5/16/2018 THIS IS YOUR BRAIN ON DIABETES I HAVE NO FINANCIAL CONFLICTS OF INTEREST

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1 THIS IS YOUR BRAIN ON DIABETES HEATHER FERRIS, MD, PHD ASSISTANT PROFESSOR, DIVISION OF ENDOCRINOLOGY AND METABOLISM CLINICAL INVESTIGATOR IN RESIDENCE, DEPARTMENT OF NEUROSCIENCE I HAVE NO FINANCIAL CONFLICTS OF INTEREST 2 3 1

2 OBJECTIVES Understnd the chnges in rin imging seen in dietes Descrie dietes medited cuses of cognitive decline Descrie the impct of hypoglycemi nd hyperglycemi on rin function Understnd the potentil role of insulin in Alzheimer s pthogenesis nd tretment 4 We re All Heding Downhill English Longitudinl Study of Aging, 5189 ptients Zheng, Dietologi, Projected Increse in Alzheimer s Disese 217 Alzheimer s Disese Fcts nd Figures: Alzheimer s Assocition 2

3 Dul Epidemics Type 2 dietes doules your risk for AD 1 Even in the non dietic rnge, fsting glucose correltes with rin volume loss 2 A1c correltes with cognitive decline cross the non dietic nd dietic rnge 3 Higher BMI is ssocited with worse cognition nd cognitive decline over time 4 1Ahtiluoto, Neurology, 21 2 Cheruin, Neurology, Zheng, Dietologi, Cournot, Neurology, 26 Type 1 Dietes Cuses Incresed Cognitive Impirment in Middle Age N=21, verge ge 68 Chytor, J Dietes Complictions 218 N=97 with Dietes N=138 controls Averge ge 49 Any 2+ Nunley, Dietes Cre 215 Possile Cuses of Cognitive Dysfunction in Dietes Metolic Syndrome Hypertension Amyloid deposition Genetic predisposition Mcrovsculr Microvsculr Dyslipidemi Dietes Advnced glyction endproducts Anorml Insulin Action Hyperglycemi Medictions Recurrent hypoglycemi Depression Modified from Strtchn MWJ, Dietes, oesity nd metolism 29 3

4 Mcrovsculr Stroke Red, Dietic Medicine Ares of trophy in dietes Atrophy pttern, not cererovsculr lesions, correlted with memory impirment. The trophy pttern is similr to preclinicl Alzheimer s. MRI 35 ptients with dietes nd 363 without dietes Morn, Dietes Cre 213 Possile Cuses of Cognitive Dysfunction in Dietes Hypertension Mcrovsculr Dyslipidemi Amyloid deposition Dietes Genetic predisposition Microvsculr Advnced glyction endproducts Anorml Insulin Action Hyperglycemi Medictions Recurrent hypoglycemi Depression Modified from Strtchn MWJ, Dietes, oesity nd metolism 29 4

5 Studies Linking Microvsculr Complictions with Outcomes in the Brin Peripherl Brin Outcomes Shred Microvsculr Microvsculr Mechnisms White Mtter Compliction Brin Atrophy Infrcts Cererl Microleeds Cognitive Function Hyperintensity Retinopthy Arteriovenous nicking Cooper et l. Qiu et l. Qiu et l. Microhemorrhges Cooper et l. Qiu et l. Qiu et l. Cooper et l.; Ikrm et Venulr diltion Ikrm et l. Qiu et l. l. Reviewed Beuchet et Verhren et l.; King et Reviewed Loitfelder et Reviewed Beuchet et Nephropthy Hypertension l. l. l. l. Cretinine Rjgopln et l. Reviewed Vogels et l. Cysttin C Rjgopln et l. Umemur et l. Glomerulr filtrtion Reviewed Vogels et l. Kurell Tmur et l. rte Islet myloid Jckson et l. polypeptide Neuropthy Hyperglycemi Mnschot et l.; Luner et l.; Ursche et l. Mnschot et l. Crne et l. AGEs, RAGE Hudson et l. Hudson et l. Vitmin B12 deficiency Tngney et l. Feng et l.; de Lu et l.; Tngney et l. Keley et l. Tngney et l. Smith et l. Adpted from Brrett, JCEM 217 Possile Cuses of Cognitive Dysfunction in Dietes Hypertension Mcrovsculr Dyslipidemi Amyloid deposition Dietes Genetic predisposition Microvsculr Advnced glyction endproducts Anorml Insulin Action Hyperglycemi Medictions Recurrent hypoglycemi Depression Modified from Strtchn MWJ, Dietes, oesity nd metolism 29 Hypoglycemi Worse cognition in Type 1 dietes in lter life correlted with Recent severe hypoglycemic event Hypoglycemic unwreness Not prospective study Type 2 dietes Evidence of more frequent hypoglycemi in those with cognitive impirment. Frequent severe hypoglycemi speeds progression of cognitive impirment. Prospective studies do not suggest tht severe hypoglycemi is the cuse of the cognitive impirment. Chytor, J Dietes Complictions 218 Feinkohl, Alz Res Ther 215 5

6 Possile Cuses of Cognitive Dysfunction in Dietes Hypertension Mcrovsculr Dyslipidemi Amyloid deposition Dietes Genetic predisposition Microvsculr Advnced glyction endproducts Anorml Insulin Action Hyperglycemi Medictions Recurrent hypoglycemi Depression Modified from Strtchn MWJ, Dietes, oesity nd metolism 29 Multiple Possile Pthwys Connecting Dietes nd Alzheimer s Disese Kleinridders & Ferris, Dietes 214 Loss of Insulin Receptor Slows Insulin Access to the Brin Konishi, PNAS

7 The Cholesterol Biosynthesis Pthwy Is Suppressed in Brin of Insulin Deficient Dietic Mice 7 Dehydrocholesterol Acetyl CoA Mevlonte Mvk Sc4mol Dhcr7 Hmgcs1 Hmgcr Cyp51 Isopentenyl 5 PP Lnosterol HMG CoA Fdps Idi1 Cholesterol Lss Gernyl PP Dimethylllyl PP 2,3 Oxidosqulene Fdps Fdft1 Sqle Frnesyl PP Squlene Suzuki et l. Cell Met, 21 [qpcr] Expression Rtio Hypothlmus CON (n=6) STZ (n=5) STZ+INS (n=7).6.5 Normlized to Tp : P <.1 vs CON : P <.1 vs STZ Hmgcs1 Hmgcr Mvk Fdps Idi1 Fdft1 Sqle Lss Cyp51 Sc4mol Dhcr7 19 Decresing Brin Cholesterol Impirs Neuronl Activity Spontneous Activity Pired Pulse Fcilittion P1 P2 Men mepsc frequency (Hz) ** (15) (15) WT HET Pired-pulse rtio (P2/P1) 2. WT (17) HET (12) 1.8 ** * *** * Interpulse durtion (ms) Suzuki, Ferris et l., PLOS Biol 11(4):213 2 Decresing Brin Cholesterol Impirs Memory Novel Oject Recognition Test Trining (5 min) Intervl (1 hr) Tril (5 min) CCD % Preference for Novel Oject ** (+/+) (+/-) Suzuki, Ferris et l., PLOS Biol 11(4):

8 Simvsttin Increses Amyloid Bet Induced Cell Deth % Annexin Positive Erly Apoptosis Lte Apoptosis Ded Cells ** * *** ** * * Cont Simv Cont Simv Cont Simv Cont Simv Cont Simv Cont Simv Vehicle Amyloid Vehicle Amyloid Vehicle Amyloid % 7-AAD nd Annexin Positive % 7-AAD Positive Fukui, Ferris nd Khn, J Biol Chem 215 Simvsttin Increses Amyloid Bet Induced Cell Deth % Annexin Positive Erly Apoptosis Lte Apoptosis Ded Cells ** * 1.4 * Cont Simv Cont Simv Vehicle Amyloid % 7-AAD nd Annexin Positive *** ** Cont Simv Cont Simv Vehicle Amyloid % 7-AAD Positive 1 *.6.2 Cont Simv Cont Simv Vehicle Amyloid GT1 7 neuron derived cell line, pretreted for 48 hours with simvsttin 2nM then treted for 12 hours with myloid frgment prior to flow cytometry. Fukui, Ferris nd Khn, J Biol Chem 215 Sttins Don t Worry, We Aren t Mking Things Worse Dementi Risk Wnnmker, Clin Crdiol 215 8

9 Type 3 Dietes?? Wht is it? Insulin nd IGF1 resistnce in the rin in Alzheimer s Is it rel? Remins controversil While much focus is on insulin, IGF1 my lso e importnt Why should I cre? Is likely relevnt to oth Alzheimer s nd Type 2 dietes 25 Insulin is Not Required for Glucose Trnsport into the Brin nd Yet. Kleinridders nd Ferris, Dietes 214 Insulin nd IGF 1 Binding Correltes with AD Progression River, J Alz Dis 25 9

10 Non dietic Alzheimer s Brins Fil to Respond Normlly to Insulin nd IGF 1 Norml Alzheimer s Disese Tlot, JCI 212 Intrnsl Insulin Improves Plques nd Behvior in n AD Mouse Model Mo, Aging Cell 216 Intrnsl Insulin There My e Improvement in Some Ptients Intrnsl Insulin Ptients with mild cognitive impirment or AD were given 2 IU (low) or 4 IU (high) of intrnsl insulin detemir once dily for 21 dys. Those with the gretest insulin resistnce lso enefited the most. Clxton, J Alz Dz 215 1

11 SNIFF Tril Study of Nsl Insulin to Fight Forgetfulness 12 month, plceo controlled study of intrnsl insulin Fully recruited nd should finish collecting dt in Decemer of this yer 24 ptients enrolled Outcomes re rin trophy, cognitive function nd iomrkers Wht is the Therpeutic Trget of Intrnsl Insulin? Blzquez, Front Endo, 215 Summry Both Type 1 nd Type 2 dietes impct cognition, proly through different mechnisms. Insulin my ply n importnt role in the development of Alzheimer s, in oth the Type 2 dietes popultion nd the non dietes popultion