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BETHESDA, MD — In January 2011, President Obama signed the National Alzheimer's Project Act (NAPA) into law to create a strategic plan to address the escalating burden of dementia. In response to that law, the National Institute of Neurological Disorders and Stroke (NINDS) released draft prioritized recommendations for Alzheimer's disease-related dementia research over the next five to 10 years at a scientific workshop here on the grounds of the National Institutes of Health (NIH). The draft recommendations highlight the most needed and promising areas for advances in the field.
“The point is that now we have a bit of a blueprint that we can follow,” said Ronald C. Petersen, MD, PhD, Mayo Clinic professor of neurology and the Cora Kanow professor in Alzheimer's Disease Research, a Mayo Clinic Distinguished Investigator and chair of the Advisory Council on Research, Care and Services for NAPA appointed by the Secretary of the Department of Health and Human Services (HHS). “This meeting really means something because something happens at the end.”
“It's really our opportunity to seize the moment” and shape future research on these dementias, added Thomas Montine, MD, PhD, scientific chair of the NINDS dementia workshop held at NIH and director of the University of Washington's Alzheimer's Disease Center at Harborview Medical Center. Dr. Montine said the draft recommendations — featured below — will be revised to incorporate comments from the NINDS workshop, reviewed, and then released in a report.
DEVELOPING IMAGING AND FLUID BIOMARKERS
Among the recommendations from the advisory council is the directive to develop imaging and fluid biomarker algorithms to detect typical versus atypical dementias and expand their accessibility in primary care settings (timeline: < five years). When dementia is indicated, algorithms for reading brain imaging to improve diagnosis with structural magnetic resonance (MR), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) “need to be available for radiologists and non-radiologists in primary care settings,” the advisory council recommended.
Speakers at the NINDS scientific workshop stressed that a major problem with Alzheimer's disease-related dementias — frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), mixed dementia, and vascular dementia — is misdiagnosis. “Treatable diagnoses are missed,” said Bruce Miller, MD, professor of neurology at the University of California, San Francisco (UCSF) and director of the UCSF Dementia Center, because too often these dementias are misdiagnosed as psychiatric disorders.
Validation would be provided by neuropathological diagnosis, said Richard O'Brien, MD, PhD, chair of neurology at the Bayview campus of the Johns Hopkins department of neurology and professor of neurology, neuroscience and medicine at Johns Hopkins. “We need automated MRI analysis,” said Dr. O'Brien.
The council also proposed that researchers focus on improving the accuracy of detecting and diagnosing DLB, including at the pre-dementia (prodromal) stage (timeline: five to 10 years).
DLB, the second most common cause of neurodegenerative dementia after Alzheimer's disease, is invariably misdiagnosed or diagnosed late, said speakers at the NINDS meeting. “We need to diagnose it better and earlier; clinical diagnosis alone is unlikely to be adequate,” said Ian McKeith, MD, professor of old age psychiatry at the Institute for Ageing (sic) and Health at Newcastle University, United Kingdom.
Dr. McKeith said, given that about 78 percent of DLB patients receive a non-DLB diagnosis initially, biomarker profiling will likely be needed to diagnose DLB accurately. “We particularly need to understand the prodromal syndrome and the factors influencing risk and progression of DLB, and how to use existing agents for optimal symptomatic treatment,” said Dr. McKeith. In order to understand this disorder more fully, “we need longitudinal studies of DLB cases from the prodromal stage to death and autopsy,” he added.
In many cases, said Dr. McKeith, patients with DLB have greater disability and a worse quality of life than patients with Alzheimer's dementia. Caregivers speaking during the question-and-answer sessions at the workshop stressed the burden that DLB places on families and the need for a better understanding of the phases of the disorder so that caregivers can plan ahead.
The NINDS draft recommendations advise capitalizing on the longitudinal cohort studies of late-life dementias, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) by enriching them with subjects with DLB risk factors, such as REM sleep behavior disorder; hyposmia; autonomic dysfunction; and non-amnestic mild cognitive impairment (MCI).
In the session on FTD and related tauopathies, speakers stressed the need to clarify the fundamental disease mechanisms associated with protein dysfunction. They discussed potential tau clearance agents, tau aggregation inhibitors, and agents that bind to extracellular forms of tau. They stressed the need to better understand the TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) proteinopathies. The draft recommendations ask, for example: Do TDP and FUS represent toxic, spreading disease proteins? Does loss of protein function play a significant role? Is intraneuronal progression unified across TDP-43 pathologies, and what is the sequence of events? What is the link between progranulin haploinsufficiency and the formation of TDP-43 inclusion pathology? Because progranulin is a secreted protein involved in wound healing and inflammation, progranulin insufficiency promotes neuroinflammation and loss of neurons. Progranulin haploinsufficiency is a major inherited cause of FTD, but how it causes neurodegeneration remains unknown.
The draft recommendations advise continued study of the normal functions of TDP-43 and FUS, and study of the normal function of progranulin, especially during the response to brain injury, as well as how haploinsufficiency leads to neurodegeneration.
“The biology of progranulin is very important to the recommendations that we're putting forth,” said William Seeley, MD, associate professor of neurology at UCSF and director of the UCSF Neurodegenerative Disease Brain Bank. Progranulin is promising as a potential target for therapy because it can be measured in the blood and cerebrospinal fluid, said Adam Boxer, MD, PhD, associate professor of neurology at UCSF, where he directs the Neurosciences Clinical Research Unit in the Sandler Neurosciences Center.
Commenting on dementia caused by human progranulin mutations, Stephen Strittmatter, MD, PhD — the Vincent Coates professor of neurology and professor of neurobiology at Yale University School of Medicine — said: “This is a loss-of-function condition.” To treat this dementia clinically, “increasing progranulin activity seems attainable,” he added. The challenge, he said, is how to develop medications for clinical use to increase progranulin activity. He noted that protein therapies delivered to the brain represent an attractive pathway, and should be tested. “We need to know the underlying cell biology and we need to have a model we can trust,” he said. Dr. Strittmatter's recent research in neurodegeneration has included identification of the glycoprotein sortilin as a high-affinity receptor for progranulin in frontotemporal lobar degeneration.
VASCULAR HEALTH INTERVENTIONS
The council recommended that researchers focus on enhancing the design of all trials of vascular health interventions to improve their applications to diverse populations (timeline: one to 10 years).
“Evidence exists that vascular health is critical to delaying onset of dementia,” according to the draft recommendations. Given that vascular processes may play a larger role in minority populations (such as African-Americans) because of the greater prevalence of many vascular risk factors, the draft document advises testing the biological mechanisms of dementias to see if they differ across populations.
The NINDS is already moving to reduce disparities in the US risk of stroke — and thus potentially to reduce vascular dementia. Compared with non-Hispanic whites, strokes disproportionately affect racial and ethnic minorities. Four research centers will receive $40 million in NINDS funding over five years to develop culturally tailored interventions designed to lower stroke risk among Americans in racial and ethnic minority populations. According to NINDS Deputy Director Walter J. Koroshetz, MD, “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.”
The NINDS draft recommendations note that a major task in reducing population disparities in the dementias is to address the many reasons for the low rate of research participation of minorities, including an inadequate connection with health systems; lower rates of screening and diagnosis; lower knowledge levels; alternative health beliefs; and distrust of research.
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