Analysis Of The Single Nucleotide Polymorphism Of ApoE Gene And DTI And Quantitive MTI Study With Patients In Subcortical Ischemic Vascular Dementia

Vascular dementia is the most common cause of dementia after Alzheimer's disease. As a clinical syndrome, VaD includes multiple subtypes based on vascular factors affecting the cognition. There is little effective treament for neurodegenerative dementia such as AD by now. However, VaD can be preventative, and most cases can get achievable therapeatic benefits after appropriate management. The early, accurate diagnosis of VaD has become more important for its prevention and treament. The term "VaD" focus on the extent and variety of cerebrovascular damage, and it's wide definition spectrum limits it's clinical application. In order to get criterial and optimum therapy scheme, the underlying vascular cause must be clearly identified before treament. However, VaD may be caused by a number of pathogenetic mechanisms and there is some degress of overlap with AD in the pathological features over 70-years-old individuals, which limit its study. VaD is categorized into subtypes according to the etiology and pathogenetic mechanisms, and the subcortical ischemic vascular dementia(SIVD) is one of the most common subtypes ,which results from small vessel disease with lacunes and white matter lesions. Although the principle of cognitive impairment between various VaD subtypes is not clear, SIVD is a more homogenous subtypes. To date we know the apolipoprotein E (APOE) ε 4 is associated with AD. Whether or not APOE ε 4 leads to a more malignant clinical course in VaD remains a matter of debate. To study the influence of APOEgenotype on risk for VaD will have important role for the prevention and treament of this condition. Though clinical researchs prove its diagnostic value, conventional MRI studies can not comfire the damage occurred and progression of SIVD in that high signal white matter lesions on T2WI which reflects varying degrees of damage from more subtle damage to severe neurona loss. Diffusion tensor MRI and magnetization transfer MRI allow microstructures of tissue to be imaged in vivo based on molecular diffusion of water and the transfer of magnetization between macromolecular protons and free water protons, and may correlate particularly strongly with cognitive status. They may detect the course of SIVD and its progression. To this day, many studies of SIVD were based on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and there was no report about DTI and quantitive MTI and their relationship with APOE genotype study with patients in SIVD.The current study had five primary aims. The first was to investigate the APOE polymorphism influence on SIVD and its relationship with clinical and imaging findings in order to ground early screening and early diagnosis in SIVD. The second aim was to determine whether SIVD-related white matter(WM) changes are ubiquitous thoughout the brain or are accelerated in prefrontal WM relative to WM associated with other cortical lobes. The third aim was to ask whether alterations in prefrontal WM are homogeneous throughout the lobe or are selective to particular regions. The fourth aim was to examine whether WM associated with primary sensory or motor circuits, such as occipital WM, was relatively preserved compared to WM in other areas. The fifth aim was to investigate the relationship between the DTI paremeters and magnetization tranfer rate(MTR) in different regions and APOE e 4.The research was performed in 34 SIVD patients and 26 age-matched nondemented older adults. All SIVD patients met the Research Criteria forSubcortical Vascular Dementia in Clinical Trails proposed by Erkinjutti in 2000. Dementia severity was assessed with Mini-Mental State Examination(MMSE). A Hachinski Ischemic Score(HIS) was also determined for each patient to exclude AD. The SIVD group aged 70.31±9.74, MMSE score was 20.15+1.56; HIS score was 10.35+2.46. The control group aged 64.78+10.37; MMSE score was 28.96+1.14. No significant difference of age and gender was found between two groups( P>0.05).Genomic DNA was prepared from blood samples. APOE genotyping was conducted using polymerase chain reaction and single nucleotide polymorphism analysis.All patients and controls received MRI examination within 3 months of phlebotomizing. MRI was done at a Philips Intera 3.0T MR scanner with SENSE-head coil. Conventional MR imaging included sagittal TSE-TjIR, axial and coronal TSE-TiIR and T2WI/DRIVE. DT images were acquired with an echo-planar imaging sequence(single shot) sensitized to diffusion by application of gradient pulse in 15 noncolinear directions. The matrix was 112x128, SENSE was added to phase encoding direction with SENSE factor of 2. The b value was 800. For each individual, regional FA(fractional anisotropy), PA(principal anisotropy, FAprj) and mean ADC measures were estimated from 13 regions of interests(ROI) in each hemisphere and within hyperintensities identified on T2WI and outside these lesions using Fiber Tracking 4.1V3 Beta software. Additionally, bivariate correlations were assessed using the Spearman correlation coefficient among DTI values, age, MMSE and APOE genotype.MT images was obtained with axial 3D-FFE [66\3.7, repetition time msec\echo time msec; flip angle, 18°; matrix, 224x256; slice thickness, 4mm]with and without off-resonance saturation pulse (Bl^O.SOx^T, BW=19.7HZ). SENSE factor at phase direction was 2. MT ratios(MTRs) were measured in six areas of normal-appearing white matter and thalamus and putamen and withinhyperintensities identified on T2WI and outside these lesions. Whole-brain magnetization transfer histograms were also analyzed. Bivariate correlations were assessed using the Spearman correlation coefficient among MTR values, HIS and MMSE.The results of APOE allele analysis were that, the e 3/ e 3 (47.1%-52%) was the most common genotypes, and next was ￡ 3/ ￡ 4 and ￡ 3/ ￡ 2, no ￡ 4/ ￡ 4 and￡ 2/ e 2 genotypes was observed in SIVD and controls. Participants were categorized ase4 allele positive (￡ 2/4, ￡ 3/4, ￡ 4/4 )ore4 allele neagnive( ￡ 2/2,e 2/3, ￡ 3/3). There was no significant difference between ApoE ￡ 4 allele between SIVD group and controls(p=0.085) although we note the trend of more ApoE e 4 allele (41.1%)in the SIVD group than control group(20%). ApoE e 4 allele showed negative association with mean MTR of whole brain. No associations of ApoE ￡ 4 allele with extent of white matter high signal and DTI parameters in each regions were observed.The DTI results were that: in addition to the areas of T2-weighted MR imaging hyperintense and perilesions areas, FA, PA and mean ADC differed significantly between SIVD group and control group in prefrontal white matter(WM), deep frontalWM, inferior frontal WM, medial orbitofrontal WM, anterior periventricular WM, genu and splenium of corpus callosum, anterior and posterior cingulated fiber tracts and thalamus. On the other hands, mean ADC values of temporal lobe WM, parietal lobe WM, occipital lobe WM and putamen significantly increased in SIVD group compared with control group. Significant positive correlation was found between MMSE and PA of posterior cingulated fibers tracts (r=0.412, P=0.015), negative correlation was found between MMSE and mean ADC values of genu of corpus callosum (r=-0.361, />=0.036); FA of temporal lobe WM showed positive correlation with degrees of education.The MTR analytic results were that: the mean MTR of whole-brain in control group was 35.78%±1.81(range from 32% to 38.90%). MTRs of right deep frontalWM, temporal lobe WM, thalamus and putamen were slightly greater than left side in both group. In addition, MTR of right prefrontal white matter was higher than left side in SIVD(P<0.05).There were significant MTR decrease in areas of T2-weighted MR imaging hyperintensity and matter adjacent to focal image abnormalities compared to normal white matter regions in SIVD patients; In addition, prefrontal white matter MTR was significantly declined in SIVD group compared with control group; The mean MTR of whole-brain was lower in SIVD group than in control group. MTR histogram peak height (MTR-HPH) showed significant decline in patients; The peak location of MTR histogram shifted to left in SIVDgroup compared to control group. The mean MTR of whole-brain were significantly negative correlated with Hachinski ischemic score(r=-0.417, p=0.001) and MMSE (r=0.416, p=0.001).From this research we concluded that:1. ApoE e 4 allele was associated with increased risk of hypertension and higher levels of serum cholesterol. The APOE e 4 allele does not increase the risk of SIVD.2. ApoE ￡ 4 carriers had lower MTR of whole brain. We may speculate on the possible mechanism underlying the findings that ApoE e 4 increases the risk of neuron loss, arteriolosclerosis and myelin loss, which results in decrease of MTR value of whole brain.3. The enhanced anisotropy in the posterior corpus callosum compared to genu in control group reflected by a higher FA and PA may due to a higher density of neuronal fibers, higher percentage of myelinated axons and thicker fiber diameter. Lower anisotropy in the genu may also be caused by a greater number of obliquely oriented fibers per voxel. The higher PA value and lower mean ADC value in the left hemisphere compared to right hemisphere may suggest that the left dominant hemisphere have more compact and extensive fibers.4. The higher FA and PA valeus of white matter in left hemispere of most brain regions compared to right side may suggest that left fibers are most vulnerable to subcortical ischemic vascular disease.The current study demonstrated regionally selective alterations in cerebral WM of SIVD group measured by FA and PA.The results showed significant decline in FA and PA in prefrontal WM, the anterior periventricular WM and occipital WM in SIVD group. The mean ADC value increased and its FA value showed no significant decrease. There were no regionally selective alterations in prefrontal WM. The microstructural tissue damages were present in the deep frontal WM, medial orbital frontal WM, inferior frontal WM. The current study also demonstrated the decreased anisotropy in the anterior and posterior corpus callosum and increased mean ADC in SIVD group, the assication between MMSE score and mean ADC in the anterior corpus callosum. These findings suggest that WM alterations varies throughout the brain and that particular fiber populations within prefrontal region and corpus callosum are most vulnerable to small vasular disease injury. These results may be helpful for early and accurate prevention and treatment of SIVD, and for preventing or reversing cognitive decline.5. The decreased FA and PA and increased mean ADC in thalamus and mean ADC in putamen in SIVD group suggest that the changes of thalamus anisotropy and diffusivity may be simple and reliable methods for evaluating the injury of thalamocortical pathways secondary to ischemic white matter damage.6. We first discovered that the decreased FA and PA, increased mean ADC of posterior cingulate fiber tracts, and the FA value of posterior cingulate fiber tracts was associated with MMSE in SIVD group. The posterior cingulate is an important part of the Papze-circuit, which subsumes necessary neural substrates of episodic memory. This finding hints SIVD-related myelin...