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  • Data used in preparation of this article

    2024-05-17

    Data used in preparation of this article were obtained from the ADNI database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
    Introduction Alzheimer's disease (AD) is characterized by a long (∼20 years) preclinical period during which pathology accumulates in the absence of overt clinical symptoms (Price et al., 2009). The neuropathological hallmarks of AD are amyloid-β (Aβ) plaques and neurofibrillary tangles, which primarily are composed of hyperphosphorylated tau protein. Disruptions in the balance of Aβ production and clearance are considered to be initiating events in a biological cascade that leads to Aβ plaque formation and neurodegenerative tau pathology (Jack et al., 2013). Metabolic dysfunction is another pathological feature that occurs early in the disease in humans (Langbaum et al., 2009). Research on glucose metabolism in the Apoptosis Inhibitor has focused on total glucose use (CMRGlc) as measured by fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and, until recently (Vlassenko et al., 2010), did not examine the use of glucose outside of oxidative phosphorylation, known as aerobic glycolysis (AG). AG, a highly investigated feature of cancer metabolism (Lunt and Vander Heiden, 2011, Vlassenko et al., 2015), in the healthy brain may support metabolic functions that Apoptosis Inhibitor include biosynthesis of glycogen, proteins, lipids, and nucleic acids; neuroprotection by managing reactive oxygen species and apoptosis; production of lactate, a potential fuel and signaling molecule (Suzuki et al., 2011); and fast local generation of energy for membrane pumps (Vlassenko and Raichle, 2015). Recent studies indicate that AG supports synaptic and neurite formation and turnover (Goyal et al., 2014, Goyal et al., 2017, Shannon et al., 2016). However, total glucose use (CMRGlc) is largely driven by oxidative metabolism for synaptic activity and therefore may mask independent information provided by AG. PET studies with multiple tracers allow measurements of AG, glucose (CMRGlc), and oxygen (CMRO2) metabolism in the same individual and may deliver various important details otherwise missed by conventional 18F-FDG PET and magnetic resonance imaging (MRI) (Vlassenko et al., 2015). PET also affords in vivo measurements of Aβ and tau deposition, which, with quantitative estimates of CMRGlc, CMRO2, and AG, allows more explicit evaluation of the pathological progression in preclinical and symptomatic stages of AD. Here, we present preliminary findings with PET on the relationship between metabolism, including AG, and tau pathology. Specifically, we evaluate this relationship in a set of brain areas vulnerable to tau burden during preclinical AD.
    Materials and methods
    Discussion Our findings demonstrate that in preclinical and very mildly symptomatic AD individuals, lower AG is associated with higher tau deposition in vulnerable regions of the brain. This finding is unaffected by adjusting for age (which itself correlates with AD pathology and lower AG) and by removing the 2 symptomatic AD individuals in our cohort. No such relationship was observed for CMRGlc or CMRO2. While the relationship between tau and metabolism may be specific to AG in this cohort, our modest sample size may be insensitive to more subtle relationships between tau and CMRGlc or CMRO2. Further research in a larger cohort is needed to explore these relationships and to pursue more detailed regional analysis. With aging, AG decreases dramatically (especially in functionally important areas, including those with high accumulation of Aβ and where AG is the highest in young adulthood), presumably resulting in loss of the biosynthetic and neuroprotective functions AG normally supports (Goyal et al., 2017). We believe that ongoing neuronal activity in the aging brain, deprived of proper AG-related synaptic maintenance and protection, might in part be responsible for the acceleration of neurodegeneration including tau pathology. However, it should be noted that aging-related decrease in AG can occur unaccompanied by AD pathology suggesting that other, presently unknown, elements may also be playing a role in the causal chain of events.