Potential Linkages Between Two Serious Problems Facing The Elderly Examined

Dementia, including Alzheimer's disease, is one of the most devastating conditions of older age. Currently affecting nearly 7 million individuals in the U.S. and 24 million worldwide, dementia leads to total loss of memory and the ability to function independently - making it one of people's greatest fears of aging.

Delirium is an acute confusional state, a common and serious complication in older individuals that often follows surgery or serious illness. Sometimes accompanied by disorientation, paranoia and hallucinations, delirium develops in 14 to 56 percent of all hospitalized seniors, complicating hospital stays for over 4 million older individuals in the U.S. each year.

For the most part, dementia and delirium have been viewed as separate and distinct conditions. But a special section of The Journal of Gerontology: Medical Sciences, appearing in January 2007, looks at their interface, asking: Can delirium itself lead to the development of a cognitive disorder? Do delirium and dementia represent opposite ends of the same spectrum of disease, rather than two separate conditions?

"I have been studying delirium for 20 years," says Sharon Inouye, MD, MPH, a geriatrician at Beth Israel Deaconess Medical Center and Director of the Aging Brain Center at the Institute for Aging Research, Hebrew SeniorLife. "And the more cases I encounter, the more linkages I see with dementia. For a large proportion of older patients, the problem [of delirium] is never resolved. I routinely hear from patients' families, 'They went into the hospital, they became very confused, and they never recovered.'"

Inouye, a professor of medicine at Harvard Medical School, together with Luigi Ferrucci, MD, PhD, Chief of the Longitudinal Studies Section of the National Institute on Aging and Editor-in-Chief of the journal, which is published by the Gerontological Society of America, examined the relationship between these two widespread conditions during the "Aging Brain Center Scientific Symposium: The Interface of Delirium and Dementia," held last spring.

"Better understanding of delirium may represent a new window of opportunity for the prevention of dementia," explains Ferrucci. "We, therefore, decided to approach the subject from a multidisciplinary perspective, exploring delirium and dementia from a number of vantage points." Findings spawned from the symposium make up the five articles featured in the special issue of the journal, including:

* Biomarkers. "There is currently no way of identifying delirium save for the observations of an astute clinician," notes Inouye. In this review article, BIDMC geriatrician Edward Marcantonio, MD, examines a number of promising biomarkers for delirium, including serum chemistries,genetic markers, serum anticholinergic activity, neurotransmitters, inflammatory markers and cortisol.

* Role of neuroimaging. Physicist David Alsop, PhD, of BIDMC's Department of Radiology, describes major advances in neuroimaging - including advanced methods using magnetic resonance (MR) imaging, positron emission tomography (PET) and single photo emission computed tomography (SPECT) -- which offer the possibility of using highly sensitive imaging techniques to detect changes in the brain following episodes of delirium and thereby investigate the mechanisms and networks involved in its onset and consequences.

* Use of SPECT scanning to assess cerebral perfusion changes in patients with delirium. Led by Tamara Fong, MD, of BIDMC's Department of Neurology, this paper describes the results of a study examining a group of hospitalized patients, which shows that frontal or parietal cerebral perfusion abnormalities occur in cases of delirium. These results suggest localized involvement in the brain's frontal and parietal lobes with delirium, which may correlate with the clinical findings and long-term outcomes.

* The link between anesthesia and development of long-term delirium. Zhongcong Xie, MD, together with senior author Rudolph Tanzi, MD, of the Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Disease, demonstrate that the commonly used anesthetic isoflurane results in neuronal cell death, and enhancement of A-beta oligomerization, for the first time, providing a direct link between the acute effects of inhalational anesthetics (recognized risk factors for delirium) and the hallmark mechanisms of Alzheimer's disease neuropathogenesis.

* The potential role for cognitive reserve. Inouye, together with BIDMC gerontologist Richard Jones, ScD, an investigator in the Institute for Aging Research at Hebrew SeniorLife, report their findings showing that hospitalized older persons with lower levels of education may be at increased risk for delirium relative to older persons with more education. "People have varying degrees of cognitive reserve, the capability to withstand insults and stresses to their system [such as might occur in a hospital setting]," explains Inouye. "Our study shows that amount of education correlates with brain resiliency, perhaps by building greater numbers of neuronal pathways."

Delirium is a tremendous expense to the country's medical system, amounting to more than $7 billion per year in hospital expenses and more than $100 billion a year when rehabilitation, institutionalization and long-term care is factored in.

In a 1999 study in The New England Journal of Medicine, Inouye demonstrated that delirium can be decreased by 40 percent by implementing a number of straightforward interventions while patients are hospitalized. These include making sure that patients are oriented and hydrated, that they are up and walking, that they are using their hearing aids and vision aids, and that they avoid the use of sleep medications.

"Our goal now is to better understand the fundamental changes that cause delirium and determine whether they result in permanent injury to the brain, in order to better devise ways to intervene and prevent this injury," explains Inouye. "Knowing that our population is rapidly aging, these figures are only going to increase unless we do something now. We hope to eventually be able to identify at-risk individuals before they develop delirium, so that we can intervene before it escalates to a chronic condition."

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In addition to Inouye, coauthors include: BIDMC investigators Edward Marcantonio, MD, and David Alsop, PhD, and Brigham and Women's Hospital investigators James Rudolph, MD, Deborah Culley, MD, and Gregory Crosby, MD, for "Serum Biomarkers for Delirium."

David Alsop, Michael Fearing, PhD, of Hebrew SeniorLife, Keith Johnson, MD, of Massachusetts General Hospital, Reisa Sperling, MD, of Brigham and Women's Hospital, and Tamara Fong, MD, of BIDMC for "The Role of Neuroimaging in Elucidating Delirium Pathophysiology."

Tamara Fong, MD, Sidney Bogardus, Jr., MD, Linda Leo-Summers, Aditya Daftary, MD, and Hal Blumenfeld, MD, and John Seibyl, MD, of Yale University School of Medicine; Eliza Auerbach, MD, of Columbia School of Medicine; Sharada Modur of Ohio State University, for "Cerebral Perfusion Changes in Older Delirious Patients Using 99mTc HMPAO SPECT."

Zhongcong Xie, PhD, Yuanlin Dong, Uta Maeda, Robert Moir, and Rudolph Tanzi, PhD, of Mass General Institute for Neurodegenerative Disease, MGH; Deborah Culley, MD, and Gregory Crosby, MD, of Brigham and Women's Hospital for "Isofluorane-Induced Apoptosis: A Potential Pathogenic Link Between Delirium and Dementia."

Richard Jones, ScD, Frances Yang, PhD, Ying Zhang, MD, MPH, Dan Kiely, MPH, MA, and Edward Marcantonio, MD, of the Institute for Aging Research, Hebrew SeniorLife for "Does Educational Attainment Contribute to Risk for Delirium? A Potential Role for Cognitive Reserve."

Funding for the studies and article was provided, in part, by grants from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the Alzheimer's Association and the Donaghue Medical Research Foundation.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and ranks third among independent hospitals nationwide in National Institutes of Health (NIH) funding. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www.bidmc.harvard.edu/.

The Aging Brain Center is housed within Hebrew SeniorLife's Institute for Aging Research, the country's largest geriatric research facility in an applied setting. It is located at Hebrew Rehabilitation Center in Boston, which is also a major teaching site for the Harvard Medical School Multi-Campus Fellowship in Geriatric Medicine. IFAR is distinguished by the multidisciplinary nature of its faculty, which includes both social and medical research scientists.

Contact: Bonnie Prescott
Beth Israel Deaconess Medical Center