Sac to the Future: Cellular Vessels Predict Likelihood of Developing Dementia

 Blood-based neuronally-derived exosomes carry tell-tale proteins that could help forecast transition from mild cognitive impairment to Alzheimer’s

disease

Newswise, July 8, 2016 — Researchers at University of California San Diego School of Medicine say tiny micro-vesicle structures used by neurons and other cells to transport materials internally or dispose of them externally carry tell-tale proteins that may help to predict the likelihood of mild cognitive impairment (MCI) developing into full-blown Alzheimer’s disease (AD).

The findings, published online this week in the journal Alzheimer’s & Dementia, represent a quicker and less invasive way to identify impending cognitive decline and begin treatment before progression to established, irreversible dementia.

“MCI is often a transitional stage between normal aging and dementia,” said senior author Robert A. Rissman, PhD, associate professor in the Department of Neurosciences at UC San Diego School of Medicine, director of the Biomarker Core for the Alzheimer’s Disease Cooperative Study (ADCS) and director of the Neuropathology Core and Brain Bank for the UC San Diego Shiley-Marcos Alzheimer’s Disease Research Center.

“It’s associated with more minor cognitive impairment and carries an increased risk of developing Alzheimer’s dementia.”

MCI patients progress to AD at rates as high as 10 to 15 percent per year, prompting an increased emphasis upon diagnosing MCI early and developing treatments that can delay or prevent conversion to AD.

The need is underscored, write the authors, by the fact that clinical trials of treatments for established AD have thus far failed.

While clinically distinguishable from normal aging and AD, MCI remains nonetheless a complex condition with many and varied causes.

“That has prompted great interest in pinpointing underlying biomarkers that can predict the conversion from MCI to AD dementia,” said Rissman.

“Finding such biomarkers would also identify persons most likely to be responsive to preventive treatments.”

Currently, the accepted methods for diagnosing preclinical AD patients is to detect protein biomarkers found in cerebrospinal fluid (CSF), in combination with advanced neuroimaging and neuropsychological testing.

But CSF sampling involves an invasive, often painful, process. Neuroimaging is expensive. Neuropsychological testing is time-consuming and can often vary from visit to visit.

The new method described in the Alzheimer’s & Dementia study evaluated the potential of exosomes – extremely small vesicles or sacs found in most cell types, including neurons. Exosomes are thought to move materials inside cells and are used to dump cellular trash into the bloodstream for disposal.

In the case of disease, Rissman’s group predicted that neuronal derived exosomes (NDEs) would carry damaged or excess proteins and metabolites out of brain cells, among them amyloid and tau biomarker proteins that are strongly associated with AD.

The researchers harvested NDEs from human blood plasma of 60 patients who participated in an 18-month ADCS clinical trial that enrolled MCI patients only.

Some of these MCI patients converted to AD over the course of the study and some did not. Rissman’s lab also gathered samples from control patients and samples from known AD patients.

They enriched the NDE content of those originating from neurons. The samples represented patients with normal cognitive function, diagnoses of stable MCI and stable AD and patients who had recently transitioned from MCI to AD.

After characterizing NDEs by size, shape and concentration, the researchers compared that data with the different patient cohorts.

They found that NDEs carried targeted biomarker proteins, which have previously been found to predict development of AD up to 10 years before onset of clinical symptoms, and correctly distinguished 100 percent of patients with AD from normal cohorts.

Moreover, the researchers showed for the first time that plasma NDEs from AD and MCI patients may propagate tau tangles in the brains of normal mice similar to what is seen in human AD brains.

The fact that these NDEs could induce pathological-like structures in “naïve” mice (animals not previously subjected to experiments) suggests that the contents of NDEs are bioactive, said Rissman. It also suggests that released NDEs can be taken up by cells, raising the possibility of NDEs potential for drug delivery.

The development of blood-based biomarkers for AD (and other neurodegenerative diseases) diagnostics could significantly improve the effectiveness and reliability of patient care and future research, said the authors, who encouraged further studies to refine and validate the approach.

Co-authors include Charisse N. Winston, Bob C. Carter, Edward M. Rockenstein, Douglas Galasko and Eliezer Masliah, all at UC San Diego; and Edward J. Goetz and Johnny C. Akers, UC San Francisco.

Funding for this research came, in part, from the National Institutes of Health (grants AG04484, BX003040, AG0051839), the Alzheimer’s Association and the Alzheimer’s Art Quilt Initiative.

Stress in Older People Increases Risk for Pre-Alzheimer’s Condition

Newswise, December 14, 2015--Feeling stressed out increases the likelihood that elderly people will develop mild cognitive impairment—often a prelude to full-blown Alzheimer’s disease.

In a new study, scientists at Albert Einstein College of Medicine and Montefiore Health System found that highly stressed participants were more than twice as likely to become impaired than those who were not. Because stress is treatable, the results suggest that detecting and treating stress in older people might help delay or even prevent the onset of Alzheimer’s. The findings were published online in Alzheimer Disease & Associated Disorders.

Each year, approximately 470,000 Americans are diagnosed with Alzheimer’s dementia. Many of them first experience mild cognitive impairment—a pre-dementia condition that significantly increases the risk of developing Alzheimer’s in the following months or years. This study looked at the connection between chronic stress and “amnestic mild cognitive impairment” (aMCI), the most common type of MCI, which is primarily characterized by memory loss.

“Our study provides strong evidence that perceived stress increases the likelihood that an older person will develop aMCI,” said Richard Lipton, M.D., senior author of the study, vice chair of neurology at Einstein and Montefiore, and professor in the Saul R. Korey Department of Neurology and the Edwin S. Lowe Chair of Neurology at Einstein. "Fortunately, perceived stress is a modifiable risk factor for cognitive impairment, making it a potential target for treatment."

“Perceived stress reflects the daily hassles we all experience, as well as the way we appraise and cope with these events,” said study first author, Mindy Katz, M.P.H., senior associate in the Saul R. Korey Department of Neurology at Einstein.

“Perceived stress can be altered by mindfulness-based stress reduction, cognitive-behavioral therapies and stress-reducing drugs. These interventions may postpone or even prevent an individual’s cognitive decline.”

The researchers studied data collected from 507 people enrolled in the Einstein Aging Study (EAS), a community-based cohort of older adults. Since 1993, the EAS has systematically recruited adults 70 and over who live in Bronx County, NY.

Participants undergo annual assessments that include clinical evaluations, a neuropsychological battery of tests, psychosocial measures, medical history, assessments of daily-living activities and reports (by participants and those close to them) of memory and other cognitive complaints.

Starting in 2005, the EAS began assessing stress using the Perceived Stress Scale (PSS).

This widely used 14-item measure of psychological stress was designed to be sensitive to chronic stress (due to ongoing life circumstances, possible future events and other causes) perceived over the previous month. PSS scores range from 0 to 56, with higher scores indicating greater perceived stress.

The diagnosis of aMCI was based on standardized clinical criteria including the results of recall tests and reports of forgetfulness from the participants or from others. All 507 enrollees were free of aMCI or dementia at their initial PSS assessment and subsequently underwent at least one annual follow-up evaluation. They were followed for an average of 3.6 years.

Seventy-one of the 507 participants were diagnosed with aMCI during the study. The greater the participants’ stress level, the greater their risk for developing aMCI: for every 5 point increase in their PSS scores, their risk of developing aMCI increased by 30 percent. Similar results were obtained when participants were divided into five groups (quintiles) based on their PSS scores.

Participants in the highest-stress quintile (high stress) were nearly 2.5 times more likely to develop aMCI than were people in the remaining four quintiles combined (low stress). When comparing the two groups, participants in the high-stress group were more likely to be female and have less education and higher levels of depression.

To confirm that stress was independently increasing risk for aMCI in this study, the researchers assessed whether depression—which increases the risk for stress as well as for cognitive impairment and Alzheimer’s disease—might have influenced the results.

They found that depression did not significantly affect the relationship observed between stress and the onset of aMCI. Similarly, stress’s impact on cognitive status was unaffected if participants possessed at least one e4 allele of the APOE gene, which increases their risk for developing late-onset Alzheimer’s.

The study is titled “Influence of perceived stress on incident amnestic mild cognitive impairment: Results from the Einstein Aging Study.”

In addition to Dr. Lipton and Ms. Katz, other Einstein-Montefiore authors were Carol Derby, Ph.D., Cuiling Wang, Ph.D., Ali Ezzati, M.D., Molly Zimmerman, Ph.D., and Jessica Zwerling, M.D., M.S. Martin Sliwinski, Ph.D., of Pennsylvania State University also contributed to the study.

The research was funded by the National Institutes of Health, the National Center for Advancing Translational Sciences, the Leonard and Sylvia Marx Foundation and the Czap Foundation. The authors report no conflicts of interest.

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About Albert Einstein College of Medicine
Albert Einstein College of Medicine is one of the nation’s premier centers for research, medical education and clinical investigation. During the 2015-2016 academic year, Einstein is home to 731 M.D. students, 193 Ph.D.students, 106 students in the combined M.D./Ph.D. program, and 278 postdoctoral research fellows. The College of Medicine has more than 1,900 full-time faculty members located on the main campus and at its clinical affiliates. In 2015, Einstein received $148 million in awards from the National Institutes of Health (NIH). This includes the funding of major research centers at Einstein in aging, intellectual development disorders, diabetes, cancer, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore Medical Center, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Through its extensive affiliation network involving Montefiore, Jacobi Medical Center—Einstein’s founding hospital, and three other hospital systems in the Bronx, Brooklyn and on Long Island, Einstein runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States. For more information, please visit www.einstein.yu.edu, read our blog, follow us on Twitter, like us on Facebook, and view us on YouTube.

About Montefiore Health System
Montefiore Health System is a premier academic health system and the University Hospital for Albert Einstein College of Medicine. Combining nationally-recognized clinical excellence with a population health perspective that focuses on the comprehensive needs of the communities it serves, Montefiore delivers coordinated, compassionate, science-driven care where, when and how patients need it most. Montefiore consists of seven hospitals and an extended care facility with a total of 2,455 beds, a School of Nursing, and state-of-the-art primary and specialty care provided through a network of more than 150 locations across the region, including the largest school health program in the nation and a home health program. The Children's Hospital at Montefiore is consistently named in U.S. News' "America's Best Children's Hospitals." Montefiore's partnership with Einstein advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. The health system derives its inspiration for excellence from its patients and community, and continues to be on the frontlines of developing innovative approaches to care. For more information please visit www.montefiorehealthsystem.org. Follow us on Twitter; like us on Facebook; view us on YouTube.