LONGITUDINAL VOLUMETRIC CHANGES IN CONTROLS, MCI AND AD SUBJECTS FROM THE ROSAS STUDY, AS COMPARED TO ADNI2

Clinical Trials on Alzheimer's Disease • Philadelphia, USA • November 20 – 22, 2014

BACKGROUND

The ROSAS study is a monocentric observational study running in

Toulouse, France, designed to identify and evaluate the clinical usefulness of AD biomarkers by collecting samples from Normal Controls (NC), Mild Cognitive Impairment (MCI) and AD subjects, following them over up to 4 years.

In this work, changes over time in whole brain, lateral ventricles and

hippocampal volumes were assessed for the ROSAS cohort. For whole brain and lateral ventricles, 2 independent methods (Boundary Shift Integral - BSI and Tensor Based Morphometry - TBM) were applied, for comparison purposes.

These atrophy rates were also compared to those from the ADNI2

cohort, as the imaging context of ADNI2 is identical to ROSAS.

In addition, we looked at relationship between initial hippocampal

volume and longitudinal change (atrophy rate and conversion to AD).

METHODS ROSAS data Subjects aged 65 years or older were enrolled in the study, including

NC (no objective memory impairments, MMSE≥26 and CDR=0), MCI (MMSE≥24 and CDR=0.5, memory impairment based on RAVLT and who did not meet DSM-IV-TR criteria for AD dementia and AD (12≤MMSE≤26 and CDR≥0.5 and meeting DSM-IV-TR criteria).

Subjects with other types of dementia and/or cognitive issues not

related to AD were excluded.

3D T1-weighted (3DT1) MRI scans were collected at Baseline and up

to twice between Month 12 and Month 48, at one site using a Philips Achieva 3T scanner, for consenting subjects.

3DT1 data consisted of a sagittal 3DTFE sequence with 1 mm thick

slices and a 175x256 acquisition matrix over a square FOV of 256 mm.

Only subjects with good quality scans (no significant imaging artifacts,

same MRI protocol used across timepoints) were considered for analysis.

For subjects who underwent a change in the MRI protocol between

their first and second scans, atrophy was only assessed between the second and third scans.

NC subjects who converted to MCI or AD during the course of the

study were discarded.

MCI subjects were further classified as non-converters or converters

(MCI-nc/MCI-c).

A total of 101 subjects were considered, including 35 NC, 15 MCI-nc,

13 MCI-c and 38 AD.

ADNI2 data

Baseline, Months 3, 6, 12 and 24 data from 593 subjects from the

ADNI2 cohort were also assessed for comparison purposes.

All subjects had been scanned on 3T scanners, providing a

comparable imaging context with ROSAS data.

Those subjects were separated into the following categories: Normal

Controls (NC, n=163), Early/Late Mild Cognitive Impairment (EMCI/LMCI, n=161/156) and AD (n=113), based on ADNI criteria.

NC who converted to MCI or AD within 36 months were discarded.

Image processing The following fully-automated MRI measures were performed on all data:

The volumes of whole brain and lateral ventricles were assessed at

Baseline using an atlas segmentation algorithm [1].

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) [2].

Volume changes at follow-up timepoints were assessed using

Boundary Shift Integral (BSI) [3] and Tensor-Based Morphometry (TBM) [4].

Hippocampal volume (HCV) was assessed at Baseline using a multi-

atlas segmentation algorithm [5].

Volume changes at follow-up timepoints were assessed using

Hippocampal Boundary Shift Integral [6].

Statistical Analysis

Annualized volume loss was estimated across all available timepoints

by fitting a linear model by robust regression using an M estimator. No adjustment against clinical characteristics was performed.

Agreement between techniques were evaluated using Intraclass

Correlation (ICC) coefficient ρ.

RESULTS and CONCLUSION Annualized mean volume changes and standard errors are

summarized in the below tables. Table 1 shows results on the ROSAS cohort using BSI and TBM methods, for brain (BBSI/BTBM), ventricles (VBSI/VTBM) and hippocampal (HBSI) volume changes. Table 2 shows similar results on the ADNI2 cohort using BSI.

A strong agreement was shown between BSI and TBM (ρ ≥ 0.97

with lower bound of 95%CI ≥ 0.96, see Fig. 1) and led to the same volume changes in whole brain and lateral ventricles in ROSAS NC, MCI-nc, MCI-c and AD.

When assessing volume changes in whole brain, lateral

ventricles and hippocampus (see Fig. 2), ROSAS controls showed less atrophy than ADNI2 controls, which is likely explained by stricter inclusion criteria (MMSE ≥ 26 for ROSAS and ≥ 24 for ADNI2). In addition, MCI subgroups always followed the same pattern of atrophy rate for all structures: EMCI (ADNI2) < MCI-nc (ROSAS) < LMCI (ADNI2) < MCI-c (ROSAS), while ROSAS and ADNI2 AD were similar.

Baseline HCV was weakly correlated to brain atrophy and

moderately correlated to hippocampal atrophy (see Fig. 3).

When looking at MCI subjects in particular, a cut-off HCV of 7000

mm3 was significantly associated with conversion to AD (Table 3).

The ROSAS cohort provides additional reference values for the

design of future clinical trials.

REFERENCES [1] Belaroussi et al., Labeling of brain MRI images using atlas propagation and classification-based

nearest-neighbor transform, Poster session, AAN 2011 [2] Leung et al., Consistent multi-time-point brain atrophy estimation from the boundary shift integral,

Neuroimage 2012 [3] Freeborough et al., The boundary shift integral: an accurate and robust measure of cerebral

volume changes from registered repeat MRI, IEEE Trans Med Imaging, 1997 [4] Vercauteren et al., Symmetric log-domain diffeomorphic Registration: a demons-based approach,

Med Image Comput Comput Assist Interv, 2008 [5] Belaroussi et al., Multi-Atlas hippocampus segmentation refined with intensity-based tissue

classification, Poster session, AAIC 2012 [6] Barnes et al., Automatic calculation of hippocampal atrophy rates using a hippocampal template

and the boundary shift integral, Neurobiology of aging, 2006

Luc Bracoud 1, Hans-Martin Schneble

2, Raluca Gramada

3, Fabrice Bonneville

3, Florent Roche

1, Isabelle Guignot

2, Joël Schaerer

1,

Françoise Lala 3, Nathalie Sastre

3, Pierre-Jean Ousset

3, Maria Pueyo

2, Chahin Pachai

1, Bruno Vellas

3 and the Alzheimer's Disease Neuroimaging Initiative

1 BioClinica, Lyon, France

2 Institut de Recherches Internationales Servier, Suresnes, France

3 C.H.U. Toulouse, France - email: luc.bracoud@bioclinica.com

Global clinical trial solutions. Real-world results.

ADNI2 NC

N = 163

EMCI N = 161

LMCI N = 156

AD N = 113

BBSI (mL) 5.0 (0.4) 5.0 (0.4) 8.2 (0.5) 12.3 (0.8)

VBSI (mL) 1.10 (0.05) 1.20 (0.06) 2.10 (0.09) 3.44 (0.15)

HBSI (mm3) 83 (6) 79 (7) 173 (9) 281 (15)

Table 2 - Annualized volume changes in ADNI2

ROSAS NC

N = 35 MCI-nc

N = 15

MCI-c N = 13

AD N = 38

BBSI (mL) 3.7 (0.6) 6.6 (0.8) 9.1 (0.8) 12.1 (0.9)

BTBM (mL) 4.0 (0.6) 6.8 (1.0) 9.7 (0.8) 11.8 (0.8)

VBSI (mL) 0.92 (0.11) 2.03 (0.26) 3.03 (0.41) 3.00 (0.24)

VTBM (mL) 1.04 (0.11) 2.19 (0.29) 3.20 (0.39) 3.14 (0.24)

HBSI (mm3) 46 (8) 132 (13) 242 (23) 281 (17)

Table 1 - Annualized volume changes in ROSAS

Cohorts

ROSAS NC

ROSAS MCI-nc

ROSAS MCI-c

ROSAS AD

ADNI2 NC

ADNI2 EMCI

Days from baseline

BB

SI (m

L)

Days from baseline

VB

SI (m

L)

Days from baseline

HB

SI (m

m3)

Fig. 2 - Longitudinal changes in BBSI, VBSI and HBSI, comparing ROSAS to ADNI2

Fig. 1 - Correlation between TBM and BSI - Left: whole brain, Right: lateral ventricles

BTBM (mL)

BB

SI (m

L)

VTBM (mL)

VB

SI (m

L)

Timepoints

Year 1

Year 2-3

Timepoints

Year 1

Year 2-3

ROSAS HCV > 7000 HCV ≤ 7000

MCI-nc 20 4

MCI-c 6 13

Table 3 - ROSAS MCI conversion to AD based on Baseline HCV

χ2 = 9.816, p < 0.01

Fig. 3 - Correlations between baseline HCV and annualized volume change (brain, ventricles and hippocampus)

Cohorts

ROSAS NC

ROSAS MCI-nc

ROSAS MCI-c

ROSAS AD

HBSI (mm3, annualized)

r = 0.48, p < 0.001

1.5

0.0

VBSI (mL, annualized)

r = 0.20, n.s.

50.0

0.0

BBSI (mL, annualized)

Ba

se

lin

e H

CV

(m

m3)

r = 0.28, p < 0.05

% s

ub

jec

ts

15.0

0.0

Baseline HCV (mm3)

% s

ub

jec

ts

0.06

0.00