Brain energy metabolism in Alzheimer's disease: Tc-99m-HMPAO SPECT imagingduring verbal fluency and role of astrocytes in the cellular mechanism of Tc-99m-HMPAO retention

The central hypothesis of the study which has been carried out as part of t he NRP38 program, is that perturbations of brain energy metabolism are crit ically involved in the neuro degeneration occurring in Alzheimer's disease (AD) and that they may correlate with early cognitive dysfunctioning. In th e present multidisciplinary study we set out to monitor brain energy metabo lism using FDG-PET and HMPAO-SPECT imaging in a cohort of individuals over 65 years of age, drawn from the general population. HMPAO-SPECT imaging, wh ich is a simpler and more widely accessible imaging procedure than FDG-PET, was performed under basal conditions and during the performance of a cogni tive task (verbal fluency test). Three groups were studied. Two groups (gro ups I and II) included individuals age 65 or more, with no cognitive impair ment and carrying an APOE4 positive or APOE4 negative phenotype, respective ly; a third group (group III) included patients with clinical signs of AD. Each subject entering the study under-went an FDG-PET, an HMPAO-SPECT and a n extensive battery of neuropsychological tests which assess various aspect s of cognitive functioning, with a strong emphasis on working memory, divid ed attention and executive functions. A total of 101 participants were subm itted to brain imaging and neuropsychological testing. Among these, 60 part icipants received the same set of imaging and neuropsychological tasks 24-3 6 months after the first set (phase II). In this article, we present a prel iminary analysis performed on ten subjects from groups I and Il and nine su bjects from group III: activation (verbal fluency task) induced a specific pattern of increase in HMPAO retention (including BA 9/10, BA 18 bilaterall y and right BA 17). In contrast to controls, in nine AD subjects no signifi cant differences in HMPAO retention were observed when comparing activation and basal conditions. The cellular and molecular mechanisms that underlie the retention of HMPAO, the tracer used for single photon emission computed tomography (SPECT) imaging has been studied in vitro in purified preparati ons of neurons and astrocytes with the aim of investigating the contributio n of different cell types to hexamethyl-propylencamineoxime labeled with te chnetium-99m (Tc-99m-HMPAO) retention in vitro. Results show that Tc-99m-HM PAO retention predominates in astrocytes over neurons by a factor of simila r to2.5. Diethyl maleate, ethacrynic acid and buthionine sulfoximine, three agents which significantly reduce glutathione levels, also decreased Tc-99 m-HMPAO retention in both astrocytes and in neurons. Decrease did not alway s correlate with glutathione levels however, thus suggesting that other fac tors could be involved. The data presented indicate that astrocytes might c onstitute a prominent site of Tc-99m-HMPAO retention and most likely contri bute significantly to the SPECT signal. In addition, they also suggest that specific alterations in glial cell metabolism could explain flow-independe nt changes in Tc-99m-HMPAO retention in the brain as observed by SPECT in c ertain pathologies (including Alzheimer's disease). In particular, these ob servations suggest a key role of astrocytes in the signal detected with the imaging procedure. which is altered in the Alzheimer's cohort subjected to the verbal fluency activation task. (C) 2001 Elsevier Science B.V. All rig hts reserved.