Among Alzheimer’s disease pathologies, synaptic loss correlates best with symptoms, but until now researchers have had no way to measure it in living people. That may be changing, with a new PET ligand that binds synaptic vesicle glycoprotein 2A (SV2A). At the Alzheimer’s Imaging Consortium symposium on the day before this year’s Alzheimer’s Association International Conference, July 22–26 in Chicago, Richard Carson of Yale University, New Haven, Connecticut, reported that the probe, UCB-J, bound significantly less in the hippocampi of people with Alzheimer’s disease than in controls. Poor retention of the ligand correlated with flagging memory, he showed. The work was published in the July 16 JAMA Neurology, and Alzforum previously reported some of the data when Christopher van Dyck, also from Yale, presented last fall at the Clinical Trials on Alzheimer Disease meeting in Boston (Dec 2017 conference news).
At AAIC, multiple attendees told Alzforum the work was a highlight of the imaging consortium session. “PET measurements of presynaptic and postsynaptic density would greatly advance the scientific study of Alzheimer’s disease and related disorders," said Eric Reiman, Banner Alzheimer’s Institute in Phoenix. "The Yale group has developed this promising 11C-labeled ligand to assess presynaptic density. They have begun to develop an 18F-labeled ligand that would advance its use by other centers, and they have begun to test these radioligands in rigorous and thoughtful ways," he wrote in an email to Alzforum (see complete comment below).
Rik Ossenkoppele, Vrije University, Amsterdam, called the work impressive and important. “The availability of a PET tracer that allows detection of structural synaptic alterations has important potential implications for clinical studies,” he wrote (see comment below).
Synapses in Decline? Coronal and axial pseudocolor maps show intensity of UCB-J binding in one cognitively normal person (top) and one AD patient (bottom). Arrows mark the right hippocampi in the coronal view. Reference MRI images are gray. [Image © (2018) American Medical Association. All rights reserved.]
Others were more reserved, asking if the probe truly bound synapses or some other vesicle fraction in the brain. Carson said that has yet to be worked out. “We need to understand the relationship between vesicles and synapses, and how it is affected by vesicle metabolism, including exocytosis and recycling, even synaptic activity,” he said. One audience member questioned if the distribution of synapses in the human brain maps to UCB-J binding. Carson replied that electron microscopy and other work to address this is ongoing. Some were concerned that the binding pattern varies from that seen with FDG, a PET ligand that measures glucose metabolism and is widely considered a surrogate for synaptic activity.
Still, the overall mood at AAIC was that this ligand could provide useful information about the brain. Developed by Carson, 11C-UCB-J binds with high affinity and specificity to SV2A, a universal marker of presynaptic vesicles. SV2A distribution closely matches that of synaptophysin, which is commonly used as a marker for synapses in postmortem human tissue. Previously, Carson and colleagues reported that it detected synaptic loss around focal seizures in people with epilepsy (Jul 2016 news).
In the AD study, Ming-Kai Chen, who works in Carson’s group and is first author on the JAMA Neurology paper, measured brain binding of 11C-UCB-J in 10 people who had mild cognitive impairment or dementia and who had tested positive on amyloid PET scans. He compared them to 11 cognitively normal, amyloid-negative, age-matched counterparts. The investigators focused their attention on the hippocampus, where they expected early synapse loss due to the degeneration of projections from the entorhinal cortex. They calculated relative binding of UCB-J using centrum semiovale white matter as a reference region, because it poorly binds the ligand.
The Alzheimer’s patients bound 41 percent less tracer in the hippocampus than did controls. That difference held even after correction for hippocampal atrophy. Chen also found lower binding in the entorhinal cortex, but that was explained by loss of tissue volume.
Postmortem examination of AD brains reveals widespread synaptic loss in the cortex, yet in this study, PET detected no difference between cortical binding of 11C-UCB-J in patient and control cortices. Why? The authors speculate the study was too small, or that most of the AD patients were at an early disease stage and had not yet lost cortical synapses. Another possibility is that remaining synapses had grown to compensate for those that had withered. This phenomenon, called synaptic hypertrophism, has been documented in mild AD (DeKosky and Scheff, 1990). Ossenkoppele wondered if the patient-selection criteria, which required poor scores on an episodic memory test, had enriched for people with primarily limbic pathology, i.e., hippocampal atrophy. Chen told Alzforum they plan follow-up studies, including postmortem analyses, with more patients in later stages of disease.
In an editorial accompanying the paper, Elizabeth Mormino of Stanford University, Palo Alto, California, and William Jagust, of University of California, Berkeley, raised the FDG issue. They point out that the decrease in UCB-J binding observed only in the hippocampi of people with AD differs dramatically from the more widespread cortical hypometabolism detected using FDG-PET. “This is surprising, because although hippocampal synaptic loss is severe, other brain regions, such as the frontal cortex, entorhinal cortex, temporal cortex, and cingulate cortex, have been reported to show a similarly high synaptic loss in postmortem studies that may even predominate in the presynaptic terminals measured with an [sic] synaptic vesicle glycoprotein 2A ligand,” they write.
Others have puzzled over this FDG/UCB-J dichotomy, as well. “Since FDG PET has been suggested to provide information about the density, activity, and metabolism of terminal neuronal fields and/or peri-synaptic glial cells, it will be important to understand the biological basis for these differences,” noted Reiman. Victor Villemagne, University of Melbourne, Australia, wondered why UCB-J did not detect synapse loss in cortical areas. “Is function (FDG) more sensitive than synaptic density?’” he asked (see comment below).
Chen and colleagues did detect less blood flow in some cortical regions of the MCI/dementia patients compared with controls. These were the regions where FDG-PET wanes in people with AD, but this blood flow reduction seemed to have no effect on UCB-J binding. Chen said this underscores that the two probes do not measure the same thing—where the FDG-PET signal provides a composite of glucose uptake by pre- and postsynaptic neurons and nearby glia, UCB-J provides a snapshot of synaptic structure and integrity. For this reason, he said, “We do not think that UCB-J-PET will replace FDG-PET, but instead that the two will complement each other.”
In a poster at AAIC, co-author Adam Mecca presented results from a preliminary analysis where he directly compared UCB-J and FDG-PET in nine people with MCI or AD, and 11 controls. He reported the expected pattern of FGD-PET hypometabolism in multiple cortical regions in the patients, and reduction of UCB-J binding in the hippocampus, but again no other regions. The investigators found a correlation between FDG-PET and UCB-J-PET signals in the hippocampus across both patients and healthy controls.
Other labs plan to test the probe. Bradley Christian, University of Wisconsin, Madison, said his group synthesized the tracer in-house, and completed animal testing before applying for FDA approval for human studies.
Carson and colleagues are developing 18F probes, which would expand use beyond centers that can make their own supply of the short-lived 11C version. Here things get tricky. UCB-J contains three fluorines. “We have labelled it with F18, but the chemistry is terribly difficult,” Carson admitted. Instead, the researchers have turned to making derivatives that contain a single fluorine. Two, called SDM8 and SDM2, look promising, said Carson. He said SDM8 has nearly identical kinetics to UCB-J, while SDM2 appears to enter and leave the brain more rapidly and might be useful for short scans. Both are being tested in human studies, he said. Independently, researchers in Belgium are working on 18F SV2A ligands (Bahri et al., 2017), as are investigators at Invicro, an imaging company based in Boston. Chen predicts the 18F probes will become more widely available in the next year or two, allowing more groups to experiment with the tracer.
UCB-J is being used in small pilot trial of CT1812, a sigma-2 receptor antagonist that purportedly protects against Aβ synaptotoxicity. The 21 patients will undergo PET scans at baseline and after six months’ treatment with either placebo or the drug. Chen said several volunteers have already completed their baseline scans.—Pat McCaffrey and Tom Fagan
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- Dekosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990 May;27(5):457-64. PubMed.
- Finnema SJ, Nabulsi NB, Mercier J, Lin SF, Chen MK, Matuskey D, Gallezot JD, Henry S, Hannestad J, Huang Y, Carson RE. Kinetic evaluation and test-retest reproducibility of [11C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab. 2017 Jan 1;:271678X17724947. PubMed.
- Chen MK, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin SF, Najafzadeh S, Ropchan J, Lu Y, McDonald JW, Michalak HR, Nabulsi NB, Arnsten AF, Huang Y, Carson RE, van Dyck CH. Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging. JAMA Neurol. 2018 Jul 16; PubMed.
- Mormino EC, Jagust WJ. A New Tool for Clinical Neuroscience-Synaptic Imaging. JAMA Neurol. 2018 Jul 16; PubMed.