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10/9/2018 Perimenopause as a Neurologic Transition State: Emergence of Vulnerabilities to Neurodegenerative Disease 2018 North American Menopause Society San Diego, Ca October 04, 2018 Roberta Diaz Brinton, Ph.D. Center for Innovation in

  1. 10/9/2018 Perimenopause as a Neurologic Transition State: Emergence of Vulnerabilities to Neurodegenerative Disease 2018 North American Menopause Society San Diego, Ca October 04, 2018 Roberta Diaz Brinton, Ph.D. Center for Innovation in Brain Science University of Arizona Health Sciences and College of Medicine Women are at Greater Lifetime Risk for Alzheimer’s Disease 33% 67% 33% 1

  2. 10/9/2018 Endocrine Aging Initiates Late ‐ Onset Alzheimer’s Risk Perimenopausal Average Age Average Age of Transition of Menopause AD Diagnosis WHY Perimenopause Prodromal AD Women? 45 51 Age 75 Perimenopause is a Bioenergetic Transition in Brain: Potential Implications for Risk of Alzheimer’s in Later Life Brinton et al., Nature Rev Endo 2015; Yao et al, PNAS, 2009; Ding et al., 2012; Yin et al., 2015, Neurobio Aging; 2

  3. 10/9/2018 Perimenopause is a Bioenergetic Transition in Brain: Potential Implications for Risk of Alzheimer’s in Later Life Brinton et al., Nature Rev Endo 2015; Yao et al, PNAS, 2009; Ding et al., 2012; Yin et al., 2015, Neurobio Aging; Perimenopause is a Bioenergetic Transition in Brain: Potential Implications for Risk of Alzheimer’s in Later Life Brinton et al., Nature Rev Endo 2015; Yao et al, PNAS, 2009; Ding et al., 2012; Yin et al., 2015, Neurobio Aging; 3

  4. 10/9/2018 Perimenopause is a Bioenergetic Transition in Brain: Potential Implications for Risk of Alzheimer’s in Later Life Brinton et al., Nature Rev Endo 2015; Yao et al, PNAS, 2009; Ding et al., 2012; Yin et al., 2015, Neurobio Aging; The Brain is the Most Lipidated Organ of the Body 4

  5. 10/9/2018 Neuron Can the starving brain utilize Its own source of Astrocyte lipids for fuel? Arachidonic Acid cPLA2 Mechanism of White H2O2 Matter Catabolism: Sphingomyelinase Activation Mitochondrial H 2 O 2 activation of cPLA 2 ‐ sphingomyelinase pathway to generate myelin derived fatty MCT MCT Astrocytes Neurons Myelin acids as a substrate Ketone Bodies Ketone Bodies Sphingomyelin for ketone body Ketogenesis TC TCA Sphingomyelinase Ketone Bodies Acetyl-CoA Ceramide generation Ketolysis SCOT Β -oxidation Ceramidase Acetyl-CoA Fatty Acids Fatty Acids Klosniski,… Brinton, EBioMedicine DOI: Thiolase (10.1016/j.ebiom.2015.11.002) Ketone Bodies Perimenopause is a Bioenergetic Transition in Brain: Coincident with White Matter / Myelin Disintegration Brinton et al., Nature Rev Endo 2015; Yao et al, PNAS, 2009; Ding et al., 2012; Yin et al., 2015, Neurobio Aging; Klosniski et.,al , EBioMedicine DOI: (10.1016/j.ebiom.2015.11.002) 5

  6. 10/9/2018 Lipid Droplet in Brain is Coincident with Myelin Dis-Integration and Fatty Acid Metabolism MYELIN Galactocerebrosid Galactocerebrosid SPHINGOMYELIN e e Phosphorylcholin Phosphorylcholin CERAMIDE Galactose Galactose e e Sphingosine Sphingosine FATTY ACIDS KETONE BODIES ng/mg tissue P-Value Reproductively Reproductively Irregular vs Irregular vs Incompetent Ceramide Panel Irregular Incompetent Aged Incompetent Aged vs Aged Sph 1.49 1.81 1.60 0.306 0.936 0.698 SPA 0.29 0.31 0.29 0.954 0.999 0.939 S1P 0.66 1.12 1.18 0.022 0.017 0.985 C14-cer 0.09 0.10 0.08 0.594 0.985 0.478 C16-cer 2.04 2.42 2.25 0.178 0.686 0.797 C18:1-cer 0.19 0.23 0.22 0.561 0.783 0.990 C18-cer 46.70 48.73 53.98 0.991 0.769 0.906 C20-cer 2.04 2.08 2.31 0.999 0.852 0.913 C22-cer 1.80 2.13 1.83 0.296 0.998 0.463 C24:1-cer 36.74 46.46 40.40 0.047 0.716 0.366 C24-cer 1.05 1.17 0.93 0.765 0.799 0.339 pmoles/mg tissue P-Value NEFA Panel Reproductively Reproductively Irregular vs Irregular vs Incompetent Irregular Incompetent Aged Incompetent Aged vs Aged EPA 9.29 10.87 14.18 0.852 0.147 0.458 Linolenic 0.58 0.69 0.65 0.976 0.991 0.999 DHA 52.5 70.2 98.4 0.631 0.052 0.343 Myristic 4.68 4.63 5.45 0.999 0.536 0.522 Palmitoleic 13.4 15.2 16.5 0.442 0.117 0.762 Arachidonic 236.8 275.6 374.6 0.733 0.023 0.136 Linoleic 25.2 31.4 33.1 0.184 0.098 0.955 Palmitic 334.3 388.0 433.1 0.156 0.009 0.347 Klosniski,… Brinton, EBioMedicine ebiom.2015.11.002) Oleic 387.5 472.4 567.4 0.393 0.031 0.385 Stearic 259.5 264.3 351.8 0.999 0.329 0.403 TCA Panel nmol/mg tissue P-Value Increased Expression of Mitochondrial Proteins Involved in Fatty Acid Transport and Metabolism is Coincident with Increase in Brain Ketone Bodies *** ** C. 140% 400% 350% ** A. ** B. CPT1 Protein Levels Relative to ** ** ** Reproductively Competent 350% 120% ** 300% ABAD Protein Levels Relative HADHA Protein Levels Relative to VDAC and Normalized to VDAC Normalized to Reproductively Competent to VDAC and Normalized to 300% Reproductively Competent 100% 250% 250% 80% 200% 200% 60% 150% 150% 40% 100% 100% 20% 50% 50% 0% 0% 0% Reproductively Reproductively Reproductively Aged Reproductively Reproductively Reproductively Aged Reproductively Reproductively Reproductively Aged Competent Irregular Incompetent Competent Irregular Incompetent Competent Irregular Incompetent ABAD CPT1 HADHA VDAC VDAC VDAC ** B. A. 0.014 C. * 0.09 Hippocampal mM β -Hydroxybutyrate Levels 0.016 ** * ** * 0.012 0.08 0.014 Cortical mM β -Hydroxybutyrate Levels /ug 0.07 0.01 Plasma mM β -Hydroxybutyrate 0.012 0.06 /ug protein Levels /ug protein 0.008 0.01 0.05 0.006 0.008 protein 0.04 0.006 0.004 0.03 0.02 0.004 0.002 0.01 0.002 0 Reproductively Reproductively Reproductively Aged 0 0 Competent Irregular Incompetent Reproductively Reproductively Reproductively Aged Reproductively Reproductively Reproductively Aged Competent Irregular Incompetent Competent Irregular Incompetent 6

  7. 10/9/2018 FDG-PET Brain Glucose in Perimenopausal / Menopausal Women Compared to Age-Matched Men Statistical parametric maps (SPMs) display 18 F ‐ fluoro ‐ 2 ‐ deoxyglucose (FDG) uptake reductions in (A) asymptomatic perimenopause by age vs. men (B) symptomatic perimenopause vs men, (C) menopause vs. men. SPMs are represented on a color ‐ coded scale (1<z<3; where z>2 correspond to p<0.001) and displayed onto a standardized MRI. Mosconi et al., Neurology Neurology. 2017 26;89(13):1382 ‐ 1390 MRI ‐ based Gray & White Matter Volumes in Perimenopausal / Menopausal Women Compared to Age ‐ Matched Men Statistical parametric maps (SPMs) display Gray Matter Volume and White Matter Volume reductions in (A) asymptomatic perimenopause by age vs. men, (B) symptomatic perimenopause vs men, and (C) menopause vs. men. SPMs are represented on different color ‐ coded scales (1<z<3; where z>2 correspond to p<0.001) and displayed onto a standardized MRI. Mosconi et al., Neurology. 2017 Sep 26;89(13):1382 ‐ 1390 7

  8. 10/9/2018 PiB ‐ PET A β deposition in Perimenopausal / Menopausal Women Compared to Age ‐ Matched Men Statistical parametric maps (SPMs) display increased 11 C ‐ PiB uptake in (A) asymptomatic perimenopause by age vs. men, (B) symptomatic perimenopause vs men, and (C) menopause vs. men. SPMs are represented on a color ‐ coded scale (1<z<3; where z>2 correspond to p<0.001) and displayed onto a standardized MRI. Mosconi et al., Neurology. 2017 26;89(13):1382 ‐ 1390 Metabolic Biomarker Strategy to Identify Women at Risk for Alzheimer’s Disease WHO IS AT RISK? 11% 11% NO AD AD Rettberg et al., Neurobiol Aging. 2016;40:155 ‐ 63. 8

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