VALIDATION OF A MULTI-ATLAS SEGMENTATION TECHNIQUE FOR THE QUANTIFICATION OF HIPPOCAMPAL VOLUME APPLICATION AS A SELECTION CRITERION IN CLINICAL TRIALS

HJ. Yu , L. Bracoud , J. Schaerer , D. Xu , F. Roche , B. Belaroussi , C. Pachai , C. DeCarli and the Alzheimer's Disease Neuroimaging Initiative 1 2 BioClinica Inc., Newtown, PA, USA and Lyon, France University of California at Davis, CA, USA
BACKGROUND
Hippocampal volume (HCV) has been proposed as a key inclusion biomarker in Alzheimers Disease (AD) studies, to improve diagnostic homogeneity and to select subjects who are likely to undergo measurable clinical change during the course of a clinical trial. An enrichment strategy based on a HCV cutpoint was previously described [1-3]. However, the optimal HCV cutpoint could differ depending on the HCV quantification methodology used to derive such threshold. This work explored the operating characteristics of low HCV measured using the BioClinica Multi-Atlas Segmentation (BMAS) technique in predicting disease progression as compared to three other published techniques. This work also examined differences in the HCV cutpoints (under the same assumptions for subject selection), as well as the corresponding operating characteristics and clinical outcomes.
Figure 1. Receiver Operating Characteristic (ROC) of Baseline HCV Predicting Progression to Dementia within 36 Months
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METHODS Data
The Alzheimers Disease Neuroimaging Initiative (ADNI) cohort (data downloaded on March 29th, 2012) of subjects with amnestic mild cognitive impairment (aMCI) was used as a testing dataset to serve as a typical clinical trial population. ADNI aMCI subjects were included if they had a baseline MRI with interpretable HCV for all four HCV quantification methods and clinical status known or inferred at 36 months (n = 324). Normal Control (NC, n = 183) subjects with interpretable HCV and with stable clinical status throughout follow-up of up to 36 months were used as a normative dataset to establish regression models allowing an adjustment for age and intracranial volume (ICV).

Figure 2. Sensitivity, Specificity, and Cumulative Proportion of Subjects Enrolled versus Adjusted Hippocampal Volume

Image processing
HCVs were computed with the previously described BioClinica Multi-Atlas Segmentation (BMAS) method combining segmentation propagation, refinement and decision fusion [4]. For comparison, HCVs quantified by the following methods were obtained from the ADNI website:

NeuroQuant (UCSDVOL: LHIPPOC & RHIPPOC) FreeSurfer Longitudinal v4.4 (UCSFFSL: ST29SV & ST88SV) FreeSurfer Cross-sectional v4.3 (UCSFFSX: ST29SV & ST88SV)

With 67% cumulative subjects, the adjusted HCV cutpoints and the corresponding operating characteristics are summarized in Table 2.
Table 2. Operating Characteristics of Low HCV as Predictor for Conversion
MCI (N = 324) UCSDVOL UCSFFSL UCSFFSX BMAS Cutpoint (mm3) Sensitivity (%) Specificity (%) PPV (%) NPV (%)

ICVs were generated using a previously described multi-atlas algorithm [5].

Methodology for adjustment of hippocampal volume

HCV values, taken as the mean of left and right hippocampi, were adjusted for age and ICV values based on multiple linear regression models derived from the ADNI NC dataset for each quantification technique. For all subjects in the aMCI dataset, HCV was adjusted according to the following equation: HCV_Adjusted = HCV_NC_Mean + Regression Residuals where 1) Regression Residuals = HCV_Measured HCV_Predicted and 2) HCV_Predicted = A + B Age + C ICV with A, B & C being the regression coefficients obtained from each method based on the NC dataset.

3349 3024 3284 3536

77.6 80.4 81.1 80.4

41.4 43.6 44.2 43.6

51.2 53.0 53.5 53.0

70.1 73.8 74.8 73.8

Table 3. Summary of Clinical Outcome for Included and Excluded aMCI Subjects
HCV < Cutpoint*
N % Conversion Baseline CDR-SOB Annualized CDR-SOB

HCV > Cutpoint* 107 26.2 1.42 0.77 0.33 1.28

P Value -<0.001 0.044 <0.001

217 53.0 1.63 0.92 0.86 1.42

Analyses

A receiver operating characteristic (ROC) curve for adjusted HCVs (in mm ) was generated, where the outcome of interest was conversion to dementia, predicted by lower HCVs for each method. The area under the curve (AUC) was calculated. With 67% cumulative subjects (i.e., no more than 1/3 subjects would be excluded using an enrichment strategy based on any of these hippocampus segmentation techniques), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) based on the HCV cutpoints were compared amongst all HCV quantification methods.

*Included (HCV < 3536 mm3) and excluded (HCV > 3536 mm3) based on BMAS

CONCLUSION
The fully automated multi-atlas segmentation method successfully compared with three published methods for the assessment of HCV and prediction of conversion from MCI to AD. The predictive value as demonstrated by the ROC curve based on this new method was similar to those obtained from the other methods. Moreover, although the optimal HCV cutpoint values differed amongst all four quantification methods, the resulting operating characteristics were within same ranges of values. Using this HCV-based enrichment criterion, cognitive decline as measured by annualized CDR-SOB was approximately 3 times higher and percentage of conversion to dementia was approximately doubled comparing included versus excluded subjects at 36 months. Finally, this work provided a concrete framework for implementing an HCV enrichment strategy in the context of AD clinical trials.

RESULTS
Subjects who progressed to dementia (i.e., converted) within 36 months were similar in age and gender but had higher CDR-SOB at baseline and lower baseline HCV quantified by BMAS, as shown in Table 1.
Table 1. Baseline Comparison of Stable and Progressed Subjects
All Subjects (N=324) Age Gender (M/F) Baseline CDR-SOB Adjusted UCSDVOL Adjusted UCSFFSL Adjusted UCSFFSX Adjusted BMAS Stable (N = 181) Progressed (N = 143)

74.47 7.26 201/123 1.56 0.88 3158.44 453.30 2841.38 445.32 3094.10 469.54 3332.49 457.19

74.67 7.41 114/67 1.36 0.76 3271.28 435.27 2969.38 431.64 3226.09 451.70 3437.18 440.20

74.22 7.08 87/56 1.81 0.95 3015.61 436.42 2679.35 409.37 2927.04 438.80 3199.98 445.15

REFERENCES
[1] G. Novak et al., Choice of Threshold Hippocampal Volume as a Selection Criterion in Prodromal Alzheimers Disease, AAIC 2012, Vancouver, Canada. [2] HJ. Yu et al., Impact of Hippocampal Volume-Based Enrichment on Clinical Outcomes in Prodromal Alzheimers Disease, AAIC 2012, Vancouver, Canada. [3] G. Novak et al., Discordance for Hippocampal Atrophy and Amyloid Burden in Amnestic Mild Cognitive Impairment May identify Distinct Subgroups of Patients, AAIC 2012, Vancouver, Canada. [4] B. Belaroussi et al., Multi-Atlas Segmentation of the Hippocampus Refined with Intensity-Based Tissue Classification, AAIC 2012, Vancouver Canada. [5] J. Schaerer et al., Accurate Intracranial Cavity Volume Estimation in Mild Cognitively Impaired Population using Multi-Atlas Segmentation, AAIC 2012, Vancouver Canada.

The AUC values for adjusted HCVs based on UCSDVOL, UCSFFSL, UCSFFSX and BMAS were 0.663, 0.686, 0.685 and 0.655 respectively (Figure 1).

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