Brain MRI and Cerebral Small Vessel Disease Burden

Appendix e-1.:

Brain MRI and cerebral small vessel disease burden.

Definitions and assessment of imaging markers in this study are described in Methods. For WMH, in addition to volumetric assessment, we graded WMH in the subcortical deep WM and in periventricular regions, according to the Fazekas scale.1

The CSVD burden ordinal scale used, has been described previously. Briefly, this score awards one point for the presence of each of the following lesions: 1) lacunar infarct; 2) early (confluent) deep white matter hyperintensities (corresponding to a Fazekas score 2 and 3) or irregular periventricular white matter hyperintensities extending into the deep white matter (corresponding to a Fazekas score 3); 3) moderate to extensive (more than 10) basal ganglia EPVS, and 4) deep brain microbleeds (located in the basal ganglia, thalamus and internal or external capsules). This score includes lesions of probable small vessel disease origin.2-4

References:

1.Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol 1987;149:351-356.

2. Klarenbeek P, van Oostenbrugge RJ, Rouhl RP, Knottnerus IL, Staals J. Ambulatory blood pressure in patients with lacunar stroke: Association with total mri burden of cerebral small vessel disease. Stroke. 2013;44: 2995-2999.

3 Xiao L, Lan W, Sun W, Dai Q, Xiong Y, Li L, Zhou Y, Zheng P, Fan W, Ma N, Guo Z, Chen X, Xie X, Xu L, Zhu W, Xu G, Liu X. Chronic kidney disease in patients with lacunar stroke: Association with enlarged perivascular spaces and total magnetic resonance imaging burden of cerebral small vessel disease. Stroke. 2015;46: 2081-2086.

4. Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, Radner H, Lechner H. Pathologic correlates of incidental mri white matter signal hyperintensities. Neurology. 1993;43: 1683-1689.

Table e-1. Baseline characteristics associated with the presence/absence of silent brain infarcts and brain microbleeds.

Characteristics / No SBIs (n=205) / SBIs (n=73) / No BMB (n=254) / BMB (n=24)
Age (years) / 63 (58-67) / 65 (60-68)** / 63 (58-67) / 67 (63-68)**
Gender, male / 108 (52.7%) / 55 (75.3%)** / 144 (56.7%) / 19 (79.2%)*
Mean office SBP / 141 (134-151) / 145 (134-156) / 141 (134-151) / 145 (134-156)
Mean office DBP / 78 (71-83) / 82 (75-88)** / 78 (72-83) / 84 (78-90)**
Duration of hypertension (years) / 8.2 (5-12.2) / 8.3 (4.6-12.0) / 8.2 (5-12.1) / 9.8 (4.7-15.9)
Total Cholesterol / 216 (194-244) / 209 (180-228) P=0.05 / 214 (191-241) / 205 (175-244)
Smoking habit / 33 (16.1%) / 11 (15.1%) / 42 (16.5%) / 2 (8.3%)
Diabetes mellitus / 45 (22%) / 28 (38.4%)** / 66 (26%) / 7 (29.2%)
Previous heart disease / 21 (10.3%) / 16 (21.9%)* / 31 (12.3%) / 6 (25%)
Atrial fibrillation / 5 (2.4%) / 3 (4.1%) / 6 (2.4%) / 2 (8.3%)
eGFR (mL/min/1.73m2) / 87.5 (76.3-95.4) / 90.1 (74.8-96.3) / 88.2 (75.9-95.6) / 87.6 (71.6-92.2)
Global CV risk (REGICOR)
-Low risk (<5%)
-Moderate risk (5-9.9%)
-High risk (10-14.9%)
-Very high risk (≥15%) / 43 (21.2%)
109 (53.7%)
26 (12.8%)
25 (12.3%) / 9 (12.5%)
23 (31.9%)
15 (20.8%)
25 (34.7%)** / 49 (19.5%)
123 (49%)
38 (15.1%)
41 (16.3%) / 3 (12.5%)
9 (37.5%)
3 (12.5%)
9 (37.5%)**
BP lowering treatment / 196 (95.6%) / 72 (98.6%) / 244 (96.1%) / 24 (100%)
Antithrombotic treatment / 26 (12.7%) / 30 (41.1%)** / 47 (18.5%) / 9 (37.5%)*
Log NT-ProBNP / 1.71+/-0.4 / 1.95+/-0.49** / 1.75+/-0.42 / 2.04+-/0.48*

*p<0.05 and **p<0.01 for group comparisons (SBIs absence/presence and BMBs absence/presence). P values for associations with Log NT-proBNP are corrected by False Discovery Rate (FDR).

SBIs means silent brain infarcts, BMBs equals to brain microbleeds. SBP: systolic blood pressure, DBP: diastolic blood pressure. eGFR: estimated glomerular filtration rate, CV: cardiovascular, BP: Blood pressure.
Table e-2. Baseline characteristics associated with the centrum semiovale and basal ganglia EPVS groups (<10 and ≥10).

Characteristics / BBGG EPVS <10 (n=201) / BBGG EPVS ≥10 (n=76) / CSO EPVS <10 (159) / CSO EPVS ≥10 (n=118)
Age (years) / 63 (58-67) / 65 (62-68)** / 63 (58-67) / 64 (60-67)**
Gender, male / 111 (55.2%) / 51 (67.1%) / 85 (53.5%) / 78 (66.1%)*
Mean office SBP / 141 (134-149) / 144 (136-156) / 140 (133-148) / 145 (134-156)**
Mean office DBP / 77 (71-83) / 81 (74-88)** / 78 (71-83) / 79 (73-86)*
Duration of hypertension (years) / 7.5 (4.9-12.0) / 9.6 (5.4-13.8) / 7.5 (4.3-12.1) / 5.0 (8.6-12.7)
Total Cholesterol / 213 (189-238) / 214 (194-245) / 215 (190-244) / 212 (190-237)
Smoking habit / 30 (14.9%) / 14 (18.4%) / 30 (14.9%) / 14 (18.4%)
Diabetes mellitus / 50 (24.9%) / 23 (30.3%) / 37 (23.3%) / 36 (30.5%)
Previous heart disease / 25 (12.5%) / 11 (14.5%) / 15 (9.5%) / 22 (18.6%)*
Atrial fibrillation / 4 (2%) / 4 (5.3%) / 2 (1.3%) / 6 (5.1%)
eGFR (mL/min/1.73m2) / 86.7 (75.3-95.4) / 89.8 (79.8-95.7) / 84.8 (73.1-95.6) / 90.2 (79.1-95.4)
Global CV risk (REGICOR)
-Low risk (<5%)
-Moderate risk (5-9.9%)
-High risk (10-14.9%)
-Very high risk (≥15%) / 42 (21.2%)
99 (50%)
28 (14.1%)
29 (14.6%) / 10 (13.2%)*
33 (43.4%)
13 (17.1%)
20 (26.3%) / 34 (21.8%)
75 (48.1%)
22 (14.1%)
25 (16%) / 17 (14.4%)
57 (48.3%)
19 (16.1%)
25 (21.2%)
BP lowering treatment / 191 (95%) / 76 (100%)* / 152 (95.6%) / 115 (97.5%)
Antithrombotic treatment / 32 (15.9%) / 23 (30.3%)** / 23 (14.5%) / 33 (28%)**
Log NT-ProBNP / 1.72+/-0.43 / 1.92+/-0.42** / 1.72+/-0.44 / 1.84+/-0.42*

*p<0.05 and **p<0.01 for group (SBIs absence/presence and BMBs absence/presence). P values for associations with Log NT-proBNP are corrected by False Discovery Rate (FDR).

BBGG EPVS means basal ganglia enlarged perivascular spaces, CSO EPVS means centrum semiovale enlarged perivascular spaces. SBP: systolic blood pressure, DBP: diastolic blood pressure. eGFR: estimated glomerular filtration rate, CV: cardiovascular, BP: Blood pressure.

Table e-3. Baseline characteristics associated with WMH volumes.

Characteristics / Normalized WMH volume
Age (years) / R=0.18**
Gender

Male
Female

/ 0.96 (0.46-4.03)
0.74 (0.39-1.85)*
Mean office SBP / R=0.075
Mean office DBP / R=0.134*
Duration of hypertension (years) / R=0.054
Total Cholesterol / R=-0.011
Smoking habit

/ 0.89 (0.43-3.20)
0.90 (0.48-2.04)
Diabetes mellitus

/ 0.83 (0.43-3.83)
1.35 (0.55-3.83)*
Previous heart disease
No
Yes / 0.89 (0.43-2.47)
1.01 (0.46-3.81)
Atrial fibrillation

/ 0.89 (0.44-2.86)
1.01 (0.28-3.40)
eGFR (mL/min/1.73m2) / R=-0.073
Global CV risk (REGICOR)

Low risk (<5%)
Moderate risk (5-9.9%)
High risk (10-14.9%)
Very high risk (≥15%)

/ 0.75 (0.35-1.37)
0.75 (0.41-1.71)
1.70 (0.40-5.62)
2.01 (0.69-4.64)**
BP lowering treatment

/ 0.76 (0.34-1.10)
0.90 (0.44-3.10)
Antithrombotic treatment

/ 0.79 (0.42-2.00)
2.01 (0.83-7.43)**
Log NT-ProBNP / R=0.18*

WMH means white matter hyperintensities. R represents the correlation coefficient (Spearman) between normalized WMH volumes and continuous variables. All other values represent median and interquartile range and intergroup differences are assessed by Mann-Whitney U test and Kruskal-Wallis test. *p<0.05 and **p<0.01. P values for associations with Log NT-proBNP are corrected by False Discovery Rate (FDR). SBP: systolic blood pressure, DBP: diastolic blood pressure. eGFR: estimated glomerular filtration rate, CV: cardiovascular, BP: Blood pressure

Table e-4. Baseline characteristics associated with the CSVD scale scores.

Characteristics / 0 point
(n=181) / 1 point
(n=54) / 2 points
(n=28) / 3 to 4 points (n=15)
Age (years) / 62 (58-67) / 65 (62-68) / 65 (61-69) / 66 (62-70)**
Gender, male / 97 (53.6%) / 33 (61.1%) / 21 (75%) / 12 (80%)**
Mean office SBP / 141 (134-150) / 142 (129-152) / 148 (137-156) / 146 (138-179)
Mean office DBP / 77 (71-83) / 78 (71-85) / 82 (77-90) / 84 (78-89)**
Duration of hypertension (years) / 8.14 (4.94-12.12) / 7.46 (4.87-11.37) / 11.03 (5.35-21.33) / 9.29 (5.03-16.51)
Total Cholesterol / 216 (191-243) / 212 (187-234) / 208 (187-227) / 215 (181-245)
Smoking habit / 29 (16%) / 7 (13%) / 6 (21.4%) / 2 (13.3%)
Diabetes mellitus / 40 (22.1%) / 20 (37%) / 9 (32.1%) / 4 (26.7%)
Previous heart disease / 21 (11.7%) / 8 (14.8%) / 7 (25%) / 1 (6.7%)
Atrial fibrillation / 4 (2.2%) / 2 (3.7%) / 2 (7.1%) / 0 (0%)
eGFR (mL/min/1.73m2) / 86.8 (76.0-95.5) / 90.8 (74.4-95.4) / 88.5 (81.9-98.0) / 83.4 (67.1-93.1)
Global CV risk (REGICOR)
-Low risk (<5%)
-Moderate risk (5-9.9%)
-High risk (10-14.9%)
-Very high risk (≥15%) / 38 (21.2%)
92 (51.4%)
23 (12.8%)
26 (14.5%) / 10 (18.9%)
25 (47.2%)
9 (17%)
9 (17%) / 3 (10.7%)
8 (28.6%)
6 (21.4%)
11 (39.3%) / 1 (6.7%)**
7 (46.7%)
3 (20%)
4 (26.7%)
BP lowering treatment / 171 (94.5%) / 54 (100%) / 28 (100%) / 15 (100%)*
Antithrombotic treatment / 23 (12.7%) / 18 (33.3%) / 10 (35.7%) / 5 (33.3%)**

*p<0.05 and **p<0.01. SBP: systolic blood pressure, DBP: diastolic blood pressure. eGFR: estimated glomerular filtration rate, CV: cardiovascular, BP: Blood pressure.