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

Neurofibrillary Tangles, phosphorylated tau protein

AD Pathology – Aβ hypothesis

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.

De la Torre, Stroke 2002; 33:1152

Alzheimer’s disease - Vascular Hypothesis

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

White matter lesions: radiologic appearance of vasculopathy of the small cerebral blood vessels. Scheltens P, et al. Lancet Neurology 1:13-21, 2002

Hemodynamic and metabolic parameters of brain

Nagata, Nuero Aging 2000; 21:301

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.

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

Nagata, Nuero Aging 2000; 21:301

Cerebral Autoregulatory and Oxidative Metabolic Reserve

Stage 1 Stage 2 Ischemia

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)

Cer

ebra

l blo

od fl

owZone of risk of cerebralhypoperfusion

24- hour bloodPressure variability

Global 24-hour bloodPressure mean.

Lower limit of CBF autoregulation

Mean arterial blood pressure

50 150

CPP ( mmHg )

CB

F

Young

Old

80

Cerebral autoregulation with aging

Aging

BP instability

Impaired baroreflex function

Stiffness and degenerative changes in cerebral vasculature

Rightward-shift or impaired cerebral autoregulation

Attenuated CBF response to hypotensive stimuli

Intermittent and transient brain ischemia, neuronal dysfunction and death

Over-expression of Aβ in AD

+

+

+

+

+

Cerebrovascular function with aging and in AD

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

CB

FV %

/ m

mH

g

0.0

0.5

1.0

1.5

2.0

2.5

CVR

I % /

mm

Hg

-2.0-1.5-1.0-0.50.00.51.01.5

Hypertension Hypotension

MBP (mmHg)60 80 100 120

CB

FV %

-60-40-20

020406080

100

MBP (mmHg)60 80 100 120

CVR

I %

-60-40-20

020406080

100

ABP

(mm

Hg)

306090

120150180

CB

FV (c

m/s

)

20406080

100120140

Young Elderly AD

Static autoregulation with aging and in AD

MAP Time Seriesm

mH

g

0

60

80

100

VMCA Time Series

Time (sec)0 60 120 180 240 300 360

cm/s

ec

0

80

100

120

Zhang et al. AJP, 1998

radi

ans

-1.5-1.0-0.50.00.51.01.5

Frequency (Hz)

cm/s

ec/m

mH

g

0.0

0.4

0.8

1.2

1.6

2.0

0.0 0.1 0.2 0.3 0.5

Inde

x

0.0

0.5

1.0

0.07

Dynamic cerebral autoregulation

Zhang et al. AJP, 1998

Young

AD

Elderly

MB

P ( m

mH

g )

-15-10-505

1015

MB

P ( m

mH

g )

-15-10-505

1015

Time (s) 0 120 240 360

MB

P ( m

mH

g )

-30

-15

0

15

30

CB

FV (

% )

-20

-10

0

10

20

CB

FV (

% )

-20

-10

0

10

20

0 120 240 360

CB

FV (

% )

-60

-30

0

30

60

MB

P (m

mH

g 2

/ Hz)

0

50

100

150

200

CB

FV (

% )

0

200

400

600

800

MB

P (m

mH

g 2

/ Hz)

0

50

100

150

200

CB

FV (

% )

0

200

400

600

800

Frequency (Hz)0.00 0.25 0.50

MB

P (m

mH

g 2

/ Hz)

0

500

1000

1500

2000

0.00 0.25 0.50

CB

FV (

% )

0

2000

4000

6000

8000

BP and CBFV variability with aging and in AD

3550.00000 3600.00000seconds

70.2

105.3140.4175.5

mm

Hg

Fina

pres

s

0.036.4

72.7109.1

cm/s

ec

TCD

0.02.0

4.05.9

%

EtC

O2

56.67047475.56063294.450790113.340948

BPM

Car

diot

ach

-1.426799-0.7133990.000000

0.713399

Volts

ECG

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

2880.0 2910.0 2940.0seconds

39.478.7118.1157.5

mm

Hg

Fina

pres

s

-1.00.01.01.9

volts

ECG

57.977.3

96.6115.9

bpm

Car

diot

ach

0.030.661.2

91.8

cm/s

ec

TCD

0.01.73.35.0

%

EtC

O2

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

Nor

mal

ized

gai

n (u

nits

)

0

1

2

3

4

5

6

Bar

oref

lex

gain

(ms

/ mm

Hg)

0

2

4

6

8

10

Young ElderlyAD

A

B

Transfer function assessment of dynamic cerebral autoregulation and baroreflex function

Conclusions1. 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

Conclusions1. 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.

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

Central hypothesis