Cerebrovascular function with aging and in Alzheimer’s disease

1. Cerebrovascular function with aging and in Alzheimer’s disease • Alzheimer’s disease, Aβ and vascular hypotheses. • Assessment of cerebral autoregulation and brain oxygen extraction reserve. • Pilot study of cerebrovascular function with aging and in patients with early Alzheimer’s disease.

2. Alzheimer's Disease, Dr. Alois Alzheimer (1906). President Ronald Reagan, Alzheimer's sufferer

3. The Impact of Alzheimer's Disease

4. AD Pathology – Aβ hypothesis AD Plaque, βamyloid deposition, amyloid precursor protein, PS1, PS2 genes Neurofibrillary Tangles, phosphorylated tau protein

5. Vascular disease increases risk of AD • Breteler MM. Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Ann N Y Acad Sci 903: 457-465, 2000. • Zhu L, et al. Incidence of dementia in relation to stroke and the apolipoprotein E epsilon4 allele in the very old. Findings from a population-based longitudinal study. Stroke 31: 53-60, 2000 • Seshadri S, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346: 476-483, 2002. • Launer LJ, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging 21: 49-55, 2000. • Haan MN, et al. Prevalence of dementia in older latinos: The influence of Type 2 diabetes mellitus, stroke, and genetic factors. J Am Geriatr Soc 51: 169-177, 2003.

6. De la Torre, Stroke 2002; 33:1152

7. Alzheimer’s disease - Vascular Hypothesis White matter lesions: radiologic appearance of vasculopathy of the small cerebral blood vessels. Scheltens P, et al. Lancet Neurology 1:13-21, 2002 Cerebral amyloid angiopathy (98%), microvascular degeneration (100%), microinfarctions (31%), intracerebral hemorrhages (7%). Kalaria RN and Ballard. Alzheimer’s Dis Assc Disord 13: s115-123, 1999

8. Hemodynamic and metabolic parameters of brain Brain tissue has a very high aerobic metabolic rate. Under resting conditions, about 15 ~ 20 % of the cardiac output is received by the brain in humans. This demand for oxygen supply is so imperative that only a few seconds of ischemia is sufficient to derange brain function profoundly and result in syncope. Nagata, Nuero Aging 2000; 21:301

9. Assessment of cerebrovascular function • Cerebral autoregulation: cerebral vessels dilate or constrict to alter cerebrovascular resistance to maintain CBF relatively constant in response to changes in cerebral perfusion pressure. • Brain oxygen-extraction reserve: The ability of cerebral vasculature and brain tissue to maintain cerebral metabolic rate for oxygen (CMRO2) utilization relatively constant in response to reduction in CBF.

10. Static cerebral autoregulation Edvinsson and Krause. Cerebral Blood Flow and Metabolism, 2002

11. Cerebral Autoregulatory and Oxidative Metabolic Reserve Stage 1 Stage 2 Ischemia Nagata, Nuero Aging 2000; 21:301

12. Is cerebrovascular function impaired in patients with Alzheimer’s disease?

13. Impaired cerebral autoregulation in transgenic mice overexpressing APP Niwa et al. Am J Physiol 283:H315, 2002

14. Correlations between autoregulation dysfunction index and brain concentrations of Aβ Niwa et al. Am J Physiol 283:H315, 2002

15. Dynamic nature and variability of arterial blood pressure Sir George Pickering. Hypertension: Pathophysiology, Diagnosis and Management. 1995 (Bevan et. Clin Sci 1969)

16. Zone of risk of cerebral hypoperfusion Lower limit of CBF autoregulation 24- hour blood Pressure variability Cerebral blood flow Global 24-hour blood Pressure mean. Mean arterial blood pressure

17. Cerebral autoregulation with aging Young CBF Old 50 80 150 CPP ( mmHg )

18. Cerebrovascular function with aging and in AD Aging Stiffness and degenerative changes in cerebral vasculature Impaired baroreflex function + + Over-expression of Aβ in AD + Rightward-shift or impaired cerebral autoregulation + + BP instability Attenuated CBF response to hypotensive stimuli Intermittent and transient brain ischemia, neuronal dysfunction and death

19. TCD measurement of beat-to-beat changes in CBF velocity

20. Static autoregulation with aging and in AD

21. MAP Time Series 100 80 mmHg 60 0 V Time Series MCA 120 100 cm/sec 80 0 0 60 120 180 240 300 360 Time (sec) Zhang et al. AJP, 1998

22. Dynamic cerebral autoregulation 2.0 mmHg 1.6 1.2 0.8 cm/sec/ 0.4 0.0 1.5 1.0 0.5 radians 0.0 -0.5 -1.0 -1.5 1.0 Index 0.5 0.0 0.07 0.0 0.1 0.2 0.3 0.5 Frequency (Hz) Zhang et al. AJP, 1998

23. BP and CBFV variability with aging and in AD

24. Changes in systemic and cerebral hemodynamics during periodical squatting in a young subject

25. Changes in systemic and cerebral hemodynamics during periodical squatting in patients with early AD

26. Transfer function assessment of dynamic cerebral autoregulation and baroreflex function

27. Conclusions • Systemic and cerebral hemodynamic instability increased in patients with early AD. • Static cerebral autoregulation during acute hypotension is impaired in the elderly and in patients with early AD. • Dynamic cerebral autoregulation as quantified by transfer function analysis is impaired in the elderly and to a greater extent in patients with early AD. • Baroreflex function is impaired with aging to a greater extent in patients with early AD.

28. Reduced cerebral vascular reserve in patients with carotid artery occlusion Derdeyn et al. Brain 125:595, 2002

29. PET study of cerebral autoregulation and brain oxygen extraction reserve

33. Conclusions • CBV responses to hypotension are attenuated in the elderly and in patients with early AD. • CBF is reduced during acute hypotension in early AD suggesting impaired cerebral autoregulation. • Brain oxygen extraction reserve (as reflected by the reduction in CMRO2 ) is reduced in patients with early AD.

34. Central hypothesis Cerebrovascular dysfunction plays an important role in the pathogenesis and development of Alzheimer’s disease.