Time Until Dementia Symptoms Appear Can be Estimated Via Brain Scan

Tamara Bhandari wrote . . . . . . . . .

Researchers at Washington University School of Medicine in St. Louis have developed an approach to estimating when a person with no cognitive symptoms will start showing signs of Alzheimer’s dementia based on data from brain scans and the person’s age.

Researchers at Washington University School of Medicine in St. Louis have developed an approach to estimating when a person who is likely to develop Alzheimer’s disease, but has no cognitive symptoms, will start showing signs of Alzheimer’s dementia.

The algorithm, available online in the journal Neurology, uses data from a kind of brain scan known as amyloid positron emission tomography (PET) to gauge brain levels of the key Alzheimer’s protein amyloid beta.

In those who eventually develop Alzheimer’s dementia, amyloid silently builds up in the brain for up to two decades before the first signs of confusion and forgetfulness appear. Amyloid PET scans already are used widely in Alzheimer’s research, and this algorithm represents a new way of analyzing such scans to approximate when symptoms will arise. Using a person’s age and data from a single amyloid PET scan, the algorithm yields an estimate of how far a person has progressed toward dementia — and how much time is left before cognitive impairment sets in.

“I perform amyloid PET scans for research studies, and when I tell cognitively normal individuals about positive results, the first question is always, ‘How long do I have until I get dementia?’,” said senior author Suzanne Schindler, MD, PhD, an assistant professor of neurology. “Until now, the answer I’d have to give was something like, ‘You have an increased risk of developing dementia in the next five years.’ But what does that mean? Individuals want to know when they are likely to develop symptoms, not just whether they are at higher risk.”

Schindler and colleagues analyzed amyloid PET scans from 236 people participating in Alzheimer’s research studies through Washington University’s Charles F. and Joanne Knight Alzheimer Disease Research Center. The participants were an average of 67 years old at the beginning of the study. All participants underwent at least two brain scans an average of 4½ years apart. The researchers applied a widely used metric known as the standard uptake value ratio (SUVR) to the scans to estimate the amount of amyloid in each participant’s brain at each time point.

The researchers also accessed over 1,300 clinical assessments on 180 of the participants. The assessments typically were performed every one to three years. Most participants were cognitively normal at the start of data collection, so the repeated assessments allowed the researchers to pinpoint when each participant’s cognitive skills began to slip.

Schindler spent years trying to figure out how to use the data in amyloid PET scans to estimate the age at which symptoms would appear. The breakthrough came when she realized that amyloid accumulation has a tipping point and that each individual hits that tipping point at a different age. After this tipping point, amyloid accumulation follows a reliable trajectory.

“You may hit the tipping point when you’re 50; it may happen when you’re 80; it may never happen,” Schindler said. “But once you pass the tipping point, you’re going to accumulate high levels of amyloid that are likely to cause dementia. If we know how much amyloid someone has right now, we can calculate how long ago they hit the tipping point and estimate how much longer it will be until they are likely to develop symptoms.”

People in the study who reached the tipping point at younger ages took longer to develop cognitive symptoms than those who reached it later in life. Participants who hit the tipping point at age 50 typically took nearly 20 years to develop symptoms; those who hit it at age 80 took less than 10 years.

“When we look at the brains of relatively young people who have died with Alzheimer’s, they typically look pretty healthy, other than Alzheimer’s,” Schindler said. “But older people more frequently have damage to the brain from other causes, so their cognitive reserves are lower, and it takes less amyloid to cause impairment.”

The power of this new technique is that it requires just one brain scan, plus the person’s age. With that data, the model can estimate the time to symptom onset, plus or minus several years. In this study, the correlation between the expected age of symptom onset and the true age at diagnosis was better than 0.9 on a scale of 0 (no correlation) to 1 (perfect correlation).

After age, the genetic variant APOE4 is the strongest risk factor for Alzheimer’s dementia. People who carry one copy of the variant are two to three times more likely to develop Alzheimer’s dementia than the general population, and people who carry two copies are 10 times more likely. In this study, people with the high-risk variant hit the tipping point younger, but once that point was passed, they followed the same trajectory as everyone else.

“APOE4 seems to have a seeding effect,” Schindler said. “At very low levels, below the tipping point, you see amyloid rising in people with APOE4 while it’s not changing in people without APOE4. That means APOE4 carriers are going to hit the tipping point sooner. People with two copies of APOE4 hit the tipping point about 10 years earlier than people with no copies. But after that point, we see no difference between the APOE4 carriers and noncarriers.”

With an out-of-pocket cost of around $6,000, amyloid PET brain scans may be financially out of reach for many people. However, this algorithm could help accelerate the pace of drug development by streamlining clinical trials.

“Most participants in clinical trials designed to prevent or slow Alzheimer’s symptoms do not develop symptoms during the trials,” Schindler said. “That’s a lot of time and effort — for the participants as well as the researchers — that doesn’t yield useful data. If we could do trials only on people who are likely to develop symptoms in the next few years, that would make the process of finding therapies much more efficient.”

Source: Washington University School of Medicine

Cerenkov Luminescence Imaging Accurately Identifies Surgical Margin Status During Radical Prostatectomy

A new intraoperative imaging technique, Cerenkov luminescence imaging (CLI), can accurately assess surgical margins during radical prostatectomy, according to a first-in-human research published in the October issue of The Journal of Nuclear Medicine. The feasibility study showed that 68Ga-PSMA CLI can image the entire excised prostate specimen’s surface to detect prostate cancer tissue at the resection margin.

Radical prostatectomy is one of the primary treatment options for men with localized prostate cancer. The goal of a radical prostatectomy is to completely resect the prostate without positive surgical margins. Incomplete removal of the cancer tissue during radical prostatectomy is often associated with poorer patient outcomes, including increased likelihood of recurrence and prostate cancer-related mortality.

Prostate-specific membrane antigen (PSMA) ligand positron emission tomography (PET) has emerged as an accurate tool to detect prostate cancer both in primary staging and at time of biochemical recurrence. As PET imaging agents also emit optical photons via a phenomenon called Cerenkov luminescence, researchers sought to evaluate the feasibility and diagnostic accuracy of CLI in detecting prostate cancer.

“Intraoperative radioguidance with CLI may help surgeons in the detection of extracapsular extension, positive surgical margins and lymph node metastases with the aim of increasing surgical precision,” stated Christopher Darr, PhD, resident at the Department of Urology of the University Medical Center Essen in Essen, Germany. “The intraoperative use of CLI would allow the examination of the entire prostate surface and provide the surgeon with real-time feedback on the resection margins.”

The single-center study included 10 patients with high-risk primary prostate cancer. 68Ga-PSMA PET scans were performed followed by radical prostatectomy and intraoperative CLI of the excised prostate. CLI images were analyzed postoperatively to determine regions of interest based on signal intensity, and tumor-to-background ratios were calculated. CLI tumor margin assessment was performed by analyzing elevated signals at the surface of the intact prostate images. To determine accuracy, tumor margin status as detected by CLI was compared to postoperative histopathology.

Tumor cells were successfully detected on the incised prostate CLI images and confirmed by histopathology. Three patients had positive surgical margins, and in two of the patients, elevated signal levels enabled correct identification on CLI. Overall, 25 out of 35 CLI regions of interest proved to visualize tumor signaling according to standard histopathology.

Boris A. Hadaschik, PhD, director of the Clinic for Urology of the University Medical Center Essen, added, “Radical prostatectomy could achieve significantly higher accuracy and oncological safety, especially in patients with high-risk prostate cancer, through the intraoperative use of radioligands that specifically detect prostate cancer cells. In the future, a targeted resection of lymph node metastases could also be performed in this way. This new imaging combines urologists and nuclear medicine specialists in the local treatment of patients with prostate cancer.”

Source: Society of Nuclear Medicine & Molecular Imaging

Study: PSMA PET/CT is Effective in Detection and Management of Recurrent Prostate Cancer

New research confirms the high impact of PSMA PET/CT in the detection and management of recurrent disease in prostate cancer patients. In initial results from a multicenter trial assessing the impact of 18F-DCFPyL prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), a PET-directed change in management was observed in two-thirds of patients. The research was presented at the Society of Nuclear Medicine and Molecular Imaging’s 2020 Virtual Annual Meeting.

Prostate cancer is the second most common cancer in men in the United States. According to the American Cancer Society, an estimated one in nine men will receive a prostate cancer diagnosis in his lifetime, and more than 191,000 men will be diagnosed with prostate cancer this year. Approximately 30 to 40 percent of men experience a biochemical recurrence of prostate cancer in which their prostate-specific antigen (PSA) levels rise after initial treatment.

DCFPyL (PSMA) PET/CT has been shown to be effective in diagnosing patients with prostate cancer. To assess its impact on the management of patients with suspected limited recurrent prostate cancer after primary therapy, researchers conducted a prospective, large-scale multicenter trial. The study included 410 men who had biochemical failure after primary therapy, had either no or limited disease on conventional imaging (CT and bone scintigraphy), and had undergone one of several prostate cancer treatments.

PSMA PET/CT identified disease in more than half of the men in whom CT and bone scan scintigraphy was negative. Additional sites of disease were observed in nearly two-thirds of patients in whom limited metastases were detected prior to PET. PSMA PET-directed management changes were recorded in 66 percent of the patients. The most common changes were conversion from observation or systemic therapy to surgery or radiation, or the addition of nodal-directed therapy to salvage surgery or radiation.

“The identification of extent of recurrence and specific sites of recurrence is crucial in determining the most appropriate mode of therapy for these men,” noted Ur Metser, MD, professor of radiology at the University of Toronto in Ontario, Canada. “Findings from this study add to the body of evidence on the utility of PSMA PET in the management of prostate cancer patients.”

He continued, “At this time, PSMA PET remains investigational in North American jurisdictions. Evidence generated from this study will help in seeking regulatory approvals to make molecular imaging with 18F-DCFPyL widely available and will pave the way for clinical studies that incorporate PSMA PET as a treatment planning tool to assess ultimate impact on patient outcomes.”

Source: EurekAlert!


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Total-body Dynamic PET Successfully Detects Metastatic Cancer; First Patient Results

Results from the first study using uEXPLORER to conduct total-body dynamic positron emission tomography (PET) scans in cancer patients show that it can be used to generate high-quality images of metastatic cancer. The research was presented at the Society of Nuclear Medicine and Molecular Imaging 2020 Virtual Annual Meeting on July 11-14.

While static PET provides a simple snapshot of radiopharmaceutical concentration, dynamic PET with tracer kinetic modeling can provide parametric images that show how tissue is actually behaving. Parametric images have the potential to better detect lesions and assess cancer response to therapy. This potential, however, has not been fully studied in the clinic because conventional PET scanners have a limited axial field-of-view and are not capable of simultaneous dynamic imaging of lesions that are widely separated in the body.

“The focus of our study was to test the capability of uEXPLORER for kinetic modeling and parametric imaging of cancer,” explained Guobao Wang, PhD, associate professor and Paul Calabresi Clinical Oncology K12 Scholar in the department of radiology at the University of California (UC), Davis, in Sacramento, California. “Different kinetic parameters can be used in combination to understand the behavior of both tumor metastases and organs of interest such as the spleen and bone marrow. Thus, both tumor response and therapy side-effects can be assessed using the same scan.”

A patient with metastatic renal cell carcinoma was injected with the radiotracer 18F-FDG and scanned on the uEXPLORER total-body PET/CT scanner. The static PET standardized uptake value (SUV) was calculated and kinetic modeling was performed for regional quantification in 16 regions of interest, including major organs and multiple metastases. The glucose influx rate was calculated and additional kinetic modeling was implemented to generate parametric images of the kinetic parameters. The kinetic data were then used to explore tumor detection and tumor characterization.

Multiple metastases were identified on the dynamic PET/CT scan, confirming that it is feasible to perform total-body kinetic modeling and parametric imaging of metastatic cancer. Parametric images of glucose influx rate showed improved tumor contrast over SUV in general, and specifically led to improved visibility of cancer lesions detection in the liver. Total-body kinetic quantification also provided multi-parametric characterization of tumor metastases and organs of interest.

“Total-body dynamic imaging and kinetic modeling enabled by total-body PET have the potential to change nuclear medicine into a multi-parametric imaging method, where many different aspects of tissue behavior can be assessed in the same clinical setting–much like the information gained from different sequences in an MRI scan,” said Ramsey D. Badawi, professor in the department of radiology and co-director of the EXPLORER molecular imaging center, UC Davis. “The total-body parametric imaging technique is not limited to 18F-FDG; it is applicable to all radiotracers. It is also not limited to cancer but can be broadly applied to evaluate disease severity and organ interactions in many other systemic diseases. We expect a profound impact in the field of nuclear medicine and molecular imaging.”

Source: EurekAlert!

Psychologists Investigate Why Some Older Adults Remember Better than Others

Taylor Kubota wrote . . . . . . . . .

Even among healthy people, a faltering memory is often an expected part of aging – but it’s not inevitable.

Researchers are studying why some healthy, older adults remember better than others. This work establishes a foundation for better understanding age-related memory decline. (Image credit: Getty Images)

“Some individuals exhibit remarkable maintenance of memory function throughout late adulthood, whereas others experience significant memory decline. Studying these differences across individuals is critical for understanding the complexities of brain aging, including how to promote resilience and longevity,” said Alexandra Trelle, a postdoctoral research fellow at Stanford University.

Building on studies that have focused on young populations, Trelle and colleagues are investigating memory recall in healthy, older adults as part of the Stanford Aging and Memory Study. In new research, published May 29 in eLife, this team has found that memory recall processes in the brains of older adults can look very similar to those previously observed in the brains of young adults. However, for those seniors who had more trouble remembering, evidence for these processes was noticeably diminished.

By gaining a better understanding of memory function in older adults, these researchers hope to someday enable earlier and more precise predictions of when memory failures signal increased risk for dementia.

A striking similarity

When Anthony Wagner, the Lucie Stern Professor in the Social Sciences at Stanford’s School of Humanities and Sciences, was a graduate student at Stanford in the ’90s, he conducted some of the first fMRI studies of memory formation. At that time, state-of-the-art imaging and analysis technologies only allowed measurement of the magnitude of activity from a centimeter-and-a-half section of the brain.

In contrast, the current study measured activity from the whole brain at high-resolution, and analyses not only focused on the magnitude of activity but also on the memory information that is contained in patterns of brain activity.

“It’s exciting to have basic science tools that allow us to witness when a memory is being replayed in an individual mind and to draw on these neural processes to explain why some older adults remember better than others,” said Wagner, who is senior author of the paper. “As a graduate student, I would never have predicted that we would do this kind of science someday.”

In the experiment, 100 participants between the ages of 60 and 82 had their brains scanned as they studied words paired with pictures of famous people and places. Then, during a scanned memory test, they were prompted with words they had seen and asked to recall the associated picture. The memory test was designed to assess one’s ability to remember specific associations between elements of an event, a form of memory that is often disproportionately affected by aging.

In the scans, the researchers observed that the brain processes that support remembering in older adults resemble those in younger populations: when people remember, there is an increase in hippocampal activity – a brain structure long known to be important for remembering events – along with the reinstatement of activity patterns in the cortex that were present when the event was initially experienced. That is, remembering entails neural time travel, replaying patterns that were previously established in the brain.

“It was striking that we were able to replicate this moment-to-moment relationship between hippocampal activity, replay in the cortex, and memory recall, which has previously been observed only in healthy younger adults,” said Trelle, who is lead author of the paper. “In fact, we could predict whether or not an individual would remember at a given moment in time based on the information carried in patterns of brain activity.”

The researchers found that, on average, recall ability declined with age. Critically, however, regardless of one’s age, stronger hippocampal activity and replay in the cortex was linked to better memory performance. This was true not only for the memory test conducted during the scan but also memory tests administered on a different day of the study. This intriguing finding suggests that fMRI measures of brain activity during memory recall are tapping into stable differences across individuals, and may provide a window into brain health.

Only the beginning

This research lays the foundation for many future investigations of memory in older adults in the Stanford Aging and Memory Study cohort. These will include work to further detail the process of memory creation and recall, studies of change in memory performance over time, and research that pairs fMRI studies with other kinds of health data, such as changes in brain structure and the build-up of proteins in the brain that are linked to Alzheimer’s disease.

The ultimate aim is to develop new and sensitive tools to identify individuals who are at increased risk for Alzheimer’s disease before significant memory decline occurs.

“We’re beginning to ask whether individual differences in the ability to mentally travel back in time can be explained by asymptomatic disease that impacts the brain and predicts future clinical diagnosis,” said Wagner. “We’re hopeful that our work, which requires rich collaborations across disciplines, will inform clinical problems and advance human health.”

Source: Stanford University


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