PET imaging of synaptic density

Reduced synaptic density has been found in many brain disorders, including Alzheimer's disease, Parkinson's disease, autism, depression, schizophrenia, TBI, and in epilepsy in the seizure onset zone. Loss of synapses and neurons can happen already in pre-symptomatic stages of neurodegenerative diseases. 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, identifying brain networks in synaptic density (Fang et al., 2021). 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. Chen et al (2021) have shown concordant reduction of [18F]FDG and [11C]UCB-J uptake in medial temporal regions in Alzheimer's disease, but in neocortical regions reductions in [18F]FDG uptake were higher than in [11C]UCB-J binding. 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).

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.

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.

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.

Nabulsi NB, Mercier J, Holden D, Carré S, Najafzadeh S, Vandergeten MC, Lin SF, Deo A, Price N, Wood M, Lara-Jaime T, Montel F, Laruelle M, Carson RE, Hannestad J, Huang Y. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med. 2016; 57(5): 777-784. doi: 10.2967/jnumed.115.168179.

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.

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Updated at: 2022-01-17
Created at: 2017-08-07
Written by: Vesa Oikonen