PET imaging of synaptic density

Reduced synaptic density has been found in many brain disorders, including Alzheimer’s disease, autism, depression, schizophrenia, 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 GABA-ergic 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. [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. [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).

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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.

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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Created at: 2017-08-07
Updated at: 2018-08-20
Written by: Vesa Oikonen