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email: luc.bracoud@bioclinica.com
ADNI NC 160 5.9 (0.5) 1.42 (0.11) 105 (5) ADNI MCI-nc 237 7.0 (0.7) 1.88 (0.17) 174 (7) ADNI MCI-c 109 10.0 (0.9) 3.08 (0.25) 266 (9) ADNI AD 123 13.7 (0.9) 4.22 (0.28) 344 (9)
HCVWhole cohort
HCVPET cohort
Table 1: Atrophy Results for the Whole Brain, Lateral Ventricles and Hippocampus
METHODS
Data CN156-018 BMS CN156-018 clinical trial included 263 subjects with predementia AD. Subjects underwent a lumbar puncture and were included if their CSF A42 levels were < 200pg/mL or total tau/A42 ratio 0.39. Subjects could not meet DSM-IV criteria for the diagnosis of dementia and met the following key entry criteria: having memory complaints documented by subject or study partner, objective memory loss on the Wechsler Memory Scale Logical Memory II or the Free & Cued Selective Reminding Test, a CDR-global score of 0.5 with a memory box score 0.5, and a MMSE of 24-30. All subjects underwent MRI examinations composed of a high-resolution 3DT1 sequence in compliance with the ADNI-1 imaging protocol, using MP-RAGE (Siemens), 3D TFE (Philips) and 3D Fast SPGR (General Electric) pulse sequences. All MRI data were sent for central processing and safety monitoring to BioClinica once acquired. All CN156-018 subjects were scanned at Baseline and followed for up to 3 years. Efficacy was assessed at Weeks 24, 56 and 104. Only subjects with good quality scans (no significant imaging artifacts, same MRI scanner used across timepoints) were considered (N = 189). ADNI Baseline, Months 6, 12 and 24 data from 629 subjects from ADNI-1 were also assessed for comparison purposes. The ADNI subjects were divided into the following categories: Normal Controls (NC), Mild Cognitive Impairment (MCI, non-converters and converters) and AD. MCI-c included subjects initially classified as MCI but that converted to AD after up to 36 months. Image processing MRI The following fully-automated MRI measurements were applied to both CN156-018 and ADNI cohorts by BioClinica: The volumes of whole brain and lateral ventricles were assessed at Baseline using the BioClinica Multi-Atlas Segmentation (BMAS-HCV) algorithm [1]. Hippocampal volume (HCV) was assessed at Baseline using a multi-atlas segmentation algorithm [2]. Intracranial cavity volume (ICV) was calculated from the Baseline 3DT1 images using a multi-atlas segmentation algorithm. ICV was used to normalize HCV values. Follow-up scans were automatically spatially realigned against Baseline scans using rigid and affine registration algorithms. Registration was performed in a so-called midway space, in order to prevent bias towards either scan (symmetric process) [3]. Brain and ventricular volume changes at follow-up timepoints were assessed using Tensor-Based Morphometry [4]. Hippocampal volume changes at follow-up timepoints were assessed using Hippocampal Boundary Shift Integral [5]. PET A subcohort of subjects underwent PET-amyloid imaging with 18F Florbetapir using a standardized acquisition protocol (N = 57). The PET data were centrally processed by Molecular NeuroImaging (MNI). SUVR values were obtained following spatial normalization of the images and after co-registration to the subjects segmented MRI. Cortical regions including a composite region were defined and compared to a cerebellar grey reference region. A total of N=43 subjects with satisfactory follow-up MRI data were analyzed. Statistical Analysis Subjects were considered as HCV+ when their total hippocampal volume was less than 6500 mm3 after adjustment by age and ICV and PET+ when SUVR was equal or greater than 1.55. The proposed HCV cut-point was derived using a methodology described in [6]. The following subject categories were analyzed: HCV+ versus HCV HCV+/PET+ versus non-(HCV+/PET+), e.g. subjects that were both HCV+ and PET+, versus the rest of the subjects. PET+ versus PET- comparison was not considered given the low number of PET- subjects. Annualized volume loss was assessed globally by fitting a linear model by robust regression using an M estimator.
Brain atrophy (TBM)
HCV + HCV HCV + / PET Non (HCV + / PET
ADNI AD BMS HCV+/PET+ ADNI MCI-c ADNI MCI-nc ADNI NC BMS non(HCV+/PET+)
HCV + HCV -
HCV + HCV -
Fig. 1: Comparison between HCV+ & HCV- (left) and HCV+/PET+ & non-(HCV+/PET+) (right)
Hippocampal atrophy (HBSI)
RESULTS & CONCLUSION Whole brain, lateral ventricles and hippocampus volume changes are
summarized in Table 1, for each group of interest.
ADNI AD ADNI MCI-c BMS HCV+/PET+ ADNI MCI-nc ADNI NC BMS non(HCV+/PET+)
HCV+ subjects had significantly greater atrophy rates than HCV- subjects
for whole brain, lateral ventricles and hippocampus on the whole CN156-018 cohort (N=189), as shown in Table 1.
REFERENCES
[1] Belaroussi et al., Labeling of brain MRI images using atlas propagation and classification-based nearest-neighbor transform, Poster session, AAN 2011 [2] Belaroussi et al., Multi-Atlas hippocampus segmentation refined with intensity-based tissue classification, Poster session, AAIC 2012 [3] Leung et al., Consistent multi-time-point brain atrophy estimation from the boundary shift integral, Neuroimage 2012 [4] Vercauteren et al., Symmetric log-domain diffeomorphic Registration: a demons-based approach, Med Image Comput Comput Assist Interv, 2008 [5] Barnes et al., Automatic calculation of hippocampal atrophy rates using a hippocampal template and the boundary shift integral, Neurobiology of aging, 2006 [6] Yu et al., Validation of a multi-atlas segmentation technique for the quantification of hippocampal volume. Application as a selection criterion in clinical trials, CTAD 2012
Adding PET to the HCV selection criterion did not significantly improve the
prediction of longitudinal atrophy patterns, which was not surprising given that an overwhelming majority of the subjects enrolled in this study were PET positive, in line with their CSF-positivity imposed by the study inclusion criteria.
Clinical Trials on Alzheimer's Disease San Diego, USA November 14-16, 2013