Early alterations in brain glucose metabolism and vascular function in a transgenic rat model of Alzheimer's disease.

Abstract

Alteration in brain metabolism predates clinical onset of Alzheimer's Disease (AD). Realizing its potential as an early diagnostic marker, however, requires understanding how early AD metabolic dysregulation manifests on non-invasive brain imaging. We presently utilized magnetic resonance imaging and spectroscopy to map glucose and ketone metabolic profiles and image cerebrovascular function in a rat model of early stage AD - 9-month-old TgF344-AD (TgAD) rats - and their age-matched non-transgenic (nTg) littermates. Compared to the nTg rats, TgAD rats displayed attenuation in global cerebral and hippocampal vasoreactivity to hypercapnia, by 49±17% and 58±19%, respectively, while their functional hyperemia to somatosensory stimulation diminished by 69±5%. To assess brain glucose uptake, rats were fasted overnight and then challenged with an intravenous infusion of 2-deoxy-D-glucose (2DG). Compared to their non-transgenic littermates, TgAD rats exhibited 99±10% and 52±5% smaller glucose uptake in the entorhinal cortex and the hippocampus, respectively. Moreover, hippocampal glucose uptake reduction in male TgAD rats compared to the nTg was 54±36% greater than the reduction seen in female TgAD rats. TgAD rats also showed a 59±42% increase in total choline level in the hippocampus, suggesting increased membrane turnover. In combination with our earlier findings of impaired electrophysiological metrics at this early stage of AD pathology progression, our findings suggest that subtle neuronal function alterations that would be difficult to assess in a clinical population may be accompanied by MRI-detectable changes in brain glucose metabolism and cerebrovascular function.