Nonlinear temporal dynamics of cerebral small vessel disease

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.

Progression of White Matter Hyperintensities Preceded by Heterogeneous Decline of Microstructural Integrity

“…Differences between participants with mild versus severe baseline WMH have been reported before with respect to progression of their WMH, suggesting heterogeneity in pathogenesis of mild versus severe WMH. 12,13,20 Our observed differences in microstructural integrity between participants with mild and severe baseline WMH in both remaining NAWM and WMH confirm and extend this hypothesis. The observation of impaired microstructural integrity in remaining NAWM in participants with baseline Fazekas 2 to 3 indicates that NAWM is not as normal as one would expect from conventional MRI and underlines the hypothesis of a continuous, ongoing disease of the WM in SVD.…”

“…Moreover, it might be an explanation for the observation that WMH progression was most pronounced in participants with severe WMH at baseline. 12 The findings that the microstructural integrity within WMH was more impaired in participants with severe baseline WMH than in participants with mild baseline WMH and also continuously declined over time within WMH in both groups suggest that not only NAWM but also WMH is heterogeneous. This heterogeneity of microstructural integrity in WMH might explain clinical variances observed in subjects with similar SVD severity.…”

“…12 Fifteen participants were additionally excluded because of insufficient scan quality, yielding 266 participants for the present study. The Medical Review Ethics Committee region Arnhem-Nijmegen approved the study, and all participants gave written informed consent.…”

“…12 Next, we created binary WM masks from the WM segmentation maps. WMH were segmented semiautomatically using FLAIR and T1 sequences.…”

“…over time. 12 Besides, progression was found most pronounced in participants with severe WMH, 12,13 suggesting differences in pathogenesis for mild versus severe WMH. More knowledge of the sequence of events that precedes the conversion of NAWM toward WMH might result in better identification of patients at risk for further WMH progression and the attendant clinical symptoms.…”