Abstract

Cerebral small vessel disease (SVD) is the primary cause of vascular cognitive impairment and is associated with decline in executive function (EF) and information processing speed (IPS). Imaging biomarkers are needed that can monitor and identify individuals at risk of severe cognitive decline. Recently there has been interest in combining several magnetic resonance imaging (MRI) markers of SVD into a unitary score to describe disease severity. Here we apply a diffusion tensor image (DTI) segmentation technique (DSEG) to describe SVD related changes in a single unitary score across the whole cerebrum, to investigate its relationship with cognitive change over a three-year period.98 patients (aged 43–89) with SVD underwent annual MRI scanning and cognitive testing for up to three years. DSEG provides a vector of 16 discrete segments describing brain microstructure of healthy and/or damaged tissue. By calculating the scalar product of each DSEG vector in reference to that of a healthy ageing control we generate an angular measure (DSEG θ) describing the patients' brain tissue microstructural similarity to a disease free model of a healthy ageing brain. Conventional MRI markers of SVD brain change were also assessed including white matter hyperintensities, cerebral atrophy, incident lacunes, cerebral-microbleeds, and white matter microstructural damage measured by DTI histogram parameters. The impact of brain change on cognition was explored using linear mixed-effects models. Post-hoc sample size analysis was used to assess the viability of DSEG θ as a tool for clinical trials.Changes in brain structure described by DSEG θ were related to change in EF and IPS (p < 0.001) and remained significant in multivariate models including other MRI markers of SVD as well as age, gender and premorbid IQ. Of the conventional markers, presence of new lacunes was the only marker to remain a significant predictor of change in EF and IPS in the multivariate models (p = 0.002). Change in DSEG θ was also related to change in all other MRI markers (p < 0.017), suggesting it may be used as a surrogate marker of SVD damage across the cerebrum. Sample size estimates indicated that fewer patients would be required to detect treatment effects using DSEG θ compared to conventional MRI and DTI markers of SVD severity.DSEG θ is a powerful tool for characterising subtle brain change in SVD that has a negative impact on cognition and remains a significant predictor of cognitive change when other MRI markers of brain change are accounted for. DSEG provides an automatic segmentation of the whole cerebrum that is sensitive to a range of SVD related structural changes and successfully predicts cognitive change. Power analysis shows DSEG θ has potential as a monitoring tool in clinical trials. As such it may provide a marker of SVD severity from a single imaging modality (i.e. DTIs).

Highlights

  • Cerebral small vessel disease (SVD) is a disease of the small perforating arteries and capillaries and results in tissue damage to the subcortical grey matter (GM) and white matter (WM) (Pantoni, 2010)

  • T1weighted images are typically used to examine whole brain atrophy as well as atrophy of grey matter (GM); T2-weighted or fluid-attenuated inversion recovery (FLAIR) images are used to quantify white matter hyperintensity (WMH) volume and presence of lacunar infarcts; T2* identify cerebral microbleeds (CMB); and diffusion tensor images (DTI) quantify white matter (WM) microstructure. Each of these measures has been associated with cognition in SVD, and in the domains of executive function (EF) and information processing speed (IPS), which are affected early in the disease

  • Patients were recruited at least three months after last stroke occurrence to avoid the influence of any acute ischaemic effects on cognitive performance and magnetic resonance imaging (MRI) measures

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Summary

Introduction

Cerebral small vessel disease (SVD) is a disease of the small perforating arteries and capillaries and results in tissue damage to the subcortical grey matter (GM) and white matter (WM) (Pantoni, 2010). T1weighted images are typically used to examine whole brain atrophy as well as atrophy of grey matter (GM); T2-weighted or fluid-attenuated inversion recovery (FLAIR) images are used to quantify white matter hyperintensity (WMH) volume and presence of lacunar infarcts; T2* identify cerebral microbleeds (CMB); and diffusion tensor images (DTI) quantify white matter (WM) microstructure. Each of these measures has been associated with cognition in SVD, and in the domains of executive function (EF) and information processing speed (IPS), which are affected early in the disease

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