (FA) in fronto-limbic, interhemispheric, and posterior pathways; higher FA was also noted in posterior bundles, relative to controls. By integrating tractography and anatomical information, BUAN effectively captures unique effects along white matter (WM) tracts, providing valuable insights into anatomical variations that may assist in the classification of diseases.

neuroscience↗

bioRxiv2022

Variation in TAF1 expression in female carrier induced pluripotent stem cells and human brain ontogeny has implications for adult neostriatum vulnerability in X-linked Dystonia Parkinsonism

X-linked Dystonia-Parkinsonism (XDP) is an inherited, X-linked, adult-onset movement disorder characterized by degeneration in the neostriatum. No therapeutics alter disease progression. The mechanisms underlying regional differences in degeneration and age of onset are unknown. Developing therapeutics that target XDP-related mechanisms requires a deeper understanding of how XDP-relevant features vary in health and disease. XDP is due, in part, to either a partial loss of TAF1 function and/or a SVA-driven pathological gain of function. A disease-specific SINE-VNTR-Alu (SVA) retrotransposon insertion occurs within intron 32 of TAF1, a subunit of TFIID involved in transcription initiation. While all XDP males are usually clinically affected, females are heterozygous carriers generally not manifesting the full syndrome. As a resource for disease modeling, we characterized eight iPSC lines from XDP female carrier individuals, and identified isogenic lines where one clonal iPSC line expressed the wild-type X, and the two other clonal iPSC lines expressed the XDP haplotype. Furthermore, we characterized XDP-relevant transcript expression variation in humans, and found that SVA-F expression decreases slightly after 30 years of age in the neurotypical human brain and that TAF1 is modestly decreased in the majority of female samples. Uniquely in the caudate nucleus, TAF1 expression is not sexually dymorphic and decreased after 15 years of age. These findings indicate that regional-, age- and sex-specific mechanisms regulate TAF1, highlighting the importance of disease-relevant models and postmortem tissue analysis. We propose that the decreased TAF1 expression in the adult caudate may synergize with the XDP-specific partial loss of TAF1 function in patients, thereby passing a minimum threshold of TAF1 function, and triggering degeneration in the neostriatum. Significance StatementXDP is an inherited, X-linked, adult-onset movement disorder characterized by degeneration in the neostriatum. No therapeutics alter disease progression. Developing therapeutics requires a deeper understanding of how XDP-relevant features vary in health and disease. XDP is possibly due to a partial loss of TAF1 function. While all XDP males are usually affected, females are heterozygous carriers generally not manifesting the full syndrome. As a resource for disease modeling, we characterized eight stem cell lines from XDP female carrier individuals. Furthermore, we found that, uniquely in the caudate nucleus, TAF1 expression decreases after adolescence in healthy humans. We hypothesize that the decrease of TAF1 after adolescence in human caudate, in general, may underlie the vulnerability of the adult neostriatum in XDP.

neuroscience↗