3917 Full

The Journal of Neuroscience, April 28, 2021 • 41(17):3917–3931 • 3917
Neurobiology of Disease
Reduced Repetition Suppression in Aging is Driven by

Tau–Related Hyperactivity in Medial Temporal Lobe
Jenna N. Adams,1 Anne Maass,1,2 David Berron,2,3 Theresa M. Harrison,1 Suzanne L. Baker,4
Wesley P. Thomas,4 Morgan Stanfill,1 and William J. Jagust1,4
1
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720, 2German Center for Neurodegenerative Diseases
(DZNE), Magdeburg 39120, Germany, 3Clinical Memory Research Unit, Lund University, Lund 223 62, Sweden, and 4Lawrence Berkeley National
Laboratory, Berkeley, California 94720
Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer’s disease (AD), and MTL neural dysfunc-
tion is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully
characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus pre-
sentations compared to novel stimuli. We used task-based functional MRI (fMRI) to assess MTL subregional activity in 21
young adults (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology
was measured with position emission tomography (PET), using 18F-Flortaucipir for tau and 11C-Pittsburgh compound B (PiB)
for amyloid-b (Ab). The MTL was segmented into six subregions using high-resolution structural images. We compared the
effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau– OA), to high tau pathology, also occur-
ring in temporal and limbic regions (Tau1 OA). Low levels of tau (Tau– OA vs YA) were associated with reduced repetition
suppression activity specifically in anterolateral entorhinal cortex (alEC) and hippocampus, the first regions to accumulate
tau. High tau pathology (Tau1 vs Tau– OA) was associated with widespread reductions in repetition suppression across
MTL. Further analyses indicated that reduced repetition suppression was driven by hyperactivity to repeated stimuli, rather
than decreased activity to novel stimuli. Increased activation was associated with entorhinal tau, but not Ab. These findings
reveal a link between tau deposition and neural dysfunction in MTL, in which tau-related hyperactivity prevents deactivation
to repeated stimuli, leading to reduced repetition suppression.
Key words: aging; Alzheimer’s disease; fMRI; PET; repetition suppression; tau
Significance Statement
Abnormal neural activity occurs in the medial temporal lobe (MTL) in aging and Alzheimer’s disease (AD). Because tau pa-
thology first deposits in the MTL in aging, this altered activity may be due to local tau pathology, and distinct MTL subregions
may be differentially vulnerable. We demonstrate that in older adults (OAs) with low tau pathology, there are focal alterations
in activity in MTL subregions that first develop tau pathology, while OAs with high tau pathology have aberrant activity
throughout MTL. Tau was associated with hyperactivity to repeated stimulus presentations, leading to reduced repetition sup-
pression, the discrimination between novel and repeated stimuli. Our data suggest that tau deposition is related to abnormal
activity in MTL before the onset of cognitive decline.
Introduction
Received Sep. 24, 2020; revised Mar. 2, 2021; accepted Mar. 5, 2021.
Alzheimer’s disease (AD) is characterized by pathological
Author contributions: J.N.A. and W.J.J. designed research; J.N.A, A.M., D.B., T.M.H., S.L.B., W.P.T., M.S., and aggregates of amyloid- b (A b ) and hyperphosphorylated
W.J.J. performed research; J.N.A., A.M., D.B., T.M.H., S.L.B., W.P.T., and M.S. analyzed data; J.N.A. and W.J.J. forms of the tau protein (Braak and Braak, 1991). These
wrote the paper. pathologies accumulate in the brains of cognitively normal
This work was supported by National Institutes of Health Grants F31-AG062090 (to J.N.A.), F32-AG057107
(to T.M.H.), and R01-AG034570 (to W.J.J.); the Tau Consortium (W.J.J.); and the Helmholtz Postdoc Grant PD-
older adults (OAs) 10–25 years before symptom onset and
306 (to A.M.). Avid Radiopharmaceuticals enabled the use of the [18] Flortaucipir tracer but did not provide are measurable with positron emission tomography (PET;
direct funding and were not involved in data analysis or interpretation. Schöll et al., 2016). While A b pathology arises multifocally
W.J.J. serves as a consultant to Biogen, Genentech, CuraSen, Bioclinica, and Novartis. All other authors throughout association cortex, tau pathology first deposits in
declare no competing financial interests.
Correspondence should be addressed to Jenna N. Adams at jnadams@berkeley.edu.
the medial temporal lobe (MTL), specifically in the transen-
https://doi.org/10.1523/JNEUROSCI.2504-20.2021 torhinal region, before spreading to temporal and limbic cor-
Copyright © 2021 the authors tex (Braak and Braak, 1985, 1991).
3918 • J. Neurosci., April 28, 2021 • 41(17):3917–3931 Adams et al. · Tau and Repetition Suppression Activity in Aging
Because the MTL is particularly vulnerable to tau pathology, and YA received high-resolution 3T structural and functional MRI dur-
determining how tau impacts the function and structure of this ing a memory task involving object and scene stimuli. A previous study
region is critical to understanding the transition from normal aging in our lab used this fMRI data to investigate object and scene processing
to disease. Abnormal neural activity in MTL regions such as ento- in anterior-temporal and posterior-medial brain networks (Maass et al.,
rhinal cortex and hippocampus has been found in OAs before evi- 2019). This previous study collapsed across trial-level performance, fo-
cusing on differences in activity between object and scene stimuli, and
dence of cognitive decline (Yassa et al., 2011; Huijbers et al., 2014;
thus did not investigate task-related memory processes. Here, we used a
Berron et al., 2018; Reagh et al., 2018), and thus may be an early subsample of 50 OAs and 22 YAs who additionally received high-resolution
response to pathology. Hippocampal hyperactivity, also found in T2 images necessary for MTL segmentation. We investigated MTL subre-
mild cognitive impairment (MCI) (Dickerson et al., 2005; Yassa et gional activity during repetition suppression, focusing on activity during
al., 2010), has been shown to be dysfunctional, as its reduction leads novel and repeated trial types. Three OA subjects had poor performance on
to improved cognitive performance (Bakker et al., 2012). the fMRI task (see below, fMRI task), and two OA and one YA had exces-
Initial studies investigating pathology and MTL activity sive motion during fMRI (see below, fMRI preprocessing); these subjects
observed A b -related hyperactivity primarily in the hippocampus were excluded, resulting in a final sample of 45 OA and 21 YA subjects. OA
(Sperling et al., 2009; Mormino et al., 2012a; Huijbers et al., subjects additionally received tau-PET with 18F-Flortaucipir, amyloid-PET
2014, 2015). However, these studies did not account for tau dep- with 11C-Pittsburgh Compound B (PiB), and neuropsychological
osition, since tau-PET is a relatively recent technology. Because assessment.
Inclusion criteria for the OA subjects included age of 60 or greater,
A b plaques do not accumulate in the MTL until late stages of
cognitively normal status (Mini-Mental State Exam 25 and neuropsy-
AD, tau may be more closely associated with abnormal MTL ac- chological scores within 1.5 SDs of age, education, and sex adjusted
tivity. Recent studies using PET or CSF measures of tau have norms), no serious neurologic, psychiatric, or medial illness, no major
supported stronger relationships between activation and tau than contraindications found on MRI or PET, and independent living in the
A b in hippocampus and cortical regions (Marks et al., 2017; community. Inclusion criteria for YA subjects were no major health
Berron et al., 2019; Huijbers et al., 2019; Maass et al., 2019). problems, no current or recent history of psychiatric illness, no history
However, a holistic characterization of how tau and/or A b may of neurologic disorders or traumatic brain injury, no substance abuse
differentially affect the activity of distinct subregions within problems, no depression or antipsychotic medications, and fluency in
English. The Institutional Review Boards of the University of California,
MTL is needed to fully understand these relationships.
Berkeley and the Lawrence National Laboratory approved this study. All
In the current study, we conduct a detailed analysis to determine participants provided written informed consent.
whether tau and Ab pathology, measured with PET, are associated
with abnormal MTL activity in cognitively normal OAs. We expand Functional and structural MRI
on previous reports focusing on hippocampus (Marks et al., 2017; 3T MRI acquisition
Huijbers et al., 2019) by measuring activity within six MTL subre- Structural and functional MRI was performed at the Henry H. Wheeler
gions using high-resolution neuroimaging. We investigate for the Jr. Brain Imaging Center with a 3T TIM/Trio scanner (Siemens Medical
first time how activity within regions that are highly vulnerable to system, software version B17A) and a 32-channel head coil. High-resolution
AD, such as entorhinal and perirhinal subregions, is related tau pro- whole brain structural images were acquired using a T1-weighted volumet-
gression and entorhinal tau pathology using PET. We use functional ric magnetization prepared rapid gradient echo image (MPRAGE; voxel
size = 1 mm isotropic, TR = 2300 ms, TE = 2.98 ms, matrix = 256 240
MRI (fMRI) to assess MTL activity during repetition suppression, a 160, FOV = 256 240 160 mm3, sagittal plane, 160 slices, 5-min acquisi-
phenomenon in which repeated stimuli show a dampened neural tion time).
response as compared to novel stimuli, presumably as the stimulus fMRI was then performed while subjects performed a mnemonic dis-
is remembered and does not require new encoding (Grill-Spector crimination task (see Berron et al., 2018; details below). High-resolution
et al., 2006). Repetition suppression is reduced in AD (Golby et al., whole-brain functional data were acquired using T2*-weighted gradient-
2005; Pihlajamäki et al., 2011), yet has been previously unexamined echo echoplanar images (GE-EPI; voxel size = 1.54 mm isotropic, multi-
in relation to tau pathology. band acceleration factor 4, TR = 2400 ms, TE = 37 ms, flip angle = 45,
We hypothesized that tau would be related to reduced repeti- matrix = 138 138, FoV = 212 212 mm2, interleaved acquisition, 88
tion suppression activity, and that this association would occur slices, PA phase encoding, two 13 min runs). Two gradient echo images
with different echo times were additionally collected to create a phase
in specific MTL subregions at different stages of tau pathological
map for distortion correction (1.54-mm isotropic resolution, R-L encod-
spread. We compared the effects of low tau pathology, restricted ing direction, TR = 1000, flip angle = 60, TE1 = 5.6 ms, TE2 = 8.06 ms).
to entorhinal cortex and hippocampus and nearly ubiquitous in To enable MTL subregion segmentation, high-resolution 3D T2-
aging (Braak and Braak, 1997), to high tau pathology, which has weighted structural turbo spin echo images were acquired in oblique
spread throughout MTL, lateral temporal, and limbic regions. coronal orientation perpendicular to the long axis of the hippocampus
We hypothesized that the low tau group would have focal reduc- (voxel size = 0.5 0.5 mm in-plane resolution, slice thickness = 1.5 mm,
tions in repetition suppression activity in the subregions that first TR = 3500 ms, TE = 353 ms, 64 slices, matrix = 384 384, GRAPPA fac-
accumulate tau: the anterolateral entorhinal cortex (alEC) and tor 2 acceleration).
perirhinal area 35 (which span the transentorhinal region) and
1.5T MRI acquisition and processing
the hippocampus. In the high tau group, individuals at a more
Structural MRIs were collected for standard PET processing at Lawrence
advanced stage of tau deposition, we expected to observe reduced Berkeley National Laboratory (LBNL). A whole brain high-resolution T1-
repetition suppression activity across the MTL. Finally, due to weighted volumetric magnetization prepared rapid gradient echo image
the lack of A b plaques in MTL in normal aging, and in line with (MPRAGE) was acquired on a 1.5T Siemens Magnetom Avanto scanner
emerging findings, we hypothesized that A b would not be asso- (Siemens, Inc; 1 mm isotropic voxels, TR = 2110 ms, TE = 3.58 ms,
ciated with MTL activation during repetition suppression. FA = 15). MRIs were used for PET coregistration, and segmented with
FreeSurfer v.5.3.0 (http://surfer.nmr.mgh.harvard.edu/) to derive native
space regions of interest (ROIs) for FTP and PiB quantification.
Materials and Methods
Participants fMRI task
Cognitively normal OAs and young adults (YAs) of either sex were Subjects performed a mnemonic discrimination task during fMRI acqui-
recruited as part of the Berkeley Aging Cohort Study (BACS). Both OA sition (Fig. 1A). Full details of the task have been described previously
Adams et al. · Tau and Repetition Suppression Activity in Aging J. Neurosci., April 28, 2021 • 41(17):3917–3931 • 3919
Figure 1. Visual representation of the fMRI task and MTL segmentation. A, OA and YA subjects performed a mnemonic discrimination task during fMRI acquisition. The first two stimuli of
each block (either object or scene sequences) are novel stimuli, while the second two stimuli are either repeated stimuli or highly similar lure stimuli. Subjects are instructed to respond old or
new to each stimulus. A perceptual baseline of scrambled noise images was shown at the start and end of the task. Repetition suppression was measured by contrasting activity between all
novel and all repeated stimuli. B, High-resolution (0.5 0.5 1.5 mm) T2 images in native space were segmented with ASHS to derive MTL ROIs for analysis. The full entorhinal cortex was
manually subdivided into alEC and pmEC subregions using template ROIs inverse warped to native space. Hippocampal subfields were merged into one hippocampal ROI before analyses.
Cortical ROIs: anterolateral entorhinal cortex (alEC), posteromedial EC (pmEC), area 35 of perirhinal cortex (A35), area 36 of perirhinal cortex (A36), parahippocampal cortex (PHC); hippocampal
subfields: subiculum (Sub), CA1, CA2, CA3, dentate gyrus (DG), hippocampal tail (Tail).
(Berron et al., 2018; Maass et al., 2019). Briefly, subjects saw blocks of ei- isotropic to increase signal-to-noise ratio while maintaining spatial spec-
ther four object or scene stimuli, where the first two stimuli each block ificity, consistent with previous studies (Berron et al., 2018, 2019). We
were novel, and the second two stimuli were either repeated stimuli or next used the function “art.m” (CONN toolbox, originally developed
highly similar lure stimuli. The subject was instructed to indicate “old” within the ArtRepair toolbox) to detect outliers in average intensity and
or “new” to each stimulus (repeated stimuli are considered old, novel/ motion, using a global intensity z-score of 5 and a movement threshold
lure stimuli are considered new). Before scanning, subjects completed a of 0.9 mm/TR. Outlier volumes were included as spike regressors, or
short training outside of the scanner. In the scanner, subjects completed “censored,” in the first-level design matrix (Lemieux et al., 2007; Power
two runs of the task, totaling 128 trials (64 first-repeat pairs, 64 first-lure et al., 2015). A threshold of 20% outlier volumes across both runs was
pairs). Each run began and ended with a perceptual baseline condition, used to exclude subjects, resulting in the exclusion of one YA and two
which consisted of scrambled noise images with similar luminosity and OA subjects. These motion thresholds are consistent with our previous
color to the test stimuli. Stimuli were presented in an event-related work (Maass et al., 2019), and chosen as a compromise to identify prob-
design using Neurobehavioral Systems (https://nbs.neurobs.com). Each lematic frames while still retaining as much data as possible with the pro-
object or scene image was shown for 3 s and separated by a white fixa- pensity of OA subjects to motion during fMRI tasks.
tion star with jittered interstimulus intervals ranging from 0.6 to 4.2 s.
As a measure of task performance, we calculated the corrected hit rate First level analysis
(hit rate–false alarm rate) for all stimuli. Subjects were excluded if cor- First level analyses were conducted with SPM12. A general linear model
rected hit rate was close to chance (corrected hit rate ,0.1; Maass et al., (GLM) was performed including novel stimuli, repeated stimuli, and
2019), leading to the exclusion of three OA subjects. lure stimuli collapsed across response, but modeling object and scene
stimuli separately. Scrambled noise images, as well as six motion regres-
fMRI preprocessing sors and outlier volumes, were also included as regressors. The two runs
Preprocessing was conducted with Statistical Parametric Mapping (SPM, were concatenated before modeling. We applied an implicit mask of 0.8
version 12, Wellcome Trust Center for Neuroimaging, London, United of the global signal (SPM default threshold) to remove areas of low sig-
Kingdom). The first five EPIs of each run were discarded to ensure T1 nal, which often include medial temporal regions. To calculate activation
equilibrium. Slice time correction was performed to correct for differen- for repetition suppression, we contrasted all novel stimuli with all
ces in acquisition, using the middle slice in time as a reference. Motion repeated stimuli, regardless of task performance. For subcomponent
and distortion correction was then performed using the FieldMap tool- measures of novel and repeated stimuli, we contrasted each with the per-
box v2.1 with the “realign and unwarp” SPM module. During this pro- ceptual baseline (scrambled noise images). For follow-up analyses inves-
cess, the T1 image was coregistered to the first EPI, and all EPIs were tigating the effects of stimulus type on repetition suppression, we
realigned to the first EPI image. EPIs were spatially smoothed with a repeated these contrasts but for object and scene stimuli separately. The
Gaussian kernel of full-width at half-maximum (FWHM) 4 mm mean b value for each contrast image was calculated for each unilateral
Figure 2. Example MTL segmentations and fMRI signal intensity. Representative images from a YA subject (A) and OA subject (B) are shown to visually demonstrate the quality of fMRI sig-
nal in each ROI. For each example subject, the MTL segmentation is overlaid on the mean functional image on the left column, and the mean functional image is shown by itself on the right
column. Slices are shown sagittally from medial to lateral (left) and coronally from anterior to posterior (right). ROIs: parahippocampal cortex (PHC), area 36 of perirhinal cortex (A36), area 35
of perirhinal cortex (A35), posteromedial EC (pmEC), anterolateral entorhinal cortex (alEC), hippocampus (hipp; all subfields merged). See Extended Data Figure 2-1 for corresponding propor-
tions of voxels retained in each region in YA and OA groups after removing voxels of low signal.
MTL ROI (after removing additional regions of low signal, see below, Table 1. Demographic characteristics of the sample
MTL segmentation). Tau– vs
Tau1 OA
YA OA Tau– OA Tau1 OA
MTL segmentation (n = 21) (n = 45) (n = 29) (n = 16) t or x 2 p
The MTL was automatically segmented into subregions with the soft-
ware package automated segmentation of hippocampal subfields (ASHS; Age (years) 26.8 (4.5) 78.1 (6.2) 79.3 (6.9) 75.9 (4.5) 1.78 0.08
Yushkevich et al., 2015) using the high-resolution structural T2 image Sex (female) 12 (57%) 28 (62%) 17 (58.6%) 11 (68.7%) 0.45 0.50
(Fig. 1B). Segmentation was based on a high-resolution atlas of the MTL Edu (years)a 16.9 (1.5) 16.9 (1.6) 17.0 (1.5) 16.9 (1.8) 0.01 0.99
trained on 38 individuals using 7T T2 structural images (Berron et al., MMSE 29.3 (0.9) 28.8 (1.1) 29.0 (0.9) 28.5 (1.4) 1.29 0.21
2017). This segmentation resulted in the following native space unilateral Global PiB DVRb n/a 1.17 (0.25) 1.12 (0.20) 1.26 (0.29) 1.62 0.12
subregions: parahippocampal gyrus, area 36 of perirhinal cortex, area 35 Ab 1 n/a 23 (51%) 12 (41.4%) 11 (68.7%) 2.74 0.10
of perirhinal cortex, entorhinal cortex, and hippocampal subfields (DG, APOE « 41c n/a 15 (33%) 7 (25.0%) 8 (50.0%) 2.83 0.09
CA1–CA3, subiculum, tail). All segmentations were manually inspected, Braak III/IV FTP n/a 1.23 (0.12) 1.16 (0.07) 1.34 (0.12) 5.96 ,0.001
and when necessary, edited for correctness. All values represent either M (SD), or N (%). Demographics for the Tau– and Tau1 OA groups were com-
Because of our interest in entorhinal subregions, the ASHS-derived pared with independent t tests or x 2 tests. Tau1 status was determined by whether the mean Braak III/IV
FTP value was .1.26. YA, young adults; OA, older adults; MMSE, Mini-Mental State Examination. APOE, alo-
entorhinal cortex was next segmented into anterolateral (alEC) and post- lipoprotein E; afour YA missing education; bone OA missing PiB; cone OA missing APOE.
eromedial (pmEC) subregions in a method similar to that of Berron et
al. (2019). Because pure anatomic segmentation of the border between
alEC and pmEC is challenging, we based our segmentation on template 2010). To do this, we created a study-specific template (separately for
space alEC and pmEC ROIs that were functionally defined at 7T in a YA and OA groups), coregistered the original template space alEC/
previous study (for details, see Maass et al., 2015). First, we inverse- pmEC ROIs to each study-specific template, and used ANTs to inverse
warped these template ROIs into native space using ANTs (Avants et al., warp the ROIs into native space for each subject. Next, we segmented
Figure 3. Tau-related differences in MTL activation for repetition suppression, novel stimuli, and repeated stimuli. A, Repetition suppression was quantified by contrasting activity between
novel and repeated stimuli, and compared across the YA, low tau (Tau– OA), and high tau (Tau1 OA) groups with ANOVAs and follow-up pairwise comparisons. Tau– OA demonstrated a sig-
nificant reduction in repetition suppression (vs YA) in bilateral hippocampus and alEC-R (independent samples t test, ps , 0.05). Tau1 OA demonstrated additional reductions in repetition
suppression across the MTL (vs YA and Tau– OA; ps , 0.05). B, C, To determine whether activity changes to novel and/or repeated stimuli were driving reduced repetition suppression, we
next investigated each subcomponent of the contrast separately. B, Activity to novel stimuli was compared to the perceptual baseline condition. There were minimal group differences in activ-
ity to novel stimuli, including both increases and decreases in activity. C, Activity to repeated stimuli was compared to the perceptual baseline condition. Hyperactivity in the Tau– OA group
(vs YA) was found in bilateral hippocampus and alEC-R, and hyperactivity in the Tau1 OA group (vs Tau– OA and YA) was found throughout the MTL. This hyperactivity to repeated stimuli
can be inferred to drive the reduction in repetition suppression seen in A. Significance above each bar reflects one sample t tests within each group, while lines across bars represent significant
group differences with independent samples t tests. Error bars represent SEM; pppp , 0.001, ppp , 0.01, pp , 0.05.
the ASHS-EC ROI into alEC and pmEC subregions using the division of concerns of signal drop out in MTL. This was performed by calculat-
produced from the functional alEC/pmEC template ROIs. The original ing the mean signal intensity across the entire bilateral MTL ROI for
borders of the ASHS-EC ROI were retained, but at each coronal slice, we each subject, and removing any individual voxels that fell below 2 SDs of
divided the EC ROI into alEC and pmEC based on the warped template the mean (Libby et al., 2012; Maass et al., 2015). Figure 2 depicts an
ROIs. Voxels falling within the warped alEC/pmEC ROIs, but outside of example YA and OA subject with their segmentation overlaid on their
the borders of the ASHS-EC ROI, were not retained in the final segmen- mean functional image to demonstrate signal quality within the MTL
tation, however this occurred infrequently. Anatomical guidelines from ROIs. Extended Data Figure 2-1 quantifies the average number of voxels
Maass et al. (2015) describing the location of the functional alEC/pmEC retained after removing low signal voxels for each ROI in each age
template ROIs were also considered for accuracy and quality assurance group. Additional implicit masking (as described above, First level analy-
of the inverse warping. In sum, this process resulted in each voxel of the sis) was applied to these corrected ROIs during fMRI modeling to ensure
original ASHS-EC ROI to be assigned to either alEC or pmEC. that low signal voxels were not affecting our results.
We next postprocessed the MTL ROIs (including the new alEC/
pmEC subregions) for fMRI analyses. First, we merged the hippocampal PET
subfields into one hippocampal ROI because of our resolution (1.5 mm PET acquisition
isotropic) not being ideal for a detailed examination of subfield activity, All OA participants received PET at LBNL within an average of
and to reduce the number of statistical tests, as we did not have subfield- 66 6 108 d (minimum = 1 d, maximum = 662 d; Tau– OA 72 6 126 d;
specific hypotheses about repetition suppression. Next, MTL ROIs were Tau1 OA 54 6 68 d) from the 3T MRI session. Tau was measured with
18
coregistered and resliced to functional image space using SPM. Finally, F-Flortaucipir (FTP; previously known as 18F-AV1451), which was
we additionally removed regions of low signal within each ROI because synthesized at the Biomedical Isotope facility at LBNL (described in
Schöll et al., 2016). Data were acquired on a BIOGRAPH PET/CT Table 2. Repetition suppression activation and group differences with older
Truepoint six scanner (Siemens, Inc) from either 75–115 min postinjec- adults divided into low (Tau–) and high (Tau1) tau groups
tion or 0–100 and 120–150 min postinjection. All data were binned into Activity within group
4 5 min frames from 80 to 100 min postinjection. CT scans were
acquired before the start of each emission acquisition. A b was measured YA Tau– OA Tau1 OA
using PiB, synthesized at the Biomedical Isotope Facility at LBNL t df p t df p t df p
(Mathis et al., 2003). Data were acquired on either the same BIOGRAPH
or an ECAT HR scanner (Siemens, Inc) across 35 dynamic frames for PHC-L 5.37 20 ,0.001 6.12 28 ,0.001 2.38 16 0.03
90 min postinjection (4 15, 8 30, 9 60, 2 180, 10 300, 2 600 PHC-R 5.53 20 0.001 5.53 28 ,0.001 3.95 16 0.001
s). A CT scan or PET transmission scan (ECAT HR) was acquired before A36-L 4.9 20 ,0.001 5.78 28 ,0.001 1.16 16 0.27
emission acquisition. Images were reconstructed with an ordered subset A36-R 5.23 20 0.001 5.23 28 ,0.001 1.60 16 0.13
expectation maximization algorithm, with attenuation correction, scatter A35-L 4.40 20 ,0.001 5.65 28 ,0.001 2.97 16 0.01
correction, and smoothing with a Gaussian kernel of FWHM 4 mm A35-R 5.01 20 ,0.001 5.01 28 ,0.001 0.14 16 0.89
isotropic. pmEC-L 5.19 20 ,0.001 4.81 28 ,0.001 1.28 16 0.22
pmEC-R 4.22 20 ,0.001 4.22 28 ,0.001 0.64 16 0.53
FTP processing alEC-L 7.11 20 ,0.001 3.09 28 0.004 0.91 16 0.38
FTP images were realigned, averaged, and coregistered to the partici- alEC-R 1.68 20 ,0.001 1.68 28 0.10 1.60 16 0.13
pant’s 1.5T structural MRI, consistent with standard PET processing in hipp-L 9.38 20 ,0.001 6.50 28 ,0.001 0.99 16 0.34
BACS. Standardized uptake value ratio (SUVR) images were calculated hipp-R 6.62 20 ,0.001 6.62 28 ,0.001 2.35 16 0.03
by averaging mean tracer uptake over the 80- to 100-min data, and nor- Activity differences between groups
malized by an inferior cerebellar gray reference region (Baker et al., YA vs Tau– OA YA vs Tau1 OA Tau– vs Tau1 OA
2017). The mean SUVR of each native space FreeSurfer ROI was
t df p t df p t df p
extracted and partial volume corrected using a modified Geometric
Transfer Matrix approach (Rousset et al., 1998; Baker et al., 2017). We PHC-L 1.70 48 0.096 3.10 35 0.004 2.31 43 0.03
used partial volume corrected data to ensure that off-target FTP signal, PHC-R 0.49 48 0.63 1.87 28.62 0.071 1.66 43 0.06
specifically in choroid plexus, did not affect measures of FTP in entorhi- A36-L 1.39 32.84 0.18 2.82 35 0.008 2.27 43 0.03
nal cortex and also to correct for the partial volume effect. A36-R 0.23 48 0.82 1.65 35 0.109 2.08 43 0.04
Two main FTP measures were used for analysis. First, to determine A35-L 0.71 48 0.48 1.48 35 0.149 1.13 43 0.26
tau group status within our sample of OA, we calculated a weighted A35-R 0.07 48 0.94 3.02 35 0.005 3.20 43 0.003
mean SUVR within Braak III/IV regions, using an SUVR threshold of pmEC-L 0.75 48 0.48 2.24 35 0.031 1.71 43 0.09
1.26 (Maass et al., 2017). OA above this threshold (Tau1 OA) have high pmEC-R 0.93 48 0.36 3.18 35 0.003 2.25 43 0.03
levels of tau within temporal and limbic regions (Braak III/IV), repre- alEC-L 1.48 48 0.15 3.46 35 0.001 1.41 43 0.17
senting a more advanced stage of tau pathology. OA below this threshold alEC-R 3.23 48 0.002 3.18 35 0.003 0.05 43 0.96
(Tau– OA) have tau either restricted to entorhinal and hippocampal hipp-L 4.92 48 ,0.001 5.94 35 ,0.001 2.76 43 0.008
regions (Braak I/II) or no measurable tau pathology. Second, to explore hipp-R 4.32 48 ,0.001 5.06 35 ,0.001 1.99 43 0.05
specific associations between activation and entorhinal tau, we extracted Activity within groups was assessed with one-sample t tests. Activity differences between groups was
the mean SUVR of the bilateral entorhinal cortex, derived from the assessed with independent samples t tests. YA, young adults; Tau– OA, older adults with low tau; Tau1
OA, older adults with high tau; PHC, parahippocampal cortex; A36, area 36 of perirhinal cortex; A35, area 35
FreeSurfer segmentation and partial volume corrected. We chose to use of perirhinal cortex; pmEC, posteromedial entorhinal cortex; alEC, anterolateral entorhinal cortex; hipp,
the FreeSurfer entorhinal ROI, rather than an ROI from our ASHS seg- hippocampus.
mentation, because the our partial volume correction method has been
validated using Freesurfer ROIs (Baker et al., 2017), and we were more
neuropsychological testing, and the z-scores for each test were averaged
confident that any signal bleed-in from off-target binding in choroid
to create one composite measure of episodic memory performance.
plexus would be attenuated.
Experimental design and statistical analyses
PiB processing
Statistical analyses were performed using SPSS version 25 (IBM Corp,
PiB images were realigned. The average of the first 20 min of acquisition
IBM SPSS Statistics, V25) and MATLAB version 2015a (The MathWorks,
was used to calculate coregistration to the participant’s 1.5T structural
Inc). Demographic variables were compared between groups using inde-
MRI using SPM12. The coregistration parameters were then applied to
pendent samples t tests for continuous variables, and x 2 tests for categori-
the individual realigned frames. Distribution volume ratio (DVR) images
cal variables. To characterize patterns of MTL activity within each group,
were calculated with Logan graphical analysis over 35- to 90-min data,
we performed one-sample t tests (two-tailed). To assess group differences
and normalized by a whole cerebellar gray reference region (Logan, in MTL activation, we performed repeated measures ANOVAs, with
2000; Price et al., 2005). A measure of global PiB DVR was calculated region (unilateral MTL ROIs) and hemisphere (right vs left) as within-
from cortical FreeSurfer ROIs, and thresholded at 1.065 to determine subjects factors, and group (YA vs Tau– vs Tau1 OA) as a between-sub-
amyloid positivity of the OA subjects (Mormino et al., 2012b; Villeneuve jects factor. Degrees of freedom and corresponding p-values were cor-
et al., 2015). One participant was missing PiB DVR data and was rected using Greenhouse–Geisser estimates in cases where sphericity was
excluded from any A b -related analyses. violated (Greenhouse and Geisser, 1959). Main effects and interactions
were considered significant at p , 0.05 (two-tailed). To further explore
Cognitive data factors driving the main effects and interactions, follow-up pairwise com-
All OA performed a standard battery of neuropsychological assessments parisons were conducted with independent samples t tests for each ROI,
as part of normal BACS protocol. The testing session closest in time to considered significant at p , 0.05 (two-tailed). Hyperactivity for novel and
the PET session was selected, occurring an average of 54 d (SD of 84 d) repeated stimuli was compared with paired-samples t tests (two-tailed).
from PET, and an average of 130 d (SD of 186 d) from the 3T fMRI ses- For all correlational analyses, we computed skipped correlation coef-
sion. Short and long delay free recall subtests from both the California ficients with the “robust correlation toolbox” implemented in MATLAB
Verbal Learning test (a measure of verbal memory) and the Visual (Wilcox, 2004; Pernet et al., 2013). This toolbox identifies bivariate out-
Reproduction test (a measure of visual memory) were selected to com- liers, which may bias traditional correlation estimates, by accounting for
pute a composite measure of episodic memory as previously described the overall structure of the data. Bivariate outliers are removed before
(Maass et al., 2018). Briefly, each subtest was z-scored on a larger sample performing skipped correlations, which reflect Pearson’s r, and boot-
of 155 cognitively normal OA subjects from BACS who received strapped 95% confidence intervals (CIs) are produced. Correlations were
Figure 4. A b -related differences in MTL activation for repetition suppression. Repetition suppression activity was compared across the YA, A b – OA, and A b 1 OA groups with ANOVAs
and follow-up pairwise comparisons. While significant differences were found between the YA group and each A b group, there were no additional significant difference between A b – and
A b 1 OA, indicating no effect of A b positivity on repetition suppression activity (ps . 0.05). Significance above each bar reflects one sample t tests within each group, while lines across bars
represent significant group differences with independent samples t tests. Error bars represent SEM; pppp , 0.001, ppp , 0.01, pp , 0.05.
considered significant if the CI did not include zero. Because the toolbox Table 3. Repetition suppression activation and group differences with older
does not support the inclusion of covariates, all covariates were regressed adults divided by Ab positivity
from the data before performing the skipped correlation. Activity within group
YA A b – OA A b 1 OA
Results
t df p t df p t df p
Sample characteristics
Table 1 reports demographic information for the YA and OA PHC-L 5.37 20 ,0.001 4.29 20 ,0.001 4.29 22 ,0.001
groups, as well as demographic comparisons between the low tau PHC-R 4.03 20 0.001 4.20 20 ,0.001 4.87 22 ,0.001
(Tau–) and high tau (Tau1) OA groups. Of our sample of 45 A36-L 4.92 20 ,0.001 3.26 20 0.004 3.34 22 0.003
OA, 29 were classified as Tau– and 16 as Tau1 based on FTP A36-R 3.77 20 0.001 3.93 20 0.01 2.93 22 0.008
A35-L 4.40 20 ,0.001 4.66 20 ,0.001 3.92 22 0.001
SUVR in Braak III/IV regions (Maass et al., 2017). By design, the
A35-R 4.21 20 ,0.001 2.11 20 0.047 3.29 22 0.003
Tau1 OA group had significantly higher mean Braak III/IV FTP pmEC-L 5.19 20 ,0.001 4.08 20 0.001 2.18 22 0.04
SUVR than the Tau– OA group (t = 5.96, p , 0.001). No other pmEC-R 5.26 20 ,0.001 2.92 20 0.009 2.25 22 0.04
demographic variables were significantly different between the alEC-L 7.11 20 ,0.001 2.71 20 0.01 1.60 22 0.12
tau groups, although there was a trend for older age in the Tau– alEC-R 7.09 20 ,0.001 1.00 20 0.33 2.34 22 0.03
OA group (t = 1.78, p = 0.08), and more A b 1 ( x 2 = 2.73, hipp-L 9.38 20 ,0.001 3.79 20 0.001 3.28 22 0.003
p = 0.10) and APOE « 41 subjects ( x 2 = 2.83, p = 0.09) in the hipp-R 8.97 20 ,0.001 3.72 20 0.001 5.16 22 ,0.001
Tau1 OA group. Activity differences between groups
YA vs A b – OA YA vs A b 1 OA A b – vs A b 1 OA
Repetition suppression is reduced with tau pathology t df p t df p t df p
To obtain a measure of repetition suppression activity, we con-
trasted the activity of all novel stimuli (ignoring lure stimuli) PHC-L 1.73 40 0.09 2.19 42 0.006 1.81 42 0.26
against the activity of all repeated stimuli, extracting the mean b PHC-R 0.58 40 0.56 1.37 29.98 0.18 0.87 42 0.39
A36-L 1.94 40 0.06 2.16 42 0.04 0.16 42 0.88
weight of each unilateral MTL ROI. First, we aimed to establish
A36-R 0.02 40 0.98 1.10 42 0.28 1.14 42 0.26
which MTL ROIs demonstrated a repetition suppression effect, A35-L 0.80 40 0.43 1.28 42 0.21 0.55 42 0.58
namely that repetition suppression activity (novel compared to A35-R 0.90 40 0.37 1.68 42 0.10 0.36 30.26 0.72
repeated stimuli) was greater than zero, within each group using pmEC-L 0.54 40 0.59 2.06 42 0.046 1.45 42 0.15
one-sample t tests. In both the YA and Tau– OA groups, virtu- pmEC-R 1.33 40 0.19 2.03 42 0.049 0.61 42 0.54
ally all MTL ROIs showed repetition suppression b values sig- alEC-L 0.92 30.34 0.37 3.87 42 ,0.001 1.61 31.13 0.12
nificantly greater than zero, confirming repetition suppression alEC-R 2.98 40 0.005 3.80 42 ,0.001 0.28 42 0.78
occurred in these ROIs (YA: ps , 0.001; Tau– OA: ps , 0.01; hipp-L 5.34 40 ,0.001 5.00 42 ,0.001 0.042 42 0.97
Fig. 3A; Table 2). In Tau1 OA, only the right hippocampus, left hipp-R 4.45 40 ,0.001 4.69 42 ,0.001 0.27 42 0.79
A35, and bilateral PHC demonstrated significant repetition sup- Activity within groups was assessed with one-sample t tests. Activity differences between groups were
assessed with independent samples t tests. A b – OA, older adults who are A b negative; A b 1 OA, older
pression (ps , 0.05; Fig. 3A; Table 2); however, this group had a adults who are A b positive; PHC, parahippocampal cortex; A36, area 36 of perirhinal cortex; A35, area 35
smaller sample size than the YA and Tau– OA groups and thus of perirhinal cortex; pmEC, posteromedial entorhinal cortex; alEC, anterolateral entorhinal cortex; hipp,
hippocampus.
reduced power to observe significant within-group effects.
We next determined whether the groups differed in repetition
suppression activity by conducting a repeated measures ANOVA, differed between groups regardless of MTL region. This corre-
including region (MTL ROIs) and hemisphere (left vs right) as sponded to the stepwise pattern of repetition suppression found
within-subjects factors and group (YA vs Tau– vs Tau1 OA) as a across the groups (Fig. 3A), with Tau– OA overall showing mod-
between-subjects factor. Our effects of interest were the main erate reductions in repetition suppression, and Tau1 OA showing
effect of group and group by region interactions, as these would more severe reductions in repetition suppression across the MTL
suggest overall and regionally specific group differences, respec- relative to YA. We additionally found a significant main effect of
tively. We found a significant main effect of group (F(2) = 8.95, region (F(3.41) = 9.01, p , 0.001), indicating that the amount of rep-
p , 0.001), indicating that the amount of repetition suppression etition suppression differed across regions regardless of group.
Figure 5. Tau-related differences in MTL activation for repetition suppression for object (A) and scene (B) stimuli modeled separately. Repetition suppression was defined as the difference
in activity between the novel and repeated stimuli. Patterns of repetition suppression were generally similar for object (A) and scene (B) stimuli, both regarding patterns within each group
and contrasts between groups. Significance above each bar reflects one sample t tests within each age group, while lines across bars represent significant group differences with independent
samples t tests. Error bars represent SEM; pppp , 0.001, ppp , 0.01, pp , 0.05.
There was no significant main effect of hemisphere (F(1) = 0.42, A b also affected repetition suppression. We found a significant
p = 0.52), or any interactions with hemisphere (ps . 0.05). Finally, main effect of group (F(2) = 6.22, p = 0.003), main effect of region
we found a significant region by group interaction (F(6.827) = 3.55, (F(3.40) = 9.92, p , 0.001) and region by group interaction
p = 0.001), indicating that the group difference in repetition sup- (F(6.81) = 3.41, p = 0.002), and no main effect of hemisphere
pression varied across MTL regions. (F(1) = 0.59, p = 0.44). However, follow-up pairwise comparisons
We further examined the region-specific group differences indicated that while there were differences in repetition suppres-
driving this interaction by conducting follow-up pairwise com- sion activity between the YA group and each A b group, there
parisons between the groups in each MTL region (Fig. 3A; Table were no significant group differences in repetition suppression
2), considered significant at p , 0.05. To determine whether rep- activity between A b – and A b 1 OA (Fig. 4; Table 3), suggesting
etition suppression was reduced in OA with low levels of tau pa- that the presence of A b , on its own, did not reduce repetition
thology, we first compared levels of repetition suppression suppression.
activity in the Tau– OA group to the YA group. Tau– OA had Additionally, because MTL regions have been shown to dem-
significantly reduced repetition suppression compared to the YA onstrate preference for processing object versus scene stimuli
group in the bilateral hippocampus and alEC-R (ps , 0.01). To (Ranganath and Ritchey, 2012; Berron et al., 2018), we repeated
determine whether a more advanced stage of tau pathology was the tau group analyses with repetition suppression activity
associated with additional changes in repetition suppression, we calculated for the object and scene stimuli separately (Fig. 5).
next compared the Tau1 OA group to the Tau– OA group. Overall, ANOVA models indicated significant main effects
Tau1 OA had significantly reduced repetition suppression com- of group (objects: F(2) = 3.02, p = 0.06; scenes: F(2) = 8.18,
pared with the Tau– OA group across many MTL regions, p = 0.001) and region (object: F(3.90) = 5.32, p , 0.001; scenes:
including the hipp-L, pmEC-R, A35-R, bilateral A36, and PHC-L F(3.52) = 4.40, p = 0.003), though the main effect of group was
(ps , 0.05). Finally, comparing the Tau1 OA group to the YA trending for object stimuli. Critically, group by region inter-
group revealed widespread reductions in repetition suppression actions for object and scene stimuli separately were signifi-
across virtually all MTL regions, including bilateral hippocam- cant (object: F(7.78) = 2.63, p = 0.01; scenes: F(7.04) = 3.05,
pus, alEC, pmEC, A35-R, A36-L, and PHC-L (ps , 0.05). p = 0.004). Follow-up pairwise comparisons revealed similar
Together, our findings suggest that low levels of tau deposition group differences for both the object and scene stimuli that
in aging are associated with focal decreases in repetition sup- were generally consistent with results from the combined
pression in alEC and hippocampus, while high levels of tau pa- stimuli. Low tau pathology (Tau– OA vs YA) was again asso-
thology are associated with widespread decreases in repetition ciated with specific decreases in repetition suppression in
suppression throughout the MTL. bilateral hippocampus and alEC-R for both object and scene
We repeated analyses comparing YA with A b – (n = 21) and stimuli (ps , 0.05). High tau pathology (Tau1 vs YA/Tau–
A b 1 (n = 23) OA groups to determine whether the presence of OA) was associated with additional reductions in repetition
Table 4. Novel stimuli activation and group differences with older adults di- Table 5. Repeated stimuli activation and group differences with older adults
vided into low (Tau–) and high (Tau1) tau groups divided into low (Tau–) and high (Tau1) tau groups
Activity within group Activity within group
YA Tau– Tau1 YA Tau– OA Tau1 OA
t df p t df p t df p t df p t df p t df p
PHC-L 6.85 20 ,0.001 7.97 28 ,0.001 8.73 15 ,0.001 PHC-L 5.45 20 ,0.001 6.41 28 ,0.001 7.07 15 ,0.001
PHC-R 9.43 20 ,0.001 7.20 28 ,0.001 7.91 15 ,0.001 PHC-R 9.14 20 ,0.001 6.55 28 ,0.001 6.65 15 ,0.001
A36-L 8.83 20 ,0.001 8.80 28 ,0.001 5.38 15 ,0.001 A36-L 5.77 20 ,0.001 5.23 28 ,0.001 4.83 15 ,0.001
A36-R 9.99 20 ,0.001 7.14 28 ,0.001 6.85 15 ,0.001 A36-R 6.92 20 ,0.001 5.01 28 ,0.001 5.23 15 ,0.001
A35-L 6.44 20 ,0.001 6.97 28 ,0.001 8.34 15 ,0.001 A35-L 4.07 20 0.001 4.48 28 ,0.001 6.71 15 ,0.001
A35-R 7.36 20 ,0.001 7.94 28 ,0.001 7.13 15 ,0.001 A35-R 5.75 20 ,0.001 5.81 28 ,0.001 8.25 15 ,0.001
pmEC-L 1.90 20 0.07 3.71 28 0.001 5.23 15 ,0.001 pmEC-L 0.20 20 0.84 1.23 28 0.23 3.54 15 0.003
pmEC-R 3.59 20 0.002 3.47 28 0.002 4.11 15 0.001 pmEC-R 1.42 20 0.17 0.38 28 0.71 3.82 15 0.002
alEC-L 0.03 20 0.98 0.48 28 0.63 1.98 15 0.07 alEC-L 2.98 20 0.007 1.01 28 0.322 0.93 15 0.37
alEC-R 1.36 20 0.19 4.23 28 ,0.001 1.20 15 0.25 alEC-R 2.60 20 0.02 2.56 28 0.016 0.25 15 0.80
hipp-L 0.78 20 0.45 2.07 28 0.048 2.13 15 0.05 hipp-L 4.06 20 0.001 1.68 28 0.10 1.59 15 0.13
hipp-R 1.67 20 0.111 2.83 28 0.009 3.54 15 0.003 hipp-R 3.15 20 0.005 0.76 28 0.45 2.55 15 0.02
Activity differences between groups Activity differences between groups
YA vs Tau– OA YA vs Tau1 OA Tau– vs Tau1 OA YA vs Tau– OA YA vs Tau1 OA Tau– vs Tau1 OA
t df p t df p t df p t df p t df p t df p
PHC-L 2.27 48 0.03 1.05 35 0.30 1.23 43 0.22 PHC-L 1.84 48 0.07 0.10 35 0.92 2.22 43 0.03
PHC-R 1.84 48 0.07 0.07 35 0.94 1.59 43 0.12 PHC-R 1.96 48 0.06 0.62 35 0.54 2.24 43 0.03
A36-L 2.18 48 0.03 0.74 35 0.46 0.96 43 0.34 A36-L 1.27 48 0.21 0.50 35 0.62 1.65 43 0.11
A36-R 1.23 48 0.23 0.04 35 0.97 1.08 43 0.29 A36-R 1.28 48 0.21 0.46 35 0.65 1.53 43 0.13
A35-L 0.98 48 0.33 1.25 35 0.22 2.40 43 0.02 A35-L 0.64 48 0.53 1.97 35 0.06 2.91 43 0.006
A35-R 0.23 48 0.82 0.04 35 0.97 0.26 43 0.80 A35-R 0.21 48 0.84 1.48 35 0.15 1.65 43 0.11
pmEC-L 0.60 48 0.55 1.88 35 0.07 1.63 43 0.11 pmEC-L 0.91 48 0.37 2.61 35 0.01 2.17 43 0.04
pmEC-R 1.52 48 0.14 1.09 35 0.29 2.76 43 0.008 pmEC-R 0.92 48 0.36 2.31 35 0.03 3.43 43 0.001
alEC-L 0.36 48 0.72 1.58 35 0.12 1.12 43 0.27 alEC-L 0.94 48 0.36 2.58 35 0.01 1.27 43 0.21
alEC-R 2.17 48 0.04 0.47 35 0.65 1.20 43 0.24 alEC-R 3.60 48 0.001 1.75 35 0.09 1.23 43 0.25
hipp-L 0.53 48 0.60 1.36 35 0.18 1.07 21.535 0.30 hipp-L 2.90 48 0.006 3.91 35 ,0.001 2.41 43 0.02
hipp-R 0.44 48 0.67 2.09 35 0.04 2.02 43 0.05 hipp-R 2.45 48 0.02 3.98 35 ,0.001 2.84 43 0.007
Activity within groups was assessed with one-sample t tests. Activity differences between groups was Activity within groups was assessed with one-sample t tests. Activity differences between groups was
assessed with independent samples t tests. YA, young adults; Tau OA, older adults with low tau; Tau1 assessed with independent samples t tests. YA, young adults; Tau– OA, older adults with low tau; Tau1
OA, older adults with high tau; PHC, parahippocampal cortex; A36, area 36 of perirhinal cortex; A35, area 35 OA, older adults with high tau; PHC, parahippocampal cortex; A36, area 36 of perirhinal cortex; A35, area 35
of perirhinal cortex; pmEC, posteromedial entorhinal cortex; alEC, anterolateral entorhinal cortex; hipp, of perirhinal cortex; pmEC, posteromedial entorhinal cortex; alEC, anterolateral entorhinal cortex; hipp,
hippocampus. hippocampus.
suppression across MTL (ps , 0.05). Although separate vs baseline) may not result in an identical “repetition sup-
object and scene analyses have reduced power because of pression” b weight.
fewer trials included in the estimation of each mean b We first compared activity to novel stimuli across the groups
weight, these analyses generally replicated the overall pattern with repeated measures ANOVAs (Fig. 3B). We did not observe
and conclusions found when collapsing across both object a significant main effect of group (F(2) = 2.25, p = 0.12), indicating
and scene stimuli, suggesting these effects are not specific to that overall, the groups did not differ in activation to novel stim-
one type of stimuli within the MTL. uli. However, we did find a significant main effect of region
(F(2.83) = 99.53, p , 0.001), main effect of hemisphere (F(1) =
Reduced repetition suppression is driven by hyperactivity to 31.59, p , 0.001), and group by region interaction (F(5.66) = 2.83,
repeated stimuli p = 0.01), indicating that there were group differences that varied
Reduced repetition suppression in the OA groups may result by region.
from two different underlying mechanisms: (1) reduction in ac- To further investigate the group by region interaction, we
tivity to novel stimuli, with no difference in repeated stimuli; or compared activity to novel stimuli across the groups within each
(2) hyperactivity to repeated stimuli, with no difference in novel region with follow-up pairwise comparisons (Fig. 3B; Table 4).
stimuli. To further understand how tau pathology was related to Overall, there were few significant reductions in activity for novel
changes in repetition suppression activity, we next sought to stimuli in the Tau– OA or Tau1 OA groups. Reductions in ac-
determine which pattern was driving our results by using the tivity to novel stimuli occurred only in the Tau– OA group (vs
perceptual baseline condition in the task (Fig. 1A). For each YA) in PHC-L and A36-L (ps ,0.05). There were no additional
MTL ROI, we extracted activity to novel stimuli compared to reductions in activity for novel stimuli in the Tau1 compared to
the perceptual baseline, and activity to repeated stimuli com- Tau– OA or YA group (ps . 0.05). However, certain regions did
pared to the perceptual baseline. Because our original repeti- show hyperactivity to novel stimuli. The Tau– OA group demon-
tion suppression contrast did not include the perceptual strated hyperactivity to novel stimuli compared to YA in alEC-R
baseline while calculating the contrast (a direct contrast (p , 0.05). The Tau1 OA group demonstrated hyperactivity in
between novel and repeated stimuli), a simple subtraction of hipp-R, pmEC-R, and A35-L compared to Tau– OA, and in
these subcomponent b weights (novel vs baseline – repeated hipp-R compared to the YA group (ps , 0.05). In sum, because
of the lack of reductions in novel activity found in either the Table 6. Hyperactivity to novel and repeated stimuli in the low (Tau–) and
Tau– or Tau1 OA groups, we concluded that group differences high (Tau1) tau groups
in activity to novel stimuli were not driving our repetition sup- First M (SD) Repeat M (SD) t df p
pression results.
Tau– OA
We next assessed group differences for repeated stimuli com- PHC-L 0.53 (0.65) 0.43 (0.64) 2.24 28 0.03
pared with baseline with repeated measures ANOVAs (Fig. 3C). PHC-R 0.57 (1.12) 0.61 (1.14) 0.77 28 0.45
We found a significant main effect of group (F(2) = 5.54, A36-L 0.57 (0.83) 0.35 (0.94) 2.76 28 0.01
p = 0.006) indicating that, unlike activity to novel stimuli, activity A36-R 0.42 (1.32) 0.41 (1.19) 0.13 28 0.90
to repeated stimuli differed across groups regardless of MTL A35-L 0.26 (0.88) 0.17 (0.86) 1.09 28 0.22
region. Generally, activity was greatest in Tau1 OA. We also A35-R 0.07 (1.04) 0.06 (1.10) 0.06 28 0.95
found a significant main effect of region (F(3.28) = 95.20, pmEC-L 0.16 (0.83) 0.24 (0.86) 1.09 28 0.28
p , 0.001), main effect of hemisphere (F(1) = 40.86, p , 0.001), pmEC-R 0.36 (0.66) 0.25 (0.90) 1.19 28 0.25
and group by region interaction (F(6.57) = 4.778, p , 0.001), indi- alEC-L 0.12 (1.27) 0.36 (1.55) 1.96 28 0.06
alEC-R 0.75 (1.33) 1.08 (1.09) 2.19 28 0.04
cating that the level of group differences in activity to repeated
hipp-L 0.14 (0.79) 0.68 (0.66) 6.99 28 ,0.001
stimuli varied across MTL regions. hipp-R 0.12 (0.92) 0.59 (0.70) 5.40 28 ,0.001
To further investigate the group by region interaction, we Tau1 OA
compared activity to repeated stimuli between the groups within PHC-L 0.29 (0.55) 0.03 (0.69) 5.55 15 ,0.001
each region. Follow-up pairwise comparisons revealed hyperac- PHC-R 0.02 (1.03) 0.24 (1.34) 2.96 15 0.01
tivity to repeated stimuli for both OA groups in MTL (Fig. 3C; A36-L 0.27 (1.23) 0.18 (1.19) 3.42 15 0.004
Table 5). Compared to the YA, Tau– OA showed hyperactivity A36-R 0.01 (1.28) 0.17 (1.29) 1.48 15 0.16
to repeated stimuli in bilateral hippocampus and alEC-R A35-L 0.39 (0.86) 0.63 (0.90) 2.32 15 0.04
(ps , 0.05), regions that show deactivation to repeated stimuli A35-R 0.01 (0.91) 0.46 (0.83) 4.10 15 0.001
pmEC-L 0.56 (0.74) 0.82 (0.88) 2.34 15 0.03
within the YA group and tau-related reductions in repetition
pmEC-R 0.38 (1.14) 0.83 (1.20) 4.60 15 ,0.001
suppression. Compared to the Tau– OA group, Tau1 OA alEC-L 0.54 (1.07) 0.93 (1.18) 3.05 15 0.008
showed hyperactivity to repeated stimuli in many MTL ROIs, alEC-R 0.20 (1.67) 0.64 (1.25) 2.36 15 0.03
including bilateral hippocampus, bilateral pmEC, A35-L, and hipp-L 0.51 (1.28) 1.25 (0.92) 4.92 15 ,0.001
bilateral PHC (ps , 0.05). Compared to YA, Tau1 OA showed hipp-R 0.79 (1.30) 1.29 (0.94) 3.46 15 0.003
hyperactivity in bilateral hippocampus, alEC-L, and bilateral Hyperactivity measures reflect z-scores based on the YA group. Hyperactivity differences between novel and
pmEC (ps , 0.05). Overall, the regions demonstrating hyperac- repeated stimuli was assessed within each tau group with paired samples t tests. Tau– OA, older adults
tivity to repeated stimuli (Fig. 3C) were consistent with the with low tau; Tau1 OA, older adults with high tau; PHC, parahippocampal cortex; A36, area 36 of perirhinal
cortex; A35, area 35 of perirhinal cortex; pmEC, posteromedial entorhinal cortex; alEC, anterolateral entorhi-
regions demonstrating reduced repetition suppression (Fig. 3A). nal cortex; hipp, hippocampus.
For example, both reduced repetition suppression and hyperac-
tivity to repeated stimuli were found in the Tau– OA group (vs
YA) in bilateral hippocampus and alEC-R, and in the Tau1 OA strongly found in entorhinal cortex and hippocampus, we next
group (vs YA) in the bilateral hippocampus, alEC-L, and bilateral determined whether levels of entorhinal tau were associated with
pmEC. hyperactivity. We extracted mean partial volume corrected FTP
Our finding of hyperactivity to repeated stimuli, with little to SUVR (Baker et al., 2017) from an entorhinal cortex ROI span-
no reduction in activity to novel stimuli, suggests the reduced ning alEC, pmEC, and A35 derived from native space FreeSurfer
repetition suppression we observed was driven by relative hyper- segmentations. We could not quantify subregional entorhinal
activity to repeated stimuli compared to that of novel stimuli. To tau pathology because of the limited resolution of PET. We
statistically test that hyperactivity to repeated stimuli was driving focused on hyperactivity in regions that may first be affected by
reduced repetition suppression, we created z-scores for activity entorhinal tau: A35, alEC, pmEC, and hippocampus. Because of
to novel and repeated stimuli based on the YA sample. Positive the relative hemispheric similarity of our results, and to reduce
z-scores could thus be considered “hyperactivity.” We then com- the number of statistical tests, we averaged both activity and tau
pared z-scored activity for novel against repeated stimuli within deposition across the two hemispheres. All correlations between
each OA subject with paired-samples t tests. Within the Tau– activity and entorhinal FTP SUVR controlled for age, sex, and
OA group, greater hyperactivity was found for repeated versus entorhinal cortical thickness to isolate the specific effects of tau
novel stimuli in the bilateral hippocampus and alEC-R over and above basic demographics and neurodegeneration due
(ps , 0.05; Table 6), the same regions that showed reduced repe- to other pathologies or vascular disease. Analyses were per-
tition suppression. PHC-L and A36-L also showed greater hyper- formed using skipped correlations, which account for bivariate
activity for repeated than novel stimuli, which may be explained outliers (see Materials and Methods).
by the fact that these two regions had demonstrated reduced ac- Across all OA, entorhinal FTP SUVR was positively corre-
tivity to novel stimuli compared to YA. Within the Tau1 OA lated with activity for both novel and repeated stimuli in A35
group, all MTL ROIs showed greater hyperactivity to repeated (novel: r = 0.51; repeated: r = 0.41; Fig. 6A), pmEC (novel:
than to novel stimuli (ps , 0.05; Table 6) except A36-L. Thus, r = 0.44; repeated: r = 0.40; Fig. 6B), and hippocampus [novel:
our analyses confirmed that hyperactivity was greatest during r = 0.48, repeated: r = 0.53 (Fig. 6D); all CIs do not include zero;
repeated stimuli, and this change in activity was the most robust see Table 7]. However, the association between entorhinal FTP
driver of reduced repetition suppression. SUVR and alEC activity did not reach significance [novel:
r = 0.19; repeated: r = 0.17 (Fig. 6C); CIs cross zero; see Table 7].
Hyperactivity is associated with entorhinal tau pathology but Next, we tested whether A b , quantified with a global measure
not Ab of cortical PiB DVR (Mormino et al., 2012b; Villeneuve et al.,
Because cortical tau first deposits in the transentorhinal region 2015), was also associated with activation. There was no associa-
(Braak and Braak, 1985, 1991), and hyperactivity was most tion between global PiB DVR and activity levels in any of the
Figure 6. Increased activation to novel and repeated stimuli is associated with entorhinal tau pathology in OAs. Mean FTP SUVR of native space entorhinal cortex (EC) was extracted and par-
tial volume corrected for each OA subject. To obtain measures of activity, the mean b value for each ROI was extracted for novel and repeated stimuli (compared to perceptual baseline).
Robust regressions were performed to reduce the effects of outliers. All correlations controlled for age, sex, and EC thickness (raw data shown). EC FTP SUVR was associated with increased activ-
ity to both novel and repeated stimuli in A35 (A), pmEC (B), and hippocampus (D), but not alEC (C); * indicates significant skipped correlations (CI does not include zero). Black data points
were identified as bivariate outliers and removed in the skipped correlation.
ROIs for novel or repeated stimuli (CIs crossed zero; see Table Associations with cognitive performance
7). We also found no significant interactions between entorhinal Finally, we investigated whether our measures of MTL repetition
FTP SUVR and A b status using linear regression models pre- suppression activity and entorhinal tau deposition in OA were
dicting to activity in each ROI, including age and sex as covari- related to task performance (corrected hit rate) or an episodic
ates (interaction ps . 0.05; see Table 7). memory composite from neuropsychological tests. We first
Table 7. Associations between activation to novel and repeated stimuli with activity changes in normal aging. This is supported by prior stud-
measures of entorhinal tau and global Ab ies that have demonstrated that the alEC is particularly vulnera-
EC FTP SUVRa Global PiB DVRb EC FTP x A b Statusc ble to the effects of age and preclinical AD (Khan et al., 2014;
Olsen et al., 2017; Reagh et al., 2018). Hippocampal activity
ROI r CI r CI b coefficient t p
(Marks et al., 2017; Berron et al., 2019; Huijbers et al., 2019) and
Novel stimuli regional homogeneity of fMRI resting state signal (Harrison et
A35 0.51* [0.29, 0.70] 0.05 [ 0.31, 0.39] 0.99 0.34 0.73 al., 2019) have also been found to be associated with tau pathol-
pmEC 0.44* [0.18, 0.65] 0.21 [ 0.08, 0.47] 0.17 0.04 0.97 ogy in aging, consistent with our findings.
alEC 0.19 [ 0.04, 0.43] 0.04 [ 0.24, 0.32] 2.38 0.67 0.51
We next hypothesized reduced repetition suppression across
hipp 0.48* [0.19, 0.68] 0.17 [ 0.14, 0.43] 4.00 1.37 0.18
Repeated stimuli
the MTL in the Tau1 OA group, as this group is at a more
A35 0.41* [0.19, 0.61] 0.19 [ 0.11, 0.47] 0.49 0.16 0.88 advanced stage of pathology possibly reflecting preclinical AD
pmEC 0.40* [0.13, 0.60] 0.20 [ 0.11, 0.46] 0.001 0.00 0.99 (Jagust, 2018). Confirming our hypothesis, the majority of MTL
alEC 0.17 [ 0.09, 0.44] 0.02 [ 0.27, 0.33] 0.86 0.19 0.85 regions demonstrated reduced repetition suppression in the
hipp 0.53* [0.27, 0.73] 0.17 [ 0.16, 0.48] 3.73 1.14 0.26 Tau1 OA group. While alEC activity was not further reduced
a,b Skipped Pearson’s r and CIs were calculated with robust regression. from the Tau– to Tau1 OA group, hippocampal activity contin-
a Controlling for effects of age, sex, and EC cortical thickness. b Controlling for effects of age and sex. ued to decrease with increasing tau pathology. This continual
c Interactions were calculated using linear models, which predicted activity in each ROI. The interaction term
of EC FTP x A b status (values shown), age, and sex were included as predictors in the model. *CI does not
reduction in hippocampal repetition suppression is consistent
cross zero, indicating significance of the skipped correlation. A35, area 35 of perirhinal cortex; pmEC, poster- with theories of hippocampal disconnection as a key mechanism
omedial entorhinal cortex; alEC, anterolateral entorhinal cortex; hipp, hippocampus. of disease progression (Hyman et al., 1984).
To probe this reduction in repetition suppression activity, we
assessed the relationship between entorhinal tau pathology and determined that hyperactivity to repeated stimuli, rather than
cognitive performance, using skipped correlations and control- hypoactivity to novel stimuli, was driving reduced repetition sup-
ling for effects of age, sex, and education. There was a significant pression activity. While entorhinal tau was correlated with
negative correlation between entorhinal FTP and the episodic increased activation to both novel and repeated stimuli, a direct
memory composite (skipped Pearson’s r = 0.33, CI [ 0.55, comparison showed greater hyperactivity for repeated stimuli
0.05]), but no significant association between entorhinal FTP compared to novel stimuli. As activity should reduce with
and corrected hit rate on the task (r = 0.10, [ 0.31, 0.14]). We repeated presentations of stimuli for successful repetition sup-
next performed skipped correlations between repetition suppres- pression, this result is consistent with findings of A b -related
sion activity in each MTL region with cognitive performance, deactivation failures in the default mode network during mem-
including the same covariates. However, there was no significant ory encoding in cognitively normal OAs (Sperling et al., 2009;
relationship between repetition suppression activity and either Huijbers et al., 2014) and patients with AD (Celone et al., 2006;
corrected hit rate (rs ranged 0.02–0.12; all CIs crossed zero) or Petrella et al., 2007; Pihlajamaki et al., 2008). Together, our find-
the episodic memory composite (rs ranged 0.06–0.13; all CIs ings suggest that task components where neuronal deactivation
crossed zero) in any region. is optimal to processing may be more vulnerable to hyperactivity,
as there may be a ceiling to activity that limits the extent to which
an already active system can hyperactivate. Therefore, tau depo-
Discussion sition functions to generally increase the system gain that dispro-
We demonstrate that reduced repetition suppression activity in portionately affects processing of repeated stimuli, possibly
the MTL is related to tau pathology in cognitively normal OAs. decreasing neural discrimination between novel and repeated
Although our data are cross-sectional, our results suggest that stimuli.
reductions are limited to the alEC and hippocampus in the con- Entorhinal tau, which occurs in almost all OAs (Braak and
text of low tau pathology restricted to these regions, but may Braak, 1997), was associated with increased activation in A35,
expand to encompass the rest of the MTL when tau pathology pmEC, and hippocampus. A recent study did not observe associ-
reaches a more advanced stage. Reduced repetition suppression ations between entorhinal tau and hippocampal hyperactivity,
was driven by hyperactivity to repeated stimuli, rather than concluding that the spread of tau outside of the MTL is necessary
hypoactivity to novel stimuli. Tau pathology in entorhinal cortex, for tau-related activity changes (Huijbers et al., 2019). Our find-
but not global A b , was related to increased activation to both ing reveals that entorhinal tau is not benign, and is related to ac-
novel and repeated stimuli in entorhinal regions and hippocam- tivity changes in key MTL subregions. The lack of association
pus. We conclude that tau deposition in cognitively normal OAs between entorhinal tau and alEC hyperactivity was unexpected
is related to hyperactivity, leading to failures of repetition sup- due to the group differences in this region. Because alEC is one
pression activity within MTL. of the first cortical regions to deposit tau (Braak and Braak, 1985,
We classified OA participants as low tau (Tau–), with either 1991), its hyperactivity may have reached a ceiling, and thus did
no measurable tau or tau deposition restricted to entorhinal/hip- not show a continuous relationship with current levels of ento-
pocampus, or high tau (Tau1), with more advanced tau pathol- rhinal tau. Alternatively, tau-related hyperactivity in alEC may
ogy expanded to other temporal and limbic regions. Reduced yield to hypoactivity as neurodegenerative processes begin to
repetition suppression activity in the Tau– OA group, compared occur (Dickerson et al., 2005; O’Brien et al., 2010).
to a young control group, occurred focally in alEC and hippo- Reduced repetition suppression activity in the MTL is ubiqui-
campus. This finding supported our hypothesis that activity tous, previously found in patients with AD (Sperling et al., 2003;
reductions in low tau individuals, where tau deposition is nearly Golby et al., 2005; Pihlajamäki et al., 2011), MCI (Johnson et al.,
universal in the transentorhinal/anterolateral entorhinal region, 2004), and across cognitively normal and impaired OAs (Düzel
would specifically co-localize with the earliest cortical tau pathol- et al., 2018). Our results expand on these observations by linking
ogy (Braak and Braak, 1985, 1991). Reduced activity within alEC this phenomenon to tau deposition. Our findings are also con-
and hippocampus suggests that tau deposition may underlie sistent with recent studies demonstrating associations between
tau and hippocampal hyperactivity in aging (Marks et al., 2017; repetition suppression. Reductions in repetition suppression ac-
Berron et al., 2019; Huijbers et al., 2019), although we expand on tivity were found focally in alEC and hippocampus in OAs with
this literature by finding that other vulnerable MTL regions low tau levels, and across the MTL in the context of high tau pa-
show tau-related activity changes in aging. This study also thology. Entorhinal tau pathology, found in nearly all OAs, was
extends our previous observation of increased activity during related to a general increase in activation across novel and
object and scene processing in this cohort (Maass et al., 2019) by repeated stimuli, while A b did not demonstrate any associations
examining trial-level activity in MTL subregions and linking the with MTL activation. The directionality of associations between
increased activity to reduced repetition suppression. Our find- tau and hyperactivity is still an open question that needs to be
ings of MTL hyperactivity are also consistent with studies dem- further explored in longitudinal studies, as determining the cau-
onstrating hyperconnectivity between MTL subregions in MCI sality would help develop interventions to prevent tau progres-
(Das et al., 2013; Pasquini et al., 2016; Berron et al., 2020). sion and cognitive decline.
Finally, consistent with other recent studies (Berron et al., 2019;
Huijbers et al., 2019; Maass et al., 2019), we did not observe a
relationship between global A b and MTL activity, supporting
References
Adams JN, Maass A, Harrison TM, Baker SL, Jagust WJ (2019) Cortical tau
the stronger role of tau on local activity in the MTL. deposition follows patterns of entorhinal functional connectivity in aging.
In contrast to our findings of tau-related hyperactivity, find- Elife 8:e49132.
ings from animal models have suggested that tau is associated Angulo SL, Orman R, Neymotin SA, Liu L, Buitrago L, Cepeda-Prado E,
with hypoactivity and silencing of neurons (Angulo et al., 2017; Stefanov D, Lytton WW, Stewart M, Small SA, Duff KE, Moreno H
Busche et al., 2019). While disconnection from entorhinal cortex (2017) Tau and amyloid-related pathologies in the entorhinal cortex have
and a lack of inhibition can explain tau-related hippocampal divergent effects in the hippocampal circuit. Neurobiol Dis 108:261–276.
Avants BB, Yushkevich P, Pluta J, Minkoff D, Korczykowski M, Detre J, Gee
hyperactivity (Hyman et al., 1984), tau-related hyperactivity in JC (2010) The optimal template effect in hippocampus studies of diseased
other cortical regions is harder to reconcile with this animal liter- populations. Neuroimage 49:2457–2466.
ature. An alternative explanation of our findings is rather than Baker SL, Maass A, Jagust WJ (2017) Considerations and code for partial vol-
tau inducing hyperactivity, hyperactivity may lead to increased ume correcting [18F]-AV-1451 tau PET data. Data Brief 15:648–657.
tau deposition. Animal models demonstrate that increased neu- Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA,
ronal activity leads to the release and spread of pathological tau Bassett SS, Shelton AL, Gallagher M (2012) Reduction of hippocampal
(Pooler et al., 2013; Wu et al., 2016). It is possible that OAs with hyperactivity improves cognition in amnestic mild cognitive impairment.
Neuron 74:467–474.
greater levels of MTL activity, perhaps because of compensatory
Berron D, Vieweg P, Hochkeppler A, Pluta JB, Ding SL, Maass A, Luther A,
mechanisms, produce more pathological tau. Functional connec- Xie L, Das SR, Wolk DA, Wolbers T, Yushkevich PA, Düzel E, Wisse
tivity driving tau spread has also been supported by recent find- LEM (2017) A protocol for manual segmentation of medial temporal
ings in human neuroimaging studies (Adams et al., 2019; lobe subregions in 7 Tesla MRI. NeuroImage Clin 15:466–482.
Franzmeier et al., 2019; Vogel et al., 2020). Longitudinal studies Berron D, Neumann K, Maass A, Schütze H, Fliessbach K, Kiven V, Jessen F,
will help elucidate the temporal relationship between tau deposi- Sauvage M, Kumaran D, Düzel E (2018) Age-related functional changes
tion and hyperactivity. in domain-specific medial temporal lobe pathways. Neurobiol Aging
Finally, we did not observe any associations between repeti- 65:86–97.
Berron D, Cardenas-Blanco A, Bittner D, Metzger CD, Spottke A, Heneka
tion suppression activity and cognitive performance. It is possi-
MT, Fließbach K, Schneider A, Teipel SJ, Wagner M, Speck O, Jessen F,
ble that repetition suppression activity may not express itself Düzel E (2019) Higher CSF tau levels are related to hippocampal hyper-
behaviorally as explicit changes to task performance or episodic activity and object mnemonic discrimination in older adults. J Neurosci
memory. Because our sample is high-performing and well-edu- 39:8788–8797.
cated, there may have not been enough variation in scores to Berron D, van Westen D, Ossenkoppele R, Strandberg O, Hansson O (2020)
observe an association, or brain resilience may overcome the Medial temporal lobe connectivity and its associations with cognition in
effects of tau pathology. Relationships between activity, tau, and early Alzheimer’s disease. Brain 143:1233–1248.
cognitive performance should be further investigated to better Braak H, Braak E (1985) On areas of transition between entorhinal allocortex
and temporal isocortex in the human brain. Normal morphology and
understand activity changes in the context of behavior. lamina-specific pathology in Alzheimer’s disease. Acta Neuropathol
There are several limitations to this study. Because some 68:325–332.
MTL regions preferentially process objects versus scenes Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related
(Ranganath and Ritchey, 2012; Berron et al., 2018), we also ana- changes. Acta Neuropathol 82:239–259.
lyzed each stimulus type separately, producing similar results. Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in
Additionally, we were not able to measure tau deposition within different age categories. Neurobiol Aging 18:351–357.
specific MTL subregions (e.g., alEC or A35) because of the reso- Busche MA, Wegmann S, Dujardin S, Commins C, Schiantarelli J, Klickstein
N, Kamath TV, Carlson GA, Nelken I, Hyman BT (2019) Tau impairs
lution of PET, or hippocampal tau because of effects of off-target
neural circuits, dominating amyloid- b effects, in Alzheimer models in
FTP binding in the adjacent choroid plexus (Baker et al., 2017). vivo. Nat Neurosci 22:57–64.
Because of the resolution and use of smoothing on the functional Celone KA, Calhoun VD, Dickerson BC, Atri A, Chua EF, Miller SL, DePeau
data, in addition to the motion threshold we selected, some sig- K, Rentz DM, Selkoe DJ, Blacker D, Albert MS, Sperling RA (2006)
nal blurring between neighboring MTL subregions may have Alterations in memory networks in mild cognitive impairment and
occurred. There may also be some uncertainty of the precise bor- Alzheimer’s disease: an independent component analysis. J Neurosci
der between alEC and pmEC. Finally, while we carefully 26:10222–10231.
removed areas of low signal before analyses, the alEC is particu- Das SR, Pluta J, Mancuso L, Kliot D, Orozco S, Dickerson BC, Yushkevich
PA, Wolk DA (2013) Increased functional connectivity within medial
larly vulnerable to signal drop out, and alEC-tau null results may
temporal lobe in mild cognitive impairment. Hippocampus 23:1–6.
be partly because of loss of signal. Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E, Rentz
In conclusion, we demonstrate that pathological tau accumu- DM, Bertram L, Mullin K, Tanzi RE, Blacker D, Albert MS, Sperling RA
lation is associated with hyperactivity in MTL, which specifically (2005) Increased hippocampal activation in mild cognitive impairment
affects the ability to deactivate to repeated stimuli and reduces compared to normal aging and AD. Neurology 65:404–411.
Düzel E, Berron D, Schütze H, Cardenas-Blanco A, Metzger C, Betts M, Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE (2003)
Ziegler G, Chen Y, Dobisch L, Bittner D, Glanz W, Reuter M, Spottke A, Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothia-
Rudolph J, Brosseron F, Buerger K, Janowitz D, Fliessbach K, Heneka M, zoles as amyloid imaging agents. J Med Chem 46:2740–2754.
Laske C, et al. (2018) CSF total tau levels are associated with hippocampal Mormino EC, Brandel MG, Madison CM, Marks S, Baker SL, Jagust WJ
novelty irrespective of hippocampal volume. Alzheimers Dement (Amst) (2012a) A b deposition in aging is associated with increases in brain
10:782–790. activation during successful memory encoding. Cereb Cortex
Franzmeier N, Rubinski A, Neitzel J, Kim Y, Damm A, Na DL, Kim HJ, Lyoo 22:1813–1823.
CH, Cho H, Finsterwalder S, Duering M, Seo SW, Ewers M; Alzheimer’s Mormino EC, Brandel MG, Madison CM, Rabinovici GD, Marks S, Baker
Disease Neuroimaging Initiative (2019) Functional connectivity associ- SL, Jagust WJ (2012b) Not quite PIB-positive, not quite PIB-negative:
ated with tau levels in ageing. Brain 142:1093–1015. slight PIB elevations in elderly normal control subjects are biologically
Golby A, Silverberg G, Race E, Gabrieli S, O’Shea J, Knierim K, Stebbins G, relevant. Neuroimage 59:1152–1160.
Gabrieli J (2005) Memory encoding in Alzheimer’s disease: an fMRI O’Brien JL, O’Keefe KM, LaViolette PS, DeLuca AN, Blacker D, Dickerson
study of explicit and implicit memory. Brain 128:773–787. BC, Sperling RA (2010) Longitudinal fMRI in elderly reveals loss of
Greenhouse SW, Geisser S (1959) On methods in the analysis of profile data. hippocampal activation with clinical decline. Neurology 74:1969–
Psychometrika 24:95–112. 1976.
Grill-Spector K, Henson R, Martin A (2006) Repetition and the brain: neural Olsen RK, Yeung LK, Noly-Gandon A, D’Angelo MC, Kacollja A, Smith
models of stimulus-specific effects. Trends Cogn Sci 10:14–23. VM, Ryan JD, Barense MD (2017) Human anterolateral entorhinal cortex
Harrison TM, Maass A, Adams JN, Du R, Baker SL, Jagust WJ (2019) Tau volumes are associated with cognitive decline in aging prior to clinical di-
deposition is associated with functional isolation of the hippocampus in agnosis. Neurobiol Aging 57:195–205.
aging. Nat Commun 10:4900. Pasquini L, Scherr M, Tahmasian M, Myers NE, Ortner M, Kurz A, Förstl H,
Huijbers W, Mormino EC, Wigman SE, Ward AM, Vannini P, McLaren Zimmer C, Grimmer T, Akhrif A, Wohlschläger AM, Riedl V, Sorg C
DG, Becker JA, Schultz AP, Hedden T, Johnson KA, Sperling RA (2014) (2016) Increased intrinsic activity of medial-temporal lobe subregions is
Amyloid deposition is linked to aberrant entorhinal activity among cog- associated with decreased cortical thickness of medial-parietal areas in
nitively normal older adults. J Neurosci 34:5200–5210. patients with Alzheimer’s disease dementia. J Alzheimers Dis 51:313–
Huijbers W, Mormino EC, Schultz AP, Wigman S, Ward AM, Larvie M, 326.
Amariglio RE, Marshall GA, Rentz DM, Johnson KA, Sperling RA (2015) Pernet CR, Wilcox R, Rousselet GA (2013) Robust correlation analyses: false
Amyloid- b deposition in mild cognitive impairment is associated with positive and power validation using a new open source MATLAB tool-
increased hippocampal activity, atrophy and clinical progression. Brain box. Front Psychol 3:1–18.
138:1023–1035. Petrella JR, Prince SE, Wang L, Hellegers C, Doraiswamy PM (2007)
Prognostic value of posteromedial cortex deactivation in mild cognitive
Huijbers XW, Schultz AP, Papp KV, Lapoint MR, Hanseeuw X, Chhatwal
impairment. PLoS One 2:e1104.
XJP, Hedden T, Johnson XA, Sperling XRA (2019) Tau accumulation in
Pihlajamäki M, Depeau KM, Blacker D, Sperling RA (2008) Impaired medial
clinically normal older adults is associated with hippocampal hyperactiv-
temporal repetition suppression is related to failure of parietal deactiva-
ity. J Neurosci 39:548–556.
tion in Alzheimer disease. Am J Geriatr Psychiatry 16:283–292.
Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL (1984) Alzheimer’s
Pihlajamäki M, O’Keefe K, O’Brien J, Blacker D, Sperling RA (2011) Failure
disease: cell-specific pathology isolates the hippocampal formation.
of repetition suppression and memory encoding in aging and
Science 225:1168–1170.
Alzheimer’s disease. Brain Imaging Behav 5:36–44.
Jagust W (2018) Imaging the evolution and pathophysiology of Alzheimer
Pooler AM, Phillips EC, Lau DHW, Noble W, Hanger DP (2013)
disease. Nat Rev Neurosci 19:687–700.
Physiological release of endogenous tau is stimulated by neuronal activ-
Johnson SC, Baxter LC, Susskind-Wilder L, Connor DJ, Sabbagh MN, Caselli
ity. EMBO Rep 14:389–394.
RJ (2004) Hippocampal adaptation to face repetition in healthy elderly
Power JD, Schlaggar BL, Petersen SE (2015) Recent progress and outstanding
and mild cognitive impairment. Neuropsychologia 42:980–989.
issues in motion correction in resting state fMRI. Neuroimage 105:536–
Khan UA, Liu L, Provenzano FA, Berman DE, Profaci CP, Sloan R, Mayeux 551.
R, Duff KE, Small SA (2014) Molecular drivers and cortical spread of lat- Price JC, Klunk WE, Lopresti BJ, Lu X, Hoge JA, Ziolko SK, Holt DP,
eral entorhinal cortex dysfunction in preclinical Alzheimer’s disease. Nat Meltzer CC, DeKosky ST, Mathis CA (2005) Kinetic modeling of amyloid
Neurosci 17:304–311. binding in humans using PET imaging and Pittsburgh Compound-B. J
Lemieux L, Salek-Haddadi A, Lund TE, Laufs H, Carmichael D (2007) Cereb Blood Flow Metab 25:1528–1547.
Modelling large motion events in fMRI studies of patients with epilepsy. Ranganath C, Ritchey M (2012) Two cortical systems for memory-guided
Magn Reson Imaging 25:894–901. behaviour. Nat Rev Neurosci 13:713–726.
Libby LA, Ekstrom AD, Ragland JD, Ranganath C (2012) Differential con- Reagh ZM, Noche JA, Tustison NJ, Delisle D, Murray EA, Yassa MA (2018)
nectivity of perirhinal and parahippocampal cortices within human hip- Functional imbalance of anterolateral entorhinal cortex and hippocampal
pocampal subregions revealed by high-resolution functional imaging. J dentate/CA3 underlies age-related object pattern separation deficits.
Neurosci 32:6550–6560. Neuron 97:1187–1198.e4.
Logan J (2000) Graphical analysis of PET data applied to reversible and irre- Rousset OG, Ma Y, Evans AC (1998) Correction for partial volume effects in
versible tracers. Nucl Med Biol 27:661–670. PET: principle and validation. J Nucl Med 39:904–911.
Maass A, Berron D, Libby L, Ranganath C, Düzel E (2015) Functional subre- Schöll M, Lockhart SN, Schonhaut DR, O’Neil JP, Janabi M, Ossenkoppele R,
gions of the human entorhinal cortex. Elife 4:e06426. Baker SL, Vogel JW, Faria J, Schwimmer HD, Rabinovici GD, Jagust WJ
Maass A, Landau S, Baker SL, Horng A, Lockhart SN, La Joie R, Rabinovici (2016) PET imaging of tau deposition in the aging human brain. Neuron
GD, Jagust WJ; Alzheimer’s Disease Neuroimaging Initiative (2017) 89:971–982.
Comparison of multiple tau-PET measures as biomarkers in aging and Sperling RA, Bates JF, Chua EF, Cocchiarella AJ, Rentz DM, Rosen BR,
Alzheimer’s disease. Neuroimage 157:448–463. Schacter DL, Albert MS (2003) fMRI studies of associative encoding in
Maass A, Lockhart SN, Harrison TM, Bell RK, Mellinger T, Swinnerton K, young and elderly controls and mild Alzheimer’s disease. J Neurol
Baker SL, Rabinovici GD, Jagust WJ (2018) Entorhinal tau pathology, ep- Neurosurg Psychiatry 74:44–50.
isodic memory decline and neurodegeneration in aging. J Neurosci Sperling RA, Laviolette PS, O’Keefe K, O’Brien J, Rentz DM, Pihlajamaki M,
38:530–543. Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA,
Maass A, Berron D, Harrison TM, Adams JN, La Joie R, Baker SL, Mellinger Johnson KA (2009) Amyloid deposition is associated with impaired
TJ, Bell RK, Swinnerton KN, Inglis B, Rabinovici GD, Düzel E, Jagust WJ default network function in older persons without dementia. Neuron
(2019) Alzheimer’s pathology targets distinct memory networks in the 63:178–188.
ageing. brain 142:2492–2509. Villeneuve S, Rabinovici GD, Cohn-Sheehy BI, Madison C, Ayakta N, Ghosh
Marks SM, Lockhart SN, Baker SL, Jagust WJ (2017) Tau and b -amyloid are PM, La Joie R, Arthur-Bentil SK, Vogel JW, Marks SM, Lehmann M,
associated with medial temporal lobe structure, function and memory Rosen HJ, Reed B, Olichney J, Boxer AL, Miller BL, Borys E, Jin LW,
encoding in normal aging. J Neurosci 37:3769–3716. Huang EJ, Grinberg LT, et al. (2015) Existing Pittsburgh compound-B
positron emission tomography thresholds are too high: statistical and Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CEL (2010)
pathological evaluation. Brain 138:2020–2033. High-resolution structural and functional MRI of hippocampal CA3 and
Vogel JW, Iturria-Medina Y, Strandberg OT, Smith R, Levitis E, Evans AC, dentate gyrus in patients with amnestic mild cognitive impairment.
Hansson O; Alzheimer’s Disease Neuroimaging Initiative (2020) Spread Neuroimage 51:1242–1252.
of pathological tau proteins through communicating neurons in human Yassa MA, Lacy JW, Stark SM, Albert MS, Gallagher M, Stark CEL (2011)
Alzheimer’s disease. Nat Commun 11:2612. Pattern separation deficits associated with increased hippocampal CA3
Wilcox RR (2004) Inferences based on a skipped correlation coefficient. J and dentate gyrus activity in nondemented older adults. Hippocampus
Appl Stat 31:131–143. 21:968–979.
Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, Yushkevich PA, Pluta JB, Wang H, Xie L, Ding SL, Gertje EC, Mancuso
Sanders DW, Cook C, Fu H, Boonen RACM, Herman M, Nahmani E, L, Kliot D, Das SR, Wolk DA (2015) Automated volumetry and re-
Emrani S, Figueroa YH, Diamond MI, Clelland CL, Wray S, Duff KE gional thickness analysis of hippocampal subfields and medial tem-
(2016) Neuronal activity enhances tau propagation and tau pathology in poral cortical structures in mild cognitive impairment. Hum Brain
vivo. Nat Neurosci 19:1085–1092. Mapp 36:258–287.

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The Journal of Neuroscience, April 28, 2021 • 41(17):3917–3931 • 3917

Reduced Repetition Suppression in Aging is Driven by

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