4.1. Summary of main findings
Compared with healthy controls, patients with MCI showed decreased hippocampal volume and WM connectivity with the SFG, as well as increased MD and RD in the amygdala (p < 0.05, Bonferroni-corrected). Given that the hippocampal volume loss is consistent with evidence supporting AD diagnosis and tracking22,23. Further, patients with MCI showed enhanced MMSE scores and increased hippocampal-ITG connectivity (p < 0.05, Bonferroni-corrected) after 6-month donepezil treatment. These results suggest that increased hippocampal-ITG WM connectivity may be attributed to donepezil treatment.
4.2. Brain volume and DTI scalars in MCI
It is well known that hippocampus atrophy is at the core of AD pathophysiology. Patients with MCI showed a significant decrease in hippocampal volume compared with healthy controls. These results support the notion that hippocampal abnormalities are associated with early detection of AD7,24-27. However, no volumetric increase across all the brain areas was detected after donepezil treatment.
Compared with healthy controls, patients with MCI showed higher MD and RD in the amygdala (p < 0.05, Bonferroni-corrected). Patients with MCI showed decreased FA in the hippocampus and amygdala (p < 0.05, not corrected for multiple comparison), but the level of significance via multiple comparison correction was not high enough to validate this finding. A DTI study28 reported a decreased FA and a three-fold increase in trace value compared with MD in the hippocampus and amygdala of patients with AD compared with healthy controls. A similar study29 also found a significantly elevated MD in the hippocampus and amygdala of AD patients. MD measures the average diffusivity in the non-colinear directions of free diffusion and RD quantifies the diffusion of water molecules in a direction perpendicular to the axon fibers30-32. The increased MD in the amygdala of patients with MCI was associated with an increase in free water diffusion and the increased RD was related to greater myelin damage. However, no change in DTI scalars in the all brain areas of patients was detected after donepezil treatment. Thus, alterations of hippocampal volume and DTI scalars in patients with MCI may be associated with early prediction of progression to AD.
4.3. Structural connectivity in MCI
Structural connectivity is potentially important for the early diagnosis of AD. We found a decreased hippocampal-SFG WM connectivity in patients with MCI compared with healthy controls. This result, which has not been reported in previous structural connectivity studies, was consistent with that of a functional connectivity study33 suggesting that AD patients manifested decreased hippocampal-SFG connectivity compared with healthy controls. Another recent study34 showed decreased hippocampal-SFG connectivity in MCI patients. The STG occupies the medial part of PFC (mPFC), which plays a critical role in multi-tasking, social cognition, attention, and emotion35. A 7T fMRI study36 revealed decreased hippocampal-SFG connectivity in AD, suggesting that lower MMSE scores were associated with reduced connectivity between the hippocampus and SFG. Thus, the decreased hippocampal-SFG WM connectivity is a potentially important biomarker for the early clinical diagnosis of AD.
4.4. Structural connectivity after donepezil treatment in MCI
To our knowledge, this is the first study evaluating hippocampus-related structural connectivity in patients with MCI following donepezil treatment. In the current study, the MMSE scores of patients with MCI improved after donepezil treatment by 7.9%. Additionally, patients with MCI showed increased hippocampal-ITG WM connectivity after 6 months of treatment. The ITG plays an important role in verbal fluency, a cognitive function affected early in the onset of AD37. A study38 investigating the cognitive function of ITG in patients with MCI reported that MMSE scores are significant positively correlated with hippocampal-ITG connectivity. AD patients with a decline in the MMSE score following nine months of donepezil treatment showed decreased volume in the inferior temporal gyrus compared with increased MMSE39. Improved K-MMSE scores concomitant with increased hippocampal-ITG WM connectivity are potentially attributed to donepezil treatment.
Donepezil activates central cholinergic transmission and enhances the survival of newborn neurons in the hippocampal dentate gyrus40. Dong et al.41 suggested that donepezil treatment reduced beta-amyloid plaques and increased synaptic density. Beta-amyloid deposition has been linked to AD pathology and induces multiple biochemical changes in cells including an increase in cytosolic calcium, which contributes to down-regulation of the expression of glutamate receptors in postsynaptic membrane42. Patients with early AD showed an increase in serum concentration of brain-derived neurotrophic factor (BDNF) during donepezil treatment. BDNF belongs to the family of nerve growth factors and plays an important role in neuronal survival and synaptic plasticity in the central nervous system43. These findings provide evidence suggesting that hippocampal atrophy and decreased hippocampal-SFG WM connectivity may be closely related to AD pathogenesis and the increased hippocampal-ITG WM connectivity in donepezil-treated patients can be attributed to the treatment.
4.5. Limitations and future directions
This study has some limitations that should be mentioned. The small sample size does not ensure sufficiently high statistical power. To address this limitation, a statistical threshold of P value less than 0.05 using Bonferroni correction was used. Another limitation is the short follow-up duration after donepezil treatment. Therefore, a placebo-controlled study of a large population of MCI patients and a long-term follow-up are needed to evaluate the time course of treatment change. In addition, such studies should investigate the changes in structural connectivity between mild and moderate AD and between moderate and severe AD in light of the effects of donepezil treatment.