The Influence of Sleep on Cognition in Breast Cancer

The Influence of Sleep on
Cognition in Breast Cancer
Sonia Ancoli
Ancoli-Israel,
Israel, PhD
Professor of Psychiatry and Medicine
U i
University
it off C
California
lif i S
San Di
Diego
Fatigue by Rodin
Supported by NIC CA112035, UL1RR031980 (CTRI),
UCSD Stein Institute for Research on Aging, the
Department of Veterans Affairs Center of Excellence for
Stress and Mental Health (CESAMH) and the UCSD
Moores Cancer Center
Cognitive Function
What Cancer Patients Say
 “It's a fuzzy feeling, like trying to think through a
fog Throw in a little bit of exhaustion and fatigue,
fog.
fatigue
and it doesn't leave you at your cognitive best. It's
hard to concentrate. It's a little bit like the feeling
yyou get
g when yyou've had one or two or drinks too
many, and you don't want to be drunk.”
 Leroy Siever
 “… 7 y
years out of chemo treatments. I have been
telling my oncologist for years that I am still foggy. I
am terrified that I might make a terrible mistake at
my job, so I live in constant fear and stress.”
 Carolyn
C l S
S. 10
10-15-2007
15 2007
 “Having just surpassed my 38 year old wife's two
year anniversary of discovering her cancer, we have
found that her chemo brain actually worsened as
the time from her treatments lengthened
 Rick L. 11-06-2006
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Inflammation
Depression
Fatigue
Poor Sleep/
Disrupted
Circadian
Rhythms
Cancer;
py
Chemotherapy
ICCTF International Cognition and Cancer Task Force Conference
Cognitive Deficit
March 15
15--17
th
2012 – PARIS - FRANCE
JT075
07/25/03
C1W-1
07/26/03
07/27/03
08/01/03
C1W1
08/02/03
08/03/03
08/08/03
C1W2
08/09/03
08/10/03
08/15/03
C1W3
08/16/03
08/17/03
10/03/03
C4W1
10/04/03
10/05/03
10/13/03
C4W2
10/14/03
10/15/03
10/19/03
C4W3
10/22/03
10/21/03
0000
1200
2400
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
1200
th
2400
2012 – PARIS - FRANCE
Rhythmicity Over Time with Chemotherapy
N=95; For comparisons
between each time point vs.
baseline: * p < .05;
05; ** p < .01;
01;
*** p < .001; **** p < .0001
****
****
***
****
These data suggest that:
-the first administration of chemotherapy is associated with
transient circadian disruption
-repeated administration of chemotherapy results in
progressively worse and more enduring rhythm impairments.
impairments
Savard,J. et al. Sleep 32:1155-1160, 2009.
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Design
 75 women
 Mean age 51.8 years; SE 1.1
 diagnosed
g
with stage
g I-III breast cancer
 undergoing adjuvant or neo-adjuvant anthracycline-based
chemotherapy
 68 ageg and education-matched women with no historyy of anyy
cancer
 Mean age 51.8 years; SE 1.1
 Neuropsychological (NP) test battery; questionnaires on fatigue,
sleep quality, depressive symptoms, QOL; Patient’s Assessment
of Own Function (PAOF)
 Actigraph (Mini Mitter/Respironics/Phillips) was worn
 for 72 hours pre-treatment
 after four cycles of chemotherapy
 One-year post-chemotherapy
 Blood; structural MRI
 Each control woman was matched to and tested at the same
time points as a patient.
patient
ICCTF International Cognition and Cancer Task Force Conference
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Permission
P
i i obtained
bt i d
for photo
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2012 – PARIS - FRANCE
Demographics
Education
Patients: 49% college grads; 40% some college
Controls: 64% college grads; 30% some college
Race/Ethnicity:
Patients: 88% Caucasian; 3% AA; 9% Hispanic
Controls: 88% Caucasian; 3% AA; 6% Hispanic
Income (annual household )
Patients: 43% >$100
>$100,000
000
Controls: 41% >$100,000
ICCTF International Cognition and Cancer Task Force Conference
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15--17
th
2012 – PARIS - FRANCE
Fatigue/Sleep/Circadian Rhythms
Patients had significantly
g
y worse sleep,
p, slept
p less at night
g and more
during the day (naps), had more depressive symptoms and more
fatigue than controls pre-chemotherapy
Post-chemotherapy (end of Cycle 4), compared to controls and
compared to themselves at baseline, patients had significantly worse
sleep slept less at night and more during the day (naps),
sleep,
(naps) had more
depressive symptoms and more fatigue
At one year,
year patients still had significantly more subjective symptoms
(depressive symptoms, worse sleep quality and more fatigue) than
controls at one yyear,, but compared
p
to themselves,, were back to their
own baseline levels.
No significant differences in objective measures of sleep
ICCTF International Cognition and Cancer Task Force Conference
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2012 – PARIS - FRANCE
Sleep/Fatigue/Mood
Higher scores are worse
Within ggroups:
p Patients:BL-C4 pp=0.004;; BL-Y1 0.685;; C4-Y1 pp=0.013
Controls BL-C4 p=0..227; BL-Y1 0.731; C4-Y1 p=0.269
Between groups: Baseline p=0.004; Cycle 4 p<0.001; Year one p=0.006
Within groups: Patients: BL-C4
BL C4 p=0.0017;
p=0 0017; BL
BL-Y1
Y1 p=0.322;
p=0 322; C4-Y1
C4 Y1 p=0
p=0.0003
0003
Controls BL-C4 p=0 .0573;BL-Y1 p=0.932; C4-Y1 p=0.974
Between groups: Baseline p<0.001; Cycle 4 p<0.001; Year one p=0.028
Within groups: Patients: BL-C4
BL C4 p=0
p=0.011;
011; BL-Y1
BL Y1 p=0.459;
p=0 459; C4-Y1
C4 Y1 p=0
p=0.0004
0004
Controls BL-C4 p=0.108; BL-Y1 0.085; C4-Y1 p=0.911
Between groups: Baseline p=0.0001; Cycle 4 p<0.0001; Year one p=0.002
Within groups:Patients:BL-C4 p=0.525;BL-Y1 p=0.004;C4-Y1 p=0.001
Controls BL-C4 0.826; BL-Y1 0.900; C4-Y1 0.493
Between groups: Baseline p=0.006; Cycle 4 p=0.0002; Year one p=0.202
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
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2012 – PARIS - FRANCE
Change in Cognitive Ability
Subjective
j
Report
p ((PAOF))
 There was no difference between groups in reports prechemotherapy
 However, compared to their pre-chemotherapy scores patients
reported significantly worse cognitive function at the end of cycle 4
and at one year
 Objective NP testing
 There no significant differences between groups at any time point
 Within groups, the patients had no significant change from preprechemotherapy
h
th
tto cycle
l 4
BUT, controls significantly improved
 By one year, patients also showed improvement
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Subjective Report of Cognition
PAOF = Patient’s Assessment of Own Function
Higher score is worse function
Within groups: Patients: BL-C4 p=0.025; BL-Y1 p=0.070; C4-Y1 p=0.824
Controls: BL-C4 p=0.284; BL-Y1 p=0.139; C4-Y1 p=0.548
Between groups: BL p=0.851; C4 p=0.153; Y1 p=0049
Within ggroups:
p Patients: BL-C4 pp=0.0009;; BL-Y1 pp=0.011;; C4-Y1 pp=0.34
Controls: BL-C4 p=0.175; BL-Y1 p=0.274; C4-Y1 p=0.939
Between groups: BL p=0.899; C4 p=0.009; Y1 p=0.021
Within groups: Patients: BL-C4 p<0.0001; BL-Y1 p=0.0022; C4-Y1 p=0.334
Controls: BL-C4 p=0
p=0.076;
076; BL-Y1 p=0.161;
p=0 161; C4-Y1 p=0
p=0.703
703
Between groups: BL p=0.527; C4 p=0.012; Y1 p=0.114
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
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2012 – PARIS - FRANCE
Change in Cognitive Ability
Subjective
j
Report
p ((PAOF))
 There was no difference between groups in reports prechemotherapy
 However, compared to their pre-chemotherapy scores patients
reported significantly worse cognitive function at the end of cycle 4
and at one year
Objective NP testing
 There no significant differences between groups at any time point
 Within groups, the patients had no significant change from prechemotherapy
h
th
tto cycle
l 4
BUT, controls significantly improved
 By one year, patients also showed improvement
ICCTF International Cognition and Cancer Task Force Conference
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2012 – PARIS - FRANCE
Neuropsychological Composite Change Scores
better
Within groups: Patients: BL-C4 p=0.286;
Controls: BL-C4 pp=0.002;;
Between groups: NS
ICCTF International Cognition and Cancer Task Force Conference
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2012 – PARIS - FRANCE
Neuropsychological Composite Change Scores
better
Within groups: Patients: BL-C4 p=0.286; BL-Y1 p=0.0252; C4-Y1 p=0.055
Controls: BL-C4 pp=0.002;; BL-Y1 pp<0.001;; C4-Y1 pp=0.0056
Between groups: NS
ICCTF International Cognition and Cancer Task Force Conference
March 15
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2012 – PARIS - FRANCE
Neuropsychological Composite Change Scores
NP Composite Change Scores
mean change (SEM )
Better score
0,25
0,2
BL-C4 p=0.286
BL-C4 p=0.002
0,15
BL-Y1 p=0.0252
BL-Y1 pp<0.0001
C4-Y1 p=0.055
C4-Y1 p=0.0056
patients
controls
0,1
0,05
0
Baseline-Cycle 4
Baseline-Year 1
Cycle 4-Year 1
Between groups NS
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2012 – PARIS - FRANCE
Percent with objective cognitive
d li
decline
Baseline–Cycle 4
Cycle 4–One Year Baseline-One Year
C
Cancer
Patients
%
46%
%
N
28/61
/
39%
Controls
26%
14/53
26%
Fisher’s test
p=0.0346
ICCTF International Cognition and Cancer Task Force Conference
%
N
16/41
%
29%
%
N
12/41
/
8/31
18%
6/33
p=0.30
March 15
15--17
p=0.30
th
2012 – PARIS - FRANCE
Predictors of Changes in Cognition –
C
Composite
it S
Score ((patients)
ti t )
Baseline Cycle 4
Baseline–Cycle
R2
p-value
Rhythm Robustness (f-statistic)
0 15
0.15
Sleep quality (PSQI)
Cycle 4–One
4 One Year Baseline-One
Baseline One Year
0 03
0.03
R2
0 18
0.18
p-value
0 03
0.03
R2
0 09
0.09
p-value
0 02
0.02
0.17
0.04
0.27
0.003
-
-
Night time sleep duration
0 16
0.16
0 02
0.02
-
-
-
-
PAOF Total
0 25
0.25
0 015
0.015
-
-
-
-
PAOF Memory
0.25
0.015
-
-
-
-
PAOF Language
L
0 31
0.31
0 0016
0.0016
-
-
-
-
NS: Fatigue, depressive symptoms, napping
All linear regression models adjusted for age, college and BL composite NP score
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Predictors of Changes in Cognition –
E i di Learning
Episodic
L
i Memory
M
Baseline–Cycle 4
R2
p-value
Rhythm Robustness (f-statistic)
0.39
Fatigue (MFSI)
Cycle 4–One Year Baseline-One Year
0.007
R2
-
p-value
-
R2
-
p-value
-
0.43
0.001
-
-
-
-
p
Symptoms
y p
(CES-D)
(
)
Depressive
0.40
0.006
-
-
-
-
Total nap duration
0.38
0.01
0.15
0.04
-
-
p
Number of naps
0.36
0.02
-
-
-
-
-
-
-
-
0.32
0.036
0.41
0.032
-
-
0.31
0.045
PAOF Total
PAOF Language
NS l
NS:sleep
(PSQI)
(PSQI); PAOF memory
All linear regression models adjusted for age, college and BL composite NP score
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2012 – PARIS - FRANCE
Predictors of Changes in Cognition –
E
Executive
ti F
Function
ti
Baseline Cycle 4
Baseline–Cycle
R2
p-value
Rhythm Robustness (f-statistic)
(f statistic)
-
Sleep quality (PSQI)
Night time sleep duration
Cycle 4–One
4 One Year Baseline-One
Baseline One Year
-
R2
0 10
0.10
p-value
0 03
0.03
R2
-
p-value
-
-
-
0.15
0.008
-
-
0 16
0.16
0 02
0.02
-
-
-
-
NS: Fatigue, depressive symptoms, nighttime sleep, napping, PAOF
All linear regressioin models adjusted for age, college and BL composite NP score
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Predictors of Changes in Cognition –
Att ti /W ki M
Attention/Working
Memory
Baseline Cycle 4
Baseline–Cycle
R2
p-value
Rhythm Robustness (f-statistic)
(f statistic)
0 10
0.10
Sleep quality (PSQI)
Fatigue
g ((MFSI))
Total nap duration
Number of naps
Cycle 4–One
4 One Year Baseline-One
Baseline One Year
0 004
0.004
R2
-
p-value
-
R2
-
p-value
-
0.11
0.05
0.08
0.06
0.004
0.03
0.008
0.02
-
-
-
-
PAOF Total
0.13
0.016
-
-
-
-
PAOF Memory
0.12
0.0246
-
-
-
-
PAOF Language
0.17
0.004
-
-
-
-
NS: depressive symptoms, nighttime sleep
All linear regression models adjusted for age, college and BL composite NP score
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March 15
15--17
th
2012 – PARIS - FRANCE
Predictors of Changes in Cognition –
P
Processing
i S
Speedd
Baseline–Cycle 4
R2
p-value
PAOF Total
0.19
PAOF Memory
PAOF Language
Cycle 4–One Year Baseline-One Year
0.016
R2
-
p-value
-
R2
-
p-value
-
0.18
0.031
-
-
-
-
0.21
0.008
-
-
-
-
NS: Rhythm robustness, sleep quality, fatigue, depressive symptoms, objective measures of sleep
All linear regression models adjusted for age, college and BL composite NP score;
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2012 – PARIS - FRANCE
Relation of Chemobrain to
Fatigue/Sleep/Rhythms: Full Model
Decrease in overall cognitive ability associated with
Low baseline NP composite score
Not having a college degree
AND
Less robust circadian activity rhythm
At all time points
Poor sleep quality (PSQI)
Night time sleep duration
PAOF
BUT not fatigue or depressive symptoms
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March 15
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2012 – PARIS - FRANCE
Circadian Rhythm of one Breast Cancer Patient
This patient shows
robust sleep-wake
rhythm at baseline
indicated by clear
contrast between
daytime and night
time activity. The
rhythm then
became disrupted
at C1TW and
remained
disrupted
p for the
duration of
chemotherapy, as
indicated by lower
amplitude and less
contrast between
bedtime and wake
time
X-axis is clock time. Y-axis is log value.
Black dots = log of activity scores calculated by the actigraphy
actigraphy.
Blue line = best-fitting traditional cosine curve. Red line = extended cosine curve.
Green line = in-bed time.
ICCTF International Cognition and Cancer Task Force Conference
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2012 – PARIS - FRANCE
Summary
Poor sleep and fatigue are present before but get worse
d i chemotherapy;
during
h
th
by
b year 1 mostt symptoms
t
are bbackk tto
baseline levels.
 Note – this is still worse than controls.
Repeated administration of chemotherapy results in
progressively worse and more enduring rhythm impairments
g
y impaired
p
Patients rate themselves as beingg more cognitively
immediately after chemotherapy and at one year
NP testing showed that controls improve after 12 weeks
(cycle 4) but patients do not; by one year they begin to show
improvement
ICCTF International Cognition and Cancer Task Force Conference
March 15
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th
2012 – PARIS - FRANCE
Summary (con’t)
In addition to college education and pre-chemotherapy
cognitive
iti llevels,
l about
b t one-third
thi d off generall cognitive
iti
dysfunction is explained by the circadian rhythm robustness,
poor sleep
l
quality,
lit andd amountt off night
i ht time
ti sleep
l
as wellll as
subjective reports of cognitive ability
Fatigue and depressive symptoms predict change in some
domains but not in overall composite scores
ICCTF International Cognition and Cancer Task Force Conference
March 15
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2012 – PARIS - FRANCE
Conclusion
Seated Yucatan Woman, Francisco Zúñiga
Sleep and fatigue, as well as
circadian rhythms and
objective measures of sleep
need to be explored in all
ppatients with breast cancer.
Studies are needed to
determine if treating and
improving these symptoms
will prevent cognitive
dysfunction in women with
b
breast
t cancer.
ICCTF International Cognition and Cancer Task Force Conference
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2012 – PARIS - FRANCE
Collaborators
Joel Dimsdale,
Dimsdale MD
Lianqi Liu, MD
Paul Mills,
Mills PhD
Loki Natarajan, PhD
Barton Palmer,
Palmer PhD
Barbara A. Parker, MD
Georgia Robins Sadler,
Sadler PhD
Richard Schwab, MD
Lavinia Fiorentino,
Fiorentino PhD
PhD.
Michelle Rissling, MA
Sue Lawton
Ariel Neikrug, MA
Vera Trofimenko
ICCTF International Cognition and Cancer Task Force Conference
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15--17
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2012 – PARIS - FRANCE
Neuropsychological Test Battery
Episodic Learning and Memory
Hopkins
p
Verbal Learningg Test - Revised ((HVLT-R))
Trials 1-2 = learning
Trial 4 = memory
Brief Visuo-Spatial Memory Test
Spatial Span Test
C lif i V
California
Verbal
b l LLearning
i T
Testt (CVLT-1)
(CVLT 1)
Executive Functioning
Wisconsin Card Sorting Test abbreviated/64-card version
(
(WCST-64)
)
Stroop Reading, Color and Color-Word (trail 3)
Trail Making Test Part B
L tt (FAS) andd Category
Letter
C t
(Animals)
(A i l ) Fluency
Fl
ICCTF International Cognition and Cancer Task Force Conference
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2012 – PARIS - FRANCE
Neuropsychological Test Battery
Attention
WAIS Digit span
Vigilance
Digit Cancellation
Psychomotor speed
WAIS Digit Symbol, and Symbol Search
Trail Making Test Part A
Processing speed and flexibility
Paced Auditory Serial Addition Test
Self-Assessment
 Patient’s Self Assessment of Function (PAOF)
ICCTF International Cognition and Cancer Task Force Conference
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2012 – PARIS - FRANCE
Neuropsychological Test Battery
A composite score was computed for the neuropsychological test
b tt
battery.
 defined as the mean of the "standardized" scores on each of the
13 tests within the neuropsychological battery
 Each observed score was converted to a z-score
standardized by subtracting the baseline mean and dividing by
the standard deviation of the sample
p
 This standardization was done for each test at each of the three
time points (baseline, C4; one year).
 The standardized scores were then averaged to yield a composite
score for each time point.
 This composite score was used as a measure of overall
neuropsychological functioning.
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE