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New PET imaging agent shows loss of synaptic density in Alzheimer’s brains

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Synaptic protein imaging agent will open new research paths

The work by Chen et al. could open a new avenue in the research of Alzheimer’s pathophysiology, Elizabeth C. Mormino, PhD, and William J. Jagust, MD, wrote in an editorial (JAMA Neurol. 2018 Jul 16. doi: 10.1001/jamaneurol.2018.1643).

“An examination of synaptic density in conjunction with spatial patterns of beta amyloid and tau (also measurable with PET) will improve our understanding of the long course of AD, beginning with the clinically asymptomatic stages of the disease,” they wrote. “Such studies could support or refute numerous proposed mechanisms of disease causation by these two protein aggregates, as well as many other pathological processes.”

Those lines of investigation might include when synaptic density changes in relation to AB and tau aggregation, and whether anti-amyloid and anti-tau drugs could rescue synapses.

“Given the strong associations between synaptic density and clinical symptoms, a reliable measurement of synaptic density in clinical trials could help establish mechanisms of drug efficacy and even potentially shorten the duration of trials,” Dr. Mormino and Dr. Jagust suggested. “... The addition of a PET ligand that measures synaptic density can provide a tool for disease monitoring and assessing treatment effects in people throughout the spectrum of AD. This approach could also be useful in examining synaptic loss as a disease mechanism in many other neurological disorders that involve brain degeneration,” including psychiatric illnesses that manifest synaptic alterations, such as autism and schizophrenia.

“These developments offer the potential for a much more complete understanding of AD, and potentially other neurodegenerative and psychiatric conditions.”

Dr. Mormino is with Stanford (Calif.) University and Dr. Jagust is with the University of California, Berkeley. They had no disclosures to report.



Patients with mild Alzheimer’s disease dementia or amnestic mild cognitive impairment due to Alzheimer’s showed 41% less binding of an investigational PET imaging marker of synaptic density when compared with cognitively normal control patients.

Dr. Ming-Kai Chen of Yale University, New Haven, Conn.

Dr. Ming-Kai Chen

The largest signal reduction occurred in the hippocampus, reported Ming-Kai Chen, MD, PhD, and his colleagues. The report was published July 16 in JAMA Neurology.

“Synaptic loss in the association cortex and the limbic system is a robust and consistent pathology in AD [Alzheimer’s disease] and is closely correlated with cognitive impairment,” wrote Dr. Chen of Yale University, New Haven, Conn., and his associates. “However, until now, the assessment of synaptic density and the quantification of pre-synaptic proteins in AD could only be performed in postmortem brain tissues. The present study demonstrated, for the first time, that noninvasive PET imaging with 11C-UCB-J is capable of measuring reductions in synaptic density in vivo in the hippocampus of individuals with amnestic MCI [mild cognitive impairment] and AD dementia.”

The marker could potentially be used to identify early synaptic loss and track disease progression and therapeutic response, the authors suggested.

The team that created 11C-UCB-J, also known as ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), conducted this study. The agent binds to synaptic vesicle glycoprotein 2A (SV2A), which is the only one of three isoforms that is expressed only in brain synapses. The team’s earlier work showed that SV2A is a marker of synaptic density and that 11C-UCB-J can effectively track changes in the glycoprotein’s presence.

The study comprised 5 patients with amnestic MCI due to AD, 5 with mild AD dementia, and 11 cognitively normal matched controls; they were a mean of 72 years old. All underwent amyloid PET scanning to confirm Alzheimer’s pathology, and then additional PET imaging with 11C-UCB-J.

In a model that corrected for age and brain atrophy, AD patients showed a 41% decrease in hippocampal binding with the agent. The decrease correlated positively with a composite score of episodic memory, the investigators noted.

Dr. Chen disclosed research support from Eli Lilly and Merck; two of his coauthors have a patent pending for a version of the agent.

SOURCE: Chen M-K et al. JAMA Neurol. 2018 July 16. doi: 10.1001/jamaneurol.2018.1836.

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