Diabetes and Dementia

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Diabetes and Dementia Michal Schnaider Beeri

2 DIABETES EPIDEMIC -PREVALENCE No Data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% >9.0% 2010 Percentage with Diabetes 8 7 Percentage with Diabetes 6 Number with Diabetes Year Number with Diabetes (Millions) Source: CDC s Division of Diabetes Translation. Available at: Slide Copyright , Michal Schnaider Beeri. All Rights Reserved.

26 million with Diabetes 79 million with Pre-Diabetes By 2050, 1 in 3

4 DEMENTIA PREVALENCE 100% 80% 17% 60% 33% 40% 26% 31% 68% 20% 0% 20% 32% 17% 22% 5% 16% 11% 4% 5% Probable dementia Possible cognitive impairment Anstey et al. BMC Neurology 2010 Slide Copyright , Michal Schnaider Beeri. All Rights Reserved.

5 Alzheimer s disease (AD) and dementia prevalence doubles itself every five years. 5% have AD at the age of 70 and ~50% have AD at the age of 85+ With increasing longevity, the prevalence of AD and dementia is expected to grow. DIABETES AND DEMENTIA are a major public health problem Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 5

6 Israel Ischemic Heart Disease (IIHD) study A longitudinal study examining approximately 10,000 Israeli men for cardiovascular risk factors in 1963, 65, and 68. Dementia follow up of 2000 survivors in 1999/2000 Prof. Uri Goldbourt Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 6

8 T2D Association with Dementia Reference Results (95% CI) Dementia Type (Leibson et al. 1997) SMR 1.60 ( ) SMR 1.59 ( ) (Curb et al. 1999) RR 1.52 ( ) Trend RR 1.37 ( ) Trend (Ott et al. 1999) RR 1.9 (1.3 to 2.8) RR 1.9 (1.2 to 3.1) Dementia AD VaD All dementia (not AD/pure AD/pureVaD) Dementia AD (Hassing et al. 2002) RR 2.54 ( ) VaD (no AD association) (MacKnight et al. 2002) RR 1.62 ( ) RR 2.03 ( ) RR 1.68 ( ) Diabetes not associated with: RR 0.87 ( ) RR 1.30 ( ) RR 1.26 ( ) (Peila et al. 2002) RR 1.5 ( ) RR 1.8 ( ) RR 2.3 ( ) Vascular cog. Impairment VaD Vascular cog. im not dementia Mixed AD/VaD AD All dementias Total dementia AD VaD (Arvanitakis et al. 2004) HR 1.65 ( ) AD (Schnaider Beeri et al. 2004) OR 2.8 ( ) Dementia (Xu et al. 2004) HR 1.5 ( ) HR 2.6 ( ) HR 1.3 ( ) Dementia VaD AD (Yaffe et al. 2004) OR 2.4 ( ) Dementia, all cause, women only (Luchsinger et al. 2005) HR 3.8 ( ) HR 4.8 ( ) (Whitmer et al. 2005) HR 1.5 ( ) Dementia (Wang et al. 2012) HR 1.45 ( ) AD Possible + probable AD Probable AD Slide Copyright , Michal Schnaider Beeri. All Rights Reserved.

9 T2D Association with MCI & Cognition Reference Results (95% CI) Cognitive Test MCI (Yaffe et al. 2004) OR 1.8 ( ) Not significant! women only (Luchsinger et al. 2007) HR 1.4 ( ) For amnestic and non-amnestic MCI (each) Cognitive Decline (Gregg et al. 2000) OR 1.7 ( ) Digit symbol and Trails B (women) (Knopman et al. 2001) Diabetics had a greater decline Digit Symbol Substitution; Word Fluency (Arvanitakis et al. 2004) 44% greater rate of cognitive decline Perceptual speed (Hassing et al. 2004a) Diabetics decline twice as fast MMSE, Perceptual Speed, Symbol Digit, Verbal Meaning, and MIR (Hassing et al. 2004b) Diabetics decline twice as fast MMSE (Logroscino et al. 2004) OR 1.3 ( ) East Boston memory test, verbal fluency, and digit span (van den Berg et al. 2006) No association with cognitive decline Letter Digit Coding test and the Stroop Test (Sanz et al. 2009) Diabetics had slower cognitive decline MMSE (patients with probable diagnosis of AD) (De Jager et al. 2012) Known susceptibility loci for T2D are (GWAS) not associated with cognitive decline (Gilmour 2011) Diabetics had low scores on each task Verbal memory immediate recall and delayed recall, semantic fluency, and processing speed (Nandipati et al. 2012) Diabetics had lower scores No difference Attention, psycho-motor function and executive function Memory or semantic memory language * No association between diabetes treatment and cognitive scores (Sanz et al. 2012) AD patients at baseline: OR 2.73 ( ) Recent AD diagnosis at follow-up: HR 1.52 ( ) Functional impairment and decline Slide Copyright , Michal Schnaider Beeri. All Rights Reserved.

10 Why to examine the relationship between diabetes characteristics and AD? Through the characteristics, potential mechanisms underlying the relationship between diabetes and dementia can be investigated. The characteristics can be studied in non-diabetic individuals and relationships then may be extrapolated to all elderly, increasing the public health impact. Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 10

11 T2D Association with Neuropathology of Dementia Reference Results (95% CI) Neurobiological Test (den Heijer et al. 2003) Diabetics had more hippocampal and amygdalar atrophy MRI (Korf et al. 2007) OR 2.9 ( ) Medial temporal lobe atrophy (Gouw et al. 2008) OR 2.4 ( ) Progression of white matter hyperintensities (Perneczky et al. 2010) No association with MMSE, nor with cerebral atrophy * AD patients only (van Elderen et al. 2010) T2D without dementia have accelerated progression of brain atrophy with cognitive decline. Atrophy: MRI Cognition: Stroop and picture learning tests (Richardson et al. 2012) No association with most neuropathology variables except: OR 1.7 ( ) OR 1.7 ( ) Severe DWML Severe hippocampal tangles Type 2 diabetes is negatively associated with Alzheimer's disease neuropathology Beeri MS et al., J Gerontol A Biol Sci Med Sci, 2005; 60(4) Slide Copyright , Michal Schnaider Beeri. All Rights Reserved.

12 Percentage of Adults with Diabetes Receiving Treatment with Insulin or Oral Medications (source: CDC National Health Interview Survey) Oral Medications 58% Insulin Only 12% No Medications 16% Insulin + Oral Meds 14% Copyright 2012, Michal Schnaider Beeri. All Rights Reserved.

14 AD-Associated Neuropathology in Type II Diabetes Adjusted Means + SEM Density of Neuritic Plaques NonDM DM No Meds DM Insulin DM Oral DM Insulin + Oral Adjusted Means + SEM Density of Neurofibrillary Tangles NonDM DM No Meds DM Insulin DM Oral DM Insulin + Oral Cortex Hippocampus Amygdala Cortex Hippocampus Amygdala Data are consistent with SALSA study (Wu et al. 2003) where persons on combination treatment had less cognitive decline than those on monotherapy

15 What may these results imply? Those are ONLY observational results but they may imply biological pathways in the brain, such as insulin receptor signaling, that might be a focus for developing new treatment strategies for AD Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 15

16 Although insulin and metformin display opposing effects on A-beta generation, in combined use, metformin enhances insulin s effect in reducing Abeta levels Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 16

17 The protection provided by insulin against downregulation of the insulin receptor by Aβ oligomers is significantly potentiated by the additional presence of rosiglitazone Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 17

A translational step Moving to gene and protein expression of the insulin

19 Gene ontology of the insulin receptor signaling pathway is associated with cognition and AD neuropathology (based on microarray data) Table 2 - Significantly scored GO categories associated with insulin receptor signaling as a function of clinical and neuropathology indices, identified by FCS. NS non significant. GO ID GO Class Name # of INDEX (p-values) Genes CDR NPD Braak Insulin receptor signaling pathway Insulin-like growth factor receptor signaling pathway 7 NS NS Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 19

20 Expression alterations of the insulin receptor signaling pathway genes are associated with cognition and AD neuropathology Table 3 - Ranking of the IRSP gene expression alterations as a function of CDR, Braak, NPD and aging. Only genes with significance p<0.01 scored against at least one neuropathological characteristic or aging are shown. Genes are arranged in order of decreasing t-scores for the CDR groups. Large positive t-scores (>4) indicate strong upregulation, negative scores (<-4) indicate strong downregulation. Genes with scores between -2 and 2 are unchanged. Gene Symbol Molecular function CDR Braak NPD INSR receptor signaling protein tyrosine kinase activity FOXO1A transcription factor activity SOS1 Ras guanyl-nucleotide exchange factor activity, Rho GTPase activator activity IGF1R insulin-like growth factor receptor activity GSK3B glycogen synthase kinase 3 activity AKT2 protein serine/threonine kinase activity RASA1 Ras GTPase activator activity CTNNB1 signal transducer activity RAF1 protein serine/threonine kinase activity PI3KR1 phosphatidylinositol 3-kinase activity FOS transcription factor activity PTPN11 non-membrane spanning protein tyrosine phosphatase activity MAPK8 protein serine/threonine kinase activity MAPK3 protein serine/threonine kinase activity FOXO3A transcription factor activity EIF4E translation initiation factor activity GRB2 SH3/SH2 adaptor activity JUN transcription factor activity AKT3 protein serine/threonine kinase activity Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 20

21 A further translational step We are beginning a study on the potential beneficial synergistic effects of diabetes combination therapy on brain gene and protein expression of insulin signaling. The study has a human tissue component as well as an animal component Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 21

23 Advanced glycation end products (AGEs) AGEs are formed by non-enzymatic reactions of amino groups of proteins and lipids with reducing sugars, such as glucose They increase in aging and in diabetes and are associated with atherosclerosis and other diabetes characteristics They are produced endogenously but also exogenously in foods and are modifiable and thus of particular interest in cognitive compromise Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 23

26 A translational step Treating mice that develop Alzheimer s type pathology and behavior with high and low AGE diet for 7 months (from the age of 3 months). Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 26

29 The Israel Diabetes and Cognitive Decline Study (IDCD) A collaboration between Mount Sinai School of Medicine, Sheba Medical Center, and Maccabi Health Services It is a longitudinal study of 1000 diabetic elderly (65+) randomly selected from the type 2 diabetics in the MHS in the area of Tel-Aviv, who are cognitively normal at baseline. Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 29

30 The Israel Diabetes and Cognitive Decline Study (IDCD) MHS screens subjects through medical records for eligibility criteria. Sheba physicians administer the consent, perform full dementia assessments, neurological exam, and draw bloods (DNA [apoe, Hp], CRP, IL-6). Eligible subjects are assessed with a broad cognitive battery as well as for depression. Subjects will be followed every 18 months. Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 30

Epigenetics -DNA methylation Glycemic Control & Brain Function - MRI

31 Pragmatic Translational Approach CSF Based Biomarkers Genetics - TOMM40 -ApoE -Hp Blood Based Biomarkers Israel Diabetes & Cognitive Decline Study Epigenetics -DNA methylation Glycemic Control & Brain Function - MRI (Structural + BBB) -fmri Nutrition -9-cys-β-carotene - Advanced glycation & products

32 The Israel Diabetes and Cognitive Decline Study (IDCD)- Sample Characteristics Table 2: Characteristics of the sample Participants* Subjects Excluded Characteristic n=1169 N=315 Age (mean (SD)) 73.8 (5.3) 72.8 (4.9) Sex (% female) Education (mean 12.7 (3.6) 12.6 (4.5) (SD)) HbA1C since 1999: Mean (SD) Minimum Maximum % with at least one HbA1c in last year Time since registry entry (%): 0 to 4 5 to 8 9+ Medication use (%): Insulin* Oral hypoglycemic** Insulin+Oral Diet 6.9 (1.0) (1.2) Hypertension(%) *Subjects=participating in the study; Excluded=refused or do not fulfill eligibility criteria. *Percentages include those on insulin + oral hypoglycemic medications Copyright 2012, Michal Schnaider Beeri. All Rights Reserved. 32

33 Patterns of cognitive performance in T2D are similar to those in non-t2d Relationships of age, education, and gender with neuropsychological test performance in the IDCD are similar to relationships found in general samples. Higher education and younger age are associated with better performance. Women perform better than men on verbal memory tasks, and men outperform women on non-verbal tasks. IDCD subjects have primacy and recency effects similarly to non diabetic individuals. With increasing age, they rely more on word recalled from recency positions. Slide 33

34 DIABETES AND COGNITION Brains of individuals who carry the APOE4 genotype may be at greatest risk for being affected by poor glycemic control Correlation * ApoE4+ ApoE * * Slide 34

35 DIABETES AND COGNITION 1.5 P=.0004 HbA1c-Mean 1 HbA1c-Mean 2 HbA1c-Mean 3 HbA1c-Mean 4 Attention/Working Memory Hp 1-1 Hp 2-1 Hp 2-2 Hp Genotype Brains of individuals who carry the Hp11 genotype may be at greatest risk for being affected by poor glycemic control Slide 35

36 Glycemic control modulates the relationship of duration of disease with cognitive performance Overall Cognition Semantic Categorization R values r=0.002 Lowest HbA1c tertile <= r=0.061 Middle HbA1c tertile r= * Highest HbA1c tertile > R values r=0.027 Lowest HbA1c tertile <= r=0.005 Middle HbA1c tertile r= * Highest HbA1c tertile > Executive Functioning Attention r=0.05 Lowest HbA1c tertile <= r=-0.126* Middle HbA1c tertile r=-0.176* Highest HbA1c tertile > R values r=0.068 Lowest HbA1c tertile <= r=0.08 Middle HbA1c tertile r= Highest HbA1c tertile > Memory R values r=-0.136* Lowest HbA1c tertile <= r=0.043 r= Middle HbA1c tertile Highest HbA1c tertile >

37 Slide 37 Empirical group trajectories of HbA1c over time

38 Relationships of HbA1c trajectories and cognition # OF PATIENTS ZOVERALL Standard Group LSMEAN Error 6 A1c10-Improve Slide 38 1 A1c6-Stable A1c7-Stable A1c7-Worsen A1c8-Worsen A1c9-Improve Pr > t Overall P- value # OF PATIENTS ZLANGUAGE Standard Pr > t Overall P- Group LSMEAN Error value 6 A1c10-Improve A1c6-Stable A1c7-Stable A1c7-Worsen A1c8-Worsen A1c9-Improve # OF PATIENTS ZEXECUTIVE Standard Pr > t Overall P- Group LSMEAN Error value 6 A1c10-Improve A1c6-Stable A1c7-Stable A1c7-Worsen A1c8-Worsen A1c9-Improve

39 Conclusions & Final Remarks Diabetes is a risk factor for cognitive compromise Diabetes medication may be one of the explanations for the discrepancy between the epidemiological and the neuropathological studies Characteristics related to diabetes (medications, glycemic control, methylglyoxal, defective insulin signaling) are associated with cognitive compromise. Our data suggest that basic cognitive patterns are maintained in T2D. Slide Copyright , Michal Schnaider Beeri. All Rights Reserved.

40 Conclusions & Final Remarks Some diabetes characteristics (such as glycemic control) seem to affect primarily cognitive functions consistently associated with cerebrovascular disease (working memory) and less so with neurodegeneration (episodic memory). Episodic memory seems to be more strongly associated with diabetic processes when genes associated with AD (such as APOE) are involved. These relationships pertain both to diabetic AND non-diabetic individuals suggesting that the characteristics rather than diabetes per se increase the risk for cognitive compromise. Long-term good glycemic control is associated with good cognitive performance, further suggesting that T2D per se may not a risk factor but rather poor control. Slide Copyright , Michal Schnaider Beeri. All Rights Reserved.

41 Thank You! Collaborators: Mount Sinai Sheba Medical Center Maccabi Vahram Haroutunian Ramit Ravona Springer Tony Heymann Jeremy Silverman Irit Lubitz Mary Sano Keren Koifman Rachel Preiss Derek Leroith Ruti Weiss Hadas Hoffman James Schmeidler Rotem Regev Tomas Karpati Erin Moshier Merav Meirovitch James Godbold Elad Omer Elizabeth Guerrero-Berroa Yofia Aharon Michael Wysocki Lital Schneider Pavel Katsel Orna Komissar Ronit Glinik Shytush Itzik Cooper Other collaborators: Claudia Kawas, UC Irvine, US Martha Clare Morris, U Rush, US John Mill, IOP, UK Andy Levy, Technion, Israel Slide 41 Funding: NIH, Helen Bader Foundation, Alzheimer s Association Israel Ministry of Science and Technology AFAR

Mild Cognitive Impairment (MCI)

October 19, 2018 Mild Cognitive Impairment (MCI) Yonas E. Geda, MD, MSc Professor of Neurology and Psychiatry Consultant, Departments of Psychiatry & Psychology, and Neurology Mayo Clinic College of Medicine