The Penn Medicine Brain Bank, established in 1985 by John Q. Trojanowski, MD, PhD, then an early-career faculty member in Pathology and Laboratory Medicine, has been crucial to discoveries over the past four decades. More than 2,000 families have donated specimens from deceased loved ones with dementia, in hopes of finding answers that will help others with these devastating diseases.
Edward Lee, MD, PhD, the co-director of Penn’s Institute on Aging and leader of the brain bank, discussed how the brain bank helps families and researchers to meaningfully support discovery and the drive toward better treatments for neurodegenerative diseases.
How and where do you get specimens for the brain bank?
Edward Lee, MD, PhD, co-director of Penn’s Institute on Aging and leader of the Penn Medicine brain bank.
We collaborate with investigators in the departments of Neurology, Medicine, Psychiatry, and others who treat and do clinical research with patients with a variety of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, frontotemporal degeneration (FTD), amyotrophic lateral sclerosis (ALS), and others. These patients are highly phenotyped, meaning that research-quality data including neuroimaging, neuropsychologic, genetic, biofluid, and other measures are obtained over the patient’s disease course.
These patients are offered a research brain autopsy, which is important because sometimes a patient’s symptoms can be caused by one of several different underlying molecular processes. We perform a comprehensive neuropathologic analysis, which means we look at the tissue under the microscope using a variety of specific stains so that we can diagnose the various neurodegenerative diseases that contributed to their symptoms during life. For example, we have found that for individuals with Alzheimer’s disease, less than a third only have Alzheimer’s disease neuropathologic change (meaning beta-amyloid plaques and neurofibrillary tangles). Other neurodegenerative disease changes, such as protein aggregates made of alpha-synuclein or TDP-43, and cerebrovascular disease are also extremely common. Understanding this heterogeneity is probably very important for future therapy development and clinical trial design.
What are the goals of the brain bank?
An important outcome is providing families and caregivers a comprehensive and final diagnosis for the neurodegenerative disease that affected their loved ones. Because some neurologic disease syndromes can be associated with a variety of underlying disease processes or pathologies, the only way to know for certain what is causing some of these syndromes is to do a brain autopsy. This knowledge may have implications for family members, as different neurodegenerative diseases are associated with variable genetic risk.
It also provides patients, families, and caregivers the knowledge that their brain donation is contributing to our fundamental understanding of these devastating diseases. On the research side, these brain examinations are linked to the deep clinical phenotyping that is done by our clinical colleagues. Being able to link data collected during life with the final autopsy diagnosis is helping us develop better biomarkers for disease. These tissues are also used for basic biochemical and molecular analyses in order to better understand the fundamental mechanisms that cause neurodegeneration.
How have these brain samples helped researchers to better understand neurodegenerative disease?
In 1991, using samples from the brain bank, Virginia M.-Y. Lee purified the protein tau and identified it as the source of neurofibrillary tangles in the brain, and in 2006 the research team purified and identified TDP-43 as the protein that aggregates in ALS and frontotemporal lobar degeneration. Tissue from this brain bank was also used to demonstrate that alpha-synuclein is the protein that comprises inclusions in Parkinson’s disease and Lewy body disease.
The demonstration that tau is the protein that comprises neurofibrillary tangles, and that TDP-43 is the protein that comprises inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis, were both watershed moments. These two proteins are still considered some of the most important targets if we are going to treat the underlying causes of Alzheimer’s disease and related dementias.
Additional discoveries include the phenomenon of cell-to-cell transmission of neurodegenerative disease pathologies. It turns out that proteins such as tau, TDP-43, alpha-synuclein, and others seem to spread through the brain’s connections (the neural connectome). This suggests that blocking this spread can be a therapy. This work, done by Trojanowski and Lee with colleagues such as Penn pathologists Kelvin Luk, PhD, and Silvia Porta, PhD, is heavily dependent on using brain bank tissues as a source of protein aggregates (or “seeds”) which are used and analyzed in various experimental models and assays.
The brain bank has been important in recent work done in my laboratory where we have identified a novel form of neurodegenerative disease called vacuolar tauopathy. Together with my Pathology colleague Vivianna Van Deerlin, MD, PhD, we found that vacuolar tauopathy was caused by a mutation in a gene called VCP. We are now trying to target VCP for the treatment of Alzheimer’s disease and related dementias.
How does Penn Medicine’s brain bank compare to similar endeavors elsewhere?
We have received well over 2,000 brain donations, a total that represents the hard work and dedication of a large group of collaborators over 35+ years. Trojanowski led this team since the days when we barely had criteria for diagnosing Alzheimer’s disease to now, where we can identify the main causes of disease in virtually every case we examine. Other brain banks do exist and each has a different focus or emphasis. For example, there are brain banks that house tissues from community cohorts, which are a better reflection of the epidemiology of neurodegenerative disease.
The focus of our brain bank is the study across diverse neurodegenerative diseases including dementias, movement disorders, and other rare neurodegenerative disease conditions. This has required an immense amount of coordination with collaborators who span different divisions and departments. One of Trojanowski’s greatest feats was his ability to bring these diverse stakeholders together which has led to the realization that these different neurodegenerative diseases share a lot of common features with each other. For example, at the outset, it was not clearly recognized that diseases such as Parkinson’s disease and ALS affected cognitive function. These were thought to be purely motor or movement disorders. However, astute Penn clinicians were recognizing that these patients were having cognitive issues, and this was solidified when we were able examine brain bank tissues and show that the spread of disease is much wider than originally appreciated.
What is your role with the brain bank?
I began working with Trojanowski in the brain bank as a graduate student, helping process tissue and trying to diagnose cases. I now lead the brain bank and help administer its operation together with two colleagues who have been working in the brain bank for decades, Terry Schuck and John Robinson. Helping to lead the brain bank with Trojanowski also afforded me the pleasure of interacting with collaborators, and to provide valuable information to families and caregivers. I have met with many families to discuss what we see, and I hope this provides them with some comfort and finality about their loved ones. Most importantly, I hope it gives them hope that by continuing these studies, we will enhance our understanding of these devastating diseases with an eye towards improved diagnostics and therapies.
Changing the picture for dementia
Read more in this collection of stories:
- Progress after decades of research in dementia: The domino chain of discovery is finally creating a path to a cure for Alzheimer’s and related diseases of the brain. Foundational discoveries at Penn were crucial to arriving at this moment
- A legacy of love and learning: Virginia-M.Y. Lee’s life in science, together with her late partner John Q. Trojanowski, is a testament to her dedication to understanding the brain.
- The connection to care: With innovative memory disorder drugs on the horizon, Penn Medicine is working to address the challenges patients and families still face, from diagnosis, to treatment, to supportive care.