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Background and purpose: Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a cerebral small vessel disease manifesting with stroke, migraine and dementia in adults. The disease displays significant phenotypic variability that 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 magnetic resonance imaging (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 2 years, new stroke or transient ischaemic attack (TIA) occurred in five (23%) subjects and new significant disability in one (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/100 g/min over 2 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. Conclusions: Cerebral blood flow predicts radiological progression of hyperintensities and thus is a potential biomarker of disease progression in CADASIL. Over 2 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. [ABSTRACT FROM AUTHOR]

Introduction: Differences in brain structure on magnetic resonance imaging (MRI) between normal ageing and early dementia are subtle. Without serial imaging, these differences may be highlighted by comparing individual scans to templates of normal brain structure. Previous templates had limitations, e.g. based on parametric assumptions that are potentially not met in brain structure data. Therefore, we describe the development of a nonparametric voxel-based method for determining the boundaries of normality, and how this might inform future templates.Methods: We used structural brain MRI from 236 normal subjects and 138 subjects diagnosed with Alzheimer's Disease (AD) (55-90 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Open Access Series of Imaging Studies (OASIS). Half (49) of the normal subjects from OASIS and 49 normal subjects from ADNI were used to create nonparametric voxel-based templates of grey matter (GM), white matter (WM), and cerebrospinal fluid (CSF), according to the calculated values of the 2.5th, 25th, 50th, 75th, and 97.5th percentile ranks of GM, WM or CSF in each voxel. For comparison, we also created a parametric voxel-based template of GM. In a validation study, we ranked each voxel from the remaining normal and AD subjects with the nonparametric templates, and compared these to the parametric methods.Results: The nonparametric GM template identified areas of atrophy known to be abnormal in AD, e.g. the hippocampus. These are shown on colour-coded brain images. There were differences between the nonparametric and parametric methods.Conclusion: Nonparametric voxel-based brain ranking may highlight subtle brain structure abnormalities and allows comparison with age-appropriate templates. This may increase the utility of brain imaging in supporting diagnoses of neurodegenerative disorders. The development of robust templates of normal brain structure using nonparametric methods will require large numbers of normal subjects (see: http://www.sinapse.ac.uk/research-resources/brains-project). [ABSTRACT FROM AUTHOR]