Transcript Cerebrovascular function with aging and in Alzheimer’s disease • Alzheimer’s disease, Aβ and vascular hypotheses. • Assessment of cerebral autoregulation and brain oxygen extraction.

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.
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
Cerebral blood flow
Lower limit of CBF autoregulation
24- hour blood
Pressure variability
Global 24-hour blood
Pressure mean.
Mean arterial blood pressure
Cerebral autoregulation with aging
CBF
Young
Old
50
80
CPP ( mmHg )
150
Cerebrovascular function with aging and in AD
Aging
Impaired baroreflex
function
Stiffness and degenerative
changes in cerebral
vasculature
+
+
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
120
2.5
90
2.0
60
140
120
100
80
60
40
20
1.5
1.0
0.5
0.0
1.5
60
80 100 120
MBP (mmHg)
1.0
100
80
60
40
20
0
-20
-40
-60
CVRI % / mmHg
100
80
60
40
20
0
-20
-40
-60
CVRI %
CBFV (cm/s)
30
CBFV %
Hypertension
Hypotension
150
CBFV % / mmHg
ABP (mmHg)
180
0.5
0.0
-0.5
-1.0
-1.5
-2.0
60
80 100 120
MBP (mmHg)
Young
Elderly
AD
MAP Time Series
mmHg
100
80
60
0
VMCA Time Series
cm/sec
120
100
80
0
0
60
120
180
Time (sec)
240
300
360
Zhang et al. AJP, 1998
cm/sec/ mmHg
Dynamic cerebral autoregulation
2.0
1.6
1.2
0.8
0.4
0.0
radians
1.5
1.0
0.5
0.0
-0.5
-1.0
-1.5
Index
1.0
0.5
0.0
0.0
0.07
0.1
0.2
Frequency (Hz)
0.3
0.5
Zhang et al. AJP, 1998
-20
Elderly
15
20
CBFV ( % )
10
5
0
-5
-10
-15
10
0
-10
-20
AD
30
60
15
CBFV ( % )
MBP ( mmHg )
0
-15
-30
30
0
-30
-60
0
120
240
360
0
Time (s)
120
240
360
150
600
200
2000
8000
1500
6000
CBFV ( % )
-10
800
100
50
400
200
0
0
800
150
600
CBFV ( % )
-10
0
200
100
50
400
200
0
0
CBFV ( % )
0
-5
10
MBP (mmHg 2 / Hz)
CBFV ( % )
MBP ( mmHg )
5
-15
MBP ( mmHg )
20
10
MBP (mmHg 2 / Hz)
Young
15
MBP (mmHg 2 / Hz)
BP and CBFV variability with aging and in AD
1000
500
0
0.00
0.25
4000
2000
0.50
0
0.00
Frequency (Hz)
0.25
0.50
Changes in systemic and cerebral hemodynamics during periodical
squatting in a young subject
140.4
105.3
mmHg
Finapress
175.5
70.2
TCD
72.7
36.4
cm/sec
109.1
EtCO2
5.9
4.0
2.0
%
0.0
0.0
75.560632
BPM
Cardiotach
113.340948
94.450790
56.670474
0.000000
-0.713399
-1.426799
3550.00000
3600.00000
seconds
Volts
ECG
0.713399
118.1
ECG
78.7
39.4
1.9
1.0
0.0
volts
Finapress
157.5
mmHg
Changes in systemic and cerebral hemodynamics during periodical
squatting in patients with early AD
Cardiotach
-1.0
TCD
91.8
61.2
EtCO2
30.6
0.0
5.0
3.3
1.7
0.0
2880.0
2910.0
seconds
2940.0
cm/sec
77.3
57.9
%
96.6
bpm
115.9
Transfer function assessment of dynamic
cerebral autoregulation and baroreflex function
Normalized gain (units)
6
A
5
4
3
2
1
0
Baroreflex gain (ms / mmHg)
10
8
6
4
2
0
B
Young
Elderly
AD
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.