Evidence for brain glucose dysregulation in Alzheimer's disease

An, Yang; Varma, Vijay R.; Varma, Sudhir; Casanova, Ramon; Dammer, Eric B.; Pletniková, Olga; Chia, Chee W.; Egan, Josephine M.; Ferrucci, Luigi; Troncoso, Juan C.; Levey, Aĺlan I.; Lah, James J.; Seyfried, Nicholas T.; Legido‐Quigley, Cristina; O’Brien, Richard; Thambisetty, Madhav

doi:10.1016/j.jalz.2017.09.011

Cited by 386 publications

(297 citation statements)

References 45 publications

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“…Some studies demonstrate a relationship between insulin resistance and amyloid levels [49], whereas others do not [50]. In previous studies from our laboratory, we found no significant association between repeated measures of glucose intolerance, diabetes, or insulin resistance and either postmortem Aβ or in vivo PET-PiB [51], yet regions associated with amyloid and tau pathology show significantly higher tissue glucose concentrations in AD [52]. Thus, the exact relationship between these factors and amyloid accumulation demonstrated by PET imaging deserves further study.…”

Section: Discussionmentioning

confidence: 66%

Metabolic Syndrome and Amyloid Accumulation in the Aging Brain

Gómez

Beason‐Held

Bilgel

et al. 2018

JAD

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Background: Recent studies show links between metabolic syndrome and Alzheimer’s disease (AD) neuropathology. Understanding the link between vascular-related health conditions and dementia will help target at risk populations and inform clinical strategies for early detection and prevention of AD. Objective: To determine whether metabolic syndrome is associated with global cerebral amyloid-β (Aβ) positivity and longitudinal Aβ accumulation. Methods: Prospective study of 165 participants who underwent (11)C-Pittsburgh compound B (PiB) PET neuroimaging to measure Aβ, from June 2005 to May 2016. Metabolic syndrome was defined using the revised Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Participants were classified as PiB+/−. Linear mixed effects models assessed the relationships between baseline metabolic syndrome and PiB status and regional Aβ change over time. Results: A total of 165 cognitively normal participants of the Baltimore Longitudinal Study of Aging (BLSA) Neuroimaging substudy, aged 55–92 years (mean baseline age = 76.4 years, 85 participants were male), received an average of 2.5 PET-PiB scans over an average interval of 2.6 (3.08 SD) years between first and last visits. Metabolic syndrome was not associated with baseline PiB positivity or concurrent regional Aβ. Metabolic syndrome was associated with increased rates of Aβ accumulation in superior parietal and precuneus regions over time in the PiB+ group. Elevated fasting glucose and blood pressure showed individual associations with accelerated Aβ accumulation. Conclusion: Metabolic syndrome was associated with accelerated Aβ accumulation in PiB+ individuals and may be an important factor in the progression of AD pathology.

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Section: Discussionmentioning

confidence: 66%

Metabolic Syndrome and Amyloid Accumulation in the Aging Brain

Gómez

Beason‐Held

Bilgel

et al. 2018

JAD

Self Cite

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“…PET imaging studies reveal impaired cerebral glucose utilization occurring very early in AD pathogenesis, even before overt clinical symptoms are evident (Friedland et al, 1989; Ceravolo et al, 2008). Findings from postmortem analyses reveal reductions in levels of glucose transporters and decrements in ETC complex activities and glycolytic flux in vulnerable brain regions of AD patients (Simpson et al, 1994; Valla et al, 2001; An et al, 2018). PD patients exhibit reduced glucose utilization in brain regions involved in motor control, and deep brain stimulation of the globus pallidus (which alleviates motor symptoms) increases glucose utilization in those brain regions (Fukuda et al, 2001).…”

Section: Perspective On How Mechanisms Of Aging Impact Neurological Dmentioning

confidence: 99%

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

2018

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During aging, the cellular milieu of the brain exhibits tell-tale signs of compromised bioenergetics, impaired adaptive neuroplasticity and resilience, aberrant neuronal network activity, dysregulation of neuronal Ca2+ homeostasis, the accrual of oxidatively modified molecules and organelles, and inflammation. These alterations render the aging brain vulnerable to Alzheimer’s and Parkinson’s diseases and stroke. Emerging findings are revealing mechanisms by which sedentary overindulgent lifestyles accelerate brain aging, whereas lifestyles that include intermittent bioenergetic challenges (exercise, fasting, and intellectual challenges) foster healthy brain aging. Here we provide an overview of the cellular and molecular biology of brain aging, how those processes interface with disease-specific neurodegenerative pathways, and how metabolic states influence brain health.

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“…In addition to the effect of S100B on RAGE-mediated ROS overproduction, this protein, at concentrations of ≥500 nM, enhances Aβ neurotoxicity. However, at lower concentrations, S100B showed a protective effect against the neurotoxicity of Aβ [25][26][27][28][29][30][31][32][33][34][35] [101]. Furthermore, recent studies suggested that elevated S100B levels have harmful effects on oligodendrogenesis and myelination through RAGE-dependent processes.…”

Section: S100 Protein Family As a Potential Biomarkers Of Admentioning

confidence: 99%

“…Cerebral regions sensitive to the aggregation of Aβ and NFTs display significantly higher glucose concentration in AD. Moreover, elevated levels of brain tissue glucose are associated with greater severity of both Aβ deposition and neurofibrillary pathology [35]. In a community-based controlled study performed together with pathological study of autopsy cases from this same community, authors have found that both T2DM as well as impaired fasting glucose were twice more prevalent in AD versus non-AD control subjects.…”

Section: Brain Energy Metabolism and Ad Onsetmentioning

confidence: 99%

The Interplay between Diabetes and Alzheimer’s Disease—In the Hunt for Biomarkers

Kubis-Kubiak

Dyba

Piwowar

2020

IJMS

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The brain is an organ in which energy metabolism occurs most intensively and glucose is an essential and dominant energy substrate. There have been many studies in recent years suggesting a close relationship between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) as they have many pathophysiological features in common. The condition of hyperglycemia exposes brain cells to the detrimental effects of glucose, increasing protein glycation and is the cause of different non-psychiatric complications. Numerous observational studies show that not only hyperglycemia but also blood glucose levels near lower fasting limits (72 to 99 mg/dL) increase the incidence of AD, regardless of whether T2DM will develop in the future. As the comorbidity of these diseases and earlier development of AD in T2DM sufferers exist, new AD biomarkers are being sought for etiopathogenetic changes associated with early neurodegenerative processes as a result of carbohydrate disorders. The S100B protein seem to be interesting in this respect as it may be a potential candidate, especially important in early diagnostics of these diseases, given that it plays a role in both carbohydrate metabolism disorders and neurodegenerative processes. It is therefore necessary to clarify the relationship between the concentration of the S100B protein and glucose and insulin levels. This paper draws attention to a valuable research objective that may in the future contribute to a better diagnosis of early neurodegenerative changes, in particular in subjects with T2DM and may be a good basis for planning experiments related to this issue as well as a more detailed explanation of the relationship between the neuropathological disturbances and changes of glucose and insulin concentrations in the brain.

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Evidence for brain glucose dysregulation in Alzheimer's disease

Abstract: Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms.

Cited by 386 publications

References 45 publications

Metabolic Syndrome and Amyloid Accumulation in the Aging Brain

Metabolic Syndrome and Amyloid Accumulation in the Aging Brain

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

The Interplay between Diabetes and Alzheimer’s Disease—In the Hunt for Biomarkers

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