{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T03:46:24Z","timestamp":1785728784663,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,27]]},"group-title":"In Review","reference-count":56,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,21]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  Impaired brain energy metabolism is an early feature of Alzheimer's disease (AD), but the standard metabolic imaging tool, [\n                  <sup>18<\/sup>\n                  F]FDG-PET, reports only glucose uptake and cannot resolve downstream metabolic flux nor inform on overall metabolic profile of the brain. In this study, we used [\n                  <sup>18<\/sup>\n                  F]FDG-PET, hyperpolarized (HP) [1-\n                  <sup>13<\/sup>\n                  C]pyruvate\n                  <sup>13<\/sup>\n                  C magnetic resonance spectroscopic imaging (MRSI), and ex vivo \u00b9H-NMR metabolomics to characterize how amyloid-\u03b2 (A\u03b2) associated pathology reshapes brain energy metabolism in the hAPP-J20 mouse model, from glucose uptake to metabolic fluxes and steady-state metabolite concentrations. HP\n                  <sup>13<\/sup>\n                  C MRSI was performed in male and female wild-type (WT) and hAPP-J20 mice at 2 and 14 months of age, with FDG-PET and metabolomics acquired at the final timepoint. HP\n                  <sup>13<\/sup>\n                  C MRSI revealed a progressive, region-specific increase in glycolytic flux in hAPP-J20 mice, with increased apparent HP [1-\n                  <sup>13<\/sup>\n                  C]Lactate\/Pyruvate conversion (relative to vascular delivery) localized to the hippocampus in females and to the cortex in males; HP\n                  <sup>13<\/sup>\n                  C urea perfusion measures confirmed comparable substrate delivery between genotypes. In contrast, [\n                  <sup>18<\/sup>\n                  F]FDG-PET showed no genotype difference in regional glucose uptake, although the sex- and weight-dependent scaling of FDG uptake observed in the WT controls was lost in hAPP-J20 mice.\n                  <italic>Ex vivo<\/italic>\n                  metabolomics uncovered sex-divergent metabolic rewiring: a succinate-centered strengthening of the TCA cycle and propanoate metabolism in females, versus altered tyrosine and ubiquinone metabolism in males. These data show that HP\n                  <sup>13<\/sup>\n                  C MRSI detects an A\u03b2-associated increase in glycolytic flux before FDG-PET registers a change, and position HP\n                  <sup>13<\/sup>\n                  C pyruvate MRS imaging as a sensitive, radiation-free, flux-based biomarker that complements glucose-uptake imaging in AD.\n                <\/p>","DOI":"10.21203\/rs.3.rs-10437814\/v1","type":"posted-content","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T06:29:03Z","timestamp":1785133743000},"source":"Crossref","is-referenced-by-count":0,"title":["Hyperpolarized 13C MRI uncovers early and progressive metabolic dysfunction in the hAPP-J20 mouse model of Alzheimer\u2019s disease"],"prefix":"10.21203","author":[{"given":"Tamara","family":"Vasilkovska","sequence":"first","affiliation":[{"name":"University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia M. 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