1. CONFIDENTIAL Pg 1 Alzheimer’s Disease International March 29, 2011 Kelly J. Murphy 1,2, Angela K. Troyer 1 & Liisa A.M. Galea 3 1 2 3 Cortisol & Cognition in Amnestic-Mild Cognitive Impairment

2. CONFIDENTIAL Pg 2 Conflict of Interest Disclosure Kelly Murphy, Ph.D. Angela Troyer, Ph.D. Liisa Galea, Ph.D. Has no real or apparent conflicts of interest to report.

3. Pg 3 Acknowledgements Triti Namiranian Angelina Polsinelli Nicole D’Souza Diana Smith Preeyam Parikha Morris Goldenberg Medical Research Endowment

4. Pg 4 Cortisol & Cognition Inverted U shaped function between cortisol levels (a main stress hormone) and memory performance Prolonged exposure to stress hormones results in decreased memory ability and hippocampal volume Google Image from nwlink.com For Review See: Lupien et al., Psychoneuroendocrinology 2005:30;225-242

5. Pg 5 Cortisol Elevated basal levels in moderate to severe level of disease No clear relationship between memory performance and cortisol level For update see: Gil-Bea et al., (2010) J Alzheimer’s Disease 22;829-838 No difference in basal levels (increased awakening levels?) Negative correlation between memory performance and cortisol level (inconsistent across tasks). Wolf et al., (2002) Psychoneuroendocrinology 27:777-789 Souza-Talarico et al., (2010) J Alzheimer’s Disease 19:839-848 Alzheimer’s DiseaseMCI

6. Pg 6 Study Questions Is there a change in cortisol response to challenge in MCI? Will sampling saliva on the same day as testing produce a more reliable association between cortisol and memory in MCI? Will a stressor influence memory behaviour differently in MCI? We attempted to answer these questions by sampling salivary cortisol both basally and across two test sessions. On the second test session we exogenously manipulated cortisol level with the application of a psychosocial stressor.

7. Pg 7 Participant Group Demographics Control (n=14) aMCI (n=14) Cohen’s d Age (yrs)75.3 (8.7)74.6 (8.0)0.08 Female: Male ratio7:75:9 Education (yrs)14.4 (3.5)14.9 (3.0)0.15 MMSE * 29.0 (1.0)27.7 (1.9)0.89 Vocabulary SS14.3 (2.5)13.3 (2.6)0.40 HADS – Depression2.6 (2.3) 0 HADS - Anxiety5.1 (3.8)5.6 (2.5)0.16 Mean scores with standard deviations in parentheses; *group differences p <.05. aMCI classification based after Petersen (2004) Journal of Internal Medicine 256:183-194.,

8. Pg 8 Basal Cortisol Circadian Fluctuations (no group differences) Error bars: 95% CI NC MCI

9. Pg 9 Memory Tests shoe violet table granite daisy boot chair stone rose slipper wood couch Episodic Memory Word List Learning Associative Memory Face-Name Spatial Working Memory

10. Pg 10 Cortisol sampling during test sessions Trier Social Stress Test (Kirshbaum et al., (1993) Neuropsychobiology 28:76-81) 1. Anticipation period2. Test period Session 2 10:10 a.m. (Anticipation) 10:30 a.m. (Test) 11:00 a.m. (30 min after challenge) ~11:30 a.m. (~60 min later). Psychosocial challenge – Session 2 Session 1 10:10 a.m. ~11:45 a.m. public speaking & mental arithmetic in front of an audience Google Image from superstock.comGoogle Image from inmagine.com

11. Pg 11 Cortisol level is elevated in MCI under test conditions Error bars: 95% CI NC MCI test

12. Pg 12 Challenge enhances episodic memory in controls and depresses it in MCI Error bars: 95% CI NC MCI

13. Pg 13 Negative impact of challenge also indicated in MCI for associative memory Error bars: 95% CI NC MCI

14. Pg 14 Summary of Findings Cortisol No differences in basal cortisol level (including awakening) MCI show greater increase in cortisol level from psychosocial stressor compared to controls Cognition Memory behavior can benefit from the immediate effects of a challenge in controls, but not in MCI. Cortisol Level & Cognitive Performance Level Inconsistent findings across tasks suggestive of an inverse relationship between memory performance and cortisol level in MCI.