5/16/2018

THIS IS YOUR ON

HEATHER FERRIS, MD, PHD ASSISTANT PROFESSOR, DIVISION OF ENDOCRINOLOGY AND CLINICAL INVESTIGATOR IN RESIDENCE, DEPARTMENT OF NEUROSCIENCE

I HAVE NO FINANCIAL CONFLICTS OF INTEREST

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OBJECTIVES

• Understand the changes in brain imaging seen in diabetes • Describe diabetes mediated causes of cognitive decline • Describe the impact of and on brain function • Understand the potential role of in Alzheimer’s pathogenesis and treatment

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We’re All Heading Downhill

English Longitudinal Study of Aging, 5189 patients Zheng, Diabetologia, 2018

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Projected Increase in Alzheimer’s Disease

2017 Alzheimer’s Disease Facts and Figures: Alzheimer’s Association

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Dual Epidemics

• doubles your risk for AD1 • Even in the non‐diabetic range, fasting correlates with brain volume loss2 • A1c correlates with cognitive decline across the non‐diabetic and diabetic range3 • Higher BMI is associated with worse and cognitive decline over time4

1Ahtiluoto, , 2010 2Cherbuin, Neurology, 2012 3Zheng, Diabetologia, 2018 4Cournot, Neurology, 2006

Type 1 Diabetes Causes Increased Cognitive Impairment in Middle Age

N=201, average age 68

Chaytor, J Diabetes Complications 2018

N=97 with Diabetes N=138 controls Any 2+ Average age 49 Nunley, Diabetes Care 2015

Possible Causes of Cognitive Dysfunction in Diabetes

Amyloid Metabolic Syndrome deposition Genetic predisposition

Macrovascular Microvascular disease disease

Advanced Dyslipidemia glycation end‐ Diabetes products

Abnormal Hyperglycemia Insulin Action

Medications Recurrent hypoglycemia Modified from Stratchan MWJ, Diabetes, and metabolism 2009

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Macrovascular disease‐Stroke

Read, Diabetic Medicine 2015

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Areas of atrophy in diabetes • Atrophy pattern, not cerebrovascular lesions, correlated with impairment. • The atrophy pattern is similar to preclinical Alzheimer’s disease.

MRI 350 patients with diabetes and 363 without diabetes Moran, Diabetes Care 2013

Possible Causes of Cognitive Dysfunction in Diabetes

Amyloid deposition Hypertension Genetic predisposition

Macrovascular Microvascular disease disease

Advanced Dyslipidemia glycation end‐ Diabetes products

Abnormal Hyperglycemia Insulin Action

Medications Depression Recurrent hypoglycemia Modified from Stratchan MWJ, Diabetes, obesity and metabolism 2009

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Studies Linking Microvascular Complications with Outcomes in the Brain

Peripheral Brain Outcomes Shared Microvascular Microvascular White Matter Mechanisms Brain Atrophy Infracts Cerebral Microbleeds Cognitive Function Complication Hyperintensity Retinopathy Arteriovenous nicking Cooper et al. Qiu et al. Qiu et al. Microhemorrhages Cooper et al. Qiu et al. Qiu et al. Cooper et al.; Ikram et Venular dilation Ikram et al. Qiu et al. al. Reviewed Beauchet et Verhaaren et al.; King et Reviewed Loitfelder et Reviewed Beauchet et Nephropathy Hypertension al. al. al. al.

Creatinine Rajagopalan et al. Reviewed Vogels et al. Cystatin C Rajagopalan et al. Umemura et al. Glomerular filtration Reviewed Vogels et al. Kurella Tamura et al. rate Islet amyloid Jackson et al. polypeptide

Manschot et al.; Neuropathy Hyperglycemia Launer et al.; Manschot et al. Crane et al. Ursache et al.

AGEs, RAGE Hudson et al. Hudson et al.

Feng et al.; de Lau et Vitamin B12 deficiency Tangney et al. Kealey et al. Tangney et al. Smith et al. al.; Tangney et al.

Adapted from Barrett, JCEM 2017

Possible Causes of Cognitive Dysfunction in Diabetes

Amyloid deposition Hypertension Genetic predisposition

Macrovascular Microvascular disease disease

Advanced Dyslipidemia glycation end‐ Diabetes products

Abnormal Hyperglycemia Insulin Action

Medications Depression Recurrent hypoglycemia Modified from Stratchan MWJ, Diabetes, obesity and metabolism 2009

Hypoglycemia • Worse cognition in in later life correlated with • Recent severe hypoglycemic event • Hypoglycemic unawareness • Not a prospective study

• Type 2 diabetes • Evidence of more frequent hypoglycemia in those with cognitive impairment. • Frequent severe hypoglycemia speeds progression of cognitive impairment. • Prospective studies do not suggest that severe hypoglycemia is the cause of the cognitive impairment. Chaytor, J Diabetes Complications 2018 Feinkohl, Alz Res Ther 2015

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Possible Causes of Cognitive Dysfunction in Diabetes

Amyloid deposition Hypertension Genetic predisposition

Macrovascular Microvascular disease disease

Advanced Dyslipidemia glycation end‐ Diabetes products

Abnormal Hyperglycemia Insulin Action

Medications Depression Recurrent hypoglycemia Modified from Stratchan MWJ, Diabetes, obesity and metabolism 2009

Multiple Possible Pathways Connecting Diabetes and Alzheimer’s Disease

Kleinridders & Ferris, Diabetes 2014

Loss of Insulin Receptor Slows Insulin Access to the Brain

Konishi, PNAS 2017

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The Cholesterol Biosynthesis Pathway Is Suppressed in Brain of Insulin Deficient Diabetic Mice 7‐Dehydrocholesterol Acetyl‐CoA Mevalonate Mvk Sc4mol Dhcr7 Hmgcs1 Hmgcr Cyp51 Isopentenyl‐5‐PP Lanosterol HMG‐CoA Fdps Idi1 Lss Cholesterol Geranyl‐PP Dimethylallyl‐PP 2,3‐Oxidosqualene Fdps Fdft1 Sqle Suzuki et al. Metab, 2010 Farnesyl‐PP Squalene

[qPCR] 1.2 Hypothalamus CON (n=6) b STZ (n=5) b b b 1.1 b bb b STZ+INS (n=7) 1.0

0.9 a a a a a 0.8 a a a Expression Ratio Expression a 0.7

0.6

0.5 Normalized to Tbp a: P < 0.01 vs CON 0.4 b: P < 0.01 vs STZ Hmgcs1 Hmgcr Mvk Fdps Idi1 Fdft1 Sqle Lss Cyp51 Sc4mol Dhcr7

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Decreasing Brain Cholesterol Impairs Neuronal Activity Spontaneous Activity Paired Pulse Facilitation P1 P2

2.0 ** 2.0 WT (17) ** HET (12) 1.5 1.8 * *** * 1.6 1.0 1.4

0.5 1.2 Paired-pulse ratio (P2/P1) (15) (15) 1.0 Mean mEPSC frequency (Hz) frequency Mean mEPSC 0.0 25 50 75 100 125 150 175 200 WT HET Interpulse duration (ms) Suzuki, Ferris et al., PLOS Biol 11(4):2013

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Decreasing Brain Cholesterol Impairs Memory

Novel Object Recognition Test Training (5 min)

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Interval (1 hr) 60

55 ** Trial (5 min) CCD

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% Preference for Novel Object Novel for Preference % (+/+) (+/-)

Suzuki, Ferris et al., PLOS Biol 11(4):2013

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Simvastatin Increases Induced Cell

Early Apoptosis Late Apoptosis Dead Cells ** 2 1.4 1 * *** ** 1.2 * 1.6 0.8 * 1 1.2 0.8 0.6

0.8 0.6 0.4 0.4

0.4 Positive 7-AAD % 0.2 % Annexin Positive 0.2 0 0 0 Cont Simv Cont Simv Annexin and 7-AAD % Positive Cont Simv Cont Simv Cont Simv Cont Simv Vehicle Amyloid  Vehicle Amyloid  Vehicle Amyloid 

Fukui, Ferris and Kahn, J Biol Chem 2015

Simvastatin Increases Amyloid Beta Induced Cell Death

Early Apoptosis Late Apoptosis Dead Cells ** 2 1.4 1 * *** ** 1.2 * 1.6 0.8 * 1 1.2 0.8 0.6

0.8 0.6 0.4 0.4

0.4 Positive 7-AAD % 0.2 % Annexin Positive 0.2 0 0 0 Cont Simv Cont Simv Annexin and 7-AAD % Positive Cont Simv Cont Simv Cont Simv Cont Simv Vehicle Amyloid  Vehicle Amyloid  Vehicle Amyloid 

GT1‐7 ‐derived cell line, pretreated for 48 hours with simvastatin 200nM then treated for 12 hours with amyloid  25‐35 fragment prior to flow cytometry. Fukui, Ferris and Kahn, J Biol Chem 2015

Statins‐ Don’t Worry, We Aren’t Making Things Worse

Dementia Risk

Wannamaker, Clin Cardiol 2015

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Type 3 Diabetes??

• What is it? • Insulin and IGF1 resistance in the brain in Alzheimer’s disease • Is it real? • Remains controversial • While much focus is on insulin, IGF1 may also be important • Why should I care? • Is likely relevant to both Alzheimer’s disease and Type 2 diabetes

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Insulin is Not Required for Glucose Transport into the Brain and Yet….

Kleinridders and Ferris, Diabetes 2014

Insulin and IGF‐1 Binding Correlates with AD Progression

Rivera, J Alz Dis 2005

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Non‐diabetic Alzheimer’s Fail to Respond Normally to Insulin and IGF‐1

Normal Alzheimer’s Disease

Talbot, JCI 2012

Intranasal Insulin Improves Plaques and Behavior in an AD Mouse Model

Mao, Aging Cell 2016

Intranasal Insulin‐ There May be Improvement in Some Patients

Intranasal Insulin Patients with mild cognitive impairment or AD were given 20 IU (low) or 40 IU (high) of intranasal insulin detemir once daily for 21 days.

Those with the greatest also benefited the most. Claxton, J Alz Dz 2015

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SNIFF Trial‐ Study of Nasal Insulin to Fight Forgetfulness

• 12 month, placebo controlled study of intranasal insulin • Fully recruited and should finish collecting data in December of this year • 240 patients enrolled • Outcomes are brain atrophy, cognitive function and biomarkers

What is the Therapeutic Target of Intranasal Insulin?

Blazquez, Front Endo, 2015

Summary

• Both Type 1 and Type 2 diabetes impact cognition, probably through different mechanisms. • Insulin may play an important role in the development of Alzheimer’s disease, in both the Type 2 diabetes population and the non‐diabetes population.

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