Dataset Information

Neurogenetic contributions to amyloid beta and tau spreading in the human cortex.

ABSTRACT: Tau and amyloid beta (A?) proteins accumulate along neuronal circuits in Alzheimer's disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal A? and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and A? accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and A? propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as 'axon related' and the A? profile as 'dendrite related'. This study reveals distinct genetic profiles that may confer vulnerability to tau and A? in vivo propagation in the human brain.

SUBMITTER: Sepulcre J

PROVIDER: S-EPMC6518398 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Neurogenetic contributions to amyloid beta and tau spreading in the human cortex.

Sepulcre Jorge J Grothe Michel J MJ d'Oleire Uquillas Federico F Ortiz-Terán Laura L Diez Ibai I Yang Hyun-Sik HS Jacobs Heidi I L HIL Hanseeuw Bernard J BJ Li Quanzheng Q El-Fakhri Georges G Sperling Reisa A RA Johnson Keith A KA

Nature medicine 20181029 12

Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer's disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain A ...[more]

PMID: 30374196

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Project description:As more biomarkers for Alzheimer's disease and age-related brain conditions become available, more sophisticated analytic approaches are needed to take full advantage of the information they convey. Most work has been done using categorical approaches but the joint relationships of tau PET, amyloid PET and cortical thickness in their continuous distributions to cognition have been under-explored. We evaluated non-demented subjects over age 50 years in the Mayo Clinic Study of Aging, 2037 of whom had undergone 3 T MRI scan, 985 amyloid PET scan with 11C-Pittsburgh compound B (PIB) and MRI, and 577 PIB-PET, 18F-AV1451 flortaucipir PET and MRI. Participants received a nine-test cognitive battery. Three test scores (logical memory delayed recall, visual reproduction delayed recall and auditory verbal learning test delayed recall) were used to generate a memory composite z-score. We used Gradient Boosting Machine models to analyse the relationship between regional cortical thickness, flortaucipir PET signal, PIB-PET signal and memory z-scores. Age, education, sex and number of test exposures were included in the model as covariates. In this population-based study of non-demented subjects, most of the associations between biomarkers and memory z-scores accrued after 70 years of age. Entorhinal cortex exhibited the strongest associations between biomarkers and memory z-scores. Other temporal regions showed similar but attenuated associations, and non-temporal regions had negligible associations between memory z-scores and biomarkers. Entorhinal flortaucipir PET signal, PIB-PET signal and entorhinal cortical thickness were independently and additively associated with declining memory z-scores. In contrast to global PIB-PET signal where only very high amyloid-β levels were associated low memory z-scores, entorhinal flortaucipir PET signal just above background levels was associated with low memory z-scores. The lowest memory z-scores occurred with the confluence of elevated entorhinal flortaucipir PET signal and lower entorhinal cortical thickness.

Project description:ObjectiveEpilepsy can be comorbid with cognitive impairments. Recent evidence suggests the possibility that cognitive decline in epilepsy may be associated with mechanisms typical of Alzheimer's disease (AD). Neuropathological hallmarks of AD have been found in brain biopsies surgically resected from patients with drug-resistant epilepsies. These include hyperphosphorylation of the tau protein (p-tau) that aggregates into neuropil threads (NT) or neurofibrillary tangles (NFT), as well as the presence of β-amyloid (Aβ) deposits. While recent studies agree on these AD neuropathological findings in epilepsy, some contrast in their correlation to cognitive decline. Thus, to further address this question we determined the abundance of p-tau and Aβ proteins along with their association with cognitive function in 12 cases of refractory epilepsy.MethodsCortical biopsies surgically extracted from the temporal lobes of patients with refractory epilepsy were processed for immunohistology and enzyme-linked immunoassays to assess distribution and levels, respectively, of p-tau (Antibodies: Ser202/Thr205; Thr205; Thr181) and Aβ proteins. In parallel, we measured the activation of mechanistic target of rapamycin (mTOR) via p-S6 (Antibodies: Ser240/244; Ser235/236). Pearson correlation coefficient analysis determined associations between these proteins and neurophysiological scores for full-scale intelligence quotient (FSIQ).ResultsWe found a robust presence of p-tau (Ser202/Thr205)-related NT and NFT pathology, as well as Aβ deposits, and p-S6 (Ser240/244; Ser235/236) in the epilepsy biopsies. We found no significant correlations between p-tau (Thr205; Thr181), Aβ, or mTOR markers with FSIQ scores, although some correlation coefficients were modest to strong.SignificanceThese findings strongly support the existence of hyperphosphorylated tau protein and Aβ deposits in patients with human refractory epilepsy. However, their relation to cognitive decline is still unclear and requires further investigation.

Dataset Information

Neurogenetic contributions to amyloid beta and tau spreading in the human cortex.

Publications

Neurogenetic contributions to amyloid beta and tau spreading in the human cortex.

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