Abstract: PURPOSE: Visual short-term memory has been suggested to be a cognitive marker for early detection of Alzheimer’s Disease (AD). However, the neural mechanism of VSTM affected by the AD pathology remained underexplored. Filling this gap, the current study focused on the hippocampus and prefrontal cortex (PFC), two brain areas both playing critical role in VSTM but also vulnerable in AD pathology, and examined how are the functional deterioration and the reorganization of external neural mechanism of hippocampus in relevant to VSTM deficit in amnestic mild cognitive impairment (aMCI) individuals.
METHODS: VSTM was assessed by an adapted change detection task. In experiment 1, structural atrophy in the medial temporal lobe (MTL) and PFC was identified and the association between structure deficiency and VSTM performance was tested by partial correlation analysis. Moreover, participants were divided into subgroups with different severity of hippocampal atrophy to see if the reorganization of VSTM-related neural mechanism would be influenced by the hippocampal deterioration. Furthermore, using these targeted areas as regions of interest (ROIs), the functional connectivity (FC) profile for each ROI was computed and compared between groups, and the FC-VSTM association was also tested by partial correlation analysis. Experiment 2 tested association between the structural alteration of subfields of hippocampus and the VSTM performance.
RESULTS: Both studies showing worse performance of VSTM task in aMCI subjects than the NC group. Experiment 1 revealed structural atrophy in the left medial temporal lobe (MTL) and the right frontal pole (FP) in the aMCI group. while gray matter volume (GMV) of both areas showing significant positively correlation with VSTM performance in the NC group, VSTM performance was significantly correlated with the GMV of the right FP but not with GVM of the left MTL in the aMCI group. Moreover, using the atrophic left MTL as a seed, its functional connectivity to a right FP area, which is overlapped with the atrophic frontal areas in structure, was significantly higher in aMCI than NC. Furthermore, for those aMCI with smaller left MTL, the compensatory involvement of the right FP in performing VSTM tasks, as assessed by the brain-behavior correlation was more prominent. Experiment 2 showed that left-lateral granule cell molecular layer of the dentate gyrus (GC-ML-DG), molecular layer, subiculum and hippocampal-amygdaloid transition region (HATA), and bilateral presubiculum and fimbria had significantly smaller GMV in the aMCI group than the NC group. GMV of left molecular layer, left subiculum and left GC-ML-DG were significantly associated with the accuracy and capacity of VSTM task in the NC group but not in the aMCI group. GMV of right fimbria was significant correlated with the RT of the VSTM task in the HC group but not in the aMCI group.
CONCLUSIONS: The current study showed an MTL-dysfunction and prefrontal-compensation mechanism for VSTM processes in aMCI. Hippocampal subfields related to information input and output may contribute to VSTM impairment by disrupting hippocampal-cortical communication and the hyperconnectivity between MTL and PFC might suggest the external compensation to maintain the VSTM process in aMCI. Such compensatory mechanism of PFC varied along the progress to AD. This finding also points to VSTM impairment as a potential neuropsychological indicator for early detection of preclinical AD.

Key words: hippocampus, visual short-term memory, brain atrophy, amnestic mild cognitive impairment