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A powerful devotion

At age 98, Sister Celeste Glovka is one of the last living participants of the original Nun Study at the School Sisters of Notre Dame's Mankato Province. The Nun Study began at the University in 1986. (Photo: Scott Streble)

The School Sisters of Notre Dame and the University make it their mission to break new ground in a famed study of aging and Alzheimer’s disease

By Jack El-Hai

On shelves behind a locked door in the basement of the University of Minnesota’s Diehl Hall sit more than 600 ordinary-looking containers carefully coded with identifying numbers that catalog their extraordinary contents: the autopsied brains of the School Sisters of Notre Dame who have died and left their primary organ to an ambitious investigation known as the Nun Study.

During the late 1990s and early 2000s, the Nun Study — a longitudinal examination of the health and lives of hundreds of the sisters — was all over the news. The study hit the cover of Time magazine and spawned the best-selling book Aging with Grace, by the study’s founder, David Snowdon, M.D. Using medical observation of the sisters (all age 75 and older) and incorporating scrutiny of their use of language in their written diaries with autopsies of their brains after death, the project broke new ground in the study of aging and the risk factors for Alzheimer’s disease. In particular, the study is well known for identifying traits that dampen or heighten the risk of Alzheimer’s and other cognitive disabilities of old age.

Of its 678 original subjects, only a couple dozen of the sisters are still living. Just as the passage of 25 years has changed the study group, time is transforming the Nun Study. The study began as a pilot project at the University of Minnesota in 1986, expanded and moved to the University of Kentucky when Snowdon relocated there four years later, and returned to Minnesota when he retired in 2008. It’s now under the direction of Kelvin Lim, M.D., an energetic and loquacious professor in the Department of Psychiatry, who is guiding the study into a new phase.

To outsiders, much about the study may still look the same as it always has. In 2009 researchers administered the 13th follow-up on the living sisters — examining brain health and the effects of aging — and the 14th round is scheduled for this spring. Each follow-up adds to the formidable body of information collected on this remarkable group of women, but by the end of the year, investigators will start collecting new information. Since the study returned to the University, researchers have been planning how they will ramp up its value while applying the technologies and talents — particularly in gene sequencing and high-field imaging — for which the institution is known.

At age 95, Sister Mary Louis Pihaley — another original Nun Study participant — is a sharp conversationalist. (Photo: Scott Streble)

The reappraisal began with a Nun Study symposium hosted by the University in 2009, which helped Lim and his colleagues determine the project’s future direction. “The attendees were leading figures in the study of Alzheimer’s and aging — they all presented here,” Lim says. “There were sessions devoted to researchers who were associated with the study in the past. From all this, we got input that helped us form our plans.” Work in the Nun Study has since flowed in two directions: activities that make innovative use of the information gathered during the previous quartercentury along with the brains of the deceased sisters that continue to arrive, and planning for future work that will carry the study in new directions.

In the brain room

When School Sisters of Notre Dame members tour the University labs and offices that house the study, they often pause for prayer in the Diehl Hall room where the brains are stored.

“They’re awed to see … their departed in one place, and they often tear up because they knew the women whose brains rest here,” says Nun Study investigator Karen Santa Cruz, M.D., a University of Minnesota pathologist and assistant professor of neurosurgery. “This room is the permanent home of these brains, at least until the study is completed and the tissues are returned to the School Sisters. We expect that won’t be for decades.” The human presence of these deceased women is real, says Santa Cruz, who admits that she is reluctant to learn the names of donating sisters when she studies the brain tissue samples.

The preservation of these brains points to one of many unique features of the Nun Study. “Part of what makes this study groundbreaking is that the participating sisters all agreed to make the brain donations, which was previously unheard of,” Lim observes. “One sister early in the study said, ‘In heaven I won’t need my brain — you can have it.’ Our actual donation rate has been 98 percent, a remarkable thing found in no other longitudinal study.”

The Nun Study ideally obtains the brains within six hours of death. Earlier in the study, the organs were fixed in formalin. The brains are now divided in half, with one section going into the traditional formalin preservative and the other conserved in frigid liquid nitrogen, which allows for biochemical testing and the isolation of such materials as DNA and RNA. In a laboratory down the hall from the brain room, technicians slice the brain tissue into thin ribbons and perform the staining that identifies the tangles and plaques strongly associated with Alzheimer’s disease. They can also search the samples for neurodegeneration and specific proteins indicative of changes in the brain.

From these samples, Nun Study researchers have prepared thousands of slides, revealing that about half of the sisters’ brains showed signs of Alzheimer’s at death. Paired with cognitive tests that the participating sisters have undergone for the past two decades, these brain images offer intriguing avenues of study. Santa Cruz is especially interested in a small number of sisters who showed no cognitive symptoms of Alzheimer’s, yet whose brains were full of the telltale tangles and plaques. How did these women resist dementia and memory loss? “It’s incredibly rare and not normal,” Santa Cruz says. She has not yet found the answer, but the wealth of pathological data available from the brains may suggest a solution to the puzzle in the future.

The University will digitally scan the brain slides to share with researchers around the world via the Internet as part of an effort to pool information with far-flung researchers of the brain and aging, including those involved in other large longitudinal studies. They plan on joining forces with such ongoing projects as the Kuakini Honolulu-Asia Aging Study and the Seattle Longitudinal Study at the University of Washington, both of which have gathered information on dementia and other brain pathologies.

“We’re establishing relationships with those other studies because of the great potential for sharing scientific information and resources,” says Laura Hemmy, Ph.D., a researcher in geriatric neuropsychiatry who serves as the Nun Study’s assistant director.

Sisters Celeste Glovka, Mary Martin Tobias, and Mary Louis Pihaley. (Photo: Scott Streble)

A unique commitment to science

The University’s interest in sharing Nun Study data means a great deal to School Sisters of Notre Dame members. “We want to contribute to the world community through education — that’s our ministry,” explains Charlene Zeisset, M.D., a St. Louis-based internist and sister who serves as the order’s liaison with the Nun Study investigators.

“And we always speak of education in the broadest sense, such as serving and administering to others. We’re very committed to collaboration. So when we see that the researchers of the Nun Study are working with other researchers following similar paths, that strikes a chord in us.” Many sisters believe that the study gives them a way to continue teaching beyond death.

Their educational mission makes the sisters highly involved participants, which adds to the study’s distinctiveness. (Strictly speaking, the sisters are not nuns because they are not cloistered, but they agree that the “Nun Study” name shouldn’t change.) When Snowdon retired and the University of Kentucky appeared unwilling to carry on the study, for example, the School Sisters of Notre Dame put out a call for proposals to keep it going. Members of the order made site visits to institutions that responded with interest.

The order now considers the study a vital part of its mission, an expression of the group’s commitment to medicine and science, which has led to an unusual relationship with the investigators that both sides value. Although the North American members of the School Sisters of Notre Dame are homogeneous, unusually healthy in their lifestyle (they don’t smoke or drink), and thus not representative of the population as a whole, they bring the spectacular advantages of their dedication to the project and motivation to participate.

“It is better to have participants who are interested in the issues raised by the study,” Lim says. “The 98 percent brain donation rate speaks volumes and generates the marvel and envy of my colleagues.”

No one would call the sisters passive in their participation. “We’re always looking for a personal relationship with the researchers: news of what’s happening in the study, what excites the investigators, what makes them want to keep working,” Zeisset says. And the interest flows both ways.

“They’re compelling people,” says Hemmy, “especially when you meet them and learn about their order. They work together as a group and act. Their personal dedication is what makes them different from other study participants.”

Santa Cruz agrees: “They’re special because they care so much.”

Sisters Mary Louis Pihaley and Celeste Glovka. (Photo: Scott Streble)

Planning for a new phase

The Nun Study will depend on that level of commitment as it shifts into the next phase, which will use new technologies to focus on health factors unexamined in earlier years. While the first decades of the study concentrated on the risk factors associated with the onset of Alzheimer’s disease, investigators in the years ahead will examine the factors that lead to a host of neurological disorders, including Parkinson’s disease and multiple sclerosis.

“The idea is to find the difference between healthy neurological aging and compromised neurological aging,” says Harry Orr, Ph.D., professor in the Department of Laboratory Medicine and Pathology and director of the Institute for Translational Neuroscience, which provides an administrative home for the Nun Study. “There’s a whole group of research approaches available now for us to incorporate into the study that were not even envisioned in the 1980s and ’90s. They center around two areas: genetics and the sequencing of the human genome, and applying [the latest in] magnetic resonance imaging. The latter approach is one area in which the University really distinguishes itself,” adds Orr.

In addition, the new phase “will examine biomarkers that identify the onset of a range of conditions including heart disease and diabetes,” Lim says. “Midlife is where that whole process begins, and you want to start there when you follow people over time.”

Because many of the sisters weren’t involved in the first part of the Nun Study, which limited participation to elderly members of the order, the investigators want to open the next stage to all interested North American sisters. A recent web survey of potential participants — in which 490 sisters, mostly women in their 60s and 70s, took part — indicated that 87 percent hoped to help in the study and most stated their willingness to undertake all of the health and cognitive tests listed in the survey. These include such invasive testing procedures as skin biopsies and lumbar punctures. Eighty-four percent expressed their readiness to participate in the study for 10 years or longer, and 75 percent said they would donate their brains following their death.

Says Orr, “We can use this very important resource — the sisters — to affect research across many areas of human brain aging and disease.” Enlightening results are sure to follow.

Jack El-Hai is the author of The Lobotomist: A Maverick Medical Genius and His Tragic Quest to Rid the World of Mental Illness.

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