Multimodal Imaging Evaluation And Monitoring Of Experimental Research On Neural Stem Cell Transplantation In The Treatment Of Alzheimer's Disease

Section I:Multimodal imaging evaluation of 8-month-old APP/PS1 mouse model of Alzheimer’s diseaseBackground:Alzheimer’s disease(AD)is the most common cause of dementia in middle-aged and elderly people,and its harm is extremely serious.Once a person gets sick,it will bring heavy burden to family and society.Genetically modified animal models of AD can simulate the pathological and behavioral changes of AD patients,and are often used to test subjects for new therapies.Effective biomarkers,especially noninvasive ones,are urgently needed to assess the diagnosis or treatment outcome of AD.However,few studies have systematically detected pathological changes in AD animal models by non-invasive methods.Methods:In this study,we tested 8-month-old APP/PS1 transgenic mice and wild-type mice of the same age using 7.0 T magnetic resonance imaging(MRI)and PET-CT.Before testing,the learning and memory impairment of APP/PS1 mice was tested by Morris water maze method.Magnetic resonance spectroscopy(MRS),diffusion tensor imaging(DTI)and arterial spin labeling(ASL)were obtained by 7.0 T MRI,and[18F]FDG PET scans were used to assess glucose metabolism in local brain regions.Immunohistochemical staining,enzyme-linked immunosorbent assay(ELISA)and ultrastructural analysis were performed on the transgenic and wild mice after scanning with MRI and PET.Results:The results of water maze experiment showed that,compared with wild type mice of the same age,APP/PS1 mice of 8 months old had significant cognitive and memory impairment.PET results showed that glucose uptake was significantly decreased in hippocampus and thalamus of APP/PS1 mice(P<0.05),but significantly increased in cortex and amygdala(P<0.01).The correlation analysis showed that glucose uptake was negatively correlated with the concentration of soluble amyloid peptide(P<0.05).On MRI,ASL showed that the cerebral blood flow(CBF)of left hippocampus,left thalamus and right cortex of APP/PS1 mice was significantly lower than that of wild control mice(P<0.05);MRS showed that NAA/Cr.Glu/Cr and mI/Cr in the hippocampus of APP/PS1 mice had significant changes,while only NAA/Cr and ml/Cr had significant differences in the cortex of AD mice;DTI imaging showed no significant differences in FA,MD,DA and DR values of AD and WT group mice.By immunohistochemistry and electron microscopy,however,we found that there were significant differences in brain neurons,cerebral blood flow and white matter fiber bundles between APP/PS1 mice and wild type mice.Conclusion:Our results preliminarily suggest that MRS,ASL or[18F]FDG PET can be used as an in vivo imaging evaluation method for 8-month-old APP/PS1 transgenic mice.Section Ⅱ:Multimodal imaging monitoring of neural stem cells in the treatment of Alzheimer’s diseaseBackground:Alzheimer’s disease(AD)is the leading cause of dementia in adults,which severely affects their quality of life;but there remain no effective measures to radically treat this disease.In recent years,the rapid development of neural stem cells(NSCs)technology has brought new hope for the treatment of AD;however,the monitoring of NSCs in AD is limited to behavioral and pathological observation.In the first part of this paper,we found that MRS,ASL,[18F]FDG PET could be used as an in vivo imaging evaluation method for 8-month-old APP/PS1 mice,which provides a possibility for monitoring the treatment of AD by NSCs.Methods:In this study,8-month-old APP/PS1 transgenic AD mice were used to transplant rat-derived NSCs into bilateral hippocampal CA1 region.Multimodal imaging(including DTI,ASL,MRS and PET sequences)was used to detect AD mice at multiple time points(1 month,1.5 months and 2.5 months)after NSCs transplantation,and compared with AD mice treated with PBS and normal control mice,to clarify the characteristics of multimodal imaging changes after NSCs transplantation.At the same time,we evaluated the viability of NSCs in AD mice,and explored the possible mechanism of NSCs and the pathological changes of AD mice brain.Results:At 2.5 months after transplantation,NSCs still survived in the hippocampus,internal capsule and adjacent cortex of AD mice,and the learning and memory abilities of AD mice were significantly improved.Pathological results showed that M2 microglia activity increased,anti-inflammatory factors increased,pro-inflammatory factors decreased,amyloid peptide degradation increased,and neurotrophic factors increased in NSC group.The results of ASL,MRS and PET showed that cerebral blood flow perfusion and brain cell metabolism increased significantly at 1 month after NSCs transplantation(P<0.05),while brain FA increased significantly at 2.5 months after NSCs transplantation(P<0.05).Ultrastructural observation showed that neurons,synapses,mitochondria,myelin sheaths and blood vessels in AD mice brain recovered well after NSCs transplantation.Conclusion:The transplanted NSCs can survive in the brain of AD mice,and improve the brain metabolism,blood flow and white matter of AD mice by regulating the activity of microglia,secreting neurotrophic factors and reducing the level of amyloid protein,so as to restore the learning and memory ability of AD mice.Multimodal imaging results showed that cerebral blood flow and brain metabolism in AD mice improved significantly at the early stage after NSCs transplantation,while the recovery of white matter fibers was slower.This study will provide theoretical support for the use of multi-modal imaging to monitor NSCs in the treatment of AD,and may also provide theoretical basis for multimodal imaging to evaluate the clinical treatment of AD.