## 4 Discussion
In this context, it has been shown that GLUT expressions at the BBB and blood-CSF barrier in the choroid plexus are strictly regulated by brain metabolic needs and can be differently modulated in several pathological conditions [29; 30]. Interestingly, we noted a weaker correlation between FDG\({}_{\text{Ventircles}}\) and FDG\({}_{\text{Cortex}}\) in patients with AD and a more pronounced decrease in FDG\({}_{\text{Ventircles}}\) compared to that in FDG\({}_{\text{Cortex}}\). As a result, the FDG\({}_{\text{Ventircles}}\)/FDG\({}_{\text{Cortex}}\) ratio was also significantly lower in patients with AD. This finding may suggest that in such a neurodegenerative condition, while there is a global reduction in cortical glucose uptake, there is an extra rate of glucose reduction in the CSF. This glucose could be extracted and directed to astrocytes, in an attempt to compensate for impaired neuronal energy metabolism, to enhance their glycolytic activity and boost lactate production [31]. Thus, the lactate increase that we observed in the CSF could be linked to the neuronal metabolic impairment reflected by 18F-FDG-PET hypometabolism, as has already been observed in AD pathology [32]. Alternatively, the downregulation of GLUT1 occurring in AD could be different at the cortex and the choroid plexus levels [33], explaining the discrepancy between FDG\({}_{\text{Ventircles}}\) and FDG\({}_{\text{Cortex}}\). Indeed, while bioenergetic failure in aging and neurodegeneration results from increased mitochondrial dysfunction, deficiencies in glucose transport may also be involved. Recent studies in mice suggest that GLUT1 deficiency in the endothelial cells triggers BBB disruption and accelerates the progression of AD neuropathology [9], and reduced GLUT expression has also been detected at the BBB and in the cerebral cortex of patients with AD [11]. Overall, the weaker correlation between 18F-FDG uptake in the cortex and in CSF compared to that in controls could indicate that in AD, the mechanisms regulating glucose transport across the blood-brain and blood-CSF barriers are compromised, leading to a greater dysregulation of glucose homeostasis in the CSF relative to the cortex. These disruptions may reflect underlying pathological changes in the brain's ability to meet its metabolic demands, potentially contributing to the neurodegenerative process. To investigate which factors were associated with our 18F-FDG-PET parameters, we conducted a multivariate regression analysis considering BBB permeability (Qalb), AD-related pathology (p-tau/A\(\beta\)42), and brain metabolic state (CSF lactates) and including potential confounders like age, sex, and basal plasma glucose levels. In CTRLs, none of these factors significantly influenced the 18F-FDG-PET parameters, except for age, with older individuals showing reduced glucose uptake in both FDG\({}_{\text{Cortex}}\) and FDG\({}_{\text{Ventircles}}\). In contrast, within the AD group, lower FDG\({}_{\text{Cortex}}\) was not linked to age but rather to higher BBB permeability. In a previous study, we already observed a similar inverse relation between BBB permeability and glucose consumption in the temporal lobes of patients with AD [34]. It is possible that progressive BBB dysfunction may be associated with reduced GLUT expression, causing an impairment in glucose transport that could exacerbate cerebral metabolic dysfunction. Further, lower FDG\({}_{\text{Ventircles}}\) was associated with increasedBBB permeability, as well as with older age and elevated CSF lactates. The relationship with advanced age may be attributed to neuronal mitochondrial failure, which is common with aging and induces astrocytes to extract glucose from both blood and CSF to produce lactate. Additionally, reduced 18F-FDG uptake in the CSF could be linked to a weakened \"pull effect\" from the brain due to mitochondrial energy dysfunction, which is further associated with elevated CSF lactate levels.