Identification of Pure Subcortical Vascular Dementia Using ...



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 burden |

| |Higher |Lower |p-valueb |

| |Higher (N = 21) |Lower (N = 40) |p-valuea |Higher (N = 21) |

|Neuropsychological tests |β (SE) |p-value |β (SE) |

|Neuropsychological tests |β (SE) |p-value |β (SE) |p-value |β (SE) |p-value |

|Attention | | | | | | |

|Digit span forward |0.12 (0.06) |0.046 |-0.04 (0.06) |0.461 |0.11 (0.06) |0.062 |

|Digit span backward |0.07 (0.09) |0.461 |0.04 (0.09) |0.642 |-0.0005 (0.08) |0.996 |

|Language | | | | | | |

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

|Visuospatial function | | | | | | |

|RCFT copy |-0.28 (0.25) |0.271 |-0.19 (0.22) |0.400 |0.07 (0.13) |0.565 |

|Verbal Memory | | | | | | |

|SVLT Immediate recall |0.03 (0.12) |0.763 |-0.24 (0.10) |0.018 |0.04 (0.09) |0.686 |

|SVLT 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) |< 0.001 |

|Visual Memory | | | | | | |

|RCFT Immediate recall |-0.22 (0.31) |0.475 |0.30 (0.74) |0.689 |-0.003 (0.29) |0.991 |

|RCFT Delayed recall |0.16 (0.45) |0.718 |0.04 (0.40) |0.912 |0.47 (0.37) |0.204 |

|RCFT Recognition: |-0.03 (0.05) |0.510 |-0.04 (0.04) |0.346 |-0.02 (0.05) |0.657 |

|Frontal/executive function | | | | | | |

|COWAT Animals |-0.26 (0.12) |0.032 |0.34 (0.45) |0.452 |-0.25 (0.15) |0.093 |

|COWAT Supermarket |-0.34 (0.17) |0.047 |0.29 (0.18) |0.098 |-0.30 (0.30) |0.318 |

|COWAT Phonemic fluency |-0.68 (0.40) |0.092 |0.07 (0.17) |0.678 |0.07 (0.17) |0.708 |

|Stroop 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) |0.046 |

|CDR SOB |-0.13 (0.07) |0.074 |0.01 (0.10) |0.933 |0.17 (0.06) |0.005 |

Abbreviations: 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) |0.362 |

| |Lower WMH burden |-0.07 (0.07) |0.316 |

|SVLT immediate recall |Higher lacunar burden |-0.16 (0.09) |0.080 |

| |Lower lacunar burden |-0.05 (0.06) |0.440 |

|SVLT delayed recall |Higher lacunar burden |-0.14 (0.32) |0.657 |

| |Lower lacunar burden |1.19 (0.53) |0.025 |

|SVLT recognition |Higher lacunar burden |-0.03 (0.03) |0.324 |

| |Lower lacunar burden |0.02 (0.02) |0.464 |

|COWAT animal |Higher WMH burden |-0.23 (0.10) |0.017 |

| |Lower WMH burden |0.08 (0.16) |0.593 |

|COWAT supermarket |Higher WMH burden |-0.39 (0.13) |0.002 |

| |Lower WMH burden |-0.09 (0.12) |0.429 |

|CDR SOB |Higher microbleed burden |0.26 (0.04) |< 0.001 |

| |Lower 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-value |

|Digit span forward |Global PiB retention ratio |-0.07 (0.05) |0.118 |

| |Higher microbleed burden |-0.21 (0.09) |0.022 |

| |Interaction (PiB × microbleed) |0.13 (0.06) |0.020 |

|Digit span backward |Global PiB retention ratio |-0.09 (0.05) |0.057 |

| |Higher lacunar burden |0.07(0.04) |0.064 |

|K-BNT |Global PiB retention ratio |-0.08 (0.05) |0.089 |

| |Higher lacunar burden |0.03 (0.03) |0.333 |

|RCFT copy |Global PiB retention ratio |-0.17 (0.09) |0.055 |

| |Higher WMH burden |-0.24 (0.07) |< 0.001 |

| |Higher lacunar burden |-0.02 (0.19) |0.900 |

| |Interaction (PiB × Lacunar) |-0.02 (0.15) |0.890 |

|SVLT immediate recall |Global PiB retention ratio |-0.10 (0.06) |0.072 |

| |Higher lacunar burden |-0.03 (0.05) |0.525 |

|SVLT delayed recall |Global PiB retention ratio |0.63 (0.27) |0.021 |

|SVLT recognition |Global PiB retention ratio |0.03 (0.03) |0.326 |

| |Higher lacunar burden |0.12 (0.09) |0.149 |

| |Interaction (PiB × Lacunar) |-0.12 (0.05) |0.017 |

|RCFT recognition |Higher WMH burden |-0.05 (0.02) |0.006 |

|COWAT animal |Global PiB retention ratio |0.02 (0.08) |0.805 |

| |Higher WMH burden |0.27 (0.18) |0.119 |

| |Interaction (PiB × WMH) |-0.27 (0.12) |0.031 |

|COWAT supermarket |Higher WMH burden |-0.24 (0.10) |0.016 |

| |Higher lacunar burden |0.12 (0.07) |0.087 |

|COWAT phonemic |Higher WMH burden |-0.36 (0.10) |< 0.001 |

| |Higher lacunar burden |0.09 (0.07) |0.196 |

|MMSE |Global PiB retention ratio |-0.10 (0.03) |0.002 |

| |Higher WMH burden |-0.08 (0.03) |0.004 |

|CDR SOB |Global PiB retention ratio |0.14 (0.03) |< 0.001 |

Abbreviations: 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 change

|Neuropsychological tests |Predictor |β (SE) |p-value |

|Digit span forward |PiB-positivity |-0.11 (0.05) |0.018 |

| |Higher WMH burden |-0.02 (0.06) |0.719 |

| |Interaction (PiB x WMH) |0.16 (0.08) |0.042 |

|K-BNT |PiB-positivity |-0.13 (0.04) |0.003 |

|RCFT Recognition |PiB-positivity |-0.07 (0.04) |0.078 |

| |Higher WMH burden |-0.06 (0.03) |0.0503 |

|COWAT animals |Higher microbleed burden |-0.16 (0.07) |0.016 |

|COWAT supermarket |Higher lacunar burden |0.17 (0.08) |0.035 |

|COWAT phonemic |PiB-positivity |0.21 (0.11) |0.073 |

| |Higher WMH burden |-0.02 (0.30) |0.934 |

| |Interaction (PiB x WMH) |-1.16 (0.32) |< 0.001 |

|MMSE |PiB-positivity |-0.15 (0.07) |0.042 |

| |Higher microbleed burden |-0.01 (0.04) |0.879 |

| |Interaction (PiB x microbleed) |0.27 (0.09) |0.003 |

|CDR SOB |PiB-positivity |0.18 (0.06) |0.002 |

Abbreviations: 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 (). 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.

eReferences

1. Fazekas F, Kleinert R, Offenbacher H, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 1993;43:1683-1689.

2. Ahn HJ, Chin J, Park A, et al. Seoul Neuropsychological Screening Battery-dementia version (SNSB-D): a useful tool for assessing and monitoring cognitive impairments in dementia patients. Journal of Korean medical science 2010;25:1071-1076.

3. Kim H, Na DL. Normative data on the Korean version of the Boston Naming Test. Journal of clinical and experimental neuropsychology 1999;21:127-133.

4. Kang Y, Na DL. Seoul Neuropsychological Screening Battery: Professional Manual. Seoul: Human Brain Research & Consulting Co., 2003.

5. Kang Y, Chin J, Na DL, Lee J, Park J. A normative study of the Korean version of Controlled Oral Word Association Test (COWAT) in the elderly. Korean J Clin Psychol 2000;19:385-392.

6. Lee J, Kang Y, Na DL. Efficiencies of Stroop interference indexes in healthy older adults and dementia patients. Korean J Clin Psychol 2000;19:801-818.

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