Major imaging initiative to shed light on little known brain disease

Howard Rosen, MD, UCSF associate professor of neurology

UCSF scientists have received a $10 million grant from the National Institutes of Health to embark on a major neuroimaging study of a degenerative brain disease that is at least as common as Alzheimer’s disease in people under age 60.

Howard Rosen, MD, UCSF associate professor of neurology

UCSF scientists have received a $10 million grant from the National Institutes of Health to embark on a major neuroimaging study of a degenerative brain disease that is at least as common as Alzheimer’s disease in people under age 60.

The fatal disease, known as frontotemporal dementia, affects decision-making, behavior, emotion and language. It gradually destroys the ability to behave in a socially appropriate manner, to empathize with others, learn, reason, make judgments, communicate and carry out daily activities. Because of the changes in personality that occur, the disease is perplexing for loved ones before a diagnosis is made and remains a particularly distressing disorder to manage. Some patients, as a result of their disease, mishandle money, commit adultery and carry out criminal behaviors, such as embezzlement.

Scientists have identified several mutated genes associated with the various forms of the disease, each of which in its own way leads to destruction of nerve cells in the frontal and temporal lobes of the brain. However, there are no therapies targeting the proteins the gene’s produce, though a multi-institutional trial is under way to test a drug that targets some of the disease’s symptoms.

The current study, led by Howard Rosen, MD, UCSF associate professor of neurology, is intended to determine how to use new imaging techniques to illuminate the changes that occur in the brain as the disease progresses. This information will enable scientists to identify biomarkers for diagnosis and, most importantly, track the impact of experimental drugs.

“Having accurate measures of the normal rates of change in FTD will be critical for planning future medication trials that will use imaging as an outcome,” says Rosen.

“While cognitive testing scores vary from day to day due to factors such as sleep quality and medication use, imaging studies measure brain structure and function precisely. They can reveal when a drug has slowed or reversed the brain shrinkage that would normally occur.”

UCSF and the Mayo Clinic in Rochester, Minnesota, will collaborate to enroll 120 FTD patients, as well as about 80 people who will serve as cognitively normal “controls.” Each participant will be followed for one and a half years with neurological examinations, cognitive and behavioral assessments, and brain imaging. Neurologist David Knopman, MD, will lead the Mayo team.

FTD is diagnosed by an assessment of a patient’s clinical history, and by neurological, cognitive and behavioral evaluations. Blood tests and neuroimaging supplement the process, but primarily help rule out other neurological disorders and provide additional evidence for FTD, rather than reveal a definitive diagnosis.

The new imaging project, which will begin in early 2010, will obtain several different types of images in each patient. Some will be obtained through structural magnetic resonance imaging, which measures the size and shape of the brain, and positron emission tomography, which examines aspects of metabolism, such as glucose consumption. Others will be obtained through promising new MRI techniques, including imaging to measure the blood content in the brain, and imaging to determine the integrity of the neural wiring, or axons, connecting various parts of the brain, using a technique called diffusion tensor imaging.

“It is possible that one or both of these techniques could replace PET scanning, which is expensive and requires exposure to radiation,” says Rosen. “This would lower the cost of clinical trials and make it possible for more patients to enroll because MRI scanners are commonly available.”

The study will investigate whether a combination of images, such as structural MRI, PET and DTI, will provide a better explanation of how a patient is doing than any one of these image types alone. It also will include serial assessments of the chemistry in the blood and cerebrospinal fluid the surrounds the brain, to see how these relate to changes in the brain images.

The new study, known as the Frontotemporal Lobar Degeneration Neuroimaging Initiative, takes advantage of the infrastructure developed for another major NIH-funded study of which UCSF is a leader, known as the Alzheimer’s Disease Neuroimaging Initiative, says Rosen.

The ADNI, begun in 2004, established procedures that make it possible to obtain comparable images at different centers, and has established procedures for ensuring high quality data. This year, the ADNI made a significant step forward in developing a test to help diagnose the beginning stages of Alzheimer’s disease sooner and more accurately by measuring levels of two biomarkers—tau and beta-amyloid proteins—in cerebrospinal fluid.

The FTLDNI is funded primarily by the National Institute on Aging and is co-funded by the National Institute of Neurological Disorders and Stroke.

Related links:

UCSF Memory and Aging Center – spotlight on FTD
http://memory.ucsf.edu/ftd/

UCSF Memory and Aging Center
http://memory.ucsf.edu/

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