Alzheimer病及轻度认知障碍的MRS、DWI和MTI随访研究及其与ApoE基因型关系的研究
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摘要
阿尔茨海默病(Alzheimer disease,AD)是严重影响老年人的生活质量、发生在老年期及老年前期的以进行性痴呆为主要特征的大脑退行性病变,早期表现为近期记忆力下降,随后逐渐出现推理、判断、计算、定向能力的进行性下降。AD的病理学特征为老年斑(淀粉斑)、神经纤维缠结及神经元缺失。AD的确诊需要靠脑组织活检或尸检,AD生前诊断主要依赖临床检查和神经心理学测试,由于缺乏客观的生物学标志,其正确诊断率不高,因此有必要提供可能的神经影像学标志以对AD、甚至对早期AD作出正确的诊断。以往的MR研究主要集中在对海马及其周围结构形态学的研究上,如海马与内嗅皮层体积测量及T2(横向弛豫时间)的测定,当海马及内嗅皮层出现明显的形态学改变时,AD病程往往已进展到较晚期;而且,海马及内嗅皮层的形态学改变并非AD的特异性改变,在其它一些疾病,如颞叶癫痫、精神分裂症时也可见到类似的改变。因此,不能单纯依赖MR体积测量来诊断早期AD,还要结合其它检查方法。本研究中将一些新的磁共振技术——磁共振波谱成像(MRspectroscopy,MRS)、扩散加权成像(diffusion-weighted imaging,DWI)及磁化传递成像(magnetization transfer imaging,MTI)用于AD、MCI的诊断中。
Alzheimer disease(AD) was a neurodegenerative disorder characterized by progressive dementia occuring in elder stage or pre-elder stage,and influenced the living quality of elders seriously. In the early stage of AD, the patients' short memory was worsen,then gradually decreased of long memory,reasoning,judging, counting and directional abilities. Pathologically, AD was characterized by the appearance of extracellular senile(amyloid) plaques,intracelular neurofibrillary tangles and nerve cells death or lost. Accurate diagnosis of AD was dependent on biopsy or autopsy, diagnosis before death was mainly dependent on clinical examinations and neuro-psychological tests,but because of lack of objective biological mark,the accuracy of diagnosis was not high,so it's necessary to offer some radiological marks to correctly diagnose AD,and even mild AD. In the past, MR studies focused on the hippocampi and surrounding structure were morphologic studies, such as MR measurement of volum or transverse relaxation time(T2) of hippocampi and entorhinal cortex. But when there were obvious changes, it indicated that the course of AD was already in late or terminal stage.Otherwise morphologic changes of hippocampi and entorhinal cortex were not characteristic appearances of AD,they can also be seen in other diseases,such as temporal epilepsy, schizophrenia.So diagnosis of early stage AD cann't only dependent on MR volum measurement,other methods should be applyed.We
applied some new MR techniques,such as MR spectroscopy(MRS),diffiision weighted imaging(DWI) and magnetization transfer imaging(MTI) to diagnose AD,mild cognitive impairment(MCI) in this study.Part I Study of MRS ,DWI, MTI in AD and MCIObjective To study the changes of metabolites (such as NAA/Cr,Cho/Cr and mI/Cr,detected by MRS), the appearent diffusion coefficient(ADC,detected by DWI), and the magnetization transfer ratio (MTR,detected by MTI) of AD patients, MCI patients,and compare with normal cognitive(NC) volunteers, to find the radiological changes of AD and MCI patients. Methods DWI,MRS and MTI were obtained by the same sites and same protocols in 23 patients with AD,50 patients with MCI,and 18 voluteers, regions of interest(ROI) were drawn to compare the NAA/Cr,Cho/Cr, mI/Cr,ADC,and MTR of bilateral hippocampi and temporoparietal regions. Result ?The ADC, NAA/Cr, Cho/Cr,ml/Cr,and MTR value of left and right hippocampi,temporoparietal region had no different among AD,MCI and NC group (P>0.05) ;?Study of DWI:the ADC of hippocampi among AD,MCI and NC groups were decreased one by one(P<0.05),ADC of temporoparietal region between AD-NQAD-MCI groups were significently different (P<0.05),but not different between MCI-NC group(P>0.05); ?Study of MRS: the NAA/Cr and ml/Cr of hippocampi among AD,MCI and NC groups were significently different (P<0.05); NAA/Cr and ml/Cr of temporoparietal region between AD-MCI, AD-NC groups were significently different(P<0.05); NAA/Cr, ml/Cr of temporoparietal region between MCI-NC group and Cho/Cr of hippocampi and temporoparietal region among three groups were not different(P>0.05);@Study of MTI:the MTR of hippocampi between AD-NC,AD-MCI were significently different(P<0.05);but that of hippocampi
between MCI-NC and that of temporoparietal region among three groups were not different(P>0.05). Conclusion DWI ,MRS and MTI of hippocampi among AD,MCI and NC groups significently different ,and can be used to reflect micropathology of AD. ?ADC ml/Cr increased and NAA/Cr decreased in hippocampi can be used to make the diagnosis of MCI; while accompanying same changes in temporoparietal region can be used to make the diagnosis of AD;? ml/Cr increase in hippocampi was more sensitive than NAA/Cr decrease when they were used to diagnose AD;(3)There was no MTR decrease in hippocampi in MCI phase, that change appeared only when the disease progressed to AD.Part II Longitudinal study of MRS ,DWI ,MTI in AD and MCIObjective To study changes of MRS,DWI and MTI in AD,MCI patients during one year course, and compare the MRS,DWI and MTI changes of those progressed to AD with those not progressed to AD. Methods 15 of 23 AD patients,40 of 50 MCI patients,and 12 of 18 NC agreed to return for a second MRS,DWI,and MTI studies one year later, protocols and sites were same as the first study, and compared the ADC, NAA/Cr -. Cho/Crs ral/Cr and MTR changes of the same patients during the two exams; Compared the ADC, NAA/Cr ^ Cho/Cr ^ ml/Cr and MTR changes of those MCI progressed to AD with those not progressed to AD. Result Compare changes of the same patient in twice exams: ?Study of MRS:changes of NAA/Cr in AD group and NC group weren't significently different (P>0.05); Only decrease of ml/Cr in hippocampi in MCI patients was significently different(P<0.05). ?Study of DWI and MTI:Changes of ADC and MTR in both hippocampi and temporoparietal region in AD, MCI and NC weren't significently different (P>0.05). Compare those progressed
to AD and those still MCI: (DStudy of MRS:NAA/Cr in hippocampi was significently different(P<0.05) between the two groups, that of temporoparietal region and ml/Cr changes of both hippocampi and temporoparietal region weren't different(P>0.05); ?Study of DWI and MTI.MTR and ADC of both hippocampi and temporoparietal region show no diffierence(P>0.05) between two groups. Conclusion ?In the progress of MCI to AD, the earliest change of hippocampi was increase of ml/Cr, next change was decrease of NAA/Cr; ?In longituadinal study of MCI, ml/Cr increase and NAA/Cr decrease in hippocampi, but not in temporoparietal regions, can indicate the progress of MCI to AD, and can be used to reflect the progress of MCI.(3)When appeared ml/Crs increase and NAA/Cr decrease in temporoparietal region, it indicated that the disease of AD was already progressed to some degree.Part III Study Apo E gene of AD,MCI and their relationship with MRS,DWI,MTIObjective To study Apolipoprotein E e 4(ApoE e 4) gene type of AD, MCI and NC, and study the relationship of ApoE e 4 gene and the changes of MRS, DWI, MTI. Methods Collected 5 ml peripheral venous blood of each of 15 AD, 40 MCI and 12 NC and extracted genome DNA. Using genome DNA as template, ApoE M gene was replicated by polymerase chain reaction (PCR), then PCR fragments were sequenced to examine the ApoE e 4 gene of AD, MCI and NC. Result ?Among three groups, ApoE e 4 genetic type were significently different (%2=1. 397, P=0. 025); positive cases in AD group were maximum and those in NC group were minimum; ?The rate of
Alzheimer disease(AD) was a neurodegenerative disorder characterized by progressive dementia occuring in elder stage or pre-elder stage,and influenced the living quality of elders seriously. In the early stage of AD, the patients' short memory was worsen,then gradually decreased of long memory,reasoning,judging, counting and directional abilities. Pathologically, AD was characterized by the appearance of extracellular senile(amyloid) plaques,intracelular neurofibrillary tangles and nerve cells death or lost. Accurate diagnosis of AD was dependent on biopsy or autopsy, diagnosis before death was mainly dependent on clinical examinations and neuro-psychological tests,but because of lack of objective biological mark,the accuracy of diagnosis was not high,so it's necessary to offer some radiological marks to correctly diagnose AD,and even mild AD. In the past, MR studies focused on the hippocampi and surrounding structure were morphologic studies, such as MR measurement of volum or transverse relaxation time(T2) of hippocampi and entorhinal cortex. But when there were obvious changes, it indicated that the course of AD was already in late or terminal stage.Otherwise morphologic changes of hippocampi and entorhinal cortex were not characteristic appearances of AD,they can also be seen in other diseases,such as temporal epilepsy, schizophrenia.So diagnosis of early stage AD cann't only dependent on MR volum measurement,other methods should be applyed.We
applied some new MR techniques,such as MR spectroscopy(MRS),diffiision weighted imaging(DWI) and magnetization transfer imaging(MTI) to diagnose AD,mild cognitive impairment(MCI) in this study.Part I Study of MRS ,DWI, MTI in AD and MCIObjective To study the changes of metabolites (such as NAA/Cr,Cho/Cr and mI/Cr,detected by MRS), the appearent diffusion coefficient(ADC,detected by DWI), and the magnetization transfer ratio (MTR,detected by MTI) of AD patients, MCI patients,and compare with normal cognitive(NC) volunteers, to find the radiological changes of AD and MCI patients. Methods DWI,MRS and MTI were obtained by the same sites and same protocols in 23 patients with AD,50 patients with MCI,and 18 voluteers, regions of interest(ROI) were drawn to compare the NAA/Cr,Cho/Cr, mI/Cr,ADC,and MTR of bilateral hippocampi and temporoparietal regions. Result ?The ADC, NAA/Cr, Cho/Cr,ml/Cr,and MTR value of left and right hippocampi,temporoparietal region had no different among AD,MCI and NC group (P>0.05) ;?Study of DWI:the ADC of hippocampi among AD,MCI and NC groups were decreased one by one(P<0.05),ADC of temporoparietal region between AD-NQAD-MCI groups were significently different (P<0.05),but not different between MCI-NC group(P>0.05); ?Study of MRS: the NAA/Cr and ml/Cr of hippocampi among AD,MCI and NC groups were significently different (P<0.05); NAA/Cr and ml/Cr of temporoparietal region between AD-MCI, AD-NC groups were significently different(P<0.05); NAA/Cr, ml/Cr of temporoparietal region between MCI-NC group and Cho/Cr of hippocampi and temporoparietal region among three groups were not different(P>0.05);@Study of MTI:the MTR of hippocampi between AD-NC,AD-MCI were significently different(P<0.05);but that of hippocampi
between MCI-NC and that of temporoparietal region among three groups were not different(P>0.05). Conclusion DWI ,MRS and MTI of hippocampi among AD,MCI and NC groups significently different ,and can be used to reflect micropathology of AD. ?ADC ml/Cr increased and NAA/Cr decreased in hippocampi can be used to make the diagnosis of MCI; while accompanying same changes in temporoparietal region can be used to make the diagnosis of AD;? ml/Cr increase in hippocampi was more sensitive than NAA/Cr decrease when they were used to diagnose AD;(3)There was no MTR decrease in hippocampi in MCI phase, that change appeared only when the disease progressed to AD.Part II Longitudinal study of MRS ,DWI ,MTI in AD and MCIObjective To study changes of MRS,DWI and MTI in AD,MCI patients during one year course, and compare the MRS,DWI and MTI changes of those progressed to AD with those not progressed to AD. Methods 15 of 23 AD patients,40 of 50 MCI patients,and 12 of 18 NC agreed to return for a second MRS,DWI,and MTI studies one year later, protocols and sites were same as the first study, and compared the ADC, NAA/Cr -. Cho/Crs ral/Cr and MTR changes of the same patients during the two exams; Compared the ADC, NAA/Cr ^ Cho/Cr ^ ml/Cr and MTR changes of those MCI progressed to AD with those not progressed to AD. Result Compare changes of the same patient in twice exams: ?Study of MRS:changes of NAA/Cr in AD group and NC group weren't significently different (P>0.05); Only decrease of ml/Cr in hippocampi in MCI patients was significently different(P<0.05). ?Study of DWI and MTI:Changes of ADC and MTR in both hippocampi and temporoparietal region in AD, MCI and NC weren't significently different (P>0.05). Compare those progressed
to AD and those still MCI: (DStudy of MRS:NAA/Cr in hippocampi was significently different(P<0.05) between the two groups, that of temporoparietal region and ml/Cr changes of both hippocampi and temporoparietal region weren't different(P>0.05); ?Study of DWI and MTI.MTR and ADC of both hippocampi and temporoparietal region show no diffierence(P>0.05) between two groups. Conclusion ?In the progress of MCI to AD, the earliest change of hippocampi was increase of ml/Cr, next change was decrease of NAA/Cr; ?In longituadinal study of MCI, ml/Cr increase and NAA/Cr decrease in hippocampi, but not in temporoparietal regions, can indicate the progress of MCI to AD, and can be used to reflect the progress of MCI.(3)When appeared ml/Crs increase and NAA/Cr decrease in temporoparietal region, it indicated that the disease of AD was already progressed to some degree.Part III Study Apo E gene of AD,MCI and their relationship with MRS,DWI,MTIObjective To study Apolipoprotein E e 4(ApoE e 4) gene type of AD, MCI and NC, and study the relationship of ApoE e 4 gene and the changes of MRS, DWI, MTI. Methods Collected 5 ml peripheral venous blood of each of 15 AD, 40 MCI and 12 NC and extracted genome DNA. Using genome DNA as template, ApoE M gene was replicated by polymerase chain reaction (PCR), then PCR fragments were sequenced to examine the ApoE e 4 gene of AD, MCI and NC. Result ?Among three groups, ApoE e 4 genetic type were significently different (%2=1. 397, P=0. 025); positive cases in AD group were maximum and those in NC group were minimum; ?The rate of
引文
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2. Fdedenberg RM. Dementia:one of the greatest fears of aging.Radiology.2003;229:632-635
3. Wisniewski HM,Wegiel J. The neuropathology of Alzheimer's disease. Neuroimaging Clin North Am.1995;5:45-57.
4. Bigler ED,Lowry CM,Anderson CV, et al. Dementia, quantitative neuroimaging, and apolipoprotein E genotype. AJNR,2000,21(10): 1857-1868
5. Chui HC,Tierney M,Zarow C. Neuropathologic diagnosis of Alzheimer disease: interrater reliability in the assessment of senile plaques and neurofibrillary tangles. Alzheimer Dis Assoc Disord. 1993 Spring;7(1):48-54
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