SUPPLEMENTAL METHODS

Exclusion of subjects

We excluded subjects with structural lesions in brain magnetic resonance (MR) imaging such as territorial infarction, intracranial hemorrhage, brain tumor, hydrocephalus or severe white matter hyperintensities. We also excluded subjects with secondary causes of cognitive dysfunction assessed with laboratory tests including complete blood count, blood chemistry, vitamin B12, folate, syphilis serology, and thyroid function tests.

Neuropsychological tests

All patients underwent a standardized neuropsychological battery called the Seoul Neuropsychological Screening Battery.1, 2 The battery includes tests for attention, language, praxis, four elements of Gerstmann syndrome, visuoconstructive function, verbal and visual memory, frontal/executive function, CDR-SB, and the MMSE. These cognitive tests were used because they were scorable and most patients had undertaken them The tests included the backward digit span,3 the Korean version of the Boston Naming Test,4 the Rey-Osterrieth Complex Figure Test including tests for copying and 20-minute delayed recall,1 the Seoul Verbal Learning Test (SVLT) including a 20-minute delayed recall trial of 12 items,1 and the semantic Controlled Oral Word Association Tests (COWAT).5

REFERENCES

1. Kang Y, Na DL. Seoul Neuropsychological Screening Battery (SNSB). Incheon, South Korea: Human Brain Research & Consulting Co., 2003.

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. J Korean Med Sci 2010;25:1071-1076.

3. Kang YW, Jin JH, Chin JH, Na DL. A Normative study of the digit span test for the elderly. Korean J Clin Psychology 2002;21:911-922.

4. Kim H, Na DL. BRIEF REPORT Normative Data on the Korean Version of the Boston Naming Test. J Clin Exp Neuropsychol 1999;21:127-133.

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

Table e-1. Comparison of regional binding values corrected for partial volume effect in 18F-florbetaben and 18F- AV1451 PET scans

18F-florbetaben

SUVR

P-value

HC

MCI

AD

MCI > HC

AD > HC

AD > MCI

Global cortex

1.26

±

0.36

1.87

±

0.47

2.34

±

0.72

0.006

< 0.001

0.008

Prefrontal

1.39

±

0.47

2.09

±

0.61

2.70

±

0.84

0.010

< 0.001

0.004

Sensorimotor

1.32

±

0.26

1.82

±

0.40

2.24

±

0.69

0.019

< 0.001

0.011

Superior parietal

1.22

±

0.34

1.98

±

0.53

2.39

±

0.93

0.005

< 0.001

0.076

Inferior parietal

1.26

±

0.38

1.97

±

0.54

2.42

±

0.86

0.005

< 0.001

0.028

Precuneus

1.18

±

0.46

2.11

±

0.70

2.79

±

1.08

0.004

< 0.001

0.009

Occipital

1.10

±

0.33

1.60

±

0.37

1.97

±

0.65

0.018

< 0.001

0.050*

Superior temporal

1.17

±

0.36

1.71

±

0.48

2.12

±

0.66

0.010

< 0.001

0.018

Middle temporal

1.27

±

0.33

1.74

±

0.45

2.15

±

0.62

0.021

< 0.001

0.010

Inferior temporal

1.14

±

0.30

1.68

±

0.41

2.12

±

0.65

0.006

< 0.001

0.008

Hippocampus

1.08

±

0.09

1.16

±

0.10

1.20

±

0.11

0.149

< 0.001

0.358

Entorhinal

1.17

±

0.19

1.23

±

0.24

1.46

±

0.31

1.000

0.002

0.017

Parahippocampal

1.16

±

0.27

1.52

±

0.34

1.92

±

0.46

0.023

< 0.001

0.002

Anterior cingulate

1.48

±

0.51

2.15

±

0.62

2.76

±

0.81

0.013

< 0.001

0.003

Posterior cingulate

1.27

±

0.43

2.07

±

0.64

2.65

±

0.84

0.003

< 0.001

0.006

Striatum

1.07

±

0.26

1.43

±

0.32

1.67

±

0.46

0.015

< 0.001

0.038

Thalamus

1.40

±

0.15

1.48

±

0.18

1.63

±

0.23

0.808

< 0.001

0.009

18F-AV-1451

SUVR

P-value

HC

MCI

AD

MCI > HC

AD > HC

AD > MCI

Global cortex

1.35

±

0.10

1.50

±

0.23

2.09

±

0.72

0.678

< 0.001

< 0.001

Prefrontal

1.45

±

0.12

1.49

±

0.20

2.13

±

0.83

1.000

< 0.001

< 0.001

Sensorimotor

1.29

±

0.11

1.33

±

0.18

1.60

±

0.43

1.000

< 0.001

0.004

Superior parietal

1.35

±

0.18

1.50

±

0.26

2.33

±

1.29

1.000

< 0.001

0.001

Inferior parietal

1.34

±

0.15

1.53

±

0.26

2.43

±

1.21

0.900

< 0.001

< 0.001

Precuneus

1.33

±

0.14

1.48

±

0.34

2.60

±

1.40

1.000

< 0.001

< 0.001

Occipital

1.28

±

0.16

1.47

±

0.27

1.92

±

0.71

0.552

< 0.001

0.013

Superior temporal

1.25

±

0.11

1.40

±

0.19

1.90

±

0.62

0.652

< 0.001

< 0.001

Middle temporal

1.37

±

0.10

1.71

±

0.39

2.37

±

0.89

0.189

< 0.001

< 0.001

Inferior temporal

1.33

±

0.10

1.68

±

0.42

2.54

±

1.04

0.248

< 0.001

< 0.001

Hippocampus

1.18

±

0.18

1.53

±

0.37

1.64

±

0.27

0.003

< 0.001

0.703

Entorhinal

1.46

±

0.25

2.32

±

0.86

2.65

±

0.58

< 0.001

< 0.001

0.291

Parahippocampal

1.35

±

0.15

1.79

±

0.60

2.33

±

0.53

0.020*

< 0.001

0.002

Anterior cingulate

1.38

±

0.14

1.40

±

0.21

1.68

±

0.52

1.000

0.010

0.027

Posterior cingulate

1.32

±

0.12

1.50

±

0.39

2.25

±

0.94

0.785

< 0.001

< 0.001

Striatum

1.50

±

0.21

1.43

±

0.23

1.63

±

0.22

0.797

0.355

0.037

Thalamus

1.17

±

0.10

1.16

±

0.16

1.20

±

0.11

1.000

1.000

0.991

*Regions did not survive region-wise correction for multiple comparisons.

Data are presented as mean ± SD.

Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; HC = healthy controls; SUVR = standardized uptake value ratio

Table e-2. Comparison of regional binding values in 18F-florbetaben and 18F- AV1451 PET scans between the amyloid-negative controls and amyloid-positive MCI and AD.

18F-florbetaben

SUVR

P-value

HC

MCI

AD

MCI > HC

AD > HC

AD > MCI

Global cortex

1.22

±

0.06

1.75

±

0.17

1.90

±

0.29

< 0.001

< 0.001

0.008

Prefrontal

1.25

±

0.06

1.89

±

0.21

2.11

±

0.32

< 0.001

< 0.001

< 0.001

Sensorimotor

1.25

±

0.06

1.64

±

0.19

1.82

±

0.33

0.003

< 0.001

0.008

Superior parietal

1.17

±

0.07

1.75

±

0.19

1.82

±

0.38

< 0.001

< 0.001

0.275

Inferior parietal

1.20

±

0.08

1.81

±

0.22

1.93

±

0.36

< 0.001

< 0.001

0.078

Precuneus

1.22

±

0.07

2.00

±

0.23

2.16

±

0.46

< 0.001

< 0.001

0.034*

Occipital

1.19

±

0.05

1.57

±

0.13

1.67

±

0.28

< 0.001

< 0.001

0.202

Superior temporal

1.17

±

0.06

1.66

±

0.21

1.78

±

0.27

< 0.001

< 0.001

0.089

Middle temporal

1.14

±

0.06

1.64

±

0.21

1.77

±

0.25

< 0.001

< 0.001

0.031*

Inferior temporal

1.17

±

0.05

1.67

±

0.17

1.81

±

0.26

< 0.001

< 0.001

0.028*

Hippocampus

1.27

±

0.07

1.29

±

0.13

1.24

±

0.15

1.000

1.000

1.000

Entorhinal

1.07

±

0.06

1.23

±

0.17

1.28

±

0.15

0.117

< 0.001

0.149

Parahippocampal

1.15

±

0.05

1.46

±

0.14

1.56

±

0.21

< 0.001

< 0.001

0.040*

Anterior cingulate

1.33

±

0.10

1.97

±

0.25

2.24

±

0.31

< 0.001

< 0.001

< 0.001

Posterior cingulate

1.31

±

0.08

2.02

±

0.23

2.18

±

0.35

< 0.001

< 0.001

0.012

Striatum

1.38

±

0.06

1.78

±

0.17

1.93

±

0.28

< 0.001

< 0.001

0.011

Thalamus

1.51

±

0.10

1.64

±

0.16

1.73

±

0.20

0.733

< 0.001

0.037*

18F-AV-1451

SUVR

P-value

HC

MCI

AD

MCI > HC

AD > HC

AD > MCI

Global cortex

1.12

±

0.09

1.28

±

0.16

1.57

±

0.36

0.097

< 0.001

0.015*

Prefrontal

1.15

±

0.09

1.22

±

0.14

1.58

±

0.44

1.000

< 0.001

0.013*

Sensorimotor

1.04

±

0.09

1.09

±

0.14

1.25

±

0.23

0.501

< 0.001

0.156

Superior parietal

1.05

±

0.11

1.21

±

0.19

1.55

±

0.54

0.248

< 0.001

0.117

Inferior parietal

1.11

±

0.12

1.29

±

0.17

1.74

±

0.59

0.240

< 0.001

0.019*

Precuneus

1.13

±

0.10

1.30

±

0.22

1.81

±

0.62

0.270

< 0.001

0.013*

Occipital

1.08

±

0.10

1.23

±

0.18

1.44

±

0.33

0.079

< 0.001

0.250

Superior temporal

1.07

±

0.09

1.22

±

0.13

1.47

±

0.35

0.210

< 0.001

0.028*

Middle temporal

1.15

±

0.08

1.48

±

0.25

1.82

±

0.47

0.021*

< 0.001

0.035*

Inferior temporal

1.17

±

0.08

1.53

±

0.26

1.94

±

0.51

0.019*

< 0.001

0.019*

Hippocampus

1.27

±

0.19

1.57

±

0.24

1.51

±

0.23

0.002

0.007

0.786

Entorhinal

1.22

±

0.17

1.84

±

0.45

1.87

±

0.29

< 0.001

< 0.001

1.000

Parahippocampal

1.14

±

0.11

1.57

±

0.32

1.72

±

0.31

< 0.001

< 0.001

0.829

Anterior cingulate

1.17

±

0.10

1.23

±

0.14

1.40

±

0.32

1.000

0.008

0.235

Posterior cingulate

1.15

±

0.10

1.36

±

0.25

1.72

±

0.48

0.112

< 0.001

0.048*

Striatum

1.53

±

0.19

1.56

±

0.19

1.63

±

0.20

1.000

0.521

0.950

Thalamus

1.31

±

0.11

1.36

±

0.17

1.31

±

0.09

0.921

1.000

0.917

*Regions did not survive region-wise correction for multiple comparisons.

Data are presented as mean ± SD.

Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; HC = healthy controls; SUVR = standardized uptake value ratio

Table e-3. Comparison of regional binding values in 18F-florbetaben and 18F- AV1451 PET scans corrected for partial volume effect between the amyloid-negative controls and amyloid-positive MCI and AD.

18F-florbetaben

SUVR

P-value

HC

MCI

AD

MCI > HC

AD > HC

AD > MCI

Global cortex

1.17

±

0.08

2.14

±

0.26

2.54

±

0.57

< 0.001

< 0.001

0.002

Prefrontal

1.28

±

0.12

2.45

±

0.35

2.94

±

0.64

< 0.001

< 0.001

< 0.001

Sensorimotor

1.26

±

0.07

2.01

±

0.28

2.41

±

0.59

< 0.001

< 0.001

0.003

Superior parietal

1.14

±

0.10

2.25

±

0.34

2.63

±

0.80

< 0.001

< 0.001

0.059

Inferior parietal

1.17

±

0.10

2.26

±

0.35

2.66

±

0.68

< 0.001

< 0.001

0.014

Precuneus

1.07

±

0.11

2.52

±

0.40

3.08

±

0.88

< 0.001

< 0.001

0.004

Occipital

1.03

±

0.12

1.79

±

0.26

2.11

±

0.61

< 0.001

< 0.001

0.108

Superior temporal

1.09

±

0.07

1.98

±

0.32

2.30

±

0.52

< 0.001

< 0.001

0.023

Middle temporal

1.19

±

0.09

1.99

±

0.32

2.32

±

0.49

< 0.001

< 0.001

0.015

Inferior temporal

1.06

±

0.08

1.91

±

0.27

2.29

±

0.53

< 0.001

< 0.001

0.007

Hippocampus

1.06

±

0.07

1.19

±

0.09

1.21

±

0.11

0.003

< 0.001

1.000

Entorhinal

1.13

±

0.13

1.26

±

0.28

1.52

±

0.29

1.000

< 0.001

0.002

Parahippocampal

1.08

±

0.09

1.69

±

0.29

2.05

±

0.37

< 0.001

< 0.001

< 0.001

Anterior cingulate

1.37

±

0.18

2.47

±

0.46

3.00

±

0.61

< 0.001

< 0.001

< 0.001

Posterior cingulate

1.16

±

0.12

2.44

±

0.37

2.89

±

0.64

< 0.001

< 0.001

0.001

Striatum

1.01

±

0.09

1.57

±

0.22

1.79

±

0.40

< 0.001

< 0.001

0.017

Thalamus

1.36

±

0.12

1.55

±

0.18

1.67

±

0.22

0.247

< 0.001

0.017

18F-AV-1451

SUVR

P-value

HC

MCI

AD

MCI > HC

AD > HC

AD > MCI

Global cortex

1.35

±

0.11

1.61

±

0.20

2.21

±

0.72

0.158

< 0.001

0.007

Prefrontal

1.44

±

0.12

1.57

±

0.19

2.25

±

0.86

1.000

< 0.001

0.010

Sensorimotor

1.29

±

0.11

1.39

±

0.19

1.65

±

0.44

0.617

< 0.001

0.151

Superior parietal

1.36

±

0.16

1.61

±

0.26

2.50

±

1.33

0.529

< 0.001

0.056

Inferior parietal

1.35

±

0.14

1.65

±

0.24

2.61

±

1.23

0.351

< 0.001

0.009

Precuneus

1.32

±

0.13

1.61

±

0.34

2.81

±

1.42

0.426

< 0.001

0.007

Occipital

1.30

±

0.16

1.57

±

0.28

2.01

±

0.73

0.226

< 0.001

0.231

Superior temporal

1.26

±

0.11

1.50

±

0.14

1.98

±

0.64

0.258

< 0.001

0.012

Middle temporal

1.37

±

0.10

1.89

±

0.34

2.53

±

0.88

0.041*

< 0.001

0.020

Inferior temporal

1.32

±

0.10

1.88

±

0.36

2.74

±

1.01

0.061

< 0.001

0.008

Hippocampus

1.18

±

0.19

1.69

±

0.33

1.66

±

0.30

< 0.001

< 0.001

1.000

Entorhinal

1.45

±

0.26

2.73

±

0.77

2.77

±

0.54

< 0.001

< 0.001

1.000

Parahippocampal

1.35

±

0.16

2.08

±

0.53

2.44

±

0.49

< 0.001

< 0.001

0.182

Anterior cingulate

1.37

±

0.15

1.46

±

0.21

1.73

±

0.54

1.000

0.013

0.205

Posterior cingulate

1.30

±

0.12

1.65

±

0.39

2.40

±

0.94

0.157

< 0.001

0.018

Striatum

1.51

±

0.22

1.52

±

0.22

1.62

±

0.23

1.000

0.432

0.616

Thalamus

1.15

±

0.09

1.21

±

0.17

1.19

±

0.11

0.755

1.000

1.000

*Regions did not survive region-wise correction for multiple comparisons.

Data are presented as mean ± SD.

Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; HC = healthy controls; SUVR = standardized uptake value ratio

Table e-4. Comparison of regional binding values in 18F-florbetaben and 18F- AV1451 PET scans between the early- and late-onset AD patients

18F-florbetaben

18F-AV-1451

SUVR

P-value

SUVR

P-value

EOAD

LOAD

EOAD > LOAD

EOAD

LOAD

EOAD > LOAD

Global cortex

1.92

±

0.24

1.74

±

0.42

0.830

1.92

±

0.24

1.33

±

0.25

0.002

Prefrontal

2.11

±

0.24

1.92

±

0.50

0.707

1.91

±

0.33

1.35

±

0.37

0.034*

Sensorimotor

1.80

±

0.27

1.70

±

0.42

0.547

1.49

±

0.19

1.10

±

0.12

< 0.001

Superior parietal

1.78

±

0.33

1.68

±

0.49

0.552

2.16

±

0.44

1.18

±

0.21

< 0.001

Inferior parietal

1.94

±

0.33

1.75

±

0.49

0.962

2.36

±

0.48

1.34

±

0.29

< 0.001

Precuneus

2.09

±

0.41

1.99

±

0.62

0.494

2.43

±

0.42

1.39

±

0.39

< 0.001

Occipital

1.75

±

0.27

1.54

±

0.31

0.640

1.79

±

0.14

1.21

±

0.20

< 0.001

Superior temporal

1.84

±

0.22

1.61

±

0.37

0.615

1.73

±

0.37

1.29

±

0.25

0.028*

Middle temporal

1.81

±

0.18

1.61

±

0.37

0.854

2.12

±

0.37

1.56

±

0.44

0.069

Inferior temporal

1.86

±

0.21

1.65

±

0.37

0.843

2.31

±

0.42

1.62

±

0.45

0.039*

Hippocampus

1.24

±

0.22

1.22

±

0.12

0.121

1.52

±

0.20

1.48

±

0.23

0.684

Entorhinal

1.25

±

0.13

1.23

±

0.20

0.704

1.91

±

0.23

1.75

±

0.36

0.329

Parahippocampal

1.55

±

0.22

1.47

±

0.27

0.985

1.81

±

0.27

1.58

±

0.34

0.207

Anterior cingulate

2.25

±

0.27

2.04

±

0.49

0.847

1.46

±

0.25

1.32

±

0.34

0.557

Posterior cingulate

2.13

±

0.30

2.01

±

0.52

0.506

2.10

±

0.29

1.43

±

0.41

0.015

Striatum

1.97

±

0.27

1.78

±

0.34

0.824

1.57

±

0.20

1.65

±

0.19

0.992

Thalamus

1.69

±

0.22

1.71

±

0.19

0.470

1.31

±

0.07

1.33

±

0.11

0.685

Two AD groups were compared after adjusting the years of education and MMSE scores.

*Regions did not survive region-wise correction for multiple comparisons.

Data are presented as mean ± SD.

Abbreviations: AD = Alzheimer’s disease; EOAD = early-onset Alzheimer’s disease; LOAD = late-onset Alzheimer’s disease; SUVR = standardized uptake value ratio

Table e-5. Comparison of regional binding values in 18F-florbetaben and 18F- AV1451 PET scans between the patients with and without Apo ε4 genotype

18F-florbetaben

18F-AV-1451

SUVR

P-value

SUVR

P-value

ε4 -

ε4 +

ε4 + > ε4 -

ε4 -

ε4 +

ε4 + > ε4 -

Global cortex

1.62

±

0.38

1.79

±

0.29

0.196

1.31

±

0.33

1.44

±

0.33

0.441

Prefrontal

1.74

±

0.45

1.96

±

0.36

0.152

1.30

±

0.33

1.44

±

0.43

0.456

Sensorimotor

1.58

±

0.33

1.70

±

0.33

0.379

1.13

±

0.21

1.17

±

0.21

0.884

Superior parietal

1.56

±

0.41

1.75

±

0.34

0.169

1.31

±

0.50

1.35

±

0.42

0.779

Inferior parietal

1.61

±

0.43

1.84

±

0.32

0.114

1.38

±

0.51

1.55

±

0.52

0.592

Precuneus

1.76

±

0.51

2.06

±

0.44

0.091

1.42

±

0.52

1.60

±

0.57

0.550

Occipital

1.52

±

0.31

1.56

±

0.21

0.810

1.30

±

0.34

1.27

±

0.22

0.455

Superior temporal

1.51

±

0.36

1.69

±

0.26

0.162

1.22

±

0.27

1.40

±

0.33

0.146

Middle temporal

1.49

±

0.36

1.68

±

0.27

0.136

1.45

±

0.43

1.70

±

0.45

0.181

Inferior temporal

1.55

±

0.36

1.70

±

0.22

0.228

1.54

±

0.54

1.72

±

0.43

0.461

Hippocampus

1.21

±

0.14

1.27

±

0.12

0.272

1.37

±

0.23

1.57

±

0.20

0.020*

Entorhinal

1.19

±

0.19

1.23

±

0.15

0.553

1.57

±

0.39

1.86

±

0.36

0.045*

Parahippocampal

1.38

±

0.25

1.48

±

0.19

0.267

1.40

±

0.34

1.67

±

0.32

0.046*

Anterior cingulate

1.87

±

0.48

2.06

±

0.37

0.272

1.21

±

0.19

1.36

±

0.32

0.172

Posterior cingulate

1.84

±

0.47

2.04

±

0.37

0.201

1.37

±

0.37

1.59

±

0.49

0.247

Striatum

1.73

±

0.35

1.80

±

0.25

0.692

1.55

±

0.20

1.57

±

0.20

0.770

Thalamus

1.62

±

0.18

1.69

±

0.19

0.361

1.31

±

0.15

1.33

±

0.10

0.622

In 34 MCI and AD patients whose ApoE genotypes were available, 17 patients had ApoE ε4 and the other 17 patients did not. We compared 17 ApoE ε4 positive and 17 negative patients after controlling for age and years of education.

*Regions did not survive region-wise correction for multiple comparisons.

Data are presented as mean ± SD.

Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; HC = healthy controls; SUVR = standardized uptake value ratio

Table e-6. Voxel-based comparison results

Cluster-level

Peak-level

Pcorrcected

KE

Puncorrected

T-value

MNI coordinates

Regions

MCI > HC in 18F-florbetaben PET

< 0.001

39991

< 0.001

4.66

50, -65, -13

right middle occipital

< 0.001

56417

< 0.001

4.56

-29, -68, 51

left superior parietal

0.006

13816

< 0.001

4.13

43, 19, 49

right middle frontal

0.022

10337

< 0.001

3.92

-49, -65, -9

left inferior temporal

AD > HC in 18F-florbetaben PET

< 0.001

1105992

< 0.001

7.80

32, -46, -24

right fusiform

AD > HC in 18F-AV-1451 PET

< 0.001

1040297

< 0.001

7.52

-63, -53, -2

left middle temporal

PET images normalized to 1mm MNI space were used for voxel-based comparison analysis.

Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; HC = healthy controls; KE = number of voxels in cluster; MNI = Montreal Neurological Institute

1

Table e-7. Correlation between the regional binding values and cognition in 35 patients with MCI and AD

18F-florbetaben

CDR-SB

MMSE

DS-B

BNT

RCFT

SVLT-DR

RCFT-DR

COWAT-S

Global cortex

0.286

-0.459a

0.176

-0.255

0.187

-0.402a

-0.290

-0.042

Prefrontal

0.354a*

-0.506b

0.147

-0.202

0.201

-0.424a

-0.339

-0.099

Superior parietal

0.129

-0.337a*

0.045

-0.228

0.155

-0.357a*

-0.256

-0.025

Inferior parietal

0.140

-0.327

0.182

-0.249

0.177

-0.418a

-0.299

-0.016

Precuneus

0.184

-0.368a

0.154

-0.249

0.120

-0.422a

-0.299

-0.040

Occipital

0.227

-0.399a

0.150

-0.338

0.016

-0.230

-0.113

0.013

Superior temporal

0.206

-0.367a

0.263

-0.230

0.163

-0.423a

-0.300

0.019

Middle temporal

0.299

-0.417a

0.256

-0.246

0.229

-0.471a

-0.327

-0.038

Inferior temporal

0.286

-0.437a

0.227

-0.330

0.250

-0.418a

-0.293

-0.026

Hippocampus

-0.577b

0.472b

0.004

-0.084

-0.101

-0.208

-0.213

-0.083

Entorhinal

0.039

-0.248

-0.089

0.016

0.277

-0.189

-0.191

0.077

Parahippocampal

0.130

-0.273

0.208

-0.271

0.236

-0.341

-0.217

0.036

Anterior cingulate

0.379a*

-0.507b

0.163

-0.142

0.178

-0.408a

-0.319

-0.056

Posterior cingulate

0.297

-0.443a

0.193

-0.210

0.199

-0.422a

-0.312

-0.050

18F-AV-1451

CDR-SB

MMSE

DS-B

BNT

RCFT

SVLT-DR

RCFT-DR

COWAT-S

Global cortex

0.550b

-0.563b

0.074

-0.006

-0.094

-0.427a

-0.490b

-0.264

Prefrontal

0.555b

-0.499b

0.177

-0.013

-0.015

-0.322

-0.300

-0.192

Superior parietal

0.484b

-0.545b

-0.289

0.172

-0.380a*

-0.242

-0.463a

-0.288

Inferior parietal

0.478b

-0.537b

-0.078

0.107

-0.321

-0.365a*

-0.476a

-0.196

Precuneus

0.512b

-0.548b

-0.031

0.089

-0.257

-0.362a*

-0.403a

-0.263

Occipital

0.679b

-0.724b

0.009

0.023

-0.022

-0.288

-0.444a

-0.334

Superior temporal

0.433a

-0.439a

0.108

-0.028

-0.125

-0.468a

-0.482b

-0.167

Middle temporal

0.418a

-0.427a

0.180

-0.162

0.044

-0.523b

-0.448a

-0.278

Inferior temporal

0.422a

-0.501b

0.121

-0.210

0.017

-0.433a

-0.406a

-0.254

Hippocampus

0.020

-0.136

0.272

-0.097

0.214

-0.431a

-0.649b

-0.068

Entorhinal

0.185

-0.226

0.191

-0.092

0.333

-0.527b

-0.634b

-0.126

Parahippocampal

0.233

-0.289

0.177

-0.176

0.123

-0.524b

-0.586b

-0.173

Anterior cingulate

0.298

-0.239

0.255

-0.123

0.126

-0.334

-0.278

-0.206

Posterior cingulate

0.488b

-0.486b

0.124

0.016

-0.066

-0.451a

-0.450a

-0.272

aP < 0.05, bP < 0.005; *Region did not survive region-wise correction for multiple comparisons.

Correlation analyses between the binding values and the global cognitive scales (CDR-SB and MMSE scores) were performed in 35 patients with MCI and AD after controlling for age and education. The correlation analyses of the tests for each cognitive domain were performed after controlling for age and years of education and global cognitive scale (MMSE score) as well. Data are presented with correlation coefficients.

Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; CDR-SB = Clinical Dementia Rating sum-of-boxes; MMSE = Mini-Mental State Examination; DS-B = Digit Span: Backward; BNT = Boston Naming Test; RCFT = Rey-Osterrieth Complex Figure Test; SVLT-DR = Seoul Verbal Learning Test: Delayed Recall; RCFT-DR = Rey-Osterrieth Complex Figure Test: Delayed Recall; COWAT-S = Controlled Oral Word Association Test: Semantics; r = correlation coefficient

Table e-8. Correlation between the regional binding values and cognition in 27 amyloid-positive patients with MCI and AD

18F-florbetaben

CDR-SB

MMSE

DS-B

BNT

RCFT

SVLT-DR

RCFT-DR

COWAT-S

Global cortex

0.237

-0.521a

0.195

-0.503a*

0.182

-0.350

-0.072

-0.007

Prefrontal

0.343

-0.583b

0.117

-0.446

0.186

-0.435a*

-0.165

-0.138

Superior parietal

0.028

-0.377

-0.026

-0.388a*

0.118

-0.213

-0.059

0.033

Inferior parietal

0.028

-0.326

0.207

-0.450a*

0.170

-0.356

-0.104

0.046

Precuneus

0.074

-0.368

0.138

-0.449a*

0.039

-0.379

-0.115

-0.004

Occipital

0.155

-0.424a

0.192

-0.437a*

-0.044

-0.020

0.154

0.111

Superior temporal

0.097

-0.330

0.313

-0.426a*

0.149

-0.390

-0.118

0.086

Middle temporal

0.235

-0.451a

0.376

-0.409a*

0.339

-0.458a*

-0.138

0.024

Inferior temporal

0.222

-0.499a

0.371

-0.452a*

0.425a*

-0.351

-0.051

0.070

Hippocampus

-0.605b

0.561b

-0.034

-0.152

-0.137

-0.271

-0.159

-0.063

Entorhinal

-0.024

-0.211

-0.259

-0.006

0.282

-0.065

-0.022

0.162

Parahippocampal

0.010

-0.229

0.234

-0.374

0.278

-0.238

0.028

0.111

Anterior cingulate

0.385a*

-0.564b

0.116

-0.355

0.079

-0.396

-0.144

-0.091

Posterior cingulate

0.259

-0.487a

0.189

-0.436a*

0.156

-0.408

-0.137

-0.047

18F-AV-1451

CDR-SB

MMSE

DS-B

BNT

RCFT

SVLT-DR

RCFT-DR

COWAT-S

Global cortex

0.502a

-0.506a

0.038

0.010

-0.119

-0.428a*

-0.442a*

-0.307

Prefrontal

0.510a

-0.429a*

0.172

-0.038

-0.006

-0.326

-0.253

-0.214

Superior parietal

0.414a*

-0.493a

-0.399a*

0.327

-0.487a*

-0.176

-0.430a*

-0.333

Inferior parietal

0.409a*

-0.481a

-0.132

0.205

-0.407a*

-0.330

-0.445a*

-0.221

Precuneus

0.444a*

-0.489a

-0.076

0.169

-0.311

-0.345

-0.366

-0.304

Occipital

0.675b

-0.716b

-0.039

0.111

-0.022

-0.231

-0.362

-0.378

Superior temporal

0.360

-0.353

0.091

-0.047

-0.150

-0.495a

-0.452a*

-0.181

Middle temporal

0.339

-0.346

0.174

-0.257

0.045

-0.530a

-0.383

-0.325

Inferior temporal

0.343

-0.445a

0.100

-0.300

0.005

-0.401a*

-0.308

-0.299

Hippocampus

-0.086

0.003

0.252

-0.090

0.249

-0.552b

-0.630b

-0.117

Entorhinal

0.034

-0.072

0.137

-0.171

0.403a*

-0.571b

-0.587b

-0.170

Parahippocampal

0.075

-0.145

0.148

-0.258

0.146

-0.578b

-0.534b

-0.213

Anterior cingulate

0.231

-0.139

0.248

-0.193

0.151

-0.380

-0.220

-0.227

Posterior cingulate

0.415a*

-0.406a*

0.106

0.045

-0.070

-0.475a

-0.411a*

-0.318

aP < 0.05, bP < 0.005; *Regions did not survive region-wise correction for multiple comparisons.

Correlation analyses between the binding values and the global cognitive scales (CDR-SB and MMSE scores) were performed in 27 amyloid-positive patients with MCI and AD after controlling for age and education. The correlation analyses of the tests for each cognitive domain were performed after controlling for age and years of education and global cognitive scale (MMSE score) as well. Data are presented with correlation coefficients.

Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; CDR-SB = Clinical Dementia Rating sum-of-boxes; MMSE = Mini-Mental State Examination; DS-B = Digit Span: Backward; BNT = Boston Naming Test; RCFT = Rey-Osterrieth Complex Figure Test; SVLT-DR = Seoul Verbal Learning Test: Delayed Recall; RCFT-DR = Rey-Osterrieth Complex Figure Test: Delayed Recall; COWAT-S = Controlled Oral Word Association Test: Semantics; r = correlation coefficient

Table e-9. Correlation between the regional binding values and volumes

18F-florbetaben

18F-AV-1451

r

P-value

r

P-value

Global cortex

-0.312

0.068

-0.539

< 0.001

Prefrontal

-0.339

0.046*

-0.588

< 0.001

Sensorimotor

-0.104

0.553

-0.451

0.007

Superior parietal

-0.156

0.370

-0.587

< 0.001

Inferior parietal

-0.313

0.067

-0.635

< 0.001

Precuneus

-0.339

0.046*

-0.548

< 0.001

Occipital

-0.210

0.225

-0.582

< 0.001

Superior temporal

-0.143

0.411

-0.329

0.054

Middle temporal

-0.286

0.096

-0.384

0.023

Inferior temporal

-0.387

0.021*

-0.461

0.005

Hippocampus

0.555

< 0.001

-0.199

0.253

Entorhinal

0.041

0.814

-0.150

0.390

Parahippocampal

-0.140

0.423

-0.133

0.447

Anterior cingulate

-0.068

0.700

0.059

0.737

Posterior cingulate

-0.377

0.026*

-0.363

0.032*

Striatum

-0.021

0.903

-0.281

0.101

Thalamus

0.183

0.292

-0.171

0.327

*Region did not survive region-wise correction for multiple comparisons.

Correlation analysis was performed in 35 patients with MCI and AD after adjusting for age and education.

Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; r = correlation coefficient

Figure e-1. Averaged standardized uptake value ratio images of 18F-florbetaben and 18F- AV-1451 PET scans

Color bars represent SUVR values.

Abbreviations: Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; HC = healthy controls; SUVR = standardized uptake value ratio

Figure e-2. Demonstration of 18F-florbetaben PET images

The 18F-florbetaben PET images of the subjects shown in the Figure 2 are displayed. Cortical amyloid uptake does not clearly reflect the severity of cognition.

Color bar represents standardized uptake value ratio (SUVR).

Abbreviations: AD = Alzheimer’s disease; MCI = mild cognitive impairment; HC = healthy controls, CDR-SB = Clinical Dementia Rating, CDR-SB = Clinical Dementia Rating sum-of-boxes; MMSE = Mini-Mental State Examination score

1

SUPPLEMENTAL METHODS

Exclusion of s

ubjects

We excluded subjects with structural lesions

in

brain

magnetic resonance (MR) imaging

such as territorial infarction, intracranial hemorrhage, brain tumor, hydrocephalus or severe

white matter hyperintensities.

We

also excluded subjects with s

econdary causes of cognitive

d

ysfunction

assessed

with

laboratory tests including

complete blood count, blood chemistry,

vitamin B12, folate, syphilis serology, and thyroid function tests.

Neuropsychological tests

All patient

s underwent a standardized neuropsychological battery called the Seoul

Neuropsychological Screening Battery.

1

,

2

The b

attery

include

s

tests for attention, language,

praxis, four elements of Gerstmann syndrome, visuoconstructive function, verbal and visual

memory, frontal/executive function

, CDR

-

SB,

and the MMSE.

These

cognitive tests

were

used

because

they were scorable a

nd

most patients had

undertaken them

The tests

included

the

backward

d

igit

s

pan

,

3

the Korean version of the Boston Naming Test

,

4

the

Rey

-

Osterrieth

Complex Figure Test

including tests for

copying and 20

-

minute delayed recall

,

1

the Seoul Verbal

Learning Test (SVLT)

including

a 20

-

min

ute delayed recall trial of 12 items

,

1

and the

semantic

Controlled Oral Word Association Tests (COWAT)

.

5

REFERENCES

1.

Kang Y, Na DL. Seoul Neuropsychological Screening Battery (SNSB). Incheon, South Korea:

Human Brain Research & Consulting Co., 2003.

1

SUPPLEMENTAL METHODS

Exclusion of subjects

We excluded subjects with structural lesions in brain magnetic resonance (MR) imaging

such as territorial infarction, intracranial hemorrhage, brain tumor, hydrocephalus or severe

white matter hyperintensities. We also excluded subjects with secondary causes of cognitive

dysfunction assessed with laboratory tests including complete blood count, blood chemistry,

vitamin B12, folate, syphilis serology, and thyroid function tests.

Neuropsychological tests

All patients underwent a standardized neuropsychological battery called the Seoul

Neuropsychological Screening Battery.

1, 2

The battery includes tests for attention, language,

praxis, four elements of Gerstmann syndrome, visuoconstructive function, verbal and visual

memory, frontal/executive function, CDR-SB, and the MMSE. These cognitive tests were used

because they were scorable and most patients had undertaken them The tests included the

backward digit span,

3

the Korean version of the Boston Naming Test,

4

the Rey-Osterrieth

Complex Figure Test including tests for copying and 20-minute delayed recall,

1

the Seoul Verbal

Learning Test (SVLT) including a 20-minute delayed recall trial of 12 items,

1

and the semantic

Controlled Oral Word Association Tests (COWAT).

5

REFERENCES

1. Kang Y, Na DL. Seoul Neuropsychological Screening Battery (SNSB). Incheon, South Korea:

Human Brain Research & Consulting Co., 2003.