脑白质高信号（white matter hyperintensities，WMH）常见于老年人的T2加权像中，因为与年龄的密切关系，它又被称作年龄相关的白质改变（age-related white matter changes，ARWMC）或者脑白质病变（white matter lesions，WML）。WML在人群中的患病率报道从11%到96%不等。它的病理变化包括髓鞘苍白化、脱髓鞘、轴突丢失、胶质增生等等。这些白质改变常见于深部白质，且往往伴随着小血管疾病。病理研究认为小血管疾病引起了深部白质的慢性低灌注以及血脑屏障的中断，使得血浆慢性渗漏到白质中。除了与正常老化有关，还与中风、多发性硬化、血管性痴呆（Vascular dementia, VaD）、阿尔茨海默病（Alzheimer’s disease，AD）等疾病密切相关。WML会增加痴呆、中风以及死亡的风险，也与AD、轻度认知障碍（mild cognitive impairment, MCI）的转化有关。很多研究在考察了WML与认知能力之间的关系后发现，不管是在一般人群中，还是在患有MCI、AD、其它脑血管疾病的人群中，WML都会加速总体认知能力、执行功能、加工速度、记忆能力的下降。关于WML与AD之间关系的潜在机制有很多猜测。第一个假说是WML引起皮层下神经网络的直接受损，这一假说的证据来自于WML中执行功能的明显下降，认为这种认知障碍源自于白质损伤引起的皮层-皮层下环路的失连接。第二种假说是，WML会与AD的病理过程产生交互作用，加重患者的临床表现以及病情发展。第三种假说认为，WML对痴呆的作用是独立于血管性风险因素或者脑缺血性对皮层的损伤的，一些研究发现在控制了血管性风险因素、中风发病率、梗塞等因素过后，WML与AD之间的关系仍然显著。还有一些研究认为，皮层萎缩可以通过淀粉样脑血管病或者沃勒变性的过程反向作用于WML，但是奥地利中风预防研究的数据显示非痴呆老年人中WML的进展是早于灰质体积萎缩的，否认了这一反向因果假说。总之，关于WML影响认知能力的神经机制还充满了争议。 我们认为出现这些争议的一个主要原因是，过去的研究几乎都集中在中重度WML患者中，此阶段的WML早已混杂了中风、AD、血管性痴呆等其它复杂的疾病因素，很难厘清中重度WML中显示出的病理改变是来自于WML本身，还是来自于其它的混杂因素。过去的研究还长期忽视了轻度WML的影响，错过了早期干预防治的最佳时期，也忽视了轻度WML这个相对“单纯”的疾病研究模型在揭示WML病理神经机制中的重要价值。随着磁共振成像技术（magnetic resonance imaging, MRI）在临床研究中的广泛应用，不少研究开始从神经影像学角度对WML的神经机制进行解读，但往往是基于某一种模态的结果，剥离了脑白质病变中结构与功能之间的重要联系，也很少从大脑网络的水平来解读WML中的认知障碍。总的来说，WML损伤大脑与认知的机制还是未知的，现有的证据也都比较片面且存在争议。因此我们把握轻度WML在病理单纯性上的优势，首次采用了全面的神经心理学测验结合多模态磁共振成像技术，探索了轻度脑白质病变对认知能力的损伤及其神经机制，系统地从全脑损伤模式、重点损伤脑区、结构连接功能连接共变、对靶网络的影响等几方面，层层深入地对轻度WML的脑损伤机制进行了解读。本研究共包含了4项具体研究。 1、轻度脑白质病变对认知功能的影响。研究被试来自于北京市老年脑健康计划数据库（Beijing Aging Brain Rejuvenation Initiative, BABRI）。通过影像科医生诊断筛选出了轻度WML患者51名，以及49名年龄、性别、教育程度均匹配的健康对照被试，对这100名被试的人口学信息以及神经心理测验得分进行统计分析，发现了轻度WML组与正常对照组相比，在总体认知能力、执行功能以及情景记忆领域出现了下降。表明早在WML的早期阶段就出现了轻微但是可察觉的认知能力的下降。2、轻度脑白质病变全脑结构和功能的异常改变模式。我们结合基于体素的形态学分析（voxel-based morphometry analysis, VBM）、基于纤维束示踪的空间统计方法（tract-based spatial statistics, TBSS）、静息态低频振荡幅度（amplitude of low frequency fluctuation analysis, ALFF）三种模态及三种不同的方法对轻度WML患者的全脑结构、功能损伤进行了初步的定位。扩散张量成像手段探测到从额叶投射出来的大部分白质纤维束出现了部分各向异性值（fractional anisotropy, FA）的下降与平均扩散率值（mean diffusivity, MD）的升高；在这些白质微结构出现损伤的脑区，静息态神经自发活动出现了升高，但是两组的全脑灰质体积却没有显著差异；同时，静息态ALFF值与执行功能、情景记忆的认知测验得分相关。说明轻度WML中额叶脑区明显的损伤可能是认知功能下降的原因。 3、轻度脑白质病变白质结构连接改变与静息态功能网络的关系研究。我们对轻度WML受损认知领域相关的默认网络、双侧额顶网络进行了研究。轻度WML患者默认网络后部脑区出现了功能连接的升高，前额叶的功能连接出现了下降，轻度WML默认网络中左侧背外侧前额叶的功能连接与左侧上额枕束、胼胝体白质完整性相关，右侧楔前叶功能连接与胼胝体压部白质连接相关。轻度WML的右侧额顶网络中，顶上小叶的功能连接出现了下降，而前额叶脑区功能连接出现了升高，这些改变的功能连接也发现了与连接额顶网络的上纵束白质完整性改变之间的相关。最后我们还发现了楔前叶功能连接上升与记忆得分下降之间的相关。揭示了轻度WML白质病变、功能网络、认知能力三者之间的关系。4、轻度脑白质病变不同工作记忆负荷下的脑激活改变。工作记忆是执行功能的子成分，它的损伤也能影响情景记忆的表现，于是我们又着重考察了轻度WML患者在工作记忆任务下脑激活模式。我们发现轻度WML在n-back工作记忆任务中的行为学成绩显著低于健康对照组，显示出了工作记忆加工成分的损伤。我们还发现随着任务负荷的升高，两组老年被试的大脑激活程度都出现了先上升后下降的趋势，且大脑激活分布于额顶网络的典型脑区。而在1-back、2-back两个任务下，轻度WML患者的额叶脑区出现了过激活，我们认为这种过激活是一种神经代偿机制。 综合上述结果，本研究发现脑白质病变在早期即已经开始对执行功能、情景记忆等认知能力产生损害，而WML早期对额叶的损伤非常明显且突出，这与额叶老化假说认为的额叶受年龄影响最大的观点一致。WML引起的认知功能的下降可能归结于额叶与其它皮层、皮层下结构之间的失连接，且额叶脑区在静息态与任务态功能MRI下都出现了大脑活动代偿性的升高；白质结构连接的中断进一步引起了功能网络失连接，阻碍了大脑网络中的信息传递效率，WML最终表现出与AD类似的“失连接综合征”。 我们的研究强调了研究轻度WML的重要临床意义。考虑到WML在中风、轻度认知障碍、痴呆疾病中的关键作用，甚至是可以作为预测AD的生物影像学标记物，我们对轻度WML脑损伤神经机制的系统研究可以更加深入全面地揭示WML的致病机制，对未来防治WML进展以及与之相关的神经退行性疾病都具有非常重要的理论价值和临床意义。

White matter lesions (WML) or white matter hyperintensities (WMH) are frequently seen on T2-weighted scans of the brain in older people. As WMH is highly related to age, it is also called age-related white matter changes (ARWMC). In the general population, it is studied that the prevalence of WML ranges from 11% to 96%. The pathological findings in regions of WML including myelin pallor, mild gliosis， widened perivascular space and tissue rarefaction which is associated with loss of myelin and axons are reported consistently. These lesions are typically located in deep white matter, which are usually accompanied with small vessel disease. The affected vessels are presumed to induce the lesions in deep white matter by chronic hypoperfusion of the white matter and disruption of the blood-brain barrier which lead to chronic leakage of plasma into the white matter. In addition to normal aging, WML are also associated with stroke, multiple sclerosis, Alzheimer’s disease (AD) and vascular dementia (VaD). WML predicts that the risk of dementia, stroke and even death is increasing. WML may predict the eventual conversion to mild cognitive impairment and dementia. Many researches have widely investigated that WML and decreased cognitive performance including global cognitive performance, executive function, psychomotor speed and memory are correlative. Several potential mechanisms were hypothesized to interpret the relationship between WML and dementia. Firstly, evidence from the executive function decline indicates WML damages the subcortical neural networks through cortical-subcortical circuits. Secondly, WML could interact with AD pathological changes and aggravate the clinical presentation. The third hypothesis holds that WML affects AD independently of vascular factors or cortical injury. Other researchers suggest that cortical atrophy could reversely lead to WML through amyloid and angiopathy or wallerian degeneration. However, the underlying neural mechanism of how WML affects the cognition is still controversial.One possible reason is, most existing studies of WML have focused on severe WML, but mild WML, which are clinically and fundamentally significant, have been largely neglected. There are a lot of confounding factors in severe WML, like stroke, AD and VaD. One can hardly clarify the effects are from these diseases or WML itself. Mild WML may offer a relatively "pure"model to study WML, and should be given attention in clinical practice. As magnetic resonance imaging (MRI) has been widely used in clinical research, most studies explored the neural mechanism of WML based on one imaging method without considering the relationship between brain structure and function. And few studies interpret cognitive impairment in WML from the network level. The underlying neural mechanism of cognitive decline in WML remains unclear, current evidence is partial and controversial. We combined serial neuropsychological tests with multimodal MRI to investigate the cognitive decline and underlying mechanism in mild WML, taking advantages of its ―pure‖ feature. We conducted more in-depth research including brain injury patterns, hub regions, co-variation of functional-structural connectivity, and target networks. Our research consists of 4 studies. 1. The effect of mild white matter lesions on cognition. Subjects were recruited from the Beijing Aging Brain Rejuvenation Initiative Study Group (BABRI). 51 mild WML examined by experienced radiologist and 49 matched healthy controls completed serial neuropsychological tests. We found declines in cognitive functions such as global function, executive function, and episodic memory in mild WML subjects. This result indicated that the mild WML already exhibit small but detectable effect on cognitive impairments. 2. Early structural and functional changes in mild white matter lesions. To investigate the injury pattern on the anatomical and functional changes, we conducted a voxel-based morphometry analysis (VBM), tract-based spatial statistics, and amplitude of low frequency fluctuation analysis (ALFF) in three different imaging modality, separately. The white matter injuries in the mild WML subjects were mainly in the fibers that projected to frontal areas, while gray matter structures were relatively intact. The overall resting state function of the frontal area was significantly increased. The ALFF value was significantly correlated with the cognitive scores in executive function and episodic memory. These findings demonstrate that mild WML subjects exhibit abnormalities in both white matter structure and functional intrinsic brain activity and that such changes are related to several types of cognitive dysfunction.3. Preclinical cerebral network connectivity evidence of deficits in mild white matter lesions. This study aimed to identify the brain functional and structural mechanisms underlying cognitive decline observed in patients with mild WML. Compared to the controls, we observed that the mild WML patients showed significantly changed functional connectivity in the default mode network (DMN) and in the right fronto-parietal network (FPN) combined with related white matter integrity disruption, but the left FPN only showed an increased trend of functional connectivity. No significant gray matter atrophy was found in the mild WML patients. The right precuneus functional connectivity in the DMN exhibited a significantly negative correlation with the AVLT score in the mild WML patients. Our results provided strong evidence of the links among white matter damage, dysfunctional patterns of resting-state networks, and the cognitive defects observed in mild WMLs. 4. Altered brain activation patterns under different working memory loads in mild white matter lesions. Working memory is a sub-component of executive function, which could further influence the episodic memory performance. We explored the related brain activation patterns under a n-back task. We found that patients with mild WML exhibited worse working memory performance than healthy controls. Furthermore, the brain activation maps changed under different working memory burdens in the mild WML patients, who exhibited increased activation in the prefrontal regions in 1-back and 2-back task. We speculate that this increased activation might be due to an underlying compensation mechanism for the frontal disconnection. In conclusion, we found that even the early WML showed impairments in general cognitive ability, episodic memory, and executive function. The mild WML patients show prominat structural and functional injury in frontal lobe, which is consistent with the frontal aging hypothesis. Cognitive decline may attributed to disconnection between the frontal lobe with other cortical-subcortical regions, dysfunction of resting state networks accompanied to decreased white matter structural connectivity, decreased brain information transmission efficiency, which further lead to a disconnection syndrome. Our results highlight the importance of mild WMLs in clinical practice and the necessity for monitoring WML in their early stages. Our systematic study of the cognitive neural mechanism in mild WML patients may offer a better understanding of the WML pathomechanism for clinicians, and has very important theoretical value to the future research on prevention and treatment of WML, as were as related neurodegenerative diseases.