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

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.A. Tuladhar is a junior staff member of the Dutch Heart Foundation (grant 2016T044). E. van Dijk received a personal fellowship from the Dutch Brain Foundation (H04-12; F2009[1]-16). L. Rutten-Jacobs is supported by a British Heart Foundation Immediate Research Fellowship (FS/15/61/31626). C. Klijn is supported by a clinical established investigator grant of the Dutch Heart Foundation (grant 2012 T077) and an Aspasia grant from The Netherlands Organisation for Health Research and Development (ZonMw grant 015.008.048). F. de Leeuw is supported by a clinical established investigator grant of the Dutch Heart Foundation (grant 2014 T060), by a VIDI innovational grant from The Netherlands Organisation for Health Research and Development (ZonMw grant 016.126.351), and the MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente