Early Brain Changes of Non-Amyloid
Pathways
Charles DeCarli, MD
Victor and Genevieve Orsi Chair in Alzheimer's
Research
Director University of California at Davis,
Alzheimer’s Disease Center
Acknowledgements
 Funded in part by Grant R13 AG030995
from the National Institute on Aging
 The views expressed in written conference
materials or publications and by speakers
and moderators do not necessarily reflect
the official policies of the Department of
Health and Human Services; nor does
mention by trade names, commercial
practices, or organizations imply
endorsement by the U.S. Government.
Outline
 Brain Aging: cognition and structural
imaging
 Potential Causes of heterogeneity
• Amyloidosis (brief)
• Vascular risk factors
 Time course of vascular risk on brain
 Inflammation and brain aging
Cross-sectional and Longitudinal
Memory Performance
Wilson et al, Arch Neuro, 1999
Wilson et al,Psychology and Aging, 2002
Clinical Consequences
Mungas, et al. Psychology and Aging, 2010
MRI Measures of Atrophy
Variability in Brain Aging
Summary
 Brain aging is heterogeneous
• Cognition
• Brain structure
Outline
 Brain Aging: cognition and structural
imaging
 Potential Causes of heterogeneity
• Amyloidosis (brief)
• Vascular risk factors
 Time course of vascular risk on brain
 Inflammation and brain aging
Percent PiB+ with Age
Morris et al, Annals of Neuro, 2010
Time Dependent
Differences
Jack, et al. JAMA Neurology, 2015
Age-Specific Prevalence of Vascular Disease and Brain
Volume
80.0%
80%
85.00%
70.0%
70%
80.00%
60.0%
60%
75.00%
50.0%
50%
70.00%
40.0%
40%
65.00%
30.0%
30%
60.00%
20.0%
20%
55.00%
10.0%
10%
0.0%
0%
50.00%
35-44
35-44
44-54
44-54
55-64
55-64
Framingham Heart Study, unpublished data
65-74
65-74
75-84
HTN
HTN
CAD
CVA
CAD
CVA
AD
AD
CVA
AD
Brain Volume
Brain
AD Volume
SBI
Brain Volume
Brain Volume
Prevalence of Vascular Risk Factors
among the Framingham Offspring
Measure
Result
Age
62 + 10
Percent Obese
33
Percent hypertensive
52
Percent treated hypertensive
40
Percent Diabetic
13
Percent current smoker
14
Percent CAD
17
Percent MI
6
Percent stroke/TIA
4
Percent atrial fibrillation
5
DeCarli, et al. Neurobiology of Aging, 2005
Women
Future Risk
of Stroke or
Dementia at
Age 65
Men
Seshadri, S. et al.
Stroke 2006;37:345-350
Spectrum of CVD
Stroke
MRI Infarction
White Matter Hyperintensities
Brain Atrophy
MRI Examples of WMH and
SBI
Normal
WMH
Extensive
WMH
Silent MRI
Infarct
Debette et al, Stroke, 2010
Age-Specific Prevalence of SBI
35
N=39
N=89
N=128
30
Prevalence of MR Infarcts (%)
Women
Men
25
Combined
N=201
N=214
N=415
20
N=300
N=322
N=622
15
N=85
N=100
N=185
N=314
N=714
N=400
10
5
0
5
6
7
Decade of Life
DeCarli, et al. Neurobiology of Aging, 2005
8
9
Aging White Matter Disease
80
70
60
0.29
50
40
0.25
30
0.23
20
10
0.20
0
30
40
50
60
70
Age
DeCarli, et al. Neurobiology of Aging, 2005
80
90
100
Vascular Risk
WMH volume (cc)
0.30
Quantification
of agerelated differences in
WMH
Define Large WMH as 1
sd above age-related
mean WMH
Vascular Risk and WMH
ECG- LVH
FSRP score
Men
127 + 16
18%
7%
17%
8%
0.7%
4%
14%
0.023 + 0.034 0.048 + 0.043
0.8
0.79
Cerebrum % TCV
SBP
HTN Rx
Diabetes
Smoker
History of CVD
Atrial fibrillation
Women
123 + 20
15%
4%
16%
4%
0.2%
0.78
0.77
0.76
0.75
0.74
Quartiles of FSRP
Q1
Q2
Q3
Q4
Risk Factors, Age and Brain Volume
Cognitive Consequences
Middle Life Vascular Risk
Factors and Dementia Risk
Whitmer, et al, Neurology, 2005
Increasing odds of Dementia with
number of Risk Factors*
*~74% Caucasian
Whitmer, et al, Neurology, 2005
Dementia Risk with MRI
Vascular Measures
Debette et al, Stroke, 2010
0 VR
Impact of Vascular
Risk (VR) on White
Matter Integrity
and Gray Matter
Atrophy
1 VR
2 VR
3 VR



Significant change in FA
Significant negative
Jacobians
Both
Maillard et al, Neurobiology of Aging, 2015
Significant FA loss
/year
Significant Atrophy
/year
**
**
*
*
**
Number of VR
1 VR
23%
2 VR
4%
27%
DIA
HTN
HYP
73%
HTN DIA
HYP DIA
59%
14%
HYP HTN
Annual change in
hippocampus volume
***
*
*
Number of Vascular Risk Factors
Summary II
 Vascular risk factors are common
 Vascular risk factors affect the brain
• Silent brain infarctions
• WMH
• Cerebral Atrophy
 Vascular risk factors affect cognition
and brain structure in a dose dependent
fashion
Outline
 Brain Aging: cognition and structural
imaging
 Potential Causes of heterogeneity
• Amyloidosis (brief)
• Vascular risk factors
 Time course of vascular risk on brain
 Inflammation and brain aging
Impact of
Vascular
Disease may
begin early
Maillard, et al, Lancet Neurology, 2013
Neurology, 2015
Diabetes and Brain Aging
Cognitive Consequences
Hypothetical Model of Vascular
Disease and Brain Atrophy
10
9
8
7
Severity
6
5
4
3
2
1
1
5
9
13
17
21
25
29
33
37
41
45
49
53
57
61
65
69
73
77
81
85
89
93
97
101
0
Amyloid
Vascular Risk
Age
CVD Brain Injury
Hypothetical Consequences
10
9
8
7
6
Cognition
VRF
VBI
5
4
3
2
SNAP?
1
Age
1
5
9
13
17
21
25
29
33
37
41
45
49
53
57
61
65
69
73
77
81
85
89
93
97
101
0
Summary III
 Advancing age is associated with comorbid diseases
• Alzheimer’s pathology
• Cerebrovascular pathology
 Vascular injury may begin early in life
• The number of vascular risk factors
appears additive to later life dementia
risk
 Vascular risk may contribute to
neurodegeneration in SNAP
Outline
 Brain Aging: cognition and structural
imaging
 Potential Causes of heterogeneity
• Amyloidosis (brief)
• Vascular risk factors
 Time course of vascular risk on brain
 Inflammation and brain aging
Atheroscler, Thromb, Vasc, Bio, 2011
Inflammation in Younger
Individuals
Interaction p-value indicates significant differences by
younger versus older
Inflammation and
Cognition
GDF-15 in Brain
Immunostaining of human cortex
from individual who had mixed
dementia (AD+vascular dementia).
Blue=cell nuclei stained with DAPI.
Green=microglia stained with IBA-1.
Red =immunostaining for GDF15.
Colocalization of GDF15 is noted in
microglia (arrows). Bar = 20um.
Model of Inflammation and
Brain Pathology in Aging
Summary IV
 Aging and atherosclerosis lead to
increasing inflammation
 Inflammation can lead to brain injury
and cognitive decline independent of
vascular risk factors
 Inflammation may lead to microglial
activation with release of harmful
cytokines
Conclusions
 Brain aging is heterogeneous
 Vascular risk factors cause subtle brain
injury and cognitive impairment in a
dose dependent manner
 Cerebral atrophy is a common
consequence of vascular risk
 Inflammation secondary to systemic
atherosclerosis may mediate some of
the atrophic process
UC Davis Alzheimer’s Disease Center
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Charles DeCarli
Dan Mungas
John Olichney
Sarah Farias
Berneet Kaur
Bruce Reed
Ladson Hinton
Laurel Beckett
Danielle Harvey
Cam Carter
Owen Carmichael
Lee-Way Jin
Joshua Miller
http://alzheimer.ucdavis.edu/
Supported by NIH:
P30 AG10129, P01 AG12435,
R01 AG010220, R01 AG021028,
R01 AG031252, R01 AG 031563,
DHS 98-14970, K01 AG030514
IDeA Lab
 Owen Carmichael
 Evan Fletcher
 Baljeet Singh
 Noel Smith
 Alexandra Roach
 Samuel Lockhart
 Jing He
 Pauline Maillard
Supported by NIH and the Dana
Foundation
http://neuroscience.ucdavis.edu/idealab/