Abstract
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.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.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.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.
Highlights
White matter hyperintensities (WMH) are a hallmark of cerebral small vessel disease (SVD)
In CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), the most frequent monogenic form of SVD, WMH are commonly seen in anterior temporal poles and superior frontal gyri, which are generally spared by WMH in age- and hypertension-related SVD [3]
We recently showed that the WMH observed in these areas in CADASIL are characterized by far longer T1 and T2∗ relaxometry values than WMH observed in the remaining white matter
Summary
White matter hyperintensities (WMH) are a hallmark of cerebral small vessel disease (SVD). We recently showed that the WMH observed in these areas in CADASIL are characterized by far longer T1 and T2∗ relaxometry values than WMH observed in the remaining white matter. This large difference, tightly linked to the local water content [4], suggests that WMH in anterior temporal poles and superior frontal gyri might result from different mechanisms than WMH observed in other brain regions. Thereafter, we aimed to determine, through the careful visual inspection of these sources and the interpretation of their relationships with the other MRI markers of the disease and clinical scores, whether we could identify different regional populations of WMH
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