Research

JAMA Neurology | Original Investigation

Comparison of Group-Level and Individualized Brain Regions

for Measuring Change in Longitudinal Tau Positron Emission Tomography
in Alzheimer Disease
Antoine Leuzy, PhD; Alexa Pichet Binette, PhD; Jacob W. Vogel, PhD; Gregory Klein, PhD; Edilio Borroni, PhD; Matteo Tonietto, PhD;
Olof Strandberg, PhD; Niklas Mattsson-Carlgren, MD, PhD; Sebastian Palmqvist, MD, PhD; Michael J. Pontecorvo, PhD; Leonardo Iaccarino, PhD;
Erik Stomrud, MD, PhD; Rik Ossenkoppele, PhD; Ruben Smith, MD, PhD; Oskar Hansson, MD, PhD; for the Alzheimer’s Disease Neuroimaging Initiative

Supplemental content
IMPORTANCE Longitudinal tau positron emission tomography (PET) is a relevant outcome
in clinical trials evaluating disease-modifying therapies in Alzheimer disease (AD). A key
unanswered question is whether the use of participant-specific (individualized) regions
of interest (ROIs) is superior to conventional approaches where the same ROI (group-level)
is used for each participant.

OBJECTIVE To compare group- and participant-level ROIs in participants at different stages

of the AD clinical continuum in terms of annual percentage change in tau-PET standardized
uptake value ratio (SUVR) and sample size requirements.

DESIGN, SETTING, AND PARTICIPANTS This was a longitudinal cohort study with consecutive
participant enrollment between September 18, 2017, and November 15, 2021. Included
in the analysis were participants with mild cognitive impairment and AD dementia from
the prospective and longitudinal Swedish Biomarkers For Identifying Neurodegenerative
Disorders Early and Reliably 2 (BioFINDER-2) study; in addition, a validation sample (the AVID
05e, Expedition-3, Alzheimer’s Disease Neuroimaging Initiative [ADNI], and BioFINDER-1
study cohorts) was also included.

EXPOSURES Tau PET (BioFINDER-2, [18F]RO948; validation sample, [18F]flortaucipir),

7 group-level (5 data-driven stages, meta-temporal, whole brain), and 5 individualized ROIs.

MAIN OUTCOMES AND MEASURES Annual percentage change in tau-PET SUVR across ROIs. Sample
size requirements in simulated clinical trials using tau PET as an outcome were also calculated.

RESULTS A total of 215 participants (mean [SD] age, 71.4 (7.5) years; 111 male [51.6%]) from
the BioFINDER-2 study were included in this analysis: 97 amyloid-β (Aβ)–positive cognitively
unimpaired (CU) individuals, 77 with Aβ-positive mild cognitive impairment (MCI), and
41 with AD dementia. In the validation sample were 137 Aβ-positive CU participants, 144 with
Aβ-positive MCI, and 125 with AD dementia. Mean (SD) follow-up time was 1.8 (0.3) years.
Using group-level ROIs, the largest annual percentage increase in tau-PET SUVR in
Aβ-positive CU individuals was seen in a composite ROI combining the entorhinal cortex,
hippocampus, and amygdala (4.29%; 95% CI, 3.42%-5.16%). In individuals with Aβ-positive
MCI, the greatest change was seen in the temporal cortical regions (5.82%; 95% CI,
4.67%-6.97%), whereas in those with AD dementia, the greatest change was seen in the
parietal regions (5.22%; 95% CI, 3.95%-6.49%). Significantly higher estimates of annual
percentage change were found using several of the participant-specific ROIs. Importantly,
the simplest participant-specific approach, where change in tau PET was calculated in Author Affiliations: Author
affiliations are listed at the end of this
an ROI that best matched the participant’s data-driven disease stage, performed best in all article.
3 subgroups. For the power analysis, sample size reductions for the participant-specific ROIs
Group Information: The members
ranged from 15.94% (95% CI, 8.14%-23.74%) to 72.10% (95% CI, 67.10%-77.20%) compared of the Alzheimer’s Disease
with the best-performing group-level ROIs. Findings were replicated using [18F]flortaucipir. Neuroimaging Initiative appear in
Supplement 2.
CONCLUSIONS AND RELEVANCE Finding suggest that certain individualized ROIs carry Corresponding Authors: Antoine
an advantage over group-level ROIs for assessing longitudinal tau changes and increase Leuzy, PhD, Clinical Memory
the power to detect treatment effects in AD clinical trials using longitudinal tau PET as Research Unit, Department of Clinical
Sciences, Lund University, SE-205 02
an outcome.
Malmö, Sweden (antoine.leuzy@
med.lu.se); Oskar Hansson, MD, PhD,
Memory Clinic, Skåne University
JAMA Neurol. 2023;80(6):614-623. doi:10.1001/jamaneurol.2023.1067 Hospital, SE-205 02 Malmö, Sweden
Published online May 8, 2023. (oskar.hansson@med.lu.se).

614 (Reprinted) jamaneurology.com

Downloaded From: https://jamanetwork.com/ on 09/04/2023

 Brain Regions for Measuring Change in Longitudinal Tau PET in Alzheimer Disease
T
he neuropathological hallmarks of Alzheimer disease
(AD) include deposition of extracellular amyloid β (Aβ)
and intracellular hyperphosphorylated tau. In con-
trast to Aβ pathology, which occurs in cortical regions de-
cades before dementia onset, tau pathology is thought to
emerge in circumscribed regions of the medial temporal lobe
in early adulthood, before spreading into cortical regions
around the time of symptom onset.1 Studies using positron
emission tomography (PET) ligands with high affinity for the
tau aggregates formed in AD have shown that the degree and
topography of cortical tau-PET retention overlap strongly with
neurodegeneration2 and associate with cognitive decline.2,3 As
such, tau accumulation is a relevant intervention target and
potential outcome measure in AD.4
The spread of tau in AD has classically been thought to fol-
low a stereotypical spatiotemporal pattern based on postmor-
tem studies5,6—from the (trans)entorhinal cortex into the hip-
pocampus and inferior temporal lobe, before reaching cortical
association areas (Braak staging scheme). However, autopsy7 and
both cross-sectional8-10 and longitudinal11-15 tau-PET studies have
found substantial interindividual differences in the deposition
and accumulation of tau, with important deviations from the tra-
ditional Braak model.7-10 Indeed, several distinct subtypes of tau
pathology were recently identified using tau PET, with these
exhibiting distinct demographic and cognitive profiles, as well
as differing longitudinal outcomes.16 Although the mechanisms
underlying this variability remain, as yet, unclear, they may be
associated with individual differences in brain organization (eg,
variation in axonal connectivity patterns), regional vulnerabil-
ity (eg, deposition of tau along different networks), or variation
in disease biochemistry (eg, individual differences in enzymatic
activity, copathology, or other biological processes).17
Longitudinal tau PET is increasingly used as an outcome
measure to detect either drug target engagement or efficacy in
AD clinical trials evaluating disease-modifying therapies.18 Re-
cent work comparing tau PET and cognition as outcomes in clini-
cal trials showed that significantly fewer participants were re-
quired to detect a meaningful change in the rate of tau accumu-
lation compared with the rate of cognitive decline.19 However,
interindividual heterogeneity in the pattern of tau spread poses
a challenge to the accurate prediction of tau progression at the
individual level.11-15 The use of participant-specific (individual-
ized) approaches for the prediction of future tau spreading may
help increase the sensitivity to detect treatment effects and help
reduce the number of patients included into these trials. Prelimi-
nary findings using one such approach showed that defining re-
gions of interest (ROIs) for each participant improved the sen-
sitivity to tau accumulation and significantly reduced required
sample sizes when compared with the use of conventional (eg,
Braak stages, temporal and whole-brain meta-ROIs) approaches
where each participant is assigned the same (group-level) ROI.20
In the present study, we aimed to expand on work on participant-
specific ROIs by comparing group-level and individualized ROIs
defined using a range of methods differing in complexity level
across several metrics using longitudinal [18F]RO948 tau PET
in participants at different stages of the AD clinical continuum.
The results were validated in an independent data set with lon-
gitudinal [18F]flortaucipir.
jamaneurology.com
Downloaded From: https://jamanetwork.com/ on 09/04/2023
Original Investigation Research
Key Points
Question Does defining regions of interest (ROIs) for each
participant (individualized) improve the sensitivity to tau
accumulation compared with the use of a conventional approach
where each participant is assigned the same ROI (group-level)?
Findings Significantly higher estimates of annual change in tau
positron emission tomography (PET) were found using several
of the participant-specific ROIs. Importantly, the simplest
individualized approach, where change in tau PET was calculated
in an ROI that best matched the participant’s data-driven disease
stage, performed best.
Meaning Individualized ROIs carry an advantage over group-level
ROIs for assessing longitudinal tau PET and can increase the
sensitivity to detect treatment effects in AD trials.
Methods
Participants
This cohort study received ethical approval from the Regional
Ethical Committee in Lund, Sweden. Approval for PET imaging
was obtained from the Swedish Medicines and Products Agency
and the local Radiation Safety Committee at Skåne University
Hospital in Sweden. All participants gave written informed con-
sent. We included cognitively unimpaired (CU) individuals, pa-
tients with mild cognitive impairment (MCI), and those with
AD dementia from the prospective and longitudinal Swedish
Biomarkers For Identifying Neurodegenerative Disorders Early
and Reliably 2 (BioFINDER-2) study.21 Participants were enrolled
between September 18, 2017, and November 15, 2021. Inclusion
and exclusion criteria have been described elsewhere (eMethods
1 in Supplement 1).22,23 CU individuals were 60 years or older and
did not have MCI or dementia.22,23 Exclusion criteria included
presence of objective cognitive impairment, severe somatic dis-
ease, and current alcohol/substance misuse. Patients with MCI
fulfilled the Diagnostic and Statistical Manual of Mental Disorders
(Fifth Edition) criteria for mild neurocognitive disorder whereas
patients with AD dementia fulfilled the DSM-5 criteria for ma-
jor cognitive impairment due to AD.24 Aβ status was defined using
CSFAβ42/Aβ40, as previously described.23 This study followed
the Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) reporting guidelines.
Image Acquisition and Processing
[18F]RO948 PET was performed on digital scanners (Discovery
MI [GE Healthcare]) 70 to 90 minutes after injection, as described
previously.22 As some off-target binding has been described in
the meninges for [18F]RO948,22 no smoothing was performed
during image reconstruction. To further reduce the possibility
an off-target signal, a more accurate meningeal segmentation was
obtained using T1/T2 magnetic resonance imaging (with Se-
quence Adaptive Multimodal Segmentation [SAMSEG] FreeSurfer
utility [Laboratory for Computational Neuroimaging]),25 which
was then used to prune the adjacent FreeSurfer ROIs (eMethods
2 in Supplement 1). The corrected ROI set was then used in a geo-
metric transfer matrix (GTM) partial volume error correction.26
(Reprinted) JAMA Neurology June 2023 Volume 80, Number 6 615
 Research Original Investigation
Figure 1. Group-Level Regions of Interest (ROIs)
A Data-driven stages
Stage I Stage II Stage III
C Braak stages
Stage I Stage II Stage III
Group-level ROIs include previously published data-driven stages for [18F]RO948 (A), temporal and whole-brain meta-ROIs (B), and Braak stages (C).
Serial high-resolution T1-weighted magnetic resonance images
were acquired (3T MAGNETOM Prisma [Siemens Healthineers])
for PET image coregistration, template normalization, and seg-
mentation using longitudinal FreeSurfer, version 6.0.27 Standard-
ized uptake value ratio (SUVR) images were created using the in-
ferior cerebellar cortex as the reference region. A sensitivity analy-
sis was performed using an alternative reference region consisting
of the whole cerebellum, brainstem, and eroded subcortical white
matter. In keeping with the ROI-based analyses that were cor-
rected for partial volume effects using GTM, voxelwise analyses
were performed using region-based voxelwise correction,28
a partial-volume technique that extends the GTM method and
performs a voxelwise correction of the entire image.
Tau-PET ROI Definition
Complete details for group-level and individualized ROIs are
included in eMethods 3 and eTables 1, 2, and 3 in Supple-
ment 1. All approaches were implemented in native space.
Group-level ROIs (Figure 1) included previously described
stages for [18F]RO948,29 established using a data-driven ap-
proach combining clustering and event-based modeling.30,31
This approach identified target ROIs that were broadly con-
sistent with widely used [18F]flortaucipir-derived Braaklike
imaging stages and covered the full spectrum of AD tau aggre-
gation, from early to later affected areas. In addition, we in-
cluded whole-brain and temporal meta-ROIs.32 A sensitivity
analysis was performed using Braak ROIs.33
For individualized ROIs (Figure 2), the following 5 approaches
were used: (1) quartile 1 (Q1), (2) probability based, (3) overlap in-
dex, (4) highest tau-PET–positive data-driven stage (DDS), and
616 JAMA Neurology June 2023 Volume 80, Number 6 (Reprinted)
Downloaded From: https://jamanetwork.com/ on 09/04/2023
Brain Regions for Measuring Change in Longitudinal Tau PET in Alzheimer Disease
B Meta-ROIs
Stage IV Stage V Temporal Whole brain
Stage IV Stage V Stage VI
(5) subtype and stage inference (SUSTAIN). In Q1, as described
elsewhere,20 Gaussian-mixture modeling (GMM) was first
performed across all 200 cortical regions of the Schaefer brain
atlas34 in order to extract the probability of being tau-PET posi-
tive for each region. After establishing participant-specific tau-
PET epicenters (ie, the top 10% regions with the highest prob-
ability of having abnormal tau-PET SUVR values), the functional
connectivity-based distance of each the remaining ROIs to the
epicenter was determined and divided into nonoverlapping
quartiles based each region’s connectivity to the epicenter.20
Q1, representing the top 25% regions with strongest functional
connectivity to the epicenter, was used to calculate change in tau-
PET SUVR. Functional connectivity data was obtained from
69 CU individuals from the ADNI cohort who were Aβ-negative
and had low (global SUVR <1.30) tau-PET binding.35 Distance
between epicenter and nonepicenter ROIs was determined by
converting average participant-specific functional connectivity
matrices to a distance-based connectivity matrix, with shorter
path length between ROIs indicating stronger connectivity.36
Using the probability-based approach, the probability of
being tau-PET positive was extracted for each region from the
FreeSurfer atlas using GMM.20 Different probability intervals
were then selected, with brain regions with probabilities within
the selected interval combined into a composite ROI for each
participant and used to calculated change in tau-PET SUVR.
The probability interval yielding the highest average change
across participants was then selected.
Overlap index is a recently proposed method that assesses
the stability of voxels above a defined threshold,37 based on the
assumption that suprathreshold voxels that remain stable over
jamaneurology.com
 Brain Regions for Measuring Change in Longitudinal Tau PET in Alzheimer Disease Original Investigation Research

Figure 2. Approaches to Derive Individualized Regions of Interest (ROIs)

A Quartile 1 approach B Probability-based approach

1. Extract probabilities of tau positivity from ROIs 2. Define tau epicenters 1. Extract probabilities of tau positivity from ROIs

GMM applied to ROI-specific tau PET SUVRs ROIs GMM applied to ROI-specific tau PET SUVRs ROIs
2.0 2.0

1.5 Tau negative 1.5 Tau negative

Participants
Density

Density
Tau-positive Tau-positive

Participants
Tau positive probabilities Tau positive probabilities
1.0 1.0

0.5 0.5

0 0
1 2 3 4 5 1 2 3 4 5
SUVR Epicenter (top 10%) SUVR

3. Identify quartile 1 using connectivity-based distance to epicenters 2. Calculate change in SUVR across different
Connectivity-based distance 72-ROI probability intervals
200-ROI brain parcellation
to epicenter 6
brain parcellation 8.18 0.2-0.7 0.2-0.8 0.2-0.9 0.2-1
4
7.42
Longitudinal change in tau PET

Mean tau PET SUVR change per y, %

6.67 Select interval
Q1 0
5.91 with highest
5.16 Aβ+CU Aβ+CU Aβ+CU Aβ+CU
Q2 annual Group
4.4
3.65 percentage
Q3 6
2.89 change in 0.3-0.7 0.3-0.8 0.3-0.9 0.3-1
4
2.14 SUVR
1.38
Q4 2
0.63 0
Connectivity-based distance to epicenter Aβ+CU Aβ+CU Aβ+CU Aβ+CU
Group

6 0.4-0.7 0.4-0.8 0.4-0.9 0.4-1

C Overlap Index approach 4

2
Apply cutoff of 0
Tau PET SUVR
SUVR >1.4 Aβ+CU Aβ+CU Aβ+CU Aβ+CU
Binary masks Group

D Highest tau PET-positive DDS approach

Spatial overlap For each of the 5 DDS ROIs

Tau PET positive
Follow-up Follow-up Apply GMM-based cutoff
Tau PET negative
DDSs

Stage I Stage IV
Select highest DDS that is tau
PET positive and calculate
Stage II Stage V
change in SUVR in that stage
Stage III
Baseline Baseline

A, In the quartile 1 approach, we extracted gaussian mixture modeling intervals. In order to limit the number of intervals, 0.2 to 0.4 (ie, 0.2, 0.3, 0.4)
(GMM)–based probabilities of being tau positive from all brain regions in the and 0.7 to 1 (ie, 0.7, 0.8 0.9, 1) were used as lower and upper start values,
Schaefer brain atlas and defined the top 10% of ROIs as tau epicenters (ie, brain respectively. The interval that resulted in the highest annual percentage change
regions in which tau emerges first). After calculating the connectivity-based in tau-PET SUVR across participants was then selected for use. The approach is
distance of each ROI to the participant-specific epicenters, ROIs were grouped illustrated for amyloid-β (Aβ)–positive cognitively unimpaired (CU) individuals.
into nonoverlapping quartiles on the basis of their connectivity-based distance C, In the overlap index approach, change in tau PET was determined using the
to the epicenter (ie, quartile 1 [Q1] is closest to the epicenter). B, In the mask resulting from the spatial overlap of the baseline and follow-up scans.
probability-based approach, GMM-based probabilities of being tau positive D, In the highest tau-PET–positive data-driven stage (DDS) approach, cutoffs
were first extracted from the FreeSurfer (Laboratory for Computational were applied to baseline SUVR data in group-level data-driven ROIs, with
Neuroimaging) atlas and change in tau–positron emission tomography (PET) change calculated using the highest (ie, latest in the tau progression cascade)
standardized uptake value ratio (SUVR) calculated across different probability ROI that was tau positive.

time represent a true positive signal due to tau pathology and hierarchical pattern in the cortex.29,38,39 We hypothesized that
not random variability. Only cortical gray matter was consid- change in tau-PET SUVRs would be highest in those regions
ered, with a mask extracted from the FreeSurfer segmenta- most recently affected. We therefore applied GMM-based
tion. After obtaining masks for the baseline and follow-up scans cutoffs to baseline SUVR values for each of the 5 DDS ROIs
using an SUVR threshold of greater than 1.40, their spatial over- (designated stages 1-5) (Figure 1) to determine which of these
lap was determined, with the resulting mask then used to cal- ROIs were affected by tau at baseline in each individual. Next,
culate change in tau-PET SUVR. In keeping with the ROI-based we measured longitudinal change in the ROI affected last in
analyses, the analysis was performed in native space. the tau accumulation cascade in each participant (eg, using
The highest tau-PET–positive DDS is based on in vivo tau- the stage 4 ROI in an individual positive in stage ROIs 1, 2, 3,
PET studies showing that tau aggregation in AD follows a and 4) (eTable 4 in Supplement 1).

jamaneurology.com (Reprinted) JAMA Neurology June 2023 Volume 80, Number 6 617

Downloaded From: https://jamanetwork.com/ on 09/04/2023

 Research Original Investigation
Table. Characteristics of Participants in the Biomarkers For Identifying Neurodegenerative Disorders Early
and Reliably 2 (BioFINDER-2) Cohort
Amyloid-β positive
Characteristic CU (n = 97) MCI (n = 77)
Age, mean (SD), y 68.89 (9.19) 72.39 (7.68)
Sex, No. (%)
Male 51 (52.6) 42 (54.5)
Female 46 (47.4) 35 (45.5)
Education, mean (SD), y 12.38 (3.57) 13.11 (4.63)
MMSE score, mean (SD) 28.68 (1.45) 26.81 (1.97)
Tau PET, mean (SD) scan 1.83 (0.36) 1.92 (0.53)
interval, y
SUSTAIN is an unsupervised machine-learning tech-
nique that identifies population subgroups with common
patterns of disease progression.40 Specifically, it first identi-
fies subtypes and then reconstructs the trajectory of stages
within each subtype, with a subtype and stage assigned to each
participant. SUSTAIN has recently been used to identify 4
tau-PET subtypes in AD using [18F]flortaucipir.16
The 4-subtype model was applied to probabilistically as-
sign individuals to 1 of 30 progressive stages along 1 of 4 sub-
type trajectories. In order to create an individualized ROI
for each participant, the FreeSurfer regions included in each
stage were grouped as follows: 1 to 10, 11 to 20, and 21 to 30.
Power and Sensitivity Analysis Comparing Change
in SUVR and Tau Extent
As preliminary data using [18F]GTP-1 has shown greater sen-
sitivity to longitudinal change in tau PET using tau extent, de-
fined as the number of voxels above a defined threshold
divided by the total number of voxels in that region (ie, the
percentage of abnormal voxels within a given region), in
the temporal meta-ROI,41 we compared sample size reduc-
tion using annual percentage change in tau extent and SUVR
for [18F]RO948 in this region (eMethods 3 in Supplement 1).
Independent Validation Sample
Participants (Aβ-positive CU individuals and those with Aβ-
positive MCI and AD dementia) with longitudinal [18F]flortaucipir
tau PET (from the AVID 05e, Expedition-3, ADNI, and Sweden
BioFINDER-1 cohorts) were included as a validation cohort. In-
clusionandexclusioncriteriaaredescribedelsewhere42;Aβ-status
was determined using amyloid-PET (AVID 05e and Expedition-
3, [18F]florbetapir; ADNI, [18F]florbetaben or [18F]florbetapir;
BioFINDER, [18F]flutemetamol) and neocortical composite
cutoffs (eMethods 4 in Supplement 1). Although the group-level
ROIs were the same as those used with [18F]RO948, individual-
ized ROIs were redefined using [18F]flortaucipir.
Statistical Analyses
Annual percentage change in tau-PET SUVR was determined
between baseline and follow-up within ROIs. This was calcu-
lated as the difference between follow-up and baseline, di-
vided by baseline uptake and divided by the time interval be-
tween scans in years. Annual change in SUVR [(follow-up SUVR
− baseline SUVR) / change in time] is reported in eTables 4 to
7 in Supplement 1. In order to test whether the annual changes
618 JAMA Neurology June 2023 Volume 80, Number 6 (Reprinted)
Downloaded From: https://jamanetwork.com/ on 09/04/2023
Brain Regions for Measuring Change in Longitudinal Tau PET in Alzheimer Disease
AD dementia
(n = 41)
72.57 (7.27)
18 (43.9)
23 (56.1) Abbreviations: AD, Alzheimer
11.70 (4.45) disease; CU, cognitively impaired;
MCI, mild cognitive impairment;
23.39 (1.82)
MMSE, Mini-Mental State
1.66 (0.34) Examination; PET, positron
emission tomography.
in tau-PET SUVR were significant, 1-sample t tests against 0
were performed groupwise for each ROI. To determine the ef-
fect of ROI on sample size requirements in theoretical trials
using tau PET as outcome, a power analysis was performed
groupwise, assuming 20%, 30%, or 40% reductions in the an-
nual percentage change in tau-PET SUVR compared with pla-
cebo. Differences between group-level and individualized
ROIs—for both annual change in SUVR and sample size reduc-
tions—were tested using bootstrapping (n = 1000; ie, does the
mean of the higher value exceed the 95% CI of the lower value).
All analyses were done with R version, 4.2.1 (R Foundation).
Results
Participant Characteristics and Change in Tau PET
A total of 215 participants (mean [SD] age, 71.4 (7.5) years;
111 male [51.6%]; 104 female [48.4%]) with longitudinal tau
PET were included in this analysis: 97 Aβ-positive CU individu-
als (45%), 77 Aβ-positive individuals with MCI (36%), and 41
individuals with AD dementia (19%) from the BioFINDER-2
study. Mean (SD) follow-up time was 1.8 (0.3) years. Partici-
pant characteristics are summarized in the Table. Group-level
ROIs are shown in Figure 1 whereas the approaches used to de-
rive individualized ROIs are shown in Figure 2 and Figure 3.
A total of 406 participants with longitudinal [18F]flor-
taucipir tau PET composed the validation sample: 137 Aβ-
positive CU individuals, 144 with Aβ-positive MCI, and 125 with
AD dementia. The validation sample included participants from
the following study cohorts AVID 05e (n = 151), Expedition-3
(n = 82), ADNI (n = 117), and Sweden BioFINDER-1 (n = 56).
Usinggroup-levelROIs,thelargestannualpercentageincrease
in [18F]RO948 SUVR in Aβ-positive CU individuals was seen in DDS
I (entorhinal cortex, hippocampus, and amygdala: 4.29%; 95%
CI, 3.42%-5.16%; P < .001) (Figure 4A). In Aβ-positive individu-
als with MCI, the greatest change was seen in DDS II (temporal cor-
tical regions: 5.82%; 95% CI, 4.67%-6.97%; P < .001) (Figure 4A),
whereas in individuals with AD dementia, the greatest change was
seen in stage III (parietal regions: 7.47%; 95% CI, 6.18%-8.78%;
P < .001) (Figure 4A; eTables 4 and 5 in Supplement 1). Findings
from 1-sample t tests are included in the eTables 4, 5, 6, and 7 in
Supplement 1. Findings using Braak ROIs were similar to those
using DDSs (eTables 6 and 7 in Supplement 1). Across both data-
driven and Braak ROIs, variation in the number of tau-positive
ROIs decreased across clinical groups (eTable 8 in Supplement 1).
jamaneurology.com
 Brain Regions for Measuring Change in Longitudinal Tau PET in Alzheimer Disease
Figure 3. Subtype and Stage Inference Regions of Interest
A Limbic-predominant phenotype B MTL-sparing phenotype
Limbic-predominant stage 5 Limbic-predominant stage 10
The 4-tau–positron emission tomography (PET) subtypes are shown.
A, Subtype 1, limbic-predominant phenotype. B, Subtype 2, medial temporal
lobe (MTL) sparing. C, Subtype 3, posterior occipitotemporal phenotype.
Estimates of annual change in SUVR were generally numerically
higher using individualized ROIs (Figure 4A). However, signifi-
cance levels varied by ROI and disease stage (eTable 9 in Supple-
ment 1). Although all individualized ROIs outperformed group-
level DDS I in Aβ-positive CU participants (DDS I, 4.29%; 95%
CI, 3.42%-5.16%; overlap index, 5.14%; 95% CI, 4.29%-6.13%;
SUSTAIN, 5.32%; 95% CI, 4.33%-6.31%; probability, 5.89%; 95%
CI, 5.23%-6.84%; highest tau-PET–positive DDS, 6.69%; 95% CI,
5.66%-7.54%; all P <.001), only the probability and highest tau-
PET–positive DDS approaches resulted in significantly higher es-
timates of annual percentage change in [18F]RO948 SUVR com-
paredwiththebest-performinggroup-leveldata-drivenROIacross
Aβ-positive CU individuals and those with MCI (DDS II, 5.82%;
95% CI, 4.67%-6.97%; probability, 7.92%; 95% CI, 6.82%-9.02%;
highest tau-PET–positive DDS, 8.67%; 95% CI, 7.49%-9.85%;
P <.001) and AD dementia (DDS III, 7.47%; 95% CI, 5.98%- 8.96%;
probability, 9.20%; 95% CI, 7.95%-10.45%; highest tau-PET–
positive DDS, 10.74%; 95% CI, 9.33%-11.84%; P <.001).
Using individualized ROIs, the highest tau-PET–positive
DDS approach performed best across diagnostic groups
(Aβ-positive CU, 6.69%; 95% CI, 5.83%- 7.55%; P < .001; Aβ-
positive MCI, 8.67%; 95% CI, 7.49%-9.85%; P < .001; AD de-
mentia, 10.74%; 95% CI, 9.33%-12.20%; P < .001) (eTable 9
in Supplement 1), even when using an alternative reference
region combining the cerebellum, brainstem, and eroded
subcortical white matter (eFigure in Supplement 1).
Power Analysis for Hypothetical Clinical Trials
Having compared annual percentage change estimates for
[18F]RO948 using group-level and individualized ROIs, we es-
timated sample size requirements for a simulated intervention
that reduced longitudinal tau accumulation by 30%. For each
group (ie, Aβ-positive CU, Aβ-positive MCI, and AD dementia),
jamaneurology.com
Downloaded From: https://jamanetwork.com/ on 09/04/2023
Original Investigation Research
C Posterior occipitotemporal phenotype D Lateral temporal phenotype
Limbic-predominant stage 15 Limbic-predominant stage 20
D, Subtype 4, lateral temporal. A representation of different stages (5, 10, 15,
20) for subtype 1 is displayed.
sample size reductions for group-level and individualized ROIs
were estimated compared with the temporal meta-ROI due to
its widespread use with tau PET in the AD field and the best-
performing group-level ROI (Figure 4B). In Aβ-positive CU in-
dividuals, sample size reductions for the individualized ROIs
ranged from 42.74% (overlap index, 95% CI, 35.44%-49.74%;
P < .001) to 72.10% (highest tau-PET positive DDS, 95% CI,
67.10%-77.20%; P < .001) compared with the temporal meta-
ROI and between 12.21% (overlap index, 95% CI, 5.91%-18.51%;
P = .01) and 56% (highest tau-PET–positive DDS, 95% CI, 51.17%-
60.10%; P < .001) compared with DDS I (Figure 4B). A similar pat-
tern was seen in Aβ-positive MCI sample size reductions be-
tween 15.94% (overlap index, 95% CI, 8.14%-23.74%; P = .001)
and 53.02% (highest tau-PET–positive DDS, 95% CI, 47.10%-
59.87%; P < .001) compared with temporal meta-ROI and be-
tween 12.22% (overlap index, 95% CI, 4.42%-18.10%; P = .01) and
50.38% (highest tau-PET–positive DDS, 95% CI, 45.43%-
55.34%; P < .001) compared with DDS II (Figure 4B). In AD de-
mentia, sample size reductions varied between 16.83% (over-
lap index, 95% CI, 8.78%-25.61%; P = .002) and 48.30% (highest
tau-PET–positive DDS, 95% CI, 41.03%-89.10%; P < .001) com-
pared with temporal meta-ROI and between 9.73% (overlap in-
dex, 95% CI, 2.68%-12.41%; P = .004) and 43.59% (highest tau-
PET–positive DDS, 95% CI, 38.39%-81.98%; P < .001) compared
with DDS III (Figure 4B). Only in Aβ-positive CU individuals were
significant differences seen between sample size reductions
using the temporal meta-ROI and best-performing DDS (quar-
tile 1: temporal meta-ROI, 50.56%; 95% CI, 44.63%-56.50%; DDS
I, 22%; 95% CI, 17.10%-26.94%; P <.001; overlap index: tempo-
ral meta-ROI, 42.74%; 95% CI, 35.44%-50.03%; DDS I, 11.65%;
95% CI, 5.36%-17.95%; P <.001; SUSTAIN; temporal meta-ROI,
47.88%; 95% CI, 38.45%-57.30%; DDS I, 17.76%; 95% CI, 9.34%-
26.18%; P <.001; probability based: temporal meta-ROI, 64.78%;
(Reprinted) JAMA Neurology June 2023 Volume 80, Number 6 619
 Research Original Investigation Brain Regions for Measuring Change in Longitudinal Tau PET in Alzheimer Disease

Figure 4. Annual Percentage Change in Tau–Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR)
and Sample Size Reductions in a Theoretical Clinical Trial Using Tau-PET as an End Point Using Different Regions of Interest (ROIs)

A Mean percentage change in [18F]RO948 SUVR per y B Mean percentage sample size reductions

Aβ-positive CU individuals Aβ-positive CU individuals

DDS I a
ROI type Quartile 1 DDS I a
DDS II a
Group level
DDS III Temporal
Individualized meta-ROI a
DDS IV Overlap index a
b
DDS V
a
Meta-temporal a
SUSTAIN a
Whole brain a
Quartile 1
a
Overlap index Probability a
a
SUSTAIN
Probability a
Highest tau-positive DDS a
Highest tau-positive DDS a

0 2 4 6 8 10 12 –100 –80 –60 –40 –20 0

Mean tau PET SUVR change per y, % Sample size reduction

Aβ-positive individuals with MCI Aβ-positive individuals with MCI

DDS I a
Quartile 1 DDS II
ROI type a
DDS II
Group level Temporal
DDS III
meta-ROI b
DDS IV Individualized Overlap index
b
DDS V
Meta-temporal a a
SUSTAIN
Whole brain b
Quartile 1
a
Overlap index Probability
a
SUSTAIN
Probability a
Highest tau-positive DDS
Highest tau-positive DDS a

0 2 4 6 8 10 12 –100 –80 –60 –40 –20 0

Mean tau PET SUVR change per y, % Sample size reduction

Individuals with AD dementia Individuals with AD dementia

DDS a
ROI type Quartile 1
DDS II DDS III a
Group level
DDS III Temporal
Individualized meta-ROI b
DDS IV Overlap index
b
DDS V
Meta-temporal a
SUSTAIN
Whole brain b
a
Quartile 1
a
Overlap index Probability
a
SUSTAIN
Probability a
Highest tau-positive DDS
Highest tau-positive DDS a
0 2 4 6 8 10 12 –100 –80 –60 –40 –20 0
Mean tau PET SUVR change per y, % Sample size reduction

A, Mean percentage change in [18F]RO948 SURV per year along with 95% CIs
for group level and individualized ROIs. P values are shown groupwise for
comparisons between individualized ROIs and the best-performing group-level
ROI. B, Mean percentage sample size reductions along with 95% CIs are shown
for group-level and individualized ROIs compared with the temporal meta-ROI
and best-performing data-driven ROIs (ie, data-driven stage I in amyloid β
(Aβ)–positive cognitively unimpaired [CU]; data-driven stage II in Aβ-positive
mild cognitive impairment [MCI]; data-driven stage III in Alzheimer disease [AD]
dementia). P values are shown for each bar for comparisons against 0.
Comparisons in sample reductions between temporal and the best-performing
data-driven stage were only significant in Aβ-positive CU individuals (ie, sample
size reductions were significantly greater in Aβ-positive CU individuals using
data driven stage I, compared with the temporal meta-ROI).
a
P <.001.
b
P <.01.

95% CI, 59.67%-69.89%; DDS I, 44.43%; 95% CI, 40.32%- (ie, the number of participants required per arm to detect an
48.54%; P <.001; highest tau-PET–positive DDS: temporal meta- intervention effect) assuming hypothetical intervention ef-
ROI, 72.10%; 95% CI, 66.60%-77.50%; DDS I, 55.90%; 95% CI, fects of 20%, 30%, and 40% are included in eTables 10, 11,
51.45%-60.35%; P <.001) (Figure 4B). Sample size estimations and 12 in the Supplement.

620 JAMA Neurology June 2023 Volume 80, Number 6 (Reprinted) jamaneurology.com

Downloaded From: https://jamanetwork.com/ on 09/04/2023

 Brain Regions for Measuring Change in Longitudinal Tau PET in Alzheimer Disease
Power and Sensitivity Analysis Comparing SUVR
and Tau Extent
When performing a sensitivity analysis comparing annual per-
centage change in tau extent and [18F]RO948 SUVR in the tem-
poral meta-ROI in a simulated intervention that reduced
longitudinal tau accumulation by 30%, sample sizes were
consistently lower for SUVR (Aβ-positive CU, 17.90%; 95%
CI, 11.47%-24.33%; P = .007; Aβ-positive MCI, 29.47%; 95% CI,
19.55%-39.39%; P = .003; AD dementia, 33.94%; 95%
CI, 25.02%-42.86%; P < .001) (eTable 13 in Supplement 1).
Independent Validation Sample
Among the 406 participants (137 Aβ-positive CU, 144 Aβ-positive
MCI, and 41 AD dementia) with longitudinal [18F]flortaucipir tau
PET, the mean (SD) age was 77.18 (7.74) years, and 41 were female
(48.32%) (eTable 14 in Supplement 1). Similar to findings in
BioFINDER-2, the largest annual increase in [18F]flortaucipir SUVR
was seen in stage I (3.88%; 95% CI, 3.17%-4.58%) in Aβ-positive
CU individuals, with Aβ-positive individuals with MCI and AD de-
mentia showing the largest increases in stages II (5.41%; 95% CI,
4.51%-6.31%) and III (6.08%; 95% CI, 4.90%-7.26%), respectively
(eTables 15, 16, 17, and 18 in Supplement 1). Further, individual-
ized ROIs resulted in significantly higher estimates of annual
percentage change compared with group-level ROIs, with the
highest tau-PET–positive DDS approach performed best across
diagnostic groups (eTables 15 and 16 in Supplement 1). Similar
to [18F]RO948, sample size reductions were greater using indi-
vidualized ROIs compared with group-level ROIs, with highest
tau-PET–positive DDS performing best (eTables 19, 20, and 21
in Supplement 1).
Discussion
In this cohort study, we compared 2 approaches to defining ROIs
for use with longitudinal tau PET: a group-level approach, where
the same ROI was used for each participant, and an individual-
ized approach where each participant received their own specific
ROI. Our main finding suggests that individualized ROIs increased
the sensitivity to detect longitudinal tau accumulation as well
as intervention effects in simulated clinical trials using tau PET
as outcome. The added value of the individualized ROIs—in terms
of sensitivity to change in tau-PET signal over time and required
sample size—was greater in the Aβ-positive CU group, compared
with the Aβ-positive MCI and AD dementia groups. Importantly,
among the methods used to generate the individualized ROIs, the
simplest approach (highest tau-PET–positive DDS, where change
in tau PET was calculated in the highest tau-PET–positive DDS)
performed best, providing the highest tau-PET change estimates
and sample size reductions.
Findings using group-level data-driven and PET-based Braak
ROIs were consistent with previous longitudinal tau-PET stud-
ies in that tau accumulation was primarily seen in the medial
temporal lobe early in the disease process (ie, DDS I and Braak
I/II in Aβ-positive CU individuals) and primarily in temporal
and parietal cortical regions (ie, DDSs II/III and Braak III/IV)
in Aβ-positive individuals with cognitive impairment,13,38,43-46
consistent with the hierarchical Braak staging model of tau
jamaneurology.com
Downloaded From: https://jamanetwork.com/ on 09/04/2023
Original Investigation Research
progression.5,47,48 The greater sensitivity of individualized
assessment of tau accumulation over spatially predefined ROIs
(eg, data-driven or Braak ROIs) across groups, however, suggests
the view that tau deposition can be heterogeneous in AD.7-10
Variation in the number of tau-PET–positive data-driven or Braak
ROIs showed that the regional heterogeneity of tau accumula-
tion decreased with disease progression. This observation, com-
bined with the fact that the differences in sample size reductions
between individualized and groupwise ROIs were only signifi-
cant in Aβ-positive CU individuals, suggests that the utility of in-
dividualized ROIs may be greatest at the preclinical stage of AD.
Heterogeneity in tau deposition may be associated with varying
tau starting sites (ie, epicenters) and the subsequent spread of
tau via connections between brain regions. Previous work using
[18F]flortaucipir found that tau accumulation rates were high-
est in brain regions with the closest connectivity-based proxim-
ity to tau epicenters (ie, Q1)20; here, we reproduced these find-
ings and extended them through our comparison with DDSs.
A similar explanation may also apply to the SUSTAIN-based
subtypes in that the distinct tau-PET patterns seen across the
4 different subtypes resembled macroscale neuronal networks
seeded from different regions within the temporal lobe.16
On the basis of earlier work showing that tau pathology may pla-
teau or decrease with more advanced disease stage,49 contrib-
uting to interindividual variation in longitudinal change, the
probability-based approach was an attempt to exclude both
low-probability regions unlikely to show tau accumulation and
high-probability regions thought to be at or approaching their
maximum possible concentrations of tau.49,50
Consistent with the hierarchical aggregation characteristic
of the Braak staging system for tau,5,47,48 we found that tau ac-
cumulation was greatest using the highest DDS showing abnor-
mal [18F]RO948 SUVR levels (highest tau-PET–positive DDS).
Though tau-PET positivity and pathological tau accumulation
were also seen in the stages preceding the highest abnormal stage,
suggesting that although there is an increasing burden of tau
across the brain—as opposed to the spread of tau from one unin-
volved area to the next—the accumulation of tau aggregates was
greatest in the most recently affected brain region. In the context
of clinical trials using tau PET as outcome, this approach would
be comparatively straightforward to implement. Using the base-
linetau-PETscan,prespecifiedtracer-specificcutoffsderivedfrom
a large academic cohort could be applied to either data-driven or
Braak ROIs, with the highest tau-PET–positive ROI then selected
for longitudinal use. However, further studies are required to as-
sess the reproducibility of the thresholds for tau positivity pre-
sented here. In addition to its simplicity, the fact that the high-
est tau-PET–positive DDS approach was the best-performing ROI
across groups suggests that it could be used in trials across the AD
continuum. Although cognitive decline is typically considered as
a primary outcome measure for clinical trials,51 recent work has
highlighted the potential role of tau PET in clinical trials.19,29 This
is further evidenced by antitau drugs entering the clinical trial
pipeline.52 Although further comparative studies are required,
due to large within- and between-patient variability in frequently
used cognitive measures,53 tau PET may allow for AD trials of
shorter duration and with fewer participants. Lastly, comparison
of sample size reductions between annual percentage change
(Reprinted) JAMA Neurology June 2023 Volume 80, Number 6 621
 Research Original Investigation Brain Regions for Measuring Change in Longitudinal Tau PET in Alzheimer Disease

in tau extent and SUVR in the temporal meta-ROI suggests that
SUVR may be the preferred metric for longitudinal tau PET.
Strengths and Limitations
Strengths of this study include that we compared several group-
level and individualized approaches to defining ROIs, with the
methods used for individualized ROIs varying in their level
of complexity. Further, our study covered the clinical con-
tinuum of AD and had a comparatively long follow-up inter-
val that was similar across groups. Importantly, we replicated
our main findings with [18F]RO948 using longitudinal [18F]flor-
taucipir PET in an independent cohort. Limitations include the
modest number of participants scanned with [18F]RO948 in the
AD dementia group and the fact that we could not esti-
mate within-participant measurement error because partici-
pants only had 2 tau-PET scans. This study contributes to the
continuing investigation of optimized trial outcomes and
precision medicine.54
Conclusions
Findings of this cohort study suggest that individualized ROIs
carried an advantage over group-level ROIs for assessing lon-
gitudinal tau changes and may increase the sensitivity to de-
tect treatment effects in AD clinical trials using longitudinal
tau-PET as an outcome. Future studies should assess addi-
tional methods for defining individualized ROIs.

ARTICLE INFORMATION
Accepted for Publication: February 15, 2023.
Published Online: May 8, 2023.
doi:10.1001/jamaneurol.2023.1067
Open Access: This is an open access article
distributed under the terms of the CC-BY License.
© 2023 Leuzy A et al. JAMA Neurology.
Author Affiliations: Clinical Memory Research
Unit, Department of Clinical Sciences, Lund
University, Malmö, Sweden (Leuzy, Binette,
Strandberg, Mattsson-Carlgren, Palmqvist,
Stomrud, Ossenkoppele, Smith, Hansson); Penn/
CHOP Lifespan Brain Institute, University of
Pennsylvania, Philadelphia (Vogel); Department of
Psychiatry, University of Pennsylvania, Philadelphia
(Vogel); F. Hoffmann-La Roche Ltd, Basel,
Switzerland (Klein, Borroni, Tonietto); Department
of Neurology, Skåne University Hospital, Lund,
Sweden (Mattsson-Carlgren, Smith); Wallenberg
Centre for Molecular Medicine, Lund University,
Lund, Sweden (Mattsson-Carlgren); Memory Clinic,
Skåne University Hospital, Lund, Sweden
(Palmqvist, Stomrud, Hansson); Avid
Radiopharmaceuticals, Philadelphia, Pennsylvania
(Pontecorvo, Iaccarino); Eli Lilly and Company,
Indianapolis, Indiana (Pontecorvo, Iaccarino);
Alzheimer Center Amsterdam, Neurology,
Vrije Universiteit Amsterdam, Amsterdam UMC
location VUmc, Amsterdam, the Netherlands
(Ossenkoppele); Amsterdam Neuroscience,
Neurodegeneration, Amsterdam, the Netherlands
(Ossenkoppele).
Author Contributions: Drs Leuzy and Hansson had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Leuzy, Vogel, Klein, Borroni,
Ossenkoppele, Hansson.
Acquisition, analysis, or interpretation of data:
Leuzy, Pichet Binette, Vogel, Klein, Tonieto,
Strandberg, Mattsson-Carlgren, Palmqvist,
Pontecorvo, Iaccarino, Stomrud, Smith, Hansson.
Drafting of the manuscript: Leuzy.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Leuzy, Vogel, Strandberg,
Mattsson-Carlgren.
Obtained funding: Mattsson-Carlgren, Palmqvist,
Ossenkoppele, Smith, Hansson.
Administrative, technical, or material support: Klein,
Borroni, Strandberg, Palmqvist, Smith, Hansson.
Supervision: Klein, Tonieto, Ossenkoppele, Hansson.
Conflict of Interest Disclosures: Dr Leuzy reported
receiving consultant fees from Enigma Biomedical
USA outside the submitted work. Drs Klein, Borroni,
and Tonietto reported being full-time employees of
F. Hoffmann-La Roche during the conduct of the
study. Dr Palmqvist reported serving on scientific
advisory boards and/or given lectures in symposia
sponsored by BioArctic, Biogen, Cytox, Eli Lilly,
Geras Solutions, and Roche. Drs Pontecorvo and
Iaccarino reported being full-time employees and
shareholders of Eli Lilly and Company. Dr Hansson
reported receiving nonfinancial support (precursor
of RO948 and AVID PET images) from AVID/Eli Lilly
during the conduct of the study and consultant/
speaker fees from AC Immune, Amylyx, Alzpath,
ADx, AVID Radiopharmaceuticals, Biogen, Cerveau,
Eli Lilly, Eisai, Fujirebio, Genentech, Novartis,
BioArctic, GE Healthcare, Pfizer, Roche, and
Siemens outside the submitted work. No other
disclosures were reported.
Funding/Support: This work was supported in part
by grants 2016-00906 and 2018-02052 from
the Swedish Research Council, grant 2017-0383
from the Knut and Alice Wallenberg Foundation,
grant 2015.0125 from the Marianne and Marcus
Wallenberg Foundation, the Strategic Research
Area MultiPark (Multidisciplinary Research in
Parkinson’s disease) at Lund University, grant
AF-939932 from the Swedish Alzheimer
Foundation, grants FO2019-0326 and
FO2022-0204 from the Swedish Brain Foundation,
grant 1280/20 from the Parkinson Foundation of
Sweden, grant 2020-O000028 from the Skåne
University Hospital Foundation, grants 2020-0314
and 2020-0383 from Regionalt Forskningsstöd,
grants 2018-Projekt0279 and 2018-Projekt0226
from the Swedish federal government from the
Swedish federal government, and grant 949570
from the European Research Council under the
European Union’s Horizon 2020 research and
innovation program. The precursor of
18
F-flutemetamol was sponsored by GE Healthcare.
The precursor of 18F-RO948 was provided by
Roche. The precursor of 18F-flortaucipir was
provided by AVID Radiopharmaceuticals.
Role of the Funder/Sponsor: The funding source
ADNI contributed to the design and implementation
of ADNI and/or provided data but did not participate
in study analysis or interpretation of data, or in the
writing, review, or approval of the manuscript.
Group Information: Members of the Alzheimer’s
Disease Neuroimaging Initiative appear in
Supplement 2.
Data Sharing Statement: See Supplement 3.
Additional Information: Data used in preparation
of this article were obtained from the Alzheimer’s
Disease Neuroimaging Initiative (ADNI) database
(http://adni.loni.usc.edu/).
REFERENCES
1. Hansson O. Biomarkers for neurodegenerative
diseases. Nat Med. 2021;27(6):954-963.
doi:10.1038/s41591-021-01382-x
2. Strikwerda-Brown C, Hobbs DA, Gonneaud J,
et al; PREVENT-AD, HABS, and AIBL Research
Groups. Association of elevated amyloid and
tau positron emission tomography signal with
near-term development of Alzheimer disease
symptoms in older adults without cognitive
impairment. JAMA Neurol. 2022;79(10):975-985.
doi:10.1001/jamaneurol.2022.2379
3. Ossenkoppele R, Smith R, Mattsson-Carlgren N,
et al. Accuracy of tau positron emission
tomography as a prognostic marker in preclinical
and prodromal Alzheimer disease: a head-to-head
comparison against amyloid positron emission
tomography and magnetic resonance imaging.
JAMA Neurol. 2021;78(8):961-971. doi:10.1001/
jamaneurol.2021.1858
4. Gauthier S, Boxer A, Knopman D, et al.
Therapeutic targets for Alzheimer disease: amyloid
vs nonamyloid—where does consensus lie today:
a CTAD task force report. J Prev Alzheimers Dis.
2022;9(2):231-235. doi:10.14283/jpad.2022.29
5. Braak H, Braak E. Neuropathological staging of
Alzheimer-related changes. Acta Neuropathol. 1991;
82(4):239-259. doi:10.1007/BF00308809
6. Kaufman SK, Del Tredici K, Thomas TL, Braak H,
Diamond MI. Tau seeding activity begins in the
transentorhinal/entorhinal regions and anticipates
phospho-tau pathology in Alzheimer disease and
PART. Acta Neuropathol. 2018;136(1):57-67.
doi:10.1007/s00401-018-1855-6
7. Murray ME, Graff-Radford NR, Ross OA,
Petersen RC, Duara R, Dickson DW.
Neuropathologically defined subtypes of Alzheimer
disease with distinct clinical characteristics:
a retrospective study. Lancet Neurol. 2011;10(9):
785-796. doi:10.1016/S1474-4422(11)70156-9
8. Day GS, Gordon BA, Jackson K, et al. Tau-PET
binding distinguishes patients with early-stage
posterior cortical atrophy from amnestic Alzheimer
disease dementia. Alzheimer Dis Assoc Disord. 2017;
31(2):87-93. doi:10.1097/WAD.
0000000000000196

622 JAMA Neurology June 2023 Volume 80, Number 6 (Reprinted) jamaneurology.com

Downloaded From: https://jamanetwork.com/ on 09/04/2023

 Brain Regions for Measuring Change in Longitudinal Tau PET in Alzheimer Disease
9. Ossenkoppele R, Schonhaut DR, Schöll M, et al.
Tau PET patterns mirror clinical and neuroanatomical
variability in Alzheimer disease. Brain. 2016;139(Pt 5):
1551-1567. doi:10.1093/brain/aww027
10. Ossenkoppele R, Lyoo CH, Sudre CH, et al.
Distinct tau PET patterns in atrophy-defined
subtypes of Alzheimer disease. Alzheimers Dement.
2020;16(2):335-344. doi:10.1016/j.jalz.2019.08.201
11. Chiotis K, Saint-Aubert L, Rodriguez-Vieitez E,
et al. Longitudinal changes of tau PET imaging in
relation to hypometabolism in prodromal and
Alzheimer disease dementia. Mol Psychiatry. 2018;
23(7):1666-1673. doi:10.1038/mp.2017.108
12. Sintini I, Graff-Radford J, Senjem ML, et al.
Longitudinal neuroimaging biomarkers differ across
Alzheimer disease phenotypes. Brain. 2020;143(7):
2281-2294. doi:10.1093/brain/awaa155
13. Jack CR Jr, Wiste HJ, Schwarz CG, et al.
Longitudinal tau PET in aging and Alzheimer
disease. Brain. 2018;141(5):1517-1528. doi:10.1093/
brain/awy059
14. Pontecorvo MJ, Devous MD, Kennedy I, et al.
A multicentre longitudinal study of flortaucipir (18F)
in normal aging, mild cognitive impairment and
Alzheimer disease dementia. Brain. 2019;142(6):
1723-1735. doi:10.1093/brain/awz090
15. Harrison TM, La Joie R, Maass A, et al.
Longitudinal tau accumulation and atrophy in aging
and Alzheimer disease. Ann Neurol. 2019;85(2):
229-240. doi:10.1002/ana.25406
16. Vogel JW, Young AL, Oxtoby NP, et al;
Alzheimer’s Disease Neuroimaging Initiative. Four
distinct trajectories of tau deposition identified in
Alzheimer disease. Nat Med. 2021;27(5):871-881.
doi:10.1038/s41591-021-01309-6
17. Vogel JW, Hansson O. Subtypes of Alzheimer
disease: questions, controversy, and meaning.
Trends Neurosci. 2022;45(5):342-345. doi:10.1016/j.
tins.2022.02.001
18. Shcherbinin S, Evans CD, Lu M, et al.
Association of amyloid reduction after donanemab
treatment with tau pathology and clinical
outcomes: the TRAILBLAZER-ALZ randomized
clinical trial. JAMA Neurol. 2022;79(10):1015-1024.
doi:10.1001/jamaneurol.2022.2793
19. Giorgio J, Jagust WJ, Baker S, Landau SM,
Tino P, Kourtzi Z; Alzheimer’s Disease
Neuroimaging Initiative. A robust and interpretable
machine learning approach using multimodal
biological data to predict future pathological tau
accumulation. Nat Commun. 2022;13(1):1887.
doi:10.1038/s41467-022-28795-7
20. Franzmeier N, Dewenter A, Frontzkowski L,
et al. Patient-centered connectivity-based
prediction of tau pathology spread in Alzheimer
disease. Sci Adv. 2020;6(48):eabd1327. doi:10.1126/
sciadv.abd1327
21. The Swedish BioFINDER 2 Study (BioFINDER 2).
ClinicalTrials.gov identifier: NCT03174938. Updated
March 2, 2021. Accessed September 10, 2022.
https://clinicaltrials.gov/ct2/show/NCT03174938
22. Leuzy A, Smith R, Ossenkoppele R, et al.
Diagnostic performance of RO948 F 18 tau positron
emission tomography in the differentiation of
Alzheimer disease from other neurodegenerative
disorders. JAMA Neurol. 2020;77(8):955-965.
doi:10.1001/jamaneurol.2020.0989
23. Palmqvist S, Janelidze S, Quiroz YT, et al.
Discriminative accuracy of plasma phospho-tau217
for Alzheimer disease vs other neurodegenerative
disorders. JAMA. 2020;324(8):772-781.
doi:10.1001/jama.2020.12134
jamaneurology.com
Downloaded From: https://jamanetwork.com/ on 09/04/2023
24. American Psychiatric Association; DSM-5 Task
Force. Diagnostic and Statistical Manual of Mental
Disorders: DSM-5. 5th ed. American Psychiatric
Publishing; 2013.
25. Puonti O, Iglesias JE, Van Leemput K. Fast and
sequence-adaptive whole-brain segmentation using
parametric bayesian modeling. Neuroimage. 2016;
143:235-249. doi:10.1016/j.neuroimage.2016.09.011
26. Rousset OG, Ma Y, Evans AC. Correction for
partial volume effects in PET: principle and
validation. J Nucl Med. 1998;39(5):904-911.
27. Reuter M, Schmansky NJ, Rosas HD, Fischl B.
Within-subject template estimation for unbiased
longitudinal image analysis. Neuroimage. 2012;61
(4):1402-1418. doi:10.1016/j.neuroimage.2012.
02.084
28. Thomas BA, Erlandsson K, Modat M, et al.
The importance of appropriate partial volume
correction for PET quantification in Alzheimer
disease. Eur J Nucl Med Mol Imaging. 2011;38(6):
1104-1119. doi:10.1007/s00259-011-1745-9
29. Leuzy A, Smith R, Cullen NC, et al.
Biomarker-based prediction of longitudinal tau
positron emission tomography in Alzheimer
disease. JAMA Neurol. 2022;79(2):149-158.
doi:10.1001/jamaneurol.2021.4654
30. Young AL, Oxtoby NP, Daga P, et al; Alzheimer’s
Disease Neuroimaging Initiative. A data-driven
model of biomarker changes in sporadic Alzheimer
disease. Brain. 2014;137(Pt 9):2564-2577.
doi:10.1093/brain/awu176
31. Hilger K, Fukushima M, Sporns O, Fiebach CJ.
Temporal stability of functional brain modules
associated with human intelligence. Hum Brain Mapp.
2020;41(2):362-372. doi:10.1002/hbm.24807
32. Jack CR Jr, Wiste HJ, Weigand SD, et al.
Defining imaging biomarker cut points for brain
aging and Alzheimer disease. Alzheimers Dement.
2017;13(3):205-216. doi:10.1016/j.jalz.2016.08.005
33. Cho H, Choi JY, Hwang MS, et al. In vivo
cortical spreading pattern of tau and amyloid in the
Alzheimer disease spectrum. Ann Neurol. 2016;80
(2):247-258. doi:10.1002/ana.24711
34. Schaefer A, Kong R, Gordon EM, et al.
Local-global parcellation of the human cerebral
cortex from intrinsic functional connectivity MRI.
Cereb Cortex. 2018;28(9):3095-3114.
doi:10.1093/cercor/bhx179
35. Franzmeier N, Neitzel J, Rubinski A, et al;
Alzheimer’s Disease Neuroimaging Initiative
(ADNI). Functional brain architecture is associated
with the rate of tau accumulation in Alzheimer
disease. Nat Commun. 2020;11(1):347.
doi:10.1038/s41467-019-14159-1
36. Rubinov M, Sporns O. Complex network
measures of brain connectivity: uses and
interpretations. Neuroimage. 2010;52(3):1059-1069.
doi:10.1016/j.neuroimage.2009.10.003
37. Lee J, Burkett BJ, Min HK, et al. The overlap
index as a means of evaluating early tau PET signal
reliability. J Nucl Med. 2022;63(11):1748-1753.
doi:10.2967/jnumed.121.263136
38. Pascoal TA, Benedet AL, Tudorascu DL, et al.
Longitudinal 18F-MK-6240 tau tangles
accumulation follows Braak stages. Brain. 2021;144
(11):3517-3528. doi:10.1093/brain/awab248
39. Therriault J, Pascoal TA, Firoza LZ, et al.
Biomarker modeling of Alzheimer disease using
PET-based Braak staging. Nat Aging. 2022;2:525-535.
doi:10.1038/s43587-022-00204-0
40. Young AL, Marinescu RV, Oxtoby NP, et al;
Genetic FTD Initiative (GENFI); Alzheimer’s Disease
(Reprinted) JAMA Neurology June 2023 Volume 80, Number 6
Original Investigation Research
Neuroimaging Initiative (ADNI). Uncovering the
heterogeneity and temporal complexity of
neurodegenerative diseases with subtype and
stage inference. Nat Commun. 2018;9(1):4273.
doi:10.1038/s41467-018-05892-0
41. Sanabria Bohórquez S, Marik J, Ogasawara A,
et al. [18F]GTP1 (Genentech Tau Probe 1),
a radioligand for detecting neurofibrillary tangle
tau pathology in Alzheimer disease. Eur J Nucl Med
Mol Imaging. 2019;46(10):2077-2089.
doi:10.1007/s00259-019-04399-0
42. Smith R, Strandberg O, Mattsson-Carlgren N,
et al. The accumulation rate of tau aggregates is
higher in females and younger amyloid-positive
subjects. Brain. 2020;143(12):3805-3815.
doi:10.1093/brain/awaa327
43. Johnson KA, Schultz A, Betensky RA, et al.
Tau positron emission tomographic imaging in
aging and early Alzheimer disease. Ann Neurol.
2016;79(1):110-119. doi:10.1002/ana.24546
44. Pontecorvo MJ, Devous MD Sr, Navitsky M,
et al; 18F-AV-1451-A05 investigators. Relationships
between flortaucipir PET tau binding and amyloid
burden, clinical diagnosis, age, and cognition. Brain.
2017;140(3):748-763. doi:10.1093/brain/aww334
45. Sanchez JS, Becker JA, Jacobs HIL, et al. The
cortical origin and initial spread of medial temporal
tauopathy in Alzheimer disease assessed with
positron emission tomography. Sci Transl Med. 2021;
13(577):eabc0655. doi:10.1126/scitranslmed.abc0655
46. Lowe VJ, Wiste HJ, Senjem ML, et al.
Widespread brain tau and its association with
ageing, Braak stage and Alzheimer dementia. Brain.
2018;141(1):271-287. doi:10.1093/brain/awx320
47. Braak H, Alafuzoff I, Arzberger T,
Kretzschmar H, Del Tredici K. Staging of Alzheimer
disease-associated neurofibrillary pathology using
paraffin sections and immunocytochemistry. Acta
Neuropathol. 2006;112(4):389-404. doi:10.1007/
s00401-006-0127-z
48. Braak H, Braak E. Staging of Alzheimer’s
disease-related neurofibrillary changes. Neurobiol
Aging. 1995;16(3):271-278. doi:10.1016/0197-4580
(95)00021-6
49. Phillips JS, Nitchie FJ IV, Da Re F, et al;
Alzheimer’s Disease Neuroimaging Initiative. Rates
of longitudinal change in 18 F-flortaucipir PET vary
by brain region, cognitive impairment, and age in
atypical Alzheimer disease. Alzheimers Dement.
2022;18(6):1235-1247. doi:10.1002/alz.12456
50. Whittington A, Gunn RN; Alzheimer’s Disease
Neuroimaging Initiative. TauIQ: a canonical
image-based algorithm to quantify tau PET scans.
J Nucl Med. 2021;62(9):1292-1300. doi:10.2967/
jnumed.120.258962
51. Sperling RA, Rentz DM, Johnson KA, et al.
The A4 study: stopping AD before symptoms
begin? Sci Transl Med. 2014;6(228):228fs13.
doi:10.1126/scitranslmed.3007941
52. Cummings J, Blennow K, Johnson K, et al.
Antitau trials for Alzheimer disease: a report from
the EU/US/CTAD task force. J Prev Alzheimers Dis.
2019;6(3):157-163. doi:10.14283/jpad.2019.14
53. Sabbagh MN, Hendrix S, Harrison JE.
FDA position statement “Early Alzheimer disease:
developing drugs for treatment, guidance for
industry”. Alzheimers Dement (N Y). 2019;5:13-19.
doi:10.1016/j.trci.2018.11.004
54. Coughlan G, Coutrot A, Khondoker M,
Minihane AM, Spiers H, Hornberger M. Toward
personalized cognitive diagnostics of at-genetic-risk
Alzheimer disease. Proc Natl Acad Sci U S A. 2019;
116(19):9285-9292. doi:10.1073/pnas.1901600116
623