Association of Blood Pressure Lowering Intensity With White Matter Network Integrity in Patients With Cerebral Small Vessel Disease

Abstract

Background and objectives: Diffusion tensor imaging (DTI) networks integrate damage from a variety of pathologic processes in cerebral small vessel disease (SVD) and may be a sensitive marker to detect treatment effects. We determined whether brain network analysis could detect treatment effects in the PRESERVE trial data set, in which intensive vs standard blood pressure (BP) lowering was compared. The primary end point of DTI had not shown treatment differences.

Methods: Participants with lacunar stroke were randomized to standard (systolic 130-140 mm Hg) or intensive (systolic ≤ 125 mm Hg) BP lowering and followed for 2 years with MRI at baseline and at 2 years. Graph theory-based metrics were derived from DTI data to produce a measure of network integrity weighted global efficiency and compared with individual MRI markers of DTI, brain volume, and white matter hyperintensities.

Results: Data were available in 82 subjects: standard n = 40 (mean age 66.3 ± 1.5 years) and intensive n = 42 (mean age 69.6 ± 1.0 years). The mean (SD) systolic BP was reduced by 13(14) and 23(23) mm Hg in the standard and intensive groups, respectively (p < 0.001 between groups). Significant differences in diffusion network metrics were found, with improved network integrity (weighted global efficiency, p = 0.002) seen with intensive BP lowering. In contrast, there were no significant differences in individual MRI markers including DTI histogram metrics, brain volume, or white matter hyperintensities.

Discussion: Brain network analysis may be a sensitive surrogate marker in trials in SVD. This work suggests that measures of brain network efficiency may be more sensitive to the effects of BP control treatment than conventional DTI metrics.

Trial registration information: The trial is registered with the ISRCTN Registry (ISRCTN37694103; doi.org/10.1186/ISRCTN37694103) and the NIHR Clinical Research Network (CRN 10962; public-odp.nihr.ac.uk/QvAJAXZfc/opendoc.htm?document=crncc_users%5Cfind%20a%20clinical%20research%20study.qvw&lang=en-US&host=QVS%40crn-prod-odp-pu&anonymous=true).

Classification of evidence: This study provides Class II evidence that intensive BP lowering in patients with SVD results in improved brain network function when assessed by DTI-based brain network metrics.

Figure 1. Tractography-Based Image Processing Pipeline

Connectome-based network analysis workflow in the MRI branch of the PRESERVE clinical trial investigating longitudinal effects on networks metrics at baseline and the follow-up visit at 2 years. (A) AAL atlas overlaid on the MRI. (B) Streamline construction. (C) Whole-brain tractography. (D) Reconstructed connectome used to calculate the measures such as global efficiency. AAL = automatic-anatomic labeling.

Figure 2. Change in Global and Local Efficiency Between Time Points

Longitudinal plots showing the change in weighted global efficiency (A) and weighted local efficiency (B) in response to antihypertensive therapy in the intention-to-treat group showing the differences in behaviors between the 2 treatment groups. Pairs of dots relate to individual participants; they are colored by study site. The triangles and thick line show the mean behavior for the group, and the shaded area around the mean line is the standard error.

Figure 3. Blood Pressure Change Across the Study Period

Reductions in blood pressure over the course of the clinical trial for the standard and the intensive treatment groups. The blue lines show the standard treatment group, and the orange lines show the intensive treatment group. Error bars show the 95% CI. Panel A shows the systolic blood pressure, and panel B the diastolic.