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Cerebrovascular Functioning with Aging and with Alzheimers Disease

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Cerebrovascular Functioning with Aging and with Alzheimers Disease Powered By Docstoc
					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.

Alzheimer's Disease, Dr. Alois Alzheimer (1906).

President Ronald Reagan, Alzheimer's sufferer

The Impact of Alzheimer's Disease

AD Pathology – Aβ hypothesis

AD Plaque, β amyloid deposition, amyloid precursor protein, PS1, PS2 genes

Neurofibrillary Tangles, phosphorylated tau protein

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.

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•
•

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De la Torre, Stroke 2002; 33:1152

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

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

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.

Static cerebral autoregulation

Edvinsson and Krause. Cerebral Blood Flow and Metabolism, 2002

Cerebral Autoregulatory and Oxidative Metabolic Reserve

Stage 1

Stage 2

Ischemia

Nagata, Nuero Aging 2000; 21:301

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

Impaired cerebral autoregulation in transgenic mice overexpressing APP

Niwa et al. Am J Physiol 283:H315, 2002

Correlations between autoregulation dysfunction index and brain concentrations of Aβ

Niwa et al. Am J Physiol 283:H315, 2002

Dynamic nature and variability of arterial blood pressure

Sir George Pickering. Hypertension: Pathophysiology, Diagnosis and Management. 1995 (Bevan et. Clin Sci 1969)

Zone of risk of cerebral hypoperfusion
Lower limit of CBF autoregulation

Cerebral blood flow

24- hour blood Pressure variability

Global 24-hour blood Pressure mean.

Mean arterial blood pressure

Cerebral autoregulation with aging

Young
CBF Old

50

80

150

CPP ( mmHg )

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

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

Static autoregulation with aging and in AD
180

ABP (mmHg)

150 120 60 30 140 120 100 80 60 40 20 100 80 60 40 20 0 -20 -40 -60 60 MBP (mmHg) 100 80 60 40 20 0 -20 -40 -60 60 80 100 120 MBP (mmHg) 2.5 90

Hypertension Hypotension

CBFV % / mmHg CVRI % / mmHg CVRI %
80 100 120

2.0 1.5 1.0 0.5 0.0 1.5 1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0

CBFV %

CBFV (cm/s)

Young

Elderly

AD

MAP Time Series
100

mmHg

80

60 0

VMCA Time Series

120

cm/sec

100

80
0 0 60 120

Time (sec)

180

240

300

360

Zhang et al. AJP, 1998

Dynamic cerebral autoregulation
cm/sec/mmHg radians Index
2.0 1.6 1.2

0.8
0.4 0.0 1.5 1.0 0.5 0.0 -0.5 -1.0

-1.5 1.0

0.5

0.0

0.0

0.07

0.1

0.2

0.3

0.5

Frequency (Hz)

Zhang et al. AJP, 1998

BP and CBFV variability with aging and in AD
MBP ( mmHg ) CBFV ( % ) CBFV ( % ) CBFV ( % )
0.25 10 5 0 -5 -10 -15 15

CBFV ( % )

10 0 -10 -20 20

MBP (mmHg 2 / Hz)

15

Young

20

200 150 100 50 0 200 150 100 50 0 2000 1500 1000 500 0 0.00

800 600 400 200 0 800 600 400 200 0 8000 6000 4000 2000 0 0.00

Elderly

MBP ( mmHg )

10 5 0 -5 -10 -15 30

CBFV ( % )

10 0 -10 -20

AD

0 -15 -30 0 120 240 360

CBFV ( % )

15

30 0 -30 -60 0 120 240 360

MBP (mmHg 2 / Hz)

60

MBP ( mmHg )

MBP (mmHg 2 / Hz)

0.50

0.25

0.50

Time (s)

Frequency (Hz)

Changes in systemic and cerebral hemodynamics during periodical squatting in a young subject
Finapress
175.5 140.4 105.3 70.2 109.1 72.7 36.4 0.0 5.9 4.0 2.0 0.0

EtCO2

Cardiotach

75.560632 56.670474 0.713399

ECG

0.000000 -0.713399 -1.426799 3550.00000 3600.00000 seconds

Volts

BPM

113.340948 94.450790

%

cm/sec

TCD

mmHg

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

Finapress

118.1 78.7 39.4 1.9 1.0 0.0 -1.0

ECG

Cardiotach

115.9 96.6 77.3 57.9

61.2 30.6 0.0 5.0 3.3 1.7 0.0 2880.0 2910.0 seconds 2940.0

EtCO2

%

cm/sec

TCD

91.8

bpm

volts

mmHg

157.5

Transfer function assessment of dynamic cerebral autoregulation and baroreflex function
6

A

Normalized gain (units)

5 4 3 2 1 0

10

B
Young Elderly AD

Baroreflex gain (ms / mmHg)

8 6 4 2 0

Conclusions
1. Systemic and cerebral hemodynamic instability increased in patients with early AD. 2. Static cerebral autoregulation during acute hypotension is impaired in the elderly and in patients with early AD. 3. Dynamic cerebral autoregulation as quantified by transfer function analysis is impaired in the elderly and to a greater extent in patients with early AD.
4. Baroreflex function is impaired with aging to a greater extent in patients with early AD.

Reduced cerebral vascular reserve in patients with carotid artery occlusion

Derdeyn et al. Brain 125:595, 2002

PET study of cerebral autoregulation and brain oxygen extraction reserve

Conclusions
1. CBV responses to hypotension are attenuated in the elderly and in patients with early AD.

2. CBF is reduced during acute hypotension in early AD suggesting impaired cerebral autoregulation.
3. Brain oxygen extraction reserve (as reflected by the reduction in CMRO2 ) is reduced in patients with early AD.

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


				
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