- Email: [email protected]
Conversion to MCI in healthy individuals with abnormal CSF Aβ42 levels is associated with specific longitudinal morphological changes of the brain
P596
P3-118
Poster Presentations: P3
CONVERSION TO MCI IN HEALTHY INDIVIDUALS WITH ABNORMAL CSF Ab42 LEVELS IS ASSOCIATED WITH SPECIFIC LONGITUDINAL MORPHOLOGICAL CHANGES OF THE BRAIN
Marco Lorenzi1, Martina Bocchetta2, Nicholas Ayache3, Xavier Pennec4, Giovanni Frisoni5, 1Asclepios Research Project - INRIA Sophia Antipolis, Sophia Antipolis, France; 2IRCCS Fatebenefratelli, Brescia, Italy; 3 Aclepios Group, INRIA Sophia Antipolis, Valbonne, France; 4Asclepios Group, INRIA Sophia Antipolis, Sophia Antipolis Cedex, France; 5IRCCS Fatebenefratelli, Brescia, Italy. Contact e-mail: [email protected] Background: Abnormal levels of Ab42 in the CSF and brain atrophy are key factors for the development of Alzheimer’s disease(AD), even though their mutual influence in the subsequent development of dementia still needs to be fully understood. The aim of this work is to provide a dynamic longitudinal model of the association between CSF Ab42 levels and structural changes of the brain in healthy elderly. This model is used to characterize potential trajectories towards AD in subjects subsequently converted to MCI. Methods: Baseline to 3-years brain T1 MR images were selected for 49 healthy subjects with normal levels of CSF Ab42 (Ab-), and for 37 with abnormal level of Ab42(Ab+) of ADNI. The images were processed according to an optimized pipeline for longitudinal data based on non-rigid registration. Group-wise models of the average longitudinal atrophy were estimated from the subject-specific time series, and statistically compared voxel-wise. Subject-specific longitudinal changes were also quantified by 1) the percentage rate of hippocampal atrophy and temporal horn expansion(atrophy score), and 2) a whole brain score of the longitudinal structural changes due to Ab42(Ab-induced score). Results: Healthy Ab42+ subjects showed an accelerated atrophy pattern associated to increased matter loss in temporal areas and hippocampi, as well as to increased ventricles expansion. The pattern was more pronounced for the Ab+ who subsequently converted to MCI (9/37), while the subjects Ab- converted to MCI (6/49) showed negligible atrophy patterns (Figure 1). Ab+ subjects had higher Ab-induced and atrophy scores, and the interaction of these two indices was strongly associated to longitudinal worsening of ADAS11 and CDRSB, and to conversion to MCI stage (Table 1). Conclusions: Abnormal Ab42 levels in healthy elderly are associated to 1) significant acceleration of longitudinal brain atrophy in the temporal areas, and 2)global specific longitudinal structural changes. In particular, the Ab+ subjects with higher specific longitudinal brain trajectories and greater atrophy did subsequently convert to MCI, and were characterized by a typical AD-like atrophy pattern. The present results point out that clinical conversion in presence amyloid is likely associated to early AD, and is already identifiable by a specific trajectory of brain changes and by a stereotypical pathological AD pattern.
Figure 1. Voxel-by-voxel comparison of the average group-wise log-jacobian determinant associated to the longitudinal trajectories (p<0.05, permutation test). Blue: significant volume loss, yellow: significant volume gain. A) Subjects positive to Ab show higher longitudinal brain matter loss when compared to the negative, prevalently localized in temporal poles and hippocampus, and correspondent expansion of the ventricles and temporal horns. B) The pattern becomes more evident if we consider only the subjects subsequently converted to MCI, who already show a specific pattern of AD progression. C) On the contrary, subjects Ab negative converted to MCI do not show a consistent pattern of longitudinal temporal atrophy. The longitudinal models of the differential progressions between the different groups are available at the link: http://www-sop.inria.fr/members/Macro.Lorenzi/ ModelAbeta
Table1 A) Mean (sd) for sociodemographic and clinical scores. The groups are similar for all the considered variables. B) Follow-up information for clinical and imaging data. The average time of conversion for the 9 Ab+ and 6 Ab- was not significantly different. C) Mean scores (sd) of longitudinal brain changes derived from the modeled trajectories. In addition to significantly higher Ab-induced scores, subjects Ab+ show also greater temporal atrophy rates. D) Association (p-values) between the interaction term Ab-induced*atrophy score and the longitudinal progression of neuropsychological scores (fitted in R: lm(neuropsywAb-induced* atrophy score)) Ab+ (37)
Ab- (49)
Difference: p-value
A) Baseline sociodemographic/clinical variables - mean (sd) Age 76 (5.29) 74.75 (5.18) n.s Gender(females) 17 (46%) 23 (47%) n.s. Education 15.91 (3.28) 15.44 (2.49) n.s MMSE 29.18 (0.93) 28.93 (1.04) n.s ADAS11 7.08 (3.18) 6.13 (2.86) n.s FDG (avg temporal+post cing) 6.43 (0.7) 6.57 (0.63) n.s Conversion to MCI (within 9 (24%) 6 (12%) n.s 70 months) B) Follow-up information (months) - mean (sd) Clinical data 32.46 (20.12) 34.03 (20.34) n.s. Imaging data 17.67 (10.76) 18.27 (11.45) n.s. Conversion time to MCI 39.33 (18.27) 40 (14) n.s. C) Longitudinal scores Ab-induced score 0.21 (0.15) 0.05 (0.15) <0.001 % Atrophy score 2.24 (1.28) 1.64 (0.72) 0.014 D) Association with Ab-induced* atrophy score - p-value Ab+ AbAb+ and AbADAS11 progression 0.048 n.s 0.023 CDRSB progression <0.001 n.s <0.001 MMSE progression n.s n.s n.s Conversion to MCI <0.001 n.s n.s (logistic model)
P3-118
Poster Presentations: P3
CONVERSION TO MCI IN HEALTHY INDIVIDUALS WITH ABNORMAL CSF Ab42 LEVELS IS ASSOCIATED WITH SPECIFIC LONGITUDINAL MORPHOLOGICAL CHANGES OF THE BRAIN
Marco Lorenzi1, Martina Bocchetta2, Nicholas Ayache3, Xavier Pennec4, Giovanni Frisoni5, 1Asclepios Research Project - INRIA Sophia Antipolis, Sophia Antipolis, France; 2IRCCS Fatebenefratelli, Brescia, Italy; 3 Aclepios Group, INRIA Sophia Antipolis, Valbonne, France; 4Asclepios Group, INRIA Sophia Antipolis, Sophia Antipolis Cedex, France; 5IRCCS Fatebenefratelli, Brescia, Italy. Contact e-mail: [email protected] Background: Abnormal levels of Ab42 in the CSF and brain atrophy are key factors for the development of Alzheimer’s disease(AD), even though their mutual influence in the subsequent development of dementia still needs to be fully understood. The aim of this work is to provide a dynamic longitudinal model of the association between CSF Ab42 levels and structural changes of the brain in healthy elderly. This model is used to characterize potential trajectories towards AD in subjects subsequently converted to MCI. Methods: Baseline to 3-years brain T1 MR images were selected for 49 healthy subjects with normal levels of CSF Ab42 (Ab-), and for 37 with abnormal level of Ab42(Ab+) of ADNI. The images were processed according to an optimized pipeline for longitudinal data based on non-rigid registration. Group-wise models of the average longitudinal atrophy were estimated from the subject-specific time series, and statistically compared voxel-wise. Subject-specific longitudinal changes were also quantified by 1) the percentage rate of hippocampal atrophy and temporal horn expansion(atrophy score), and 2) a whole brain score of the longitudinal structural changes due to Ab42(Ab-induced score). Results: Healthy Ab42+ subjects showed an accelerated atrophy pattern associated to increased matter loss in temporal areas and hippocampi, as well as to increased ventricles expansion. The pattern was more pronounced for the Ab+ who subsequently converted to MCI (9/37), while the subjects Ab- converted to MCI (6/49) showed negligible atrophy patterns (Figure 1). Ab+ subjects had higher Ab-induced and atrophy scores, and the interaction of these two indices was strongly associated to longitudinal worsening of ADAS11 and CDRSB, and to conversion to MCI stage (Table 1). Conclusions: Abnormal Ab42 levels in healthy elderly are associated to 1) significant acceleration of longitudinal brain atrophy in the temporal areas, and 2)global specific longitudinal structural changes. In particular, the Ab+ subjects with higher specific longitudinal brain trajectories and greater atrophy did subsequently convert to MCI, and were characterized by a typical AD-like atrophy pattern. The present results point out that clinical conversion in presence amyloid is likely associated to early AD, and is already identifiable by a specific trajectory of brain changes and by a stereotypical pathological AD pattern.
Figure 1. Voxel-by-voxel comparison of the average group-wise log-jacobian determinant associated to the longitudinal trajectories (p<0.05, permutation test). Blue: significant volume loss, yellow: significant volume gain. A) Subjects positive to Ab show higher longitudinal brain matter loss when compared to the negative, prevalently localized in temporal poles and hippocampus, and correspondent expansion of the ventricles and temporal horns. B) The pattern becomes more evident if we consider only the subjects subsequently converted to MCI, who already show a specific pattern of AD progression. C) On the contrary, subjects Ab negative converted to MCI do not show a consistent pattern of longitudinal temporal atrophy. The longitudinal models of the differential progressions between the different groups are available at the link: http://www-sop.inria.fr/members/Macro.Lorenzi/ ModelAbeta
Table1 A) Mean (sd) for sociodemographic and clinical scores. The groups are similar for all the considered variables. B) Follow-up information for clinical and imaging data. The average time of conversion for the 9 Ab+ and 6 Ab- was not significantly different. C) Mean scores (sd) of longitudinal brain changes derived from the modeled trajectories. In addition to significantly higher Ab-induced scores, subjects Ab+ show also greater temporal atrophy rates. D) Association (p-values) between the interaction term Ab-induced*atrophy score and the longitudinal progression of neuropsychological scores (fitted in R: lm(neuropsywAb-induced* atrophy score)) Ab+ (37)
Ab- (49)
Difference: p-value
A) Baseline sociodemographic/clinical variables - mean (sd) Age 76 (5.29) 74.75 (5.18) n.s Gender(females) 17 (46%) 23 (47%) n.s. Education 15.91 (3.28) 15.44 (2.49) n.s MMSE 29.18 (0.93) 28.93 (1.04) n.s ADAS11 7.08 (3.18) 6.13 (2.86) n.s FDG (avg temporal+post cing) 6.43 (0.7) 6.57 (0.63) n.s Conversion to MCI (within 9 (24%) 6 (12%) n.s 70 months) B) Follow-up information (months) - mean (sd) Clinical data 32.46 (20.12) 34.03 (20.34) n.s. Imaging data 17.67 (10.76) 18.27 (11.45) n.s. Conversion time to MCI 39.33 (18.27) 40 (14) n.s. C) Longitudinal scores Ab-induced score 0.21 (0.15) 0.05 (0.15) <0.001 % Atrophy score 2.24 (1.28) 1.64 (0.72) 0.014 D) Association with Ab-induced* atrophy score - p-value Ab+ AbAb+ and AbADAS11 progression 0.048 n.s 0.023 CDRSB progression <0.001 n.s <0.001 MMSE progression n.s n.s n.s Conversion to MCI <0.001 n.s n.s (logistic model)