9/26/2016 Natural History of Cognitive Changes Across the - PDF document

9/26/2016 Natural History of Cognitive Changes Across the DISCLOSURES Menopause Transition • None Pauline M. Maki, PhD Professor of Psychiatry and Psychology University of Illinois at Chicago OBJECTIVES OBJECTIVES 1. Understand cognitive complaints and cognitive function 1. Understand cognitive complaints and cognitive function across menopause stages across menopause stages 2. Understand the role of vasomotor symptoms (VMS) on 2. Understand the role of vasomotor symptoms (VMS) on cognitive changes across the menopause cognitive changes across the menopause 3. Describe the “treated history” of cognitive changes across 3. Describe the “treated history” of cognitive changes across the menopausal transition. the menopausal transition. 1

9/26/2016 Memory declines are the second most frequent symptom In the SWAN, memory decline was the third most frequent symptom. among women in the Pan Asia Menopause Study 7899 healthy women from a multi-ethnic 9 Ethnic Asian groups cohort n =977 40–55 Years of Age 2 nd most frequent symptom among early perimenopausal women Haines CJ, Xing SM, Park KH, Holinka CF, Ausmanas MK. Prevalence of menopausal symptoms in different ethnic groups of Asian women and responsiveness to therapy with three doses of conjugated estrogens/medroxyprogesterone acetate: the Pan-Asia Menopause (PAM) study. Maturitas. 2005 Dec 31;52(3):264-76. 6 Adapted from Gold et al. Am J Epidemiol Vol. 152, No. 5, 2000. Complaints of forgetfulness increase during the More severe memory complaints are associated with worse menopausal transition even after controlling for age. performance on memory tests. n = 68 Gold EB et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol. Drogos LL, Rubin LH, Geller SE, Banuvar S, Shulman LP, Maki PM. Objective cognitive performance is related to subjective memory complaints in midlife women with 2000 ; 152, 463-73 . moderate to severe vasomotor symptoms. Menopause. 2013;20(12):1236-1242. 2

9/26/2016 Memory performance worsens during the perimenopause even after controlling for age Penn Ovarian Aging Study Subjective memory complaints have also been shown to relate to scores on tests of attention in midlife women Drogos LL, Rubin LH, Geller SE, Banuvar S, Shulman LP, Maki PM. Objective cognitive performance is related to subjective memory complaints in midlife women with moderate to severe vasomotor symptoms. Menopause. 2013;20(12):1236-1242. n = 403 followed for 14 years Epperson CN, Sammel MD, Freeman EW. Menopause effects on verbal memory: findings from a longitudinal community cohort. J Clin Endocrinol Metab. Sep Weber MT, Mapstone M, Staskiewicz J, Maki PM. Reconciling subjective memory complaints with objective memory performance in the menopausal transition. Menopause . 2013;98(9):3829-3838. 2012;19:735-741 Memory, fine motor skills and attention/working memory/executive function is lower in the 12 months Endocrine changes around the FMP after the FMP n = 117 n = 1216 Weber, M., Rubin, L.H., Maki, P.M. Cognition in the perimenopause: The effect of transition stage. Menopause. 2013;20(5):511-517 Randolph et al. Change in Follicle-Stimulating Hormone and Estradiol Across the Menopausal Transition: Effect of Age at the Final Menstrual Period J Clin Endocrinol Metab , March 2011, 96(3):746–754 3

9/26/2016 Memory performance is unrelated to reported vasomotor symptoms OBJECTIVES • Ford N, Slade P, Butler G. An absence of evidence linking perceived memory 1. Understand cognitive complaints and cognitive function problems to the menopause. Br J Gen Pract . 2004;54(503):434-8. across menopause stages • Polo-Kantola P, Erkkola R. Sleep and the menopause. J Br Menopause Soc . 2004;10(4):145-50. • LeBlanc ES, Neiss MB, Carello PE, Samuels MH, Janowsky JS. Hot flashes 2. Understand the role of vasomotor symptoms (VMS) on and estrogen therapy do not influence cognition in early menopausal women. cognitive changes across the menopause Menopause . 2007;14(2):191-202. • Maki PM, Drogos LL, Rubin LH, et al. Objective hot flashes are negatively related to verbal memory performance in midlife women. Menopause. 3. Describe the “treated history” of cognitive changes across 2008;15(5):848-856. • Greendale GA, Wight RG, Huang MH, et al. Menopause-associated symptoms the menopausal transition. and cognitive performance: results from the Study of Women's Health Across the Nation. Am J Epidemiol. 2010;171(11):1214-1224. Measuring Physiologic VMS Objectively with Ambulatory Validation of monitor-measured VMS: Placebo effect is not Monitors evident when VMS are measured on monitors Subjective • Biolog Skin Conductance Monitor 25 Baseline 20 1-year 15 • Objective hot flash defined as 10 5 a 2 mmho increase in skin 0 conductance across a 30 Placebo Red Clover Black Cohosh Prempro second period Objective • Button press used for 25 Baseline 20 1-year subjective recognition of hot 15 10 flash 5 0 Placebo Red Clover Black Cohosh Prempro Maki PM, et al. Menopause. 2009;16(6):1167-77. See also: Carpenter JS, et al. Oncologist. 2007;12(1):124-135. Walega DR et al. Menopause. 2014. 4

9/26/2016 Objective VMS are associated with worse verbal Women report less than 60% of monitor-measured VMS memory (score adjusted for other significant predictors) (score adjusted for other significant predictors) 6 6 5 5 29 midlife women (mean 4 4 age = 53 y) with Delayed Paragraph Recall Delayed Paragraph Recall 3 3 moderate to severe hot flashes 2 2 1 1 Number of hours of 0 0 sleep independently -1 -1 predicted worse memory -2 -2 -3 -3 -4 -4 -5 -5 -6 -6 -6 -6 -5 -5 -4 -4 -3 -3 -2 -2 -1 -1 0 0 1 1 2 2 3 3 4 4 5 5 6 6 Total Number of Objective Hot Flashes during Sleeping Hours Total Number of Objective Hot Flashes during Sleeping Hours Maki PM, Drogos LL, Rubin LH, et al. Objective hot flashes are negatively related to verbal memory performance in midlife women. Menopause. 2008;15(5):848-856. Maki PM, Drogos LL, Rubin LH, et al. Objective hot flashes are negatively related to verbal memory performance in midlife women. Menopause . 2008;15(5):848- 856. Decreases in physiologic VMS relate to improvements in verbal Physiologic VMS are associated with adverse brain memory in a clinical trial of stellate ganglion blockade outcomes More white matter hyperintensities Hyperconnectivity in brain at rest, especially in Moderate to severe VMS r=0.51, p<0.05 hippocampus Walega DR, Rubin LH, Banuvar S, Shulman LP, Maki PM. Effects of stellate ganglion block on vasomotor symptoms: findings from a randomized controlled clinical trial in postmenopausal women. Menopause. Aug 2014;21(8):807-814. Thurston RC, Aizenstein HJ, Derby CA, Sejdic E, Maki PM. Menopausal hot flashes and white matter hyperintensities. Menopause. 2016 Jan 1;23(1):27-32. Maki PM, Rubin LH, Savarese A, Drogos L, Shulman LP, Banuvar S, Walega DR. Stellate ganglion blockade and verbal memory in midlife women: Evidence from a randomized trial. Maturitas. 2016 Oct 31;92:123-9. Thurston RC, Maki PM, Derby CA, Sejdi ć E, Aizenstein HJ. Menopausal hot flashes and the default mode network. Fertility and sterility. 2015 Jun 30;103(6):1572-8. 5

9/26/2016 “Induced” menopause and verbal memory performance OBJECTIVES 1. Understand cognitive complaints and cognitive function • Verbal memory decreases following oophorectomy across menopause stages and following pharmacological suppression of estrogen 2. Understand the role of vasomotor symptoms (VMS) on cognitive changes across the menopause • Adding estrogen therapy reverses those effects 3. Describe the “treated history” of cognitive changes across the menopausal transition. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology. 1988;13(4):345-357. Sherwin BB, Tulandi T. "Add-back" estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. Journal of Clinical Endocrinology and Metabolism. 1996;81(7):2545-2549. Early use of HT has neutral effect on cognitive function Prefrontal activation during a verbal memory task decreases after GNRHa in early postmenopause treatment and rebounds afterward WHIMSY (WHI Memory Study of Younger Women) 1 • CEE alone or with MPA in women (50 to 54 y) upon enrollment; n =1326 • Published: neutral cognitive effects when tested on average 7.2 years after the trials ended • “CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50–55 years”  * Keeps (Kronos Early Estrogen Prevention Study) 2 5-yr cyclic transdermal E2 (50  g/wk) or CEE (0.45 mg) plus micro P (200 mg,12 d/month) in 693 • women (42-58 yrs) < 36 m of FMP • Neutral cognitive effects after 48 m; some mood benefit with CEE on depression and anxiety ELITE (Early Versus Late Intervention Trial with Estradiol) 3 • Oral E2 1 mg/d + vaginal P gel for 10 days per month in 567 younger (< 6 y since FMP) and older (> 10 y since FMP) • Neutral effects * P <0.05 for main effect of condition; Ph = Probability of a hit; Pfa = Probability of a false alarm Craig et al. Reversibility of the effects of acute ovarian hormone suppression on verbal memory and prefrontal function in premenopausal women 1Espeland et al. 2014, JAMA Intern Med. 2Gleason et al. 2015, Plos Med. 3Henderson et al. 2016, Neurology. Psychoneuroendocrinology (2008) 33, 1426-31. 6