The Relationship Between Risk, Cognition and Structural Changes in the Brain

1. The Relationship Between Risk, Cognition and Structural Changes in the Brain

2. Investigators and Project Staff • Regina McGlinchey, Ph.D, Co-leader, Stats/Design • Christopher Brady, Ph.D, Co-leader, Geropsych • Farzaneh Sorond, M.D. and Jorge Serrador, Ph.D • Shannon Downey, Marcie Freeman, M.Ed., Sheila Burch, MSW, Subject Recruitment • Laura Grande, Ph.D, Project • coordinator/Neuropsychologist • James Rudolph, M.D., Project Physician • Margaret Ahlquist,BS, Lab Tech/Research Assistant • David Schnyer, Ph.D, neuroimaging consultant • Lew Lipsitz, M.D., hypertension and gait consultant • William Milberg, Ph.D, Humble Project Leader

3. Vascular Dementia between 1980’s and the 1990’s: An Epidemiological Mystery? Skoog et al (NEJM 1993: 826 , 85 y.o.’s in Gothenberg: Prevalance of all dementias: 29.8% of whom: 43.5% Alzheimer’s Disease 46.5% Vascular Dementia (MID, Hypoperfusion etc.)

4. Vascular Dementia between 1980’s and the 1990’s: An Epidemiological Mystery? Knopman et al (Arch Neurol 2003: 419 patients with dementia (Rochester Epi Project), 51% Alzheimer’s Disease 13% Vascular Dementia 12% Mixed

5. So What Happened: • Ante-Mortem versus Post-Mortem Methods • Cultural Differences Between Minnesota and Sweden • Vascular Dementia was cured! • The DSM III versus DSM IV

6. DSM-III: Definition of Dementia(circa 1980) • “a loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning”. • “the deficit is multifaceted and involves memory, judgment, abstract thought, and a variety of other higher cortical functions (page 107)”

7. memory impairment (impaired ability to learn new information or to recall previously learned information) one (or more) of the following cognitive disturbances: Diagnostic criteria for Dementia of the Alzheimer’s Type The development of multiple cognitive deficits manifested by both memory impairment (impaired ability to learn new information or to recall previously learned information) one (or more) of the following cognitive disturbances: aphasia (language disturbance) apraxia (impaired ability to carry out motor activities despite intact motor function) agnosia (failure to recognize or identify objects despite intact sensory function) disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting) The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. The course is characterized by gradual onset and continuing cognitive decline. The cognitive deficits in Criteria A1 and A2 are not due to any of the following: other central nervous system conditions that cause progressive deficits in memory and cognition (e.g., cerebrovascular disease, Parkinson’s disease, Huntington’s disease, subdural hematoma, normal-pressure hydrocephalus, brain tumor) systemic conditions that are known to cause dementia (e.g., hypothyroidism, vitamin B12 or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection) substance-induced conditions The deficits do not occur exclusively during the course of a delirium. The disturbance is not better accounted for by another Axis I disorder (e.g., Major Depressive Disorder, Schizophrenia). (DSM-IV-TR p. 157) (Page 157: DSM-IV 1994, TR in 2000)

8. memory impairment (impaired ability to learn new information or to recall previously learned information) one (or more) of the following cognitive disturbances: (DSM-IV-TR p. 160) Diagnostic criteria for 290.4x Vascular Dementia The development of multiple cognitive deficits manifested by both memory impairment (impaired ability to learn new information or to recall previously learned information) one (or more) of the following cognitive disturbances: aphasia (language disturbance) Apraxia (impaired ability to carry out motor activities despite intact motor function))agnosia (failure to recognize or identify objects despite intact sensory function) disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting) The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. Focal neurological signs and symptoms (e.g., exaggeration of deep tendon reflexes, extensor plantar response, pseudobulbar palsy, gait abnormalities, weakness of an extremity) or laboratory evidence indicative of cerebrovascular disease (e.g., multiple infarctions involving cortex and underlying white matter) that are judged to be etiologically related to the disturbance. The deficits do not occur exclusively during the course of a delirium. (Page 160: DSM-IV 1994, TR in 2000)

9. Most AD Begins in TemporalLimbic Cortex

10. Cognitive Disorders Accompany Disease of theCerebral White Matter

11. Sub- Cortical Microvascular Disease May Have its Greatest Impact on Frontal Association Cortex

12. Executive Functions • Starting • Stopping • Sustaining • Socialization • Switching • Sequencing • Self-Organization • Source Monitoring • Scheduling

13. Brady, CB, Spiro A, McGlinchey-Berroth, R, Milberg, W. and Gaziano, M. Stroke Risk Predicts Verbal Fluency Decline J. Gerontology (2001)56, 340-346:

14. CVD risk factors: Health Normative Aging Study (NAS) An ongoing longitudinal research project started in 1963 at the VA Boston Healthcare System. The NAS has collected an extensive database of medical, psychological, and lifestyle information on a cohort of 2,280 initially-healthy men. 1,461 participants currently active; 1,000 receive triennial examinations.

15. Cerebrovascular Risk Factors • Note: SBP = systolic blood pressure; • Hyp Rx = under hypertensive therapy; • DM = history of diabetes mellitus; • Cigs = smokes cigarettes; • CHD = history of myocardial infarction, • angina pectoris, or coronary insufficiency; • AF = history of atrial fibrillation; • LVH = left ventricular hypertrophy on electrocardiogram

16. Data collection points from NAS sample: Visit 1Visit 2 Neuropsychological tests Neuropsychological tests Medical exam Medical exam Note. There were 3 years between visits.

17. NAS stroke-free sample in Brady et al. (2001) n 256 Age 66.5 (range 50 - 85) Education 14.2 (range 6 - 24) Stroke risk score 8.4 (range 1 - 17) Neuropsychological exam (started 1993) Verbal fluency (animal) Digit span backward Word list learning (10 item) - immediate and delayed recall Pattern comparison

18. Variables predicting 3-year test score decline • Age • Education • Stroke risk score Question addressed by this analysis: Does CVD risk status at visit 1 predict cognitive change seen 3 years later at visit 2?

19. Stroke risk was associated only with decline in verbal fluency

20. Summary: Results in relatively healthy older men • Increasing age was associated with decline on all tests. • Increasing stroke risk was associated only with decline in verbal fluency, an index of executive function. • The relation between stroke risk and executive decline was nearly (89%) as large as the relation between age and executive decline. • These results suggest that even in relatively healthy older men, stroke risk exerted specific effects on a test of executive function but not on memory or visuospatial functions, and that the magnitude of these effects rivaled those of age effects.

21. The Relationship of CV Risk to Cognitionin Older African-Americans • Pugh • Kiely • Lipsitz • Milberg

22. Prevalence of Most Risk Factors is Higher in the African-American than General Population! -Lynch et al (2001): African-American Antiplatelet Stroke Prevention Study vs. 23 other stroke prevention studies Hypertension: 84% vs. c. 47% Diabetes: 39.1% vs. 17.1% -Brancati et al (1996) population based study Diabetes: 10.3% vs. 4.6% (double even controlling for SES!)

23. Pugh, KG., Kiely DK, Milberg WP, Lipsitz, (2003) Selective impairment of frontal-subcortical cognitve function in african-americans with cardiovascular risk Factors.

24. Pugh, Kiely, Milberg and Lipsitz (JAGS 2003)

25. Pugh, Kiely, Milberg and Lipsitz (JAGS 2003)

26. A Causal Triangle of Age Related Cognitive Disorders Risk Normal Aging----------Disease Cognition Brain

27. Risk, MRI Morphometry and Cognition Data From Harvard Older Americans Independence Center (AG08812 Lewis Lipsitz, PI) and VA Merit Review Collaborators: E. Leritz, D. Salat, L. Lipsitz, R. McGlinchey

28. * 4 (*completed sample expected 300-400 by 2008)

29. Neuropsych Factor Analysis

30. Physio Factor Analysis

31. Item v. Source Memory • Male v. Female Speaker • Forced Choice Sentence Recognition The seat on the bus was empty I will go to the movies on Saturday night.

32. NS *

33. NS *

34. Three MRI Morphometric Techniques: • Regional Morphometry • Cortical Thickness Maps • Diffusion Tensor Imaging 34

35. Morphometry and Factor Analysis

36. APOE and hippocampal volume NS *

37. Freesurfer Finds Pial Surface and the Grey/White Matter Junction

38. Inflates the Cortical Surface Showing Sulcal and Gyral Surfaces

39. APOE and cortical thickness Left Hemisphere Right Hemisphere

41. Physio Factor Analysis

42. Physio factor 1 & Thickness(BP Factor)

43. Physio 2 and Thickness(metabolic/cholesterol)

44. Physio 3 & Thickness(Cholesterol)

45. Physio 4 (Glucose)

46. Neuropsych Factor Analysis

47. NP CVLT Factor

48. NP Factor 2 (Executive Function)

49. NP Factor 3 (Logical Memory)

50. NP Factor 4(“retrieval-based” factor)