Brain imaging factors associated with progression of subcortical hyperintensities in CADASIL over two year follow up

Background: Mutations in the NOTCH3 gene cause CADASIL, a cerebral small vessel disease manifesting with stroke, migraine and dementia in adults. The disease displays significant phenotypic variability which is incompletely explained. Early abnormalities in vascular function have been shown in animal models. We postulated that studying changes in vascular function may offer insights into disease progression. Methods: Twenty two subjects with CADASIL (50% female, 50 (±11) years) from 19 pedigrees were included in a longitudinal multimodality study using brain MRI, clinical measures, neuropsychology, and measures of peripheral vascular function. MRI studies included measurement of structural brain changes, cerebral blood flow (CBF) and cerebrovascular reactivity by arterial spin labelling and a CO2 respiratory challenge. Results: Over two years, new stroke or TIA occurred in 5 (23%) subjects and new significant disability in 1 (5%). There were significant increases in number of lacunes, subcortical hyperintensity volume and microbleeds, and a decrease in brain volume. CBF declined by 3.2 (±4.5) ml/100g/min over two years. CBF and carotid‐femoral pulse wave velocity at baseline predicted change in subcortical hyperintensity volume at follow up. Carotid‐intima‐media thickness and age predicted brain atrophy. Baseline CBF was lower in subjects who showed a decline in attention and working memory. Conclusion: CBF predicts radiological progression of hyperintensities and thus is a potential biomarker of disease progression in CADASIL. Over two years, there were changes in several relevant imaging biomarkers (CBF, brain volume, lacunes, microbleeds, and hyperintensity volume). Future studies in CADASIL should consider assessment of CBF as prognostic factor