There are many active research projects accessing and applying shared ADNI data. Use the search above to find specific research focuses on the active ADNI investigations. This information is requested annually as a requirement for data access.
| Principal Investigator | |
| Principal Investigator's Name: | Jason Chan |
| Institution: | University of Calgary |
| Department: | Department of Clinical Neurosciences |
| Country: | |
| Proposed Analysis: | Alzheimer's disease (AD) is characterized neuropathologically by amyloid-beta (AB) plaques and tau neurofibrillary tangles (Dubois et al., 2007). AB plaques are formed by the aggregation of AB-42 peptides and imbalance between the production and clearance of AB-42 is thought to underlie plaque formation (Huang et al., 2009). Mutations in genes that upregulate the production of AB-42, including APP, PSEN1, and PSEN2, are known to cause autosomal dominant familial AD and implicate AB-42 accumulation in the pathogenesis of AD (Zhang et al., 2013). However, the specific mechanisms by which AB contributes to sporadic AD are less clear. Interestingly, sporadic AD has a characteristic AB deposition pattern, predominately involving the frontal, temporal, and parietal association cortices, that is distinct from a neurodegeneration pattern that predominately involves the medial temporal lobe and is associated with tau (Price et al., 1991). Overall, the relationships between AB deposition, tau deposition, and neurodegeneration are poorly understood, and AD pathophysiology likely involves a combination of dysfunction in AB-42 and tau production and clearance (Tanzi et al., 2004). We hypothesize that baseline expression levels of genes associated with AB-42 and tau production and clearance in normal tissue predispose some brain regions to AB deposition, tau deposition, and neurodegeneration. Accordingly, regional gene expression profiles that favour increased production or decreased clearance may increase regional vulnerability to protein deposition and neurodegeneration. We will investigate how normal expression patterns of genes associated with AB-42 and tau production and clearance spatially relate to neuroimaging patterns of AB deposition, tau deposition, and neurodegeneration in AD using datasets from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (Weiner et al., 2017) and Allen Human Brain Atlas (AHBA) (Hawrylycz et al., 2012). We will use baseline 3T T1-weighted structural MRI, [18F]florbetaben amyloid-PET, and [18F]flortaucipir tau-PET from participants diagnosed with AD and age-matched cognitively normal controls enrolled in ADNI3. Structural MRI images will be segmented into grey matter, white matter, and CSF maps and spatially normalized to MNI152 space. Amyloid-PET and tau-PET images will be co-registered and spatially normalized to their corresponding structural MRI images, and standardized uptake value ratio (SUVR) images will be created. To determine patterns of AB deposition, tau deposition, and neurodegeneration, Z-score maps will be created for amyloid-PET SUVR, tau-PET SUVR, and structural MRI grey matter volume, respectively. Voxel-wise Z-scores in AD participants will be calculated by subtracting the voxel-wise mean of the control group from each voxel and dividing by the standard deviation of the control group. Z-score maps for amyloid-PET SUVR, tau-PET SUVR, and structural MRI grey matter volume will be mapped onto the Desikan-Killiany atlas (Desikan et al., 2006), which parcellates cerebral cortex into 34 regions per hemisphere. Genes associated with AB-42 processing include APP, BACE1, PSEN1, PSEN2, APOE, LRP1, MME. APP, BACE1, PSEN1, and PSEN2 are implicated in AB-42 production, whereas APOE, LRP1, and MME are implicated in AB-42 clearance (Yoon et al., 2012). Genes associated with tau processing include MAPT, tau kinase genes CDK5, GSK3B, MARK1, MARK2, MARK3, and MARK4, and tau phosphatase genes PPP2CA and PPP2CB (Boutajangout et al., 2011). Normal expression patterns of these genes will be extracted from the Allen Human Brain Atlas and mapped onto the Desikan-Killiany atlas (French and Paus, 2015). Spatial expression patterns for each gene will then be correlated with spatial patterns of AB deposition, tau deposition, and neurodegeneration across the 34 cortical regions of the Desikan-Killiany atlas. Furthermore, spatial co-expression of different genes can be assessed and related to spatial patterns of AB deposition, tau deposition, and neurodegeneration. Taken together, these analyses of ADNI data will use human gene expression mapping to examine how different elements of normal amyloid and tau processing interact and are involved in AB deposition, tau deposition, and neurodegeneration in AD. These findings will contribute to understanding of the role of AB and tau in AD pathogenesis. |
| Additional Investigators | |
| Investigator's Name: | Aaron Switzer |
| Proposed Analysis: | Alzheimer's disease (AD) is characterized neuropathologically by amyloid-beta (AB) plaques and tau neurofibrillary tangles (Dubois et al., 2007). AB plaques are formed by the aggregation of AB-42 peptides and imbalance between the production and clearance of AB-42 is thought to underlie plaque formation (Huang et al., 2009). Mutations in genes that upregulate the production of AB-42, including APP, PSEN1, and PSEN2, are known to cause autosomal dominant familial AD and implicate AB-42 accumulation in the pathogenesis of AD (Zhang et al., 2013). However, the specific mechanisms by which AB contributes to sporadic AD are less clear. Interestingly, sporadic AD has a characteristic AB deposition pattern, predominately involving the frontal, temporal, and parietal association cortices, that is distinct from a neurodegeneration pattern that predominately involves the medial temporal lobe and is associated with tau (Price et al., 1991). Overall, the relationships between AB deposition, tau deposition, and neurodegeneration are poorly understood, and AD pathophysiology likely involves a combination of dysfunction in AB-42 and tau production and clearance (Tanzi et al., 2004). We hypothesize that baseline expression levels of genes associated with AB-42 and tau production and clearance in normal tissue predispose some brain regions to AB deposition, tau deposition, and neurodegeneration. Accordingly, regional gene expression profiles that favour increased production or decreased clearance may increase regional vulnerability to protein deposition and neurodegeneration. We will investigate how normal expression patterns of genes associated with AB-42 and tau production and clearance spatially relate to neuroimaging patterns of AB deposition, tau deposition, and neurodegeneration in AD using datasets from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (Weiner et al., 2017) and Allen Human Brain Atlas (AHBA) (Hawrylycz et al., 2012). We will use baseline 3T T1-weighted structural MRI, [18F]florbetaben amyloid-PET, and [18F]flortaucipir tau-PET from participants diagnosed with AD and age-matched cognitively normal controls enrolled in ADNI3. Structural MRI images will be segmented into grey matter, white matter, and CSF maps and spatially normalized to MNI152 space. Amyloid-PET and tau-PET images will be co-registered and spatially normalized to their corresponding structural MRI images, and standardized uptake value ratio (SUVR) images will be created. To determine patterns of AB deposition, tau deposition, and neurodegeneration, Z-score maps will be created for amyloid-PET SUVR, tau-PET SUVR, and structural MRI grey matter volume, respectively. Voxel-wise Z-scores in AD participants will be calculated by subtracting the voxel-wise mean of the control group from each voxel and dividing by the standard deviation of the control group. Z-score maps for amyloid-PET SUVR, tau-PET SUVR, and structural MRI grey matter volume will be mapped onto the Desikan-Killiany atlas (Desikan et al., 2006), which parcellates cerebral cortex into 34 regions per hemisphere. Genes associated with AB-42 processing include APP, BACE1, PSEN1, PSEN2, APOE, LRP1, MME. APP, BACE1, PSEN1, and PSEN2 are implicated in AB-42 production, whereas APOE, LRP1, and MME are implicated in AB-42 clearance (Yoon et al., 2012). Genes associated with tau processing include MAPT, tau kinase genes CDK5, GSK3B, MARK1, MARK2, MARK3, and MARK4, and tau phosphatase genes PPP2CA and PPP2CB (Boutajangout et al., 2011). Normal expression patterns of these genes will be extracted from the Allen Human Brain Atlas and mapped onto the Desikan-Killiany atlas (French and Paus, 2015). Spatial expression patterns for each gene will then be correlated with spatial patterns of AB deposition, tau deposition, and neurodegeneration across the 34 cortical regions of the Desikan-Killiany atlas. Furthermore, spatial co-expression of different genes can be assessed and related to spatial patterns of AB deposition, tau deposition, and neurodegeneration. Taken together, these analyses of ADNI data will use human gene expression mapping to examine how different elements of normal amyloid and tau processing interact and are involved in AB deposition, tau deposition, and neurodegeneration in AD. These findings will contribute to understanding of the role of AB and tau in AD pathogenesis. |
