SPECT study of GABAA/BZD receptors and cerebral blood flow in mild cognitive imparment (MCI)

GABAA/BZD receptors' reduction in specific brain regions (i.e., medial temporal cortex/hippocampus, posterior cingulate, temporo-parietal cortex and at a lesser extent frontal cortex) has been reported post-mortem and in vivo in patients with moderate-severe Alzheimer's disease (AD). These changes may reflect loss and/or dysfunction of cortical intrinsic inhibitory GABA-ergic and/or pyramidal neurons. Whether in vivo neocortical and limbic GABAA/BZD receptors alterations characterize subjects with mild cognitive impairment (MCI), in particular, MCI converters, and whether the pattern of possible changes in MCI is different and/or parallel to that of rCBF alterations has not been investigated. Aims: To evaluate with SPECT cortical GABAA/BZD receptors and rCBF in subjects with MCI and to assess the possible contribution of these markers in identifying MCI converters from MCI nonconverters. Materials and methods: Using a brain-dedicated SPECT camera, we studied with [123I]-Iomazenil and [99mTc]HMPAO 16 amnestic MCI subjects (age: 72 ± 7 years, MMSE : 26.8 ± 2.2) and controls ([123I]-Iomazenil: n = 7, age: 66 ± 10 years, [99mTc]HMPAO: n = 10, age: 65 ± 10 years). At follow-up (12 months), 7 MCI developed AD (MCI-C) while 9 remained stable (MCI-NC). Data analysis was performed using ROIs and SPM2 on [123I]-Iomazenil delayed receptor distribution images (acquired 3 hours post-injection) and rCBF images, spatially normalized in the MNI space. For ROIs analysis, regional counts were normalized to the occipital counts. Statistical analysis was performed using t test (MCI and controls comparison) and ANOVA (controls, MCI-C and MCI-NC comparisons). Single subject conditions (controls, MCI-C, MCI-NC) and covariates (age as nuisance covariate) model was used for SPM analysis of delayed [123I]-Iomazenil images normalized to occipital counts and rCBF images scaled to global counts. Significant threshold: P < 0.001, corrected for cluster extent at P < 0.05. Results: Compared to controls, MCI did not show significant [123I]-Iomazenil binding changes. A trend for reduction was found in the left posterior cingulate (-8, -44, 20 x, y, z) in MCI-C as compared to controls and to MCI-NC. Compared to controls, both MCI and MCI-C showed significant rCBF decrease in the left /right precuneus (-2, -42, 50/16-58, 28 x, y, z). MCI-C/MCI-NC comparison showed in MCI-C a trend for rCBF reduction in left posterior cingulate (-14, -48, 30 x, y, z). ROIs analysis showed similar results. Conclusions: These results suggest that neocortical GABAergic/pyramidal neurons are relatively preserved in MCI, even in MCI-C. Compensatory GABAA/BZD receptors up-regulation may in part also explain the lack of significant reduction in hippocampus and parahippocampal areas, the regions involved neuropathologically in MCI. The highly significant rCBF decrease found in the precuneus of MCI and MCI-C suggests that functional alterations more than neuronal loss are involved in these areas in MCI and that this functional pattern is specific of MCI-C.