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Cerebral hemodynamics and white matter hyperintensities in CADASIL
Rivka van den Boom1, Saskia A Lesnik Oberstein, Aart Spilt
1Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. t.van_den_boom@lumc.nl
Insights
Reduced cerebral blood flow precedes white matter changes in CADASIL. This hereditary small-vessel disease, caused by NOTCH3 gene mutations, shows decreased baseline total cerebral blood flow (TCBF) in carriers, even before MRI-visible lesions appear.
Area of Science:
- Neurology
- Genetics
- Vascular Biology
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small-vessel disease linked to NOTCH3 gene mutations.
- MRI reveals white matter hyperintensities and lacunar infarcts in CADASIL patients.
- The primary cause of these MRI findings—reduced cerebral blood flow or impaired cerebrovascular reactivity—remains unclear.
Purpose of the Study:
- To investigate whether decreased baseline cerebral blood flow or impaired cerebrovascular reactivity is the primary factor in CADASIL pathogenesis.
- To assess total cerebral blood flow (TCBF) and cerebrovascular reactivity in NOTCH3 mutation carriers versus non-carriers.
Main Methods:
- Phase-contrast MRI was employed to measure baseline TCBF and cerebrovascular reactivity post-acetazolamide administration.
- The study included 40 NOTCH3 mutation carriers and 22 non-carriers from affected families.
- Participants' ages ranged from young adults to older individuals.
Main Results:
- NOTCH3 mutation carriers exhibited significantly lower baseline TCBF compared to non-carriers, particularly noticeable in younger subjects.
- Baseline TCBF was reduced even in mutation carriers with minimal white matter hyperintensities, suggesting an early disease process.
- No significant differences in cerebrovascular reactivity were observed between mutation carriers and non-carriers.
Conclusions:
- A decrease in baseline cerebral blood flow appears to be an early event in CADASIL, preceding the development of white matter hyperintensities.
- These findings suggest that reduced TCBF is a primary factor in the pathogenesis of CADASIL.
- Targeting cerebral blood flow may offer a therapeutic strategy for CADASIL.
Abstract:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19. On magnetic resonance imaging (MRI), subcortical white matter hyperintensities and lacunar infarcts are visualized. It is unknown whether a decrease in cerebral blood flow or cerebrovascular reactivity is primarily responsible for the development of white matter hyperintensities and lacunar infarcts. The authors used phase-contrast MRI in 40 NOTCH3 mutation carriers (mean age 45 +/- 10 years) and 22 nonmutated family members (mean age 39 +/- 12 years), to assess baseline total cerebral blood flow (TCBF) and cerebrovascular reactivity after acetazolamide. Mean baseline TCBF was significantly decreased in NOTCH3 mutation carriers. In young subjects, baseline TCBF was significantly lower than in nonmutation carriers (mean difference 124 mL/min). Furthermore, baseline TCBF did not differ significantly between mutation carriers with minimal and mutation carriers with moderate or severe white matter hyperintensities. No significant difference in mean cerebrovascular reactivity was found between mutation carriers and nonmutation carriers. This study suggests that a decrease in baseline TCBF in NOTCH3 mutation carriers precedes the development of white matter hyperintensities.
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