Lower cerebral oxygen utilization is associated with Alzheimer’s disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers

Robb, W. Hudson; Khan, Omair A.; Ahmed, Humza A.; Li, Judy; Moore, Elizabeth E.; Cambronero, Francis E.; Pechman, Kimberly R.; Liu, Dandan; Gifford, Katherine A.; Landman, Bennett A.; Donahue, Manus J.; Hohman, Timothy J.; Jefferson, Angela L.

doi:10.1177/0271678x211056393

Cited by 5 publications

(2 citation statements)

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“…135 Studies have shown that the APOE ε4 allele imposes a great risk for developing dementia, since it regulates several key genes which are involved in function of brain. 136 A cohort study conducted by Robb et al 137 on 246 APOE ε4 carriers and non-carriers aimed to test whether APOE ε4 status could impact cerebral oxygen homeostasis and cognitive performance. The authors found that APOE4 carriers are often manifested with lower cerebral oxygen metabolism, interacting with the pathogenesis of AD and related neurodegeneration.…”

Section: Mtor and Vascular Dysfunctionmentioning

confidence: 99%

mTOR signaling and Alzheimer's disease: What we know and where we are?

Davoody,

Asgari Taei,

Khodabakhsh

et al. 2023

CNS Neurosci Ther

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Despite the great body of research done on Alzheimer's disease, the underlying mechanisms have not been vividly investigated. To date, the accumulation of amyloid‐beta plaques and tau tangles constitutes the hallmark of the disease; however, dysregulation of the mammalian target of rapamycin (mTOR) seems to be significantly involved in the pathogenesis of the disease as well. mTOR, as a serine–threonine protein kinase, previously known for controlling many cellular functions such as cell size, autophagy, and metabolism. In this regard, mammalian target of rapamycin complex 1 (mTORC1) may leave anti‐aging impacts by robustly inhibiting autophagy, a mechanism that inhibits the accumulation of damaged protein aggregate and dysfunctional organelles. Formation and aggregation of neurofibrillary tangles and amyloid‐beta plaques seem to be significantly regulated by mTOR signaling. Understanding the underlying mechanisms and connection between mTOR signaling and AD may suggest conducting clinical trials assessing the efficacy of rapamycin, as an mTOR inhibitor drug, in managing AD or may help develop other medications. In this literature review, we aim to elaborate mTOR signaling network mainly in the brain, point to gaps of knowledge, and define how and in which ways mTOR signaling can be connected with AD pathogenesis and symptoms.

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Section: Mtor and Vascular Dysfunctionmentioning

confidence: 99%

mTOR signaling and Alzheimer's disease: What we know and where we are?

Davoody,

Asgari Taei,

Khodabakhsh

et al. 2023

CNS Neurosci Ther

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“…The brain has a high metabolic demand for oxygen compared to other organs since the human brain comprises just 2% of the total body mass but consumes 20% of available oxygen for normal function (Rolfe and Brown, 1997), so regulation of cerebral blood flow (CBF) and oxygen delivery is critically important. Oxygen extraction fraction (OEF) is a key hemodynamic parameter to measure the brain's energy metabolism and is altered in aging and disease processes, including cerebrovascular disorders (Watchmaker et al, 2018;Fan et al, 2022;Liu et al, 2023), neurodegeneration (Jiang et al, 2020;Robb et al, 2022), and neuroinflammation (Cleland et al, 2021). In some pathological mechanisms, OEF is reduced concurrently with hypoperfusion due to decreased neural activity and lower oxygen metabolic demand (Ishii et al, 1996;Brown and Thore, 2011); while in other distinct mechanisms, OEF is elevated in areas of hypoperfusion, indicating physiological compensation in tissue that is at ischemic risk (Gupta et al, 2014;Fan et al, 2020;Lin et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Cortical oxygen extraction fraction using quantitative BOLD MRI and cerebral blood flow during vasodilation

Le,

Wheeler,

Holy

et al. 2023

Front. Physiol.

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Introduction: We aimed to demonstrate non-invasive measurements of regional oxygen extraction fraction (OEF) from quantitative BOLD MRI modeling at baseline and after pharmacological vasodilation. We hypothesized that OEF decreases in response to vasodilation with acetazolamide (ACZ) in healthy conditions, reflecting compensation in regions with increased cerebral blood flow (CBF), while cerebral metabolic rate of oxygen (CMRO2) remained unchanged. We also aimed to assess the relationship between OEF and perfusion in the default mode network (DMN) regions that have shown associations with vascular risk factors and cerebrovascular reactivity in different neurological conditions.Material and methods: Eight healthy subjects (47 ± 13 years, 6 female) were scanned on a 3 T scanner with a 32-channel head coil before and after administration of 15 mg/kg ACZ as a pharmacological vasodilator. The MR imaging acquisition protocols included: 1) A Gradient Echo Slice Excitation Profile Imaging Asymmetric Spin Echo scan to quantify OEF, deoxygenated blood volume, and reversible transverse relaxation rate (R2’) and 2) a multi-post labeling delay arterial spin labeling scan to measure CBF. To assess changes in each parameter due to vasodilation, two-way t-tests were performed for all pairs (baseline versus vasodilation) in the DMN brain regions with Bonferroni correction for multiple comparisons. The relationships between CBF versus OEF and CBF versus R2’ were analyzed and compared across DMN regions using linear, mixed-effect models.Results: During vasodilation, CBF significantly increased in the medial frontal cortex (P=0.004), posterior cingulate gyrus (pCG) (P=0.004), precuneus cortex (PCun) (P=0.004), and occipital pole (P=0.001). Concurrently, a significant decrease in OEF was observed only in the pCG (8.8%, P=0.003) and PCun (8.7%,P=0.001). CMRO2 showed a trend of increased values after vasodilation, but these differences were not significant after correction for multiple comparisons. Although R2’ showed a slightly decreasing trend, no statistically significant changes were found in any regions in response to ACZ. The CBF response to ACZ exhibited a stronger negative correlation with OEF (β=−0.104±0.027; t=−3.852,P<0.001), than with R2’ (β=−0.016±0.006; t=−2.692,P=0.008).Conclusion: Quantitative BOLD modeling can reliably measure OEF across multiple physiological conditions and captures vascular changes with higher sensitivity than R2’ values. The inverse correlation between OEF and CBF across regions in DMN, suggests that these two measurements, in response to ACZ vasodilation, are reliable indicators of tissue health in this healthy cohort.

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