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Individual markers of cerebral small vessel disease and cerebral atrophy explain a small proportion of variance in vascular risk factors and cognitive function. Combining these markers into a single measure of neurovascular and neurodegenerative disease may be more powerful. We assessed this using data contained in the Virtual International Stroke Trials Archive - Prevention sub-archive.We extracted white matter hyperintensities (WMH) and cerebrospinal fluid (CSF) volumes from 317 people with ischemic stroke or transient ischemic attack who had baseline magnetic resonance imaging. We assessed progression of volumes in 208 people who had 2-year follow-up magnetic resonance imaging. WMH and CSF volumes were segmented from fluid attenuated inversion recovery and T1 images. The combined neurovascular and neurodegenerative measure was the sum of WMH and CSF volume normalized by intracranial volume. We assessed (1) the relationship between baseline vascular risk factors and imaging markers; and (2) the relationship between baseline imaging markers and Mini-Mental State Examination score at follow-up using multiple linear regression. We also assessed implications for sample size calculations using n=208 participants with follow-up magnetic resonance imaging.Vascular risk factors accounted for 7%, 11%, and 12% of the variance in WMH, CSF, and combined volume, respectively (all P<0.001). The association between baseline combined volume and 6-month follow-up Mini-Mental State Examination (β=−0.442; SE, 0.07; P<0.0001) was 32% greater than WMH (β=−0.302; SE, 0.06; P<0.0001) and 12% greater than CSF (β=−0.391; SE, 0.07; P<0.0001) alone. The combined volume required between 207 and 3305 (20%) fewer patients per arm than WMH alone to detect reductions of 10% to 40% in volume progression over 2 years.A combined neurovascular and neurodegenerative magnetic resonance imaging measure including WMH and CSF volume was more closely related to vascular risk factors and cognitive function than either WMH or CSF volume alone. The combined volume may be a more sensitive measurement for clinical trials.