Received: 8 September 2021 Revised: 23 November 2021 Accepted: 12 December 2021

DOI: 10.1002/alz.12582

F E AT U R E D A R T I C L E

Synaptic density and cognitive performance in Alzheimer’s

disease: A PET imaging study with [11C]UCB-J

Adam P. Mecca1,2 Ryan S. O’Dell1,2 Emily S. Sharp1,3 Emmie R. Banks1,2

Hugh H. Bartlett1,2 Wenzhen Zhao1,2 Sylwia Lipior1,2 Nina G. Diepenbrock1,2
Ming-Kai Chen4 Mika Naganawa4 Takuya Toyonaga4 Nabeel B. Nabulsi4
Brent C. Vander Wyk5 Amy F. T. Arnsten1,6 Yiyun Huang5 Richard E. Carson5
Christopher H. van Dyck1,2,3,6
1
Alzheimer’s Disease Research Unit, Yale University School of Medicine, New Haven, Connecticut, USA
2
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
3
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA
4
Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut, USA
5
Program on Aging, Yale University School of Medicine, New Haven, Connecticut, USA
6
Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut, USA

Correspondence
Adam P. Mecca, MD, PhD, Alzheimer’s Dis- Abstract
ease Research Unit, Yale University School of
Medicine, One Church Street, 8th Floor, New
Introduction: For 30 years synapse loss has been referred to as the major pathological
Haven, CT 06510, USA. correlate of cognitive impairment in Alzheimer’s disease (AD). However, this statement
E-mail: adam.mecca@yale.edu
is based on remarkably few patients studied by autopsy or biopsy. With the recent
Funding information advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET)
The National Institute on Aging, Grant/Award
imaging, we have begun to evaluate the consequences of synaptic alterations in vivo.
Numbers: P30AG066508, P50AG047270,
K23AG057784, R01AG052560, Methods: We examined the relationship between synaptic density measured by
R01AG062276, RF1AG057553,
[11 C]UCB-J PET and neuropsychological test performance in 45 participants with
P30AG021342; The American Brain Foun-
dation; The Dana Foundation; Thomas P. Detre early AD.
Fellowship Award in Translational Neuro-
Results: Global synaptic density showed a significant positive association with global
science Research in Psychiatry; The National
Institute of Mental Health, Grant/Award Num- cognition and performance on five individual cognitive domains in participants with
ber: T32MH019961; National Center for
early AD. Synaptic density was a stronger predictor of cognitive performance than gray
Advancing Translational Science, Grant/Award
Number: UL1TR000142 matter volume.
Conclusion: These results confirm neuropathologic studies demonstrating a significant
association between synaptic density and cognitive performance, and suggest that this
correlation extends to the early stages of AD.

KEYWORDS
Alzheimer’s disease, cognition, synaptic density, synaptic vesicle glycoprotein 2A, [11 C]UCB-J

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
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© 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association

Alzheimer’s Dement. 2022;18:2527–2536. wileyonlinelibrary.com/journal/alz 2527


2528
1 INTRODUCTION
For 30 years, synapse loss has been referred to as the major patholog-
ical correlate of cognitive impairment in Alzheimer’s disease (AD).1–3
However, this statement is based on remarkably few patients studied
by autopsy or biopsy in limited brain regions, largely at the moderate
to severe stages of disease. The earliest efforts to correlate synapse
loss with cognitive impairment in AD came from a single brain biopsy
study1 and a single autopsy study,2,3 both conducted primarily in par-
ticipants with moderate to severe dementia. A subsequent clinico-
pathological investigation incorporated individuals with mild cognitive
impairment (MCI) and focused on the hippocampus,4 demonstrating
that synapse number in the dentate gyrus (outer molecular layer) cor-
related with ante mortem cognitive performance in a pooled sample,
including patients with advanced dementia and normal controls. How-
ever, these results derived partially from the inclusion of cognitively
normal (CN) and neuropathologically confirmed controls and thus may
not apply to synapse loss within the AD continuum.
With the recent advent of synaptic positron emission tomogra-
phy (PET) imaging, we have begun to evaluate synaptic alterations
in vivo. Synaptic vesicle glycoprotein 2A (SV2A) is expressed in vir-
tually all synapses and is located in synaptic vesicles at presynap-
tic terminals.5 [11 C]UCB-J was recently developed as a PET tracer
for SV2A and advanced for human studies.6 In our recent study of
[11 C]UCB-J PET, we observed widespread reductions of SV2A binding
in medial temporal and neocortical brain regions in early AD compared
to CN participants.7 However, initial attempts using PET imaging to
associate synaptic density with cognitive performance have been hin-
dered by the use of limited cognitive measures.7–9
In this study, we examined the relationship between synaptic den-
sity and cognitive performance in early AD using [11 C]UCB-J PET
and an extensive neuropsychological test battery. We aimed to test
the hypothesis that synaptic density, as assessed by [11 C]UCB-J in
brain regions that are typically affected by AD, is associated with neu-
ropsychological function globally and in individual cognitive domains.
We also examined the effects of tissue loss on these associations—
compared to previous clinicopathological studies. Finally, we exam-
ined the relationship between gray matter (GM) volume—compared to
synaptic density—and neuropsychological function in this sample.
2 METHODS
Detailed methods are in supporting information (Supplement).
2.1 Study participants and design
Participants aged 50 to 85 years were screened for eligibility as pre-
viously described.7 Individuals with dementia met diagnostic criteria
for probable AD dementia,10 had a Clinical Dementia Rating global
score (CDR-global) of 0.5 to 1.0, and a Mini-Mental State Examina-
tion (MMSE) score of ≤ 26. Participants with MCI met diagnostic cri-
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MECCA ET AL .
RESEARCH IN CONTEXT
1. Systematic review: Synapse loss has been referred to as
the major pathological correlate of cognitive impairment
in Alzheimer’s disease (AD). With the recent advent of
synaptic vesicle glycoprotein 2A (SV2A) positron emis-
sion tomography (PET) imaging, we have begun to evalu-
ate the consequences of synaptic alterations in vivo.
2. Interpretation: In 45 participants with early AD, global
synaptic density showed a significant positive associa-
tion with global cognition and performance on five indi-
vidual cognitive domains. These results confirm neu-
ropathologic studies, demonstrating a significant associa-
tion between synaptic density and cognitive performance
and suggest that this correlation extends to the early
stages of AD.
3. Future directions: These results further support the use
of synaptic imaging as a potential surrogate biomarker
outcome for therapeutic trials that is well-correlated
with clinical measures. Longitudinal studies are needed
to relate change in synaptic density as measured by
[11 C]UCB-J PET with change in cognitive performance.
teria for amnestic MCI (aMCI),11 had a CDR-global score of 0.5, and
a MMSE score of 24 to 30, inclusive. Participants with dementia and
MCI were required to demonstrate impaired episodic memory, as evi-
denced by a Logical Memory (LM) II score 1.5 standard deviations
(SD) below an education-adjusted norm. Older CN participants were
enrolled solely to provide additional normative data for neuropsycho-
logical test scores and were required to have a CDR-global score of 0,
a MMSE score of > 26, and a normal education-adjusted LMII score.
All participants received a PET scan with [11 C]Pittsburgh compound B
([11 C]PiB) to assess for the accumulated presence of brain amyloid beta
(Aβ), and a PET scan with [11 C]UCB-J to measure synaptic density. Par-
ticipants with dementia and MCI were required to be Aβ+ and CN par-
ticipants were required to be Aβ–.7 All participants provided written
informed consent as approved by the Yale University Human Investi-
gation Committee.
Validated neuropsychological tests were administered to assess
performance in five cognitive domains: verbal memory (LMI and II, Rey
Auditory Verbal Learning Test [RAVLT] total words recalled across tri-
als 1–5, RAVLT delayed recall), language (Boston Naming Test, Cat-
egory Fluency), executive function (Stroop Color Word, Trail Making
Test-Part B, Letter Fluency), processing speed (Stroop Word, Trail Mak-
ing Test-Part A, Wechsler Adult Intelligence Scale [WAIS]-III Digit Sym-
bol Substitution), and visuospatial ability (Rey-Osterrieth Complex Fig-
ure, WAIS-III Block Design, WAIS-3 Picture Completion). Raw scores
from each test were converted to z-scores using means and SDs of the
entire sample (CN and AD). Cognitive domain scores were generated
for each AD participant by averaging the z-scores for the tests in each

MECCA ET AL .
domain. A global cognition score was generated for each participant by
averaging all five cognitive domain scores.
2.2 Brain imaging
T1-weighted magnetic resonance imaging (MRI) was performed to
define regions of interest (ROI) and to perform partial volume cor-
rection (PVC) using the iterative Yang (IY) approach.12,13 PET scans
were performed on the HRRT (207 slices, resolution < 3 mm full width
half max).14 List-mode data were reconstructed using the MOLAR
algorithm15 with event-by-event motion correction based on an opti-
cal detector (Vicra, NDI Systems).16 Dynamic [11 C]PiB scans were
acquired for 90 minutes after a bolus of up to 555 MBq of tracer17
and dynamic [11 C]UCB-J scans were acquired for 60 or 90 minutes
after administration of a bolus of up to 740 MBq.18 Software motion
correction was applied to the dynamic PET images using a mutual-
information algorithm (FSL-FLIRT) to perform frame-by-frame regis-
tration to a summed image (0 to 10 minutes). A summed motion-
corrected PET image was registered to each MRI. Cortical reconstruc-
tion and volumetric segmentation was performed using FreeSurfer
(version 6.0).19 Regions defined by the FreeSurfer segmentation were
used for both PET and MRI analyses in native participant space. Brain
volume was normalized using estimated total intracranial volume.20
A composite ROI of AD-affected regions (prefrontal, lateral temporal,
medial temporal, lateral parietal, anterior cingulate, posterior cingu-
late, precuneus, and lateral occipital) was defined (Table S1 in support-
ing information).
2.3 Tracer kinetic modeling
For [11 C]PiB image analysis, parametric images of BPND were gener-
ated using a simplified reference tissue model-2 step (SRTM2)21
previously described.7,17 For [11 C]UCB-J image analysis, parametric
images of BPND were generated using a SRTM2 from 0 to 60 minutes21
with the centrum semiovale (CS) as the reference region.22,23 Distribu-
tion volume ratio (DVR) using a whole cerebellum reference was com-
puted as (BPND +1)/(BPND [cerebellum]+1).7
2.4 Statistical analyses
Statistical methods are detailed in supporting information. Group
comparisons were performed using χ2 tests for categorical variables
and unpaired t-tests for continuous variables. Multiple variable linear
regression analyses used synaptic density or GM volume as the main
explanatory variables and cognitive scores as outcomes and controlled
for age, sex, and years of education. The Benjamini-Hochberg proce-
dure was used to control the false discovery rate (FDR) for multiple
comparisons (five cognitive domains). Pearson’s r (effect size) maps
were created with the voxels in each region set uniformly to the cal-
culated effect size. P < 0.05 was used as a threshold for significance.
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2529
3 RESULTS
3.1 Participant characteristics
The study sample consisted of 64 participants—45 with AD (28 with
mild dementia, 17 with aMCI), and 19 who were CN and provided nor-
mative neuropsychological data—whose characteristics are shown in
Table 1. The sample had substantial overlap with those of our previous
reports7,8,24 and included seven additional participants (three aMCI
and four mild dementia). CN and AD groups were balanced for age and
sex, but the CN group had a higher education level. Neuropsychological
testing was performed an average of 1.6 (SD 6.5) weeks after synaptic
density PET with a range of 16.1 weeks before to 15.6 weeks after the
PET scan. As expected, the AD group had lower MMSE scores, higher
CDR-global scores, and significantly lower performance on a compos-
ite of global cognition, as well as in all cognitive domains. As in our pre-
vious analyses of a largely overlapping sample, synaptic density in both
a composite of AD-affected regions, as well as in the hippocampus were
significantly lower in the AD group.
3.2 Association between synaptic density (DVR)
and cognition in AD
The primary analysis investigated the association between global
synaptic density (DVR) in a composite of AD-affected regions and
global cognition within the AD group. A multiple linear regression
model with DVR as the predictor and global cognition as the outcome
was significant (F[4, 40] = 6.19, P = 0.001, R2 = 0.38) and synaptic den-
sity was a significant predictor of global cognition (β = 3.21, η2 = 0.29,
P = 0.0001, Figure 1A, Table S2a in supporting information).
To investigate the association between synaptic density and perfor-
as mance in specific cognitive domains, separate models were fit with per-
formance in each of the five domains (verbal memory, language, exec-
utive function, processing speed, and visuospatial ability) as the out-
come (Table S2b). Each model was significant and synaptic density was
a significant predictor of performance in every domain (Table S2b, Fig-
ure 1B-1F).
Additional exploratory analyses assessed the association between
synaptic density in all brain regions and global cognition. Pearson’s r
was calculated for the correlation between synaptic density and global
cognition (Figure 2A, Table S3 in supporting information). Synaptic den-
sity had a significant positive association with global cognition across
many prefrontal, temporal, parietal, and occipital cortical regions. Sim-
ilar regional patterns were observed for specific cognitive domain
scores, including language, executive function, processing speed, and
visuospatial ability (Figure 3). By contrast, associations between synap-
tic density and verbal memory performance were more restricted
within temporal, parietal, and occipital cortical regions. Interestingly,
synaptic density in hippocampus and entorhinal cortex was not signifi-
cantly correlated with global cognition (Figure 2A, Table S3) or domain-
specific cognitive performance (Figure 3).
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2530 MECCA ET AL .

TA B L E 1 Participant characteristics

Cognitively normal Alzheimer’s disease P

Participants (n) 19 45 (mild dementia: 28, MCI: 17) –
Sex (M/F) 9/10 23/22 0.78
Age (years) 70.84 (7.78) (59–82) 70.82 (7.48) (50–83) 0.99
Education (years) 17.74 (2.00) (12–20) 16.13 (2.31) (12–20) 0.0093
CDR-global 0 (0) (0) 0.76 (.25) (0.5–1) < 0.00001
CDR-SB 0.00 (0.00) (0) 4.11 (1.81) (0.5–9.0) < 0.00001
MMSE 29.21 (1.06) (27–30) 23.64 (3.37) (14–30) < 0.00001
Global cognition 0.93 (0.25) (0.44–1.25) –0.41 (0.62) (–1.68–0.69) < 0.00001
Executive functions 0.85 (0.40) (0.20–1.71) –0.42 (0.77) (–1.74–1.00) < 0.00001
Processing speed 0.75 (0.28) (0.38–1.41) –0.32 (0.87) (–2.32–1.00) < 0.00001
Language 0.89 (0.32) (0.29–1.90) –0.38 (0.79) (–2.16–0.85) < 0.00001
Visuospatial ability 0.85 (0.41) (–0.15–1.54) –0.37 (0.78) (–2.05–1.07) < 0.00001
Verbal memory 1.29 (0.52) (0.29–2.01) –0.54 (0.42) (–1.19–0.51) < 0.00001
Amyloid ± 0/19 45/0 < 0.00001
Composite synaptic density (DVR) 1.57 (0.08) (1.44–1.73) 1.45 (0.11) (1.27–1.70) 0.00004
Hippocampal synaptic density (DVR) 1.03 (0.08) (0.86–1.20) 0.88 (0.12) (0.66–1.17) < 0.00001
APOE ε4 copy number (n)
2 copies 0 12 (26.7%) –
1 copy 4 (21%) 23 (51.1%) –
0 copies 15 (79%) 10 (22.2%) –

Abbreviations: APOE, apolipoprotein E: CDR-global, Clinical Dementia Rating global score; CDR-SB, Clinical Dementia Rating Sum of Boxes; DVR, distribution
volume ratio of [11 C]UCB-J calculated with a whole cerebellum reference region; MMSE, Mini-Mental State Examination; SD, standard deviation.
Notes: Data are mean (SD) (range). Scores for cognitive measures are z-scores. P-values are for unpaired t-tests (continuous variables) or χ2 (categorical
variables).

3.3 Association between partial volume corrected 3.4 Association between GM volume
synaptic density (PVC-DVR) and cognition in AD and cognition in AD

Because volume loss related to AD can lead to underestimation of
synaptic density, we repeated the previous analyses after PVC. A mul-
tiple linear regression model with global PVC-DVR as the predictor
and global cognition as the outcome was significant (F[4, 40] = 4.93,
P = 0.003, R2 = 0.33) and synaptic density was a significant predictor
of global cognition (β = 2.16, η2 = 0.23, P = 0.001, Figure 4A, Table S4a
in supporting information).
Separate models were fit with performance on each of the five cog-
nitive domains as the outcomes (Table S4b). Each model was signifi-
cant, and synaptic density was a significant predictor of performance
in every domain (Table S4b, Figure 4B-4F).
The correlation between regional synaptic density (PVC-DVR) and
global cognition was again assessed (Figure 2B, Table S3). Similar to
the analysis without PVC, synaptic density had a significant positive
association with global cognition across many prefrontal, temporal,
parietal, and occipital cortical regions. Compared to the analysis using
global cognition, similar regional patterns were present with significant
positive associations between regional synaptic density and language,
executive function, processing speed, and visuospatial ability (Figure
S1 in supporting information).
As a comparator to synaptic density, we examined the relationship
between GM volume and cognition in this sample. A multiple linear
regression model with GM volume as the predictor and global cog-
nition as the outcome was significant (F[4, 40] = 3.57, P = 0.014,
R2 = 0.26) and GM volume was a significant predictor of global cogni-
tion (β = 0.012, η2 = 0.17, P = 0.005, Figure S2A, Table S5a in supporting
information).
Separate models were again fit with performance in each of the five
cognitive domains as the outcomes (Table S5b). In contrast to synap-
tic density, GM volume was only a significant predictor of language and
executive function, but not the other cognitive domains (Table S5b). In
addition, the effect sizes for correlations between GM volume and cog-
nition (Figure S2) were generally smaller than the effect sizes for corre-
lations between synaptic density and cognition (Figure 1 and Figure 4).
When regional GM volume was correlated with global cognition,
there were positive associations (Figure 2C, Table S3), but with fewer
significant regions compared to synaptic density (Figure 2A, B). When
regional GM volume was correlated with individual cognitive domains,
similar regional patterns as for global cognition were observed, with
significant positive associations between regional GM volume and
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MECCA ET AL . 2531

F I G U R E 1 Correlation of synaptic density (DVR) and cognition in participants with AD. Global synaptic density in a composite of AD-affected
regions, represented as DVR, was plotted with (A) global cognition, (B) verbal memory, (C) language, (D) executive function, (E) processing speed, or
(F) visuospatial ability. Multiple variable linear regression analysis included predictors of synaptic density, years of education, age, and sex. η is
displayed for the main explanatory variable of synaptic density as it contributes to the overall model (*P < 0.05). Data points and line of best fit
(dotted line) are unadjusted values. AD, Alzheimer’s disease; DVR, distribution volume ratio of [11 C]UCB-J calculated with a whole cerebellum
reference region

language, executive functions, processing speed, and visuospatial abil-
ity (Figure S3 in supporting information).
4 DISCUSSION
resulted from floor effects on the cognitive measures that comprised
this domain. The observed associations between synaptic density and
global cognition remained significant after correction for partial vol-
ume effects, and synaptic density was a stronger predictor of cognitive
performance than GM volume.

In this study we examined the relationship between synaptic density

and cognitive performance in early AD using [11 C]UCB-J PET and an
extensive neuropsychological test battery. In a multiple linear regres-
sion model controlling for age, sex, and education, global synaptic den-
sity ([11 C]UCB-J DVR) was a significant predictor of global cognitive
performance in participants with AD. Synaptic density was also a signif-
icant predictor of performance in all five cognitive domains: language,
executive function, processing speed, visuospatial ability, and verbal
memory. The relatively weak association with verbal memory likely
4.1 Comparison with post mortem and biopsy
specimen human studies
These results confirm neuropathologic studies demonstrating a sig-
nificant association between synaptic density and cognitive perfor-
mance, and suggest that this correlation extends to the mild and pro-
dromal stages of AD. The early evidence for synapse loss as the major
pathological correlate of cognitive impairment in AD1 came from a
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2532 MECCA ET AL .

F I G U R E 2 Correlation maps of synaptic density (DVR) and global cognition in all regions for participants with AD. (A) Pearson’s r was
calculated for the correlation between synaptic density ([11 C]UCB-J DVR) and global cognition in all FreeSurfer regions. A similar analysis was
conducted (B) after PVC of [11 C]UCB-J PET images, and (C) with gray matter volume. Brain maps were created by producing images with the
voxels in each FreeSurfer region set uniformly to the calculated Pearson’s r for that region and overlaid on an MNI template T1 MRI. The color
scale represents Pearson’s r, which is displayed only for regions that had an uncorrected P < 0.05. AD, Alzheimer’s disease; DVR, distribution
volume ratio of [11 C]UCB-J calculated with a whole cerebellum reference region; MNI, Montreal Neurological Institute; MRI, magnetic resonance
imaging; PET, positron emission tomography; PVC, partial volume correction

single brain biopsy study and a single autopsy study2 both conducted
largely at the moderate to severe stages of disease. DeKosky and
Scheff first reported synapse loss in eight individuals with AD who
had undergone frontal cortex biopsies.1 They found that in eight AD
patients with MMSE scores ranging from 12 to 20, synapse counts
correlated with MMSE performance.1 The next year, Terry et al.2
reported on autopsy data from 15 patients with AD and nine neu-
ropathologically confirmed controls and found that within the AD
group (MMSE = 3–20), synapse density in midfrontal and inferior pari-
etal regions was correlated with ante mortem cognitive performance
on the Blessed Information-Memory-Concentration Test, the MMSE,
and the Mattis Dementia Rating Scale. Masliah et al. then investi-
gated a subset of the cases in Terry et al. (AD: 9, neuropathologi-
cally normal controls: 4) and demonstrated that the strongest corre-
lation was between synapse density and Blessed score of cognitive
impairment.3
In 2006 Scheff et al. reported for the first time on synaptic data in
the hippocampus4 and found that synapse number in dentate gyrus
(outer molecular layer) correlated with ante mortem cognitive perfor-
mance in a pooled sample, including normal controls (MMSE = 8–
30). The AD sample included nine with dementia and nine with MCI.
However, the inclusion of 10 cognitively normal and neuropatholog-
ically confirmed controls in the analyses left unclear the extent to
which associations were with synapse loss along the AD continuum
as opposed to the presence or absence of AD. Another limitation of
that study—as with most post mortem studies—was that the overall AD
sample had a mean age of 88, and 87 in the MCI group. These indi-
viduals were likely prodromal for dementia onset in their 90s and per-
haps similar to very old AD samples, which have been shown to have
unique characteristics, particularly multiple neuropathologies.25–27
Therefore, they are not necessarily representative of the broad sam-
ples of early AD that are studied in vivo.
4.2 Comparison with previous human synaptic
density imaging studies
With the recent advent of synaptic PET imaging, we have begun to eval-
uate synaptic alterations in vivo. However, initial attempts using PET
imaging to associate synaptic density with cognitive performance in
AD have been hindered by the use of limited cognitive measures. In
our preliminary report,8 we observed that hippocampal SV2A-specific
binding (BPND ) was correlated with a composite episodic memory score
and a measure of global functioning (CDR-Sum of Boxes [SB]) in a
pooled sample of participants who had early AD or were cognitively
normal. In a follow-up study of a larger sample (19 CN and 35 early
AD, a subset of the present sample of 45), in which we demonstrated
widespread synaptic loss in AD using a more robust SV2A outcome
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MECCA ET AL . 2533

F I G U R E 3 Correlation maps of synaptic density (DVR) and domain specific cognitive performance in all regions for participants with AD.
Pearson’s r was calculated for the correlation between synaptic density ([11 C]UCB-J DVR) and (A) verbal memory, (B) language, (C) executive
function, (D) processing speed, and (E) visuospatial ability domain scores. Brain maps were created by producing images with the voxels in each
FreeSurfer region set uniformly to the calculated Pearson’s r for that region and overlaid on an MNI template T1 MRI. The color scale represents
Pearson’s r, which is displayed only for regions that had an uncorrected P < 0.05. AD, Alzheimer’s disease; DVR, distribution volume ratio of
[11 C]UCB-J calculated with a whole cerebellum reference region; MNI, Montreal Neurological Institute; MRI, magnetic resonance imaging

measure (DVR with cerebellum as reference region), we again exam-
ined the relationship between synaptic density and clinical measures.7
Specifically, we investigated the association of DVR in either hippocam-
pus or a composite ROI of AD-affected regions (identical to those in the
present study) with episodic memory or CDR-SB. In the overall sam-
ple, statistically significant correlations were observed between DVR
in either the hippocampus or the composite region and either episodic
memory or CDR-SB. However, none of these correlations were signifi-
cant within the AD or CN groups alone.
We believe that the negative results using more limited cognitive
and clinical measures may relate to at least two factors. The mem-
ory score is comprised of difficult memory tasks that produce “floor
effects” in the participants with early AD and a lack of dynamic range.
The verbal memory score in the present study incorporated a measure
with more range (the total of trials 1 through 5 on the RAVLT and LMI
[immediate recall], instead of only the delayed recall score). However,
the correlation between global SV2A and verbal memory remained the
weakest correlation between global SV2A and any cognitive domain.
 15525279, 2022, 12, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12582 by Cochrane Portugal, Wiley Online Library on [07/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2534 MECCA ET AL .

F I G U R E 4 Correlation of synaptic density with PVC (PVC–DVR) and cognition in participants with AD. PVC was applied to [11 C]UCB-J PET
images. Global synaptic density in a composite of AD-affected regions, represented as DVR, was plotted with (A) global cognition, (B) verbal
memory, (C) language, (D) executive function, (E) processing speed, or (F) visuospatial ability. Multiple variable linear regression analysis included
predictors of synaptic density, years of education, age, and sex. η is displayed for the main explanatory variable of synaptic density as it contributes
to the overall model (*P < 0.05). Data points and line of best fit (dotted line) are unadjusted values. AD, Alzheimer’s disease; DVR, distribution
volume ratio of [11 C]UCB-J calculated with a whole cerebellum reference region; PET, positron emission tomography; PVC, partial volume
correction

Moreover, the brain regions that are most likely to correlate with ver-
bal memory are those that already demonstrate marked degeneration
in early AD, thus yielding a lack of dynamic range in both the memory
and the SV2A imaging variables.
Apart from our own work, Bastin et al., using a different SV2A lig-
and ([18 F]UCB-H with partial volume correction), reported in 24 par-
ticipants with AD that reduced hippocampal uptake was related to cog-
nitive decline (MMSE score) and unawareness of memory problems.9
Coomans et al. explored cognitive associations and synaptic density in
a small sample of seven AD participants and found that MMSE score
was not associated with a global measure of synaptic density using
[11 C]UCB-J BPND but was strongly associated with a global measure
of tau deposition using [18 F]flortaucipir BPND. 28
4.3 Limitations and future directions
This study has a number of important limitations. First, we cannot com-
ment on the relative strength or spatial patterns of association with
different cognitive domains, as these comparisons are limited by test
selection. Specifically, individual tests may differ in relative difficulty,
and some may exhibit floor effects, thus hindering our ability to evalu-
ate associations with PET measures. Second, the cross-sectional nature
of this study is susceptible to many confounding factors that may result
in considerable inter-individual variability in synaptic density and neu-
ropsychological performance. Longitudinal studies will better enable
us to test directly the hypothesis that synaptic loss is associated with
a decline in cognitive performance. In particular, longitudinal studies

MECCA ET AL .
that enroll participants at pre-symptomatic stages of disease may cap-
ture the early emergence of both synaptic loss and cognitive symp-
toms. Longitudinal studies—by minimizing inter-individual sources of
variance—will also confer greater statistical power to detect more spe-
cific associations between regional synaptic loss and the decline in spe-
cific cognitive domains. If synaptic loss is the major pathological corre-
late of cognitive impairment in AD, then the heterogeneity of decline in
cognitive domains should be related to the regional patterns of synap-
tic loss.
4.4 Conclusion
These results confirm neuropathologic studies demonstrating a signifi-
cant association between synaptic density and cognitive performance,
and suggest that this correlation extends to the mild and prodromal
stages of AD. They further support the use of synaptic imaging as a
potential surrogate biomarker outcome for therapeutic trials that is
well-correlated with clinical measures. Longitudinal studies are needed
to relate change in synaptic density as measured by [11 C]UCB-J PET
with change in cognitive performance.
ACKNOWLEDGMENTS
We wish to thank the research participants for their contributions,
and the staff of the Yale AD Research Unit and PET Center for
their excellent technical assistance. We also thank UCB for pro-
viding the [11 C]UCB-J radiolabeling precursor and the unlabeled
reference standard. This research was supported by the National
Institute on Aging (P30AG066508, P50AG047270, K23AG057784,
R01AG052560, R01AG062276, RF1AG057553, and P30AG021342),
The American Brain Foundation (APM), and The Dana Foundation
(MKC), the Thomas P. Detre Fellowship Award in Translational Neu-
roscience Research in Psychiatry (RSO), and the Ruth L. Kirschstein
National Research Service Award, Clinical Neuroscience Research
Training in Psychiatry (T32MH019961). This publication was made
possible by CTSA Grant Number UL1TR000142 from the National
Center for Advancing Translational Science (NCATS), a component of
NIH. Its contents are solely the responsibility of the authors and do not
necessarily represent the official view of NIH. The funders had no role
in the design and conduct of the study; collection, management, analy-
sis, and interpretation of the data; preparation, review, or approval of
the manuscript; and decision to submit the manuscript for publication.
CONFLICTS OF INTEREST
APM, REC, and CHvD report grants from National Institutes of Health
(NIH) for the conduct of the study. APM, ESS, TT, BCV, AFTA, YH,
and REC report grant support from the NIH for work not related to
this manuscript. APM reports grants for clinical trials from Genentech,
Eisai, and Eli Lilly outside the submitted work. MKC reports research
support from the Dana Foundation and Eli Lilly outside the submit-
ted work. YH reports research grants from UCB and Eli Lilly outside
the submitted work. REC reports grants from Bristol Myers Squibb,
Cerevel Therapeutics, Invicro, and UCB outside the submitted work.
15525279, 2022, 12, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12582 by Cochrane Portugal, Wiley Online Library on [07/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2535
CHvD reports grants for clinical trials from Biogen, Novartis, Eli Lilly,
Eisai, Biohaven, and the Alzheimer’s Association outside the submitted
work. YH, REC, and NBN have a patent for a newer version of the SV2A
tracer. MKC reports consulting fees from Eisai and Actinum. AFTA
reports consulting fees from Vallon, Supernus, and Ludbeck. CHvD
reports consulting fees from Roche, Esai, and Ono Pharmaceuticals.
APM received honoraria for presentations at University of Connecti-
cut and Stanford University. NBN received honoraria for presentations
from UCLA Semel Institute for Neuroscience & Human Behavior. AFTA
received honoraria for presentations at McGill University, Killam Insti-
tute, Montreal Neurological Institute, Harvard, Massachusetts General
Hospital, Western Connecticut State University, and the University of
Massachusetts. APM received support from ACTC/ATRI for travel to
ACTC/ATRI meetings. TT received travel support from the conference
for the 2019 Brain and Brain PET meeting. AFTA received support from
the conference for travel to give a presentation at ACNP. APM is a
member of the ISTAART Neuroimaging PIA executive committee. NN
receives royalties from MD Anderson Cancer Center. AFTA and Yale
receive royalties from Shire/Takada from USA sales of Intuniv. ERB,
HHB, WZ, SL, NGD, and MN have nothing to disclose.
AUTHOR CONTRIBUTIONS
Dr. Mecca had full access to the data and takes responsibility for the
integrity of the data and the accuracy of the data analysis. Study con-
cept and design: Mecca, Sharp, Chen, O’Dell, Carson, van Dyck. Acqui-
sition, analysis, or interpretation of data: Mecca, Sharp, O’Dell, Banks,
Bartlett, Naganawa, Diepenbrock, Lipior, Zhao, Toyonaga, Nabulsi, Arn-
sten, Huang, Carson, van Dyck. Drafting of the manuscript: Mecca,
Sharp, O’Dell, Banks, Bartlett, Arnsten, Carson, van Dyck. Critical
revision of the manuscript for important intellectual content: Mecca,
Sharp, O’Dell, Banks, Bartlett, Naganawa, Diepenbrock, Lipior, Zhao,
Toyonaga, Nabulsi, Arnsten, Huang, Carson, van Dyck. Statistical analy-
sis: Mecca, O’Dell, Banks, Bartlett, Carson, van Dyck. Obtained funding:
van Dyck, Carson, Mecca, Chen. Administrative, technical, or material
support: Mecca, Sharp, O’Dell, Banks, Bartlett, Naganawa, Toyonaga,
Diepenbrock, Lipior, Nabulsi, Huang, Chen, Carson, van Dyck. Study
supervision: Mecca, Chen, Carson, van Dyck.
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SUPPORTING INFORMATION
Additional supporting information may be found in the online version
of the article at the publisher’s website.
How to cite this article: Mecca AP, O’Dell RS, Sharp ES, et al.
Synaptic density and cognitive performance in Alzheimer’s
disease: A PET imaging study with [11 C]UCB-J. Alzheimer’s
Dement. 2022;18:2527–2536.
https://doi.org/10.1002/alz.12582