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).
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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
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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
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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
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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
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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.
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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
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Test-Delayed Recall; COWAT = Controlled Oral Word Association Test-Semantics; n.a. = not
applicable or not available
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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
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
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
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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
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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.
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
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
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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
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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.
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
dementia; +/- = Aβ-positivity; ΔSUVR = amount of change of standardized uptake value ratio;
PVE = partial volume effect
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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+
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who showed progression; ΔSUVR = amount of change of standardized uptake value ratio; PVE =
partial volume effect
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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.
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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,
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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
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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
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
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; PERSI = Parametric Estimation of Reference Signal Intensity
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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
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
dementia; +/- = Aβ-positivity; ΔSUVR = amount of change in standardized uptake value ratio
during the two-years’ follow-up period, BL/FU = baseline and follow-up
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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,
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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
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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
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
dementia; +/- = Aβ-positivity; ΔVol = 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
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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
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
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
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Supplemental Figure 1. Longitudinal changes in PVE-uncorrected 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
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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.
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
dementia; +/- = Aβ-positivity; ΔSUVR = amount of change of standardized uptake value ratio;
PVE = partial volume effect
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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
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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.
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
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
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Supplemental Figure 3. Longitudinal changes in PVE-corrected 18F-flortaucipir SUVR values
obtained with the PERSI 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
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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.
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
dementia; +/- = Aβ-positivity; ΔSUVR = amount of change of standardized uptake value ratio;
PVE = partial volume effect; PERSI = Parametric Estimation of Reference Signal Intensity
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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+
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who showed progression; ΔSUVR = amount of change of standardized uptake value ratio; PVE =
partial volume effect; PERSI = Parametric Estimation of Reference Signal Intensity
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Supplemental Figure 5. Longitudinal changes in PVE-uncorrected 18F-flortaucipir SUVR
values obtained with the PERSI 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
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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.
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
dementia; +/- = Aβ-positivity; ΔSUVR = amount of change of standardized uptake value ratio;
PVE = partial volume effect; PERSI = Parametric Estimation of Reference Signal Intensity
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Supplemental Figure 6. Longitudinal changes in PVE-corrected 18F-florbetaben 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
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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-florbetaben 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.
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
dementia; +/- = Aβ-positivity; ΔSUVR = amount of change of standardized uptake value ratio;
PVE = partial volume effect
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Supplemental Figure 7. Longitudinal changes in regional volume and cortical thickness
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 volume 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
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correcting for multiple comparisons.
Surface-based analyses of longitudinal changes are shown in the lower panel. Mean amounts of
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.
Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; DEM =
dementia; +/- = Aβ-positivity; ΔCT = amount of change in cortical thickness
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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
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