. Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging. JAMA Neurol. 2018 Oct 1;75(10):1215-1224. PubMed.


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  1. PET measurements of presynaptic and postsynaptic density would greatly advance the scientific study of Alzheimer’s disease and related disorders. 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 developed and tested these radioligands in extremely rigorous and thoughtful ways. The group has also found surprising but potentially informative differences between the pattern of UCB-J and FDG PET reductions in clinically affected persons with AD. 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. Additional studies are needed to clarify the role of this promising PET method to the detection and tracking of AD-related synaptic loss and in the evaluation of putative disease-modifying treatments.

    View all comments by Eric M. Reiman
  2. This is very impressive and important work. I commend the authors for their well-executed study and the PET methodology is truly excellent. The authors demonstrated for the first time reduced synaptic density in the hippocampi of living persons with early stage Alzheimer’s disease compared to healthy controls. The availability of a PET tracer like 11C]UCB-J that allows detection of structural synaptic alterations has important potential implications for use in clinical (synaptic loss is intimately linked to cognitive impairment and could be used to improve diagnosis and prognosis), investigational (combining the three key elements of AD pathophysiology, i.e., Aβ, tau, and synaptic density), or clinical trial (surrogate outcome measure for therapies tailored to rescue/restore synapses) settings. However, my excitement about 11C]UCB-J PET was slightly lowered by two observations.

    1. The spatial pattern of decreased 11C]UCB-J binding was restricted to the hippocampus and entorhinal cortex, and there were no significant differences between patients and controls in neocortical areas. Also, there was quite substantial overlap in hippocampal 11C]UCB-J binding between AD patients and controls. Although very little postmortem data exists on synaptic density in early AD, it seems unlikely that the ongoing disease process (i.e., accumulation of Aβ and presumably tau proteins) for ~10–15 years has no consequences for the vitality of neocortical synapses. The authors and accompanying editorial by Mormino and Jagust offer several explanations, including limited statistical power due to the relatively small sample size, the mild disease stage of patients and synaptic hypertrophy as a potential compensatory mechanism. Another explanation could be that the AD patients were selected for an amnestic-predominant phenotype based on a memory test. This category of patients is overrepresented in the “limbic-predominant” subtype of AD (Murray et al., 2011; Whitwell et al., 2012), which has been associated with spatially more confined patterns of neurofibrillary tangle pathology and brain atrophy in limbic regions. Future work including clinically more advanced patients and non-amnestic variants of AD are needed to better understand the lack of neocortical 11C]UCB-J signal.

    2. The associations between 11C]UCB-J binding and cognition were less strong than would be expected from neuropathological data. In this proof-of-concept study, the authors show significant associations when combining controls and AD patients, but within the AD group there seems to be no relationship between hippocampal 11C]UCB-J binding and memory impairment, as equivalent memory scores were observed in AD patients with 11C]UCB-J binding potentials around 0.5 and 1.5 (Figure 2B in the paper). This also needs further investigation in larger and more heterogeneous samples of AD patients, preferentially in longitudinal studies.

    Overall, this study adds a new and promising PET technique to the existing set of biomarkers that are currently used to study AD. I am looking forward to studies investigating longitudinal changes in synaptic densities and its associations with clinical progression and structural, functional, and pathophysiological biomarkers of AD. However, based on the presented spatially confined 11C]UCB-J binding pattern in a neurodegenerative disease with such a clear neural signature, I have some reservations about the usefulness of 11C]UCB-J PET for studying psychiatric disorders such as depression, autism, or schizophrenia, in which the distinction with normal controls is expected to be much smaller.

    View all comments by Rik Ossenkoppele
  3. Imaging synaptic density opens a new avenue to assess neurological conditions, in particular neurodegenerative conditions such as Alzheimer’s disease where a synaptopathy, either as a consequence of the toxic effects of aggregated proteins and/or other factors, is at the center of its pathophysiology.

    11C-UCB-J, or its F-18 derivative, will need to be validated. On the other hand, the discrepancy of the perfusion as well as persistent significance in the hippocampus even after partial volume correction, indicates 11C-UCB-J measures a different variable than FDG. Also, as Chen and colleagues point out, it is not clear if there are compensatory mechanisms to maintain the number of presynaptic vesicles, or a compensatory sprouting in nigrostriatal pathways as observed in Parkinson’s disease.

    The association with cognitive performance—where participants from all clinical categories were pooled together—moves in the right direction, with lower synaptic density associated with worse cognitive performance. When we look at the discrepancy in the extent and pattern with FDG and atrophy we need to assess where the synaptopathy is worst. Is it pre- or postsynaptic? On the postsynaptic, de novo-formed tau aggregates inside dendrites might lead to their shrinking. And the relationship with tau has other connotations, too. Hyperphosphorylation of tau leads to it detaching from microtubules, disrupting axonal transport, and lowering the transport of proteins and organelles to the presynaptic terminal.

    The data also raise other questions: Why is there no decrease of synaptic density in other cortical areas, especially those known to be associated with affected cognitive domains in AD? Is function (FDG) more sensitive than synaptic density? The data also generate a wish list of areas to be explored: How does synaptic density change in early onset AD, with marked parietal atrophy? In atypical presentations of AD? In hippocampal sclerosis? In autosomal-dominant cases?

    We need to emphasize the importance of being able to assess synaptic density in vivo both in cross-sectional and longitudinal fashion that, similar to amyloid imaging, will translate in better patient selection, assessment of target engagement, and efficacy at trial of therapies aimed at preventing neurodegeneration.

    View all comments by Victor L. Villemagne

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