Nonlinear temporal dynamics of cerebral small vessel disease

Leijsen, Esther M.C. van; Uden, Ingeborg W.M. van; Ghafoorian, Mohsen; Bergkamp, Mayra I.; Lohner, Valerie; Kooijmans, Eline C. M.; Holst, Helena M. van der; Tuladhar, Anil M.; Norris, David G.; Dijk, Ewoud J. van; Rutten-Jacobs, Loes C.A.; Platel, Bram; Klijn, Catharina J.M.; Leeuw, Frank‐Erik de

doi:10.1212/wnl.0000000000004490

Cited by 110 publications

(151 citation statements)

References 30 publications

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“…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.…”

Section: Discussionsupporting

confidence: 82%

“…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.…”

Section: Discussionmentioning

confidence: 94%

“…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.…”

Section: Study Populationmentioning

confidence: 99%

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

Section: Brain Tissue Segmentation and Volumetrymentioning

confidence: 99%

“…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.…”

mentioning

confidence: 97%

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

Leijsen¹,

Bergkamp²,

Uden³

et al. 2018

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Background and Purpose-White matter hyperintensities (WMH) are frequently seen on neuroimaging of elderly and are associated with cognitive decline and the development of dementia. Yet, the temporal dynamics of conversion of normalappearing white matter (NAWM) into WMH remains unknown. We examined whether and when progression of WMH was preceded by changes in fluid-attenuated inversion recovery and diffusion tensor imaging values, thereby taking into account differences between participants with mild versus severe baseline WMH. Methods-From 266 participants of the RUN DMC study (Radboud University Nijmegen Diffusion Tensor and MagneticResonance Imaging Cohort), we semiautomatically segmented WMH at 3 time points for 9 years. Images were registered to standard space through a subject template. We analyzed differences in baseline fluid-attenuated inversion recovery, fractional anisotropy, and mean diffusivity (MD) values and changes in MD values over time between 4 regions: (1) remaining NAWM, (2) NAWM converting into WMH in the second follow-up period, (3) NAWM converting into WMH in the first follow-up period, and (4)

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 94%

Section: Study Populationmentioning

confidence: 99%

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

Section: Brain Tissue Segmentation and Volumetrymentioning

confidence: 99%

mentioning

confidence: 97%

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

Leijsen¹,

Bergkamp²,

Uden³

et al. 2018

Stroke

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Superficial white matter microstructure affects processing speed in cerebral small vessel disease

Wang

Zhang

Huang

et al. 2022

Human Brain Mapping

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White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD). This condition contributes to about 50% of dementias worldwide, a massive health burden in aging. Microstructural alterations in the deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in the superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In this paper, 141 patients with CSVD were studied. Processing speed was assessed by the completion time of the Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (lesion volume on T2-FLAIR) and diffusion MRI, including DTI and free-water (FW) imaging microstructure measures. The results of our study indicate that the superficial white matter may play a particularly important role in cognitive decline in CSVD. SWM imaging measures resulted in a large contribution to processing speed, despite a relatively small WMH burden in the SWM. SWM FW had the strongest association with processing speed among all imaging markers and, unlike the other diffusion MRI measures, significantly increased between two patient subgroups with the lowest WMH burdens (possibly representing early stages of disease). When comparing two patient subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Given significant effects of WMH volume and regional FW on processing speed, we performed a mediation analysis. SWM FW was found to fully mediate the association between WMH volume and processing speed, while no mediation effect of DWM FW was observed. Overall, our findings identify SWM abnormalities in CSVD and suggest that the SWM has an important contribution to processing speed. Results indicate that FW in the SWM is a sensitive marker of microstructural changes associated with cognition in CSVD. This study extends the current understanding of CSVD-related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes in future research.

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Memory decline in elderly with cerebral small vessel disease explained by temporal interactions between white matter hyperintensities and hippocampal atrophy

et al. 2018

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White matter hyperintensities (WMH) constitute the visible spectrum of cerebral small vessel disease (SVD) markers and are associated with cognitive decline, although they do not fully account for memory decline observed in individuals with SVD. We hypothesize that WMH might exert their effect on memory decline indirectly by affecting remote brain structures such as the hippocampus. We investigated the temporal interactions between WMH, hippocampal atrophy and memory decline in older adults with SVD. Five hundred and three participants of the RUNDMC study underwent neuroimaging and cognitive assessments up to 3 times over 8.7 years. We assessed WMH volumes semi‐automatically and calculated hippocampal volumes (HV) using FreeSurfer. We used linear mixed effects models and causal mediation analyses to assess both interaction and mediation effects of hippocampal atrophy in the associations between WMH and memory decline, separately for working memory (WM) and episodic memory (EM). Linear mixed effect models revealed that the interaction between WMH and hippocampal volumes explained memory decline (WM: β = .067; 95%CI[.024–0.111]; p < .01; EM: β = .061; 95%CI[.025–.098]; p < .01), with better model fit when the WMH*HV interaction term was added to the model, for both WM (likelihood ratio test, χ2[1] = 9.3, p < .01) and for EM (likelihood ratio test, χ2[1] = 10.7, p < .01). Mediation models showed that both baseline WMH volume (β = −.170; p = .001) and hippocampal atrophy (β = 0.126; p = .009) were independently related to EM decline, but the effect of baseline WMH on EM decline was not mediated by hippocampal atrophy (p value indirect effect: 0.572). Memory decline in elderly with SVD was best explained by the interaction of WMH and hippocampal volumes. The relationship between WMH and memory was not causally mediated by hippocampal atrophy, suggesting that memory decline during aging is a heterogeneous condition in which different pathologies contribute to the memory decline observed in elderly with SVD.

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Nonlinear temporal dynamics of cerebral small vessel disease

Cited by 110 publications

References 30 publications

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

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

Superficial white matter microstructure affects processing speed in cerebral small vessel disease

Memory decline in elderly with cerebral small vessel disease explained by temporal interactions between white matter hyperintensities and hippocampal atrophy

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