5 research outputs found
A registration method for improving quantitative assessment in probabilistic diffusion tractography
Diffusion MRI-based probabilistic tractography is a powerful tool for non-invasively investigating normal brain architecture and alterations in structural connectivity associated with disease states. Both voxelwise and region-of-interest methods of analysis are capable of integrating population differences in tract amplitude (streamline count or density), given proper alignment of the tracts of interest. However, quantification of tract differences (between groups, or longitudinally within individuals) has been hampered by two related features of white matter. First, it is unknown to what extent healthy individuals differ in the precise location of white matter tracts, and to what extent experimental factors influence perceived tract location. Second, white matter lacks the gross neuroanatomical features (e.g., gyri, histological subtyping) that make parcellation of grey matter plausible â determining where tracts âshouldâ lie within larger white matter structures is difficult. Accurately quantifying tractographic connectivity between individuals is thus inherently linked to the difficulty of identifying and aligning precise tract location. Tractography is often utilized to study neurological diseases in which the precise structural and connectivity abnormalities are unknown, underscoring the importance of accounting for individual differences in tract location when evaluating the strength of structural connectivity. We set out to quantify spatial variance in tracts aligned through a standard, whole-brain registration method, and to assess the impact of location mismatch on groupwise assessments of tract amplitude. We then developed a method for tract alignment that enhances the existing standard whole brain registration, and then tested whether this method improved the reliability of groupwise contrasts. Specifically, we conducted seed-based probabilistic diffusion tractography from primary motor, supplementary motor, and visual cortices, projecting through the corpus callosum. Streamline counts decreased rapidly with movement from the tract center (â35% per millimeter); tract misalignment of a few millimeters caused substantial compromise of amplitude comparisons. Alignment of tracts âpeak-to-peakâ is essential for accurate amplitude comparisons. However, for all transcallosal tracts registered through the whole-brain method, the mean separation distance between an individual subject's tract and the average tract (3.2âŻmm) precluded accurate comparison: at this separation, tract amplitudes were reduced by 74% from peak value. In contrast, alignment of subcortical tracts (thalamo-putaminal, pallido-rubral) was substantially better than alignment for cortical tracts; whole-brain registration was sufficient for these subcortical tracts. We demonstrated that location mismatches in cortical tractography were sufficient to produce false positive and false negative amplitude estimates in both groupwise and longitudinal comparisons. We then showed that our new tract alignment method substantially reduced location mismatch and improved both reliability and statistical power of subsequent quantitative comparisons.</p
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Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1
X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. This unique insertion coincides with six additional noncoding sequence changes in TAF1, the gene that encodes TATA-binding proteinâassociated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)n. The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression