- Email: [email protected]
Neuropsychological differences between PiB-negative subcortical vascular dementia and PiB-positive Alzheimer's disease
Developing Topics: P4 Posters found increased exon 19 inclusion in TrkB minigene transcripts (to generate TrkB-Shc) following cellular exposure to amyloid beta 1-42 (Ab42) oligomers and fibrils (all p<0.045). As this suggested dysregulation in TrkB premRNA splicing in AD, we conducted an in silico screening for putative splice regulatory protein binding sites in the intron/exon splice regulatory regions of exons 18 and 19 of the TrkB gene. From the candidate splice regulatory proteins identified, we assessed their gene expression profiles using a microarray database of control/AD postmortem human hippocampal brain tissue. We found significant alterations in Srp20 gene expression in AD cases. When we assessed Srp20 gene expression in our postmortem brain cohort of control and AD (n¼6/6), we found elevated Srp20 mRNA levels in the AD hippocampus (t¼3.44, df¼8, p¼0.009). Furthermore, Srp20 mRNA levels were significantly increased in SHSY5Y cells treated with Ab42 fibrils (t¼3.84, df¼15, p¼0.002). When Srp20 was overexpressed, we found increased exon 19 inclusion in TrkB minigene transcripts and corresponding increases in endogenous TrkB-Shc mRNA levels (t¼3.76, df¼4, p¼0.04). Conversely, when we knocked down Srp20 expression, we observed the opposite effect on TrkBShc expression (t¼-3.50, df¼6, p¼0.01). Conclusions: We identify a novel mechanism by which BDNF signaling is compromised in AD. Our findings suggest that dysregulation of factors regulating pre-mRNA splicing may underlie gene expression changes that occur in AD. P4-373
disease (AD) is a striking example, where the presence of the disease is so ubiquitous in daily life. Methods: This presentation is divided into two parts. First, I will first describe the history of AD. I will review its initial description by Alois Alzheimer and Emil Kraepelin, and how it made no sense to call senile dementia a disease since they viewed it as a standard course of aging. That AD has transformed from an insignificant pathology into the "disease of the century" is largely due to the way it is socially represented. Second, I will turn to Serge Moscovici’s theory of social representations which accounts for how any science - including the science of AD - becomes reified into a social reality. I will summarize Moscovici’s theory about how the science of AD becomes socially shared and practiced, and the mode of exchange between the scientific and public realms of AD. Results: The surprising history of AD and Moscovici’s theory of social representations helps foster curiosity about the way that our understanding of AD is significantly shaped by non-scientific, social factors. To be clear, I do not wish to suggest that the type of dementia attributed to AD is socially fabricated. Cognitive decline has always been an observable trait in elderly populations, and we ought to continue investigating the etiology and possible treatments for it. Conclusions: More research should be directed to investigate the way that AD is socially represented, and the implications this carries for ambitions in the field.
SOCIAL REPRESENTATIONS OF ALZHEIMER’S DISEASE: PRELIMINARY CONSIDERATIONS
P4-374
Jonathan Yahalom, Duquesne University, Pittsburgh, Pennsylvania, United States. Background: Insofar as knowledge and practice of science extends beyond the scientific community, it has become socially constructed. Alzheimer’s
S789
NEUROPSYCHOLOGICAL DIFFERENCES BETWEEN PIB-NEGATIVE SUBCORTICAL VASCULAR DEMENTIA AND PIB-POSITIVE ALZHEIMER’S DISEASE
Cindy Yoon, Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea.
Table 2 Comparison of neuropsychological performances of three groups Pair wise p value PIB (+) AD (N¼59) Attention Digit span forward Digit span backward Language & related function Naming-K-BNT Calculation Praxis (ideomotor) Visuospatial function Rey-CFT copy score Memory RCFT immediate recall RCFT delayed recall RCFT recognition score SVLT immediate recall SVLT delayed recall SVLT recognition score Frontal/executive function COWAT animal COWAT supermarket COWAT phonemic Stroop test Word reading Stroop test Color reading Domain score Attention (17) Language & related function (27) Visuospatial function (36) Memory (150) Frontal/Executive function (70) Total (300)
PIB (-) SVaD (N¼44)
NC (N¼51)
AD versus SVaD
NC versus SVaD
NC versus AD
5.2 6 1.4 2.7 6 1.2
4.8 6 1.3 2.4 6 1.3
7.0 6 1.3 4.5 6 1.3
0.208 0.160
< 0.001 < 0.001
< 0.001 < 0.001
31.1 6 11.3 8.7 6 3.4 3.6 6 1.4
31.5 6 11.0 8.0 6 3.5 3.5 6 1.6
51.0 6 5.1 11.9 6 0.2 5.0 6 0.2
0.957 0.053 0.286
< 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001
23.5 6 10.0
21.4 6 10.4
34.4 6 1.4
0.241
< 0.001
< 0.001
3.5 6 3.0 2.2 6 2.8 14.7 6 3.6 10.5 6 4.9 0.6 6 1.5 1 5.3 6 3.8
5.3 6 4.8 4.4 6 4.4 16.3 6 3.6 12.3 6 4.5 1.8 6 2.0 17.5 6 2.7
20.1 6 5.5 19.6 6 5.7 20.5 6 1.5 22.7 6 4.7 7.8 6 2.0 21.9 6 1.5
0.090 0.005 0.005 0.052 < 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
9.0 6 4.1 8.0 6 4.4 12.9 6 9.2 93.1 6 29.4 38.7 6 29.2
7.9 6 3.3 6.3 6 4.5 7.2 6 5.6 76.9 6 38.5 28.3 6 26.2
19.4 6 3.8 21.5 6 5.1 37.1 6 11.6 111.9 6 0.9 100.0 6 15.1
0.173 0.021 0.002 0.008 0.019
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
7.9 6 2.2 15.9 6 5.5 23.5 6 10.0 26.4 6 13.0 31.6 6 15.0 104.9 6 36.3
7.2 6 2.4 15.9 6 5.3 21.4 6 10.4 40.3 6 17.0 25.5 6 12.1 108.7 6 40.0
11.6 6 2.2 24.7 6 2.7 34.4 6 1.4 94.7 6 15.2 63.7 6 5.9 229.1 6 21.8
0.512 0.395 0.241 < 0.001 0.030 0.206
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
AD, Alzheimer’s disease; SVaD, Subcortical vascular dementia; NC, Normal control; K-BNT, Korean version of the Boston naming test; RCFT, Rey-Osterrieth complex figure test; SVLT, Seoul verbal learning test; COWAT, Controlled oral word association test p ¼ adjusted by age and education
S790
Developing Topics: P4 Posters
Table 1 Demographics and dementia severity measures of three groups
No. of patients Age, mean 6 SD, yr Female, n (%) Education, mean 6 SD, yrs MMSE, mean 6 SD Global CDR, mean 6 SD CDR-SOB, mean 6 SD
Normal controls PIB (+) AD
PIB (-) SVaD
51 66.6 6 4.9 * 34 (66.7) 13.9 6 3.7* 29.1 6 1.3*
44 71.4 6 7.2 * 23 (52.3) 8.1 6 4.6*,y 21.8 6 4.4*,y 1.0 6 0.6 5.9 6 3.7
59 68.9 6 9.6 37 (62.7) 10.9 6 5.3*,y 18.6 6 5.7*,y 0.9 6 0.4 4.9 6 2.4
* P < 0.05 between Normal controls and PIB (+) AD or Normal controls and PIB (-) SVaD. y P < 0.05 between PIB (+) AD and PIB (-) SvaD
Background: Differentiation of subcortical vascular dementia (VaD) from Alzheimer’s disease (AD) is important from the therapeutic point of view. Despite many neuropsychological studies to differentiate VaD from AD, only a few studies focused on subcortical VaD (SVaD), among the heterogeneous VaD. Furthermore, these studies on SVaD did not eliminate confounding effects of mixed Alzheimer and vascular pathology. We aimed to investigate neuropsychological differences between patients with Pittsburgh compound-B (PIB) negative SVaD and those with PIB-positive AD. Methods: We recruited patients who were clinically diagnosed with SVaD or AD, and underwent a 11 C-PIB PET scan and MRI at Samsung Medical Center or Asan Medical Center, Seoul Korea, between September 2008 and May 2011. All patients met SVaD (N¼69) or AD (N¼67) criteria as described in the study from our group. The final patient sample consisted of 44/69 (63.8%) SVaD patients who tested negative for PIB retention [PIB (-) SVaD] and 59/67 (88.1%) AD patients who tested positive for PIB retention [PIB (+) AD]. Results: Neuropsychological profile differences among the groups were analyzed by applying an analysis of covariance (ANCOVA) with Bonferroni post hoc analysis. Age and education were entered as covariates. As shown in Table 1, post hoc comparisons showed that both PIB (+) AD and PIB (-) SVaD patients were significantly more impaired than NC on every neuropsychological test. Patients with PIB (-) SVaD performed better than PIB (+) AD patients on both verbal and visual memory tests including delayed recalls of the verbal learning test and Rey Complex Figure test. In contrast, PIB (-) SVaD patients were worse than PIB (+) AD patients on frontal executive tests including the semantic/phonemic fluency of the Controlled Oral Word Association Test (COWAT) and Stroop word/color tests. The two patient groups performed comparably in attention, language, calculation, praxis, and visuospatial domains. Domain score using SNSB-D showed the same trend. Conclusions: Our study is unique in selecting each patient group based on amyloid imaging, which minimized the possibility of contaminating mixed vascular and AD pathologies.
P4-375
late cortex (ICCs) as seed regions, functional correlation and fiber tracking connectivity distribution to all other voxels of the brain were calculated. Between-group t tests were carried. Correlation analyses were obtained between the functional connectivity of default-mode network components and (1) pons-normalized PET signal, (2) cortical thickness/volume and (3) cognitive performance. Results: Whole-brain group analyses showed significant functional connectivity differences (NC > AD) from the right and left ICCs to medial frontal gyrus /anterior cingulate cortex and surrounding regions. There was a general trend of NC > MCI > AD on both functional and structural connectivity from the right and left ICCs to these frontal regions (Fig. 1). Significant correlations were found between PET signal in the right and left ICCs, right and left hippocampi and left ICC-right hippocampus functional connectivity (Table 1, Fig. 2). Significant correlations between PET signal and cortical thickness/volume were also found (Table 1). Significant correlations were found between the left ICC-right hippocampus functional connectivity and SLUMS score (r ¼ 0.459, p ¼ 0.0082) as well as LM-dr score (r ¼ 0.375, p ¼ 0.0347). Conclusions: There is a clear reduction of structural and functional connectivity within the default-mode network in AD, consistent with the reduction of metabolic activity and cortical atrophy in this network. The multi-modal correlation analyses suggest that neuronal damage in the left ICC is associated with declines in metabolic activity in this
Fig. 1. The integrated visualization of the functional and structural connections for normal, MCI and AD subjects (left to right) with the seed regions at the (a) right isthmus of cingulate cortex (ICC), (b) left ICC and (c) left lateral occipital cortex (LOC) and associated white matter regions. Thresholds: The mean correlation of > 0.2 for functional connectivity and mean connectivity distribution of > 1000 for structural connectivity. Green: functional connection only. Orange: structural connection only. Red: coexistence of both connections. GM: gray matter. WM: white matter. R ¼ right. L ¼ left. MeFG ¼ medial frontal gyrus.
ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT WEAKEN CONNECTIONS WITHIN THE DEFAULT-MODE NETWORK: A MULTIMODAL STUDY WITH RESTING-STATE FMRI, DIFFUSION MRI AND FDG-PET
David Zhu, Shantanu Majumdar, Igor Korolev, Kevin Berger, Andrea Bozoki, Michigan State University, East Lansing, Michigan, United States. Background: A multi-modal imaging approach was applied to understand alterations in the default-mode network from normal aging to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods: Participants included 10 probable AD, 11 amnestic MCI, and 12 age and educationmatched normal control (NC) subjects. Whole-brain resting-state functional, diffusion tensor and volumetric MRI as well as FDG-PET data were acquired. Cognitive assessment on all subjects included St. Louis University test of Mental Status (SLUMS) and Wechsler Memory Scale III Logical Memory delayed recall (LM-dr) test. With the right and left isthmi of cingu-
Fig. 2. With all subjects included, the significant correlations were shown between the left ICC-right hippocampus functional connection (the Fisher’s Z-transformed values of the correlations) and the normalized PET signals in (a) left ICC and (b) right hippocampus. R ¼ right, L ¼ left and ICC¼ isthmus of cingulate cortex.
disease (AD) is a striking example, where the presence of the disease is so ubiquitous in daily life. Methods: This presentation is divided into two parts. First, I will first describe the history of AD. I will review its initial description by Alois Alzheimer and Emil Kraepelin, and how it made no sense to call senile dementia a disease since they viewed it as a standard course of aging. That AD has transformed from an insignificant pathology into the "disease of the century" is largely due to the way it is socially represented. Second, I will turn to Serge Moscovici’s theory of social representations which accounts for how any science - including the science of AD - becomes reified into a social reality. I will summarize Moscovici’s theory about how the science of AD becomes socially shared and practiced, and the mode of exchange between the scientific and public realms of AD. Results: The surprising history of AD and Moscovici’s theory of social representations helps foster curiosity about the way that our understanding of AD is significantly shaped by non-scientific, social factors. To be clear, I do not wish to suggest that the type of dementia attributed to AD is socially fabricated. Cognitive decline has always been an observable trait in elderly populations, and we ought to continue investigating the etiology and possible treatments for it. Conclusions: More research should be directed to investigate the way that AD is socially represented, and the implications this carries for ambitions in the field.
SOCIAL REPRESENTATIONS OF ALZHEIMER’S DISEASE: PRELIMINARY CONSIDERATIONS
P4-374
Jonathan Yahalom, Duquesne University, Pittsburgh, Pennsylvania, United States. Background: Insofar as knowledge and practice of science extends beyond the scientific community, it has become socially constructed. Alzheimer’s
S789
NEUROPSYCHOLOGICAL DIFFERENCES BETWEEN PIB-NEGATIVE SUBCORTICAL VASCULAR DEMENTIA AND PIB-POSITIVE ALZHEIMER’S DISEASE
Cindy Yoon, Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea.
Table 2 Comparison of neuropsychological performances of three groups Pair wise p value PIB (+) AD (N¼59) Attention Digit span forward Digit span backward Language & related function Naming-K-BNT Calculation Praxis (ideomotor) Visuospatial function Rey-CFT copy score Memory RCFT immediate recall RCFT delayed recall RCFT recognition score SVLT immediate recall SVLT delayed recall SVLT recognition score Frontal/executive function COWAT animal COWAT supermarket COWAT phonemic Stroop test Word reading Stroop test Color reading Domain score Attention (17) Language & related function (27) Visuospatial function (36) Memory (150) Frontal/Executive function (70) Total (300)
PIB (-) SVaD (N¼44)
NC (N¼51)
AD versus SVaD
NC versus SVaD
NC versus AD
5.2 6 1.4 2.7 6 1.2
4.8 6 1.3 2.4 6 1.3
7.0 6 1.3 4.5 6 1.3
0.208 0.160
< 0.001 < 0.001
< 0.001 < 0.001
31.1 6 11.3 8.7 6 3.4 3.6 6 1.4
31.5 6 11.0 8.0 6 3.5 3.5 6 1.6
51.0 6 5.1 11.9 6 0.2 5.0 6 0.2
0.957 0.053 0.286
< 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001
23.5 6 10.0
21.4 6 10.4
34.4 6 1.4
0.241
< 0.001
< 0.001
3.5 6 3.0 2.2 6 2.8 14.7 6 3.6 10.5 6 4.9 0.6 6 1.5 1 5.3 6 3.8
5.3 6 4.8 4.4 6 4.4 16.3 6 3.6 12.3 6 4.5 1.8 6 2.0 17.5 6 2.7
20.1 6 5.5 19.6 6 5.7 20.5 6 1.5 22.7 6 4.7 7.8 6 2.0 21.9 6 1.5
0.090 0.005 0.005 0.052 < 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
9.0 6 4.1 8.0 6 4.4 12.9 6 9.2 93.1 6 29.4 38.7 6 29.2
7.9 6 3.3 6.3 6 4.5 7.2 6 5.6 76.9 6 38.5 28.3 6 26.2
19.4 6 3.8 21.5 6 5.1 37.1 6 11.6 111.9 6 0.9 100.0 6 15.1
0.173 0.021 0.002 0.008 0.019
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
7.9 6 2.2 15.9 6 5.5 23.5 6 10.0 26.4 6 13.0 31.6 6 15.0 104.9 6 36.3
7.2 6 2.4 15.9 6 5.3 21.4 6 10.4 40.3 6 17.0 25.5 6 12.1 108.7 6 40.0
11.6 6 2.2 24.7 6 2.7 34.4 6 1.4 94.7 6 15.2 63.7 6 5.9 229.1 6 21.8
0.512 0.395 0.241 < 0.001 0.030 0.206
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
AD, Alzheimer’s disease; SVaD, Subcortical vascular dementia; NC, Normal control; K-BNT, Korean version of the Boston naming test; RCFT, Rey-Osterrieth complex figure test; SVLT, Seoul verbal learning test; COWAT, Controlled oral word association test p ¼ adjusted by age and education
S790
Developing Topics: P4 Posters
Table 1 Demographics and dementia severity measures of three groups
No. of patients Age, mean 6 SD, yr Female, n (%) Education, mean 6 SD, yrs MMSE, mean 6 SD Global CDR, mean 6 SD CDR-SOB, mean 6 SD
Normal controls PIB (+) AD
PIB (-) SVaD
51 66.6 6 4.9 * 34 (66.7) 13.9 6 3.7* 29.1 6 1.3*
44 71.4 6 7.2 * 23 (52.3) 8.1 6 4.6*,y 21.8 6 4.4*,y 1.0 6 0.6 5.9 6 3.7
59 68.9 6 9.6 37 (62.7) 10.9 6 5.3*,y 18.6 6 5.7*,y 0.9 6 0.4 4.9 6 2.4
* P < 0.05 between Normal controls and PIB (+) AD or Normal controls and PIB (-) SVaD. y P < 0.05 between PIB (+) AD and PIB (-) SvaD
Background: Differentiation of subcortical vascular dementia (VaD) from Alzheimer’s disease (AD) is important from the therapeutic point of view. Despite many neuropsychological studies to differentiate VaD from AD, only a few studies focused on subcortical VaD (SVaD), among the heterogeneous VaD. Furthermore, these studies on SVaD did not eliminate confounding effects of mixed Alzheimer and vascular pathology. We aimed to investigate neuropsychological differences between patients with Pittsburgh compound-B (PIB) negative SVaD and those with PIB-positive AD. Methods: We recruited patients who were clinically diagnosed with SVaD or AD, and underwent a 11 C-PIB PET scan and MRI at Samsung Medical Center or Asan Medical Center, Seoul Korea, between September 2008 and May 2011. All patients met SVaD (N¼69) or AD (N¼67) criteria as described in the study from our group. The final patient sample consisted of 44/69 (63.8%) SVaD patients who tested negative for PIB retention [PIB (-) SVaD] and 59/67 (88.1%) AD patients who tested positive for PIB retention [PIB (+) AD]. Results: Neuropsychological profile differences among the groups were analyzed by applying an analysis of covariance (ANCOVA) with Bonferroni post hoc analysis. Age and education were entered as covariates. As shown in Table 1, post hoc comparisons showed that both PIB (+) AD and PIB (-) SVaD patients were significantly more impaired than NC on every neuropsychological test. Patients with PIB (-) SVaD performed better than PIB (+) AD patients on both verbal and visual memory tests including delayed recalls of the verbal learning test and Rey Complex Figure test. In contrast, PIB (-) SVaD patients were worse than PIB (+) AD patients on frontal executive tests including the semantic/phonemic fluency of the Controlled Oral Word Association Test (COWAT) and Stroop word/color tests. The two patient groups performed comparably in attention, language, calculation, praxis, and visuospatial domains. Domain score using SNSB-D showed the same trend. Conclusions: Our study is unique in selecting each patient group based on amyloid imaging, which minimized the possibility of contaminating mixed vascular and AD pathologies.
P4-375
late cortex (ICCs) as seed regions, functional correlation and fiber tracking connectivity distribution to all other voxels of the brain were calculated. Between-group t tests were carried. Correlation analyses were obtained between the functional connectivity of default-mode network components and (1) pons-normalized PET signal, (2) cortical thickness/volume and (3) cognitive performance. Results: Whole-brain group analyses showed significant functional connectivity differences (NC > AD) from the right and left ICCs to medial frontal gyrus /anterior cingulate cortex and surrounding regions. There was a general trend of NC > MCI > AD on both functional and structural connectivity from the right and left ICCs to these frontal regions (Fig. 1). Significant correlations were found between PET signal in the right and left ICCs, right and left hippocampi and left ICC-right hippocampus functional connectivity (Table 1, Fig. 2). Significant correlations between PET signal and cortical thickness/volume were also found (Table 1). Significant correlations were found between the left ICC-right hippocampus functional connectivity and SLUMS score (r ¼ 0.459, p ¼ 0.0082) as well as LM-dr score (r ¼ 0.375, p ¼ 0.0347). Conclusions: There is a clear reduction of structural and functional connectivity within the default-mode network in AD, consistent with the reduction of metabolic activity and cortical atrophy in this network. The multi-modal correlation analyses suggest that neuronal damage in the left ICC is associated with declines in metabolic activity in this
Fig. 1. The integrated visualization of the functional and structural connections for normal, MCI and AD subjects (left to right) with the seed regions at the (a) right isthmus of cingulate cortex (ICC), (b) left ICC and (c) left lateral occipital cortex (LOC) and associated white matter regions. Thresholds: The mean correlation of > 0.2 for functional connectivity and mean connectivity distribution of > 1000 for structural connectivity. Green: functional connection only. Orange: structural connection only. Red: coexistence of both connections. GM: gray matter. WM: white matter. R ¼ right. L ¼ left. MeFG ¼ medial frontal gyrus.
ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT WEAKEN CONNECTIONS WITHIN THE DEFAULT-MODE NETWORK: A MULTIMODAL STUDY WITH RESTING-STATE FMRI, DIFFUSION MRI AND FDG-PET
David Zhu, Shantanu Majumdar, Igor Korolev, Kevin Berger, Andrea Bozoki, Michigan State University, East Lansing, Michigan, United States. Background: A multi-modal imaging approach was applied to understand alterations in the default-mode network from normal aging to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods: Participants included 10 probable AD, 11 amnestic MCI, and 12 age and educationmatched normal control (NC) subjects. Whole-brain resting-state functional, diffusion tensor and volumetric MRI as well as FDG-PET data were acquired. Cognitive assessment on all subjects included St. Louis University test of Mental Status (SLUMS) and Wechsler Memory Scale III Logical Memory delayed recall (LM-dr) test. With the right and left isthmi of cingu-
Fig. 2. With all subjects included, the significant correlations were shown between the left ICC-right hippocampus functional connection (the Fisher’s Z-transformed values of the correlations) and the normalized PET signals in (a) left ICC and (b) right hippocampus. R ¼ right, L ¼ left and ICC¼ isthmus of cingulate cortex.