The Nun Study: Past, Present and Future Kelvin O. Lim, M.D. Director, Nun Study Drs. T.J. and Ella M. Arneson Land-Grant Chair in Human Behavior Professor and Vice Chair Department of Psychiatry University of Minnesota

Outline A Brief History of the Nun Study Key Findings of the Nun Study Present Future

School Sisters of Notre Dame (SSND) International congregation of Roman Catholic sisters Founded in 1833 in Germany to teach poor girls Began in North America in 1847 Seven provinces in the United States

School Sisters of Notre Dame (SSND)

Sister Carmen to David Snowdon “No matter what you do, I want you to remember who these women are … I don’t want you to treat them as research subjects. Get to know them. …we treat them with the care and respect they deserve. We will expect nothing less from you.”

Nun Study Timeline 1986 – Study begun by David Snowdon in Mankato while at the University of Minnesota 1990 – Snowdon moves the Study to the Sanders-Brown Center for Aging at the University of Kentucky (1R01AG009862) 2008 October – Agreement signed by UKY, UMN and SSND to move study back to Minnesota

Unique Features of Nun Study Multiple evaluations over many years Extensive data from early life Homogeneity in living conditions, working conditions, lifestyle Brain donation is a requirement Follow-up easy – live in congregation Single cohort – 75 years old or older

SSND population strengths Dedicated research participants Sisters see the Study as their job Minimal attrition (98% for autopsy) Complete collection of data Study is done in partnership with the SSND Ideal for longitudinal study with multiple and demanding measures

Findings Idea Density Positive Emotions Infarcts

Autobiographical Essays at Entry to Convent Written on entry into the convent Instructed to write a short sketch of [her] life. “This account should not contain more than two to three hundred words and should be written on a single sheet of paper... include place of birth, parentage, interesting and edifying events of childhood, schools attended, influences that led to the convent, religious life, and outstanding events.”

Low and High Idea Density I was born in Eau Claire, Wis., on May 24, 1913 and was baptized in St. James Church. (ID 3.9) The happiest day of my life so far was my First Communion Day which was in June nineteen hundred and twenty when I was but eight years of age, and four years later in the same month I was confirmed by Bishop D.D. McGavick. (ID 8.6)

Idea Density and % with Alzheimer’s Disease pathology Snowdon et al., JAMA, 1996

Idea Density and number of neocortex lesions Snowdon et al., JAMA, 1996

Positive Emotions Coding system was developed for rating positive emotions Autobiographies were rated without knowledge of the status of the participant

Low Positive Emotion Example I was born on September 26, 1909, the eldest of seven children, five girls and two boys.... My candidate year was spent in the Motherhouse, teaching Chemistry and Second Year Latin at Notre Dame Institute. With God's grace, I intend to do my best for our Order, for the spread of religion and for my personal sanctification.

High Positive Emotion Example God started my life off well by bestowing upon me a grace of inestimable value.... The past year which I have spent as a candidate studying at Notre Dame College has been a very happy one. Now I look forward with eager joy to receiving the Holy Habit of Our Lady and to a life of union with Love Divine.

Survival and Positive Emotions Danner et al., J. Personality and Social Psychology, 2001

Influence of Infarcts on dementia Quantify size and location of infarcts throughout the brain Examined in those who met Neuropathologic Criteria for Alzheimer Disease

Influence of infarcts on dementia in subjects with AD pathology Snowdon et al., JAMA, 1997

Present Completed Waves 13 and 14 Complete the study – 21 of 678 Sisters remain Make the materials from the Nun Study an international scientific and teaching resource Perform analyses that take advantage of the longitudinal data Design the next generation of studies

Cognitive Reserve What characteristics are related to… –Lower risk of diagnosis & age of symptom onset –Slower progression of disease –Greater clinical resistance to pathology –Lower risk of death Genetic risk: APOE e4 / e2 Demographic factors: Age, Education, IQ Linguistic abilities

Nun Study Wave 13 sample (n=48) –Sisters aged 75+ years followed since 1991 –Sisters who completed 13 evaluations (approx 17 yrs) Semantic space: verbal fluency measures –How many animals can you think of without “switching” subcategory (pets, zoo, farm, safari, etc.) Semantic space at baseline was related to –Significantly lower risk of dementia at follow-up –Significantly slower rate of decline over time * All analyses included age as a covariate Semantic Space - Risk of Dementia & Rate of Cognitive Decline (Hemmy)

Study Design Goal “A study that any Sister can be a participant”

Goals: –Characterize a younger cohort of SSNDs –Open to any Sister –Provide pilot data (time 1) for future work –Longitudinal follow-up Data collection –Demographics & genetics –Medical history & health risk factors –Cognition –Mood, personality, & psychological resiliency –Activity level, physical function, & quality of life UMN-SSND Foundation Study

Future Shift in focus to pre-disease state Identify early predictors that could serve as intervention targets Earlier age: years old Longitudinal

Center for Magnetic Resonance Research Human 3 Tesla (2) 4 Tesla 7 Tesla (2) 10.5 Tesla PET/CT Animal 9.4 Tesla 16.4 Tesla

Studying the “Vascular” Effect Infarcts are a binary determination Scales of vascular risk (diabetes, smoking, HTN) have limitations Need for a continuous, quantitative measure of tissue vulnerability Combine this with other measures of brain pathology (amyloid,tau)

Midlife Risk Factors for Dementia Hypertension Diabetes Obesity Smoking Dyslipidemia

Artery-Arterioles-Capillaries- Venules-Veins

CO 2 is a potent vasodilator Acetazolamide –Carbonic anhydrase inhibitor –CO 2 + H 2 O >> CA >> H 2 CO 3 >> H+ + HCO 3 Non invasive CO 2 manipulation –Breathhold –Increased CO 2 in air mixture –Control of end tidal CO 2

Control End Tidal CO 2

BOLD Signal Change in Response to PCO 2 change

Cerebrovascular Reactivity

PET Amyloid imaging (AV45) Clark et al., JAMA, 2011

Acknowledgements School Sisters of Notre Dame David Snowdon and team Funding –National Institutes of Aging –UMN – Academic Health Center –UMN – Institute for Translational Neuroscience –Mohl Estate Gift

That you may have life to the full