cerebrovascular function with aging and in alzheimer’s disease
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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. - PowerPoint PPT PresentationTRANSCRIPT
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