Part 2 of a 2-part story
Scientists are increasingly optimistic that PET tracer UCB-J, which recognizes a presynaptic vesicle protein, can reliably detect synapse loss in the Alzheimer’s brain (see Part 1 of this series). And it’s not just for Alzheimer’s. Synapses are vulnerable to protein pathologies besides plaques and tangles, and the tracer may become broadly useful for detecting the earliest signs of degeneration in numerous brain disorders, reported scientists at the Human Amyloid Imaging Conference, held January 15–17 in Miami. To investigate how disease progresses in these disorders, researchers are combining multiple PET tracers and fluid biomarkers in observational cohort studies.
- PET tracer UCB-J flags dramatic synapse disappearance in several neurodegenerative diseases.
- Synapse loss correlates with increased mitochondrial stress as seen by PET.
- Scientists are comparing synaptic PET to fluid biomarkers and inflammation as well.
Beyond Alzheimer’s: Synapse Loss Marks Neurodegeneration
Eugenii (Ilan) Rabiner of King’s College and Invicro, an imaging services company based in London, leads MIND MAPS, a London-based public-private consortium that characterizes new imaging markers across several diseases. In Miami, Rabiner and Roger Gunn, at Imperial College and Invicro, reported preliminary data from 31 healthy volunteers, 12 Alzheimer’s patients, 12 Parkinson’s patients, and six with frontotemporal dementia, all of whom underwent scans with three different tracers.
One is the synapse marker UCB-J. One is BCPP-EF, a tracer that detects mitochondrial complex 1 as a measure of cellular energy generation (Harada et al., 2013; Tsukada, 2014). The third is SA4503, a tracer that binds the sigma-1 receptor (Mansur et al., 2020). This receptor regulates calcium signaling between the endoplasmic reticulum and mitochondria. It maintains neuronal homeostasis, is considered to be a marker of cellular stress, and has been a drug development target (see Edonerpic, Blarcamesine, Nuedexta). All participants are invited to return for follow-up scans after one year, and longitudinal scans are ongoing.
In AD and FTD, uptake of both the synapse and the mitochondria marker was down one-tenth to one-third across multiple brain regions, reaching a maximum drop of 40 percent in the hippocampus. This correlated with declining MMSE scores. AD patients also had some increases in SA4503 uptake. The Parkinson’s patients, who currently have early stage disease, had only modest declines in the synapse and mitochondrial markers, and no change in SA4503. The PD cohort has completed follow-up, but did not progress either clinically or by biomarkers in this time frame.
Jonathan Rohrer and Mica Clarke, University College London, lead the FTD portion of this study. It is still recruiting participants, and aiming for 12 people. The six enrolled so far all have behavioral variant FTD. Compared with 17 healthy controls, they had a marked loss of UCB-J uptake, particularly in frontotemporal regions, but also in parietal and the cingulate cortex and in subcortical regions such as hippocampus and amygdala. BCPP-EF binding was down in most of the same regions, as well. Some participants had a distinct pattern, with a more global decrease in uptake of both tracers across the brain. Overall, the magnitude of the loss was similar to that in AD patients, and perhaps more consistent across the cohort, Rabiner noted. The drop-off in tracer uptake exceeded atrophy in a given region, hinting that synapses die before the tissue shrinks.
“The magnitude of the change was quite surprising to me, especially when you compare it to flortaucipir change in FTD, which isn’t very large and doesn’t show much presymptomatically,” Rohrer told Alzforum. He noted that this FTD cohort comes from GENFI, i.e., it has familial forms of FTD due to mutations in tau, progranulin, or C9ORF72. Eventually, the researchers hope to have enough participants to characterize differences between these variants.
Rabiner speculated that mitochondrial dysfunction might precipitate synaptic loss, although he has not yet seen any sign that low BCPP-EF uptake precedes changes in UCB-J. Intriguingly, Rosa-Neto and Tatsuhiro Terada at McGill reported in Miami that increased tau tracer uptake in the entorhinal cortices of AD patients correlates with lower uptake of BCPP-EF there, hinting that tangles could precede mitochondrial failure.
Meanwhile, in a preprint on medRxiv, researchers led by James Rowe and Negin Holland at the University of Cambridge report lower UCB-J uptake in two sporadic primary tauopathies, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). In 10 people with PSP and 12 with CBD, UCB-J uptake was down as much as 50 percent in numerous cortical and subcortical regions, including frontal, parietal, temporal, and occipital cortex, and hippocampus, insula, and amygdala. This decrease correlated with disease severity (Holland et al., 2020).
Another recent study from the U.K., led by Oliver Howes at the MRC London Institute of Medical Sciences, describes lower UCB-J binding in the frontal and anterior cingulate cortices of 18 middle-aged people with schizophrenia compared with 18 controls. They report a large effect size, with a Cohen’s d of 0.8 to 0.9 (Onwordi et al., 2020).
The Next Generation
One drawback of UCB-J is that it can only be labeled with C11, limiting its use to facilities that have a cyclotron on site. Scientists at Yale and Invicro have developed an 18F-labelled version of UCB-J, originally called MNI-1126/SDM8 and recently renamed SynVesT1 (Patel et al., 2019; Li et al., 2019; Constantinescu et al., 2019). Pedro Rosa-Neto of McGill University, Montreal, is testing its usefulness.
Rosa-Neto runs the Translational Biomarkers of Aging and Dementia (TRIAD) study at McGill. This longitudinal project enrolls 504 participants ranging from cognitively healthy to MCI, AD dementia, and atypical dementia. Each of these volunteers agreed to slide into the scanner for amyloid PET with AZD4694, tau PET with MK-6240, plus MRI. In addition, one-third will be scanned with SynVesT1 PET, another third with the inflammation marker PBR28, and the final third with martinostat, a marker for epigenetic dysregulation.
“The idea is to create a benchmark system for comparing new biomarkers,” Rosa-Neto told Alzforum.
Besides PET, the TRIAD group also investigates fluid biomarkers. Andrea Benedet and Nesrine Rahmouni of McGill presented some of these data at HAI, reporting, for example, that neurogranin levels in cerebrospinal fluid correlate with amyloid and tau tracer uptake in temporal, parietal, and occipital cortex. This substudy comprised 99 healthy controls, 36 people with MCI, and 23 with AD. The rise in CSF neurogranin was apparent already at the MCI stage.
Neurogranin is a marker of synaptic damage, again linking synapse loss to AD pathology at early disease stages, but there is no PET tracer for it. There is, however, a fluid assay for SV2A (Heurling et al., 2019). Rosa-Neto will try to correlate CSF levels of the protein with the SynVesT1 PET signal.—Madolyn Bowman Rogers
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