White matter changes and gait decline in cerebral small vessel disease

Abstract

The relation between progression of cerebral small vessel disease (SVD) and gait decline is uncertain, and diffusion tensor imaging (DTI) studies on gait decline are lacking. We therefore investigated the longitudinal associations between (micro) structural brain changes and gait decline in SVD using DTI. 275 participants were included from the Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort (RUN DMC), a prospective cohort of participants with cerebral small vessel disease aged 50-85 years. Gait (using GAITRite) and magnetic resonance imaging measures were assessed during baseline (2006-2007) and follow-up (2011 - 2012). Linear regression analysis was used to investigate the association between changes in conventional magnetic resonance and diffusion tensor imaging measures and gait decline. Tract-based spatial statistics analysis was used to investigate region-specific associations between changes in white matter integrity and gait decline. 56.2% were male, mean age was 62.9 years (SD8.2), mean follow-up duration was 5.4 years (SD0.2) and mean gait speed decline was 0.2 m/s (SD0.2). Stride length decline was associated with white matter atrophy (β = 0.16, p = 0.007), and increase in mean white matter radial diffusivity and mean diffusivity, and decrease in mean fractional anisotropy (respectively, β = - 0.14, p = 0.009; β = - 0.12, p = 0.018; β = 0.10, p = 0.049), independent of age, sex, height, follow-up duration and baseline stride length. Tract-based spatial statistics analysis showed significant associations between stride length decline and fractional anisotropy decrease and mean diffusivity increase (primarily explained by radial diffusivity increase) in multiple white matter tracts, with the strongest associations found in the corpus callosum and corona radiata, independent of traditional small vessel disease markers. White matter atrophy and loss of white matter integrity are associated with gait decline in older adults with small vessel disease after 5 years of follow-up. These findings suggest that progression of SVD might play an important role in gait decline.

Keywords: Cerebral small vessel disease (SVD); Diffusion tensor imaging (DTI); Gait; MRI; Tract-based spatial statistics (TBSS).

Fig. 1

Flowchart of the study sample Abbreviations: DTI: diffusion tensor imaging; MRI: magnetic resonance imaging; SVD: small vessel disease. Of the 503 baseline participants, 2 participants were lost to follow-up, 49 had died and 54 refused an in-person follow-up examination, but their clinical endpoints were available; 398 participated in the follow-up assessment. For the present study, we included 275 participants, 123 participants were additionally excluded because of because of (i) MRI contra-indications, MRI artifacts or missing values at follow-up (n = 46), (ii) missing data on follow-up GAITRite (n = 12) (because they were wheelchair bound, because of home visit or because of technical problems), (iii) territorial infarcts at baseline and follow-up imaging (n = 43), because these infarcts were considered as a potential confounder, (iv) conditions associated with gait impairment other than SVD which prevented participants from walking unaided at baseline and follow-up (n = 13) (joint fusion, severe arthritis, severe polyneuropathy, leg amputation, severe vision problems, severe cardiopulmonary diseases, severe peripheral arterial disease and psychogenic gait disturbance), (v) parkinsonism during follow-up examination (n = 6), because apart from SVD other pathologies as amyloid pathology, Lewy body pathology and nigrastriatal dopaminergic loss could play a role in gait deterioration in these patients, and (vi) DTI artifacts (n = 3).

Fig. 2

Association between decrease in stride length and changes in diffusion tensor imaging measures after 5 years of follow-up. Voxel-wise analysis of the association between changes in stride length (in centimeters) and changes in different diffusion tensor imaging measures, thresholded at P < 0.05 and corrected for multiple comparisons. Adjustments were made for age, sex, follow-up duration, height and baseline stride length (model 1) and additionally for changes in cerebral small vessel disease characteristics (white matter hyperintensities, number of lacunes, microbleeds and gray matter and white matter volume) (model 2). These images are superimposed onto the spatially normalized Montreal Neurological Institute (MNI) stereotactic space fractional anisotropy map. The x, y, and z coordinates represent the MNI coordinates of each slide.

Fig. 3

The scatterplots shows the relation (linear regression) between changes in mean diffusivity and radial diffusivity values of the significant white matter tracts found in tract-based spatial statistic (TBSS) analysis and changes in stride length (in centimeters), respectively.