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Brain activation during scene encoding fMRI in the Alzheimer’s disease continuum: Association with amyloid and tau burden in PET
Get PDFBackground and Hypothesis: This project assessed brain activation during a scene encoding task in 4 groups: older adults who were cognitively normal (CN), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia due to Alzheimer’s disease (AD). Associations between scene encoding related brain activation and tau, amyloid, and other biomarkers were analyzed. Our hypothesis was that higher levels of cerebral tau and amyloid would be associated with reduced scene encoding activation. In addition, we hypothesized that scene encoding activation would be significantly different between cognitively normal and cognitively impaired groups.
Methods: 234 individuals from the Indiana Memory and Aging Study (79 CN, 67 SCD, 70 MCI, and 18 AD) completed structural and functional MRI, clinical/cognitive assessment and biomarkers; 155 underwent amyloid ([18F] florbetapir/[18F]florbetaben) PET, while 111 also underwent [18F]flortaucipir PET. For the fMRI scene encoding task, participants were asked to view and remember a set of images. A one-way ANOVA test was used to analyze scene encoding related activation differences among the 4 groups. Regression was used to identify associations between scene encoding activation and tau and amyloid deposition.
Results: Significant differences in activation were observed between the MCI and CN groups, including less activation in widespread regions during the task and reduced deactivation in the default mode network (DMN) in MCI participants relative to CN. Significant associations between higher amyloid and tau deposition and altered scene encoding activation were also observed.
Conclusion and Potential Impact: Cognitive decline is associated with activation changes during scene encoding, as well as reduced deactivation in the DMN, especially in the posterior cingulate region. Higher cerebral amyloid deposition predicted decreased scene encoding related activation. These findings are consistent with models linking cognitive status, functional brain activation during episodic encoding, and pathophysiological processes in the AD continuum. The positive association with tau is a new finding that should be explored with further studies
Silencing COQ8B in Aortic Smooth Muscle Cells Reveals Cellular Dysfunction Related to Changes in Cell Proliferation
Get PDFBackground/Objective: Thoracic aortic aneurysm (TAA) is a prevalent disorder that predisposes to aortic dissection. Prior work identified the ubiquinone biosynthesis gene COQ8B as a genetic modifier of TAA progression. We sought to determine the impact of decreased COQ8B on global transcription in aortic smooth muscle cells (SMCs).
Methods: Primary human aortic SMCs from a healthy donor were seeded in 12-well plates. Six experimental conditions were created, each with 3 replicates: 1) siRNA targeting COQ8B (siCOQ8B); 2) siRNA targeting the dominant TAA gene SMAD3 (siSMAD3); 3) negative control siRNA (siNeg); 4) siCOQ8B and siSMAD3; 5) siCOQ8B with Angiotensin II (AngII) stimulation (siCOQ8B+AngII); 6) siNeg+AngII. RNA was extracted approximately 48 hours post-siRNA transfection and, for AngII conditions, after 1 hour of incubation with AngII (100 nM). mRNA-sequencing was performed and downstream analysis utilized R packages EdgeR and topGO.
Results: Multidimensional scaling identified distinct clustering of samples by experimental condition. Downregulated genes in siCOQ8B were enriched for Gene Ontology pathways related to cell proliferation including cell cycle regulators, DNA replication, and mitosis. MYOCD, a master regulator of SMC homeostasis, was downregulated. Similar proliferation-related pathways were enriched in siCOQ8B+siSMAD3 and siCOQ8B+AngII compared to siNeg. Pathways related to cell proliferation in siCOQ8B+AngII cells were downregulated when compared to siCOQ8B which indicates that AngII infusion in the context of COQ8B silencing may further dysregulate cell proliferation pathways.
Conclusion/Implications: The results indicate that COQ8B has an important role in cell cycle processes in aortic SMCs, including when SMCs are exposed to stressors associated with TAA development. Stimulation of angiotensin receptors may exacerbate the effects of decreased COQ8B in these processes. To investigate these experimental results in human pathology, bulk RNA samples and intact nuclei have been isolated from frozen human aortic specimens and prepared for transcriptomic analysis