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This Way In: Scientists Set Dementia Research Goals

Eastman, Peggy

doi: 10.1097/01.NNN.0000436393.29242.88
Departments: The Waiting Room

This Way In: Highlights from the recent National Institute of Neurological Disorders and Stroke conference on Alzheimer's-related dementias.

To watch a video interview with Dr. Petra Kauffman of NINDS, go to



Not all dementia is caused by Alzheimer's disease. To address this, the National Institute of Neurological Disorders and Stroke (NINDS) recently held the “Alzheimer's Disease-Related Dementias” meeting on the grounds of the National Institutes of Health in Bethesda, MD.

Attendees convened in May to set research goals for these other dementias, including vascular dementia, which affects nearly 600,000 Americans and is caused by decreased blood supply to the brain; Lewy body dementia, which affects approximately 1.3 million Americans; and dementia due to frontotemporal degeneration, which affects 50,000 to 60,000 Americans. In one dementia and memory study, about 3.8 million Americans aged 71 and older were found to have dementia not caused by Alzheimer's disease (AD). Some of those cases are likely due to more than one cause. In fact, dementia due to multiple causes is common, according to David Knopman, M.D., professor of neurology at the Mayo Clinic College of Medicine in Rochester, MN.

The NINDS meeting was held in response to the National Alzheimer's Project Act, which President Obama signed into law in January 2011. The Act calls for a plan to reduce the escalating burden of all forms of dementia in the United States. Attendees discussed a draft report recommending priorities for the next five to 10 years of research. Their comments are being incorporated into a final report that will guide future studies, says Thomas Montine, M.D., Ph.D., scientific chair of the meeting and director of the University of Washington's Alzheimer's Disease Research Center in Seattle. “It's really our opportunity to seize the moment,” he notes.

The following are key research goals in AD-related dementias, according to experts who attended.

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Researchers agreed that the track record for diagnosing dementias other than AD needs a great deal of improvement. “These are almost invariably misdiagnosed,” says Bruce Miller, M.D., professor of neurology at the University of California, San Francisco. He notes that primary care doctors such as internists and family physicians—usually the first stop when someone shows signs of dementia—are often pressed for time, may think nothing can be done to help patients (despite the availability of some U.S. Food and Drug Administration-approved drugs for cognitive impairment), may misread images from brain scans, or may fail to refer patients to an expert such as a neurologist.

Even when primary care doctors offer a referral, it may be to a psychiatrist. Psychiatric symptoms, such as delusions and mood swings, are often the first inkling that someone has dementia. Unfortunately, the field of psychiatry tends to overlook the dementias, says Dr. Miller. Psychiatrists may not realize that symptoms such as impaired judgment, agitation, and socially deviant behavior are often the first signs of frontotemporal degeneration. And while no treatment can slow progression of this disease, the approved drug trazodone (Desyrel) has been found to help symptoms such as irritability and agitation.

“I think psychiatry has a poor record in diagnosing these disorders,” agrees Edward Huey, M.D., a geriatric psychiatrist in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University in New York City.

To improve dementia diagnosis, the draft recommendations propose developing standardized methods for analyzing brain images. “Automated analysis technology should help in that regard,” says Richard O'Brien, M.D., Ph.D., chair of neurology at the Bayview Campus of the Johns Hopkins University in Baltimore, MD.

Improved methods of early, accurate diagnosis are especially critical for Lewy body dementia (LBD), according to Ian McKeith, M.D., professor of old age psychiatry at the Institute for Ageing and Health at Newcastle University, United Kingdom. One reason: antipsychotic drugs can cause extreme adverse reactions in people with the disease, such as worsening of confusion and excessive sleepiness—so a psychiatric misdiagnosis may be harmful. Early diagnosis is also important because people with LBD may be helped by treatment for sleep disturbances and by cholinesterase inhibitors, which are drugs prescribed for dementia symptoms.

People with LBD often have mood and behavior changes, decreased judgment, slow movements, and hallucinations. In many cases, says Dr. McKeith, these patients have greater disability and a worse quality of life than people with AD. Unfortunately, LBD is underdiagnosed; approximately 78 percent of patients receive another diagnosis first, he says, adding that research on biomarkers—biological signs of the disease process—is urgently needed to help improve diagnosis.

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Researchers know that a protein called tau, which is important for the normal function of brain cells, can also cause (when it goes awry) abnormally twisted tangles in the brains of people with AD. Now, researchers are probing the role of tau in dementia due to frontotemporal degeneration (FTD). The draft recommendations advise continued study of the normal role of tau and other proteins in brain function. Speakers also discussed the development of potential therapies for tau dysfunction, such as drugs that could clear tau from the brain or prevent it from clumping together.

In addition, the draft recommendations advise study of a protein called progranulin involved in wound healing and inflammation. A deficiency in progranulin leads to inflammation and loss of neurons. People who have an inherited condition that causes a lack of progranulin are more likely to develop FTD, but why this happens is unknown.

“The biology of progranulin is very important to the recommendations we're putting forth,” says William Seeley, M.D., associate professor of neurology at the University of California, San Francisco, and director of the university's Neurodegenerative Disease Brain Bank.

“Increasing progranulin seems attainable as a research goal,” adds Stephen Strittmatter, M.D., Ph.D., professor of neurology and neurobiology at Yale University School of Medicine in New Haven, CT. The challenge, he says, is how to develop medications that increase progranulin activity.

As a potential target for FTD therapy, progranulin is attractive because it can be measured in the spinal fluid, according to Adam Boxer, M.D., Ph.D., associate professor of neurology at University of California, San Francisco, where he directs the Neurosciences Clinical Research Unit in the Sandler Neurosciences Center. It should be possible, he says, to design a clinical trial of a drug that elevates progranulin levels in hopes of slowing or stopping FTD; the drug's effectiveness could be monitored by checking progranulin levels in spinal fluid.

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Everyone can reduce the risk of vascular dementia by not smoking, eating a healthy diet, maintaining normal weight, and controlling blood pressure and cholesterol levels.

“Evidence exists that vascular health is critical to delaying onset of dementia,” the draft recommendations state. Racial minorities, such as African Americans, are more likely to have risk factors that put them at higher risk of stroke—and stroke can lead to vascular dementia. The recommendations advise testing the biological basis of dementias to see if they differ across populations.

“Much of the disparity in stroke risk in the United States is due to the higher prevalence of cardiovascular risk factors, such as elevated blood pressure, among racial and ethnic minorities,” according to NINDS Deputy Director Walter J. Koroshetz, M.D.

The NINDS is already moving forward to reduce racial and ethnic disparities in stroke incidence and thus hopefully reduce vascular dementia. Over the next five years, four U.S. research centers will receive $40 million in NINDS funding to develop culturally sensitive healthcare interventions that reduce stroke risk in minorities.

The draft recommendations also note that more members of racial and ethnic minorities are needed for clinical research.

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Caregivers attending the NINDS meeting emphasized how hard it is to get an accurate diagnosis for a loved one with the “other” dementias. “I cannot underscore enough how difficult it is for the families,” says Angela Taylor, director of programs for the Lewy Body Dementia Association in Lilburn, GA ( Taylor was a caregiver for her father, who had the disease. She says what families need, in addition to effective new therapies, is a better understanding of the phases of LBD, so that caregivers can plan for the future.

Eloise F. Nenon of Chatham, VA, who is active with the Older Adult Ministry of the Virginia United Methodist Conference, cared for her late husband, who had LBD. But Nenon didn't know the diagnosis until her husband died and an autopsy was performed. Nenon's advice to caregivers: “Figure out what works at home”—such as installing grab bars to prevent falling, and hiring a home health aide.

Heather Robinson of Wilton, CT, a hospice volunteer and former emergency medical technician whose mother has mixed dementia, recommends that family members keep track of symptoms in order to help the doctor arrive at an accurate diagnosis. For years, her mother had violent dreams which can be symptoms of LBD.

Robinson, who is writing a fictional book on dementia, also emphasizes that caregivers have to have a generous supply of patience and love—and a sense of humor. “Sometimes you have to laugh; otherwise, you're going to cry all the time.”

© 2013 American Academy of Neurology