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ARTICLE IN BRIEF
Researchers used a new imaging tool to measure synaptic density and loss in patients with Alzheimer's disease.
The findings of the first known attempt to study synaptic density in living humans in place of post-mortem brain tissue may help to better understand the pathophysiology of Alzheimer's disease, leading to the development of new treatments. JAMA Neurology.
Using positron emission tomography (PET) imaging, researchers at the Yale University School of Medicine have compared the binding of synaptic vesicle 2A glycoprotein to individuals with high blood pressure. Alzheimer's to normal cognitive participants. They found that, compared with older cognitively-matched and cognitively-unaffected participants, people with Alzheimer's disease had a significant 41% reduction in synaptic densities in the hippocampus. .
The synaptic damage associated with toxic beta-amyloid oligomers occurs in the early clinical stages of Alzheimer's disease, when patients with mild cognitive impairment exhibit loss of synapses and synaptic proteins. "So," write the authors, "the ability to assess synaptic density in vivo would greatly improve clinical research on Alzheimer's disease and specifically provide a valuable biomarker result for therapeutic trials.
Although PET imaging is commonly used to measure glucose metabolism in Alzheimer's disease studies, the authors pointed to the need for new molecular targets, particularly for assessing synaptic density.
"We wanted to demonstrate that we can quantify the loss of synaptic density in the living brain by imaging. In the past, synaptic density could only be evaluated by a post-mortem pathology, "said lead author Ming-Kai Chen, MD, PhD, associate professor of radiology and biomedical imaging and co-medical director PET Center at Yale University. Neurology today. The study was a collaboration between the Department of Radiology and Biomedical Imaging and the Department of Psychiatry.
Dr. Chen added that the team of researchers was already applying this research to evaluate the effectiveness of new treatments. In an ongoing trial, they monitor patients with Alzheimer's initially after administering medications. The goal is to track the preservation or potential restoration of synaptic density, he said.
Although it is too early to apply this approach in clinical practice, Dr. Chen noted that many colleagues use this biomarker to study other neuropsychiatric conditions such as Parkinson's disease, schizophrenia, seizures and autism.
STUDY THE DESIGN
The researchers hypothesized that synaptic vesicle glycoprotein 2A (SV2A) decreased Alzheimer's disease. Their theory was based on the early degeneration of entorhinal cortical cell projections at the hippocampus and hippocampus reduction by SV2A occurring in post mortem studies.
Between November 2015 and June 2017, they conducted a cross-sectional study via PET imaging of specific brain regions. Five men and five women (mean age 72.7 years) had Alzheimer's forms ranging from mild cognitive impairment to mild dementia. A control group consisted of five male participants and six female participants (mean age 72.9 years) who were completely negative for beta-amyloid protein.
The researchers studied the effects of high-resolution PET with two radiotracers, a compound more commonly known as 11C-UCB-J for SV2A and an agent known as the carbon-labeled 11 Pittsburgh B compound (11C-GDP). They also performed magnetic resonance imaging exams for beta-amyloid and cognitive and neurological assessments of participants.
Participants with Alzheimer's disease showed a substantial reduction in the specific binding of hippocampal SV2A (41%) compared with cognitively normal participants (p = 0.005) as indicated by PET 11C-UCB-J. These reductions remained stable after taking into account atrophy (p = 0.02).
The study was funded by the Dana Foundation, a David Mahoney Neuroimaging Research Fellowship, the Alzheimer Disease Research Center, the National Institutes of Health and the Swedish Research Council.
EXPERT COMMENT
Several experts said Neurology today that the PET imaging study of synaptic density could have a positive impact on the surveillance and treatment of patients with Alzheimer's and other neurodegenerative diseases.
"It's really a groundbreaking study," said Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging at the National Institutes of Health (NIA). Dr. Masliah noted that research on living subjects represents a considerable advance since he received his first NIA grant to study Alzheimer's disease as a university researcher three decades ago.
"The dream was always to do that in vivo, "he said, with PET imaging," this goal has been achieved. "
A new PET tracer capable of exploring synapses will help researchers deepen the pathophysiology of Alzheimer's disease, said Arthur W. Toga, PhD, professor and director of the Stevens Neuroimaging and Informat Institute at Keck School of Medicine. University of Southern California.
"This is yet another tool in the arsenal PET, with amyloid imaging and tau using PET, glucose metabolism using PET, and now this technique, which really improves the others," said the Dr. Toga added that "linking these observations together, hopefully, will provide a very complete signature of where this patient is in the course of his illness."
However, Dr. Toga found it surprising that most of the study results only relate to the hippocampus, as opposed to other areas of the brain, such as the cortex, where researchers find themselves at home. Usually wait to visualize synaptic changes. "More studies are needed to better understand its sensitivity and specificity," he said.
Elizabeth Mormino, Ph.D., Assistant Professor in the Department of Neurology and Neurological Sciences at the Stanford University School of Medicine, pointed out this restriction to the hippocampus in an editorial that she was co-author of 'study. She suggested several possible reasons for the lack of detection of neocortical synaptic loss.
Participants in this trial were relatively unaffected, while post mortem studies often examined the terminal stages of the disease. In addition, synaptic loss associated with aging may have masked the differences between people with Alzheimer's disease and control participants. There is also post-mortem evidence of synaptic hypertrophy in mild Alzheimer's disease, which could counteract synaptic loss and make synaptic protein reductions less substantial, said Dr. Mormino.
The authors of the study acknowledged that limitations include a lack of clarity as to whether SV2A binding in Alzheimer's disease is a direct measure of synaptic density. "Larger samples are needed to clarify cognitive associations with regional SV2A binding in AM samples," they wrote. "Internal longitudinal analyzes of participants can be more powerful in this regard."
While highlighting the need for additional research with more participants, Dr. Mormino said Neurology today that it makes sense to initially test the discovery of a PET ligand on a small number of topics "as it is really difficult to perform this type of studies, and it is important to 39, examine the data closely before starting.
Funding for such larger-scale studies, which would involve collecting data on a hundred or more subjects, is "difficult to justify," Dr. Mormino said. Even at a reduced search rate, she estimated that each PET scanner cost between $ 3,000 and $ 5,000. "Thus, this first study, although limited by the size of the sample, is an important step before larger studies are conducted," she said.
Despite the very small sample size of the study, "it's a really exciting job," said Kaitlin B. Casaletto, PhD, assistant professor at the Center for Memory and Aging. University of California at San Francisco. "It's absolutely where the ground has to go, and it's very promising."
In addition to recruiting more participants, Dr. Casaletto suggested that future trials should assess the linguistic and spatial deficiencies occurring in the spectrum of Alzheimer's disease, not just the memory problems that were the focus of this study .
Another major challenge is to determine how to develop the PET tracer at different clinical trial sites to ensure that each site can reproduce the same ligand in a standardized way and validate more than the tracer actually measures what we think – synaptic density, she said.
"If we could map when each of these bad proteins (amyloid and tau) are in the brain, as well as how synapses are evolving with them in real time, that would be a big step forward." Dr. Casaletto said said.
DISCLOSURES
Dr. Chen revealed having received research support from the Dana Foundation and support for Eli Lilly's research and Merck's clinical trials, outside of the submitted work.
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