- Email: [email protected]
Cortical thinning in early-stage and late-stage amnestic mild cognitive impairment
Poster Presentations: P2 right cingulate gyrus and left angular gyrus at baseline, reduced gray matter (GM) density in right inferior parietal lobule, lower CDR-SOB score, and lower mini-mental state examination (MMSE) score. The ApoE genotyping and CERAD neuropsychological tests except MMSE, and fractional anisotropy (FA) and mean diffusivity (MD) values derived from DTI were not significantly different between MCIc and MCInc. In terms of AD prediction after two-years in MCI, logistic regression analyses showed that the combination model including right inferior parietal lobule density on MRI and MMSE score (accuracy: 87.5%) was significantly better than any other models. Conclusions: The combination of GM density information on MRI and global cognitive score is probably the most cost-effective model to predict AD in MCI patients after a two-year follow-up period. P2-208
CORTICAL THINNING IN EARLY-STAGE AND LATE-STAGE AMNESTIC MILD COGNITIVE IMPAIRMENT
Byoung Seok Ye, Geon Ha Kim, Hanna Cho, Ji Soo Shin, Young Noh, Duk L. Na, Sang Won Seo, Samsung Medical Center, Sunkyunkwan University, School of Medicine, Seoul, South Korea. Background: Amnestic mild cognitive impairment (aMCI) represents a pre-dementia stage of Alzheimer’s disease (AD). According to the severity of objective memory impairment, aMCI patients can be classified into subjects with milder degree of impairment and those with more severe impairment. Although previous studies showed that aMCI subjects with milder memory impairment have slower rates of AD progression than those with
P329
more severe memory impairment, there has been no study comparing regional cortical thickness according to this classification of aMCI. Methods: Cortical thickness across the entire brain and neuropsychological performance were measured in 271 patients with aMCI and 234 subjects with normal cognition (NC). According to the performances in delayed recall items of memory tests, aMCI patients were divided into early-stage aMCI (EMCI, N ¼ 91) with milder degree of memory impairment (scores between -1.5 SD and -1.0 SD compared to age-, sex-, and education-matched norms) and latestage MCI (LMCI, N ¼ 180) with more severe memory impairment (lower than -1.5 SD). We performed ANCOVAs to compare neuropsychological performances and vertex-wise cortical thinning in EMCI, LMCI, and NC. Results: Compared to NC subjects, EMCI patients showed cortical thinning in the left medial temporal lobe, and LMCI patients showed cortical thinning in bilateral medial temporal lobes, bilateral medial and lateral parietal cortices, bilateral dorsolateral prefrontal cortices, right posterior cingulate cortex, and bilateral anterior temporal cortices. When the two aMCI groups were directly compared, LMCI patients showed more cortical thinning in the right medial temporal lobe, right posterior cingulate cortex, right lateral parietal cortex, and right dorsolateral prefrontal cortex. Both EMCI and LMCI patients showed lower performances in all neuropsychological tests compared to NC. When directly compared with EMCI, LMCI subjects had poorer performance in all memory tests and COWAT supermarket test, while having comparable scores in other tests. Conclusions: Our study suggests that the cortical thinning in aMCI initiates in the left medial temporal lobe and then progresses into other regions including the right medial temporal lobe, right posterior cingulate cortex, right lateral parietal cortex,
Table 1 Demographic variables, Mini-Mental State Examination (MMSE) scores of E-aMCI and L-aMCI
Age: years, mean (SD) Gender: female, N (%) Education: years, mean (SD) MMSE: score, mean (SD) CDR Sum of Boxes, score (SD)
E-aMCI (N ¼ 91)
L-aMCI (N ¼ 180)
Controls (N ¼ 234)
P
69.2 (7.6) 55 (60.4) 10.1 (5.9) 26.9 (2.9) 1.0 (0.8)
70.4 (8.7) 115 (63.9) 10.9 (4.8) 25.8 (2.8) 1.4 (0.9)
64.2 (8.5) 164 (70.1) 11.8 (4.9) 28.7 (1.6) 0.6 (0.4)
< 0.001 0.181 0.023 < 0.001 < 0.001
E-aMCI: Early-stage amnestic mild cognitive impairment, L-aMCI: Late-stage amnestic mild cognitive impairment.
Table 2 Neuropsychological results in early-stage aMCI, late-stage aMCI, and subjects with normal cognition. Neuropsychological test (Possible maximum score) Attention Digit span forward Digit span backward Language K-BNT (60) Visuospatial function RCFT (36) Memory SVLT immediate recall (36) SVLT delayed recall (12) SVLT recognition score (24) RCFT immediate recall (36) RCFT delayed recall (36) RCFT recognition score (24) Frontal/Executive function COWAT animal COWAT supermarket COWAT phonemic Stroop color reading (112) MMSE (30)
NC (N ¼ 234)
EMCI (N ¼ 91)
LMCI (N ¼ 180)
P value* (NC vs. EMCI)
P value* (NC vs. LMCI)
P value* (EMCI vs. LMCI)
6.6 (1.4) 4.5 (1.5)
5.4 (1.5) 3.6 (1.0)
5.6 (1.4) 3.5 (1.1)
< 0.001 < 0.001
< 0.001 < 0.001
0.937 > 0.999
50.3 (6.0)
41.7 (9.1)
40.9 (9.4)
< 0.001
< 0.001
> 0.999
33.2 (2.8)
29.9 (6.3)
29.2 (7.0)
0.001
< 0.001
0.207
22.5 (4.8) 7.7 (2.2) 21.7 (1.7) 18.3 (5.8) 18.1 (5.2) 20.2 (1.7)
16.9 (4.8) 4.3 (2.3) 20.0 (2.2) 9.5 (5.1) 9.0 (4.7) 18.9 (2.1)
15.3 (4.3) 2.4 (2.6) 18.4 (2.7) 7.1 (4.9) 6.4 (5.1) 18.2 (2.4)
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
0.001 < 0.001 < 0.001 0.001 < 0.001 0.039
17.1 (4.6) 18.7 (5.5) 30.0 (11.8) 93.8 (18.8) 28.7 (1.6)
13.1 (4.0) 14.5 (5.1) 22.5 (11.3) 73.5 (25.7) 26.9 (2.9)
12.0 (4.1) 13.0 (5.1) 20.8 (10.6) 71.4 (25.3) 25.8 (2.8)
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
0.084 0.037 0.284 > 0.999 < 0.001
Data are expressed in mean (SD). * P values are results of analyses of covariance using age, gender, and education as covariates.
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Poster Presentations: P2
and bilateral anterior temporal cortices. EMCI represents an early clinical stage between normal aging and late-stage aMCI.
tained. Results: Relative to controls AD had reduced NAA/Cr levels in hippocampus (55.0% to 29.3 %, p<.001), posterior cingulate gyrus (23.0% to 3.8 %, P ¼ .008) and parietal lobe (37.5 % to 4.5 %, P ¼ .015). No differences of Cho/Cr and mI/Cr were observed. NAA/Cr of the hippocampus yielded the highest sensitivity (93.8 %) and specificity (100 %) to differentiate AD from controls and was the only metabolite that was associated to general cognition (R ¼ .65, P ¼ .001). Higher NAA/Cr in the hippocampus was related to a higher CSF Ab42 while in the parietal lobe lower NAA/Cr was associated with a higher CSF T-tau and p- tau181P. mI/Cr of the posterior cingulate gyrus was related to CSF T-tau, as well as to NAA/mI. Conclusions: 1H-MRS is an appropriate measure in AD. Measurement at different regions presumably reflects different pathological changes. P2-211
RATES OF BRAIN AND HIPPOCAMPAL ATROPHY IN PRESYMPTOMATIC FAMILIAL ALZHEIMER’S DISEASE: ACCELERATION AND MUTATION EFFECTS
David Cash1, Yuying Liang1, Kelvin Leung2, Natalie Ryan3, Marc Modat1, Manuel Cardoso4, Tom Yeatman1, Sebastian Crutch1, Felix Woodward1, Ian Malone1, Jonathan Bartlett5, Kirsi Kinnunen4, Martin Rossor6, Sebastien Ourselin1, Nick Fox1, 1University College of London, London, United Kingdom; 2UCL Institute of Neurology, London, United Kingdom; 3 Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom; 4University College London, London, United Kingdom; 5London School of Hygiene and Tropical Medicine, London, United Kingdom; 6 Dementia Research Centre, London, United Kingdom. P2-210
1
ASSOCIATION OF H-MR SPECTROSCOPY AND CEREBROSPINAL FLUID BIOMARKERS IN ALZHEIMER’S DISEASE: DIVERGING BEHAVIOR AT THREE DIFFERENT BRAIN REGIONS
Daniel Bittner1, Hans-Jochen Heinze2, J€orn Kaufmann3, 1University of Magdeburg, Department of Neurology, Germany, Magdeburg, Germany; 2 University of Magdeburg, Department of Neurology, Magdeburg, Germany; 3University of Magdeburg, Magdeburg, Germany. Background: N-acetylaspartate (NAA) is diminished, choline (Cho) and myo-inositol (mI) is increased in medial temporal lobe, posterior cingulate gyrus and parietal lobe in Alzheimer’s disease (AD). In cerebrospinal fluid (CSF) tau and phosphoylated tau (P- tau181P) is increased and amyloid-b(142) (Ab42) decreased. Objectives: 1) to compare metabolites of different 1 H-MRS voxels and assess it’s utility to differentiate AD from controls 2) to examine the relationship to cognitive functioning 3) to assess its relationship to CSF markers. Methods: 10 healthy controls and 17 AD subjects were studied using 1 H-MRS. In AD additionally CSF analysis was ob-
Background: Subjects at risk of familial Alzheimer’s disease (FAD) offer the best chance to observe the earliest effects of the disease and would be candidates for presymptomatic trials. Currently there is relatively little longitudinal data available on subjects in the earliest stages of disease. Here, we analyze the atrophy rates of key structures in a local longitudinal FAD cohort which has been followed for up to two decades. Methods: 36 individuals (24 from PS1 families and 12 from APP families, mean (SD) age 46.3 (8.6) years) with FAD or at risk were recruited into the study. Each had 2 to 11 MRI scans approximately annually and were followed for up to 16 years. For each subject the scan at first onset of symptoms was identified. Fortyfour age- and sex-matched control subjects (mean [sd] age 48.4 [11.2] years) were scanned twice on average 1.3 [0.6] years apart. Brain, ventricles, and hippocampi were segmented using automated techniques. Linear mixed models were fitted to estimate atrophy rates according to time to symptom onset and to test for acceleration in rates. The models also adjusted for TIV and scanner. Results: At time of symptom onset, mutation carriers already had significantly increased rates of atrophy for all structures compared to controls (see Table). Whole brain atrophy rates at symptom onset were similar in the two mutation groups (APP 1.51%/year (95% CI 0.92, 2.10), PS1
Table Atrophy and acceleration rates (with 95% confidence intervals) for controls and subjects with FAD, grouped by mutation status. In all three structures the atrophy rate at symptom onset was significantly higher than controls. The p-values listed test whether the value for acceleration is non-zero.
Demographics
Whole Brain
Ventricles
Hippocampi (L+R averaged)
# of scans Male % Age at First Scan Atrophy rate (%/year) at symptom onset Acceleration of atrophy rate (%/year2) P-value for acceleration Atrophy rate (%/year) at symptom onset Acceleration of atrophy rate (%/year2) P-value for acceleration Atrophy rate (%/year) at symptom onset Acceleration of atrophy rate (%/year2) P-value for acceleration
Controls (n¼44)
APP (n¼12)
PS1 (n¼24)
88 20 (45.5) 48.4 (11.2) -0.01 (-0.27, 0.25) 0.2 (-1.9, 2.3) -0.09 (-0.40, 0.23) -
56 6 (50) 51.3 (5.5) 1.51 (0.92, 2.10) -0.03 (-0.09, 0.03) 0.40 13.5 (9.1, 18.1) 0.41 (0.13, 0.69) 0.004 2.17 (1.68, 2.65)* 0.23 (0.13, 0.32) <0.001
93 10 (41.7) 43.8 (8.9) 1.25 (0.76, 1.74) 0.17 (0.09, 0.25)+ <0.001 11.6 (7.9, 15.4) 1.14 (0.69, 1.59)+ <0.001 1.13 (0.70, 1.56) 0.20 (0.08, 0.31) 0.001
A * indicates that there is strong evidence that hippocampal atrophy rates at symptom onset differ between APP and PS1 (P¼0.001). A + indicates that there is evidence that the acceleration rates of whole brain (P < 0.001) and ventricular atrophy (P¼0.006) differ between APP and PS1.
CORTICAL THINNING IN EARLY-STAGE AND LATE-STAGE AMNESTIC MILD COGNITIVE IMPAIRMENT
Byoung Seok Ye, Geon Ha Kim, Hanna Cho, Ji Soo Shin, Young Noh, Duk L. Na, Sang Won Seo, Samsung Medical Center, Sunkyunkwan University, School of Medicine, Seoul, South Korea. Background: Amnestic mild cognitive impairment (aMCI) represents a pre-dementia stage of Alzheimer’s disease (AD). According to the severity of objective memory impairment, aMCI patients can be classified into subjects with milder degree of impairment and those with more severe impairment. Although previous studies showed that aMCI subjects with milder memory impairment have slower rates of AD progression than those with
P329
more severe memory impairment, there has been no study comparing regional cortical thickness according to this classification of aMCI. Methods: Cortical thickness across the entire brain and neuropsychological performance were measured in 271 patients with aMCI and 234 subjects with normal cognition (NC). According to the performances in delayed recall items of memory tests, aMCI patients were divided into early-stage aMCI (EMCI, N ¼ 91) with milder degree of memory impairment (scores between -1.5 SD and -1.0 SD compared to age-, sex-, and education-matched norms) and latestage MCI (LMCI, N ¼ 180) with more severe memory impairment (lower than -1.5 SD). We performed ANCOVAs to compare neuropsychological performances and vertex-wise cortical thinning in EMCI, LMCI, and NC. Results: Compared to NC subjects, EMCI patients showed cortical thinning in the left medial temporal lobe, and LMCI patients showed cortical thinning in bilateral medial temporal lobes, bilateral medial and lateral parietal cortices, bilateral dorsolateral prefrontal cortices, right posterior cingulate cortex, and bilateral anterior temporal cortices. When the two aMCI groups were directly compared, LMCI patients showed more cortical thinning in the right medial temporal lobe, right posterior cingulate cortex, right lateral parietal cortex, and right dorsolateral prefrontal cortex. Both EMCI and LMCI patients showed lower performances in all neuropsychological tests compared to NC. When directly compared with EMCI, LMCI subjects had poorer performance in all memory tests and COWAT supermarket test, while having comparable scores in other tests. Conclusions: Our study suggests that the cortical thinning in aMCI initiates in the left medial temporal lobe and then progresses into other regions including the right medial temporal lobe, right posterior cingulate cortex, right lateral parietal cortex,
Table 1 Demographic variables, Mini-Mental State Examination (MMSE) scores of E-aMCI and L-aMCI
Age: years, mean (SD) Gender: female, N (%) Education: years, mean (SD) MMSE: score, mean (SD) CDR Sum of Boxes, score (SD)
E-aMCI (N ¼ 91)
L-aMCI (N ¼ 180)
Controls (N ¼ 234)
P
69.2 (7.6) 55 (60.4) 10.1 (5.9) 26.9 (2.9) 1.0 (0.8)
70.4 (8.7) 115 (63.9) 10.9 (4.8) 25.8 (2.8) 1.4 (0.9)
64.2 (8.5) 164 (70.1) 11.8 (4.9) 28.7 (1.6) 0.6 (0.4)
< 0.001 0.181 0.023 < 0.001 < 0.001
E-aMCI: Early-stage amnestic mild cognitive impairment, L-aMCI: Late-stage amnestic mild cognitive impairment.
Table 2 Neuropsychological results in early-stage aMCI, late-stage aMCI, and subjects with normal cognition. Neuropsychological test (Possible maximum score) Attention Digit span forward Digit span backward Language K-BNT (60) Visuospatial function RCFT (36) Memory SVLT immediate recall (36) SVLT delayed recall (12) SVLT recognition score (24) RCFT immediate recall (36) RCFT delayed recall (36) RCFT recognition score (24) Frontal/Executive function COWAT animal COWAT supermarket COWAT phonemic Stroop color reading (112) MMSE (30)
NC (N ¼ 234)
EMCI (N ¼ 91)
LMCI (N ¼ 180)
P value* (NC vs. EMCI)
P value* (NC vs. LMCI)
P value* (EMCI vs. LMCI)
6.6 (1.4) 4.5 (1.5)
5.4 (1.5) 3.6 (1.0)
5.6 (1.4) 3.5 (1.1)
< 0.001 < 0.001
< 0.001 < 0.001
0.937 > 0.999
50.3 (6.0)
41.7 (9.1)
40.9 (9.4)
< 0.001
< 0.001
> 0.999
33.2 (2.8)
29.9 (6.3)
29.2 (7.0)
0.001
< 0.001
0.207
22.5 (4.8) 7.7 (2.2) 21.7 (1.7) 18.3 (5.8) 18.1 (5.2) 20.2 (1.7)
16.9 (4.8) 4.3 (2.3) 20.0 (2.2) 9.5 (5.1) 9.0 (4.7) 18.9 (2.1)
15.3 (4.3) 2.4 (2.6) 18.4 (2.7) 7.1 (4.9) 6.4 (5.1) 18.2 (2.4)
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
0.001 < 0.001 < 0.001 0.001 < 0.001 0.039
17.1 (4.6) 18.7 (5.5) 30.0 (11.8) 93.8 (18.8) 28.7 (1.6)
13.1 (4.0) 14.5 (5.1) 22.5 (11.3) 73.5 (25.7) 26.9 (2.9)
12.0 (4.1) 13.0 (5.1) 20.8 (10.6) 71.4 (25.3) 25.8 (2.8)
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
0.084 0.037 0.284 > 0.999 < 0.001
Data are expressed in mean (SD). * P values are results of analyses of covariance using age, gender, and education as covariates.
P330
Poster Presentations: P2
and bilateral anterior temporal cortices. EMCI represents an early clinical stage between normal aging and late-stage aMCI.
tained. Results: Relative to controls AD had reduced NAA/Cr levels in hippocampus (55.0% to 29.3 %, p<.001), posterior cingulate gyrus (23.0% to 3.8 %, P ¼ .008) and parietal lobe (37.5 % to 4.5 %, P ¼ .015). No differences of Cho/Cr and mI/Cr were observed. NAA/Cr of the hippocampus yielded the highest sensitivity (93.8 %) and specificity (100 %) to differentiate AD from controls and was the only metabolite that was associated to general cognition (R ¼ .65, P ¼ .001). Higher NAA/Cr in the hippocampus was related to a higher CSF Ab42 while in the parietal lobe lower NAA/Cr was associated with a higher CSF T-tau and p- tau181P. mI/Cr of the posterior cingulate gyrus was related to CSF T-tau, as well as to NAA/mI. Conclusions: 1H-MRS is an appropriate measure in AD. Measurement at different regions presumably reflects different pathological changes. P2-211
RATES OF BRAIN AND HIPPOCAMPAL ATROPHY IN PRESYMPTOMATIC FAMILIAL ALZHEIMER’S DISEASE: ACCELERATION AND MUTATION EFFECTS
David Cash1, Yuying Liang1, Kelvin Leung2, Natalie Ryan3, Marc Modat1, Manuel Cardoso4, Tom Yeatman1, Sebastian Crutch1, Felix Woodward1, Ian Malone1, Jonathan Bartlett5, Kirsi Kinnunen4, Martin Rossor6, Sebastien Ourselin1, Nick Fox1, 1University College of London, London, United Kingdom; 2UCL Institute of Neurology, London, United Kingdom; 3 Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom; 4University College London, London, United Kingdom; 5London School of Hygiene and Tropical Medicine, London, United Kingdom; 6 Dementia Research Centre, London, United Kingdom. P2-210
1
ASSOCIATION OF H-MR SPECTROSCOPY AND CEREBROSPINAL FLUID BIOMARKERS IN ALZHEIMER’S DISEASE: DIVERGING BEHAVIOR AT THREE DIFFERENT BRAIN REGIONS
Daniel Bittner1, Hans-Jochen Heinze2, J€orn Kaufmann3, 1University of Magdeburg, Department of Neurology, Germany, Magdeburg, Germany; 2 University of Magdeburg, Department of Neurology, Magdeburg, Germany; 3University of Magdeburg, Magdeburg, Germany. Background: N-acetylaspartate (NAA) is diminished, choline (Cho) and myo-inositol (mI) is increased in medial temporal lobe, posterior cingulate gyrus and parietal lobe in Alzheimer’s disease (AD). In cerebrospinal fluid (CSF) tau and phosphoylated tau (P- tau181P) is increased and amyloid-b(142) (Ab42) decreased. Objectives: 1) to compare metabolites of different 1 H-MRS voxels and assess it’s utility to differentiate AD from controls 2) to examine the relationship to cognitive functioning 3) to assess its relationship to CSF markers. Methods: 10 healthy controls and 17 AD subjects were studied using 1 H-MRS. In AD additionally CSF analysis was ob-
Background: Subjects at risk of familial Alzheimer’s disease (FAD) offer the best chance to observe the earliest effects of the disease and would be candidates for presymptomatic trials. Currently there is relatively little longitudinal data available on subjects in the earliest stages of disease. Here, we analyze the atrophy rates of key structures in a local longitudinal FAD cohort which has been followed for up to two decades. Methods: 36 individuals (24 from PS1 families and 12 from APP families, mean (SD) age 46.3 (8.6) years) with FAD or at risk were recruited into the study. Each had 2 to 11 MRI scans approximately annually and were followed for up to 16 years. For each subject the scan at first onset of symptoms was identified. Fortyfour age- and sex-matched control subjects (mean [sd] age 48.4 [11.2] years) were scanned twice on average 1.3 [0.6] years apart. Brain, ventricles, and hippocampi were segmented using automated techniques. Linear mixed models were fitted to estimate atrophy rates according to time to symptom onset and to test for acceleration in rates. The models also adjusted for TIV and scanner. Results: At time of symptom onset, mutation carriers already had significantly increased rates of atrophy for all structures compared to controls (see Table). Whole brain atrophy rates at symptom onset were similar in the two mutation groups (APP 1.51%/year (95% CI 0.92, 2.10), PS1
Table Atrophy and acceleration rates (with 95% confidence intervals) for controls and subjects with FAD, grouped by mutation status. In all three structures the atrophy rate at symptom onset was significantly higher than controls. The p-values listed test whether the value for acceleration is non-zero.
Demographics
Whole Brain
Ventricles
Hippocampi (L+R averaged)
# of scans Male % Age at First Scan Atrophy rate (%/year) at symptom onset Acceleration of atrophy rate (%/year2) P-value for acceleration Atrophy rate (%/year) at symptom onset Acceleration of atrophy rate (%/year2) P-value for acceleration Atrophy rate (%/year) at symptom onset Acceleration of atrophy rate (%/year2) P-value for acceleration
Controls (n¼44)
APP (n¼12)
PS1 (n¼24)
88 20 (45.5) 48.4 (11.2) -0.01 (-0.27, 0.25) 0.2 (-1.9, 2.3) -0.09 (-0.40, 0.23) -
56 6 (50) 51.3 (5.5) 1.51 (0.92, 2.10) -0.03 (-0.09, 0.03) 0.40 13.5 (9.1, 18.1) 0.41 (0.13, 0.69) 0.004 2.17 (1.68, 2.65)* 0.23 (0.13, 0.32) <0.001
93 10 (41.7) 43.8 (8.9) 1.25 (0.76, 1.74) 0.17 (0.09, 0.25)+ <0.001 11.6 (7.9, 15.4) 1.14 (0.69, 1.59)+ <0.001 1.13 (0.70, 1.56) 0.20 (0.08, 0.31) 0.001
A * indicates that there is strong evidence that hippocampal atrophy rates at symptom onset differ between APP and PS1 (P¼0.001). A + indicates that there is evidence that the acceleration rates of whole brain (P < 0.001) and ventricular atrophy (P¼0.006) differ between APP and PS1.