Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, 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 Jul 20;8(348):348ra96. PubMed.

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  1. This study by Finnema et al. with the new SV2A PET radioligand, [11C]UCB-J, a putative marker of synaptic density, could be an important advance for neurodegenerative disease studies. [11C]UCB-J is highly selective for the SV2A protein, has low nanomolar affinity for SV2A, has a relatively high Bmax value in the 100-400 nM range, has high brain uptake, is well-behaved pharmacokinetically, has a relatively high specific signal in cortical areas, and a relatively low non-specific signal in a reference region (centrum semiovale), and in in vivo displacement studies using levetiracetam it demonstrated rapid loss of cortical signal.

    Correspondence of the staining and western blots of SV2A and synaptophysin (an established marker of synaptic density) in postmortem tissues were encouraging, but additional fully quantitative comparison studies would be helpful in making a solid case for UCB-J as a synaptic density marker equivalent to synaptophysin. The use of the relatively small centrum semiovale as a reference region is problematic in PET scanners not possessing the relatively high 3mm resolution of the HRRT scanner used. Additionally, the centrum semiovale showed a slightly perceptible decrease in signal following injection of displacement doses of levetiracetam, potentially indicating a small level of specific signal in that reference region. While use of the 11C radiolabel is expedient for research studies, the longer-lived 18F radiolabel is preferred for more widespread distribution of the radiotracer. The authors suggest that UCB-J could be radiolabeled with 18F, but this has not been demonstrated to date. Overall, [11C]UCB-J appears to be a very promising PET radiotracer to access regional brain synaptic densities in vivo.

    Important questions it could help address include: How early in neurodegenerative disease   processes do synaptic losses appear and how important will assessment of synaptic losses prove to be? It is widely assumed that regional FDG brain metabolic signal is primarily reflective of local synaptic activity. Would a more direct measure of regional synaptic densities be more sensitive to early dysfunction in synaptic processes than FDG? The answer to this and other questions appears to now be possible with [11C]UCB-J PET studies.

    View all comments by Chester Mathis

  2. Synaptic loss is a key event in Alzheimer’s disease—so this imaging would help us better study timeline and triggers for AD and identify neuroprotective drugs. This ligand looks promising but needs more validation. For example, we still don’t know if it will convey different information from FDG-PET. If it works out, it could become a critical part of the gold standard of diagnosis and we could be rewriting our diagnostic criteria and disease timelines. But it will be at least three more years before this comes to market in a best case scenario for approval.

    View all comments by P. Murali Doraiswamy

  3. The potential to obtain a reliable quantitative imaging measure of synaptic density would be a great advance in AD biomarker research. This report of 11C UCB-J, which binds to protein SV2A, may be a good first step toward this goal. Though the pathological validation was limited to a single baboon and the human sample involved imaging in only three patients with partial complex epilepsy, the preliminary data is encouraging that the tracer is binding to a meaningful synaptic marker. Much work needs to be done to develop this compound. A much larger validation study is needed, followed by testing in other disorders, including across the stages of AD. Further exploration is required to identify the optimum reference region. If the findings hold up, then labeling one of the fluorine atoms for widespread use would be essential. This type of tracer, once validated, could be a potential marker of AD risk, staging, and treatment outcome.

    View all comments by Stephen Salloway

  4. This is potentially very interesting, and may be usable in a number of diseases in which synapse number is thought to be an important variable. It is not clear what is the sensitivity of this method; while differences were noted in temporal lobe epilepsy, this may be detected with other methods, too. In a similar vein, the amount of signal (specific to synapses) and background from the human images is not clear (I'm not very familiar with the levetiracetam method of displacement; how specific this is for synapses, etc.). It would be important to determine this. Obtaining quantitative data is important; correlating this to actual synapse density would be important; it seems this could be done in a baboon (EM analysis of a different regions after they are imaged in vivo).

    View all comments by Roberto Malinow

  5. Advances in PET imaging, particularly development of radioligands binding to biologically important sites, has helped with major advances in clinical neuroscience research. This paper shows what appears to be the first radioligand to bind to sites at synapses in brain. If confirmed in other studies, this could provide a way to measure synaptic density in living humans and also to track changes in density regionally and with disease. These scans would complement other newly developed radioligands that allow imaging of amyloid plaques, neurofibrillary ranges, and other types of brain pathology.

    This radioligand could be helpful in providing a pharmacodynamic marker of drug effects to enhance synaptic density. As such, it could help select among various drug candidates for clinical testing and for setting doses to be tested for clinical efficacy.

    Overall, a very positive development if confirmed.

    View all comments by Richard C. Mohs

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