Unlocking the Mysteries of Delirium

What is delirium and how should we handle it?

EdwardMarcantonio_FlyerLast month, Edward Marcantonio, MD, MS, the IOA’s most recent visiting scholar and professor of Medicine at Harvard Medical School*, offered some answers to these questions during his lecture at the University of Pennsylvania.

In the 1980’s, as he was just beginning his career in the medical field, Dr. Marcantonio was taught that it was essentially “normal” for older people to go a little crazy – or “bonkers” as he calls it – during their hospital stay. The belief was that there really was not much that could be done about it, but if the symptoms became overly bothersome, prescription medications such as haloperidol or diazepam — drugs commonly used for mental or psychiatric disorders — would “take care of it.”

Today, while we are much better at recognizing what delirium actually is – and understanding that it is not “normal” – there is still some confusion across disciplines in the terminology used to identify this condition. Delirium is often referred to as acute confusional state, altered mental status, subacute befuddlement, or postoperative psychosis.

Regardless of what term is used, the diagnosis of delirium, or any of the other aforementioned names, is characterized by confusion, restlessness, and a disturbance in attention and awareness that develops acutely and tends to fluctuate. Delirium is typically referred to as one of two types—prevalent delirium or incident delirium. Prevalent delirium is when the condition is present and observed at the time of hospital admission and incident delirium develops during the hospital stay.

Delirium is even more common than most people realize. According to Dr. Marcantonio, it is experienced in 30-40% of medical inpatients over 70 years old, 15-50% of surgery patients over 70 years old, and at least 75-80% of intensive care unit patients over 18 years old.

In his line of research, Dr. Marcantonio focuses on two main aims: 1) improving delirium identification at the bedside and 2) understanding the pathophysiology of delirium and its association with dementia.

Improving delirium identification at the bedside

Because symptoms of delirium can come and go and vary in severity, identifying it can be quite a challenge. “When I got started in the field there were a number of studies that sent research teams out doing gold standard delirium assessments and then compared that to what was diagnosed in clinical care and it turned out that less than 50% of cases were recognized,” said Dr. Marcantonio.

In the 1990’s, the Confusion Assessment Method (CAM) was developed to help detect delirium in patients. The CAM looks at four key features: 1) acute change/fluctuating course, 2) inattention, 3) disorganized thinking, and 4) altered level of consciousness. In order to officially diagnose delirium according to the CAM diagnostic algorithm, the patient must be experiencing both features 1 and 2, in addition to either 3 or 4. While recognizing these features as signs of delirium can produce a successful diagnosis, there still needed to be a standardized way to identify these features in the patients. With this in mind, Dr. Marcantonio developed a series of methods and assessments for detecting delirium – some taking as little as 30 seconds to administer.

Learn more about these assessments in Dr. Marcantonio’s full lecture starting at 0:20:28:
Full lecture

Understanding the pathophysiology of delirium and its association with dementia

Although a variety of situations, such as dehydration, visual or hearing impairment, immobility, and sleep deprivation, can increase the chances of developing delirium, current research suggests that one of the strongest risk factors – aside from aging – is dementia.

One emerging hypothesis is that delirium may represent a state of neuroinflammation. It is believed that this neuroinflammation could be the link between delirium and dementia and if this theory is confirmed, it could have some very important therapeutic effects for both conditions.

Learn more about the link between dementia and delirium in Dr. Marcantonio’s full lecture starting at 0:40:05:
Full lecture

Although we have come a long way over the years to better understand delirium, there is still much work left to do. The ultimate goals are to establish effective and efficient assessments of delirium as a part of daily hospital vital sign checks and to develop pathophysiologically-based treatments to improve the short and long-term outcomes of this condition.

To view the full lecture, click here.

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* Dr. Marcantonio is also the Section Chief for Research in the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center (BIDMC).

 

CNDR Researcher receives second place prize for poster on Alpha-Synuclein at 2016 Udall Center Directors Meeting

Last month, Chao Peng, a post-doctoral researcher at the University of Pennsylvania’s Center for Neurodegenerative Disease Research, won a second place poster prize at the 2016 Udall Center Directors Annual Meeting.

Title: “Distinct Pathological a-Synuclein Strains in Glial Cytoplasmic Inclusions and Lewy Bodies”
Presenter: Chao Peng
Authors: Chao X. Peng, Ronald Gathagan, Dustin J. Covell, Anna Stieber, Coraima Medellin, John L. Robinson, Bin Zhang, Kelvin C. Luk, John Q. Trojanowski, Virginia M.-Y. Lee

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Chao Peng (second from the right) with Walter Koroshetz, MD, Director of NINDS (far left), and his fellow poster winners at the Udall Center Directors Meeting.

Peng’s poster was on the properties of the misfolded alpha-synuclein protein in different neurodegenerative diseases.

Alpha-synuclein is known for playing a key role in the development of Parkinson’s disease (PD), however, this protein is not unique to PD. Alpha-synuclein is also present in the brains of patients with Lewy body dementia (LBD) and Multiple system atrophy (MSA).

During a video interview with the Institute on Aging (see below), Chao Peng explains that alpha-synuclein accumulation is also present in almost 50% of Alzheimer’s disease cases.

While these diseases all show signs of this same misfolded protein, they actually exhibit very different pathological and clinical behaviors than one would experience with Parkinson’s disease—but how?

Chao Peng and his colleagues at CNDR are using multiple different cell and animal models to better understand not only how this occurs and why the same misfolded protein can cause one disease in one patient but something different in others, but what this could mean for potential treatments. Learn more here:

Developing Breakthrough Treatments for Alzheimer’s Disease

“Alzheimer’s disease (AD) is our #1 public health problem in terms of cost and burden of care and it is projected that over 100 million people will be diagnosed with Alzheimer’s worldwide by 2050,” said Stephen Salloway, MD, MS, a professor of Neurology and Psychiatry at Brown University and the Institute on Aging (IOA) at the University of Pennsylvania’s most recent Visiting Scholar.

On Tuesday, November 15, 2016, Dr. Salloway visited the University of Pennsylvania to present a lecture on “Developing Breakthrough Treatments for Alzheimer’s Disease” in which he shared some of the latest advances, and challenges, in the field of Alzheimer’s disease research.

“Our goal, and the goal of the National Plan developed by the U.S. Congress, is to develop breakthrough treatments by 2025.” – Stephen Salloway, MD, MS

It’s no secret that the world is getting older. In fact, according to Dr. Salloway, there are many regions of the world where more than 30 percent of the population will be 60 or older and coming into the risk state for cognitive impairment. Aside from the staggering and rising cost of care for Alzheimer’s disease and related dementias, it is the disease that older people fear most — fearing the disability and loss of identity.

With this in mind, you would assume that Alzheimer’s research would be a top priority, but “funding for Alzheimer’s disease at a federal level has paled in comparison to other diseases like cancer and heart disease,” said Dr. Salloway. However, things are starting to look up and we have recently started to see some improvement. For the first time, there is a strong potential for Alzheimer’s federal research funding to reach over $1 billion.

Researchers are steadily working to build a worldwide infrastructure to fight Alzheimer’s disease with a number of private/public partnerships, collaborative initiatives such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) one component of which is right here at Penn, and many other alliances across the board. We’ve already seen several important benefits emerge from these initiatives; for example, real time data sharing to trigger an increase in publications and shape new trials and views on Alzheimer’s research.

Several advances in AD research have been made over the years, from the discovery of plaques and tangles to the development of new imaging techniques and biomarker breakthroughs. “We now know that plaques and tangles begin accumulating 15-20 years before the onset of cognitive decline,” explained Dr. Salloway. Through these findings, we are able to better understand the progression of Alzheimer’s disease as a process starting with a long pre-clinical period, moving on to an early symptomatic period of mild cognitive impairment (MCI), then followed by the actual dementia period. The significance of understanding this process is that it opens the door of opportunity to eventually intervene before a patient reaches the late stage of Alzheimer’s disease.

In terms of current treatments, there are two classes of medications approved to treat the symptoms of the dementia phase of Alzheimer’s disease—cholinesterase inhibitors and memantine. Both drugs have been found to have a very mild multi-symptomatic clinical effect, but cannot cure the disease or stop it from progressing, which is the ultimate aim for researchers.

Since 2003, there have been no new treatments approved by the U.S. Food and Drug Administration (FDA), but there have been several clinical trials focusing on the amyloid pathway — some disappointing and some encouraging.

Two major phase-3 trials were the bapineuzumab trial and the solanuzumab trial. While the bapineuzumab trial was stopped after showing no clinical benefit, the solanuzumab trial raised some hope after findings showed some modest slowing of cognitive decline in a milder subgroup. We are expecting to see some new results soon from a replication trial.

Most recently, some very encouraging results emerged from a phase 1b trial focusing on the antibody, aducanumab. This study showed a substantial dose-dependent lowering of a-beta on amyloid PET scans and also suggested dose-dependent lowering of cognitive decline. There are currently two phase-3 trials underway hoping to reproduce these findings in early Alzheimer’s disease.

“This is very exciting to enter the era of Alzheimer’s prevention, but there are many challenges,” said Dr. Salloway. One of the biggest challenges that researchers face is recruitment of a much larger sample size and population than they’ve used in the past. “In the past, we have tested medicine for people who are cognitively impaired, mostly with dementia, and now we have to reach people who may be at risk for Alzheimer’s in a community who is not coming specifically for care,” he explained. This means they will need hundreds of thousands, if not millions, of people to be enrolled in order to find the highest group at risk and to test medications.

For Dr. Salloway, trying to figure out how to reach and engage this community “is a vastly new undertaking and a second career.” However, he believes that a big avenue is going to be through all types of media—social media, print media, broadcast media, etc.

“The media is critical for getting the word out” – Dr. Salloway

Following the publication and coverage of the results of the aducanumab trial, Dr. Salloway’s center had over 500 calls from people looking to volunteer for research.

In terms of future research, Dr. Salloway has a vision. Through the eventual use of combination treatments and therapies, “Alzheimer’s disease will be much more treatable and manageable than it is today,” he believes.

“Our goal is to detect risk, initiate treatments early, engage the public, develop new public/private partnerships, and to make investments in research to succeed [in fighting Alzheimer’s disease].” – Dr. Salloway  

Dr. Salloway is also the Director of Butler Hospital’s Memory and Aging Center.

Delirium and Aging

screen-shot-2016-11-10-at-10-41-51-amDelirium, a medical condition characterized by acute confusion, disorientation, or other mental health disruptions that affect thinking and behavior, affects nearly 7 million hospitalized Americans annually. While this condition can occur at any age, it mainly affects individuals 65 years or older and is often misdiagnosed as dementia.

As stated in an article originally published by Kaiser Health News and shared by Next Avenue, “while delirium and dementia can coexist, they are distinctly different illnesses. Dementia develops gradually and worsens progressively, while delirium occurs suddenly and typically fluctuates during the course of a day.” Particularly susceptible patients are those on ventilators or being heavily sedated in intensive care units, as well as those recovering from surgery.

“After an older adult undergoes anesthesia, they can often experience postoperative delirium,” explained Lee A. Fleisher, MD, chair of Anesthesiology and Critical Care at Penn, in a recent Penn Medicine News Blog on postoperative delirium and the uncertainties of anesthesia. “Patients in this state may hallucinate, they may forget why they are in the hospital, or have difficulty communicating or understanding what is going on around them.”

However, delirium can also result from something as simple and easily treated as a urinary tract infection.

According to research published in 2009 and referenced by Next Avenue, an estimated 40% of delirium cases are actually preventable; yet, the underlying cause is still unknown.

With all of this in mind, health care professionals, government agencies, and related nonprofit organizations gathered at the American Society of Anesthesiologists’ Brain Health Summit to discuss, among other topics, the postoperative risks of delirium and delayed cognitive recovery and whether or not they are significant enough to include in consent and patient education materials. They also considered ways to reduce the risks and to increase research funding.

The Penn Medicine News Blog says that “while the Summit provided some direction and tactics for industry leaders to act upon, there are still other options that can be explored and implemented to advance learning, protect patients, and uncover the uncertainties around anesthesia and postoperative delirium.”

“Encouraging patients to follow a balanced diet and exercise regularly in the lead up to surgery, allowing patients to bring mementos and family photos to their hospital room after surgery, even asking families and caregivers to keep a close eye on small declines in patients’ cognitive function preoperatively – simple things like the patient not being as sharp as he or she once were – may help clinicians properly prepare for patient care, and may help patients readjust after surgery and avoid postoperative delirium,” Fleisher said. “While these have not been scientifically proven to help, we think that even the smallest measures may make a difference for patients who are coming out of anesthesia.”

To learn more about delirium and aging, join the Institute on Aging on Tuesday, April 18, 2017 for our Visiting Scholars Series lecture by Edward Marcantonio, MD, SM.

Dr. Marcantonio is the Section Chief for Research in the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center and Professor of Medicine at Harvard Medical School. His research concentrations focus on delirium and cognitive function.

For more information, visit: www.med.upenn.edu/aging/events


Photo credit: news.pennmedicine.org/blog

Could treating one disease lead to another? The possible link between prostate cancer treatment and dementia

The possible link between prostate cancer treatment and dementia is a topic that has been making quite a few headlines over the last several weeks. According to a recent Penn Medicine News Release that seems to have started the conversation, researchers at the University of Pennsylvania have found that “a common hormone therapy [used] to treat prostate cancer may double a man’s risk of dementia, regardless of his age.”

Last year, lead author Kevin T. Nead, MD, MPhil, a resident in the department of Radiation Oncology at the Perelman School of Medicine at the University of Pennsylvania, and his colleagues discovered an association between Alzheimer’s disease and androgen deprivation therapy (ADT) — a treatment for prostate cancer that is used in over half a million men in the U.S. However, the new findings, published in JAMA Neurology, lead them to believe that the neurocognitive risk involved is actually broader than just Alzheimer’s.

As stated in the news release, “while the findings do not prove that ADT increases the risk of dementia, the analysis comparing the medical records of almost 9,500 prostate cancer patients who received ADT vs. those who did not strongly supports that possibility.”

“We have two papers here showing very similar outcomes and magnitude of risk, which I think supports the case for this to be studied prospectively,” explained Dr. Nead.

This raises the question – do the benefits of ADT outweigh the risk of dementia?

In a recent feature in NY Times Well, Dr. Nead addressed this question explaining that this is a discussion that patients should have with their physician. “This study is important and urges us toward future research, but I don’t think it should impact clinical practice,” he said.

Read the full Penn Medicine News Release here.

Several other local and national news outlets have also picked up the story including

 

 

Penn Medicine Celebrates a Milestone with its 5th Annual 5K for the IOA and the Memory Mile Walk

On Sunday, September 25, 2016, Penn Medicine celebrated the 5th anniversary of its annual 5K for the IOA and Memory Mile Walk!

Nearly 500 runners, walkers, and spectators turned up bright and early for the 3.1-mile race through Penn Park and 1-mile walk across the University of Pennsylvania’s campus. The event continues to provide fun for the whole family, even your four-legged friends, and brings together hundreds of people for one universal cause — to support Alzheimer’s and aging-related research at Penn’s Institute on Aging (IOA).

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P.J. Brennan, MD, with his sister, Sheila Connor, at this year’s event.

The 5K for the IOA and the Memory Mile Walk was started in 2012 by the University of Pennsylvania Health System’s Chief Medical Officer and Senior Vice President and IOA External Advisory Board member, P.J. Brennan, MD. After losing his father to Alzheimer’s disease, Dr. Brennan wanted to create a way to get involved in the efforts of finding a cure for this devastating disease. “I wanted to provide support for investigators to test novel ideas that could someday lead to groundbreaking therapies,” he said.

This year, the event raised an impressive $34,245 for the cause and had one of its largest turnouts yet.

As the numbers continue to grow over the years, so do the reasons to attend. In addition to great “SWAG” bags and various raffle prizes, generous awards were given to the top male and female runners in each age category. The overall winners were James Murphy, age 25, with a time of 16:57 and Zandra Walton, age 28, with a  time of 19:19.

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We would like to extend our sincerest gratitude to all of the race organizers, sponsors, volunteers, donors, and participants who make this event a success! Thank you!

The full list of race results, courtesy of Run the Day, can be found here.

To view all of the photos from the event, click here.

To view the 6ABC news coverage of the event, click here.

For more information, visit: www.pennmedicine.org/5kioa

ADNI3 launches with the help of a donation of over $14 million from patient advocacy groups, industry, and individuals to support critical Alzheimer’s research.

The Foundation for the National Institutes of Health (FNIH) announced last week that it has received a donation of more than $14 million to launch the third phase of the Alzheimer’s Disease Neuroimaging Initiative, or ADNI3, a study aimed at identifying biomarkers from brain scans, genetics, blood, and cerebrospinal fluid (CSF) to detect the progression of Alzheimer’s disease.

The donation comes from a united effort among several patient advocacy groups, private foundations, industry, and individual donors dedicated to helping make a difference in the field of Alzheimer’s research.

“Additions to the third phase of ADNI include recruiting 1,200 volunteers to join about 800 current participants to enrich the existing dataset, using state-of-the-art imaging techniques to monitor brain levels of tau, a protein that is often abnormal in Alzheimer’s patients, and performing cutting-edge analyses to assess complex interactions between the brain and body,” according to the official FNIH press release. “ADNI3 also will assess cognitive function through computer tests at home and in the doctor’s office and measure changes in subjects’ ability to handle money, which can be a warning sign of the disease.”

The University of Pennsylvania’s John Q. Trojanowski, MD, PhD, director of the Institute on Aging and professor of Pathology and Laboratory Medicine, and Leslie M. Shaw, PhD, professor of Pathology and Laboratory Medicine, are heavily involved in ADNI and co-direct its Biomarker Core.

johnheadshot“This phase of ADNI will bring us close to defining highly informative AD biomarkers for the diagnosis of AD even before its clinical onset, thereby making it possible to conduct prevention trials of therapies that could arrest the AD process in presymptomatic individuals even before AD begins to manifest clinically in patients,” said Dr. Trojanowski. “We are so grateful to the donors who have helped make this possible.”

In addition to banking biofluids from their unique cohort of subjects, the Biomarker Core also conducts studies including those to identify new biomarkers and species of tau and a-beta in CSF and plasma.

lesshaw_hsDr. Shaw explained “the ADNI3 study enables us to build on the progress of validation and standardization of AD biomarker tests that detect neuropathologic hallmarks of the disease and track disease progression over years of time within individual study subjects. As a result of the generous support of donors to the ADNI3 study, this work now continues and we expect to see these tests used to determine subject eligibility in therapeutic trials at all stages of the disease and to reflect therapeutic effects.”

To learn more about ADNI, visit: http://www.adni-info.org

Full FNIH Press Release.