journal of nuclear medicine, published on march 29, 2019...

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Progressive tau accumulation in Alzheimer’s disease: two-year follow-up study

Hanna Cho,1 Jae Yong Choi,2,3 Hye Sun Lee,4 Jae Hoon Lee,2

Young Hoon Ryu,2 Myung Sik Lee,1 Clifford R. Jack, Jr.,5 Chul Hyoung Lyoo1

1Department of Neurology, Gangnam Severance Hospital, Yonsei University College of

Medicine, Seoul, South Korea 2Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of

Medicine, Seoul, South Korea 3Division of RI-Convergence Research, Korea Institute Radiological and Medical Sciences,

Seoul, South Korea 4Biostatistics Collaboration Unit, Gangnam Severance Hospital, Yonsei University College of

Medicine, Seoul, South Korea 5Department of Radiology, Mayo Clinic, Rochester, MN, USA

Running Title: Longitudinal tau PET in AD

Corresponding author: Chul Hyoung Lyoo, M.D., Ph.D. Professor Department of Neurology Gangnam Severance Hospital Yonsei University College of Medicine 20 Eonjuro 63-gil, Gangnam-gu, Seoul, South Korea Email: [email protected] Tel: +82-2-2019-3326 Fax: +82-2-3462-5904

First author: Hanna Cho, M.D., Ph.D. Assistant Professor Department of Neurology Gangnam Severance Hospital Yonsei University College of Medicine 20 Eonjuro 63-gil, Gangnam-gu, Seoul, South Korea Email: [email protected] Tel: +82-2-2019-3327 Fax: +82-2-3462-5904

Character count for Title: 77

Word count for Abstract: 337

Word count for Main Text: 5254

Word count for Manuscript: 8232

Journal of Nuclear Medicine, published on March 29, 2019 as doi:10.2967/jnumed.118.221697by on April 23, 2020. For personal use only. jnm.snmjournals.org Downloaded from

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FUNDING

This research was supported by Basic Science Research Program through the National Research

Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-

2017R1A2B2006694), funded by the Ministry of Education (NRF-2018R1D1A1B07049386),

and a grant of the Korea Health Technology R&D Project through the Korea Health Industry

Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea

(grant number : HI18C1159), and a faculty research grant of Yonsei University College of

Medicine for (6-2018-0068).

by on April 23, 2020. For personal use only. jnm.snmjournals.org Downloaded from


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ABSTRACT

Background: Tau positron emission tomography (PET) enabled in vivo visualization and

quantitation of tau pathology in Alzheimer disease (AD). In cross-sectional tau PET studies, tau

burden reflected disease severity and phenotypic variation. We investigated longitudinal change

in cortical tau accumulation and its associations with cognitive decline in patients with

Alzheimer disease (AD).

Methods: We enrolled 107 participants [45 amyloid β (Aβ)-negative cognitively unimpaired

(CU-), 7 Aβ-positive cognitively unimpaired (CU+), 31 prodromal AD (mild cognitive

impairment; MCI+), and 24 AD dementia (DEM+)] who completed two baseline PET scans

(18F-flortaucipir and 18F-florbetaben), magnetic resonance imaging, and neuropsychological tests.

All participants underwent the same assessments after two years. After correcting for partial

volume effect, standardized uptake value ratio (SUVR) images were created. By using a linear

mixed effect model, the changes in SUVR values across time points were investigated within

each group. We also investigated a correlation between the progression of tau accumulation and

cognitive decline.

Results: In contrast to no change in global cortical SUVR values in CU- and CU+ groups during

the two-year period, global cortical SUVR values increased by 0.06 (2.9%) in MCI+ and 0.19

(8.0%) in DEM+ at follow-up. MCI+ was associated with additional tau accumulation

predominantly in the medial and inferior temporal cortices, while the DEM+ showed increases in

the lateral temporal cortex. Progressive tau accumulation occurred in the diffuse cortical areas in

the MCI+ patients who developed dementia and DEM+ patients who showed deterioration of

global cognition, while there was only a small increase of additional tau accumulation in the

lateral temporal cortex in those who did not show worsening of cognition. Deterioration of



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global cognition and language functions was associated with the progression of tau accumulation

in the diffuse association neocortex.

Conclusions: Progressive tau accumulation occurs in prodromal AD and AD dementia patients

in the cortical areas at different levels of tau stages. Progression of cognitive dysfunction may be

related to the additional tau accumulation in regions for higher Braak’s stages. 18F-flortaucipir

PET is an imaging biomarker for monitoring the progression of AD.

KEY WORDS

Alzheimer’s disease, positron emission tomography, tau, 18F-flortaucipir, longitudinal study



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INTRODUCTION

Positron emission tomography (PET) imaging with tau-selective radiotracers enables in

vivo visualization and quantification of pathological tau protein in Alzheimer’s disease (AD) (1).

In the last three years, cross-sectional tau PET studies in AD have shown distinct binding

patterns corresponding to the known topographical distribution pattern of neurofibrillary tangle

(NFT) pathology and have been shown to reflect clinical and pathological disease severity and

phenotypic variations (2-10). For this reason, tau PET is now considered to be a useful imaging

biomarker for the diagnosis and disease severity in AD.

Two longitudinal tau PET studies from separate groups were recently published (11,12).

In one study, patients with cognitive impairment and Aβ-positivity showed an annual increase in

cortical standardized uptake value ratio (SUVR) by 0.053 (3%) in a large longitudinal 18F-

flortaucipir PET study involving 126 participants with a median time interval of 1.2 years

between the scans (11). The other large longitudinal 18F-flortaucipir PET study, in which 142

participants were followed up at 18 months after the baseline, showed an annual increase in

SUVR by about 0.05 with data-driven Parametric Estimation of Reference Signal Intensity

(PERSI) reference region in Aβ-positive AD patients (12).

In this study, we sought to investigate longitudinal changes in cortical 18F-flortaucipir

uptake over the course of two years in 107 individuals including healthy controls and patients

with prodromal AD and AD dementia. We also investigated the association between tau

propagation and Braak’s NFT stage and whether the progression of tau accumulation is

associated with concomitant cognitive decline.



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METHODS

Participants

For this longitudinal study, we included the participants who had completed baseline 18F-

flortaucipir PET scans at Gangnam Severance Hospital from January 2015 to July 2016 under

the previous tau PET study protocols (Supplemental Table 1). At baseline, all participants

underwent the neuropsychological tests, two PET scans [18F-flortaucipir for tau and 18F-

florbetaben for amyloid-β (Aβ)], and magnetic resonance (MR) imaging studies. Based on the

cognitive status, neuropsychological test performances and Aβ-positivity determined by

agreement of two nuclear medicine specialists using a validated visual assessment method for

18F-florbetaben PET (13,14), we selected the AD dementia (DEM) patients who fulfilled the

diagnostic criteria for “Probable AD dementia with evidence of the AD pathophysiological

process” (15) and mild cognitive impairment (MCI) patients who fulfilled the criteria for “MCI

due to AD with intermediate or high likelihood” proposed by the National Institute on Aging-

Alzheimer’s Association (16). A second diagnosis at follow-up was confirmed based on the same

diagnostic criteria. All AD patients initially presented with memory impairment without showing

atypical features suggesting posterior cortical atrophy, logopenic aphasia, or frontal-variant AD.

We also included healthy controls who were “cognitively unimpaired (CU)” by showing normal

performances on baseline neuropsychological tests and no abnormalities in brain MR imaging.

Finally, 107 participants were included in this longitudinal study, and we classified the

participants into four diagnostic groups [45 Aβ-negative CU (CU-), 7 Aβ-positive CU (CU+), 31

Aβ-positive MCI (MCI+), and 24 Aβ-positive DEM (DEM+)].

At follow-up, all participants underwent the same neuropsychological tests, PET scans,

and MR imaging studies as the baseline assessments. Apolipoprotein E (ApoE) genotypes were



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determined at baseline. Follow-up assessments were performed within 3 months from the

presumed date for the two-year follow-up.

This study was approved by the institutional review board of Gangnam Severance

Hospital and written informed consent was obtained from all subjects.

Neuropsychological Tests

Using the Seoul Neuropsychological Screening Battery, cognitive function was evaluated

at both baseline and follow-up (17). The battery includes scorable items for global cognitive

function and six cognitive domains: Korean version of the Mini-Mental State Examination

(MMSE) and Clinical Dementia Rating Sum of Boxes (CDR-SB), Digit Span Backward test

(DS-BW; attention), Boston Naming Test (BNT; language), Rey-Osterrieth Complex Figure Test

(RCFT; visuospatial function), Seoul Verbal Learning Test-Delayed Recall (SVLT-DR; verbal

memory), Rey-Osterrieth Complex Figure Test-Delayed Recall (RCFT-DR; visual memory), and

Controlled Oral Word Association Test-Semantics (COWAT; frontal/executive function).

Acquisition of PET and MR Images

All participants underwent 18F-flortaucipir and 18F-florbetaben PET scans on separate

days. At 80 mins (18F-flortaucipir) or 90 mins (18F-florbetaben) after the injection of radiotracers,

emission scans were acquired for 20 mins with a Biograph mCT PET/CT scanner (Siemens

Medical Solutions; Malvern, PA, USA) after applying a head holder to minimize head motion.

Prior to the PET scan, brain computed tomography images were acquired for later attenuation

correction. Finally, PET images were reconstructed in a 256×256×223 matrix with a



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1.591×1.591×1 mm voxel size by using the ordered-subsets expectation maximization algorithm

after attenuation and scatter correction.

T1-weighted MR images were also acquired with 3D-spoiled gradient-recalled sequences

(3D-SPGR sequences; repetition time = 8.28 ms, echo time = 1.6 to 11.0 ms, flip angle = 20°,

512×512 matrix, voxel spacing 0.43×0.43×1 mm) in a 3.0 Tesla MR scanner (Discovery MR750,

GE Medical Systems, Milwaukee, WI).

Image Processing Steps

We used Freesurfer 5.3 (Massachusetts General Hospital, Harvard Medical School;

http://surfer.nmr.mgh.harvard.edu) software for creating participant-specific volumes-of-interest

(VOIs), extracting surface structures, and measuring the cortical thickness as described in

previous study (2). By using the parcellated segments, we created participant-specific composite

VOI mask images including 16 cortical and 5 subcortical regions after merging anatomically

related regions. Regional volumes were measured by counting the voxels within each region.

Statistical parametric mapping 12 (Wellcome Trust Centre for Neuroimaging, London,

UK) and in-house software implemented in MATLAB R2015b (MathWorks, Natick, MA, USA)

were used to process the PET images and measure the regional uptake values. PET images were

coregistered to individual MR images. By using the masks for parcellated regions, the partial

volume effect (PVE) was corrected with the region-based voxel-wise method (18). For creating

standardized uptake value ratio (SUVR) images, we primarily used the cerebellar crus median

obtained by overlaying the template VOI for the cerebellar crus on the spatially normalized PET

images (11), and additionally used the PERSI reference region for 18F-flortaucipir PET studies

(12). Finally, by overlaying the participant-specific composite VOI masks, we measured regional



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SUVR values. We also measured 18F-flortaucipir SUVR values for the composite regions

corresponding to each Braak’s stage by volume-weighted average of VOI values. The

hippocampus was excluded due to known off-target binding of 18F-flortaucipir. We primarily

focused on the PVE-corrected data for analysis, but also analyzed the PVE-uncorrected data.

To obtain the participant-specific PERSI reference region, we selected the white matter

voxels with the intensity within the full width at half maximum range of imaginary non-specific

intensity curve obtained by fitting the white matter intensity histogram into the binominal

Gaussian distribution (12). Same PERSI reference VOI mask was used for creating both PVE-

uncorrected and corrected 18F-flortaucipir SUVR images.

Cortical uptake was also mapped on the white matter surface by overlaying the values of

voxels corresponding to the mid-point between a vertex on the white matter surface and the

corresponding vertex on gray matter surface. As with the volume-based correction for PVE, we

first created PVE-corrected surface maps and then created surface SUVR maps. Surface-based

SUVR and cortical thickness maps were spatially normalized to a template surface and smoothed

on the 2D-surface by Gaussian kernel with 8 mm full width at half maximum.

Statistical Analysis

SPSS 23 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis of

demographic data. Chi-square test and a correction for multiple comparisons with Bonferroni’s

method were used for the comparison of categorical variables. For the comparisons of

continuous demographic data and cognitive test performances, we used an ANOVA model with

Bonferroni’s post-hoc test. Performances on cognitive function tests were compared between the



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groups by using general linear model with age, gender, years of education and presence of ApoE

ε4 as covariates and Bonferroni’s method for correcting multiple comparisons.

We primarily analyzed longitudinal changes of cognitive test performances, regional

SUVR values and volumes in each group by using the linear mixed effect model implemented in

MATLAB with baseline age, gender, years of education, presence of ApoE ε4 allele, and time

interval between the baseline and follow-up as fixed factors and subject as random factor under

the assumption that the intercepts can be different between the subjects. Likewise, longitudinal

changes in the SUVR maps on the surface were analyzed with the same model in MATLAB. For

both VOI- and surface-based analysis, we chose random intercept model rather than random

intercept and slope model to reduce computational burden, and later confirmed no difference

between the results driven by two models.

For the correlation analysis assessing the change in SUVR value and cognitive function,

we used multiple regression model with the regional changes in SUVR value over the course of

the two-year follow-up period as independent variable and cognitive function as dependent

variable and with age, gender, years of education, and presence of ApoE ε4 allele as covariates.

For both VOI- and surface-based analysis, multiple comparisons were corrected by using

the Benjamini-Hochberg’s false-discovery rate (FDR) method (19).

RESULTS

Demographic Characteristics and Neuropsychological Tests

The demographic data and neuropsychological tests are summarized in Table 1. MCI+

and DEM+ groups were older than CU-. A higher proportion of females and longer disease



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duration were observed in the DEM+ group compared to MCI+. Frequency of ApoE ε4 carriers

was higher in the MCI+ and DEM+ groups than CU-. Years of education were not different

between the groups. All participants completed the baseline and follow-up assessments with an

average time interval of 24.0 ± 1.5 months. Mean time intervals were slightly shorter for the

MCI+ and DEM+ groups (23.7 and 23.1 months, respectively) compared to the CU- group

(mean 24.7 months).

During the two-year follow-up period, 10 of 45 CU- and 3 of 7 CU+ progressed to MCI

and 20 of the 31 MCI+ progressed to clinically-overt dementia. All 24 DEM+ remained in the

dementia state at follow-up. Meanwhile, 5 MCI+ patients reverted to normal cognition. 13

DEM+ showed a worsening in global cognition (decrease of MMSE score ≥ 3), while the other

11 DEM+ did not progress (decrease of MMSE score < 3).

At both baseline and follow-up, the DEM+ group performed significantly worse on all

neuropsychological tests compared to the CU- and on all tests other than the attention function

test when compared to CU+. When compared to MCI+, the DEM+ group showed worse

performances on the global cognition, visuospatial, and frontal/executive function tests at

baseline and follow-up, and on the attention and language functions at follow-up. With the

exception of the attention and visuospatial function tests at both baseline and follow-up, MCI+

showed worse performances than the CU-. When compared to CU+, MCI+ performed worse on

memory functions at baseline and follow-up. Three groups (CU-, MCI+ and DEM+) showed a

significant deterioration in global cognitive function as determined by MMSE (P < 0.001) and

CDR-SB scores (CU-: P = 0.005, MCI+: P < 0.001, and DEM+: P = 0.001) during the time

interval. CU- showed a significant deterioration in verbal memory (P < 0.001) and visuospatial



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function (P < 0.001), MCI+ in language (P = 0.009) and visual memory functions (P = 0.007),

and DEM+ in language function (P < 0.001).

Longitudinal Changes in 18F-flortaucipir Uptake

Some examples of the baseline and follow-up 18F-flortaucipir PET images are shown in

Fig. 1A. 18F-flortaucipir uptake tended to increase in and around the cortical regions with intense

uptake at baseline in MCI+ and DEM+ in visual inspection of individual PET images.

Conversely, CU- did not show such an increase at follow-up, although there was a small increase

in the medial temporal regions in some CU- participants.

Over the course of the two-year follow-up period, global cortical 18F-flortaucipir SUVR

values of the MCI+ and DEM+ increased by 0.06 (2.9%) and 0.19 (8.0%), respectively. Those

groups showed an increase in uptake most prominently in the medial and lateral temporal regions

corresponding to Braak’s NFT stage I-IV (ΔSUVR in the composite region for stage I-IV: MCI+

= 0.14 / 6.7%, DEM+ = 0.29 / 11.0%), and the increase was attenuated in the regions for higher

Braak’s stages. Interestingly, the region for stage I-II showed maximal increase in SUVR values

(0.27 / 9.3%) in the MCI+, whereas the increase of SUVR value in the regions for stage III-IV

(0.29 / 11.2%) was maximal in the DEM+ group. Although the global cortical SUVR values

barely changed in CU- (-0.01 / -0.7%) and CU+ (-0.01 / -0.3%), maximal increase was found in

the region for stage I-II (CU-: 0.03 / 1.8%, CU+: 0.13 / 6.6%) (Fig. 1B and Table 2).

When not corrected for PVE, the changes in SUVR values were almost half of those

obtained after correcting for PVE. Global cortical SUVR values of the MCI+ and DEM+

increased at follow-up by only 0.03 / 1.5% and 0.08 / 5.0%, respectively and the increase in



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SUVR values in the composite region for Braak’s stage I-IV were 0.07 / 4.0% in MCI+ and 0.13

/ 6.7% in DEM+ (Table 2).

In VOI-based statistical analyses of smaller regions, a significant increase in the 18F-

flortaucipir SUVR values was found in the lateral temporal, entorhinal, parahippocampal,

posterior cingulate and insula cortices and amygdala in the MCI+ (most prominently in the

inferior temporal and parahippocampal cortices) and also in diffuse cortical areas except for the

sensorimotor, superior parietal and cingulate cortices in the DEM+ (most prominently in the

middle temporal cortex). Very small increases in the SUVR values in the medial temporal

regions were observed in both CU- and CU+, but these regions did not reach statistical

significance (Fig. 2). In 62 Aβ-positive participants, there was a positive correlation between the

baseline SUVR values and the change in SUVR values in all cortical regions except for the

sensorimotor, superior parietal, precuneus and posterior cingulate cortices, and amygdala (P <

0.05). No cortical region showed negative correlation. Although the baseline global cortical

SUVR values negatively correlated with the baseline age in these 62 Aβ-positive participants (P

= 0.003), there was only a weak trend of negative correlation between the baseline age and the

change in global cortical SUVR values (P = 0.087), and only the change in prefrontal SUVR

values showed weak negative correlation (P = 0.030), which did not survive correcting for

multiple comparisons. Additionally, in 45 CU- individuals, only the changes in SUVR values in

the entorhinal cortex showed weak positive correlation with the baseline age (P = 0.015), but it

did not survive correcting for multiple comparisons.

Similar to the VOI-based analysis, surface-based analysis revealed an increase in cortical

18F-flortaucipir uptake during the two-year follow-up period. The increase was greatest in the

DEM+, followed by the MCI+. These patient groups showed a prominent increase in the medial,



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basal, and lateral temporal regions. Interestingly, DEM+ showed a less significant increase in the

medial and basal temporal regions when compared to the significance map in the MCI+.

Although the increase was small and not significant, even the CU- showed a small increase in

uptake in the medial and basal temporal regions (Fig. 2).

PVE-uncorrected data showed similar patterns of increase in the regions found in the

results of PVE-corrected data. However, the amount of increase in the PVE-uncorrected SUVR

values in the DEM+ was much smaller than that in the PVE-corrected SUVR values

(Supplemental Fig. 1).

Eleven MCI+ patients who did not progress to clinical dementia showed an increase in

SUVR values in the inferior temporal cortex, which did not survive correcting for multiple

comparisons. Meanwhile, 20 MCI progressors showed an increase in cortical SUVR values in all

cortical regions except for the sensorimotor cortex, most prominently in the inferior and middle

temporal cortices and medial temporal regions (Fig. 3A). 11 DEM+ patients who did not show a

progression of global cognitive function exhibited an increase in cortical SUVR values in the

middle temporal cortex, which did not survive correcting for multiple comparisons. The other 13

DEM+ patients whose global cognition worsened showed an increase in cortical SUVR values in

the cortical areas except for the sensorimotor and anterior cingulate cortices, most prominently in

the lateral temporal cortices and medial temporal regions (Fig. 3B).

In 62 Aβ-positive individuals, the change in global cognition as determined by the

MMSE score correlated with the change in the SUVR values in the prefrontal, sensorimotor,

parietal, occipital, lateral temporal, cingulate, and insula cortices, and the changes in the

language function correlated with the change in the diffuse cortical SUVR values in the

prefrontal, sensorimotor, parietal, occipital, lateral temporal, cingulate, and insula cortices even



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after correcting for multiple comparisons (Supplemental Table 2). These changes still correlated

even after adjusting for baseline SUVR values in smaller number of regions (MMSE: prefrontal,

sensorimotor, superior parietal, precuneus, and occipital cortices, language: prefrontal,

sensorimotor, superior parietal, precuneus, and posterior cingulate cortices). Meanwhile, changes

in memory, attention, visuospatial, frontal/executive functions did not correlate with the changes

in cortical 18F-flortaucipir uptake.

Longitudinal Changes in 18F-flortaucipir Uptake Measured with PERSI Reference Region

We repeated same analyses with the white matter-based PERSI reference region (12). In

all groups, the areas with significant increase of 18F-flortaucipir uptake obtained by the PERSI

reference region were similar to but wider than those by the cerebellar crus (Supplemental Table

3, 4 and Supplemental Fig. 2 to 5). PVE-corrected global cortical 18F-flortaucipir SUVR values

increased at follow-up in the MCI+ and DEM+ by 0.12 / 6.7% and 0.14 / 7.6%, respectively

(Supplemental Table 3 and 4). Like the results of cerebellar crus reference region, both MCI+

and DEM+ groups exhibited most prominently increased uptake in the medial and lateral

temporal regions. Greatest increase was observed in the stage I-II region in MCI+ (ΔSUVR =

0.34 / 13.3%) and in the stage III-IV region in DEM+ (ΔSUVR = 0.23 / 11.1%). Although, the

surface-based ΔSUVR map of CU+ showed increase in uptake in the diffuse basal temporal and

lateral temporal cortices, no region reached statistical significance in CU+ (Supplemental Fig. 3).

Widespread cortical areas exhibited significant increase in 18F-flortaucipir uptake in the MCI+

who progressed to dementia and in DEM+ whose global cognition worsened (Supplemental Fig.

4). The change in global cognition, language and visuospatial function correlated with the

change in 18F-flortaucipir uptake, especially in the prefrontal cortex (Supplemental Table 5). The



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changes in PVE-uncorrected global cortical SUVR values (ΔSUVR in MCI+ and DEM+ = 0.03 /

3.0%) and the extent of regions with significant increase in DEM+ group were much smaller

than those after PVE-correction (Supplemental Table 3, 4 and Supplemental Fig. 5).

Longitudinal Changes in 18F-florbetaben Uptake and Progression of Atrophy

Only the MCI+ and DEM+ showed significant increase in 18F-florbetaben SUVR values

(global cortical ΔSUVR: MCI+ = 0.13 / 6.0% and DEM+ = 0.16 / 6.7%) (Supplemental Fig. 6).

MCI+ exhibited an increase in widespread cortical areas including the lateral temporal, occipital,

insula, parahippocampal, prefrontal, precuneus, posterior cingulate and superior parietal cortices,

and DEM+ in the lateral temporal, occipital, parahippocampal, insula, precuneus, inferior

parietal and posterior cingulate cortices, and hippocampus. CU- did not show significant increase

in 18F-florbetaben SUVR values in any regions, and the changes in the global cortical SUVR

values were close to zero (ΔSUVR: CU- = -0.005).

Progression of volume atrophy and cortical thinning was most prominent in the DEM+

group in the temporal cortex, and in the diffuse fronto-parieto-occipital cortices as well

(Supplemental Table 6 and Supplemental Fig. 7). MCI+ showed a significant progression of

cortical atrophy in the prefrontal, occipital, lateral temporal, entorhinal, and parahippocampal

cortices. DEM+ exhibited additional cortical areas (superior and inferior parietal cortices,

hippocampus, and amygdala) with progressive volume atrophy. The CU- showed progressive

atrophy in the prefrontal, middle temporal, and parahippocampal cortices, hippocampus, and

amygdala, while only the middle temporal cortex showed progressive atrophy in the CU+

(Supplemental Fig. 7).



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In 62 Aβ-positive individuals, there was a correlation between the changes in cortical 18F-

flortaucipir and 18F-florbetaben SUVR values in the occipital cortex and hippocampus. The

change in cortical 18F-flortaucipir SUVR values correlated with the progression of volume

atrophy in the diffuse fronto-temporo-parietal cortices, and the prefrontal, superior parietal,

lateral temporal and entorhinal cortices and thalamus. Meanwhile, the changes in cortical 18F-

florbetaben SUVR values weakly correlated with the progression of volume atrophy in the

prefrontal, inferior temporal, parahippocampal cortices, hippocampus, and striatum. However,

these regions failed to survive correcting for multiple comparisons (Supplemental Fig. 8).

DISCUSSION

In this study, we identified progressive cortical tau accumulation in the prodromal AD

and AD dementia patients. During the two-years follow-up period, global cortical SUVR values

after correcting for PVE increased in the MCI+ and DEM+ groups by 0.06 (2.9%) and 0.19

(8.0%), respectively. Uptake increased in the diffuse cortical areas, most prominently in the

medial and inferior temporal regions in the MCI+ and also most prominently in the lateral

temporal cortices in the DEM+. Meanwhile, the global cortical uptake in the CU- and CU+

groups barely changed during the follow-up period, although there was a small trend of increase

in the medial temporal areas. Additional tau accumulation occurred in the widespread association

neocortex in the MCI+ patients who progressed to dementia and in the DEM+ patients with

worsening global cognition. A deterioration in global cognition and language functions

correlated with the progressive tau accumulation in the association neocortex.



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NFT pathology first appears in the transentorhinal and entorhinal cortex and then in the

neighboring medial and basal temporal cortices. Distant neocortical association areas are later

involved, and finally the pathology reaches the primary cortices (20,21). Likewise, in vivo tau

PET studies in AD patients also showed distinct regional uptake patterns (3,4,6,7) and regional

frequency of tau involvement (2), which closely resemble the sequential pattern of postmortem

NFT pathology. These findings support the hypothesis that tau spreads hierarchically through

anatomically and functionally-connected networks (2,20,22,23). Similar to these cross-sectional

observations, our longitudinal study showed that the tau accumulation rate in the entorhinal

cortex (stage I-II) was greatest in the MCI+ (0.27 / 9.3%), followed by DEM+ (0.21 / 6.9%) and

CU+ (0.13 / 6.6%). In addition, the tau accumulation rate was greatest in the entorhinal cortex

and was lower in the regions for higher Braak’s stages in both CU+ and MCI+ groups, while it

was greatest in the composite region for stage III-IV in DEM+. Likewise, the regions showing

the most significant increase in uptake in MCI+ were more ventral to the regions in DEM+ at the

VOI and surface level. These findings provide indirect evidence for hierarchical tau spreading

from the entorhinal cortex with the progression of disease.

In a large-scaled longitudinal 18F-flortaucipir PET study, tau accumulation rates in the

entorhinal cortex and amygdala were not different between the Aβ-positive groups with and

without cognitive impairment, and continuous tau accumulation even in the regions for early

Braak’s stages was suggested (11). Meanwhile, saturation of tau load may be expected by the

pathological changes occurring in the regions for early Braak’s stage. In Braak’s original report,

tau pathology steadily increased even in the transentorhinal and entorhinal cortices beyond stage

I-II. After neuronal death, intraneuronal NFTs are replaced by ghost tangles in the

transentorhinal cortex from the stage IV, and numerous ghost tangles can be found throughout



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the medial temporal cortex in stage VI (20). When we consider that ghost tangles can be strongly

labelled by flortaucipir (24), its uptake in the transentorhinal and entorhinal cortex can be

expected to increase until the advanced stages and to reach plateau. Although we did not find a

negative correlation between the baseline uptake and the rate of accumulation, the increase in

uptake in the entorhinal cortex was greater in the MCI+ than that in the DEM+. We suspect there

is an attenuation of tau accumulation rate in the areas below the tau stage in which the most

active pathological process of tau occurs. In addition, there was a high variability in the regional

changes in MCI+ and DEM+ groups like the previous longitudinal studies (11,12). Although

there might be a bias caused by image processing steps, this may imply that individual patients

might have different regions where the most active tau accumulation occurs, which seems likely

given that AD can present with different phenotypes which in turn correspond to the topography

of tau uptake.

We also found a relationship between progressive tau accumulation and cognitive decline.

MCI+ patients who progressed to dementia and DEM+ patients whose global cognition

worsened exhibited progressive tau accumulation in the diffuse temporal and extratemporal

association cortices, while the non-progressors showed small trend of increase in small areas in

the basal temporal (MCI+ non-progressors) and lateral temporal cortices (DEM+ non-

progressors). Likewise, the extent of change in uptake in the diffuse association cortices

correlated with the degree of decline in the global cognition and language functions. Therefore,

the progression of cognitive dysfunction is related to additional tau accumulation in the regions

for higher Braak’s stages. Unlike the language function which deteriorates later than the memory

function (25), the change in uptake did not correlate with the change in the memory function.



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This may be due to a floor effect in memory performance such that changes in memory

performances were too small to show a correlation with the uptake change.

It is interesting to note that CU- group showed a weak age-related increase of tau

accumulation rate in the entorhinal cortex, a small trend of increase in medial temporal uptake in

VOI-based analysis, and an additional increase in the portions of the basal temporal regions in

surface-based analysis. This trend was better visualized when the PERSI reference region was

used. This suggests that tau pathology in the medial temporal regions in elderly, the primary age-

related tauopathy (PART) (26), may not be stationary, but may steadily increase within or even

beyond the medial temporal regions. However, it still remains unclear whether PART is a

continuum of AD pathology. To support this hypothesis, we need to observe a progression of tau

accumulation beyond the medial temporal regions after the conversion of Aβ-positivity in the

elderly suspected of having PART in a long-term follow-up study.

According to the hypothetical model of the dynamic biomarkers for AD (27), the surge of

Aβ accumulation precedes that of tau accumulation, and then the neurodegeneration follows.

This model was replicated in our cross-sectional tau and amyloid PET studies (2,25). In the

present longitudinal study, the increase in the 18F-florbetaben uptake in the MCI+ was as high as

the increase in the DEM+, while the amount of increase in the 18F-flortaucipir uptake in the

DEM+ was almost three times greater than that in the MCI+. Progressive tau accumulation

occurred in the widespread cortical areas and attenuated in the entorhinal cortex in the DEM+.

Unlike this pattern, the progression of volume atrophy appeared prominently in the lateral

temporal cortex and a part of the medial temporal regions in the MCI+, and still prominently in

the medial temporal regions in the DEM+. These suggest that the acceleration of Aβ

accumulation may occur in the MCI stage of AD and then may be followed by the acceleration



21

of tau accumulation in the later dementia stage of AD. A progression of volume atrophy may be

sustained even after the tau accumulation reaches plateau. These patterns of longitudinal changes

in the imaging biomarkers for Aβ, tau and neurodegeneration strongly support the hypothetical

model.

Compared to the previous longitudinal study using the PERSI reference region (PVE-

uncorrected and weighted ΔSUVR in the Aβ-positive AD patients = 0.05/year) (12), PVE-

uncorrected ΔSUVR values obtained with the PERSI reference region in the present study was

lower than previously reported (global cortical ΔSUVR in the DEM+ = 0.015/year). Although

Southekal et al. reported the change in SUVR values which were more weighted on temporal

cortex and thereby the ΔSUVR values should be greater than our global cortical ΔSUVR, annual

change in SUVR values of composite region for Braak’s stage I-IV was still lower (ΔSUVR in

the DEM+ = 0.028/year) than theirs. Likewise, compared to previous longitudinal 18F-

flortaucipir PET study using cerebellar crus as a reference tissue (11), annual increase in global

cortical 18F-flortaucipir SUVR value uncorrected for PVE was smaller in our 55 patients with

cognitive impairment (Jack et al. = 0.040/year vs. ours = 0.026/year). We suspect that this

discrepancy might be attributable to differences in severity of patients, image processing steps

and VOI for measuring regional uptake. However, PVE-correction greatly affected the results in

our study and thereby the annual increase was almost similar after correction for PVE (Jack et al.

= 0.053/year vs. ours = 0.060/year). Due to the large effect of progressive atrophy in DEM+, the

change was less than half of that obtained after PVE-correction, and only the lateral temporal

cortices showed a significant increase in uptake in DEM+ without PVE-correction. We also

calculated the change in uptake with data corrected for PVE by Meltzer’s method (28), and

found almost similar results (global cortical ΔSUVR in 55 CI+ = 0.059/year) (Supplemental



22

Table 7). However, there still remains a concern of overcorrection of cortical uptake by PVE-

correction and thereby overestimation of the change.

In DEM+ group, the ΔSUVR as well as the SUVR values obtained by the PERSI

reference region were generally lower than those obtained by cerebellar crus reference, possibly

due to incomplete elimination of voxels with high target binding from the PERSI reference

region. Although the 18F-flortaucipir PET exhibits no prominent white matter uptake compared

to the 18F-THK series tau tracers, the 18F-flortaucipir SUV values in the global white matter of

CU- group was about 8% greater than those in the global cortex in our study. Nevertheless, the

PERSI reference region provided greater effect size for group-wise longitudinal change in uptake

than the cerebellar crus in the PVE-uncorrected data (Cohen’s d for global cortical ΔSUVR in

MCI+: PERSI = 0.741 vs. crus = 0.294, Cohen’s d in DEM+: PERSI = 0.467 vs. crus = 0.433) as

well as in the PVE-corrected data (Cohen’s d for global cortical ΔSUVR in MCI+: PERSI =

0.927 vs. crus = 0.418, Cohen’s d in DEM+: PERSI = 0.958 vs. crus = 0.566). Additionally,

small increase of uptake in the medial temporal region in CU- were visualized by using the

PERSI reference region. Therefore, we suspect that PERSI reference region is more sensitive for

showing the changes in uptake in longitudinal 18F-flortaucipir PET study than the classic

cerebellar crus reference.

Although a greater change in SUVR values in the MCI+ and DEM+ groups than the

variability of SUVR values in a test-retest study of 18F-flortaucipir PET suggests true increase in

tau burden (29), instability and overestimation bias of 18F-flortaucipir SUVR values might have

caused some bias in estimating change in SUVR values in our longitudinal study (30).

According to the previous cross-sectional tau PET studies showing greater amount of tau

accumulation in early-onset AD (5,8,9), we may expect a negative correlation between the



23

baseline age and the change in SUVR values. However, there was only a small trend of negative

correlation between two variables in this longitudinal study. This negative result may be

attributable to the small number of younger AD patients included in our study (6 patients with

age < 65 years in 62 Aβ-positive participants) and the fact that patients with atypical clinical

presentations (who tend to be younger) were not included in this study. Younger AD patients are

likely to show rapid progression (31,32) and were unable to undergo entire assessments due to

markedly progressed cognitive dysfunction at follow-up. This limited the extent of areas with

significantly increased uptake in DEM+ group at follow-up.

CONCLUSIONS

Our study revealed progressive tau accumulation predominantly in the medial and basal

temporal cortices in prodromal AD and in the lateral temporal cortices in AD dementia patients.

These progressive tau accumulation patterns support Braak’s hypothetical model of pathological

tau propagation. In addition, the propagation of tau pathology to the regions of higher Braak’s

stage is associated with worsening of cognitive dysfunction in AD. We confirmed that 18F-

flortaucipir PET is an imaging biomarker for monitoring the progression of AD.

DISCLOSURE

Dr. Jack consults for Lily and serves on an independent data monitoring board for Roche

but he receives no personal compensation from any commercial entity. He receives research

support from NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the



24

Mayo Clinic. No other potential conflicts of interest relevant to this article exist. The other

authors report that no potential conflicts of interest relevant to this article exist.

ACKNOWLEDGEMENTS

We express our special appreciation to Tae Ho Song and Won Taek Lee (PET

technologists) who managed all PET scans with enthusiasm.

KEY POINTS

Question: Does longitudinal change in cortical tau burden measured by 18F-flortaucipir PET

reflect progression of Alzheimer’s disease (AD)?

Pertinent Findings: Our two-year longitudinal tau PET study showed 2.9% increase of cortical

18F-flortaucipir standardized uptake value ratio in prodromal AD and 8% increase in AD

dementia patients. Deterioration of global cognition and thereby conversion to more advanced

clinical status of AD were associated with the progression of tau accumulation in the diffuse

association neocortex.

Implications for Patient Care: 18F-flortaucipir PET is an imaging biomarker for monitoring the

progression of AD.



25

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29

Table 1. Baseline demographic characteristics and changes in cognitive functions

CU- CU+ MCI+ DEM+

n 45 7 31 24

Baseline age (years) 66.8 ± 9.7 71.7 ± 4.2 73.2 ± 7.3a 73.3 ± 8.9a

Gender (M : F) 18 : 27 3 : 4 18 : 13 4 : 20c

Education (years) 12.2 ± 5.0 13.0 ± 4.1 11.9 ± 4.9 9.5 ± 5.7

Duration (years) n.a. n.a. 2.8 ± 1.4 3.8 ± 1.3c

ApoE ε4+ (ε4+:ε4-) 8 : 37 (18%) 2 : 5 (29%) 16 : 15 (52%)a 17 : 7 (71%)a

Interval (months) 24.7 ± 1.4 24.4 ± 1.9 23.7 ± 1.1a 23.1 ± 1.4a

Baseline centiloid 9.1 ± 11.2 81.4 ± 46.4a 79.7 ± 40.8a 110.6 ± 36.7ac

Cognitive tests baseline follow-up baseline follow-up baseline follow-up baseline follow-up

MMSE 28.2 ± 1.8 27.1 ± 3.3* 28.1 ± 2.1 27.3 ± 2.9 25.2 ± 3.2a 22.2 ± 5.0ab* 19.1 ± 4.5abc 15.7 ± 5.2abc*

CDR-SB 0.0 ± 0.0 1.3 ± 3.0* 0.0 ± 0.0 0.7 ± 1.1 1.7 ± 0.9ab 3.1 ± 1.9a* 4.8 ± 1.8abc 7.0 ± 3.0abc*

DS-BW 4.1 ± 1.6 4.2 ± 1.3 3.3 ± 0.8 3.4 ± 0.5 3.7 ± 1.5 3.8 ± 1.4 2.8 ± 1.3 2.4 ± 1.5ac

BNT 50.2 ± 7.7 49.2 ± 8.3 48.7 ± 3.0 48.3 ± 5.7 42.1 ± 8.2a 39.5 ± 9.4a* 34.3 ± 11.5ab 26.2 ± 10.2abc*

RCFT 32.9 ± 4.7 31.4 ± 5.7* 34.0 ± 2.0 33.0 ± 2.7 30.4 ± 6.8 28.6 ± 7.5 22.7 ± 10.7abc 18.8 ± 11.3abc

SVLT-DR 6.6 ± 2.5 5.5 ± 2.4* 6.0 ± 2.2 4.6 ± 3.2 1.4 ± 2.2ab 1.5 ± 2.4ab 0.8 ± 2.1ab 0.3 ± 1.1ab

RCFT-DR 16.0 ± 7.3 16.0 ± 8.4 15.5 ± 5.3 15.5 ± 6.9 6.5 ± 5.7ab 4.2 ± 6.1ab* 2.1 ± 3.7ab 0.7 ± 1.9ab

COWAT 16.2 ± 4.4 15.7 ± 4.2 15.3 ± 6.1 14.7 ± 6.4 13.1 ± 4.9 12.4 ± 5.3a 8.6 ± 4.1abc 7.0 ± 4.0abc

Data are presented as mean ± SD. Intervals represent the time interval between baseline and

follow-up.

aP < 0.05 for the comparisons between the CU- and each group. bP < 0.05 for the comparisons

between the CU+ and MCI/DEM+ groups. cP < 0.05 for the comparisons between the MCI+ and

DEM+ groups. *P < 0.05 for significant changes between baseline and follow-up.

Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =

dementia; +/- = Aβ-positivity; ApoE = apolipoprotein E; MMSE = Mini-Mental State

Examination; CDR-SB = Clinical Dementia Rating sum-of-boxes; DS-BW = 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



30

Test-Delayed Recall; COWAT = Controlled Oral Word Association Test-Semantics; n.a. = not

applicable or not available



31

Table 2. Longitudinal changes in cortical 18F-flortaucipir SUVR values obtained with the

cerebellar crus as a reference region

Data corrected for partial volume effect

CU- CU+ MCI+ DEM+

cGM ΔSUVR -0.01 ± 0.10 -0.01 ± 0.16 0.06 ± 0.15 0.19 ± 0.34

(%) -0.7 ± 6.6 -0.3 ± 10.6 2.9 ± 7.4 8.0 ± 11.9

Stage I-II ΔSUVR 0.03 ± 0.15 0.13 ± 0.27 0.27 ± 0.49 0.21 ± 0.39

(%) 1.8 ± 8.9 6.6 ± 14.2 9.3 ± 13.4 6.9 ± 11.3

Stage III-IV ΔSUVR 0.00 ± 0.08 0.02 ± 0.12 0.14 ± 0.18 0.29 ± 0.34

(%) 0.0 ± 5.0 1.2 ± 7.9 6.8 ± 7.5 11.2 ± 10.0

Stage V ΔSUVR -0.02 ± 0.11 -0.01 ± 0.17 0.06 ± 0.17 0.20 ± 0.38

(%) -0.9 ± 7.2 -0.5 ± 11.4 2.5 ± 8.2 8.2 ± 13.6

Stage VI ΔSUVR -0.03 ± 0.12 -0.03 ± 0.18 0.00 ± 0.13 0.07 ± 0.24

(%) -1.4 ± 8.0 -1.7 ± 12.3 -0.5 ± 7.7 3.4 ± 11.7

Data uncorrected for partial volume effect

CU- CU+ MCI+ DEM+

cGM ΔSUVR -0.02 ± 0.08 -0.01 ± 0.12 0.03 ± 0.09 0.08 ± 0.19

(%) -1.2 ± 6.5 -0.7 ± 10.9 1.5 ± 6.4 5.0 ± 10.1

Stage I-II ΔSUVR 0.00 ± 0.09 0.04 ± 0.17 0.04 ± 0.11 0.03 ± 0.21

(%) 0.1 ± 6.4 2.1 ± 12.8 2.4 ± 6.5 1.4 ± 10.0

Stage III-IV ΔSUVR -0.01 ± 0.06 0.01 ± 0.11 0.07 ± 0.10 0.13 ± 0.19

(%) -0.6 ± 5.1 0.3 ± 9.3 4.1 ± 5.7 6.9 ± 8.4

Stage V ΔSUVR -0.02 ± 0.09 -0.01 ± 0.13 0.02 ± 0.10 0.09 ± 0.22

(%) -1.3 ± 7.0 -0.7 ± 11.4 1.3 ± 7.2 5.3 ± 11.6

Stage VI ΔSUVR -0.02 ± 0.09 -0.02 ± 0.13 -0.01 ± 0.08 0.03 ± 0.15

(%) -1.6 ± 7.6 -1.7 ± 12.0 -0.7 ± 6.9 2.2 ± 10.5


dementia; +/- = Aβ-positivity; ΔSUVR = amount of change in standardized uptake value ratio

during the two-years’ follow-up period; (%) = percent change of SUVR compared to baseline

value; cGM = global cortical gray matter; Stage = regions corresponding to Braak’s

neurofibrillary tangle stages



32

FIGURE LEGENDS

Figure 1. Examples of 18F-flortaucipir PET SUVR images created with the cerebellar crus as a

reference region and their longitudinal changes in PVE-corrected SUVR values obtained at

baseline and follow-up



33

Examples are spatially normalized PET images uncorrected for PVE, and 18F-florbetaben and

18F-flortaucipir SUVR values and MMSE scores are presented in the table (A). 18F-flortaucipir

SUVR values measured in the global cortical gray matter and the composite regions

corresponding to different Braak’s stages are displayed (B). Color bars represent SUVR values.


dementia; +/- = Aβ-positivity; B = baseline; F = follow-up; G/A = gender/age; MMSE = mini-

mental state examination score; A or T = global cortical SUVR value of 18F-florbetaben (A) or

18F-flortaucipir (T) PET; subscript COR or UNC = SUVR values with (COR) or without (UNC)

partial volume effect correction; Aβ = amyloid positivity; ΔSUVR = amount of change of

standardized uptake value ratio; (%) = percent change of SUVR; cGM = global cortical gray

matter; Stage = regions corresponding to Braak’s neurofibrillary tangle stages; PVE = partial

volume effect



34

Figure 2. Longitudinal changes in PVE-corrected 18F-flortaucipir SUVR values obtained with

the cerebellar crus as a reference region

Regional changes and their statistical significances are shown in the upper panel. Horizontal bars

in leftward (green) and rightward (red) direction represent P-values in log scale with decrease

and increase of regional uptake at follow-up, respectively. Vertical blue dotted-lines represent



35

the cut-off P-value 0.05 (-log10P = 1.3), and asterisks represent the regions that survived

correcting for multiple comparisons.

Surface-based analyses of longitudinal changes are shown in the lower panel. Mean amounts of

increase in cortical 18F-flortaucipir SUVR values (lower left) and the cortical areas with

significantly increased uptake at follow-up compared to those at baseline (lower right) are

displayed on cortical surface. Only the vertices that survived correcting for multiple comparisons

are displayed. For simplicity, negative changes are not displayed. Color bars represent ΔSUVR

and P-values in log scale.


dementia; +/- = Aβ-positivity; ΔSUVR = amount of change of standardized uptake value ratio;

PVE = partial volume effect



36

Figure 3. Longitudinal changes in PVE-corrected 18F-flortaucipir SUVR values obtained with

the cerebellar crus as a reference region in MCI patients who progressed or did not progress to

dementia and in AD patients who showed progression of cognitive dysfunction or not.

In VOI-based analysis (A), color bars represent P-values in log scale, and horizontal bars in

leftward (green) and rightward (red) direction represent P-values in log scale with decrease and

increase of regional uptake at follow-up, respectively. Vertical blue dotted-lines represent the

cut-off P-value 0.05 (-log10P = 1.3), and asterisks represent the regions that survived correcting

for multiple comparisons. In surface-based analysis (B), only the vertices that survived

correcting for multiple comparisons are displayed. For simplicity, negative changes are not

displayed.

Abbreviations: npMCI+ = MCI+ who did not progress to dementia; pMCI+ = MCI+ who

progressed to dementia; npDEM+ = DEM+ who did not show progression; pDEM+ = DEM+



37

who showed progression; ΔSUVR = amount of change of standardized uptake value ratio; PVE =

partial volume effect



1

Supplemental Table 1. Numbers of participants who completed baseline scans under different

study protocols and follow-up scans for this follow-up study

CU- CU+ MCI+ DEM+ Scanned at baseline 66 8 38 46 Included in follow-up study 45 7 31 24 Reasons for exclusion Refused 14 1 5 6 Follow-up loss 4 0 1 0 Died 0 0 0 3 Severe dementia 0 0 0 6 Immobility 0 0 1 5 Other diseases* 2 0 0 1 Scan failure 1 0 0 1 % included (%) 68.2 87.5 81.6 52.2

*Two individuals with CU- were excluded due to Parkinson’s disease and spasmodic dysphonia

diagnosed after the baseline study. One DEM+ patient was excluded due to insertion of cardiac

pacemaker after the baseline study.



2

Supplemental Table 2. Correlation between the longitudinal changes in PVE-corrected cortical

18F-flortaucipir SUVR values obtained with the cerebellar crus as a reference region and

cognitive decline in 62 Aβ-positive individuals

Regions MMSE CDR-SB DS-BW BNT RCFT SVLT-DR RCFT-DR COWAT

Global cortex B -0.426 0.369 -0.030 -0.443 -0.144 -0.150 -0.056 -0.272 P 0.001* 0.004* 0.831 0.001* 0.306 0.293 0.685 0.048

Prefrontal B -0.492 0.480 -0.021 -0.484 -0.246 -0.128 -0.073 -0.258 P < 0.001* < 0.001* 0.878 < 0.001* 0.075 0.369 0.596 0.059

Sensorimotor B -0.394 0.244 -0.078 -0.386 -0.082 -0.189 -0.108 -0.379 P 0.003* 0.061 0.568 0.003* 0.554 0.176 0.426 0.004

Sup. parietal B -0.421 0.242 -0.034 -0.413 -0.109 -0.242 -0.119 -0.289 P 0.001* 0.062 0.804 0.001* 0.430 0.081 0.383 0.032

Inf. parietal B -0.274 0.230 -0.101 -0.421 -0.063 -0.180 -0.048 -0.262 P 0.041 0.078 0.470 0.001* 0.655 0.207 0.729 0.057

Precuneus B -0.451 0.311 -0.025 -0.427 -0.098 -0.142 -0.047 -0.221 P < 0.001* 0.014* 0.857 0.001* 0.478 0.309 0.729 0.104

Occipital B -0.393 0.314 0.101 -0.299 -0.142 -0.094 0.041 -0.191 P 0.003* 0.015* 0.470 0.028* 0.316 0.512 0.771 0.173

Sup. temporal B -0.288 0.320 -0.078 -0.351 -0.056 -0.131 -0.023 -0.240 P 0.032 0.013* 0.577 0.009* 0.695 0.360 0.867 0.084

Mid. temporal B -0.375 0.334 -0.040 -0.388 -0.105 -0.076 -0.042 -0.200 P 0.005* 0.011* 0.781 0.004* 0.465 0.604 0.765 0.158

Inf. temporal B -0.390 0.409 -0.001 -0.423 -0.189 -0.110 -0.001 -0.189 P 0.003* 0.001* 0.993 0.001* 0.174 0.438 0.996 0.172

Hippocampus B -0.060 0.080 0.050 -0.203 -0.026 -0.075 -0.007 -0.088 P 0.686 0.580 0.739 0.172 0.866 0.633 0.963 0.568

Entorhinal B -0.077 0.132 -0.021 -0.040 0.207 -0.162 0.005 -0.168 P 0.560 0.303 0.874 0.763 0.122 0.238 0.970 0.211

Parahippocampal B -0.243 0.323 0.011 -0.319 -0.137 -0.084 0.004 -0.204 P 0.068 0.011* 0.937 0.017* 0.325 0.550 0.978 0.136

Amygdala B -0.172 0.171 0.073 -0.220 0.088 -0.140 -0.027 -0.256 P 0.204 0.192 0.599 0.108 0.533 0.323 0.843 0.062

Ant. cingulate B -0.347 0.397 0.073 -0.310 -0.101 -0.033 -0.008 -0.189 P 0.008* 0.002* 0.596 0.019* 0.462 0.812 0.950 0.165

Post. cingulate B -0.321 0.285 0.017 -0.366 -0.097 -0.105 -0.028 -0.245 P 0.013* 0.023* 0.900 0.005* 0.480 0.450 0.834 0.068

Insula B -0.317 0.327 -0.001 -0.381 -0.107 -0.167 -0.067 -0.216 P 0.019* 0.012* 0.992 0.005* 0.454 0.249 0.634 0.125

Regions which survived correcting for multiple comparisons marked with asterisks.

Abbreviations: B = Standardized regression coefficient, P = P-value, MMSE = Mini-Mental

State Examination score, CDR-SB = Clinical Dementia Rating Sum of Boxes, DS-BW = Digit

Span Backward test, BNT = Boston Naming Test, RCFT = Rey-Osterrieth Complex Figure Test,



3

SVLT-DR = Seoul Verbal Learning Test-Delayed Recall, RCFT-DR = Rey-Osterrieth Complex

Figure Test-Delayed Recall, and COWAT = Controlled Oral Word Association Test-Semantics



4

Supplemental Table 3. Longitudinal changes in cortical 18F-flortaucipir SUVR values obtained

with the PERSI reference region

Data corrected for partial volume effect CU- CU+ MCI+ DEM+ cGM ΔSUVR 0.01 ± 0.08 0.02 ± 0.09 0.12 ± 0.13 0.14 ± 0.15

(%) 0.7 ± 5.8 1.5 ± 5.6 6.7 ± 6.7 7.6 ± 7.4 Stage I-II ΔSUVR 0.05 ± 0.14 0.16 ± 0.19 0.34 ± 0.39 0.18 ± 0.35

(%) 3.4 ± 9.0 8.5 ± 9.7 13.3 ± 13.2 6.9 ± 11.1 Stage III-IV ΔSUVR 0.02 ± 0.10 0.05 ± 0.11 0.20 ± 0.17 0.23 ± 0.20

(%) 1.6 ± 7.0 3.4 ± 7.6 10.8 ± 8.7 11.1 ± 8.3 Stage V ΔSUVR 0.00 ± 0.09 0.02 ± 0.09 0.12 ± 0.15 0.15 ± 0.18

(%) 0.5 ± 6.1 1.3 ± 5.7 6.3 ± 7.1 7.8 ± 8.5 Stage VI ΔSUVR -0.01 ± 0.08 0.00 ± 0.10 0.05 ± 0.11 0.04 ± 0.10

(%) -0.1 ± 5.9 0.0 ± 6.6 3.1 ± 6.8 2.9 ± 5.9 Data uncorrected for partial volume effect CU- CU+ MCI+ DEM+ cGM ΔSUVR 0.00 ± 0.02 0.00 ± 0.02 0.03 ± 0.04 0.03 ± 0.06

(%) -0.5 ± 2.6 0.1 ± 2.4 3.0 ± 3.9 3.0 ± 4.8 Stage I-II ΔSUVR 0.01 ± 0.06 0.03 ± 0.08 0.05 ± 0.11 -0.01 ± 0.14

(%) 0.9 ± 5.7 2.9 ± 6.3 4.1 ± 8.3 -0.3 ± 8.5 Stage III-IV ΔSUVR 0.00 ± 0.04 0.01 ± 0.03 0.07 ± 0.06 0.06 ± 0.10

(%) 0.2 ± 4.1 1.3 ± 3.4 5.7 ± 5.6 5.1 ± 6.5 Stage V ΔSUVR -0.01 ± 0.03 0.00 ± 0.03 0.03 ± 0.05 0.03 ± 0.07

(%) -0.6 ± 2.7 0.0 ± 2.7 2.8 ± 4.2 3.3 ± 5.5 Stage VI ΔSUVR -0.01 ± 0.02 -0.01 ± 0.03 0.01 ± 0.03 0.00 ± 0.03

(%) -0.9 ± 2.7 -1.0 ± 3.7 0.7 ± 3.7 0.2 ± 3.3





neurofibrillary tangle stages; PERSI = Parametric Estimation of Reference Signal Intensity



5

Supplemental Table 4. A comparison between the global cortical 18F-flortaucipir SUVR values

obtained with the cerebellar crus and PERSI reference regions at baseline and follow-up

Reference region Data corrected for partial volume effect

CU- CU+ MCI+ DEM+

Cerebellar crus SUVRBL 1.47 ± 0.13 1.50 ± 0.07 1.71 ± 0.31 2.12 ± 0.63 SUVRFU 1.46 ± 0.12 1.49 ± 0.16 1.78 ± 0.44 2.31 ± 0.84 ΔSUVR -0.01 ± 0.10 -0.01 ± 0.16 0.06 ± 0.15 0.19 ± 0.34

PERSI SUVRBL 1.48 ± 0.16 1.57 ± 0.15 1.68 ± 0.25 1.99 ± 0.50 SUVRFU 1.48 ± 0.15 1.59 ± 0.16 1.80 ± 0.36 2.13 ± 0.51 ΔSUVR 0.01 ± 0.08 0.02 ± 0.09 0.12 ± 0.13 0.14 ± 0.15

Reference region Data uncorrected for partial volume effect

CU- CU+ MCI+ DEM+

Cerebellar crus SUVRBL 1.15 ± 0.10 1.15 ± 0.06 1.29 ± 0.20 1.51 ± 0.35 SUVRFU 1.14 ± 0.09 1.14 ± 0.13 1.31 ± 0.27 1.59 ± 0.46 ΔSUVR -0.01 ± 0.10 -0.01 ± 0.16 0.06 ± 0.15 0.19 ± 0.34

PERSI SUVRBL 0.95 ± 0.04 0.97 ± 0.04 1.01 ± 0.09 1.12 ± 0.22 SUVRFU 0.95 ± 0.04 0.97 ± 0.04 1.04 ± 0.13 1.15 ± 0.20 ΔSUVR 0.00 ± 0.02 0.00 ± 0.02 0.03 ± 0.04 0.03 ± 0.06



during the two-years’ follow-up period, BL/FU = baseline and follow-up



6

Supplemental Table 5. Correlation between the longitudinal changes in PVE-corrected cortical

18F-flortaucipir SUVR values obtained with the PERSI reference region and cognitive decline in

62 Aβ-positive individuals

Regions MMSE CDR-SB DS-BW BNT RCFT SVLT-DR RCFT-DR COWAT

Global cortex B -0.473 0.320 0.002 -0.328 -0.397 -0.162 -0.134 -0.162 P < 0.001* 0.012 0.987 0.014 0.004* 0.260 0.336 0.247

Prefrontal B -0.542 0.482 -0.003 -0.395 -0.538 -0.105 -0.144 -0.154 P < 0.001* < 0.001* 0.983 0.003* < 0.001* 0.470 0.303 0.276

Sensorimotor B -0.430 0.180 -0.047 -0.256 -0.266 -0.230 -0.221 -0.380 P 0.001* 0.162 0.731 0.054 0.050 0.097 0.099 0.004

Sup. parietal B -0.428 0.169 0.010 -0.333 -0.227 -0.274 -0.181 -0.233 P 0.001* 0.180 0.942 0.010* 0.089 0.042 0.169 0.079

Inf. parietal B -0.246 0.125 -0.109 -0.351 -0.168 -0.229 -0.092 -0.183 P 0.061 0.333 0.419 0.007* 0.220 0.098 0.496 0.179

Precuneus B -0.502 0.262 0.012 -0.371 -0.219 -0.156 -0.087 -0.143 P < 0.001* 0.039 0.929 0.005* 0.113 0.270 0.524 0.299

Occipital B -0.291 0.190 0.184 -0.040 -0.251 -0.022 0.010 -0.043 P 0.023 0.131 0.172 0.764 0.062 0.874 0.941 0.750

Sup. temporal B -0.240 0.217 -0.105 -0.162 -0.244 -0.136 -0.064 -0.095 P 0.079 0.103 0.458 0.243 0.087 0.353 0.651 0.508

Mid. temporal B -0.281 0.161 -0.034 -0.150 -0.268 -0.018 -0.069 0.016 P 0.036 0.222 0.807 0.275 0.055 0.899 0.618 0.910

Inf. temporal B -0.355 0.297 0.020 -0.246 -0.384 -0.082 -0.038 -0.001 P 0.009* 0.025 0.890 0.078 0.006* 0.575 0.788 0.994

Hippocampus B 0.027 -0.058 0.063 0.065 -0.159 -0.010 -0.049 0.139 P 0.851 0.673 0.662 0.646 0.272 0.944 0.730 0.335

Entorhinal B -0.043 0.066 -0.034 0.099 0.150 -0.143 -0.020 -0.041 P 0.747 0.609 0.805 0.462 0.269 0.298 0.879 0.760

Parahippocampal B -0.210 0.253 0.029 -0.148 -0.363 -0.068 -0.026 -0.045 P 0.149 0.071 0.847 0.324 0.014* 0.660 0.863 0.766

Amygdala B -0.180 0.140 0.171 -0.070 -0.070 -0.188 -0.096 -0.144 P 0.239 0.346 0.269 0.651 0.655 0.232 0.530 0.350

Ant. cingulate B -0.302 0.306 0.174 -0.062 -0.344 0.044 -0.026 0.038 P 0.021 0.016 0.220 0.660 0.013* 0.761 0.852 0.788

Post. cingulate B -0.373 0.254 0.070 -0.316 -0.261 -0.122 -0.073 -0.178 P 0.005* 0.054 0.624 0.022 0.066 0.404 0.605 0.212

Insula B -0.279 0.226 0.036 -0.172 -0.391 -0.189 -0.141 0.021 P 0.044 0.094 0.802 0.226 0.006* 0.202 0.325 0.887

Regions which survived correcting for multiple comparisons marked with asterisks.

Abbreviations: B = Standardized regression coefficient, P = P-value, MMSE = Mini-Mental

State Examination score, CDR-SB = Clinical Dementia Rating Sum of Boxes, DS-BW = Digit

Span Backward test, BNT = Boston Naming Test, RCFT = Rey-Osterrieth Complex Figure Test,



7

SVLT-DR = Seoul Verbal Learning Test-Delayed Recall, RCFT-DR = Rey-Osterrieth Complex

Figure Test-Delayed Recall, and COWAT = Controlled Oral Word Association Test-Semantics



8

Supplemental Table 6. Longitudinal changes in cortical volume

CU- CU+ MCI+ DEM+ cGM ΔVol (mL) -2.8 ± 10.3 -6.9 ± 5.4 -8.1 ± 11.3 -12.9 ± 12.8

(%) -0.6 ± 2.4 -1.6 ± 1.3 -1.9 ± 2.7 -3.1 ± 3.1 Stage I-II ΔVol (mL) -0.4 ± 0.4 -0.4 ± 0.3 -0.6 ± 0.9 -0.9 ± 0.7

(%) -3.3 ± 3.5 -3.5 ± 3.2 -6.5 ± 9.2 -10.0 ± 7.4 Stage III-IV ΔVol (mL) -0.8 ± 2.9 -2.3 ± 1.9 -3.1 ± 3.3 -4.4 ± 3.3

(%) -0.8 ± 3.2 -2.5 ± 2.1 -3.6 ± 3.7 -5.3 ± 3.9 Stage V ΔVol (mL) -1.6 ± 5.9 -4.1 ± 4.0 -4.2 ± 7.7 -6.9 ± 8.2

(%) -0.5 ± 2.3 -1.6 ± 1.5 -1.6 ± 3.0 -2.8 ± 3.4 Stage VI ΔVol (mL) 0.0 ± 2.6 -0.2 ± 3.3 -0.2 ± 2.5 -0.6 ± 2.5

(%) 0.1 ± 3.8 -0.2 ± 5.0 -0.3 ± 3.5 -0.8 ± 3.8


dementia; +/- = Aβ-positivity; ΔVol = amount of change in standardized uptake value ratio






9

Supplemental Table 7. Longitudinal changes in cortical 18F-flortaucipir SUVR values obtained

with the cerebellar crus as a reference region and corrected for partial volume effect by Metzer’s

method

Data corrected for partial volume effect CU- CU+ MCI+ DEM+ cGM ΔSUVR -0.02 ± 0.13 0.00 ± 0.19 0.07 ± 0.18 0.19 ± 0.35

(%) -0.9 ± 6.7 -0.2 ± 10.4 2.6 ± 7.4 6.8 ± 10.9 Stage I-II ΔSUVR 0.03 ± 0.15 0.14 ± 0.24 0.28 ± 0.41 0.26 ± 0.33

(%) 1.4 ± 8.2 6.7 ± 11.8 9.3 ± 11.3 8.3 ± 9.6 Stage III-IV ΔSUVR 0.00 ± 0.10 0.03 ± 0.13 0.14 ± 0.19 0.28 ± 0.34

(%) -0.1 ± 5.6 1.3 ± 7.5 6.1 ± 7.2 9.9 ± 9.5 Stage V ΔSUVR -0.02 ± 0.14 -0.01 ± 0.21 0.06 ± 0.20 0.19 ± 0.39

(%) -1.0 ± 7.1 -0.4 ± 11.2 2.3 ± 8.1 7.0 ± 12.2 Stage VI ΔSUVR -0.04 ± 0.15 -0.03 ± 0.22 -0.01 ± 0.15 0.07 ± 0.28

(%) -2.0 ± 7.7 -1.5 ± 12.0 -0.8 ± 7.4 2.8 ± 10.7 Data uncorrected for partial volume effect CU- CU+ MCI+ DEM+ cGM ΔSUVR -0.02 ± 0.08 -0.01 ± 0.12 0.03 ± 0.09 0.08 ± 0.19

(%) -1.2 ± 6.5 -0.7 ± 10.9 1.5 ± 6.4 5.0 ± 10.1 Stage I-II ΔSUVR 0.00 ± 0.09 0.04 ± 0.17 0.04 ± 0.11 0.03 ± 0.21

(%) 0.1 ± 6.4 2.1 ± 12.8 2.4 ± 6.5 1.4 ± 10.0 Stage III-IV ΔSUVR -0.01 ± 0.06 0.01 ± 0.11 0.07 ± 0.10 0.13 ± 0.19

(%) -0.6 ± 5.1 0.3 ± 9.3 4.1 ± 5.7 6.9 ± 8.4 Stage V ΔSUVR -0.02 ± 0.09 -0.01 ± 0.13 0.02 ± 0.10 0.09 ± 0.22

(%) -1.3 ± 7.0 -0.7 ± 11.4 1.3 ± 7.2 5.3 ± 11.6 Stage VI ΔSUVR -0.02 ± 0.09 -0.02 ± 0.13 -0.01 ± 0.08 0.03 ± 0.15

(%) -1.6 ± 7.6 -1.7 ± 12.0 -0.7 ± 6.9 2.2 ± 10.5








10

Supplemental Figure 1. Longitudinal changes in PVE-uncorrected 18F-flortaucipir SUVR

values obtained with the cerebellar crus as a reference region






11














12

Supplemental Figure 2. Examples of 18F-flortaucipir PET SUVR images created with the

PERSI reference region and their longitudinal changes in PVE-corrected SUVR values obtained

at baseline and follow-up



13

Examples are spatially normalized PET images uncorrected for partial volume effect, and 18F-

florbetaben and 18F-flortaucipir SUVR values and MMSE scores are presented in the table (A).

18F-flortaucipir SUVR values measured in the global cortical gray matter and the composite

regions corresponding to different Braak’s stages are displayed (B). Color bars represent SUVR

values.


dementia; +/- = Aβ-positivity; B = baseline; F = follow-up; G/A = gender/age; MMSE = mini-

mental state examination score; A or T = global cortical SUVR value of 18F-florbetaben (A) or

18F-flortaucipir (T) PET; subscript COR or UNC = SUVR values with (COR) or without (UNC)

partial volume effect correction; Aβ = amyloid positivity; ΔSUVR = amount of change of

standardized uptake value ratio; (%) = percent change of SUVR; cGM = global cortical gray

matter; Stage = regions corresponding to Braak’s neurofibrillary tangle stages; PVE = partial

volume effect; PERSI = Parametric Estimation of Reference Signal Intensity



14

Supplemental Figure 3. Longitudinal changes in PVE-corrected 18F-flortaucipir SUVR values

obtained with the PERSI reference region






15











PVE = partial volume effect; PERSI = Parametric Estimation of Reference Signal Intensity



16

Supplemental Figure 4. Longitudinal changes in PVE-corrected 18F-flortaucipir SUVR values

obtained with the PERSI reference region in MCI patients who progressed or did not progress to

dementia and in AD patients who showed progression of cognition or not.

In VOI-based analysis (A), color bars represent P-values in log scale, and horizontal bars in

leftward (green) and rightward (red) direction represent P-values in log scale with decrease and

increase of regional uptake at follow-up, respectively. Vertical blue dotted-lines represent the

cut-off P-value 0.05 (-log10P = 1.3), and asterisks represent the regions that survived correcting

for multiple comparisons. In surface-based analysis (B), only the vertices that survived

correcting for multiple comparisons are displayed. For simplicity, negative changes are not

displayed.

Abbreviations: npMCI+ = MCI+ who did not progress to dementia; pMCI+ = MCI+ who

progressed to dementia; npDEM+ = DEM+ who did not show progression; pDEM+ = DEM+



17

who showed progression; ΔSUVR = amount of change of standardized uptake value ratio; PVE =

partial volume effect; PERSI = Parametric Estimation of Reference Signal Intensity



18

Supplemental Figure 5. Longitudinal changes in PVE-uncorrected 18F-flortaucipir SUVR

values obtained with the PERSI reference region






19











PVE = partial volume effect; PERSI = Parametric Estimation of Reference Signal Intensity



20

Supplemental Figure 6. Longitudinal changes in PVE-corrected 18F-florbetaben SUVR values

obtained with the cerebellar crus as a reference region






21




increase in cortical 18F-florbetaben SUVR values (lower left) and the cortical areas with










22

Supplemental Figure 7. Longitudinal changes in regional volume and cortical thickness



and increase of regional volume at follow-up, respectively. Vertical blue dotted-lines represent




23



decrease in cortical thickness (lower left) and the cortical areas with significantly decreased

thickness at follow-up compared to those at baseline (lower right) are displayed on cortical

surface. Only the vertices that survived correcting for multiple comparisons are displayed. For

simplicity, positive changes are not displayed. Color bars represent ΔCT and P-values in log

scale.


dementia; +/- = Aβ-positivity; ΔCT = amount of change in cortical thickness



24

Supplemental Figure 8. Correlation between the longitudinal changes in PVE-corrected cortical

18F-flortaucipir and 18F-florbetaben SUVR values obtained with the cerebellar crus as a reference

region and volume in 62 Aβ-positive individuals

Horizontal bars in leftward (green) and rightward (red) direction represent P-values in log scale

with negative and positive correlation, respectively. Vertical blue dotted-lines represent the cut-

off P-value 0.05 (-log10P = 1.3). Asterisks mean the regions that survived correcting for multiple

comparisons.

Abbreviations: ΔSUVR = amount of change of standardized uptake value ratio; PVE = partial

volume effect; cGM = global cortical gray matter; pFR = prefrontal; SM = sensorimotor; sPR =

superior parietal; iPR = inferior parietal; PC = precuneus; OC = occipital; sTE = superior

temporal; mTE = middle temporal; iTE = inferior temporal; meTE = medial temporal; HI =

hippocampus; EN = entorhinal; PH = parahippocampal; AM = amygdala; aCI = anterior

cingulate; pCI = posterior cingulate; IN = insula regions; TH = thalamus; ST = striatum; GP =

globus pallidus



Doi: 10.2967/jnumed.118.221697Published online: March 29, 2019.J Nucl Med. Hyoung LyooHanna Cho, Jae Yong Choi, Hye Sun Lee, Jae-Hoon Lee, Young Hoon Ryu, Myung Sik Lee, Clifford R. Jack, Jr. and Chul Progressive tau accumulation in Alzheimer's disease: two-year follow-up study

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