【作者】 马文；

【导师】 史丽；

【作者基本信息】 山东大学 ， 临床医学（耳鼻咽喉科学）（专业学位）， 2016， 博士

【摘要】 老年性聋(presbycusis,PC)是老年人群中发病率较高的感觉功能障碍之一。老年性聋的主要临床表现为:以高频听力下降为主的感音神经性听力损失,以及言语识别能力的下降,特别在噪声环境下。老年性聋会对老年人的生活质量造成严重影响,并可以导致抑郁症等精神疾病,从而给社会带来沉重的压力。我国的大样本调查数据显示,老年人听力致残的首要原因是老年性聋。随着我国人口老龄化的加速,老年性聋患者的人数将会逐年增加。所以,深化研究老年性聋的发病机制,为老年性聋的有效防治和疗效监控提供理论支持,具有重要的临床意义和社会价值。以往,耳蜗是老年性聋研究的重点,但是PC患者主要表现在噪声环境下言语识别能力的降低。而且,即使助听器补偿听力到正常范围后,PC患者言语识别能力的降低依然可以存在。这些都提示听觉皮层对声音信号的处理障碍。近期研究表明,PC不只是耳蜗病变的结果,更主要取决于中枢听觉系统的改变。但是,目前对老年性聋患者中枢听觉系统,特别是听觉皮层的研究较少。所以,PC的中枢发病机制未被完全阐明。以往由于缺乏有效的测量技术,我们无法研究老年性聋患者活体听觉皮层的代谢改变以及听觉神经通路的受损情况。神经影像学的发展,尤其是功能磁共振成像(Functional Magnetic Resonance Imaging,fMRI)技术的不断进步为研究老年性聋提供了有力工具。磁共振波谱(Magnetic Resonance Spectroscopy,MRS)是目前唯一可以在无创状态下对活体组织器官内代谢物含量进行定量分析的新技术;而弥散张量成像(Diffusion tensor imaging,DTI)是一项可以检测活体脑白质完整性的磁共振新技术。因此,本研究将联合以上两种技术深化研究老年性聋的中枢发病机制,为诊断和治疗老年性聋提供影像学标记,具有重要的临床意义。论文包括两个部分,摘要如下:第一部分:利用磁共振波谱检测老年性聋患者听觉皮层GABA含量的改变目的:γ-氨基丁酸(y-amino butyric acid,GABA)是重要的抑制性神经递质,主要存在于中枢神经系统。动物研究发现,老年性聋模型小鼠下丘、蜗神经核和听觉皮层的GABA能神经递质系统存在功能紊乱。但是,利用常规磁共振波谱(MRS)技术无法准确检测人脑GABA含量。目前,一种新的磁共振波谱编辑技术——MEGA-PRESS序列解决了这一难题,并己成功在健康志愿者、神经疾病和精神疾病中检测了人脑GABA含量。因此,在这部分研究中我们将利用MEGA-PRESS序列检测老年性聋患者和健康志愿者听觉皮层的GABA含量,分析组间GABA含量是否存在差异,并探讨听觉皮层GABA含量与听学功能测试结果的关系。材料和方法:本研究招募16名老年性聋患者(5男/11女,平均年龄63.1±2.6岁,右利手)和20名年龄性别与其匹配的健康志愿者(6男/14女,平均年龄62.5 ±2.3岁,右利手)。应用纯音听力测试(0.125-8 KHZ)和声导抗测试评估所有受试者的听觉功能。利用飞利浦3.0T磁共振扫描仪对所有受试者进行MEGA-PRESS扫描。感兴趣区以双侧颞横回(Heschl’s gyrus,HG)为中心,大小为40×30×30 mm3。结果:患者组的GABA含量明显低于健康对照组(左侧听觉皮层感兴趣区:p =0.002;右侧听觉皮层感兴趣区:p=0.008)。患者组的GABA含量与PTA值呈明显负相关(r=-0.57,p=0.02)。健康对照组的GABA含量与PTA值也呈负相关,但没有统计学意义(r=-0.40,p=0.08)。所有受试者的GABA含量与PTA值呈明显负相关(r=-0.72,p<0.001)。结论:本部分研究发现老年性聋患者听觉皮层的GABA含量明显降低;而且,老年性聋患者听觉皮层的GABA含量与PTA值明显负相关。因此,我们认为老年性聋患者中枢听觉系统存在GABA能神经传递的紊乱,GABA能神经递质系统有希望成为治疗老年性聋的一个潜在靶点。第二部分:利用基于体素分析的弥散张量成像检测老年性聋患者脑白质的改变目的:老年性聋是一种常见的老年疾病,表现为双耳听力进行性下降,以高频听力下降为主,并伴言语识别率明显降低。近期研究者利用基于感兴趣区(region of interest,ROI)的分析方法——神经纤维示踪技术,发现老年性聋患者听觉通路的结构连接存在改变。但是,DTI神经纤维示踪技术存在一些局限性。首先,听觉通路的重建易被视觉通路所干扰,目前仍没有检验纤维重建结果的"金标准",尤其是用于检验纤维交叉区域的方法。其次,基于ROI的分析方法对于局部解剖结构变化的敏感性较低,尤其是这种变化仅发生于ROI的其中一部分区域时。因此,基于体素的分析方法在发现微细病变方面比基于ROI的分析方法更有优势。因此,本研究拟应用基于体素分析的扩散张量成像,在全脑探讨老年性聋患者白质完整性的改变。材料与方法:本研究招募15名老年性聋患者(5男/10女,平均年龄63.2 ± 2.6岁,右利手)和14名年龄性别与其匹配的健康志愿者(6男/8女,平均年龄62.4± 2.0岁,右利手)。应用纯音听力测试(0.125-8 KHZ)和声导抗测试评估所有受试者的听觉功能。利用飞利浦3.0T磁共振扫描仪对所有受试者进行扩散张量成像扫描。通过正交变换计算出DTI数据每个像素点的描述参数,包括三个特征值与三个特征向量,以及FA、MD、DA和DR。应用diffeomap将目标图像配准至标准模板,然后对包括FA、MD、DA和DR几种类型的参数图像进行了基于体素的组间比较。结果:相比年龄和性别匹配的健康志愿者,老年性聋患者右侧颞横回区域的DA值增加;右侧颞横回和左侧额下回区域的DR值增高;右侧额下回、右侧角回,以及右侧颞极、颞中回区域(属于听辐射区域)的FA值减低;右侧颞横回和左侧额下回区域的MD值增加。结论:本研究应用基于体素分析的扩散张量成像,揭示了老年性聋患者听觉功能区和语言功能区存在脑白质完整性的改变,为预防和治疗老年性聋提供了影像学标记。而且,基于体素的分析方法在老年性聋患者的应用,为以往基于ROI的分析方法提供了另外一种思路。更多还原

【Abstract】 Presbycusis(PC)is the most common sensory deficit in the ageing population.Presbycusis is most often characterized by a progressive hearing loss at high frequencies and a poor speech discrimination,especially in a noisy environment.Presbycusis may cause serious influence to the quality of life of the elderly,and can lead to depression and other psychiatric disorders,which brings heavy pressure to the society.A large-scale sample study of our country has showed that presbycusis is the principal cause of hearing disability in the elderly.With the acceleration of population aging in our country,the number of patients with presbycusis will increase year by year.Therefore,it is crucial to investigate the central pathogenesis in presbycusis and provide the theoretical basis for preventing,treating and monitoring presbycusis.Hypofunction of the inner ear is the main reason for the peripheral component of presbycusis.However,poor speech discrimination and deteriorated temporal sound processing reflect a possible central component of presbycusis.Moreover,many studies have showed the existence of a central component of presbycusis.However,the central pathogenesis in presbycusis still remain unclear.In the past,because of the lack of effective measurement technology,it was very difficult for us to study the changes of metabolism in auditory cortex and the changes of auditory nerve pathways in patients with presbycusis in vivo.The development of neuroimaging,especially functional magnetic resonance imaging(fMRI),provides us a powerful tool to investigate presbycusis.Magnetic resonance spectroscopy(MRS)is a noninvasive technique that permits the estimation of the concentrations of various metabolites in the human brain in vivo.A widely used technique,diffusion tensor imaging(DTI),has been considered as the most effective method for characterizing white matter organization.Therefore,this study will combine two kinds of fMRI technology to investigate the central pathogenesis in presbycusis and provide the theoretical basis for preventing,treating and monitoring presbycusis.This study contains two parts,as follows:Part 1.Decreased auditory GABA+ concentrations in presbycusis demonstrated by edited magnetic resonance spectroscopyBACKGROUND AND PURPOSE:Gamma-aminobutyric acid(GABA)is the main inhibitory neurotransmitter in the central auditory system.Altered GABAergic neurotransmission has been found in both the inferior colliculus and the auditory cortex in animal models of presbycusis.Edited magnetic resonance spectroscopy(MRS),using the MEGA-PRESS sequence,is the most widely used technique for detecting GABA in the human brain.However,to date there has been a paucity of studies exploring changes to the GABA concentrations in the auditory region of patients with presbycusis.MATERIALS AND METHODS:In this study,sixteen patients with presbycusis(5 males/11 females,mean age 63.1± 2.6 years)and twenty healthy controls(6 males/14 females,mean age 62.5 ± 2.3 years)underwent audiological and MRS examinations.Pure tone audiometry from 0.125 to 8 kHz and tympanometry were used to assess the hearing abilities of all subjects.The pure tone average(PTA;the average of hearing thresholds at 0.5,1,2 and 4 kHz)was calculated.The MEGA-PRESS sequence was used to measure GABA+ concentrations in 4 x 3×3 cm3 volumes centered on the left and right Heschl’s gyri.RESULTS:GABA+ concentrations were significantly lower in the presbycusis group compared to the control group(left auditory regions:p = 0.002,right auditory regions:p＝0.008).Significant negative correlations were observed between PTA and GABA+ concentrations in the presbycusis group(r =-0.57,p = 0.02),while a similar trend was found in the control group(r =-0.40,p = 0.08).CONCLUSIONS:These results are consistent with a hypothesis of dysfunctional GABAergic neurotransmission in the central auditory system in presbycusis and suggest a potential treatment target for presbycusis.Part 2.Diffusion tensor imaging Analysis of Presbycusis Using Voxel-Based AnalysisBACKGROUND AND PURPOSE:Presbycusis is the most common sensory deficit in the aging population.A recent study reported using a DTI-based tractography technique to identify a lack of integrity in a portion of the auditory pathway in patients with presbycusis.The aim of our study was to investigate the white matter pathology of patients with presbycusis by using a voxel-based analysis that is highly sensitive to local intensity changes in DTI data.MATERIALS AND METHODS:Fifteen patients with presbycusis and 14 age-and sex-matched healthy controls were scanned on a 3T scanner.Fractional anisotropy,mean diffusivity,axial diffusivity,and radial diffusivity were obtained from the DTI data.Intergroup statistics were implemented on these measurements,which were transformed to Montreal Neurological Institute coordinates by using a nonrigid image registration method called large deformation diffeomorphic metric mapping.RESULTS:Increased axial diffusivity,radial diffusivity,and mean diffusivity and decreased fractional anisotropy were found near the right-side hearing-related areas in patients with presbycusis.Increased radial diffusivity and mean diffusivity were also found near a language-related area(Broca area)in patients with presbycusis.CONCLUSIONS:Our findings could be important for exploring reliable imaging evidence of presbycusis and could complement an ROI-based approach.更多还原