Vardy et al
Supplementary Information
SI Table 1.Neuropsychological tests and cognitive domains
Clinical Neuropsychological Battery:
Domains / Tests
Pre-morbid intellectual ability / WRAT 3 Reading Test
Factor 1.
Visual attention/speed/working memory / WAIS-III Digit Symbol - raw score
Trail Making Test Part A - raw score (secs)
Trail Making Test Part B - raw score (secs)
WMS-III Spatial span – total –raw score
Factor 2.
Verbal Learning and memory / Hopkins Verbal Learning Test-Revised:
HVLT Total Recall - raw score
HVLT Delayed recall -raw score
Factor 3.
Visual Learning and Memory / Brief Visuospatial Memory Test (BVMT):R
BVMT Total recall - raw score
BVMT Delayed recall -raw score
Factor 4. / Letter-Number Sequencing – raw score
Auditory attention/working memory / WMS-III Digit Span – Total –raw score
Verbal fluency test (letter C) –raw score
Verbal fluency test (letter A)- raw score
Factor 5.
Visual-motor co-ordination / Grooved Pegboard –dominant hand -secs
Grooved Pegboard - non dominant hand-secs
CANTAB (computer-based):*
Factor 1
Memory 1
(Recognition memory) / Delayed Match to Sample (DMS):
DMS Mean correct latency (simultaneous)
DMS Mean Correct latency (all delays)
Factor 2
Executive Function 1
(Visual discrimination and attention) / Intra/Extra Dimensional (IED)
IED Total errors (adjusted)
IED Stages completed
IED Total errors
IED EDS errors
Factor 3
Executive function 2 (Visual spatial) / Spatial Working Memory (SWM)
SWM Total errors
SWM Strategy
Stockings of Cambridge (SOC)
SOC Problems solved in minimum moves
Factor 4
Memory + Induction*
(Verbal memory recognition accuracy) / Verbal Recognition Memory (VRM)
VRM Delayed Recognition - total correct (correct targets)
VRM Immediate Recognition - total correct (correct targets)
VRM Immediate Free recall - total correct
Motor Screen (MOT) Mean latency
Factor 5
Memory + Attention + Executive function
(Verbal memory recognition novelty) / *Verbal Recognition Memory (VRM)
VRM Immediate Free recall - total novel words
*VRM Immediate Recognition - total false positives
RVP Total false alarms
SOC Mean subsequent thinking time (2 moves)
Factor 6
Memory 2
(Forced choice recognition memory) / DMS Total correct (0 seconds delay)
DMS Total correct (4 seconds delay)
DMS Total correct (12 seconds delay)
Factor 7
Attention + Memory + Induction
(Reaction time) / Reaction Time (RTI)
RTI Five-choice reaction time
Big/Little Circle (BLC)
BLC Mean correct latency
*VRM Delayed Recognition - total false positives
RTI Five-choice movement time
Factor 8
Attention
(Sustained attention) / Rapid Visual Info. Processing (RVP)
RVP Mean latency
RVP Total hits
Factor 9
Executive Function 3
(Spatial planning) / SOC Mean initial thinking time (3 moves)
SOC Mean subsequent thinking time (3 moves)
SOC Mean initial thinking time (2 moves)
Factor 10
Memory 3
(Forced choice recognition memory – simultaneous) / DMS Total correct (simultaneous)
Six Elements Test
WRAT -3 = Wide Range Achievement Test -3
WAIS III = Wechsler Adult Intelligence Scale – Third edition
WMS-III = Wechsler Memory Scale – Third edition
Letter-Number Sequencing = WAIS-III Letter-Number Sequencing
Digit Span = WMS-III Digit Span
Spatial Span = WMS-III Spatial Span
HVLT = Hopkin’s Verbal Learning Test-Revised
BVMT= Brief Visuospatial Memory Test-Revised
Digit Symbol = WAIS-III Digit Symbol
TMTA = Trail Making Test Part A; TMTB = Trail Making Test Part B
RVP = Rapid Visual Information Processing
RTI = Reaction Time Five Choice
SWM = Spatial Working Memory
* CANTAB Verbal Recognition Memory (and Factor 4) not used for Global Deficit Score due to lack of normative data.
Neuropsychological domains were derived using principal components analysis (Varimax with Kaiser normalisation).
SITable 2.
Mean (standard deviation) of Global Deficit Score and T-scores/Z-scores (standard deviation) for neuropsychological (NP) domains and individual tests by study group
CTh+CS+N = 43 / CTh+CS-
N =50 / CTh-
N=30 / P-value# / P-value
CTh+ vs CTh-
Clinical Neuropsychological Tests
Global Deficit Score (GDS) / 0.26 (0.35) / 0.22 (0.43) / 0.23 (0.33) / .418 / .728
Clinical NP Domains: T-scores / N= 43 / N = 49-50 / N = 27
Visual attention/speed/working memory
Verbal Learning and memory
Visual Learning and memory
Auditory attention/working memory
Visual motor coordination / 48.8 (6.4)
49.8 (7.35)
50.0(10.35)
49.6 (6.1)
44.8 (10.3) / 50.0 (6.6)
50.4 (8.7)
52.3 (10.7)
52.6(7.4)
44.2(9.3) / 49.5 (7.7)
46.5 (9.0)
50.4 (10.0)
47.4 (7.1)
49.0 (8.1) / .457
.145
.399
.008
.052 / .785
.054
.630
.019
.018
Individual NP tests – T-scores
WAIS-III Digit Symbol
Trail Making Test A
Trail Making Test B
WMS-III Spatial Span
Hopkins Verbal Learning Test-Revised:
HVLT Total recall
HVLT Delayed recall
Brief Visuospatial Memory Test
BVMT-R Total recall
BVMT –R Delayed recall
WAIS-III Letter-Number Sequencing
WMS-III Digit Span
Verbal fluency test (letter C)
Verbal fluency test (letter A)
Grooved Pegboard
dominant hand
non-dominant hand / 52.7 (8.8)
44.1 (9.8)
45.7 (9.3)
53.6 (8.4)
48.8 (8.3)
50.8 (7.1)
48.3 (10.7)
51.7 (11.6)
51.2 (11.5)
51.4 (10.5)
49.7 (8.7)
46.1 (9.4)
44.7 (12.2)
44.9 (9.5) / 54.28(9.1)
44.5(9.0)
46.5(10.7)
54.6 (8.7)
50.0(9.4)
50.8(8.8)
50.1(11.6)
55.8 (8.9)
58.7(12.8)
53.7(10.6)
50.4(8.8)
47.6 (7.6)
43.3(10.2)
45.1 (10.2) / 54.5 (9.7)
45.2 (10.9)
44.1 (11.0)
54.6 (8.7)
44.8 (9.3)
48.15 (9.7)
48.1 (10.95)
52.7 (10.4)
50.0 (11.2)
48.9 (7.2)
45.8 (8.8)
44.85 (9.0)
48.1 (8.7)
49.8 (10.0) / .729
.933
.298
.530
.070
.564
.562
.205
.002
.134
.082
.482
.097
.043 / .824
.930
.261
.604
.028
.287
.589
.500
.035
.121
.026
.367
.055
.012
CANTAB / N = 34 - 36 / N = 48 -50 / N = 23 - 26
Global Deficit Score (SD) / 0.24 (0.27) / 0.16 (0.32) / 0.23 (0.41) / .100 / .724
CANTAB mean of total Z-scores / -0.04 (0.39) / 0.03(0.53) / -0.06 (0.53) / .343 / .631
CANTAB Domains* - Z-scores
CANTAB 1
CANTAB 2
CANTAB 3
CANTAB 5
CANTAB 6
CANTAB 7
CANTAB 8
CANTAB 9
CANTAB 10 / 0.2 (0.7)
0.2 (0.7)
-0.1 (0.7)
0.1 (0.3)
-0.1 (0.8)
-0.4 (1.2)
-0.1 (1.05)
-0.0 (1.1)
0.1 (0.8) / 0.28(0.6)
0.06(0.75)
0.28 (0.8)
-0.03(0.4)
0.21(0.8)
-0.25(0.7)
-0.06(0.85)
-0.17(1.8)
0.31 (0.7) / 0.15 (0.75)
0.1 (0.65)
-0.10(0.85)
-0.5 (1.3)
0.2 (0.6)
-0.7 (1.1)
-0.45 (0.9)
0.3 (0.3)
0.2 (0.6) / .852
.582
.053
.336
.078
.257
.185
.198
.254 / .713
.300
.262
.195
.908
.099
.068
.189
.800
Six Elements Test / 3.6 (0.7) / 3.5 (0.8) / 3.4 (0.9) / .687 / .687
CTh = chemotherapy; CS = cognitive symptoms
# P-value = CTh+CS+ vs CTh+CS- vs Ch-
WAIS III = Wechsler Adult Intelligence Scale – Third edition
WMS-III = Wechsler Memory Scale – Third edition
HVLT = Hopkin’s Verbal Learning Test-Revised
BVMT= Brief Visuospatial Memory Test-Revised
*CANTAB domain 4 could not be derived due to lack of normative data.
SI Table 3. Associations between cognitive function and patient reported outcome scores: Spearman Correlation coefficients Rho
Clinical GDS / CANTAB GDS / FACT-CogClinical GDS / 1.00 / 0.29
CANTAB GDS / 0.29 / 1.00
FACT-Cogtotal score / -0.13 / -0.16
Perceived cognitive impairments / -0.06 / -0.11
Perceived cognitive abilities / -0.22 / -0.24
Impact on QOL / -0.09 / -0.09
Comments from others / -0.09 / -0.16
PAFI Total score / -0.11 / -0.25 / 0.76
Memory / -0.09 / -0.18 / 0.69
Language / -0.12 / -0.18 / 0.70
Sensory / -0.07 / -0.11 / 0.24
Cognitive / -0.11 / -0.27 / 0.73
FACT-G / 0.004 / -0.10
FACT-F standardized subscale / -0.10 / -0.15
GHQ / -0.06 / -0.05
GDS = Global Deficit Score
FACT-Cog = Functional Assessment of Cancer Therapy -Cognition
PAFI = Patients Assessment of Own Functioning Inventory
FACT-F = Functional Assessment of Cancer Therapy – Fatigue
FACT-G = Functional Assessment of Cancer Therapy -General
GHQ = General Health Questionnaire 12 (lower score denotes more symptoms)
SITable 4. Median value (10th – 90th percentile) and standard deviation (SD) of Mean Immunofluoresence (MIF) of cytokine levels by group*
CTh+CS+N = 21 / CTh+CS-N = 38 / CTh-
N = 10 / P-value# / P-value
CTh+ vs CTh- / Healthy volunteers
* N=56 / P-value§
cancer groups vs HV
IL-1b / 25.00
(6-114)
1054.0 / 28.50
(6-690)
2114.62 / 69.00
(9.5-118)
43.9 / .395 / .195 / 9.25
(6-24)
8.3 / <.001
IL-2 / 12.25
(5-102.5)
44.1 / 16.00
(5-138)
55.7 / 51.25
(6-116)
44.0 / .444 / .315 / 10.50
(6-27)
11.4 / .043
IL-4 / 11.75
(5-117.5)
76.0 / 19.50
(5-222)
107.8 / 85.00
(7-162)
59.3 / .347 / .185 / 7.25
(5-18)
5.6 / <.001
IL-6 / 22.00
(11-150)
1870.0 / 39.50
(10.5-1850)
2373.5 / 75.50
(10-112)
40.4 / .776 / .512 / 10.00
(6-30)
12.3 / <.001
IL-8 / 49.00
(17-313)
1296.5 / 69.50
(21-2424.5)
1596.2 / 68.75
(12.5-156.5)
54.7 / .615 / .740 / 14.00
(7-45)
21.7 / <.001
IL-10 / 27.00
(10-124.5)
55.7 / 17.25
(10-114)
46.2 / 80.25
(18.5-147)
50.5 / .105 / .036 / 13.50
(7-27)
12.9 / <.001
IL-12 / 17.00
(7-131.5)
53.8 / 13.50
(7-114.5)
55.9 / 68.75
(11-165)
60.7 / .119 / .043 / 9.00
(6-50)
9.2 / .001
TNF- / 16.50
(5-1095.5)
234.3 / 32.50
(4.5-258)
272.2 / 73.50
(5-132)
49.0 / .475 / .267 / 8.00
(4-20)
53.2 / <.001
GM-CSF / 13.0
(5-115)
91.5 / 28.50
(5-125)
97.4 / 73.75
(6.5-134)
51.1 / .413 / .232 / 7.00
(4-21)
6.8 / <.001
IFN- / 13.00
(5-106)
85.6
/ 19.75
(5-125.5)
139.1 / 62.75
(7-117)
43.8 / .336 / .213 / 9.00
(4-18)
6.6 / <.001
CTh = chemotherapy; CS = cognitive symptoms
#P-valueCTh+CS+ vs CTh+CS- vs CTh-
§ All cancer groups vs healthy volunteers^Wilcoxon Two-Sample Test, t Approximation, Two-Sided Pr > |Z|
IL = interleukin
TNF- = tumor necrosis factor- alpha
GM-CSF = granulocyte-macrophage colony-stimulating factor
IFN- = interferon gamma
* Healthy volunteers (HV) are combined from two previous studies: includes 56 women, aged 23-60 years, with no history of cancer.
SI Table 5. Associations between clinical neuropsychological global deficit score and cytokine levels: Spearman Correlation Coefficients (Rho)
SpearmanCorrelationCoefficients
Prob|r|underH0:Rho=0
Clinical Global Deficit Score / CANTAB Global Deficit Score
IL-1b / 0.21
0.07 / 0.04
0.75
IL-2 / 0.21
0.09 / -0.02
0.85
IL-4 / 0.15
0.24 / 0.03
0.81
IL-6 / 0.15
0.21 / 0.04
0.74
IL-8 / 0.27
0.03 / 0.11
0.38
IL-10 / 0.18
0.15 / -0.04
0.72
IL-12 / 0.10
0.41 / 0.02
0.88
TNF- / 0.15
0.22 / 0.01
0.94
GM-CSF / 0.12
0.33 / -0.03
0.83
IFN- / 0.17
0.17 / -0.03
0.81
IL = interleukin
TNF- = tumor necrosis factor- alpha
GM-CSF = granulocyte-macrophage colony-stimulating factor
IFN- = interferon gamma
SI Table 6. Functional (f)MRI between group analyses for n-back task
SI Table 6. Functional (f)MRI between group analyses for n-back task
MNI coordinatesBetween group analyses / Region / x / y / z / Cluster (k) / t value / z value
2+3>1
CTh- > CTh+CS+ / Precentral gyrus / R / 52 / 4 / 30 / 30 / 3.75 / 3.61
CTh+CS+ > CTh- / no significant clusters
CTh- > CTh+CS- / Occipital lobe / L / -36 / -78 / 32 / 16 / 3.65 / 3.52
CTh+CS- > CTh- / no significant clusters
CTh+CS- > CTh+CS+ / no significant clusters
CTh+CS+ > CTh+CS- / no significant clusters
3>1
CTh- > CTh+CS+ / no significant clusters
CTh+CS+ > CTh- / no significant clusters
CTh- > CTh+CS- / no significant clusters
CTh+CS- > CTh- / no significant clusters
CTh+CS- > CTh+CS+ / no significant clusters
CTh+CS+ > CTh+CS- / Middle frontal gyrus / R / 40 / 38 / 16 / 23 / 3.43 / 3.32
2>1
CTh- > CTh+CS+ / Putamen / R / 16 / -10 / -8 / 13 / 3.45 / 3.34
Precentral gyrus / R / 52 / 4 / 30 / 30 / 3.54 / 3.42
Cerebellum / R / 8 / -32 / -12 / 21 / 3.51 / 3.39
Amygdala/Putamen / L / -28 / -6 / -8 / 16 / 3.50 / 3.39
Caudate / L / -22 / 16 / 16 / 21 / 3.63 / 3.50
CTh+CS+ > CTh- / no significant clusters
CTh- > CTh+CS- / Putamen / L / -32 / -8 / 8 / 27 / 3.81 / 3.67
Cerebellum / L / -8 / -32 / -12 / 17 / 3.37 / 3.27
Amygdala/Putamen / L / -28 / -4 / -10 / 15 / 3.36 / 3.26
CTh+CS- > CTh- / no significant clusters
CTh+CS- > CTh+CS+ / no significant clusters
CTh+CS+ > CTh+CS- / no significant clusters
CTh+ vs. CTh-
2+3>1
CTh- > CTh / Precentral gyrus / R / 52 / 4 / 28 / 39 / 3.93 / 3.77
CTh+ > CTh- / no significant clusters
3>1 / no significant clusters
CTh- > CTh+ / no significant clusters
CTh+ > CTh- / no significant clusters
2>1
CTh- > CTh+ / Precentral gyrus / R / 52 / 4 / 30 / 36 / 3.57 / 3.45
Cerebellum / R / 8 / -32 / -10 / 27 / 3.51 / 3.39
Putamen / L / -32 / -10 / 10 / 45 / 3.91 / 3.76
Amygdala/Putamen / L / -28 / -6 / -8 / 48 / 3.73 / 3.59
Cerebellum / L / -6 / -32 / -12 / 18 / 3.51 / 3.49
CTh+ > CTh- / no significant clusters
Group CTh+CS+: received adjuvant chemotherapy and had perceived cognitive impairment (FACT-COG 85/156);
Group CTh+CS-: completed adjuvant chemotherapy and self-reported lack of cognitive symptoms (FACT-COG100);
Group CTh-: Did not receive adjuvant chemotherapy (irrespective of FACT-COG score).
Group CTh+ : received adjuvant chemotherapy (includes CTh+CS+ and CTh+CS-)
MNI= Montreal Neurologic Institute
R= right, L=left
All P-values are p<0.001 uncorrected.