PET imaging of synaptic density

Reduced synaptic density has been found in many brain disorders, including Alzheimer's disease, Parkinson's disease, Huntigton's disease, depression, schizophrenia, TBI, stroke, and in epilepsy in the seizure onset zone. Loss of synapses and neurons can happen already in pre-symptomatic stages of neurodegenerative diseases. Alternatively, inadequate synaptic pruning may lead to excess of synapses, and for instance autism (Serrano et al., 2022).

Men have higher synaptic density than women (Alonso-Nanclares et al., 2008), but CMRO2 is similar in both sexes, and CBF is even higher in women than in men (Aanerud et al., 2017).

Immunohistochemical post-mortem studies have utilized labelled antibodies targeted to the key proteins located in pre- or postsynaptic neurons, such as synaptophysin and synaptotagmin, which is present in the membrane of synaptic vesicles (Finnema et al., 2016; Acebes, 2017; Rabiner, 2018).

Large proportion of the neurons utilize GABAergic or glutamatergic transmitter systems. GABAA receptor tracer [11C]flumazenil has been widely used to study neuronal integrity, for example in epilepsy.

Synaptic vesicle glycoprotein 2A (SV2A) is ubiquitously and homogeneously located in most if not all presynaptic terminals (Bajjalieh et al., 1994), in both glutamatergic and GABAergic neurons. Number of presynaptic vesicles is closely linked to capacity for neurotransmitter release (Valtorta et al., 1990). Levetiracetam-based radioligands [11C]UCB-J and [18F]UCB-H bind specifically to SV2A, and have favourable kinetics to be used to assess the synaptic density in vivo in humans (Becker et al., 2020). [11C]UCB-J has higher affinity and specificity than [18F]UCB-H (Nabulsi et al., 2016). [11C]UCB-J binding was reduced (VT by 28% and BPND by 44%) in hippocampus in AD, while hippocampal volume was reduced by 22% (Chen et al., 2018); reductions are widespread and maintained after correction for grey matter volume loss (Mecca et al., 2020). VT of [11C]UCB-J is also markedly reduced in major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) (Holmes et al., 2019). [11C]UCB-J binding correlates negatively with BMI in patients with stress-related psychiatric diagnosis but not in mentally healthy subjects (Asch et al., 2021). [11C]UCB-J binding maps can be characterized into organized covariance patterns using ICA, identifying brain networks in synaptic density (Fang et al., 2021; Akkermans et al., 2022). It is not known whether a decrease in SV2A binding strictly reflects neuronal loss, or merely decreased density of SV2A in vesicles, dysfunctional SV2A, or decreased number of synaptic vesicles, or whether SV2A density is necessarily decreased in damaged neurons (Heurling et al., 2019).

[18F]FDG PET has been widely used in studies of neurodegeneration, assuming that decreased uptake reflects synaptic loss; ∼40% of all cortical ATP is spent on synaptic neurotransmission. Chen et al (2021) have shown concordant reduction of [18F]FDG and [11C]UCB-J uptake in medial temporal regions in AD, but in neocortical regions reductions in [18F]FDG uptake were higher than in [11C]UCB-J binding. Also comparison of control subjects and non-demented and demented patients with PD or dementia with Lewy bodies revealed regional differences in reduced [18F]FDG and [11C]UCB-J uptake (Andersen et al., 2023). Regional differences in relative [18F]FDG and [11C]UCB-J uptake can be seen in healthy subjects, possibly related to regional differences in aerobic glycolysis (van Aalst et al., 2021). [11C]UCB-J and [18F]FDG study in 6-OHDA rat model of Parkinson's disease has shown that these radiopharmaceuticals can detect divergent changes especially in cortical regions (Raval et al., 2021).

Reduced grey matter volume and thickness in neurodegenerative diseases leads to increased partial volume effect in PET imaging, affecting the observed group differences in synaptic density. Partial volume correction methods reduce the bias, but the results are dependent on the correction algorithm (Lu et al., 2021).

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Acebes A. Brain mapping and synapse quantification in vivo: it's time to imaging. Front Neuroanat. 2017; 11:17. doi: 10.3389/fnana.2017.00017.

Becker G, Dammicco S, Bahri MA, Salmon E. The rise of synaptic density PET imaging. Molecules 2020; 25(10): 2303. doi: 10.3390/molecules25102303.

Cai Z, Li S, Matuskey D, Nabulsi N, Huang Y. PET imaging of synaptic density: a new tool for investigation of neuropsychiatric diseases. Neurosci Lett. 2019; 691: 44-50. doi: 10.1016/j.neulet.2018.07.038.

Carson RE, Naganawa M, Toyonaga T, Koohsari S, Yang Y, Chen MK, Matuskey D, Finnema SJ. Imaging of synaptic density in neurodegenerative disorders. J Nucl Med. 2022; 63(suppl 1): 60S-67S. doi: 10.2967/jnumed.121.263201.

Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin S, Chen M-K, Dhaher R, Matuskey D, Baum E, Holden D, Spencer DD, Mercier J, Hannestad J, Huang Y, Carson RE. Imaging synaptic density in the living human brain. Sci Transl Med. 2016; 8: 348ra96. doi: 10.1126/scitranslmed.aaf6667.

Prieto GA, Cotman CW. On the road towards the global analysis of human synapses. Neural Regen Res. 2017; 12(10): 1586-1589. doi: 10.4103/1673-5374.217321.

Rabiner EA. Imaging synaptic density: a different look at neurological diseases. J Nucl Med. 2018; 59(3): 380-381. doi: 10.2967/jnumed.117.198317.

Serrano ME, Kim E, Petrinovic MM, Turkheimer F, Cash D. Imaging synaptic density: the next holy grail of neuroscience? Front Neurosci. 2022; 16: 796129. doi: 10.3389/fnins.2022.796129.

Toyonaga T, Fesharaki-Zadeh A, Strittmatter SM, Carson RE, Cai Z. PET imaging of synaptic density: challenges and opportunities of synaptic vesicle glycoprotein 2A PET in small animal imaging. Front Neurosci. 2022; 16: 787404. doi: 10.3389/fnins.2022.787404.

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Updated at: 2023-03-17
Created at: 2017-08-07
Written by: Vesa Oikonen