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Amyloid And Tau Proteins In Cortical Brain Biopsy And Alzheimer'S Disease
e16
Hot Topics TOMM40 group had significantly less gray matter volume in the ventral posterior cingulate and precuneus, a region of the brain affected early in LOAD. Conclusions: To our knowledge, this is the first study to associate TOMM40 523 genotypes to brain imaging in people at risk for AD. These findings suggest that the group with very long TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes. The participants in this study are being followed over time to determine genetic and other factors that predict cognitive decline and dementia.
Figure 1. Statistical parametric maps (SPMs) showing higher PiB retention in NL with AD-mothers compared to controls (top two rows) and to NL with AD-fathers (middle two rows), and in NL with AD-fathers compared to controls (bottom two rows). Areas of increased PiB retention are represented on a red-to-yellow color-coded scale, reflecting P values between 0.01-0.001, as indicated on the right side of figure. SPMs are displayed onto the axial and sagittal views of a standard, spatially normalized MRI.
Figure 2. Statistical parametric maps (SPMs) showing reduced glucose metabolism in NL with AD-mothers compared to controls (top two rows) and to NL with AD-fathers (bottom two rows). Areas of reduced metabolism are represented on a blue-to-yellow color-coded scale, reflecting P values between 0.01-0.001, as indicated on the right side of figure. SPMs are displayed onto the axial and sagittal views of a standard, spatially normalized MRI.
O4-03-04
TOMM40 IS ASSOCIATED WITH GRAY MATTER VOLUME IN MIDDLE-AGED PERSONS WITH APOE 33/33 GENOTYPE
Sterling C. Johnson1,2, Asenath La Rue1, Bruce P. Hermann1, Guofan Xu1, Rebecca L. Koscik1, Erin M. Jonaitas1, Barbara B. Bendlin1,2, Allen D. Roses3, Ann M. Saunders3, Michael W. Lutz3, Sanjay Asthana1,2, Robert C. Green4, Mark A. Sager1, 1University of Wisconsin, Madison, WI, USA; 2William S. Middleton Veterans Hospital, Madison, WI, USA; 3Duke University, Durham, NC, USA; 4Boston University, Boston, MA, USA. Background: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late onset Alzheimer’s disease (LOAD), with APOE 34 having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the TOMM40 gene has very recently been shown to influence age of onset in LOAD, where very long poly-T length was associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain changes antedating symptomatic LOAD may be associated with this TOMM40 polymorphism. Methods: Among healthy APOE 33 homozygous adults (mean age 57), we compared those homozygous for very long (VL/VL; n ¼ 33) TOMM40 poly-T lengths (who are presumably at higher risk) to those homozygous for short (S/S; n ¼ 37) poly-T lengths on structural brain imaging. Voxel-based morphometry was used to assess gray matter volume using the software SPM8. Gray matter probability maps were entered into a voxel-wise ANCOVA where Age and Intracranial volume were covariates Results: Results were that the VL/VL
O4-03-05
AMYLOID AND TAU PROTEINS IN CORTICAL BRAIN BIOPSY AND ALZHEIMER’S DISEASE
Ville Leinonen1, Anne M. Koivisto1,2, Sakari Savolainen1, Jaana Rummukainen1, Okko T. Pyykko¨1, Mikael Fraunberg1, Juha E. Ja¨a¨skela¨inen1, Hilkka Soininen1,2, Irina Alafuzoff2,3, 1Kuopio University Hospital, Kuopio, Finland; 2University of Eastern Finland, Kuopio, Finland; 3University of Uppsala, Uppsala, Sweden.
Hot Topics Background: Amyloid-b (Ab) aggregates are presumed to be found in the brain at an early stage of Alzheimer’s disease (AD) but have seldom been assessed by brain biopsy during life. The aim of this study was to analyze whether Ab and/or HPt in frontal cortical biopsies, obtained during evaluation of suspected normal pressure hydrocephalus (NPH), would predict later development of clinical AD. Methods: Between 1991 and 2006, we had evaluated 468 patients with suspected NPH with intraventricular pressure monitoring and a right frontal cortical biopsy sample immunostained for Ab and HPt. Adequate samples and the clinical follow-up data until death or the end of 2008, available in 433 cases, were reviewed for the clinical signs of dementia, including AD. Logistic regression analysis was used to analyze whether Ab and/or HPt in the biopsy samples obtained during life predicted development of clinical AD. Results: Of the 433 frontal cortical samples, 42 (10%) displayed both Ab and HPt, 144 (33%) Ab only, and 247 (57%) neither Ab nor HPt. In a median follow-up time of 4.4 years, 94 patients (22%) had developed clinical AD. The presence of both Ab and HPt associated strongly (odds ratio [OR], 72.5; 95% confidence interval [CI], 23.7-222) and Ab alone significantly (OR, 11.2; 95% CI, 5.1-24.7) with the clinical diagnosis of AD. Conclusions: (1) The presence of Ab and HPt in frontal cortical brain biopsy sample spoke strongly for the presence or later development of clinical AD, (2) Ab alone was suggestive of AD, and (3) the absence of Ab and HPt spoke against later clinical diagnosis of AD. In conclusion, our results support the concept of preclinical AD and use of brain biopsy when available for validation of non-invasive diagnostic methods.
O4-03-06
FAMILIAL ALS-ASSOCIATED FUSED IN SARCOMA (FUS) MUTATIONS DISRUPT TRANSPORTINMEDIATED NUCLEAR IMPORT
Christian Haass1, Ramona Rodde1, Dieter Edbauer2, Eva Bentmann1, Ingeborg Fischer3, Alexander Hruscha1, Manuel Than4, Ian Mackenzie5, Anja Capell1, Bettina Schmid2, Manuela Neumann3, Dorothee Dormann1, 1 DZNE and Ludwig Maimilians University Munich, Munich, Germany; 2 DZNE Munich, Munich, Germany; 3Institute of Neuropathology, Zurich, Switzerland; 4Leibniz Institute for Age Research, Jena, Germany; 5Vancouver General Hospital, Vancouver, BC, Canada. Background: Mutations in FUS are a cause of familial amyotrophic lateral sclerosis (fALS). Patients carrying point mutations in the C-terminus of FUS show neuronal cytoplasmic FUS-positive inclusions, whereas in healthy controls FUS is predominantly nuclear. Cytoplasmic FUS inclusions have also been identified in a subset of frontotemporal lobar degeneration (FTLD-FUS).Methods: All methods used were published previously. Results: We demonstrate that a non-classical PY nuclear localization signal (NLS) in the C-terminus of FUS is necessary and sufficient for nuclear import. The majority of fALS-associated mutations occur within the NLS and impair nuclear import to a degree that correlates with the age of disease onset. This presents the first case of disease-causing mutations within a PYNLS. Nuclear import of FUS is dependent on Transportin, and interference with this transport pathway leads to cytoplasmic redistribution and recruitment of FUS into stress granules. Moreover, proteins known to be stress granule markers co-deposit with FUS inclusions in all FUS-opathies investigated, implicating stress granule formation in the pathogenesis of these diseases. Conclusions: Mutations within the C-terminal region of FUS cause fALS by interfering with its nuclear transport. We propose that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS-opathies.
O4-03-07
A COMPARISON OF NETWORK CONNECTIVITY AND ATROPHY PATTERNS IN BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA
Jennifer L. Whitwell, David T. Jones, Ramesh Avula, Guang Zeng, Prashanthi Vemuri, Jeffrey L. Gunter, Eric McDade, Mary Machulda, David S. Knopman, Bradley F. Boeve, Ronald C. Petersen, Clifford R. Jack, Jr, Mayo Clinic, Rochester, MN, USA.
e17
Background: The relationship between the topography of atrophy and resting state networks in different neurodegenerative diseases is of current interest. We aimed to compare the distribution of atrophy and network connectivity in behavioral variant frontotemporal dementia (bvFTD). Methods: We identified 18 subjects with bvFTD and 22 age and gendermatched controls that had 3T task free functional MRI and volumetric MRI. Independent component analysis (ICA) was performed using controls. The salience network and default mode network (DMN) were identified from the ICA networks and used to select seed regions of interest for a voxel-wise connectivity analysis that was performed across all subjects. Seeds were placed in the left anterior cingulate (salience) and precuneus (DMN). Two sample t-tests were used to compare bvFTD and controls in voxel-wise connectivity maps, with age and gender entered as covariates. Voxel-based morphometry was used to assess patterns of grey matter loss in bvFTD compared to controls. Results: Grey matter loss was observed predominantly in the medial frontal and bilateral temporal lobes in bvFTD (Figure). Resting state fMRI results will be reported in four categories (Figure). In bvFTD relative to controls, the magnitude of direct connectivity was: 1) Reduced in right anterior insula and inferior frontal lobes for the salience seed. Grey matter loss was observed in these same regions. 2) Increased in anterior dorsolateral frontal lobes for the salience seed. These regions are not typically considered a major salience hub, and no grey matter loss was observed in these regions. 3) Reduced in bilateral temporal lobe and medial prefrontal cortex for the DMN seed. Grey matter loss was observed in these regions. 4) Increased in precuneus and posterior cingulate for the DMN seed. These regions are considered to be part of the DMN, and did not show grey matter loss. Conclusions: Both the salience and DMN networks show functional reorganization in a similar way. Direct connectivity was reduced in areas of neurodegenerative grey matter loss, and new areas of connectivity were formed in areas of relatively healthy brain. The areas of new connectivity can occur either inside or outside the topographic distribution of the two networks.
O4-03-08
CELL-MEDIATED NEUROPROTECTION IN P301S HUMAN TAU TRANSGENIC MICE, A MODEL OF HUMAN TAUOPATHY
David W. Hampton1,2, Daniel J. Webber1, Bilada Bilican1,2, Michel Goedert3, Maria Grazia Spillantini1, Siddharthan Chandran1,4, 1 Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom; 2Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom; 3Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom; 4Centre for Regeneratiive Medicine, University of Edinburgh, Edinburgh, United Kingdom. Background: Several diseases of the brain including Alzheimer’s disease and Pick’s disease are characterized by the presence of intracellular filamentous aggregates made of hyperphosphorylated microtubule-associated protein tau. Tau is involved in microtubule assembly, stabilization and axonal transport. Mutations in the Tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17, establishing that dysfunction of tau
Hot Topics TOMM40 group had significantly less gray matter volume in the ventral posterior cingulate and precuneus, a region of the brain affected early in LOAD. Conclusions: To our knowledge, this is the first study to associate TOMM40 523 genotypes to brain imaging in people at risk for AD. These findings suggest that the group with very long TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes. The participants in this study are being followed over time to determine genetic and other factors that predict cognitive decline and dementia.
Figure 1. Statistical parametric maps (SPMs) showing higher PiB retention in NL with AD-mothers compared to controls (top two rows) and to NL with AD-fathers (middle two rows), and in NL with AD-fathers compared to controls (bottom two rows). Areas of increased PiB retention are represented on a red-to-yellow color-coded scale, reflecting P values between 0.01-0.001, as indicated on the right side of figure. SPMs are displayed onto the axial and sagittal views of a standard, spatially normalized MRI.
Figure 2. Statistical parametric maps (SPMs) showing reduced glucose metabolism in NL with AD-mothers compared to controls (top two rows) and to NL with AD-fathers (bottom two rows). Areas of reduced metabolism are represented on a blue-to-yellow color-coded scale, reflecting P values between 0.01-0.001, as indicated on the right side of figure. SPMs are displayed onto the axial and sagittal views of a standard, spatially normalized MRI.
O4-03-04
TOMM40 IS ASSOCIATED WITH GRAY MATTER VOLUME IN MIDDLE-AGED PERSONS WITH APOE 33/33 GENOTYPE
Sterling C. Johnson1,2, Asenath La Rue1, Bruce P. Hermann1, Guofan Xu1, Rebecca L. Koscik1, Erin M. Jonaitas1, Barbara B. Bendlin1,2, Allen D. Roses3, Ann M. Saunders3, Michael W. Lutz3, Sanjay Asthana1,2, Robert C. Green4, Mark A. Sager1, 1University of Wisconsin, Madison, WI, USA; 2William S. Middleton Veterans Hospital, Madison, WI, USA; 3Duke University, Durham, NC, USA; 4Boston University, Boston, MA, USA. Background: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late onset Alzheimer’s disease (LOAD), with APOE 34 having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the TOMM40 gene has very recently been shown to influence age of onset in LOAD, where very long poly-T length was associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain changes antedating symptomatic LOAD may be associated with this TOMM40 polymorphism. Methods: Among healthy APOE 33 homozygous adults (mean age 57), we compared those homozygous for very long (VL/VL; n ¼ 33) TOMM40 poly-T lengths (who are presumably at higher risk) to those homozygous for short (S/S; n ¼ 37) poly-T lengths on structural brain imaging. Voxel-based morphometry was used to assess gray matter volume using the software SPM8. Gray matter probability maps were entered into a voxel-wise ANCOVA where Age and Intracranial volume were covariates Results: Results were that the VL/VL
O4-03-05
AMYLOID AND TAU PROTEINS IN CORTICAL BRAIN BIOPSY AND ALZHEIMER’S DISEASE
Ville Leinonen1, Anne M. Koivisto1,2, Sakari Savolainen1, Jaana Rummukainen1, Okko T. Pyykko¨1, Mikael Fraunberg1, Juha E. Ja¨a¨skela¨inen1, Hilkka Soininen1,2, Irina Alafuzoff2,3, 1Kuopio University Hospital, Kuopio, Finland; 2University of Eastern Finland, Kuopio, Finland; 3University of Uppsala, Uppsala, Sweden.
Hot Topics Background: Amyloid-b (Ab) aggregates are presumed to be found in the brain at an early stage of Alzheimer’s disease (AD) but have seldom been assessed by brain biopsy during life. The aim of this study was to analyze whether Ab and/or HPt in frontal cortical biopsies, obtained during evaluation of suspected normal pressure hydrocephalus (NPH), would predict later development of clinical AD. Methods: Between 1991 and 2006, we had evaluated 468 patients with suspected NPH with intraventricular pressure monitoring and a right frontal cortical biopsy sample immunostained for Ab and HPt. Adequate samples and the clinical follow-up data until death or the end of 2008, available in 433 cases, were reviewed for the clinical signs of dementia, including AD. Logistic regression analysis was used to analyze whether Ab and/or HPt in the biopsy samples obtained during life predicted development of clinical AD. Results: Of the 433 frontal cortical samples, 42 (10%) displayed both Ab and HPt, 144 (33%) Ab only, and 247 (57%) neither Ab nor HPt. In a median follow-up time of 4.4 years, 94 patients (22%) had developed clinical AD. The presence of both Ab and HPt associated strongly (odds ratio [OR], 72.5; 95% confidence interval [CI], 23.7-222) and Ab alone significantly (OR, 11.2; 95% CI, 5.1-24.7) with the clinical diagnosis of AD. Conclusions: (1) The presence of Ab and HPt in frontal cortical brain biopsy sample spoke strongly for the presence or later development of clinical AD, (2) Ab alone was suggestive of AD, and (3) the absence of Ab and HPt spoke against later clinical diagnosis of AD. In conclusion, our results support the concept of preclinical AD and use of brain biopsy when available for validation of non-invasive diagnostic methods.
O4-03-06
FAMILIAL ALS-ASSOCIATED FUSED IN SARCOMA (FUS) MUTATIONS DISRUPT TRANSPORTINMEDIATED NUCLEAR IMPORT
Christian Haass1, Ramona Rodde1, Dieter Edbauer2, Eva Bentmann1, Ingeborg Fischer3, Alexander Hruscha1, Manuel Than4, Ian Mackenzie5, Anja Capell1, Bettina Schmid2, Manuela Neumann3, Dorothee Dormann1, 1 DZNE and Ludwig Maimilians University Munich, Munich, Germany; 2 DZNE Munich, Munich, Germany; 3Institute of Neuropathology, Zurich, Switzerland; 4Leibniz Institute for Age Research, Jena, Germany; 5Vancouver General Hospital, Vancouver, BC, Canada. Background: Mutations in FUS are a cause of familial amyotrophic lateral sclerosis (fALS). Patients carrying point mutations in the C-terminus of FUS show neuronal cytoplasmic FUS-positive inclusions, whereas in healthy controls FUS is predominantly nuclear. Cytoplasmic FUS inclusions have also been identified in a subset of frontotemporal lobar degeneration (FTLD-FUS).Methods: All methods used were published previously. Results: We demonstrate that a non-classical PY nuclear localization signal (NLS) in the C-terminus of FUS is necessary and sufficient for nuclear import. The majority of fALS-associated mutations occur within the NLS and impair nuclear import to a degree that correlates with the age of disease onset. This presents the first case of disease-causing mutations within a PYNLS. Nuclear import of FUS is dependent on Transportin, and interference with this transport pathway leads to cytoplasmic redistribution and recruitment of FUS into stress granules. Moreover, proteins known to be stress granule markers co-deposit with FUS inclusions in all FUS-opathies investigated, implicating stress granule formation in the pathogenesis of these diseases. Conclusions: Mutations within the C-terminal region of FUS cause fALS by interfering with its nuclear transport. We propose that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS-opathies.
O4-03-07
A COMPARISON OF NETWORK CONNECTIVITY AND ATROPHY PATTERNS IN BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA
Jennifer L. Whitwell, David T. Jones, Ramesh Avula, Guang Zeng, Prashanthi Vemuri, Jeffrey L. Gunter, Eric McDade, Mary Machulda, David S. Knopman, Bradley F. Boeve, Ronald C. Petersen, Clifford R. Jack, Jr, Mayo Clinic, Rochester, MN, USA.
e17
Background: The relationship between the topography of atrophy and resting state networks in different neurodegenerative diseases is of current interest. We aimed to compare the distribution of atrophy and network connectivity in behavioral variant frontotemporal dementia (bvFTD). Methods: We identified 18 subjects with bvFTD and 22 age and gendermatched controls that had 3T task free functional MRI and volumetric MRI. Independent component analysis (ICA) was performed using controls. The salience network and default mode network (DMN) were identified from the ICA networks and used to select seed regions of interest for a voxel-wise connectivity analysis that was performed across all subjects. Seeds were placed in the left anterior cingulate (salience) and precuneus (DMN). Two sample t-tests were used to compare bvFTD and controls in voxel-wise connectivity maps, with age and gender entered as covariates. Voxel-based morphometry was used to assess patterns of grey matter loss in bvFTD compared to controls. Results: Grey matter loss was observed predominantly in the medial frontal and bilateral temporal lobes in bvFTD (Figure). Resting state fMRI results will be reported in four categories (Figure). In bvFTD relative to controls, the magnitude of direct connectivity was: 1) Reduced in right anterior insula and inferior frontal lobes for the salience seed. Grey matter loss was observed in these same regions. 2) Increased in anterior dorsolateral frontal lobes for the salience seed. These regions are not typically considered a major salience hub, and no grey matter loss was observed in these regions. 3) Reduced in bilateral temporal lobe and medial prefrontal cortex for the DMN seed. Grey matter loss was observed in these regions. 4) Increased in precuneus and posterior cingulate for the DMN seed. These regions are considered to be part of the DMN, and did not show grey matter loss. Conclusions: Both the salience and DMN networks show functional reorganization in a similar way. Direct connectivity was reduced in areas of neurodegenerative grey matter loss, and new areas of connectivity were formed in areas of relatively healthy brain. The areas of new connectivity can occur either inside or outside the topographic distribution of the two networks.
O4-03-08
CELL-MEDIATED NEUROPROTECTION IN P301S HUMAN TAU TRANSGENIC MICE, A MODEL OF HUMAN TAUOPATHY
David W. Hampton1,2, Daniel J. Webber1, Bilada Bilican1,2, Michel Goedert3, Maria Grazia Spillantini1, Siddharthan Chandran1,4, 1 Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom; 2Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom; 3Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom; 4Centre for Regeneratiive Medicine, University of Edinburgh, Edinburgh, United Kingdom. Background: Several diseases of the brain including Alzheimer’s disease and Pick’s disease are characterized by the presence of intracellular filamentous aggregates made of hyperphosphorylated microtubule-associated protein tau. Tau is involved in microtubule assembly, stabilization and axonal transport. Mutations in the Tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17, establishing that dysfunction of tau