Supplementary Online Content

Table e-1. Demographic, clinical, and MRI characteristics of patients with higher and lower cerebral small vessel disease (SVD) burden Table e-2. Baseline neuropsychological scores of patients with higher and lower cerebral small vessel disease (SVD) burden

Table e-3. Univariate analyses: Association of baseline PiB-positivity or the burden of small vessel disease (SVD) MRI markers with

neuropsychological change

Table e-4. Interaction effect of the burden of each small vessel disease MRI marker and PiB-positivity on longitudinal cognitive decline

Table e-5. Effects of PiB-positivity on longitudinal cognitive decline in subgroups with higher and lower small vessel disease burden

Table e-6. Independent and interaction effects of baseline global PiB retention ratio and the burden of small vessel disease MRI markers on

neuropsychological change

Table e-7. Multivariate analyses after exclusion of the third follow-up data: Independent effects of baseline PiB-positivity and the burden of

small vessel disease MRI markers on neuropsychological change

Methods e-1. Study participants and AMPETIS study procedures

Methods e-2. Detailed description of the Seoul Neuropsycholgical Screening Battery

Methods e-3. Imaging parameters for MR image acquisition

Methods e-4. Measurement of WMH volume and rating of lacunes and microbleeds on MRI

Methods e-5. [11C]PiB-PET scanning protocol and methods for the calculation of global PiB retention ratio

Methods e-6. The rate of MMSE decrease and CDR SOB increase

eReferences

Table e-1. Demographic, clinical and MRI characteristics of patients with higher and lower cerebral small vessel disease (SVD) burden

WMH burden Lacunar burden Microbleed burdenHigher Lower p-valueb Higher Lower p-valueb Higher Lower p-valueb

Number 21 40 23 38 20 41Female, N (%) 9 (42.8) 27 (67.5) 0.063 12 (52.2) 24 (63.2) 0.398 9 (45.0) 27 (65.9) 0.120Baseline age (years) 74.1 ± 5.7 73.3 ± 7.3 0.655 70.6 ± 6.5 75.7 ± 5.3 0.002 70.3 ± 7.4 75.5 ± 4.8 0.008Disease duration (years) 5.4 ± 4.2 3.9 ± 2.4 0.135 4.7 ± 3.2 4.9 ± 4.0 0.875 6.1 ± 4.3 4.2 ± 3.2 0.073Education (years) 9.0 ± 4.6 10.0 ± 6.0 0.430 9.6 ± 5.1 9.1 ± 5.2 0.722 10.8 ± 4.7 8.6 ± 5.2 0.117Risk factors, N (%)

DM 4 (19.0) 14 (35.0) 0.194 6 (26.1) 12 (31.6) 0.649 7 (35.0) 11 (26.8) 0.511HTN 16 (76.2) 33 (82.5) 0.736 19 (82.6) 30 (78.9) > 0.999 17 (85.0) 32 (78.0) 0.734Hyperlipidemia 9 (42.9) 16 (40.0) 0.829 9 (39.1) 16 (42.1) 0.819 9 (45.0) 16 (39.0) 0.656Cardiac disease 2 (9.5) 6 (15.0) 0.703 0 8 (21.1) 0.020 0 8 (19.5) 0.044Previous stroke 8 (38.1) 11 (27.5) 0.396 9 (39.1) 10 (26.3) 0.295 10 (50.0) 9 (22.0) 0.026

Geriatric Depression Scale 15.7 ± 7.0 17.7 ± 10.1 0.444 20.2 ± 8.6 14.2 ± 7.2 0.005 17.4 ± 9.3 15.9 ± 7.6 0.496WMH volume 32.2 ± 8.6 59.9 ± 16.5 < 0.001 41.4 ± 15.9 41.9 ± 19.0 0.917 46.6 ± 24.5 39.4 ± 13.0 0.136Number of lacunes 13.8 ± 13.2 21.2 ± 21.7 0.160 32.2 ± 17.9 6.7 ± 4.3 < 0.001 25.4 ± 21.0 11.9 ± 12.5 0.014Number of microbleeds 8.4 ± 16.4 13.1 ± 21.5 0.350 19.8 ± 26.2 4.1 ± 6.3 0.009 26.6 ± 24.9 1.9 ± 2.3 < 0.001APOE ε4 allele, N (%)a 20 38 0.120 21 37 0.020 20 38 0.752

Carrier 3 (15.0) 13 (34.2) 2 (9.5) 14 (37.8) 4 (22.2) 12 (30.0)Non-carrier 17 (85.0) 25 (65.8) 19 (90.5) 23 (62.2) 14 (77.8) 28 (70.0)

Hippocampal volume (cc) 2.9 ± 0.5 2.7 ± 0.8 0.254 3.2 ± 0.5 2.6 ± 0.5 < 0.001 3.0 ± 0.5 2.7 ± 0.6 0.028Intracranial volume (*103cc) 1.4 ± 0.1 1.4 ± 0.2 0.127 1.4 ± 0.1 1.4 ± 0.2 0.771 1.4 ± 0.1 1.4 ± 0.2 0.070Follow-up information, N (%)

Incident stroke 1 (4.8) 5 (12.5) 0.654 2 (8.7) 4 (10.5) > 0.999 1 (5.0) 5 (12.2) 0.653MMSE < 10 during follow-up 2 (9.5) 5 (12.5) > 0.999 1 (4.3) 6 (15.8) 0.238 1 (5.0) 6 (14.6) 0.409Dropout 2 (9.5) 5 (12.5) > 0.999 4 (17.4) 3 (7.9) 0.409 5 (25.0) 2 (4.9) 0.033Cancer occurrence 0 1 (2.5) > 0.999 0 1 (2.6) > 0.999 1 (5.0) 0 0.328Death 2 (9.5) 1 (2.5) 0.270 1 (4.3) 2 (5.3) > 0.999 1 (5.0) 2 (4.9) > 0.999

Abbreviations: APOE, apolipoprotein E; DM, Diabetes mellitus; HTN, hypertension; MMSE, Mini-Mental State Examination; PiB, Pittsburgh Compound B.aAPOE genotyping was analyzed in 58 patients because three patients refused the test.bp-values are results of independent t-tests or chi-square tests.

Table e-2. Baseline neuropsychological scores of patients with higher and lower cerebral small vessel disease (SVD) burden

WMH burden Lacunar burden Microbleed burdenHigher (N = 21) Lower (N = 40) p-valuea Higher (N = 21) Lower (N = 40) p-valuea Higher (N = 20) Lower (N = 41) p-valuea

AttentionDigit span forward 4.7 (1.1) 5.1 (1.1) 0.432 5.0 (1.2) 4.9 (1.1) 0.943 5.1 (1.3) 4.9 (1.0) 0.880Digit span backward 2.6 (1.4) 2.8 (0.9) 0.448 2.3 (1.1) 3.0 (1.1) 0.290 2.7 (1.0) 2.7 (1.2) 0.767

Language and related functionsK-BNT 29.9 (11.2) 31.8 (10.7) 0.138 34.7 (10.5) 29.4 (10.6) 0.638 33.7 (9.8) 30.0 (11.2) 0.492

Visuospatial functionRCFT copy 18.4 (10.6) 22.2 (10.1) 0.325 19.8 (11.2) 21.5 (10.0) 0.465 20.5 (10.3) 21.1 (10.5) 0.432

MemorySVLT Immediate recall 11.6 (5.7) 11.6 (5.1) 0.857 11.8 (5.3) 11.4 (5.3) 0.536 12.7 (4.1) 11.0 (5.7) 0.851SVLT Delayed recall 2.3 (2.4) 1.2 (1.8) 0.078 1.7 (2.1) 1.4 (2.1) 0.587 1.7 (2.1) 1.5 (2.1) 0.735SVLT Recognition 16.8 (3.6) 17.0 (3.0) 0.993 17.0 (2.8) 16.9 (3.4) 0.776 17.8 (2.5) 16.5 (3.4) 0.369RCFT Immediate recall 4.3 (5.7) 3.7 (3.8) 0.802 4.4 (5.2) 3.6 (4.1) 0.427 4.9 (5.2) 3.4 (4.2) 0.504RCFT Delayed recall 2.8 (5.0) 3.4 (3.7) 0.139 3.7 (4.7) 2.9 (3.8) 0.670 3.7 (4.8) 2.9 (3.8) 0.692RCFT Recognition 16.6 (2.3) 16.5 (3.1) 0.786 17.2 (3.2) 16.2 (2.6) 0.698 16.9 (3.2) 16.4 (2.7) 0.695

Frontal/executive functionCOWAT Animals 7.4 (3.8) 7.5 (3.1) 0.711 7.4 (2.7) 7.5 (3.6) 0.346 8.6 (3.1) 7.0 (3.3) 0.227COWAT Supermarket 6.7 (4.2) 6.3 (4.5) 0.441 5.2 (3.1) 7.1 (4.8) 0.174 6.3 (3.2) 6.5 (4.9) 0.688COWAT Phonemic fluency 8.5 (5.5) 10.0 (6.0) 0.350 8.1 (5.4) 10.2 (6.0) 0.580 9.7 (5.2) 9.3 (6.1) 0.462Stroop Test color reading 31.9 (23.2) 36.7 (26.5) 0.531 32.2 (24.4) 36.4 (26.0) 0.646 30.8 (20.3) 37.1 (27.5) 0.526

MMSE 19.8 (5.0) 21.3 (4.8) 0.216 20.8 (4.8) 20.7 (4.9) 0.540 21.6 (4.4) 20.3 (5.0) 0.346CDR SOB 6.4 (3.7) 6.1 (3.7) 0.675 6.2 (3.0) 6.2 (4.1) 0.460 6.7 (4.0) 6.0 (3.5) 0.108Abbreviations: APOE4, apolipoprotein E ε4; CDR SOB, Clinical Dementia Rating sum of boxes; COWAT, Controlled Oral Word Association Test; K-BNT, Korean version of the Boston Naming Test; MMSE, Mini-Mental State Examination; PiB, Pittsburgh Compound B; RCFT, Rey-Osterrieth Complex Figure Test; SVLT, Seoul Verbal Learning Test.ap-values are results of the generalized linear models with a negative binomial distribution comparing neuropsychological scores between patients with higher cerebrovascular disease burden and those with lower burden after controlling for age, gender, education, and APOE4 allele.

Table e-3. Univariate analyses: Association of baseline PiB-positivity or the burden of small vessel disease (SVD) MRI markers with neuropsychological change

PiB-positivity Higher WMH burden Higher lacunar burden Higher microbleed burdenNeuropsychological tests β (SE) p-value β (SE) p-value β (SE) p-value β (SE) p-valueAttention

Digit span forward -0.05 (0.07) 0.528 -0.04 (0.03) 0.239 0.02 (0.04) 0.687 -0.02 (0.03) 0.553Digit span backward -0.10 (0.04) 0.026 0.005 (0.04) 0.890 0.08 (0.04) 0.042 0.05 (0.04) 0.167

LanguageK-BNT -0.09 (0.05) 0.081 -0.07 (0.04) 0.125 0.07 (0.03) 0.046 0.002 (0.04) 0.967

Visuospatial functionRCFT copy -0.19 (0.10) 0.066 -0.16 (0.08) 0.048 0.09 (0.06) 0.168 0.12 (0.10) 0.226

Verbal MemorySVLT Immediate recall -0.10 (0.05) 0.058 -0.04 (0.05) 0.402 -0.03 (0.06) 0.637 -0.07 (0.05) 0.226SVLT Delayed recall 0.30 (0.29) 0.302 -0.19 (0.12) 0.108 -0.06 (0.13) 0.665 -0.16 (0.17) 0.360SVLT Recognition -0.04 (0.04) 0.325 -0.02 (0.02) 0.425 0.02 (0.02) 0.367 0.02 (0.02) 0.381

Visual MemoryRCFT Immediate recall -0.39 (0.43) 0.361 -0.18 (0.16) 0.263 0.09 (0.12) 0.478 -0.06 (0.12) 0.626RCFT Delayed recall -0.42 (0.21) 0.046 -0.11 (0.13) 0.376 0.15 (0.13) 0.241 -0.09 (0.14) 0.524RCFT Recognition: -0.003 (0.03) 0.915 -0.05 (0.02) 0.006 0.002 (0.02) 0.935 -0.01 (0.02) 0.588

Frontal/executive functionCOWAT Animals 0.02 (0.08) 0.848 -0.10 (0.06) 0.106 0.07 (0.05) 0.197 -0.04 (0.06) 0.456COWAT Supermarket -0.13 (0.13) 0.327 -0.25 (0.11) 0.018 0.16 (0.08) 0.046 -0.01 (0.10) 0.925COWAT Phonemic fluency 0.07 (0.09) 0.446 -0.37 (0.10) < 0.001 0.17 (0.09) 0.047 -0.11 (0.18) 0.550Stroop Test color reading -0.04 (0.20) 0.831 -0.08 (0.09) 0.370 0.01 (0.17) 0.954 0.16 (0.20) 0.415

MMSE -0.09 (0.03) 0.002 -0.07 (0.04) 0.069 0.06 (0.04) 0.107 0.05 (0.04) 0.268CDR SOB 0.17 (0.04) < 0.001 -0.001 (0.05) 0.984 -0.03 (0.05) 0.541 -0.05 (0.04) 0.265Abbreviations: APOE4, apolipoprotein E4; CDR, Clinical Dementia Rating; COWAT, Controlled Oral Word Association Test; K-BNT, Korean version of the Boston Naming Test; MMSE, Mini-Mental State Examination; PiB, Pittsburgh Compound B; RCFT, Rey-Osterrieth Complex Figure Test; SVLT, Seoul Verbal Learning Test; WMHs, white matter hyperintensities.Summary of generalized estimation equations used to measure cognitive change. Covariates included baseline age, gender, education, APOE4 allele, and follow-up interval from baseline. Predictors were baseline PiB-positivity and the burden of SVD markers including WMH, lacune, and microbleed. The burden of SVD markers was dichotomized using the second tertile of WMH volume and the number of lacunes and

microbleeds as cut-off values. To study the longitudinal effect of each predictor, the interaction effect between each predictor and follow-up interval from baseline was investigated. Regression coefficients (β), standard errors (SE), and p-values for the interaction between predictors and follow-up interval are presented.

Table e-4. Interaction effect of the burden of each small vessel disease MRI marker and PiB-positivity on longitudinal cognitive decline

PiB × WMH burden PiB × Lacunar burden PiB × microbleed burdenNeuropsychological tests β (SE) p-value β (SE) p-value β (SE) p-valueAttention

Digit span forward 0.12 (0.06) 0.046 -0.04 (0.06) 0.461 0.11 (0.06) 0.062Digit span backward 0.07 (0.09) 0.461 0.04 (0.09) 0.642 -0.0005 (0.08) 0.996

LanguageK-BNT -0.23 (0.13) 0.081 0.04 (0.07) 0.574 -0.26 (0.18) 0.142

Visuospatial functionRCFT copy -0.28 (0.25) 0.271 -0.19 (0.22) 0.400 0.07 (0.13) 0.565

Verbal MemorySVLT Immediate recall 0.03 (0.12) 0.763 -0.24 (0.10) 0.018 0.04 (0.09) 0.686SVLT Delayed recall * -1.70 (0.48) < 0.001 *

SVLT Recognition -0.03 (0.04) 0.348 -0.13 (0.05) 0.005 -0.12 (0.03) < 0.001Visual Memory

RCFT Immediate recall -0.22 (0.31) 0.475 0.30 (0.74) 0.689 -0.003 (0.29) 0.991RCFT Delayed recall 0.16 (0.45) 0.718 0.04 (0.40) 0.912 0.47 (0.37) 0.204RCFT Recognition: -0.03 (0.05) 0.510 -0.04 (0.04) 0.346 -0.02 (0.05) 0.657

Frontal/executive functionCOWAT Animals -0.26 (0.12) 0.032 0.34 (0.45) 0.452 -0.25 (0.15) 0.093COWAT Supermarket -0.34 (0.17) 0.047 0.29 (0.18) 0.098 -0.30 (0.30) 0.318COWAT Phonemic fluency -0.68 (0.40) 0.092 0.07 (0.17) 0.678 0.07 (0.17) 0.708Stroop Test color reading -0.22 (0.24) 0.361 -0.28 (0.16) 0.083 -0.47 (0.32) 0.132

MMSE -0.04 (0.08) 0.627 -0.09 (0.08) 0.233 -0.15 (0.08) 0.046CDR SOB -0.13 (0.07) 0.074 0.01 (0.10) 0.933 0.17 (0.06) 0.005Abbreviations: APOE4, apolipoprotein E4; CDR, Clinical Dementia Rating; COWAT, Controlled Oral Word Association Test; K-BNT, Korean version of the Boston Naming Test; MMSE, Mini-Mental State Examination; PiB, Pittsburgh Compound B; RCFT, Rey-Osterrieth Complex Figure Test; SVLT, Seoul Verbal Learning Test; WMHs, white matter hyperintensities.Summary of generalized estimation equations used to measure cognitive change. Covariates included baseline age, gender, education, APOE4 allele, and follow-up interval from baseline. Predictor was a 3-way interaction effect between PiB-positivity, each SVD marker, and follow-up interval from baseline. Regression coefficients (β), standard errors (SE), and p-values for the interaction effects between predictors and follow-up interval are presented.*Results could not be obtained due to the lack of model fitness.

Table e-5. Effects of PiB-positivity on longitudinal cognitive decline in subgroups with higher and lower small vessel disease burden Neuropsychological tests Subgroup β (SE) p-valuea

Digit span forward Higher WMH burden 0.03 (0.04) 0.362Lower WMH burden -0.07 (0.07) 0.316

SVLT immediate recall Higher lacunar burden -0.16 (0.09) 0.080Lower lacunar burden -0.05 (0.06) 0.440

SVLT delayed recall Higher lacunar burden -0.14 (0.32) 0.657Lower lacunar burden 1.19 (0.53) 0.025

SVLT recognition Higher lacunar burden -0.03 (0.03) 0.324Lower lacunar burden 0.02 (0.02) 0.464

COWAT animal Higher WMH burden -0.23 (0.10) 0.017Lower WMH burden 0.08 (0.16) 0.593

COWAT supermarket Higher WMH burden -0.39 (0.13) 0.002Lower WMH burden -0.09 (0.12) 0.429

CDR SOB Higher microbleed burden 0.26 (0.04) < 0.001Lower microbleed burden 0.14 (0.05) 0.006

Abbreviations: APOE4, apolipoprotein E ε4; CDR SOB, Clinical Dementia Rating Sum of Boxes; COWAT, Controlled Oral Word Association Test; K-BNT, Korean version of the Boston naming test; MMSE, Mini-Mental State Examination; RCFT, Rey-Osterrieth Complex Figure Test.Results were obtained from the generalized estimation equations with a negative binomial distribution and reflect the influence of PiB-positivity on longitudinal changes of neuropsychological scores, separately performed in subgroups with higher SVD burden and that with lower burden. Covariates included age, gender, education, APOE4 allele, and follow-up interval from baseline.

Table e-6. Independent and interaction effects of baseline global PiB retention ratio and the burden of small vessel disease MRI markers on neuropsychological change

Neuropsychological tests Predictor β (SE) p-valueDigit span forward Global PiB retention ratio -0.07 (0.05) 0.118

Higher microbleed burden -0.21 (0.09) 0.022Interaction (PiB × microbleed) 0.13 (0.06) 0.020

Digit span backward Global PiB retention ratio -0.09 (0.05) 0.057Higher lacunar burden 0.07(0.04) 0.064

K-BNT Global PiB retention ratio -0.08 (0.05) 0.089Higher lacunar burden 0.03 (0.03) 0.333

RCFT copy Global PiB retention ratio -0.17 (0.09) 0.055Higher WMH burden -0.24 (0.07) < 0.001Higher lacunar burden -0.02 (0.19) 0.900Interaction (PiB × Lacunar) -0.02 (0.15) 0.890

SVLT immediate recall Global PiB retention ratio -0.10 (0.06) 0.072Higher lacunar burden -0.03 (0.05) 0.525

SVLT delayed recall Global PiB retention ratio 0.63 (0.27) 0.021SVLT recognition Global PiB retention ratio 0.03 (0.03) 0.326

Higher lacunar burden 0.12 (0.09) 0.149Interaction (PiB × Lacunar) -0.12 (0.05) 0.017

RCFT recognition Higher WMH burden -0.05 (0.02) 0.006COWAT animal Global PiB retention ratio 0.02 (0.08) 0.805

Higher WMH burden 0.27 (0.18) 0.119Interaction (PiB × WMH) -0.27 (0.12) 0.031

COWAT supermarket Higher WMH burden -0.24 (0.10) 0.016Higher lacunar burden 0.12 (0.07) 0.087

COWAT phonemic Higher WMH burden -0.36 (0.10) < 0.001Higher lacunar burden 0.09 (0.07) 0.196

MMSE Global PiB retention ratio -0.10 (0.03) 0.002Higher WMH burden -0.08 (0.03) 0.004

CDR SOB Global PiB retention ratio 0.14 (0.03) < 0.001Abbreviations: APOE4, apolipoprotein E4; CDR, Clinical Dementia Rating; COWAT, Controlled Oral Word Association Test; K-BNT, Korean version of the Boston naming test; MMSE, Mini-Mental State Examination; PiB, Pittsburgh Compound B; RCFT, Rey-Osterrieth Complex Figure Test; SVLT, Seoul Verbal Learning Test; WMHs, white matter hyperintensities.Results summarize the generalized estimation equations used to measure cognitive change Covariates included baseline age, gender, education, APOE4 allel,e and follow-up interval from baseline. Predictors were variables with P < 0.1 in the univariate analysis and interactions with P < 0.05 in the interaction analysis. The burden of SVD markers was dichotomized using the second tertile of WMH volume, and the number of lacunes and microbleeds as cut-off values. Regression coefficients (β), standard errors (SE), and p-values for the interaction between predictors and follow-up interval are presented.

Table e-7. Multivariate analyses after exclusion of the third follow-up data: Independent effects of baseline PiB-positivity and the burden of small vessel disease MRI markers on neuropsychological changeNeuropsychological tests Predictor β (SE) p-value

Digit span forward PiB-positivity -0.11 (0.05) 0.018Higher WMH burden -0.02 (0.06) 0.719Interaction (PiB x WMH) 0.16 (0.08) 0.042

K-BNT PiB-positivity -0.13 (0.04) 0.003RCFT Recognition PiB-positivity -0.07 (0.04) 0.078

Higher WMH burden -0.06 (0.03) 0.0503COWAT animals Higher microbleed burden -0.16 (0.07) 0.016COWAT supermarket Higher lacunar burden 0.17 (0.08) 0.035COWAT phonemic PiB-positivity 0.21 (0.11) 0.073

Higher WMH burden -0.02 (0.30) 0.934Interaction (PiB x WMH) -1.16 (0.32) < 0.001

MMSE PiB-positivity -0.15 (0.07) 0.042Higher microbleed burden -0.01 (0.04) 0.879Interaction (PiB x microbleed) 0.27 (0.09) 0.003

CDR SOB PiB-positivity 0.18 (0.06) 0.002Abbreviations: APOE4, apolipoprotein E4; CDR, Clinical Dementia Rating; COWAT, Controlled Oral Word Association Test; FDR = false discovery rate corrected p-value; K-BNT = Korean version of the Boston naming test; MMSE, Mini-Mental State Examination; PiB, Pittsburgh Compound B; RCFT, Rey-Osterrieth Complex Figure Test; SVLT, Seoul Verbal Learning Test; WMHs, white matter hyperintensities.Results summarize the generalized estimation equations used to measure cognitive change after exclusion of the third follow-up data. Covariates included baseline age, gender, education, APOE4 allele, and follow-up interval from baseline. Predictors were variables with P < 0.1 as shown in eTable 3 and interactions with P < 0.05 are shown in eTable 5. The burden of SVD markers was dichotomized using the second tertile of WMH volume and the number of lacunes and microbleeds as cut-off values. Regression coefficients (β), standard errors (SE), and p-values for the interaction between predictors and follow-up interval are presented.

Methods e-1. Study participants and AMPETIS study procedures

1) Patients were evaluated by clinical interview and neurologic and neuropsychological

examinations and the presence of dementia was defined according to DSM IV. As DSM IV

criteria include the presence of focal signs suggestive of CVD, all patients had focal signs

suggestive of cerebrovascular disease, which was operationally defined as at least 2 of the

following focal neurologic signs: corticobulbar signs (facial palsy, dysarthria, dysphagia, or

pathologic laughing or crying), pyramidal signs (hemiparesis, hyperactive deep tendon

reflexes, or extensor plantar responses), or parkinsonism (short-stepped gait, festinating gait,

shuffling gait, decreased arm swing while walking, rigidity, bradykinesia, or postural

instability).

2) To exclude secondary causes of cognitive deficits, all patients underwent laboratory tests,

including a complete blood count, blood chemistry, vitamin B12/ folate levels, syphilis

serology, and thyroid function tests.

3) All patients with SVaD had significant white matter hyperintensities (WMH) on their MRI

scans which were defined as (1) a cap or band ≥ 10 mm and (2) a deep white matter lesion ≥

25 mm, as modified from Fazekas ischemia criteria. These imaging criteria are consistent

with the “predominantly white matter cases” stated in Erkinjuntti’s SVaD criteria, where

WMHs were defined as extending caps (> 10 mm in diameter as measured parallel to

ventricle) or irregular halos (> 10 mm in diameter, broad, irregular margins and extending

into deep white matter) and diffusely confluent hyperintensities (> 25 mm in the longest

diameter, irregular shape) or extensive white matter changes (diffuse hyperintensity without

focal lesions), and lacune(s) in the deep grey matter.

4) We excluded patients with territory infarctions and those with high signal abnormalities on

MRI due to radiation injury, multiple sclerosis, vasculitis, or leukodystrophy. Brain MR

images also confirmed the absence of other structural lesions such as brain tumor, subdural

hematoma, hydrocephalus, hippocampal sclerosis, and vascular malformation.

5) These diagnostic tests were performed 3 months before or after the PiB-PET scans were

taken.

Methods e-2. Detailed description of the Seoul Neuropsycholgical Screening Battery

All patients underwent neuropsychological testing with the Seoul Neuropsychological

Screening Battery.2 Scorable tests comprised the Digit Span (forward and backward), Korean

version of the Boston Naming Test,3 Rey-Osterrieth Complex Figure Test (RCFT; copying,

immediate and 20-min delayed recall, and recognition),4 Seoul Verbal Learning Test (SVLT;

three learning-free recall trials of 12 words, 20-min delayed recall trial for these 12 items, and

a recognition test),2 phonemic and semantic Controlled Oral Word Association Test

(COWAT),5 and the Stroop Test (word and color reading of 112 items during a 2-min period).6

Age- and education-specific norms for each test based on 447 normal subjects were available,

and the scores were considered to be abnormal when they were lower than -1.0 SD (16th

percentiles) of the age- and education-adjusted norms.4

Methods e-3. Imaging parameters for MR image acquisition

We acquired 3D T1 TFE MR images with the following imaging parameters: sagittal slice

thickness 1.0 mm, over contiguous slices with 50% overlap; no gap; repetition time (TR) of

9.9 ms; echo time (TE) of 4.6 ms; flip angle, 8°; and matrix size of 240 × 240 pixels,

reconstructed to 480 × 480 over a field of view (FOV) of 240 mm. 3D FLAIR MR images

were acquired in the axial plane with the following parameters: axial slice thickness, 2 mm;

no gap; repetition time (TR), 11000.0 ms; echo time (TE), 125.0 ms; flip angle, 90°; and

matrix size of 512 x 512 pixels. FFE images were obtained by using the following

parameters: axial slice thickness, 5.0 mm; inter-slice thickness, 2 mm; TR 669 ms; TE 16 ms;

flip angle, 18°; and matrix size of 560 x 560 pixels.

Methods e-4. Measurement of WMH volume and rating of lacunes and microbleeds on

MRI

We used FLAIR images to quantify WMH volume through fully automated segmentation and

classification of WMH. First, from the acquired T1 images, a mask of the WMH candidate

region was generated by removing known sources of false-positive segmentation in the

subarachnoid space and brain-cerebrospinal fluid (CSF) interface. WMH segmentation was

performed only in the WMH candidate region by applying the FMRIB automatic

segmentation tool (FAST) of the FSL software (http://www.fmrib.ox.ac.uk/fsl/). FAST is

based on a hidden Markov random field model and an associated expectation-maximization

algorithm.

Two neurologists, blinded to clinical information, counted the total numbers of

lacunes and microbleeds. Lacunar infarction was defined as a small lesion less than 15 mm in

diameter with a low signal on T1-weighted images, a high signal on T2-weighted images and

a peri-lesional halo on FLAIR images. A microbleed was defined as a homogeneous round

signal loss lesion with a diameter ≤ 10 mm on the FFE-MRI. The rate of agreement between

the two neurologists was 83.0% for lacunes and 92.3% for microbleeds and consensus was

reached in all cases of discrepancy.

Methods e-5. [11C]PiB-PET scanning protocol and methods for the calculation of global

PiB retention ratio

[11C] PiB-PET scanning was performed at Samsung Medical Center or Asan Medical Center

using a Discovery STe PET/CT scanner (GE Medical Systems, Milwaukee, WI) in a 3-

dimensional scanning mode that examined 35 slices of 4.25-mm thickness that spanned the

entire brain. The [11C] PiB was injected into an antecubital vein as a bolus with a mean dose

of 420 MBq (i.e., range 259 – 550 MBq). A CT scan was performed for attenuation correction

at 60 min after the injection. A 30-min emission static PET scan was then initiated. The

specific radioactivity of [11C] PiB at the time of administration was more than 1,500 Ci/mmol

for patients and the radiochemical yield was more than 35%. The radiochemical purity of the

tracer was more than 95% in all the PET studies.

PiB PET images were co-registered to the individual MRIs, which were then normalized to a

T1-weighted MRI template. Using these parameters, MRI co-registered PiB PET images

were normalized to the MRI template. The quantitative regional values of PiB retention on

the spatially normalized PiB images were obtained by an automated VOIs analysis using the

automated anatomical labeling (AAL) atlas. Data processing was performed using SPM

version 5 (SPM5) within Matlab 6.5 (MathWorks, Natick, MA, USA).

To measure PiB retention, we used the cerebral cortical region to cerebellum uptake ratio

(UR). The cerebellum was used as a reference region as it did not show group differences. We

selected 28 cortical VOIs from the left and right hemispheres using the AAL atlas. The

cerebral cortical VOIs that were chosen for this study consisted of the bilateral frontal

(superior and middle frontal gyri, the medial portion of superior frontal gyrus, the opercular

portion of inferior frontal gyrus, the triangular portion of inferior frontal gyrus, the

supplementary motor area, orbital portion of the superior, middle and inferior orbital frontal

gyri, rectus and olfactory cortex), posterior cingulate gyri, parietal (superior and inferior

parietal, supramarginal and angular gyri, and precuneus), lateral temporal (superior, middle

and inferior temporal gyri, and Heschl gyri) and occipital (superior, middle, and inferior

occipital gyri, cuneus, calcarine fissure, and lingual and fusiform gyri). Regional cerebral

cortical URs were calculated by dividing each cortical VOI’s UR by the mean uptake of the

cerebellar cortex (cerebellum crus1 and crus2). Global PiB uptake ratio was calculated from

the volume-weighted average UR of bilateral 28 cerebral cortical VOIs. We defined PiB

uptake ratio to be a continuous variable. Patients were considered PiB-positive if their global

PiB uptake ratio was more than two standard deviations (PiB retention ratio > 1.5) away from

the mean of the normal controls.

Methods e-6. The rate of MMSE decrease and CDR SOB increase

The rate of MMSE decline was -1.28/year vs. -0.71/year for higher vs. lower WMH burden

groups; -0.43/year vs. -1.21/year for higher vs. lower lacunar burden groups; and -0.59/year

vs. -1.03/year for higher vs. lower microbleed burden groups.

The rate of CDR SOB increase was 0.84/year vs. 0.92/year for the higher vs. lower WMH

burden group; 0.35/year vs. 1.20/year for the higher vs. lower lacunar burden group; and

0.45/year vs. 1.10/year for higher vs. lower microbleed burden.

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