| 1. |
- Groot, Colin, et al.
(författare)
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Differential patterns of gray matter volumes and associated gene expression profiles in cognitively-defined Alzheimer's disease subgroups
- 2021
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 30
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Tidskriftsartikel (refereegranskat)abstract
- The clinical presentation of Alzheimer's disease (AD) varies widely across individuals but the neurobiological mechanisms underlying this heterogeneity are largely unknown. Here, we compared regional gray matter (GM) volumes and associated gene expression profiles between cognitively-defined subgroups of amyloid-β positive individuals clinically diagnosed with AD dementia (age: 66 ± 7, 47% male, MMSE: 21 ± 5). All participants underwent neuropsychological assessment with tests covering memory, executive-functioning, language and visuospatial-functioning domains. Subgroup classification was achieved using a psychometric framework that assesses which cognitive domain shows substantial relative impairment compared to the intra-individual average across domains, which yielded the following subgroups in our sample; AD-Memory (n = 41), AD-Executive (n = 117), AD-Language (n = 33), AD-Visuospatial (n = 171). We performed voxel-wise contrasts of GM volumes derived from 3Tesla structural MRI between subgroups and controls (n = 127, age 58 ± 9, 42% male, MMSE 29 ± 1), and observed that differences in regional GM volumes compared to controls closely matched the respective cognitive profiles. Specifically, we detected lower medial temporal lobe GM volumes in AD-Memory, lower fronto-parietal GM volumes in AD-Executive, asymmetric GM volumes in the temporal lobe (left < right) in AD-Language, and lower GM volumes in posterior areas in AD-Visuospatial. In order to examine possible biological drivers of these differences in regional GM volumes, we correlated subgroup-specific regional GM volumes to brain-wide gene expression profiles based on a stereotactic characterization of the transcriptional architecture of the human brain as provided by the Allen human brain atlas. Gene-set enrichment analyses revealed that variations in regional expression of genes involved in processes like mitochondrial respiration and metabolism of proteins were associated with patterns of regional GM volume across multiple subgroups. Other gene expression vs GM volume-associations were only detected in particular subgroups, e.g., genes involved in the cell cycle for AD-Memory, specific sets of genes related to protein metabolism in AD-Language, and genes associated with modification of gene expression in AD-Visuospatial. We conclude that cognitively-defined AD subgroups show neurobiological differences, and distinct biological pathways may be involved in the emergence of these differences.
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| 2. |
- Grothe, Michel J, et al.
(författare)
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Molecular properties underlying regional vulnerability to Alzheimer's disease pathology.
- 2018
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 141:9, s. 2755-2771
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid deposition and neurofibrillary degeneration in Alzheimer's disease specifically affect discrete neuronal systems, but the underlying mechanisms that render some brain regions more vulnerable to Alzheimer's disease pathology than others remain largely unknown. Here we studied molecular properties underlying these distinct regional vulnerabilities by analysing Alzheimer's disease-typical neuroimaging patterns of amyloid deposition and neurodegeneration in relation to regional gene expression profiles of the human brain. Graded patterns of brain-wide vulnerability to amyloid deposition and neurodegeneration in Alzheimer's disease were estimated by contrasting multimodal amyloid-sensitive PET and structural MRI data between patients with Alzheimer's disease dementia (n = 76) and healthy controls (n = 126) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen brain atlas of the adult human brain transcriptome. In a hypothesis-driven analysis focusing on the genes coding for the amyloid precursor (APP) and tau proteins (MAPT), regional expression levels of APP were positively correlated with the severity of regional amyloid deposition (r = 0.44, P = 0.009), but not neurodegeneration (r = 0.01, P = 0.96), whereas the opposite pattern was observed for MAPT (neurodegeneration: r = 0.46, P = 0.006; amyloid: r = 0.08, P = 0.65). Using explorative gene set enrichment analysis, amyloid-vulnerable regions were found to be characterized by relatively low expression levels of gene sets implicated in protein synthesis and mitochondrial respiration. By contrast, neurodegeneration-vulnerable regions were characterized by relatively high expression levels of gene sets broadly implicated in neural plasticity, with biological functions ranging from neurite outgrowth and synaptic contact over intracellular signalling cascades to proteoglycan metabolism. At the individual gene level this data-driven analysis further corroborated the association between neurodegeneration and MAPT expression, and additionally identified associations with known tau kinases (CDK5, MAPK1/ERK2) alongside components of their intracellular (Ras-ERK) activation pathways. Sensitivity analyses showed that these pathology-specific imaging-genetic associations were largely robust against changes in some of the methodological parameters, including variation in the brain donor sample used for estimating regional gene expression profiles, and local variations in the Alzheimer's disease-typical imaging patterns when these were derived from an independent patient cohort (BioFINDER study). These findings highlight that the regionally selective vulnerability to Alzheimer's disease pathology relates to specific molecular-functional properties of the affected neural systems, and that the implicated biochemical pathways largely differ for amyloid accumulation versus neurodegeneration. The data provide novel insights into the complex pathophysiological mechanisms of Alzheimer's disease and point to pathology-specific treatment targets that warrant further exploration in independent studies.
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