Significance of White Matter
Hyperintensities in MCI
Charles DeCarli
University of California at Davis
Alzheimer’s Disease Center
Imaging of Dementia and Aging
(IDeA) Laboratory
MCI is Early AD
AD Process
Hippocampal
Injury
MCI
AD
Petersen et al, Arch Neurol, 2001
White Matter Hyperintensities
T1
PD
T2
Vascular Risk Factors Predict WMH
Risk Factor
P-value
Age
<0.0001
Diabetes
0.0113
Heart Disease
<0.0001
Systolic Blood Pressure
<0.0001
Left Ventricular
Hypertrophy
Treated Hypertension
0.0001
<0.0001
Jeerakathil, et al, Stroke, 2004
WMH Quantification
White Matter Hyperintensities
and MCI
Predictor Variable
Adjusted RR and
95% CL
Age
1.18 [1.03,1.35]
WMH
5.34 [1.80,15.9]
ApoE4
3.54 [1.43,8.78]
Diastolic BP
1.70 [1.07,2.71]
DeCarli et al, Arch Neurol, 2001
WMH are Associated with
Episodic Memory Deficits
•
•
•
•
DeCarli et al, Arch Neurol, 2001
Wu et al, Neurology, 2002
Lopez et al, Arch Neurol, 2003
Petkov et al, J Int Neuropsychol Soc, 2004
Role of AD and WMH
In MCI
AD Process
Hippocampal
Injury
MCI
White Matter
Injury
CVD
Executive
Control
Deficit
Different Mechanisms of Episodic Memory
Failure in MCI
Christine Wu Nordahl, Charan Ranganath, Andrew Yonelinas, Charles DeCarli,
Bruce Reed,William J. Jagust
Neuropsychologia 43(11) 1688-1697; 2005
IDeA Lab
aMCI Subtypes
.126 = 25th percentile
19.375 = 75th percentile
80
40
70
MCI-HA
35
MCI-WMH
60
30
50
Count
Count
25
20
40
30
15
20
10
10
5
0
0
.04
.06
.08
.1
.12 .14 .16 .18
Normalized hippocampal volume
.2
.22
-20
0
20
40
60
80
WMH volume volume
White matter hyperintensity
Based on SALSA dataset, n=122
100
Subject Characteristics
Controls
MCI-HA
MCI-WMH
n
20
11
11
Age
78.65 (6.34)
74.55 (5.65)
77.64 (3.56)
Education
15.6 (2.79)
15.8 (3.46)
13.5 (1.51)
Gender (M/F)
5/15
4/7
5/6
MMSE
29.63 (0.49)
27.46 (1.81)*
27.27(2.45)*
Left HC
.150 (.03)
.102 (.03)*
.148 (.02)
Right HC
.152 (.02)
.107 (.03)*
.147 (.01)
WMH load
13.15 (15.185)
7.66 (2.93)
34.38 (12.2)*
Hypertension
47%
45%
82%
Type II Diabetes
12%
0%
27%
* differs from other groups, p < .05
Behavioral Tasks
1. Episodic Memory Task: Object-Color Association
study
18 red/18 green
delay
~60m
test
red or green?
MCI-HA and MCI-WMH are equally impaired on the
color association episodic memory task
.9
.8
Accuracy
*
*
.7
.6
.5
.4
episodic memory
control
MCI-HA
MCI-WMH
* Differs from controls and MCI-HA p < .01
Behavioral Tasks
2. Working Memory Task: Item Recognition
2, 4, 6 - item verbal
4 - item spatial
A
D
+
B
+
b
R
study
delay
2 sec
probe
MCI-WMH are impaired on the item recognition task
1
.9
*
*
**
*
Accuracy
.8
.7
.6
.5
.4
2-item verbal
4-item verbal
control
6-item verbal
MCI-HA
4-item spatial
MCI-WMH
* Differs from controls and MCI-HA p < .01
** Differs from controls p < .01, Differs from MCI-HA p = .08
Behavioral Tasks
3. Working Memory Task: N-back
- 1-back
- 2-back
S
…
S
X
B
1-back target
x
t
T
2-back target
1-back target
MCI-WMH are also impaired on the n-back
working memory tasks
S
S
X
…
B
x
t
T
1
Accuracy
.9
*
*
.8
.7
.6
.5
.4
1-back
2-back
control
control MCI-HA
MCI-HC MCI-WMH
MCI-WM
* Differs from controls and MCI-HA p < .01
Summary of Behavioral Data
• MCI-HC and MCI-WMH are equally impaired on
the episodic memory task
• MCI-WMH are impaired on working memory,
both in simple maintenance as well as a more
complicated task involving manipulation and
maintenance
White Matter Changes Compromise Prefrontal
Cortex Function in Healthy Elderly
Christine Wu Nordahl, Charan Ranganath, Andrew Yonelinas, Charles DeCarli,
Evan Fletcher,William J. Jagust
In Press: Journal Cognitive Neuroscience
IDeA Lab
Behavioral Tasks
Episodic Retrieval
delay
~60m
Study (prior to scanning)
18 red/18 green
A
Working memory:
Low and high loads
D
+
B
Test (during scanning)
red or green?
+
b
delay
2 sec
probe
R
study
Working memory activations
• Bilateral dorsal prefrontal cortex activations
• Bilateral ventral prefrontal cortex activations
Working memory task:
Dorsal prefrontal cortex function is negatively
correlated with WMH severity
Left Dorsal PFC
Right Dorsal PFC
9
8
7
6
5
4
3
2
1
0
-1
12
10
8
6
4
r = -. 718
p = .004
2
0
-2
-1.5
-1
-.5
0
.5
1
1.5
-2
-2
-1.5
WMH severity
-1
-.5
0
.5
1
1.5
WMH severity
Anterior Cingulate
10
Consistent with evidence suggesting
that dorsal PFC is more affected in aging
9
8
7
6
5
4
4
3
2
1
0
-1
4
r = -. 718
Working memory task:
p = .004
Anterior cingulate cortex function is negatively
correlated with WMH
WMH
severity severity
WMH severity
2
0
-2
-1.5
-1
-.5
0
.5
1
-2
1.5
-2
-1.5
-1
-.5
Anterior Cingulate
10
9
8
7
6
5
4
3
2
1
0
-1
-2
-1.5
-1
-.5
0
.5
1
1.5
WMH severity
Anterior cingulate activity is associated with cognitive control (ie. ability to
guide thought and action in accordance with internal intentions)
Functional connectivity between anterior cingulate and PFC mediates
successful task performance (Kondo et al 2004)
0
.5
Summary of fMRI Data
•
WMH a presumed indicator of cerebrovascular
brain injury is associated with working memory
impairment
•
Executive control processes are likely involved
and related to amount of WMH
Disconnection of Working Memory
Processes by White Matter Hyperintensities
Adriane Mayda
Graduate Student, IDeA Lab
University of California at Davis
Disconnection Hypothesis
Vascular
Factors
White Matter
Injury
WMH
?
 FA
Cognitive
Deficits
Anisotropy Mapping
Location of WMH in MCI
Normal Controls (n=30)
MCI (n=29)
Location of WMH and ROI
R
A
A
P
P
A
P
Correlations
1.02
1.02
1
1
0.98
0.98
R2 = 0.62
0.96
0.96
2
Accuracy
Acccuracyy
R = 0.20
0.94
0.92
0.94
0.92
0.9
0.9
0.88
0.88
0.86
0.86
0.84
0.82
-1
-0.8
-0.6
-0.4
-0.2
0
Log WMH (%TCV)
Total WMH
0.2
0.4
0.6
0.8
0.84
200
250
300
350
Fractional Anisotropy
FA within WMH
400
Summary
• aMCI has at least 2 subtypes
– Hi WMH
– Small Hippocampi
• Amnesia in MCI-WMH results from
– Impairments in executive control
– Reduced prefrontal activation
– Disconnection from posterior targets
Conclusions
• WMH are common to the elderly
• WMH alone can be associated with episodic
memory impairments
• WMH likely contribute to susceptibility to
late life cognitive impairment and dementia
• WMH are potentially modifiable
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•
•
•
•
Adriane Mayda
Christine Nordahl
Evan Fletcher
Owen Carmichael
IDeA Lab
Supported by NIH:
P30 AG10129, R01 AG09029,
R01 AG021028, R01 NS 29993,
P01 AG12435, P01 AG0027232,
R01 AG111101, R01 AG08122,
R01 AG16495, U01 AG024904
http://neuroscience.ucdavis.edu/idealab/