Nothing to disclose
Dodge, Ganguli et. al. Cohort Effects in Age-Associated Cognitive Trajectories. Journal of Gerontology: Medical Sciences. In press.
time (age)
Aim/Data
To examine which components ---baseline values or biomarker progressions-explains more variability in cognitive declines in memory and executive functions. DATA: the Alzheimers Disease Neuroimaging Initiative (ADNI 1). 526 subjects with valid data in at least one of our variables of interest were used in this study.
Cognitive Outcomes
Trajectory (slope) of cognitive functions:
The scores are psychometrically optimized composite scores of memory and executive function, derived from items from ADNI neuropsychological tests
Approach: 2-stage
Stage 1. Individual-specific slope of the longitudinal trajectory of each biomarker was estimated using mixed effects models.
where (0 , 1 ) ~ 2 (0, ). ~
0, and
Approach
Stage 2. Estimated individual-specific slope of each biomarker and observed baseline values were used as predictors of cognitive declines using mixed effects models.
= + 10 1*<0.5+ + 2 1*0.5+ ( 0.5) + ; = 0 + 1 Age at baseline + 2 Sex + 3 Education + 4 Apoe4 + 5 0 + 0 ; 2 = 20 + 21 Sex + 22 Apoe4 + 23 Changes in diagnosis + 24 0 + 25 1 + 2 ;
Approach
Variability in cognitive declines explained by subject-specific baseline biomarker values was compared with variability explained by biomarker progressions.
Results
Outcome: memory
Normal Group
Standardized effect size
Biomarker % of variability _bl: baseline values explained by _prog: progression biomarkers ttau_bl (1 sd=51) -5.40% ttau_prog (1 sd=0.21) -3.00% Abeta42_bl (1 sd=56) -7.70% Abeta42_prog (1 sd=0.14) -14.80%
-0.01
0.02
0
0.02
A positive percentage indicates that the corresponding predictor explains the variation in cognitive decline, while a negative percentage indicates that inclusion of the predictor adds more estimation error instead of improving model fitting.
Outcome: memory
Biomarker % of variability _bl: baseline values explained by _prog: progression biomarkers FDG-PET_bl (1 sd=0.15) -0.60% FDG-PET_prog (1 sd=0.18) 1.50%
0.04
0.1
Outcome: memory
Normal Group
Biomarker _bl: baseline values _prog: progression Log_wmh/icv_bl (1 sd=1.57) Log_wmh/icv_prog (1 sd=0.05) Hpcv/icv_bl (1 sd=3.7E-04) Hpcv/icv_prog ( 1 sd=0.07) Ventricles/icv_bl (1 sd=5.8E-03) Ventricles/icv_prog (1 sd=0.11) Total brain/icv_bl (1 sd=0.04) Total brain/icv_prog (1 sd=0.09)
0.03
-0.29 0.04 0 0.01 -0.06 0.02 0.02
Precuneus Thickness/icv_bl (1 sd=2.3E-07) Precuneus Thickness/icv_prog (1 sd=0.10) Medial Temporal Thickn./icv_bl (1 sd=2.3E-07) Medial Temporal Thickn./icv_prog (1 sd=0.10)
-2.36%
0.01
-0.48%
-0.01
-3.62%
-0.01
-0.05%
0.1
Outcome: memory Biomarker _bl: baseline values _prog: progression ttau_bl (1 sd=51) ttau_prog (1 sd=0.21) Abeta42_bl (1 sd=56) Abeta42_prog (1 sd=0.14) FDG-PET_bl (1 sd=0.15) FDG-PET_prog (1 sd=0.18)
Among MCI* % of variability explained by biomarkers -1.90% 0.30% Standardized effect size 0 -0.04
5.10%
10.30%
-0.15
-0.48
12.20%
12.70%
0.09
0.08
Outcome: memory Biomarker _bl: baseline values _prog: progression Log_wmh/icv_bl (1 sd=1.57) Log_wmh/icv_prog (1 sd=0.05) Hpcv/icv_bl (1 sd=3.7E-04) Hpcv/icv_prog ( 1 sd=0.07) Ventricles/icv_bl (1 sd=5.8E-03) Ventricles/icv_prog (1 sd=0.11) Total brain/icv_bl (1 sd=0.04) Total brain/icv_prog (1 sd=0.09)
0.50%
0.10% 9.00% 19.80% 8.70% 39.40% 2.40%
-0.03
0.01 0.07 0.08 -0.04 -0.12 0.06
16.00%
0.05
Among MCI
% of variability explained by biomarkers Standardized effect size
Precuneus Thickness/icv_bl (1 sd=2.3E-07) Precuneus Thickness/icv_prog (1 sd=0.10) Medial Temporal Thickness/icv_bl (1 sd=2.3E-07) Medial Temporal Thickness/icv_prog (1 sd=0.10)
3.49%
0.09
5.38%
0.07
4.36%
0.09
25.52%
0.11
Outcome: memory Biomarker _bl: baseline values _prog: progression ttau_bl (1 sd=51) ttau_prog (1 sd=0.21) Abeta42_bl (1 sd=56) Abeta42_prog (1 sd=0.14) FDG-PET_bl (1 sd=0.15) FDG-PET_prog (1 sd=0.18)
Among AD % of variability explained by biomarkers -7.90% -17.80% Standardized effect size -0.19 -0.08
-8.60%
6.60%
-0.05
-0.04
30.00%
84.00%
0.1
0.12
Outcome: memory Biomarker _bl: baseline values _prog: progression Log_wmh/icv_bl (1 sd=1.57) Log_wmh/icv_prog (1 sd=0.05) Hpcv/icv_bl (1 sd=3.7E-04) Hpcv/icv_prog ( 1 sd=0.07) Ventricles/icv_bl (1 sd=5.8E-03) Ventricles/icv_prog (1 sd=0.11) Total brain/icv_bl (1 sd=0.04) Total brain/icv_prog (1 sd=0.09)
Among AD
% of variability explained by biomarkers
Standardized effect size
-4.70%
3.00% 4.70% 26.00% 4.20% 63.80% -4.50% 26.00%
0.1
0.1 -0.07 0.15 0.11 -0.18 0.05 0.17
Outcome: memory
Among AD % of variability Standardized effect size explained by biomarkers 5.14% 5.13% 0.07 0.08
Precuneus Thickness/icv_bl (1 sd=2.3E-07) Precuneus Thickness/icv_prog (1 sd=0.10) Medial Temporal Thickness/icv_bl (1 sd=2.3E-07) Medial Temporal Thickness/icv_prog (1 sd=0.10)
6.14%
0.09
64.65%
0.17
Conclusions
A number of studies have shown support for the hypothetical AD progression model developed by Jack et al (Jack et al., 2013; Jack et al., 2010). Our study results also coincides with the model; Across diagnostic groups, the percentages of variability in cognitive declines explained by functional (FDG-PET) or structural (brain morphometric) biomarkers (either their baseline values or progressions) increased significantly as disease progressed from normal to AD.
For most biomarkers, biomarker progressions were more predictive of (associated with) memory decline than baseline values. This suggests that clinical trials which require recruiting at risk subjects could be improved by using progression rather than baseline values in biomarkers to enrich the study subjects. Future studies are warranted to estimate the incremental effectiveness of improving clinical trial statistical power by using biomarker progression criteria
Michigan ADC pilot grant R13 AG030995, Friday Harbor Advanced Psychometric Work Shop 2011
MCI Symposium