Cerebral Microbleeds Are Associated with Loss of White Matter Integrity

J.-Y. Liu; Y.-J. Zhou; F.-F. Zhai; F. Han; L.-X. Zhou; J. Ni; M. Yao; S. Zhang; Z. Jin; L. Cui; Y.-C. Zhu

doi:10.3174/ajnr.A6622

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Fig 1.
Flow diagram of the study population.
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Fig 2.
DTI parameters related to deep CMBs. Tract-Based Spatial Statistics analysis of FA and the CMB location (deep CMBs with or without lobar CMBs). Deep CMBs were associated with decreased FA and increased MD, axial diffusivity, and radial diffusivity, adjusted for age, sex, hypertension, hyperlipidemia, smoking, and diabetes (A), or age, sex, hypertension, hyperlipidemia, smoking, diabetes, white matter hyperintensity volume, and lacunes (B), thresholded at P < .05, and corrected for multiple comparisons. The red colormap indicates a positive relationship, and the blue colormap indicates a negative relationship. The statistical maps are superimposed onto the spatially normalized (Montreal Neurological Institute stereotactic space) and averaged (n = 931) FA map. Threshold-free cluster enhancement corrected P < .05.
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Fig 3.
DTI parameters related to strictly lobar CMB. Tract-Based Spatial Statistics analysis of FA and CMB location (strictly lobar). Lobar CMBs were associated with decreased FA and increased MD, axial diffusivity, and radial diffusivity, adjusted for age, sex, hypertension, hyperlipidemia, smoking, and diabetes (A), or age, sex, hypertension, hyperlipidemia, smoking, diabetes, white matter hyperintensity volume and lacunes (B), thresholded at P < .05 and corrected for multiple comparisons. The red colormap indicates a positive relationship, and the blue colormap indicates negative relationship. The statistical maps are superimposed onto the spatially normalized (Montreal Neurological Institute stereotactic space) and averaged (n = 922) FA map. Threshold-free cluster enhancement corrected P < .05.
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Fig 4.
FA and MD of the lesioned tract expressed as a ratio relative to the control tract. The x-axis shows the distance in millimeters from the microbleed location. Data show the mean and its 95% CI. The asterisk indicates that the difference was significant between the CMB tract and control tract (P < .05).

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Table 1:

Characteristics of the study population^{^a}

Variables	Normal	Deep CMBs	Lobar CMBs	P^{^b}	P^{^c}
Demographics
Age (yr)	55.3 (9.1)	62.6 (7.5)	60.8 (9.0)	<.001	.314
Men	296 (34%)	36 (60%)	20 (39%)	<.001	.048
Cardiovascular risk factors
Hypertension	427 (49%)	48 (80%)	27 (53%)	<.001	.002^{^b}
Diabetes mellites	148 (17%)	14 (23%)	12 (24%)	.212	.981
Hyperlipidemia	427 (49%)	29 (48%)	27 (53%)	.869	.628
Smoking	231 (26.5%)	25 (41.7%)	15 (29.4%)	.038	.180
Neuroimaging characteristics
Presence of lacunes	122 (14%)	35 (58%)	15 (29%)	<.001	.002^{^d}
WMH volume (mL)	0.82 (0.25–2.62)	5.82 (2.09–12.81)	3.56 (0.99–7.11)	<.001	.086
Total brain volume (mL)	1402.7 (123.2)	1421.0 (132.6)	1424.2 (136.3)	.285	.893
CMB numbers				–	.003^{^d}
1	–	29 (48.3%)	36 (70.5%)
2∼3	–	17 (28.3%)	13 (25.5%)
>4	–	14 (23.3%)	2 (4.0%)
DTI parameters
Mean global FA, NAWM	0.37 (0.02)	0.35 (0.03)	0.35 (0.02)	<.001	.143
Mean global MD, ×10^–3mm²/s, NAWM	0.84 (0.04)	0.89 (0.06)	0.87 (0.05)	<.001	.031
Axial diffusivity, ×10⁻³ mm²/s, NAWM	1.18 (0.04)	1.22 (0.05)	1.20 (0.05)	<.001	.023
Radial diffusivity, ×10⁻³ mm²/s, NAWM	0.67 (0.05)	0.73 (0.07)	0.71 (0.06)	<.001	.042

Note:—–indicates no CMBs.
↵a Data represent mean (SD), median (interquartile range), or frequency (percentage).
↵b Significance test among 3 groups, using the ANOVA, χ² test, or the Kruskal-Wallis test.
↵c Post hoc analysis between the deep CMB and lobar CMB groups.
↵d The difference was significant between deep CMBs and lobar CMBs groups (Bonferroni-corrected, P < .017).

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Table 2:

Microbleeds (yes versus no) and white matter microstructure integrity^{^a}

	FA		MD		Axial Diffusivity		Radial Diffusivity
	β	P	β	P	β	P	β	P
Model 1	−0.450 (−0.616 to −0.285)	<.001	0.433 (0.282−0.584)	<.001	0.378 (0.221−0.535)	<.001	0.446 (0.295−0.597)	<.001
Model 2	−0.433 (−0.597 to −0.269)	<.001	0.420 (0.271−0.570)	<.001	0.368 (0.212−0.524)	<.001	0.432 (0.282−0.581)	<.001
Model 3	−0.238 (−0.394 to −0.083)	.003	0.204 (0.068−0.340)	.003	0.165 (0.019−0.310)	.026	0.217 (0.081−0.352)	.002
Model 4	−0.241 (−0.396 to −0.086)	.002	0.206 (0.070−0.342)	.003	0.167 (0.021−0.312)	.025	0.218 (0.083−0.354)	.002

Note:—β indicates regression coefficient.
↵a Values represent differences in z scores of mean FA, MD, axial diffusivity, and radial diffusivity of NAWM for the presence of any microbleeds compared with no microbleeds. Model 1: adjusted for age and sex; model 2: same as model 1, additionally adjusted for hypertension, hyperlipidemia, smoking, diabetes; model 3: adjusted for age, sex, lacunes, and white matter hyperintensity volume (log-transformed); model 4: adjusted for sex, cardiovascular risk factors as in model 2, and CSVD imaging markers as in model 3.

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Table 3:

Microbleeds by location and white matter microstructure integrity^{^a}

	FA		MD		Axial Diffusivity		Radial Diffusivity
	β	P	β	P	β	P	β	P
None vs lobar
Model 1	−0.396 (−0.622 to −0.169)	.001	0.339 (0.135−0.543)	.001	0.270 (0.055−0.484)	.014	0.363 (0.159−0.566)	<.001
Model 2	−0.396 (−0.619 to −0.173)	.001	0.340 (0.138−0.541)	.001	0.270 (0.058−0.485)	.013	0.362 (0.162−0.563)	<.001
Model 3	−0.258 (−0.467 to −0.048)	.016	0.191 (0.010−0.372)	.038	0.131 (−0.065−0.327)	.191	0.215 (0.034−0.395)	.020
Model 4	−0.264 (−0.472 to −0.056)	.013	0.195 (0.014−0.376)	.034	0.134 (−0.062−0.330)	.180	0.218 (0.039−0.398)	.017
None vs deep
Model 1	−0.509 (−0.726 to −0.293)	<.001	0.530 (0.335−0.725)	<.001	0.486 (0.283−0.689)	<.001	0.534 (0.339−0.729)	<.001
Model 2	−0.481 (−0.697 to −0.266)	.001	0.512 (0.317−0.706)	<.001	0.472 (0.268−0.675)	<.001	0.514 (0.319−0.708)	<.001
Model 3	−0.244 (−0.450 to −0.038)	.020	0.243 (0.065−0.421)	.008	0.218 (0.028−0.408)	.025	0.246 (0.068−0.424)	.007
Model 4	−0.242 (−0.448 to −0.036)	.021	0.245 (0.071−0.424)	.007	0.220 (0.029−0.411)	.024	0.248 (0.069−0.426)	.007

Note:—β indicates regression coefficient.
↵a Values represent differences in z scores of mean FA, MD, axial diffusivity and radial diffusivity of NAWM for the presence of any microbleeds by their location compared with no microbleeds. Model 1: adjusted for age and sex; model 2: same as model 1, additionally adjusted for hypertension, hyperlipidemia, smoking, diabetes; model 3: adjusted for age, sex, lacunes, white matter hyperintensity volume (log-transformed); model 4: adjusted for sex, cardiovascular risk factors as in model 2, and CSVD imaging markers as in model 3.