[O1–02–03]: Examining Longitudinal Neuroimaging Patterns in Autosomal Dominant Alzheimer Disease: Findings From the Dominantly Inherited Alzheimer Network

Gordon, Brian A.; Blazey, Tyler; Su, Yi; Hari-Raj, Amrita; Dincer, Aylin; Flores, Shaney; Christensen, Jon; McDade, Eric; Wang, Guoqiao; Xiong, Chengjie; Cairns, Nigel J.; Hassenstab, Jason; Marcus, Daniel S.; Jack, Clifford R.; Koeppe, Robert A.; Hornbeck, Russ C.; Paumier, Katrina L.; Ances, Beau M.; Holtzman, David M.; Raichle, Marcus E.; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.

doi:10.1016/j.jalz.2017.07.041

Cited by 4 publications

(5 citation statements)

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“…Glucose hypometabolism is implicated in the initiation of sporadic AD, as it is associated with many AD risk factors (10)(11)(12)(13). Glucose hypometabolism occurs in patients with amnestic mild cognitive impairment (aMCI), widely thought to be a prodromal stage of AD (10,14,15), and has also been detected in AD patients almost two decades prior to the onset of clinical symptoms.…”

Section: Discussionmentioning

confidence: 99%

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Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

Malkov

Popova

Ivanov

et al. 2020

Preprint

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A paramount driver of sporadic Alzheimer's disease (AD) is the synergy of oxidative stress and glucose hypometabolism in the brain. Oxidative stress damages cellular macromolecules such as DNA, lipids and proteins, whereas glucose hypometabolism impairs cellular energy supply and antioxidant defence; Together, these cellular and functional alterations may be primary triggers of AD. However, the exact molecular basis of AD-associated glucose hypometabolism has remained unknown, hampering the search for effective interventions. Here, we identify NADPH oxidase 2 (NOX2) activation by beta-amyloid peptide (Aβ1-42) as the main molecular source of oxidative stress driving brain glucose hypometabolism and network hyperactivity. Using a combination of electrophysiology with dynamic recordings of autofluorescence and metabolic biosensors, we show that in hippocampal brain slices, Aβ1-42 application reduced network activity-driven glucose consumption and glycolysis by half, while NOX2 antagonism prevented this effect. In vivo, intracerebroventricular injection of Aβ1-42 exerted a profound inhibitory effect on brain glucose consumption, resulting in long-lasting network hyperactivity and changes in animal behavioral profile. Critically, the novel bioavailable NOX2 antagonist GSK2795039 prevented all of the observed Aβ-related detrimental effects. These data suggest that targeting NOX2-induced oxidative stress is a promising approach to both the prevention and treatment of AD.

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Section: Discussionmentioning

confidence: 99%

“…Initial Aβ pathology is often detected concurrently with another pre-symptomatic marker of AD, glucose hypometabolism (10)(11)(12) (13). Indeed, glucose hypometabolism is an accurate predictor of progression to AD in mild cognitive impairment (MCI) patients (10,14,15).…”

Section: Introductionmentioning

confidence: 99%

Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

Malkov

Popova

Ivanov

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Thus, HSV-1 infection imposes a metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis, which undermines the proper functions of neurons. This dysregulated metabolism, characterized by increased glucose consumption, inefficient ATP production and excessive lactate secretion, has been observed as a prevalent feature in the early stages of AD (Crane et al, 2013;Croteau et al, 2018;Gordon et al, 2018). However, a possible causative role of HSV-1-induced glycolysis in AD pathogenesis has not been reported.…”

Section: Glycolysis and Oxidative Phosphorylationmentioning

confidence: 99%

Mechanistic insights into the role of herpes simplex virus 1 in Alzheimer’s disease

Feng,

Liu,

Zhou

et al. 2023

Front. Aging Neurosci.

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Alzheimer’s Disease (AD) is an aging-associated neurodegenerative disorder, threatening millions of people worldwide. The onset and progression of AD can be accelerated by environmental risk factors, such as bacterial and viral infections. Human herpesviruses are ubiquitous infectious agents that underpin numerous inflammatory disorders including neurodegenerative diseases. Published studies concerning human herpesviruses in AD imply an active role HSV-1 in the pathogenesis of AD. This review will summarize the current understanding of HSV-1 infection in AD and highlight some barriers to advance this emerging field.

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“…Previous longitudinal studies commonly use the subject's initial observation time point as the baseline and artificially treat subjects in different stages before AD onset as though they have the same starting point. In a study conducted by Gordon et al (2018), the time to symptom onset was estimated for participants and defined as the participant's current age minus the age of symptom onset to facilitate a longitudinal analysis of neuroimaging biomarkers in autosomal dominant Alzheimer's disease. The actual time to AD onset may more accurately reflect the subject's condition.…”

Section: Introductionmentioning

confidence: 99%

The characteristics of brain atrophy prior to the onset of Alzheimer’s disease: a longitudinal study

Hu,

Zhu,

Zhang

2024

Front. Aging Neurosci.

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ObjectiveWe aimed to use the onset time of Alzheimer’s disease (AD) as the reference time to longitudinally investigate the atrophic characteristics of brain structures prior to the onset of AD.Materials and methodsA total of 328 participants from the ADNI database with clear onset of AD and structural imaging data were included in our study. The time before the onset of AD (abbreviated as BAD) was calculated. We investigated the longitudinal brain changes in 97 regions using multivariate linear mixed effects regression models.ResultsThe average BAD was −28.15 months, with a range from −156 to 0 months. The 54 brain regions showed significant atrophy prior to the onset of AD, and these regions were mainly distributed in the frontal and temporal lobes. The parietal and occipital lobe exhibited relatively less atrophy than the other brain lobes. Sex, age, and magnetic field strength had greater direct impacts on structural indicators than APOE genotype and education. The analysis of interaction effects revealed that the APOE ε4 mutation carriers exhibited more severe structural changes in specific brain regions as the BAD increased. However, sex, age, and education had minimal regulatory influence on the structural changes associated with BAD.ConclusionLongitudinal analysis, with the onset time point of AD as the reference, can accurately describe the features of structural changes preceding the onset of AD and provide a comprehensive understanding of AD development.

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[O1–02–03]: Examining Longitudinal Neuroimaging Patterns in Autosomal Dominant Alzheimer Disease: Findings From the Dominantly Inherited Alzheimer Network

Cited by 4 publications

References 0 publications

Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

Mechanistic insights into the role of herpes simplex virus 1 in Alzheimer’s disease

The characteristics of brain atrophy prior to the onset of Alzheimer’s disease: a longitudinal study

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