Dataset Information

Entorhinal cortex tau, amyloid-?, cortical thickness and memory performance in non-demented subjects.

ABSTRACT: 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-? 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.

SUBMITTER: Knopman DS

PROVIDER: S-EPMC6439321 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Entorhinal cortex tau, amyloid-β, cortical thickness and memory performance in non-demented subjects.

Knopman David S DS Lundt Emily S ES Therneau Terry M TM Vemuri Prashanthi P Lowe Val J VJ Kantarci Kejal K Gunter Jeffrey L JL Senjem Matthew L ML Mielke Michelle M MM Machulda Mary M MM Boeve Bradley F BF Jones David T DT Graff-Radford Jon J Albertson Sabrina M SM Schwarz Christopher G CG Petersen Ronald C RC Jack Clifford R CR

Brain : a journal of neurology 20190401 4

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 ...[more]

PMID: 30759182

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Project description:Disruption of functional connectivity between brain regions may represent an early functional consequence of ?-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Project description:OBJECTIVE:The ε4 allele of the apolipoprotein E (APOE) gene increases risk for cognitive decline in normal and pathologic aging. However, precisely how APOE ε4 exerts its negative impact on cognition is poorly understood. The present study aimed to determine whether APOE genotype (ε4+ vs. ε4-) modifies the interaction of medial temporal lobe (MTL) resting cerebral blood flow (CBF) and brain structure (cortical thickness [CT], volume [Vo]) on verbal memory performance. METHODS:Multiple linear regression models were employed to investigate relationships between APOE genotype, arterial spin labeling MRI-measured CBF and FreeSurfer-based CT and Vo in four MTL regions of interest (left and right entorhinal cortex and hippocampus), and verbal memory performance among a sample of 117 cognitively normal older adults (41 ε4+, 76 ε4-) between the ages of 64 and 89 (mean age = 73). RESULTS:Results indicated that APOE genotype modified the interaction of CBF and CT on memory in the left entorhinal cortex, such that the relationship between entorhinal CBF and memory was negative (lower CBF was associated with better memory) in non-carriers with higher entorhinal CT, positive (higher CBF was associated with better memory) in non-carriers with lower entorhinal CT, and negative (higher CBF was associated with worse memory) in ε4 carriers with lower entorhinal CT. CONCLUSIONS:Findings suggest that older adult APOE ε4 carriers may experience vascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect memory even in the absence overt clinical symptoms, providing potential insight into the mechanistic link between APOE ε4 and detriments in cognition. Moreover, findings suggest a distinct multimodal neural signature in ε4 carriers (higher CBF and lower CT in the entorhinal cortex) that could aid in the identification of candidates for future clinical trials aimed at preventing or slowing cognitive decline. Differential findings with respect to ε4 carriers and non-carriers are discussed in the context of neurovascular compensation.

Dataset Information

Entorhinal cortex tau, amyloid-?, cortical thickness and memory performance in non-demented subjects.

Publications

Entorhinal cortex tau, amyloid-β, cortical thickness and memory performance in non-demented subjects.

Similar Datasets

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