1. NEUROLOGICALSEQUELAE of DIABETESHYPERTENSION “NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION ” 1 Patrick A. GRIFFITH, MD, FAAN Professor Clinical Medicine (Retired). Former Professor of Neurology and Medical Director of the Clinical Research Center at Meharry Medical College in Nashville, Tennessee.

2. Disclosure Statement Patrick A. Griffith, MD, FAAN : Speakers’ Bureaus  Sunovion NIH Study Sections: A.N.I.E.  N.I.N.R.  Consultant/Advisory Board  Duke University, Bryan ADRC.  Emory University, ADRC Honoraria Wayne State University NMA, FM section. University of Wisconsin, SOM, Madison. Norman Seay Foundation, Knight ADRC, Washington Univ.,St.Louis, MO. MIMA Conference, Columbia,Missouri,” STAYING SHARP” lectures :Dana Foundation,” STAYING SHARP” lectures : Gainesville, GA. Grant/Research Support 0 2

3. 3 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

4. 4

5. 5

6. NEUROLOGICAL SEQUELAE of DIABETES : 6

7. 7 NEUROLOGICAL SEQUELAE of DIABETES:

8. NEUROLOGICAL SEQUELAE of DIABETES : 8

9. 9

10. 10

11. 11

12. NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION : 12

13. 13 NEUROLOGICAL SEQUELAE NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION

14. 14 NEUROLOGICAL SEQUELAE NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION

15. 15 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

16. 16 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

17. 17

18. 18

19. Willis Dementia Occurring Post-apoplexy Binswanger, Alzheimer Arteriosclerotic Dementia, SAE Kraepelin Arteriosclerotic Dementia DSM-I Chronic Brain Syndrome Hachinski Scale Roman Lacunar Dementia Erkinjuntti Cortical vs. Subcortical NINDS- AIREN Criteria DSM-IV Executive Dysfunction Katzman AD is the Main Cause of Atrophy and Dementia DSM-III MID NINDS- ADRDA Criteria for AD 1672 1894 1907 1952 1974 1976 1980 1984 1985 1987 1993 1994 1996 VaD AD VaD DEMENTIADEMENTIA Pathological Reports of Alzheimer’s disease (AD) CADASIL First Genetic Form of VaD VASCULAR DEMENTIA[VaD]: An historical perspective – Salloway, S. 03/2000 19

20. 20

21. NEUROLOGICAL SEQUELAE of HYPERTENSION : 21

22. NEUROLOGICAL SEQUELAE of HYPERTENSION : 22

23. NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION 23

24. Genes Vascular Risk Factors Capillary Brain Injury Symptoms/Signs Large ArteryMajor Infarct STROKE ArterioleLacune WML Stroke or “Silent” Stroke LDL-C Homo Cysteine CAA HTN DM ApoE4 FAD CapillaryMicroinfarctOther Behavior Other Genes:*** ACE (D/D) NO Synthase Prorenin Chui, H. C. April, 2004. 24 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

25. NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION 25 Abrupt “Stepwise” PresentPresentPresentCADASIL “Spotty deficits” Executive dysfunction often prominent “Spotty deficits” Executive dysfunction often prominentInsidious Slow, gradual Usually absent May be present Present Memory, naming  with typical progression OnsetProgression Focal neurologic signs or symptoms Vascular Risk Factors (eg, HTN, DM, TIA/CVA, CAD ) Genetics Cognitive profile VASCULAR DEMENTIA AD

26. 26 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

27. NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION : 1.Clues to a NON-Alzheimer's Etiology for Dementia Youth Sleepiness or reduced state of alertness History of STROKE Prominent headache Rapid course Fever 27 Ethnicity & Disease, 2002, Volume 12(1) s2-25 + s2-27 Caplan, L. 1976

28. NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION : 2.Clues to a NON-Alzheimer‘s Etiology for Dementia Seizures Prominent early motor, reflex, or visual abnormalities Focal neurological signs Abnormal gait History of STROKE 28 Ethnicity & Disease, 2002, Volume 12(1) s2-25 + s2-27 Caplan, L. 1976

29. Type of Dementia by Ethnicity (percentage of cases in Ethnic group) Note: p <.001; N = 4,875. For 271 (6%), the diagnosis was another type of Dementia; for 325 (7%), Amnestic Syndromes; and for 244 (5%), the diagnosis was deferred. Yeo, et al; in Ethnicity and Dementia, Taylor & Francis Eds, 1996,pp. 21-30. Types of DEMENTIA by Ethnicity : 29

30. 30 p.188: Karger,Basel 1999. “Stroke in Blacks” “Stroke in Blacks” Eds.: Gillum, RF Gorelick, PB & Cooper, ES. NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

31. Non-modifiable VaD risk factors Age Race Gender Genetics Gorelick PB, Griffith P. In: Gillum RF, Gorelick PB, Cooper ES, eds. Stroke in Blacks. Basel: Karger; 1999:188-197.

32. 32

33. VASCULAR DEMENTIA: Risk Factors Gorelick & Nyenhuis 1998 DEMOGRAPHIC Age Male sex RACE/Ethnicity (e.g. Asians, African-Americans ?Caribbean-Africans ? Caribbean Hispanics) Lower educational level Stroke 2004;35[Suppl 1]:2620-2622. GENETIC  CEREBRAL AUTOSOMAL DOMINANT ARTERIOPATHY with SUBCORTICAL INFARCTS and LEUCOENCEPHALOPATHY [C.A.D.A.S.I.L.]  ApoE : e4 allele 33

34. NEUROLOGICAL COMPLICATIONS of DIABETES & HYPERTENSION Vascular Dementia Clinical Profile: Older more Men Higher HACHINSKI Score More CV diagnoses More CV medications More Cerebro-Vascular Disease on Imaging 34 Salloway,S.- Neurology 2003;60:A141-A142.

35. NEUROLOGICAL SEQUELAE NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION : 35

36. 36 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

37. 37 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

38. 38 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

39. 39 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION

40. NEUROLOGICAL COMPLICATIONS of DIABETES & HYPERTENSION 40

41. 41 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION

42. 42 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

43. 43

44. the NEUROLOGICAL SEQUELAE DIABETES & HYPERTENSION: LEARNING Objectives : After attending this lecture, participants will know - How to Diagnose & Treat the NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION: 44

45. 45 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

46. 46 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

47. 47

48. 48

49. NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION : 49

50. 50 St. LOUIS UNIVERSITY SCHOOL of MEDICINE, St. Louis,MO,USA

51. VASCULAR DEMENTIA [VaD] NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION = VASCULAR DEMENTIA [VaD] An Historical Perspective; Salloway,S.2003. 51 Willis Dementia Occurring Post-apoplexy Binswanger, Alzheimer Arteriosclerotic Dementia, SAE Kraepelin Arteriosclerotic Dementia DSM-I Chronic Brain Syndrome Hachinski Scale Roman Lacunar Dementia Erkinjuntti Cortical vs. Subcortical NINDS- AIREN Criteria DSM-IV Executive Dysfunction Katzman AD is the Main Cause of Atrophy and Dementia DSM-III MID NINDS- ADRDA Criteria for AD 1672 1894 1907 1952 1974 1976 1980 1984 1985 1987 1993 1994 1996 VaD AD VaD DEMENTIADEMENTIA Pathological Reports of Alzheimer’s disease (AD) CADASIL First Genetic Form of VaD

52. NINDS-AIREN criteria for VaD Developed for use in clinical trials Evidence for CEREBRO-VASCULAR DISEASE[CVD] from neurologic examination & neuro-imaging Impaired memory plus two other cognitive domains Temporal relationship between Dementia & CVD – Probable VaD – Possible VaD Roman GC, et al. Neurology. 1993;43:250-260. 52

53. VASCULAR DEMENTIA Clinical Differences Between VASCULAR DEMENTIA & AD : 53 NEUROLOGICAL SEQUELAE of DIABETES &HYPERTENSION :

54. 54

55. Two Extremes of VaD and AD Description Pure AD Plaque only AD AD with Severe CAA CAA with Plaques AD with Vascular Lesions AD with Cerebrovascular Disease VaD with AD changes VaD with AD changes VaD with Small-vessel Disease VaD with Small-vessel Disease Pure VaD Pure VaD Identifying Features Plaque with Neurofibrillary Pathology Only Lack of Neurofibrillary Pathology Profound Vascular Amyloid Deposition Mild AD with Vascular Involvement Vascular Lesions include Microinfarcts Mixed Dementia Mixed Dementia or Coincidental AD Pathology Prominent Micro-vascular Changes Infraction only and White Matter Lesions R Kalaria/Journal of Nerological Sciences 203-204 (2002) 29-34 55

56. NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION: 56 VASCULAR DEMENTIA[VaD] = 15% patients SECOND VaD is the SECOND most common form of Dementia in the elderly VaD Incidence increases with age Primary Care Physicians[PCPs] are the main gatekeepers. VaD is an unsatisfied market DLB DLB=dementia with Lewy bodies.  Small GW, et al. JAMA. 1997;278:1363-1371.  Morris JC. Clin Geriatr Med. 1994;10:257-276. Alzheimer’s disease (AD) 65% VaD VaD and AD 5% DLB and Parkinson’s Other dementias 8% 7% AD and DLB 10% 5%

57. NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION 57 Mild Cognitive Impairment [MCI] Alzheimer’s disease VASCULAR Dementia VASCULAR Dementia Dementia with Lewy bodies Traditional dementia concept Other dementia VASCULAR Dementia Other dementia Dementia with Lewy bodies Alzheimer’s disease The emerging consensus Salloway,S.- Neurology 2003;60:A141-A142.

58. …” I tell you,when you were YOUNGER, you used to fasten your own belt and to go wherever you wished. But when you grow OLD, you will stretch out your hands, and someone else will fasten a belt around you and take you where you did NOT wish to go NEUROLOGICAL SEQUELAE of DIABETES & HYPERTENSION …” I tell you,when you were YOUNGER, you used to fasten your own belt and to go wherever you wished. But when you grow OLD, you will stretch out your hands, and someone else will fasten a belt around you and take you where you did NOT wish to go “….. JOHN 21: 18. 58. Patrick A. GRIFFITH, MD,FAAN Prof. Clinical Medicine [Ret’d] patrickgriffith30@gmail.com Mobile:1-404-216-6971