Nonlinear temporal dynamics of cerebral small vessel disease: The RUN DMC study

Abstract

Objective: To investigate the temporal dynamics of cerebral small vessel disease (SVD) by 3 consecutive assessments over a period of 9 years, distinguishing progression from regression.

Methods: Changes in SVD markers of 276 participants of the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) cohort were assessed at 3 time points over 9 years. We assessed white matter hyperintensities (WMH) volume by semiautomatic segmentation and rated lacunes and microbleeds manually. We categorized baseline WMH severity as mild, moderate, or severe according to the modified Fazekas scale. We performed mixed-effects regression analysis including a quadratic term for increasing age.

Results: Mean WMH progression over 9 years was 4.7 mL (0.54 mL/y; interquartile range 0.95-5.5 mL), 20.3% of patients had incident lacunes (2.3%/y), and 18.9% had incident microbleeds (2.2%/y). WMH volume declined in 9.4% of the participants during the first follow-up interval, but only for 1 participant (0.4%) throughout the whole follow-up. Lacunes disappeared in 3.6% and microbleeds in 5.7% of the participants. WMH progression accelerated over time: including a quadratic term for increasing age during follow-up significantly improved the model (p < 0.001). SVD progression was predominantly seen in participants with moderate to severe WMH at baseline compared to those with mild WMH (odds ratio [OR] 35.5, 95% confidence interval [CI] 15.8-80.0, p < 0.001 for WMH progression; OR 5.7, 95% CI 2.8-11.2, p < 0.001 for incident lacunes; and OR 2.9, 95% CI 1.4-5.9, p = 0.003 for incident microbleeds).

Conclusions: SVD progression is nonlinear, accelerating over time, and a highly dynamic process, with progression interrupted by reduction in some, in a population that on average shows progression.

Figure 1. Temporal dynamics of white matter hyperintensities (WMH) progression

(A) Change in WMH volume (mL) over 3 time points by age at individual level. (B) Acceleration of WMH volume change over 2 follow-up periods (mL/y) by age at individual level. (C) Change in WMH volume (mL) over 3 time points by age at individual level stratified by baseline WMH severity. Baseline WMH severity was classified as mild (Fazekas 0–1; n = 211), moderate (Fazekas 2; n = 33), or severe (Fazekas 3; n = 20). Smoothed curves using loess smoothing express average WMH change with increasing age.

Figure 2. Lacunes and microbleeds no longer visible on follow-up imaging

Examples of a lacune that is no longer detectable on follow-up imaging (A), which appears to be assimilated by the ventricle. Microbleeds (B) appear to have faded away over time.

Figure 3. White matter hyperintensities (WMH) probability maps stratified by baseline WMH severity

Probabilities of presence of WMH stratified by baseline WMH severity, color-coded in percentage from 5% to 75%. Baseline WMH severity is determined as mild (Fazekas 0–1; n = 211), moderate (Fazekas 2; n = 33), or severe (Fazekas 3; n = 20). The overall 9-year change is shown in the right column. Probability maps through the whole brain can be seen in video 4.