News | Radiopharmaceuticals and Tracers | November 02, 2016

Earlier Alzheimer's Diagnosis May Be Possible with New Imaging Compound

Compound offers promise of detecting smaller amyloid beta clumps to help catch disease earlier

Alzheimer's disease, early diagnosis, PET scans, imaging compound, Fluselenamyl

Researchers at Washington University School of Medicine in St. Louis have developed a chemical compound that detects the Alzheimer’s protein amyloid beta better than current FDA-approved agents. The compound potentially may be used in brain scans to identify people in the earliest stages of Alzheimer’s disease. In the image, the compound has passed from the bloodstream of a living mouse into its brain, where it is detected by a positron emission tomography (PET) scan. Arrows indicate clumps of amyloid beta. Credit Ping Yan and Jin-Moo Lee.

November 2, 2016 — By the time unambiguous signs of memory loss and cognitive decline appear in people with Alzheimer’s disease, their brains already are significantly damaged, dotted with clumps of a destructive protein known as amyloid beta. For years, scientists have sought methods and clues to help identify brain changes associated with Alzheimer’s earlier in the disease process, so they can try to stop or even reverse the changes before they severely affect people’s lives.

Now, researchers at Washington University School of Medicine in St. Louis have developed a chemical compound, named Fluselenamyl, that detects amyloid clumps better than current U.S. Food and Drug Administration (FDA)-approved compounds. If a radioactive atom is incorporated into the compound, its location in a living brain can be monitored using positron emission tomography (PET) scans.

The compound, described in a paper published Nov. 2 in Scientific Reports, one of the Nature journals, potentially could be used in brain scans to identify the signs of early-stage Alzheimer’s disease or to monitor response to treatment.

“Fluselenamyl is both more sensitive and likely more specific than current agents,” said Vijay Sharma, Ph.D., a professor of radiology, of neurology and of biomedical engineering, and the study’s senior author. “Using this compound, I think we can reduce false negatives, potentially do a better job of identifying people in the earliest stages of Alzheimer’s disease and assess the effects of treatments.”

Amyloid plaques are one of the most telltale findings in the brains of people with Alzheimer’s disease. The neurons near such plaques are often dead or damaged, and this loss of brain cells is thought to account for difficulty with thinking, memory loss and confusion experienced by Alzheimer’s patients.

Amyloid plaques can be either diffuse or compact. The compact kind has long been associated with the disease, but conventional wisdom has held that diffuse plaques are benign, since they can be found in the brains of elderly people without any symptoms of Alzheimer’s disease, as well as the brains of those with Alzheimer’s. Sharma believes that diffuse plaques may mark the earliest stages of the disease.

“It is a relatively underexplored area in the development of Alzheimer’s pathology,” Sharma said. “Since current approved agents don’t detect diffuse plaques, there is no reliable noninvasive imaging tool to investigate this aspect in animal models or in patients. Our compound could be used to study the role of diffuse plaques.”

Using human amyloid beta proteins, Sharma and colleagues showed that Fluselenamyl bound to such proteins two to 10 times better than each of the three FDA-approved imaging agents for detecting amyloid beta. In other words, Fluselenamyl detected much smaller clumps of the protein, indicating that it may be able to detect the brain changes associated with Alzheimer’s disease earlier.

To determine whether Fluselenamyl can detect plaques in the brain, the researchers used the compound to stain brain slices from people who had died of Alzheimer’s disease and, as controls, people of similar ages who had died of other causes. The brain slices from the Alzheimer’s patients, but not the controls, were identified as containing plaques.

When a radioactive atom was incorporated into the compound, the researchers found very little interaction between Fluselenamyl and the healthy white matter in the human brain slices.

“A huge obstacle with existing state-of-the-art PET agents approved for plaque detection is that they tend to bind indiscriminately to the brain’s white matter, which creates false positives on the scans,” Sharma said. Nonspecific binding to other parts of the brain creates “noise,” which makes it difficult to distinguish samples with plaques from those without.

A similar experiment comparing mice genetically predisposed to develop amyloid plaques with normal control mice showed the same pattern of high sensitivity for amyloid beta and low binding to healthy white matter.

Furthermore, Sharma and colleagues showed that when Fluselenamyl with the radioactive atom is injected intravenously into mice, the compound can cross the blood-brain barrier, bind to any plaques in their brains and be detected by PET scan. In mice without plaques, the compound is quickly flushed from the brain and then excreted from the body.

The next step is to move to testing in patients. Sharma already has submitted an application to the National Institutes of Health (NIH) for a phase 0 trial, to establish whether Fluselenamyl is safe for use in humans and behaves in the human body the same way it behaves in mice. Phase 0 trials involve a low dose given to a small number of people to learn how a molecule is processed in the body and how it affects the body.

“Ideally, we’d like to look at patients with very mild symptoms who are negative for Alzheimer’s by PET scan to see if we can identify them using Fluselenamyl,” Sharma said. “One day, we may be able to use Fluselenamyl as part of a screening test to identify segments of the population that are going to be at risk for development of Alzheimer’s disease. That’s the long-term goal.”

For more information: www.nature.com/srep

Related Content

In I-131 cancer therapy, decay events damage sensitive DNA within a tumor cell nucleus, causing catastrophic single and double strand breaks. Clinical use of antibody-delivered Auger emitters could open a window for the targeted destruction of extracellular COVID-19 virions, decreasing the viral load during active infection and potentially easing the disease burden for a patient. View all figures from this study.  http://jnm.snmjournals.org/content/early/2020/07/16/jnumed.120.249748.full.pdf+html

In I-131 cancer therapy, decay events damage sensitive DNA within a tumor cell nucleus, causing catastrophic single and double strand breaks. Clinical use of antibody-delivered Auger emitters could open a window for the targeted destruction of extracellular COVID-19 virions, decreasing the viral load during active infection and potentially easing the disease burden for a patient. View all figures from this study.

 

News | Coronavirus (COVID-19) | July 22, 2020 | Dave Fornell, Editor
July 22, 2020 — One of the first studies has been published that looks at the use of...
Tau (blue) and amyloid (orange) distribution patterns for super-agers, normal-agers and MCI patients, when compared to a group of younger, healthy, cognitively normal, amyloid-negative individuals. Brain projections are depicted at an uncorrected significance level of p < .0001. Color bars represent the respective t-statistic. Image courtesy of Merle C. Hoenig, Institute for Neuroscience and Medicine II - Molecular Organization of the Brain, Research Center Juelich, Juelich, Germany, and Department of Nucle

Tau (blue) and amyloid (orange) distribution patterns for super-agers, normal-agers and MCI patients, when compared to a group of younger, healthy, cognitively normal, amyloid-negative individuals. Brain projections are depicted at an uncorrected significance level of p < .0001. Color bars represent the respective t-statistic. Image courtesy of Merle C. Hoenig, Institute for Neuroscience and Medicine II - Molecular Organization of the Brain, Research Center Juelich, Juelich, Germany, and Department of Nuclear Medicine, University Hospital Cologne, Cologne, Germany.

News | PET Imaging | July 16, 2020
July 16, 2020 — Super-agers, or individuals whose cognitive skills are above the norm even at an advanced age, have b
PSMA PET/CT accurately detects recurrent prostate cancer in 67-year-old man. 18F-DCFPyL-PSMA PET/CT shows extensive, intensely PSMA-avid local recurrence in prostate (bottom row; solid arrow) in keeping with the known tumor recurrence in the prostate. Right: PET shows extensive, intensely PSMA-avid local recurrence in prostate (top row; solid arrow) and a solitary bone metastasis in left rib 2 (bottom row; dotted arrow). Image courtesy of Ur Metser, et al.

PSMA PET/CT accurately detects recurrent prostate cancer in 67-year-old man. 18F-DCFPyL-PSMA PET/CT shows extensive, intensely PSMA-avid local recurrence in prostate (bottom row; solid arrow) in keeping with the known tumor recurrence in the prostate. Right: PET shows extensive, intensely PSMA-avid local recurrence in prostate (top row; solid arrow) and a solitary bone metastasis in left rib 2 (bottom row; dotted arrow). Image courtesy of Ur Metser, et al.

News | PET-CT | July 16, 2020
July 16, 2020 — New research confirms the high impact of...
Total-body dynamic 18F-FDG PET imaging with the uEXPLORER scanner allows us to monitor the spatiotemporal distribution of glucose concentration in metastatic tumors in the entire body (a). As compared to a typical clinical standardized uptake value image (b), the parametric image of FDG influx rate (Ki) can achieve higher lesion-to-background (e.g., the liver) contrast. In addition to glucose metabolism imaging by Ki, total-body dynamic PET also enables multiparametric characterization of tumors and organs

Total-body dynamic 18F-FDG PET imaging with the uEXPLORER scanner allows us to monitor the spatiotemporal distribution of glucose concentration in metastatic tumors in the entire body (a). As compared to a typical clinical standardized uptake value image (b), the parametric image of FDG influx rate (Ki) can achieve higher lesion-to-background (e.g., the liver) contrast. In addition to glucose metabolism imaging by Ki, total-body dynamic PET also enables multiparametric characterization of tumors and organs using additional physiologically important parameters, for example, glucose transport rate K1 (d), across the entire body. Image courtesy of G.B. Wang, M. Parikh, L. Nardo, et al., University of California Davis, Calif.

News | PET Imaging | July 16, 2020
July 16, 2020 — Results from the first...
Representative maximum-intensity projection PET images of a healthy human volunteer injected with 64Cu-NOTA-EB-RGD at 1, 8, and 24 hours after injection. Axial MRI and PET slices of glioblastoma patient injected with 64Cu-NOTA-EB-RGD at different time points after injection. Image courtesy of Jingjing Zhang et al., Peking Union Medical College Hospital, Beijing, China/ Xiaoyuan Chen et al., Laboratory of Molecular Imaging and Nanomedicine, NIBIB/NIH, Bethesda, USA

Representative maximum-intensity projection PET images of a healthy human volunteer injected with 64Cu-NOTA-EB-RGD at 1, 8, and 24 hours after injection. Axial MRI and PET slices of glioblastoma patient injected with 64Cu-NOTA-EB-RGD at different time points after injection. Image courtesy of Jingjing Zhang et al., Peking Union Medical College Hospital, Beijing, China/ Xiaoyuan Chen et al., Laboratory of Molecular Imaging and Nanomedicine, NIBIB/NIH, Bethesda, USA

News | PET Imaging | July 15, 2020
July 15, 2020 — A first-in-human study presented at the Society of...
PET/CT imaging showing uptake and retention of 86Y-NM600 (imaging agent) in immunocompetent mice bearing prostate tumors. PET imaging data was employed to estimate tumor dosimetry and prescribe an immunomodulatory 90Y-NM600 (therapy agent) injected activity. Image courtesy of R Hernandez et al., University of Wisconsin-Madison, WI.

PET/CT imaging showing uptake and retention of 86Y-NM600 (imaging agent) in immunocompetent mice bearing prostate tumors. PET imaging data was employed to estimate tumor dosimetry and prescribe an immunomodulatory 90Y-NM600 (therapy agent) injected activity. Image courtesy of R Hernandez et al., University of Wisconsin-Madison, WI.

News | PET-CT | July 15, 2020
July 15, 2020 — ...
Adult male with decades of right neck pain, discomfort and tightening following birth injury. The patient had failed multiple standard therapeutic maneuvers before presenting for 18F-FDG PET/MR imaging. Images shows abnormally elevated FDG uptake (white arrows; SUVmax = 1.2) observed in a linear pattern in the space in the posterolateral right neck, between the oblique capitis inferior and the semispinalis capitis muscles, where the greater occipital nerve resides. By comparison, the same region on the cont

Adult male with decades of right neck pain, discomfort and tightening following birth injury. The patient had failed multiple standard therapeutic maneuvers before presenting for 18F-FDG PET/MR imaging. Images shows abnormally elevated FDG uptake (white arrows; SUVmax = 1.2) observed in a linear pattern in the space in the posterolateral right neck, between the oblique capitis inferior and the semispinalis capitis muscles, where the greater occipital nerve resides. By comparison, the same region on the contralateral, asymptomatic side of the neck has an SUVmax = 0.7. This result encouraged a surgeon to explore the area. The surgeon ultimately found a collection of small arteries wrapped around the nerve in this location. The small arteries underwent lysis by the surgeon and the patient reported tremendous relief of symptoms. (A) Coronal thick slab MIP of 18F-FDG PET. (B) Axial LAVA FLEX MRI through the cervical spine. (C) Axial PET at the same slice as the axial MRI. (D) Fused axial PET/MRI. Image courtesy of Cipriano, et al., Stanford University, CA.

News | SNMMI | July 14, 2020
July 14, 2020 — A new molecular imaging approach utilizing 18F-FDG...
Left: Total-body PET/CT in psoriatic arthritis: multiple joints affected, shoulders, elbows, wrists, knees, ankles and small joints of the hands/feet. Arrow: left wrist; arrowhead: right wrist. Middle: Total-body PET/CT in rheumatoid arthritis: multiple joints affected, right shoulder, small joints of the left hand. Arrowhead at the 4th proximal interphalangeal joint shows classic ring-like uptake pattern. Arrow on the foot images demonstrates the hammer toe deformity besides big toe arthritis. Right: Total

Left: Total-body PET/CT in psoriatic arthritis: multiple joints affected, shoulders, elbows, wrists, knees, ankles and small joints of the hands/feet. Arrow: left wrist; arrowhead: right wrist. Middle: Total-body PET/CT in rheumatoid arthritis: multiple joints affected, right shoulder, small joints of the left hand. Arrowhead at the 4th proximal interphalangeal joint shows classic ring-like uptake pattern. Arrow on the foot images demonstrates the hammer toe deformity besides big toe arthritis. Right: Total-body PET/CT in osteoarthritis: affected joints include the left elbow, right knee (arrow) and right big toe (arrowhead). Image courtesy of YG Abdelhafez et al., University of California Davis, Sacramento, CA.

News | SNMMI | July 14, 2020
July 14, 2020 — For the first time, physicians can examine the systemic burden of inflammatory arthritis simultaneous