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

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Natural History of Cognitive Changes Across the Menopause Transition

Pauline M. Maki, PhD Professor of Psychiatry and Psychology University of Illinois at Chicago

DISCLOSURES

• None

OBJECTIVES

• 1. Understand cognitive complaints and cognitive function

across menopause stages

• 2. Understand the role of vasomotor symptoms (VMS) on

cognitive changes across the menopause

• 3. Describe the “treated history” of cognitive changes across

the menopausal transition. OBJECTIVES

• 1. Understand cognitive complaints and cognitive function

across menopause stages

• 2. Understand the role of vasomotor symptoms (VMS) on

cognitive changes across the menopause

• 3. Describe the “treated history” of cognitive changes across

the menopausal transition.

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Adapted from Gold et al. Am J Epidemiol Vol. 152, No. 5, 2000.

In the SWAN, memory decline was the third most frequent symptom.

7899 healthy women from a multi-ethnic cohort 40–55 Years of Age 2nd most frequent symptom among early perimenopausal women

Memory declines are the second most frequent symptom among women in the Pan Asia Menopause Study

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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.

9 Ethnic Asian groups n =977

Complaints of forgetfulness increase during the menopausal transition even after controlling for age.

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. 2000; 152, 463-73.

More severe memory complaints are associated with worse performance on memory tests.

n = 68 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.

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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. Weber MT, Mapstone M, Staskiewicz J, Maki PM. Reconciling subjective memory complaints with objective memory performance in the menopausal transition. Menopause. 2012;19:735-741

Subjective memory complaints have also been shown to relate to scores on tests of attention in midlife women

Memory performance worsens during the perimenopause even after controlling for age

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 2013;98(9):3829-3838.

Penn Ovarian Aging Study

Memory, fine motor skills and attention/working memory/executive function is lower in the 12 months after the FMP

n = 117 Weber, M., Rubin, L.H., Maki, P.M. Cognition in the perimenopause: The effect of transition stage. Menopause. 2013;20(5):511-517

Endocrine changes around the FMP

n = 1216 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

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OBJECTIVES

• 1. Understand cognitive complaints and cognitive function

across menopause stages

• 2. Understand the role of vasomotor symptoms (VMS) on

cognitive changes across the menopause

• 3. Describe the “treated history” of cognitive changes across

the menopausal transition.

Memory performance is unrelated to reported vasomotor symptoms

• Ford N, Slade P, Butler G. An absence of evidence linking perceived memory

problems to the menopause. Br J Gen Pract. 2004;54(503):434-8.

• 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

and estrogen therapy do not influence cognition in early menopausal women.

• 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. 2008;15(5):848-856.

• Greendale GA, Wight RG, Huang MH, et al. Menopause-associated symptoms

and cognitive performance: results from the Study of Women's Health Across the Nation. Am J Epidemiol. 2010;171(11):1214-1224.

• Biolog Skin Conductance

Monitor

• Objective hot flash defined as

a 2 mmho increase in skin conductance across a 30 second period

• Button press used for

subjective recognition of hot flash

Measuring Physiologic VMS Objectively with Ambulatory Monitors Validation of monitor-measured VMS: Placebo effect is not evident when VMS are measured on monitors

5 10 15 20 25 Placebo Red Clover Black Cohosh Prempro Baseline 1-year 5 10 15 20 25 Placebo Red Clover Black Cohosh Prempro Baseline 1-year

Subjective Objective

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.

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Women report less than 60% of monitor-measured VMS

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.

Objective VMS are associated with worse verbal memory

6 5 4 3 2 1

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Total Number of Objective Hot Flashes during Sleeping Hours 6 5 4 3 2 1

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Delayed Paragraph Recall (score adjusted for other significant predictors)

6 5 4 3 2 1

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Total Number of Objective Hot Flashes during Sleeping Hours 6 5 4 3 2 1

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Delayed Paragraph Recall (score adjusted for other significant predictors)

29 midlife women (mean age = 53 y) with moderate to severe hot flashes Number of hours of sleep independently predicted worse memory

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 memory in a clinical trial of stellate ganglion blockade

r=0.51, p<0.05

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.

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.

Moderate to severe VMS

Physiologic VMS are associated with adverse brain

• utcomes

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.

More white matter hyperintensities Hyperconnectivity in brain at rest, especially in hippocampus

Thurston RC, Maki PM, Derby CA, Sejdić E, Aizenstein HJ. Menopausal hot flashes and the default mode network. Fertility and sterility. 2015 Jun 30;103(6):1572-8.

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OBJECTIVES

• 1. Understand cognitive complaints and cognitive function

across menopause stages

• 2. Understand the role of vasomotor symptoms (VMS) on

cognitive changes across the menopause

• 3. Describe the “treated history” of cognitive changes across

the menopausal transition. “Induced” menopause and verbal memory performance

• Verbal memory decreases following oophorectomy

and following pharmacological suppression of estrogen

• Adding estrogen therapy reverses those effects

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

• f Clinical Endocrinology and Metabolism. 1996;81(7):2545-2549.

Prefrontal activation during a verbal memory task decreases after GNRHa treatment and rebounds afterward

*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 Psychoneuroendocrinology (2008) 33, 1426-31.

Early use of HT has neutral effect on cognitive function in early postmenopause

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

1Espeland et al. 2014, JAMA Intern Med. 2Gleason et al. 2015, Plos Med. 3Henderson et al. 2016, Neurology.

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Neuroimaging in KEEPS

Kantarci K et al. Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. Journal of Alzheimer's Disease. 2016 May 7(Preprint):1-0. Kantarci K et al. Effects of hormone therapy on brain structure A randomized controlled trial. Neurology. 2016 Aug 30;87(9):887-96. Month

BETA-AMYLOID DEPOSITION VENTRICLE VOLUME

• No large clinical trials have been conducted in women

with moderate-to-severe vasomotor symptoms, so it is unclear whether HT improves cognition in symptomatic women In SWAN, hormone use, taken before the FMP, but not after, was associated with improved processing speed and memory

Former hormone use, taken prior to the FMP, was associated with:

• better processing speed (6% higher)
• better verbal learning and memory (4-5% higher)

Current hormone use among postmenopausal women predicted:

• worse processing speed
• worse verbal episodic memory performance over time compared to

premenopausal performance

Greendale GA et al. Effects of the menopause transition and hormone use on cognitive performance in midlife

• women. Neurology. 2009 May 26;72(21):1850-7.

Decreased parahippocampal blood flow

Maki et al. Brain Research Perimenopausal use of hormone therapy is associated with enhanced memory and hippocampal function later in life. 2011 Brain Research 1379: 232-43.

10 20 30 40 50 60 70 80 90 100 Recognition Score Users Nonusers

Women who initiate HT before the final menstrual period show better memory and hippocampal function

Increased left hippocampal blood flow Better delayed verbal recognition memory

(Mean age 60.5, n=28)

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OBJECTIVES

• 1. Understand cognitive complaints and cognitive function

across menopause stages

• 2. Understand the role of vasomotor symptoms (VMS) on

cognitive changes across the menopause

• 3. Describe the “treated history” of cognitive changes across

the menopausal transition. Take-home Messages

• Women report and show declines in memory during the menopausal

transition; memory might rebound in postmenopause

• Vasomotor symptoms, when measured objectively with ambulatory

monitors, are linked to memory declines and structural and functional brain abnormalities; unknown if causal

• HT has neutral effects on cognition in early postmenopausal women;

cognitive effects on women with bothersome VMS and in Perimenopausal women are unknown

• HT is not recommended for cognitive complaints