Multimodal Quantitative MRI In Detecting Sub-visible Brain Damage Of Vascular Cognitive Impairment

Objective:The main purposes were desired of this dissertation are :(1) to investigate the early metabolic changes in hippocampal of vascular cognitive impairment rats during the disease progression by longitudinal quantitative 1H-MRS, and to find marks for preclinical diagnosis of vascular cognitive impairment by whole brain quantitative DTI;(2) to identify the metabolic changes in left frontal white matter, left thalamus, posterior cingulum and the sub-visible white matter abnormalities of vascular cognitive impairment(VCI) patients with small vessel disease by quantitative 1H-MRS and whole brain quantitative DTI respectively, and also, to investigate the role of 1H-MRS and DTI in diagnosis of VCI and differential diagnosis of VCI with Alzheimer’s disease(AD);(3) to investigate the potential diagnostic value of cerebral microbleeds in patients with vascular cognitive impairment by evaluating the location and number of cerebral microbleeds(CMB);More over, to evaluate the role of DTI in identifying the sub-visible white matter abnormalities of relapsing–remitting multiple sclerosis(RRMS) patients with motor or/and visual disability and further to validate the value of DTI in detecting sub-visible damage with related to neurological dificits. Methods: 1. The 90 male rats were divided randomly into two groups, 50 rats in experimental group and 40 rats in contrast group. The experimental models of vacular cognitive impairment were established by method employing improved four vessel occlusion(4-VO) in rats, and Morris Water Maze test were used to assment the ability of spacial learning and memory of the rats. In vivo 1H-MRS was explored in experimental group and contrast group at two weeks, one month and three month after the models established. The single voxel PRESS(Point Resolved Spectroscopy Sequence) was performed to detect metabolic disturbance in the hippocampus, partial striatum and visual cortex of VCI rats. The datas were collected and absolute quantitation of the main metabolites were calculated by LCModel software, these metabolites include N-acetylaspartate(NAA), Creatine(Cr), Myo-Inositol(MI/Ins), Glutamate(Glu), Glutamine(Gln), γ-Aminobutyric Acid(GABA) and Taurine(Tau). The whole brain DTI scan was explored in VCI rats and the data were analysed by method of VBA. Histopathological changes in brains of rats were detected by the staining methods including hematoxylin–eosin(HE) and Nissl. All kinds of metabolites concentrations changes of the two groups were compared respectively by t test of paired data, in which the P values<0.05 was statistical differences. 2. The 9 cases of VCI patients with small vessel disease, 11 cases of AD patients and 20 healthy control subjects were collected in this study. The quantitative 1H-MRS was explored with single voxel PRESS and the NAA, t Cr, Ins, Glx, Cho, GPC concentrations were calculated by LCModel software. The whole brain DTI measurements were performed and the datas were analysed with the TBSS method. To look for the reduction of FA values in white matter and deep gray matter in VCI patients and AD patients compared with the healthy control subjects respectively. Furthermore to search the more obvious decreased FA values of the brain areas in VCI patients compared with the FA mapping of AD patients. 3. There are 78 cases of patients detected CMB by SWI, in which 10 cases were cerebral small vessel disease accompanied with cognitive function impairment(group of VCI) and 21 cases were cerebral small vessel disease with no cognitive impairment(control group).The locations of CMB were determined according to Microbleed Anatomical Rating Scale(MARS) and the number of CMB were rated as four grades. The difference of microbleed number and severity in deep, lobar, and infratentorial categories were compared with each group respectively. 4. DTI measurements were performed in 18 relapsing–remitting multiple sclerosis(RRMS) patients with motor(MS+) or/and visual disability(MS++) and 20 age-matched healthy control subjects,combined with TBSS and region of interest(ROI) analysis. Multiple scalar measurements, including fractional anisotropy(FA), mean diffusivity(MD), axial dififusivity(Da), and radial diffusivity(Dr), were investigated to capture the various types of changes in inferior longitudinal fasciculum, thalamus, genu of corpus collasum, portion of the corticospinal tracts. Results: 1. The ability of spacial learning and memory of the experimental group were impaired by using Morris Water Maze test Morris. After the VCI models established at 2 weeks, we found that NAA, GABA, Glu concentrations were decreased significantly compared to that in control rats(P<0.05); The reduction of NAA concentratios was found at one month(P<0.05), and the GABA and Glu concentrations were back to normal level; The NAA, GABA and Glu concentrations were all back to normal level at three months. There are no areas in red where the FA was significantly lower(p<0.05) in the VCI models at 2 weeks after established; The left hippocampus, left thalamus, bilateral caudate putamen and corpus callosum in red where the FA was significantly lower(p<0.05) in the VCI models at 1 month after established; The bilateral thalamus, bilateral caudate putamen, bilateral internal capsule, corpus callosum and right cingulum in red where the FA was significantly lower(p<0.05) in the VCI models at 3 months after established. 2. When compared with the normal contrast group or AD group.The NAA concentrations of the left thalamus and the cingulum decreased in VCI patients. The Cho and GPC concentrations of the posterior cingulum were elevated, but the Glx concentrations were decreased in VCI patients. The Glx concentrations of the left frontal white matter were decreased in AD patients.The VCI patients exhibited significantly lower FA values in widespread white matter and deep gray matter when compared with the healthy control subjects, including the bilateral corona radiata, bilateral external capsule, right internal capsule, fornix, genu and splenium of corpus callosum, bilateral thalamus, bilateral sagittal stratum, bilateral inferior longitudinal fasciculum, right superior longitudinal fasciculum, bilateral cingulum and bilateral uncinate fasciculum. The AD patients exhibited significantly lower FA values in the bilateral corona radiata, bilateral external capsule, fornix, genu and splenium of corpus callosum, bilateral thalamus, bilateral sagittal stratum, bilateral inferior longitudinal fasciculum, right superior longitudinal fasciculum, bilateral cingulum. When compared VCI patients with AD patients, the VCI patients exhibited significantly lower FA values in the left anterior corona radiata, left superior corona radiate, bilateral cingulum and body of corpus callosum. 3. The microbleed number and severity in lobar category of VCI group were higher than that of control group, and the difference of the two group was statistically significant(P<0.05); No significant difference of microbleed number and severity in deep,infratentorial category in the two group(P>0.05). 4. The MS patients exhibited significantly lower fractional anisotropy(FA) in the white matter tracts of the whole brain, including the cerebellar peduncle, corona radiata, external capsule, optic tract, posterior thalamic, corticospinal tract, superior and inferior longitudinal fasciculum, cingulum, uncinate fasciculum, fornix, sagittal stratum and corpus callosum. Analysis of diffusion indices based on region of interest(ROI) revealed that regions involved in motor and visual functions had lower FA and higher radial diffusivity in MS patients. The reduction of FA in the thalamus and corticospinal tract of MS++ patients was greater than MS+ patients. Conclusion: 1. The metabolic changes in hippocampus of VCI rats could be detected longitudinally by in vivo absolutely quantitative 1H-MRS. The reduction of NAA concentrations in hippocampus could predict the early decrease of cognitive function. The GABA, Glu concentrations of VCI rats decreased at the early stage and they were back to normal level after one month, which could reflect the pathophysiology changes of neuronal function. DTI could detect multiple brain areas of white damage which related to cognitive impairment. 1H-MRS and DTI may help to further investigate the pathogenesis of VCI. 2. The reduction of NAA concentrations of the left thalamus and the elevated Cho and GPC concentrations of the posterior cingulum, but the decreased Glx concentrations of the cingulum may help to diagnosis and differential diagnosis in VCI patients. The damage of white matter relate to cognitive function could be detected by quantitative DTI and may help to diagnosis of VCI. The exhibited lower FA values in the left anterior corona radiata, left superior corona radiate, bilateral cingulum and body of corpus callosum in VCI patients may help to differential diagnosis of AD. 3.The numerous microbleeds, especially in a lobar location, probably plays a pivotal role in cerebral small vessel disease accompanied with cognitive function impairment. The location and severity of CMB may be a potential biomarker for diagnosis of VCI. 4. DTI may be valuable for detecting MS-associated abnormalities in brain white matter with motor and visual impairment, as well as validating the value of DTI in detecting sub-visible damage with related to neurological dificits.