Intra-class correlation coefficient between ADC and MD histogram parameters (n denotes the number of scans).

<p>Values of 0.833* and of 0.719** after removal of two outliers.</p

Effects of clinical scores, age and sex (represented by their regression coefficients) compared to the random scanner effect (represented by its standard deviation) on different ADC histogram parameters.

<p>Note that no test was performed for random effects.</p

Bland–Altman plots for parameters derived from ADC histograms with and without application of different image corrections.

<p>Bland–Altman plots for parameters derived from ADC histograms with and without application of different image corrections.</p

Bland–Altman plots for the mean value of ADC vs MD histograms after CSF removal on GE scanners with upgrade Signa 11 new and Signa 12+.

<p>Bland–Altman plots for the mean value of ADC vs MD histograms after CSF removal on GE scanners with upgrade Signa 11 new and Signa 12+.</p

Correlation coefficients between ADC and MD histogram parameters (n denotes the number of scans); all p-values are less than 0.0001

<p>Values of 0.935* and 0.779** after removal of two outliers.</p

Intra-class correlation between ADC histogram parameters obtained with and without different image corrections (n denotes the number of scans) (only baseline scans were used in these analyses).

<p>All p-values are less than 0.0001</p

Linear regression analysis of mean value derived from ADC histograms vs mean MD values obtained with DTI after CSF removal (x 10⁻⁴ mm²/s) on the GE scanner.

<p>The graph shows the large effects of different scanner versions (software and hardware updates). If the ADC and MD measures appear well correlated overall, the graph illustrates that they clearly depend on the scanner version and are not concordant since all regression lines significantly differ from the perfect concordance line (dashed line).</p

Linear regression analysis of mean value of ADC with and without CSF removal, showing the effects of different scanner versions.

<p>Linear regression analysis of mean value of ADC with and without CSF removal, showing the effects of different scanner versions.</p

Data_Sheet_1_Different Types of White Matter Hyperintensities in CADASIL.DOCX

<p>Objective: In CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), white matter hyperintensities (WMH) are considered to result from hypoperfusion. We hypothesized that in fact the burden of WMH results from the combination of several regional populations of WMH with different mechanisms and clinical consequences.</p><p>Methods: To identify regional WMH populations, we used a 4-step approach. First, we used an unsupervised principal component algorithm to determine, without a priori knowledge, the main sources of variation of the global spatial pattern of WMH. Thereafter, to determine whether these sources are likely to include relevant information regarding regional populations of WMH, we tested their relationships with: (1) MRI markers of the disease; (2) the clinical severity assessed by the Mattis Dementia Rating scale (MDRS) (cognitive outcome) and the modified Rankin's score (disability outcome). Finally, through careful interpretation of all the results, we tried to identify different regional populations of WMH.</p><p>Results: The unsupervised principal component algorithm identified 3 main sources of variation of the global spatial pattern of WMH, which showed significant and sometime inverse relationships with MRI markers and clinical scores. The models predicting clinical severity based on these sources outperformed those evaluating WMH by their volume (MDRS, coefficient of determination of 39.0 vs. 35.3%, p = 0.01; modified Rankin's score, 43.7 vs. 38.1%, p = 0.001). By carefully interpreting the visual aspect of these sources as well as their relationships with MRI markers and clinical severity, we found strong arguments supporting the existence of different regional populations of WMH. For instance, in multivariate analyses, larger extents of WMH in anterior temporal poles and superior frontal gyri were associated with better outcomes, while larger extents of WMH in pyramidal tracts were associated with worse outcomes, which could not be explained if WMH in these different areas shared the same mechanisms.</p><p>Conclusion: The results of the present study support the hypothesis that the whole extent of WMH results from a combination of different regional populations of WMH, some of which are associated, for yet undetermined reasons, with milder forms of the disease.</p

The Atherosclerosis Risk Variant rs2107595 Mediates Allele-Specific Transcriptional Regulation of HDAC9 via E2F3 and Rb1

Background and Purpose- Genome-wide association studies have identified the HDAC9 (histone deacetylase 9) gene region as a major risk locus for atherosclerotic stroke and coronary artery disease in humans. Previous results suggest a role of altered HDAC9 expression levels as the underlying disease mechanism. rs2107595, the lead single nucleotide polymorphism for stroke and coronary artery disease resides in noncoding DNA and colocalizes with histone modification marks suggestive of enhancer elements. Methods- To determine the mechanisms by which genetic variation at rs2107595 regulates HDAC9 expression and thus vascular risk we employed targeted resequencing, proteome-wide search for allele-specific nuclear binding partners, chromatin immunoprecipitation, genome-editing, reporter assays, circularized chromosome conformation capture, and gain- and loss-of-function experiments in cultured human cell lines and primary immune cells. Results- Targeted resequencing of the HDAC9 locus in patients with atherosclerotic stroke and controls supported candidacy of rs2107595 as the causative single nucleotide polymorphism. A proteomic search for nuclear binding partners revealed preferential binding of the E2F3/TFDP1/Rb1 complex (E2F transcription factor 3/transcription factor Dp-1/Retinoblastoma 1) to the rs2107595 common allele, consistent with the disruption of an E2F3 consensus site by the risk allele. Gain- and loss-of-function studies showed a regulatory effect of E2F/Rb proteins on HDAC9 expression. Compared with the common allele, the rs2107595 risk allele exhibited higher transcriptional capacity in luciferase assays and was associated with higher HDAC9 mRNA levels in primary macrophages and genome-edited Jurkat cells. Circularized chromosome conformation capture revealed a genomic interaction of the rs2107595 region with the HDAC9 promoter, which was stronger for the common allele as was the in vivo interaction with E2F3 and Rb1 determined by chromatin immunoprecipitation. Gain-of-function experiments in isogenic Jurkat cells demonstrated a key role of E2F3 in mediating rs2107595-dependent transcriptional regulation of HDAC9. Conclusions- Collectively, our findings imply allele-specific transcriptional regulation of HDAC9 via E2F3 and Rb1 as a major mechanism mediating vascular risk at rs2107595