This presentation explored Mecca et al, 2020. The goal of this paper is to introduce SV2A PET imaging as an effective means of measuring synaptic density reductions in Alzheimer's Disease.

1. In vivo measurement of widespread
synaptic loss in Alzheimer’s Disease
with SV2A PET
Rachel Dickinson
McNay Lab

2. Background
Why imaging?
- Staging – determines what stage of AD the individual is in, in terms of damage
- Clinicians can provide more specific/accurate treatment
- May be helpful in predicting when the patient will progress further in AD since usefulness
of neuroimaging in understanding AD is still not well understood
Why synapses?
- Malfunction and loss of synapses directly impacts cognitive function – one of the earliest
events seen in AD

3. Overview
Synaptic loss is strongly correlated with cognitive impairment in AD. Until
recently it could only be measured postmortem.
Existing neuroimaging techniques include:
1. MRI for brain volume
2. Amyloid-PET for brain amyloid
3. FDG-PET for glucose uptake (proxy measure for overall brain
metabolism)
Synaptic positron emission tomography (PET) imaging has allowed us to
study synaptic alterations in vivo.
Scheff 2007
Mild AD group had
significantly less synaptic
density and total brain
volume

4. Synaptic Vesicle Glycoprotein 2A (SV2A)
SV2A
- Synaptic vesicle glycoprotein expressed in
almost all synapses
- Located in synaptic vesicles at presynaptic
terminals
- Promising biomarker for synaptic density

5. PET – Positron Emission Tomography
Creates a 3D image of the distribution of a particular tracer in the brain
- The tracer is radioactively labeled, making it detectable by the PET imager
For SV2A-PET imaging, the tracer is [11C]-UCB-J
- [11C] → smaller version of carbon that is radiolabeled
- UCB-J → small molecule that binds to SV2A
The amount of tracer detected in a particular brain region corresponds to the amount of
SV2A
- This allows for evaluation of synaptic density in vivo

6. Methods (Study Participants and Cognitive Tests)
- Participants: 55 - 85 years old
- Participants with AD Dementia:
- Met diagnostic criteria for probable dementia due to AD
- CDR → 0.5 - 1.0
- MMSE → <26
- Participants with MCI (mild cognitive impairment):
- Met diagnostic criteria for amnestic MCI
- CDR → 0.5
- MMSE → 24-30 inclusive
- Cognitively Normal (CN) Participants
- CDR → 0
- MMSE → >26
Clinical Dementia Rating (CDR)
0 = no cognitive impairment
0.5 = questionable/mild cognitive impairment
1.0 = mild dementia
Mini Mental State Examination (MMSE)
30 = maximum
25+ = cognitively normal
> 24 = abnormal; indicates cognitive impairment

7. Methods (PET imaging and analysis)
All participants received a PET scan with [11C]Pittsburgh Compound B to determine the
presence of brain amyloid β accumulation
- CN: (-) for amyloid
- MCI/AD Dementia: (+) for amyloid
- Amyloid presence indicates AD progression and prognosis
Distribution volume ratio (DVR-Cb) was measured using the cerebellum as a reference region
and the presence of [11C]-UCB-J to indicate presence of SV2A
- Measurements were repeated to account for partial volume effects
Measured brain volume with MRI to account for AD patients likely having less brain volume
- Without this, results would be skewed because the size of the brain regions would be
different

8. Results
Participants:
53 total
- 34 with mild AD or amnestic MCI due to AD – MMSE = (23.1) and CDR = (0.74)
- 19 cognitively normal
Comparisons of synaptic density between AD and CN using DVR-Cb revealed significant SV2A
reductions in the AD group, specifically in medial temporal and neocortical regions
- Results remained consistent following partial volume corrections

9. Figure 1
Comparison of synaptic
density in AD and CN
groups (A) before and (B)
after partial volume
corrections
Partial volume correction
made results less extreme

10. Figure 2
"Heat-map" version of
Figure 1. Synaptic density
in AD and CN groups
determined by [11C]-UCB-J
PET
Lower DVR-Cb in AD
compared to CN groups.
Most significant in medial
temporal lobe and
throughout the cortex.

11. Results
Whole brain analysis – remained consistent with primary regional analysis
- Largest reductions in SV2A binding were found in the hippocampus and a wide range of
cortical and subcortical regions
- After PVC the affected regions were consistent, but effects themselves were smaller
Volumetric MRI analysis revealed GM atrophy
- Significant reductions in all medial temporal regions in AD group
- Reductions in neocortical regions in AD group were less widespread than for synaptic loss

12. Figure 3
Effect-size maps
of synaptic density
(DVR-Cb) and GM
volume between
AD and CN groups.
Cohen’s d:
Yellow - big
difference in
SV2A amounts
between AD and
CN groups
Orange:
moderate
difference
Red: small
difference

13. Discussion
Possible limitations:
- The study did not assess biomarkers of tau pathology
- Ignored potential hyperphosphorylated (abnormal) tau that would have been present in AD
participants
- Due to modest sample size , the study has limited power for investigating the effects of
demographic variables
Future:
- Future studies with larger samples might expose a better understanding of how demographic
variables interact with AD to alter synaptic density
- [11C]UCB-J as a biomarker for evaluating the effectiveness of AD treatment through monitoring
changes in synaptic density during treatment process
- Is treatment causing synaptic density to increase or decrease?

14. Questions?
My question:
- What is the significance of arterial blood sampling in PET imaging?

15. References
“Clinical Dementia Rating.” Clinical Dementia Rating - an Overview | ScienceDirect Topics, https://www.sciencedirect.com/topics/medicine-and-dentistry/clinical-dementia-
rating#:~:text=Clinical%20Dementia%20Rating%20(CDR),-The%20CDR%20(Berg&text=Ratings%20are%20assigned%20on%20a,patients%20on%20severity%20of%20dementia.
Johnson, Keith A, et al. “Brain Imaging in Alzheimer Disease.” Cold Spring Harbor Perspectives in Medicine, U.S. National Library of Medicine, Apr. 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312396/.
Mecca AP;Chen MK;O'Dell RS;Naganawa M;Toyonaga T;Godek TA;Harris JE;Bartlett HH;Zhao W;Nabulsi NB;Wyk BCV;Varma P;Arnsten AFT;Huang Y;Carson RE;van Dyck CH; “In Vivo Measurement of
Widespread Synaptic Loss in Alzheimer's Disease with SV2A Pet.” Alzheimer's & Dementia : the Journal of the Alzheimer's Association, U.S. National Library of Medicine,
https://pubmed.ncbi.nlm.nih.gov/32400950/.
“Mini-Mental State Examination (MMSE).” Healthdirect, Healthdirect Australia, https://www.healthdirect.gov.au/mini-mental-state-examination-mmse#:~:text=GP%20or%20specialist.-
,How%20is%20the%20MMSE%20scored%3F,abnormal%2C%20indicating%20possible%20cognitive%20impairment.
“Pet Scan.” Positron Emission Tomography, PET Scan Mayfield Brain & Spine Cincinnati, Ohio, https://mayfieldclinic.com/pe-
pet.htm#:~:text=Before%20the%20PET%20scan%2C%20a,detected%20by%20the%20PET%20scanner.
Positron Emission Tomography: Function and Uses, http://large.stanford.edu/courses/2015/ph241/krishnamurthi1/.
Scheff SW;Price DA;Schmitt FA;DeKosky ST;Mufson EJ; “Synaptic Alterations in CA1 in Mild Alzheimer Disease and Mild Cognitive Impairment.” Neurology, U.S. National Library of Medicine,
https://pubmed.ncbi.nlm.nih.gov/17470753/
Toyonaga, Takuya, et al. “In Vivo Synaptic Density Imaging with 11C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease.” Journal of Nuclear Medicine : Official Publication,
Society of Nuclear Medicine, U.S. National Library of Medicine, Dec. 2019, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894376/.

16. THANK YOU!