Lea T. Grinberg, M.D., Ph.D.
Memory and Aging Center, University of California at San Francisco
Recipient of a 2009 New Investigator Research Grant
Banking on Understanding the Aging Brain
Neuropathologist Lea T. Grinberg, M.D., Ph.D., and her colleagues at Brazil's University of Sao Paulo Medical School knew that the Sao Paulo Autopsy Service held a potential gold mine of information for understanding the aging brain. The autopsy service, operated at the medical school since 1931, performs legally required postmortem examination for any of Sao Paulo's 11 million residents who die naturally but whose exact cause of death has not been determined.
"The broad legal mandate underpinning the Sao Paulo Autopsy Service offers a uniquely powerful scope of biological information about the aging brain. There are excellent brain banks worldwide, but they lack samples from donors who die without dementia. The autopsy service casts a broad net over the whole population. About 60 percent of Sao Paulo residents who die undergo examination through autopsy service."
In 2003, Dr. Grinberg and her colleagues established the Brain Bank of the Brazilian Aging Brain Study Group to tap into that biological powerhouse. The Brazilian Brain Bank has two overarching goals: (1) to develop a large collection of donated brains and other body tissues from individuals aged 50 and older who die with and without dementia and (2) to correlate physical autopsy findings with a person's cognitive status, day-to-day function, and dementia risk factors as reported by the next of kin or another knowledgeable informant.
By 2007, the Brazilian Brain Bank included samples and data from more than 1,600 individuals. Today, the archive includes samples from more than 2,500 donors. These samples support studies under way at over a dozen research laboratories. One of the most significant insights to date validates a result noted in more limited study populations—not everyone with typical Alzheimer's brain changes develops dementia. In Dr. Grinberg's Brain Bank drawn from the entire population of Sao Paulo, about 25 percent of samples with pathology levels associated with Alzheimer's were from donors who showed no symptoms of the disease.
That finding confirms the importance of one of the most pressing questions in Alzheimer's research: Why do some people—and not others—develop the disease?
Is Ethnic Background a Factor in Who Gets Alzheimer's?
As the Brazilian Brain Bank grew and began to yield data relevant to key questions, Dr. Grinberg sought additional support for the initiative. Like millions of annual visitors to the Alzheimer's Association Web site, Dr. Grinberg found the Alzheimer's Association through Google—she searched on “Alzheimer's research funding" and discovered our International Research Grant Program.
What she learned inspired her to apply for a 2009 New Investigator Research Grant to explore whether individuals of distinct ethnic backgrounds have different risks for Alzheimer's, and whether they have different levels of Alzheimer's pathology associated with the same degree of symptoms. Her proposal to explore Multi-ethnic Neuropathological Comparison of Alzheimer's Disease: Focus on Control Cases was selected for funding after it scored among the 84 projects ranked highest by peer reviewers in an extremely competitive field of 815 applications.
"I was thrilled to find such an extensive grants program that funded investigators worldwide," says Dr. Grinberg. "I thought the peer review process was extremely rigorous but very fair. I now serve as a peer reviewer for new grant applicants."
With Dr. Grinberg's Alzheimer's Association grant, her team examines brain tissue from more than 500 Brain Bank participants to assess hallmark Alzheimer's pathologies—plaques (abnormal deposits of beta-amyloid protein) and tangles (abnormal deposits of tau protein). The researchers also assess levels of abnormal protein deposits associated with other types of dementia. In addition, investigators evaluate the health of brain blood vessels by documenting the presence of clots and other blood vessel lesions, the amount of beta-amyloid inside vessels, and bleeding in the brain. The study will determine whether the number, type, and distribution of these pathological benchmarks differ among donors of African, southern European and Asian ancestry. Individuals are classified based on 128 small DNA variations widely accepted as markers of ethnic background. Dr. Grinberg's colleague David Schlesinger, M.D., Ph.D., conducts this genetic analysis.
The team is also exploring how ethnic background may influence the impact of Alzheimer's risk factors, including age, sex, education, cigarette smoking, alcohol abuse, high blood pressure, diabetes, stroke, heart disease and major depression. The project also documents each individual's status for the apolipoprotein E (APOE) gene. The APOE-ε4 variation is the strongest known risk gene for Alzheimer's. Those who have it experience a significantly increased likelihood—but not a certainty—of developing Alzheimer's disease. Understanding why some individuals with APOE-ε4 develop Alzheimer's and others don't is a core thread in solving the mystery of who gets Alzheimer's.
Preliminary data from Dr. Grinberg's Association-funded work suggest that African ancestry may be a risk factor for Alzheimer's, even when the analysis excludes the influence of vascular changes.
"If this link holds up as we complete our study, it may suggest that there's a yet-to-be discovered Alzheimer's risk gene that occurs more frequently in those of African descent," says Dr. Grinberg.
Protocol Embraces Broad Biological Goals and Humane Vision
Under Brazilian Brain Bank protocol, when the body of someone age 50 or older arrives for an autopsy, trained nurses explain the goals of the initiative and ask the next of kin for permission to include results and informant input in the sample archive and electronic database.
When permission is granted, the brain and heart are removed from the body and digitally photographed. Both organs undergo thorough overall assessment and extensive microscopic analysis. The brain examination documents levels of beta-amyloid and tau as well as signature proteins linked to other types of dementia.
Researchers also remove the carotid arteries and the circle of Willis, a ring of arteries at the base of the brain that supplies more than 80 percent of the brain's oxygenated blood. They evaluate the amount of atherosclerosis in each artery and microscopically examine its most obstructed area. In addition, they obtain samples of kidney tissue, cerebrospinal fluid (CSF), blood and DNA.
The breadth of these biological samples—especially the heart and vascular tissues—is another unique strength of this "brain" bank. Understanding the connection between cardiovascular changes and Alzheimer's—and how each condition may fuel the damage caused by the other—has enormous implications for prevention and treatment.
Biological changes linked to dementia take on meaning when researchers understand how they affect memory, personality, behavior and day-to-day activity. Either during the autopsy or later, trained nurses interview the informant in a private room, asking questions designed to elicit information about the donor's memory, thinking skills, behavior and function. The interview also covers demographics, medications, medical history, cardiovascular risk factors and family history. Researchers verify informant input in medical records when they're available.
The Brain Bank stores all samples and data anonymously under numbered codes, but there's a mechanism to link specimens with donors should a legal or public health need arise.
A Personal Investment in Progress
Dr. Grinberg's strong professional interest in Alzheimer's disease is matched by a personal investment in advancing the field.
"My father's mother has had Alzheimer's disease for 18 years," Dr. Grinberg notes. "She still lives with my family. Even though she stopped speaking and no longer recognized us after three years, she still eats dinner with our family."
"My personal experience makes me so grateful that the Alzheimer's Association mission includes caregiving as well as research," Dr. Grinberg says. "The information and support that the Association provides on its Web site and through its chapters—there's nothing else like it. And there's such a huge need."
Dr. Grinberg gained first-hand experience of our local Alzheimer's Association chapters through the Alzheimer's Association of Northern California and Nevada. She recently moved from the University of Sao Paulo Medical School to the University of California at San Francisco (UCSF) to join the staff of the UCSF Neurodegenerative Disease Brain Bank. Her move is one aspect of several collaborative initiatives by UCSF and the University of Sao Paulo Medical School to combine their organizational strengths and expertise to advance knowledge of the aging brain. Dr. Grinberg's special expertise is in frontotemporal lobar degeneration, one of UCSF's research strengths and the area in which she focused when she earned her Ph.D. degree in 2006.
At UCSF, Dr. Grinberg conducts neuropathological studies on the earliest stages of diseases like Alzheimer's that cause brain cells to deteriorate and die. The research aims to pinpoint which brain areas are first affected by each disease and to identify the mechanisms underlying the vulnerability of those specific regions. Despite significant progress toward understanding hallmark lesions of Alzheimer's and related disorders, it's not yet understood precisely which areas are vulnerable to the earliest biological changes caused by each disease—or why this vulnerability exists. Answering these questions may help identify new biological markers of disease, improve diagnosis and suggest novel therapeutic targets.
As part of her cross-organizational collaboration, Dr. Grinberg continues to analyze Brazilian Brain Bank tissue samples in her lab at UCSF. Her passion for sharing knowledge extends to nonspecialists as well as across borders. At her lab, she recently hosted a visit by seven guests from the Alzheimer's Association of Northern California and Nevada.
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