practice effects on neuropsychological tests can …...practice effects on neuropsychological tests...
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Practice effects on neuropsychological tests can last for several years and make them unsuitable for long-term clinical trialsKeith A. Wesnes1,2,3, Lon S. Schneider4
1Practice Leader, Bracket Global, Goring-on-Thames, RG8 0EN, UK, 2Division of Psychology, Northumbria University, Newcastle, UK3Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia, 4Keck School of Medicine of the University of Southern California, USA
BACKGROUND RESULTS THE CDR SYSTEM
METHOD
DISCUSSION & CONCLUSIONSCOGNITIvE FUNCTION DECLINES IN NORMAL AGEING
In an extensive research program over 20 years Timothy Salthouse (U Virginia) has demonstrated that all major domains of cognitive function decline from the 20s to the 90s in healthy individuals
Timothy Salthouse. What is normal cognitive aging?Alzheimer’s Association Research RoundtableEarly Risk Assessment for Alzheimer’s Disease
November 13, 2007vALIDATED COMPOSITE SCORES USED IN THIS ANALYSISFactor analysis has identified major domains of cognition assessed by the various tests:n Power of Attention– The ability to focus attention and process information
n Quality of Working Memory– The ability to hold numeric, verbal and spatial information on-line, which is
crucial for everyday tasks which involve executive function
n Quality of Episodic Memory– The ability to encode, store, retain and subsequently retrieve verbal and non-
verbal information (declarative memory) over minutes, hours, weeks and years.
n Speed of Memory Retrieval– A measure of how quickly information held in both working and episodic
memory can be retrieved
n Three tasks had problems with ceiling effects
n 7 of the 14 task measures showed significant improvements in the ADNI controls
n Of the 10 measures assessed at 5 years 3 were still improved
n The effect sizes of these improvements ranged from 0.2 to 0.72
n No test showed consistent evidence of impairments
n While such tests are well-suited for cross-sectional use, their suitability for repeated administration is questionable
n The failure to detect consistent declines in this elderly sample was likely the result of training effects
n Such training effects indicate that the tests used in ADNI may not be able to detect cognitive decline in preclinical AD
n Training effects reduce the likelihood of detecting treatment benefits in therapeutic trials
n Tests designed for repeated administration in clinical trials have shown consistent age-related cognitive impairments in the same population as tested in ADNI (see right)
n The selection of tests and composites for preclinical AD and prevention trials must take into account training effects
Such training effects have been seen previously
n= 694 persons (443 women)Mean age 75.9 years (SD 6.9)
MMSE 28.3 (SD 1.7)Tested yearly over 6 years
PRECLINICAL ADn Research criteria have been proposed (Sperling et al, 2011)n Large long term trials are underway and many others are being
plannedn Requirements for tests in such trials are that they are free of ceiling
& floor effects and sensitive to change over time
RESEARCH QUESTION
How will neuropsychological tests as used in ADNI perform over the long term?
n Downloaded from ADNI database 19th September 2012
n 249 non-cognitively impaired individuals
– mean age 76 years (range 60-90)
– MMSE 24-30
n Repeatedly administered a range of neuropsychological tests up to 6 years
Word Recall (N = 4172)
Chronological Age
20 30 40 50 60 70 80 90
Z-Sc
ore
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.575th Percentile50th Percentile25th Percentile
Chronological Age
20 30 40 50 60 70 80 90
Z-S
core
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
Word Recall (N = 4172)Matrix Reasoning (N = 4358)Spatial Relations (N = 3534)Pattern Comparison (N = 8479)
84
69
50
31
16
7
Per
cent
ile
Year of Study
0 1 2 3 4 5 6 Controls 249 229 214 193 118 109 64
Baseline to next 6 years
Year 1 to next 5 years
Year 2 to next 4 years
Significant Training Effects
Story retention Yes
Word retention Yes
Word generation Yes Yes Yes
Word knowledge Yes
Working memory Yes
Perceptual speed Yes Yes Yes
Visuospatial ability Yes Yes Wilson RS, Beckett LA, Barnes LL, et al. Individual differences in rates of change in cognitive abilities of older persons. Psychology and Aging 2002; 17: 179-193.
n Data analysed using mixed modelling repeated measures with SAS PROC MIXED
n Data are plotted as least squares means changes from study entry, with 95% confidence intervals (CI)
n Improvements are plotted to ascend
n Where CIs do not cross zero line, improvement or impairment is significant
n All figures are plotted over at least a range of 1 SD
Effect Sizes of peak improvements for measures on which significant training effects were seen
TESTS ADMINISTERED
n Rey AVLT
n WMS Logical Memory I/II
n Category Fluency
n DSST
n Digit Span
n Boston Naming Test
n Trail Making Test
n Clock Copying Task
n Clock Drawing Task
CEILING EFFECTS ON CLOCK TASK AND BOSTON NAMING
Clock Drawing & Copying Tasks % of controls scoring 0 to 5 at baseline
Boston Naming TestScore 0 to 30 - % scoring 25 to 30
0 1 2 3 4 5 Drawing 0 0.8 0.4 4.4 17.6 76.7 Copying 0 0 0.4 1.6 8.9 89.1
25 26 27 28 29 30 Total Controls 5.6 6.8 12.4 16.5 21.3 28.5 91.2
LSMeans with 95% Confidence Intervals
Years
1 2 3 4
# C
orre
ct
-2
-1
0
1
2
3
Digit Symbol Substitution TestADNI Controls
LSMeans with 95% Confidence Intervals
Years
0 1 2 3 4 5 6
# C
orre
ct
-0.2
0.0
0.2
0.4
0.6
0.8
Boston Naming TestADNI Controls
LSMeans with 95% Confidence Intervals
Years
0 1 2 3 4 5 6
# C
orre
ct
-4
-2
0
2
LSMeans with 95% Confidence Intervals
Years
0 1 2 3 4 5 6
# C
orre
ct
-1.0
-0.5
0.0
0.5
1.0
= Form B
Years Effect Size Trails A 0.5,1, 2 0.22 - 0.31 Trails B 1 0.28 DSST 1, 2 0.19 - 0.20 Boston Naming Test 0.5, 1, 2, 3, 5 0.31 - 0.48 Rey AVLT Delayed 1, 2 0.2 - 0.31 Logical Immediate 1, 2, 3, 4, 5, 6 0.43 - 0.72 Logical Delayed 1, 2, 3, 4, 5, 6 0.25 - 0.53
LSMeans with 95% Confidence Intervals
Years
0 1 2 3 4 5 6
seco
nds
-4
-2
0
2
Trail Making - Part AADNI Controls
LSMeans with 95% Confidence Intervals
Years
0 1 2 3 4 5 6
seco
nds
-10
-5
0
5
10
Trail Making - Part BADNI Controls
LSMeans with 95% Confidence Intervals
Years
0 1 2 3 4 5 6
# C
orre
ct
-0.2
-0.1
0.0
0.1
0.2
Clock Drawing TestADNI Controls
LSMeans with 95% Confidence Intervals
Years
0 1 2 3 4 5 6
# C
orre
ct
-0.1
0.0
0.1
0.2
Clock Copying TaskADNI Controls
LSMeans with 95% Confidence Intervals
Years
1 2 3 4
# D
igits
-0.4
-0.2
0.0
0.2
0.4
0.6
Digit Span - ForwardsADNI Controls
LSMeans with 95% Confidence Intervals
Years
1 2 3 4
# D
igits
-0.4
-0.2
0.0
0.2
0.4
0.6
Digit Span - BackwardsADNI Controls
LSMeans with 95% Confidence Intervals
Years
1 2 3 4 5 6
# C
orre
ct
0.0
0.5
1.0
1.5
2.0
Logical Memory Test - ImmediateADNI Controls
LSMeans with 95% Confidence Intervals
Years
1 2 3 4 5 6
# C
orre
ct
0.0
0.5
1.0
1.5
2.0
2.5
Logical Memory Test - DelayedADNI Controls
LSMeans with 95% Confidence Intervals
Years
1 2 3 4
# Ite
ms
-2
-1
0
1
2
Category FluencyADNI Controls
DECLINES PER YEAR IMPAIRMENTS AT 5 YEARS MEDIUM TO LARGE EFFECT SIzES
CDR SYSTEM DATA
n 256 Healthy volunteers, mean age 76 years (range 70-90), MMSE 28.8 range 23-30
n Administered the following tests over 5 years:
– Simple Reaction Time
– Choice Reaction Time
– Digit Vigilance
– Numeric Working Memory
– Spatial Working Memory
– Immediate & Delayed Word Recognition
– Delayed Picture Recognition
Poster presentation at the CNS Summit 15-18 November 2012, Boca Raton, Florida
This presentation including the statistical analyses were supported by Bracket.
Power of AttentionMeans with 95% Confidence Intervals
Years
1 2 3 4 5
mse
c
0
20
40
60
80
100
120
140
160
180
Speed of MemoryMeans with 95% Confidence Intervals
Years
1 2 3 4 5
mse
c
0
100
200
300
Quality of Working MemoryMeans with 95% Confidence Intervals
Years1 2 3 4 5
SI U
nits
-0.20
-0.15
-0.10
-0.05
0.00
0.05
Quality of Episodic Recognition MemoryMeans with 95% Confidence Intervals
Years1 2 3 4 5
SI U
nits
-0.20
-0.15
-0.10
-0.05
0.00
Wesnes K et al (2012). The year by year changes in cognitive function in a non-demented population aged 70 to 90 over a five year period. The Journal of Frailty & Aging 1: 76.
CNS_ADNI_poster.indd 1 11/8/12 3:19 PM