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Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [11C]UCB‐J

Alzheimer's & Dementia

February 2022
18(12)

DOI:10.1002/alz.12582

License
CC BY-NC 4.0

Authors:

Adam Mecca

Yale University

Ryan S O'Dell

Yale University

Emily Schoenhofen Sharp

Yale University

Emmie Banks

Emory University

Show all 17 authorsHide

Introduction: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo. Methods: We examined the relationship between synaptic density measured by [11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD. Results: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray 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.

The sample had substantial overlap with those of our previous

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

DOI: 10.1002/alz.12582

FEATURED ARTICLE

Synaptic density and cognitive performance in Alzheimer’s

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

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

Hugh H. Bartlett1,2Wenzhen Zhao1,2Sylwia Lipior1,2Nina G. Diepenbrock1,2

Ming-Kai Chen4Mika Naganawa4Takuya Toyonaga4Nabeel B. Nabulsi4

Brent C. Vander Wyk5AmyF.T.Arnsten

1,6Yiyun Huang5Richard E. Carson5

Christopher H. van Dyck1,2,3,6

1Alzheimer’s Disease Research Unit, Yale University School of Medicine, New Haven,Connecticut, USA

2Department of Psychiatry, Yale University School of Medicine, New Haven,Connecticut, USA

3Department of Neurology, Yale University School of Medicine, New Haven,Connecticut, USA

4Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven,Connecticut, USA

5Program on Aging, Yale UniversitySchool of Medicine, New Haven, Connecticut, USA

6Department of Neuroscience, Yale University School of Medicine, New Haven,Connecticut, USA

Correspondence

Adam P. Mecca, MD, PhD,Alzheimer’s Dis-

ease Research Unit, YaleUniversity School of

Medicine, One Church Street, 8th Floor,New

Haven, CT 06510, USA.

E-mail: adam.mecca@yale.edu

Funding information

The National Institute on Aging, Grant/Award

Numbers: P30AG066508, P50AG047270,

K23AG057784, R01AG052560,

R01AG062276, RF1AG057553,

P30AG021342; The American Brain Foun-

dation; The Dana Foundation; Thomas P. Detre

Fellowship Award in Translational Neuro-

science Research in Psychiatry; The National

Institute of Mental Health, Grant/AwardNum-

ber: T32MH019961; National Center for

Advancing TranslationalScience, Grant/Award

Number: UL1TR000142

Abstract

Introduction: For 30 years synapse loss has been referred to as the major pathological

correlate of cognitive impairment in Alzheimer’s disease (AD). However, this statement

is based on remarkably few patients studied by autopsy or biopsy. With the recent

advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET)

imaging, we have begun to evaluate the consequences of synaptic alterations in vivo.

Methods: We examined the relationship between synaptic density measured by

[11C]UCB-J PET and neuropsychological test performance in 45 participants with

early AD.

Results: Global synaptic density showed a significant positive association with global

cognition and performance on five individual cognitive domains in participants with

early AD. Synaptic density was a stronger predictor of cognitive performance than gray

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, [11C]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

medium, provided the original work is properly cited and is not used for commercial purposes.

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

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2528 MECCA ET AL.

1INTRODUCTION

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

study1and 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,4demonstrating

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[11C]UCB-J was recently developed as a PET tracer

for SV2A and advanced for human studies.6In our recent study of

[11C]UCB-J PET, we observed widespread reductions of SV2A binding

in medial temporal and neocortical brain regions in early AD compared

to CN participants.7However, 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 [11C]UCB-J PET

and an extensive neuropsychological test battery. We aimed to test

the hypothesis that synaptic density, as assessed by [11C]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.

2METHODS

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.7Individuals 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-

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

[11C]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 [11C]Pittsburgh compound B

([11C]PiB) to assess for the accumulated presence of brain amyloid beta

(Aβ), and a PET scan with [11C]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–.7All 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]-IIIDigit 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.2529

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 [11C]PiB scans were

acquired for 90 minutes after a bolus of up to 555 MBq of tracer17

and dynamic [11C]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 as

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 χ2tests 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.

3RESULTS

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

Ta b l e 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,TableS2a in supporting information).

To investigate the association between synaptic density and perfor-

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,TableS3 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,TableS3)or domain-

specific cognitive performance (Figure 3).

2530 MECCA ET AL.

TAB 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 [11C]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

synaptic density (PVC-DVR) 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,TableS4a

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,Figure4B-4F).

The correlation between regional synaptic density (PVC-DVR)and

global cognition was again assessed (Figure 2B,TableS3). 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).

3.4 Association between GM volume

and cognition in AD

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,TableS5a 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 1and Figure 4).

When regional GM volume was correlated with global cognition,

there were positive associations (Figure 2C,TableS3), 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

MECCA ET AL.2531

FIGURE 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. ηis

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 [11C]UCB-J calculated with a whole cerebellum

reference region

language, executive functions, processing speed, and visuospatial abil-

ity (Figure S3 in supporting information).

4DISCUSSION

In this study we examined the relationship between synaptic density

and cognitive performance in early AD using [11C]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 ([11C]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

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.

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 AD1came from a

2532 MECCA ET AL.

FIGURE 2 Correlation maps of synaptic density (DVR) and global cognition in all regions for participants with AD. (A) Pearson’s rwas

calculated for the correlation between synaptic density ([11C]UCB-J DVR) and global cognition in all FreeSurfer regions. A similar analysis was

conducted (B) after PVC of [11C]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 [11C]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 study2both 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.1They found that in eight AD

patients with MMSE scores ranging from 12 to 20, synapse counts

correlated with MMSE performance.1The 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 hippocampus4and 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,8we 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

MECCA ET AL.2533

FIGURE 3 Correlation maps of synaptic density (DVR) and domain specific cognitive performance in all regions for participants with AD.

Pearson’s rwas calculated for the correlation between synaptic density ([11C]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 rfor 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

[11C]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.

2534 MECCA ET AL.

FIGURE 4 Correlation of synaptic density with PVC (PVC–DVR) and cognition in participants with AD. PVC was applied to [11C]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. ηis 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 [11C]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 ([18F]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

[11C]UCB-J BPND but was strongly associated with a global measure

of tau deposition using [18F]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.2535

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 [11C]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 [11C]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.

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 receivedhonoraria 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 [11C]UCB-J. Alzheimer’s

Dement. 2022;18:2527–2536.

https://doi.org/10.1002/alz.12582

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Full-text available

Feb 2021

Background The mechanism of synaptic loss in Alzheimer’s disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([¹⁸F]flortaucipir PET), synaptic density (synaptic vesicle 2A [¹¹C]UCB-J PET) and synaptic function (MEG) in Alzheimer’s disease. Methods Seven amyloid-positive Alzheimer’s disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [¹⁸F]flortaucipir PET, dynamic 60-min [¹¹C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [¹⁸F]flortaucipir- and [¹¹C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [¹⁸F]flortaucipir BPND, [¹¹C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. Results Across subjects, higher regional [¹⁸F]flortaucipir uptake was associated with lower [¹¹C]UCB-J uptake. Within subjects, the association between [¹¹C]UCB-J and [¹⁸F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [¹⁸F]flortaucipir and lower [¹¹C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. Conclusions These results indicate that in Alzheimer’s disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

Association of Aβ deposition and regional synaptic density in early Alzheimer’s disease: a PET imaging study with [11C]UCB-J

Article

Full-text available

Jan 2021

Background Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in Alzheimer’s disease (AD) have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration—at least in the dementia stage—as deposition of Aβ reaches a ceiling. In this study, we examined in vivo the association between fibrillar Aβ deposition and synaptic density in early AD using positron emission tomography (PET). We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI; a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau). Methods We measured SV2A binding ([ ¹¹ C]UCB-J) and Aβ deposition ([ ¹¹ C]PiB) in 14 participants with aMCI due to AD and 24 participants with mild AD dementia. Distribution volume ratios ( DVR ) with a cerebellar reference region were calculated for both tracers to investigate the association between global Aβ deposition and SV2A binding in hippocampus. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches. Results We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI ( r = − 0.55, P = 0.04), but not mild dementia ( r = 0.05, P = 0.82; difference statistically significant by Fisher z = − 1.80, P = 0.04). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a “paradoxical” positive association between local Aβ deposition and SV2A binding in the hippocampus. Conclusions Our findings lend support to a model in which fibrillar Aβ is still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research should investigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers.

In vivo measurement of widespread synaptic loss in Alzheimer's disease with SV2A PET

Article

Full-text available

May 2020

Introduction: Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density. Methods: We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [11 C]UCB-J PET and a cerebellar reference region for calculation of the distribution volume ratio. Results: We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume. Conclusion: We were able to measure widespread synaptic loss due to AD using [11 C]UCB-J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies.

In vivo imaging of synaptic loss in Alzheimer’s disease with [18F]UCB-H positron emission tomography

Article

Full-text available

Feb 2020
EUR J NUCL MED MOL I

Purpose Loss of brain synapses is an early pathological feature of Alzheimer’s disease. The current study assessed synaptic loss in vivo with positron emission tomography and an 18F-labelled radiotracer of the synaptic vesicle protein 2A, [18F]UCB-H. Methods Twenty-four patients with mild cognitive impairment or Alzheimer’s disease and positive [18F]Flutemetamol amyloid-PET were compared to 19 healthy controls. [18F]UCB-H brain uptake was quantified with Logan graphical analysis using an image-derived blood input function. SPM12 and regions-of-interest (ROI) analyses were used for group comparisons of regional brain distribution volumes and for correlation with cognitive measures. Results A significant decrease of [18F]UCB-H uptake was observed in several cortical areas (11 to 18% difference) and in the thalamus (16% difference), with the largest effect size in the hippocampus (31% difference). Reduced hippocampal uptake was related to patients’ cognitive decline (ROI analysis) and unawareness of memory problems (SPM and ROI analyses). Conclusions The findings thus highlight predominant synaptic loss in the hippocampus, confirming previous autopsy-based studies and a recent PET study with an 11C-labelled SV2A radiotracer. [18F]UCB-H PET allows to image in vivo synaptic changes in Alzheimer’s disease and to relate them to patients’ cognitive impairment.

Cortical β-Amyloid Burden, Gray Matter, and Memory in Adults at Varying APOE ε4 Risk for Alzheimer's Disease

Article

Full-text available

Oct 2017
NEUROBIOL AGING

Models of preclinical Alzheimer's disease (AD) propose that cerebral amyloidosis leads to neurodegeneration and subsequent cognitive decline. This study investigated whether APOE genotype is related to β-amyloid (Aβ) burden in brain regions preferentially affected by AD and whether Aβ burden is associated with gray matter fraction (as a marker of neurodegeneration) and episodic memory performance in cognitively normal middle-aged individuals at varying genetic risk for AD. Three groups of cognitively normal participants aged 50-65 with a first-degree family history of AD [APOE genotype ε4ε4 (n=15), ε3ε4 (n=15), and ε3ε3 (n=15)], underwent [¹¹C]PiB PET scans to quantify cortical Aβ, brain MRI and neuropsychological testing. APOE ε4ε4 participants demonstrated significantly higher cortical Aβ burden than APOE ε3ε3 (p<0.001). Furthermore, cortical Aβ burden was inversely associated with cortical gray matter fraction (p=0.017), but not episodic memory performance. In cognitively normal, middle-aged individuals, Aβ burden is significantly associated with gray matter fraction but not episodic memory performance. These findings are consistent with models of preclinical AD in which neurodegeneration occurs before manifest cognitive decline.

Association of Aß deposition and regional synaptic density in early Alzheimer's disease: a PET imaging study with [11C]UCB-J

Article

Apr 2021
AM J GERIAT PSYCHIAT

Introduction Synaptic loss is an early pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. We have recently demonstrated extensive synaptic loss in the medial temporal and neocortical regions of participants with AD, using in vivo positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A), a promising biomarker of synaptic density. Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in AD however, have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration—at least in the dementia stage—as deposition of Aβ reaches a ceiling. In this study, we examined in vivothe association between fibrillar Aβ deposition and synaptic density in early AD using [¹¹C]PiB and [¹¹C]UCB-J PET. We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI, a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau). Methods [¹¹C]UCB-J (for SV2A) and [¹¹C]PiB (Aβ deposition) binding were measured in 14 participants with aMCI due to AD, 24 participants with mild AD dementia, and 19 cognitively normal (CN) participants aged 55-85 years. For [¹¹C]PiB data analysis, parametric images of binding potential (BPND) were generated using SRTM2 with cerebellum as a reference region and converted to distribution volume ratios (DVR). For [¹¹C]UCB-J, BPNDwas computed using SRTM2 with a shrunken centrum semiovale reference region and converted to DVR with a cerebellum reference region. For the primary analysis of the association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI and dementia, separate univariate regression analyses were performed for each diagnostic group with Pearson r and associated two-tailed P values reported for each model. Fisher z-transformation assessed significant differences in correlation coefficients between the aMCI and dementia groups, with one-tailed P values reported. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches. Global Aβ deposition was determined for a composite of regions commonly affected by Aβ deposition in AD which included: prefrontal, lateral temporal, posterior cingulate/precuneus, and lateral parietal ROIs. Results The AD group showed significant widespread reductions in cortical and subcortical synaptic density, most pronounced in the medial temporal lobe, and significantly elevated cortical amyloid in regions commonly affected by AD pathology (Figure 1). We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI (r = -0.55, P = 0.04), but not mild dementia (r = 0.05, P = 0.82; difference statistically significant by Fisher z= -1.80, P = 0.04; Figure 2).This stronger association was observed to survive partial volume correction (aMCI r= -0.56, P= 0.04; dementia r= -0.01, P= 0.96; Fisher z= -1.67, P= 0.047). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a nominal inverse association in the dementia group between local Aβ deposition and SV2A binding in medial occipital cortex and a more compelling, larger positive correlation between local Aβ accumulation and synaptic density in hippocampus (Table 1). Conclusions To our knowledge, we have conducted the first in vivo study investigating the relationship between Aβ deposition and synaptic alterations in participants with AD. We observed significant inverse associations between measures of global Aβ deposition and hippocampal synaptic density within participants with aMCI but not with dementia. Our findings lend support to a model in which fibrillar Aβ may still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research shouldinvestigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers. Funding P50-AG047270 (CHvD), P30-AG066508 [CHvD], K23-AG057794 (APM), R01-AG052560 (REC, CHV), R01-AG062276 (CHvD), Dana Foundation (MKC), T32-MH019961 (RSO), and Thomas P. Detre Fellowship (RSO).

Assessment of a white matter reference region for 11 C-UCB-J PET quantification

Article

Sep 2019

C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of ¹¹ C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in ¹¹ C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution ( V T ) to nondisplaceable uptake in gray matter, V ND . Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS V T and V ND . However, even with these corrections, CS V T overestimated V ND by ∼35–40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.

Validation of Parametric Methods for [11C]UCB-J PET Imaging Using Subcortical White Matter as Reference Tissue

Article

Jun 2019

Purpose The aim of this study was to evaluate different non-invasive methods for generating (R)-1-((3-([¹¹C]methyl)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([¹¹C]UCB-J) parametric maps using white matter (centrum semi-ovale–SO) as reference tissue. Procedures Ten healthy volunteers (8 M/2F; age 27.6 ± 10.0 years) underwent a 90-min dynamic [¹¹C]UCB-J positron emission tomography (PET) scan with full arterial blood sampling and metabolite analysis before and after administration of a novel chemical entity with high affinity for presynaptic synaptic vesicle glycoprotein 2A (SV2A). A simplified reference tissue model (SRTM2), multilinear reference tissue model (MRTM2), and reference Logan graphical analysis (rLGA) were used to generate binding potential maps using SO as reference tissue (BPSO). Shorter dynamic acquisitions down to 50 min were also considered. In addition, standard uptake value ratios (SUVR) relative to SO were evaluated for three post-injection intervals (SUVRSO,40-70min, SUVRSO,50-80min, and SUVRSO,60-90min respectively). Regional parametric BPSO + 1 and SUVRSO were compared with regional distribution volume ratios of a 1-tissue compartment model (1TCM DVRSO) using Spearman correlation and Bland-Altman analysis. Results For all methods, highly significant correlations were found between regional, parametric BPSO + 1 (r = [0.63;0.96]) or SUVRSO (r = [0.90;0.91]) estimates and regional 1TCM DVRSO. For a 90-min dynamic scan, parametric SRTM2 and MRTM2 values presented similar small bias and variability (− 3.0 ± 2.9 % for baseline SRTM2) and outperformed rLGA (− 10.0 ± 5.3 % for baseline rLGA). Reducing the dynamic acquisition to 60 min had limited impact on the bias and variability of parametric SRTM2 BPSO estimates (− 1.0 ± 9.9 % for baseline SRTM2) while a higher variability (− 1.83 ± 10.8 %) for baseline MRTM2 was observed for shorter acquisition times. Both SUVRSO,60-90min and SUVRSO,50-80min showed similar small bias and variability (− 2.8 ± 4.6 % bias for baseline SUVRSO,60-90min). Conclusion SRTM2 is the preferred method for a voxelwise analysis of dynamic [¹¹C]UCB-J PET using SO as reference tissue, while reducing the dynamic acquisition to 60 min has limited impact on [¹¹C]UCB-J BPSO parametric maps. For a static PET protocol, both SUVRSO,60-90min and SUVRSO,50-80min images are an excellent proxy for [¹¹C]UCB-J BPSO parametric maps.

Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging

Article

Jul 2018

Importance Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density. Objective To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging. Design, Setting, and Participants This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as ¹¹C-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11–labeled Pittsburgh Compound B (¹¹C-PiB) for β-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation. Main Outcomes and Measures Outcomes were ¹¹C-UCB-J–specific binding (binding potential [BPND]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal. Results Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%] β-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] β-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by ¹¹C-UCB-J–PET BPND (cognitively normal participants: mean [SD] BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50]; P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). Hippocampal SV2A-specific binding BPND was correlated with a composite episodic memory score in the overall sample (R = 0.56; P = .01). Conclusions and Relevance To our knowledge, this is the first study to investigate synaptic density in vivo in AD using ¹¹C-UCB-J–PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and restoration of synapses.

Kinetic evaluation and test–retest reproducibility of [ 11 C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans

Article

Aug 2017

Synaptic vesicle glycoprotein 2A (SV2A) is ubiquitously present in presynaptic terminals. Here we report kinetic modeling and test–retest reproducibility assessment of the SV2A positron emission tomography (PET) radioligand [¹¹C]UCB-J in humans. Five volunteers were examined twice on the HRRT after bolus injection of [¹¹C]UCB-J. Arterial blood samples were collected for measurements of radiometabolites and free fraction. Regional time–activity curves were analyzed with 1-tissue (1T) and 2-tissue (2T) compartment models to estimate volumes of distribution (VT). Parametric maps were generated using the 1T model. [¹¹C]UCB-J metabolized fairly quickly, with parent fraction of 36 ± 13% at 15 min after injection. Plasma free fraction was 32 ± 1%. Regional time–activity curves displayed rapid kinetics and were well described by the 1T model, except for the cerebellum and hippocampus. VT values estimated with the 2T model were similar to 1T values. Parametric maps were of high quality and VT values correlated well with time activity curve (TAC)-based estimates. Shortening of acquisition time from 120 min to 60 min had a negligible effect on VT values. The mean absolute test–retest reproducibility for VT was 3–9% across regions. In conclusion, [¹¹C]UCB-J exhibited excellent PET tracer characteristics and has potential as a general purpose tool for measuring synaptic density in neurodegenerative disorders.

Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [11C]UCB‐J

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