detection of preclinical alzheimer’s diseas for the ... · center for development of advanced...
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National Center for Geriatrics and GerontologyCenter for Development of Advanced Medicine for Dementia
Katsuhiko Yanagisawa
Detection of preclinical Alzheimer’s diseasfor the preemptive therapy
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Stop Alzheimer Disease Before It Starts !
Greg Miller, Science 337, 790-792, 2012
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Mangialasche et al., Lancet Neurology, 9:702-716, 2010
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Illustration by Gracia Lam
A tangled web of targetsDrugs in development for Alzheimer's disease take aim at a variety of neural mechanisms.But despite a wealth of possibilities, there have been few successes. Lauren Gravitz
Nature 475, S9, 2011
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too late for therapeutic intervention
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Bateman et al, New Engl J Med, 367: 795-804, 2012
Carriers
Noncarriers
Estimated Yr fromSymptom Onset -20 -10 0
PiB-amyloid imaging on PET- Study on familial Alzheimer disease -
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clinical threshold
time
degr
ee
preclinicalAD
MCI AD muc
h co
gniti
ve re
serv
ele
ss c
ogni
tive
rese
rve
synapse loss
neuron loss
tangle formation
inflammation etc
Yanagisawa, Cognition and Dementia, 2012
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amyloid-dependent phase
amyloid-independent phase
Alzheimer Disease
・inflammation・oxidative stress
・mitochondria injuryetc
・impairment of calcium homeostasis・energy failureetc
・disruption of neuronal network
switch
modified from Yanagisawa. Igaku-no-Ayumi 239: 379-382, 2011
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amyloid-dependent phase
amyloid-independent phase
Alzheimer Disease
・inflammation・oxidative stress
・mitochondria injuryetc
・impairment of calcium homeostasis・energy failureetc
・disruption of neuronal network
anti-amyloid therapy
effective ineffective
switch
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Pathological stage of Alzheimer Disease
Modified Jack et al. The Lancet Neurology, 2010
previous and current clinical trials
preemptive therapysecondary prevention
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Alzheimer Disease
How should you know the pathological change before clinical onset?
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Cerebrospinal fluid examination
(Yahoo Japanより取得)
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Amyloid imaging on PET
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Plasma!
obtained from Yahoo Japan
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Rembach A et al., Alzheimer’s and Dementia,10: 53-61, 2014
Plasma amyloid ß-proteins Baseline
18-months later
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**
* **
* * * * **
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** * **
* * * *Aβ
[1-4
0]3000 3500 4000 4500 5000 5500m/z
x5 x5
n
n
nn
n
n nn n
0
20
40
60
80
100
*various Aßs and Aß-approximate peptides
Aβ[1
-42]
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Novel procedure to detect Aß from plasma usingmass spectrometry
Kaneko et al., Proc. Jpn. Acad. Ser. B,104-117, 2014
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