[PPT] - Population Neuroscience of Sex Differences in the Alzheimers PowerPoint Presentation

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Population Neuroscience of Sex Differences in the Alzheimer’s Disease (AD) Cascade: The Role of Cerebral Small Vessel Disease

Beth Shaaban

OSCAR Symposium September 16, 2020

Beth.Shaaban@pitt.edu @PopNeurosci

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Have you ever heard that psychology & neuroscience are WEIRD?

Sample Population

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Subject Matter Expertise Psychology Biostatistics & Data Science Neuroscience & Neuroimaging Epidemiology

Population Neuroscience Framework

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Proposed order of events in the AD cascade

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Jack, et al., 2013

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Jack, et al., 2013

Are there sex differences in the AD cascade?

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Women bear a greater burden of AD than men

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Men 2,200,000 37.9% Women 3,600,000 62.1% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

US AD Prevalence By Sex, Age 65+

Based on 2020 Alzheimer’s Facts & Figures

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Different causal pathways to AD suggest different intervention targets.

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Are there sex differences in AD neuropathology?

AD-like amyloid-b AD-like tau ♀ > ♂ ♀ = ♂ ♂ > ♀ ♀ > ♂ ♀ = ♂ ♂ > ♀ postmortem ++++ + +++++ neuroimaging ++ ** +++++ ++ + cerebrospinal fluid +++ + +++ * = non-significant trend.

(Barnes et al., 2005; Hohman et al., 2018; Liesinger et al., 2018; Oveisgharan et al., 2018; Filon et al., 2016; Luchsinger et al., 2020; Sundermann, et al., 2018; Buckley, et al., 2019; Jack et al., 2015; Buckley et al., 2018; Mielke et al., 2012; Morris et al., 2010; Sperling et al., 2020; Ziontz et al., 2019; Altmann, et al., 2014)

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AD-like amyloid-b AD-like tau ♀ > ♂ ♀ = ♂ ♂ > ♀ ♀ > ♂ ♀ = ♂ ♂ > ♀ postmortem ++++ + +++++ neuroimaging ++ ** +++++ ++ + cerebrospinal fluid +++ + +++ * = non-significant trend.

Women may have more AD neuropathology than men, but most results are from highly selected samples

(Barnes et al., 2005; Hohman et al., 2018; Liesinger et al., 2018; Oveisgharan et al., 2018; Filon et al., 2016; Luchsinger et al., 2020; Sundermann, et al., 2018; Buckley, et al., 2019; Jack et al., 2015; Buckley et al., 2018; Mielke et al., 2012; Morris et al., 2010; Sperling et al., 2020; Ziontz et al., 2019; Altmann, et al., 2014)

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Are there other brain pathologies which might be important for AD-cascade sex differences?

Debette, et al., 2019 Jorgensen/Shaaban, et al., 2018, AJP-Heart Circ Physiol

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Are there other brain pathologies which might be important for AD-cascade sex differences?

Debette, et al., 2019 Lee, et al., 2016

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Debette, et al., 2019 Lee, et al., 2016

Cerebral small vessel disease (cSVD) is a risk factor for AD and may be an integral feature

f the disease

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cSVD and dementia share cardiovascular and metabolic risk factors

Unadjusted risk of all-cause dementia Variables HR Stroke 9.90 Congestive heart failure (CHF) 2.91 APOE4 carrier 2.02 Hypertension 1.64 High cholesterol 1.64 Physical inactivity (based on min/week) 1.54 Cardiac arrhythmia 1.52

Jorgensen/Shaaban, et al., 2018, AJP-Heart Circ Physiol Shaaban, et al., 2018, Int Psychogeriatrics

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How does cerebral small vessel disease (cSVD) look by sex?

Results Methods

0.00 0.02 0.04 0.06 Men Women Sex White Matter Hyperintensities MRI sub-study of a

larger observational cohort study of function in community dwelling

lder adults

3T MRI N=250 Age: 82 58% women 39% Black

Spearman partial correlation adjusted for age: rho=0.13, p=0.04

Shaaban, et al., In Preparation. Accepted as part of a symposium at Gerontological Society of America Annual Meeting, Nov 2020

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15 Results Methods

0.00 0.02 0.04 0.06 Men Women Sex White Matter Hyperintensities MRI sub-study of a

larger observational cohort study of function in community dwelling

lder adults

3T MRI N=250 Age: 82 58% women 39% Black

Spearman partial correlation adjusted for age: rho=0.13, p=0.04

Shaaban, et al., In Preparation. Accepted as part of a symposium at Gerontological Society of America Annual Meeting, Nov 2020

In late-life, women have greater burden and risk of cerebral small vessel disease (cSVD) than men

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0.5 1 1.5 2 2.5 APOE4 Presence APOE4 Absence Venous Tortuosity Ratio 2.15 1.21 p=0.01

Results Methods

MRI sub-study of a

larger randomized controlled trial

N=53 Age: 76 79% women 57% white 7T Susceptibility-

weighted MRI

Shaaban, et al., 2017, AJNR

Existing measures of cSVD are limited because they are tissue-based. What if we look directly at the vessels?

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Earlier methods of measuring cerebral small vessel integrity are available and appear to have important connections to AD

0.5 1 1.5 2 2.5 APOE4 Presence APOE4 Absence Venous Tortuosity Ratio 2.15 1.21 p=0.01

Results Methods

MRI sub-study of a

larger randomized controlled trial

N=53 Age: 76 79% women 57% white 7T Susceptibility-

weighted MRI

Shaaban, et al., 2017, AJNR

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Intervening on this vascular pathway is possible

Intensive Standard

LIFE Study

SPRINT MIND Investigators, 2019

Physical Activity (N=8) Health Education (N=16) Small vein measure Baseline Follow-up %Δ p Baseline Follow-up %Δ p between arm p Straight length 99.9 (49.9) 153.2 (82.7) 93.6 (112.9) 0.02 105.0 (104.8) 144.9 (131.6) 28.4 (90.6) 0.21 0.07 Tortuous length 147.2 (93.3) 154.7 (52.0) 11.6 (64.5) 0.31 137.7 (69.5) 155.9 (79.9)

12.9 (49.9)

0.63 0.41 Tortuosity ratio 1.4 (1.1) 1.1 (0.7)

33.2 (63.5)

0.15 1.2 (1.1) 1.0 (1.5)

10.8 (105.9)

0.98 0.38

Shaaban, et al., 2019, Med Sci Sports Exerc. SPRINT MIND Investigators, 2019

SPRINT Study

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But my ability to assess relationships of the small vessels with AD was limited because we did not have measures of amyloid (Aβ) and tau

Created with BioRender.com

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FUTURE K01 WORK: Are there sex differences in the cSVD-AD cascade?

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Test for sex differences in cSVD, Aβ, tau, and the cSVD-AD pathway

Hypothesis 1a: Women have worse

cSVD and greater amyloid and tau levels than men.

Hypothesis 1b: cSVD partially

explains sex differences in Aβ and tau levels.

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Created with BioRender.com

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Methods

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N=910; 59% women Combine 5 Pitt cohorts Use causal inference approaches to generalize back to the source population

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Assess the cross-sectional relationship of vessel- and tissue-based markers of cSVD with Aβ and tau

Hypothesis 2a: Greater cSVD is

related to greater Aβ and tau.

Hypothesis 2b: cSVD has both a

direct and an indirect (through Aβ) association with tau.

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Created with BioRender.com

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Methods

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Images Courtesy of Tamer Ibrahim

7T TOF: small arteries 7T SWI: small veins MYHAT Neuroimaging (PI: Snitz) N~50, 55% women

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Training aims, mentors, & consultants

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Neuroimaging cohort harmonization and generalizability Multimodal neuroimaging of cSVD & AD pathology Sex and gender effects on pathophysiology Career and leadership development

Snitz, Co-Primary Mentor Ganguli, Tudorascu

Glymour

Cohen, Co-Primary Mentor Klunk

Andreescu, Ibrahim, Wu

Thurston

Rosano, Aizenstein, Lingler

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There may be sex specific pathways to AD, and cerebral small vessel disease is a key pathway to interrogate

26 Advanced epidemiologic and neuroscience methods, integrated in a population neuroscience approach, are needed to determine this

WEIRD

Created with BioRender.com

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Acknowledgements

Co-authors

Caterina Rosano

Howard Aizenstein

Dana Jorgensen

Rebecca Mahbubani

Joe Mettenburg

Tamer Ibrahim

Andrea Rosso

Minjie Wu

Sara Godina

Heather Shattuck- Heidorn

Mentors & Grant

Collaborators

Beth Snitz

Ann Cohen

Mary Ganguli

Bill Klunk

Dana Tudorascu

Rebecca Thurston

Maria Glymour

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Mentors & Grant

Collaborators

Carmen Andreescu

Tamer Ibrahim

Minjie Wu

Caterina Rosano

Howard Aizenstein

Jennifer Lingler

Funding

NIA

Population Neuroscience T32

ADRC REC

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Thank you!

28 Beth Shaaban

OSCAR Symposium September 16, 2020

Beth.Shaaban@pitt.edu @PopNeurosci