《国际循环》：应采取哪些策略改善脑小血管病的早发现、早诊断与早治疗，以减少继发性损害？

　　International Circulation: What strategies should be taken to improve the early detection， diagnosis and treatment of cerebral small vessel disease in order to reduce its secondary damage?

　　Greenberg教授：脑小血管病的多种不同标志物均可通过MRI来发现，随着MRI的应用，我们在脑小血管病的识别方面已做得比较好。多年来，很多人已习惯通过MRI检查白质高信号（WMH）来发现脑小血管病。现在，微出血及其他改变越来越多地被MRI发现。例如，一直被视为是退行性疾病标志的皮质萎缩在血管疾病时也可出现。我们在识别和发现脑小血管病方面已做的比较好，但问题是还不清楚应如何治疗这种疾病。目前人们已达成广泛共识，即与阿尔茨海默病及神经退行性疾病一样，脑小血管病也是导致认知功能障碍的重要原因，且在东西方人群中其对认知功能障碍的贡献相似。当然，大多数认知功能障碍可能是多种因素共同作用所致，既包括退行性变化，也包括血管变化。可喜的是，我们已发现问题所在，目前的困难在于缺乏正确治疗方法。首先，大家已认识到危险因素控制的重要性，其中，高血压是最主要的危险因素。因此，控制危险因素尤其高血压有助于改善脑小血管病，已有几项研究提示，经此治疗，校正年龄后的认知功能障碍得到改善。这并非因为更好地治疗了阿尔茨海默病，而是我们能更好地治疗脑小血管病的危险因素。我认为，改善危险因素控制只是改善脑小血管病治疗的开始，并非终点。我们需不断努力探寻小动脉硬化及淀粉样血管病等脑小血管病的更特异治疗方法。

　　Dr Greenberg: We are very good at detection mainly because of MRI. There are so many different markers of small vessel disease that can be seen on MRIs. For many years， many people were used to seeing the white matter hyperintensity (WMH) but now microbleeds are increasingly detected on MRI along with other changes. Cortical atrophy， for example， which had always been thought of as a marker of degenerative diseases， is also affected in vascular disease. So I think we are very good， if not too good， at detecting small vessel disease， but it is unclear how to treat it. There is also widespread agreement that there is a major contributor to cognitive impairment in Western and Eastern populations with a similar order of magnitude as Alzheimer’s and neurodegenerative diseases as a cause of cognitive impairment. Of course， most cognitive impairment is probably multi-factorial with both degenerative and vascular changes. The good news is that we have identified the problem. The difficulty is knowing what the correct treatment should be. The starting point that everyone would agree on would be risk factor control and that hypertension is the primary risk factor. So improvements in the treatment of risk factors particularly hypertension， should improve small vessel disease and we have been getting hints that there has been improved age-adjusted cognitive impairment in several different studies. That is not because we are treating Alzheimer’s disease better (in fact there haven’t been any improvements in Alzheimer’s) but it is because we have got better at treating risk factors for small vessel disease. I believe that this will be the beginning of the story though and not the end of the story as we move towards more specific treatments for small vessel disease both for arteriolar sclerosis and for amyloid angiopathy.

　　《国际循环》：脑淀粉样血管病是脑小血管病的重要类型，您曾就脑淀粉样血管病开展了相关研究。从您的临床及研究经验来看，该病的特征及临床表现有哪些？其常用的治疗措施是什么？这些治疗措施的有效性如何？

　　International Circulation: Cerebral amyloid angiopathy is an important type of cerebral small vessel diseases and a condition you have researched. According to your clinical and research experience， what is the characteristic and clinical manifestation of this disease? What are the commonly used treatments and how efficacious are those treatments?

　　Greenberg教授：脑淀粉样血管病是脑小血管病的一种，与高血压所致小动脉硬化性小血管病存在很多差异。虽然血压在淀粉样血管病发病中发挥了一定作用，但可能作用并不太大。淀粉样血管病表现为淀粉样肽在脑血管沉积，是与年龄普遍相关的病理过程。目前，微出血是诊断淀粉样血管病的重要指标，通过早期发现微出血，我们在识别淀粉样血管病方面做得越来越好。淀粉样血管病患者通常存在大脑皮层及皮质/皮质下区域（灰白质交界处）的多处微出血或大量出血。此外，出血还可出现在皮质表面铁沉积区及皮质沟。当患者出血均位于上述区域时，根据尸检在内的现有数据，我们可非常自信地诊断淀粉样血管病。问题是，正确治疗方法是什么？从目前来看，控制血压对上述患者有益，但仍有一些患者即使血压得到良好控制，病情仍会进展。因此，并非仅控制血压即可。临床实践中面临的最常见困惑是应如何对这些患者行抗凝、抗血小板及抗栓治疗？对既往出现过淀粉样蛋白相关出血患者，我们通常会停用抗栓药。在有充分理由情况下，患者必须行抗血小板治疗时，应确保其获益大于风险，但一般来说，我们对这类患者会停用抗凝药，并告知患者避免大量饮酒，有证据表明酒精摄入与出血相关。总的来说，对淀粉样血管病患者，我们需探寻特异性治疗方法。目前，淀粉样血管病治疗尚处非常早期阶段，我们不清楚这些治疗是否有效。有一项抗淀粉样蛋白抗体相关研究正在进行，我们不确定这种新疗法是否有应用前景。当然，我们也在探寻其他可能方法，相信我们最终会找到治疗该病的方法。

　　Dr Greenberg: Cerebral amyloid angiopathy is one type of small vessel disease. In a lot of ways， it is in a different category from the classical hypertension-driven arteriolesclerosis. Amyloid angiopathy is probably not driven very much by blood pressure although it may play some role. It represents the deposition of amyloid peptide in cerebral vessels and is a very common age-associated pathology. Again， we have got much better at recognizing it mostly by the detection of microbleeds. That is the mainstay for diagnosing amyloid angiopathy. In those patients who have multiple microbleeds or larger bleeds that are strictly located in the cortical regions and cortical/subcortical regions (the grey-white matter junction). We also see them in the cortical superficial siderosis and the cortical sulci. When all of the bleeds are in those locations， we can be pretty confident based on the data we have (which includes autopsy data) that it is amyloid angiopathy. The question is， what is the right treatment? For some reason， blood pressure control is helpful although some people will progress even with excellent control of blood pressure， so that is not the whole answer. The most common practical question that comes up is what to do about anticoagulants or antiplatelet and antithrombotic treatments? In people who have had a past amyloid-related hemorrhage， we will generally discontinue antithrombotics. If there is a strong reason for antiplatelets， then there might be a benefit which outweighs the risk， but in general we try to withdraw anticoagulation agents. We tell patients to avoid high alcohol use because there is some evidence that alcohol intake is related to bleeding. But this is a situation where we need a specific disease-modifying treatment. What we have are in the very early stages and we don’t know whether these will be effective. There is an ongoing trial with an anti-amyloid antibody study and we don’t know yet whether this will be a promising approach. There are many other schools of thought on a solution and I believe that we will eventually have a disease-modifying treatment， but we don’t have it yet.

　　《国际循环》：脑小血管病所导致的认知功能障碍是血管性认知功能障碍（VCI）的重要亚型，与其他疾病所致VCI相比，小血管病性VCI的特点有哪些？评估方法有哪些？

　　International Circulation: Cerebral small vessel disease-induced cognitive impairment is an important subtype of vascular cognitive impairment (VCI). Compared with other disease-induced VCIs， what are the characteristics of cerebral small vessel disease-induced VCI and how do we evaluate it?

　　Greenberg教授：在讨论差异时，我们必须清醒地意识到二者有很多重叠。大多数年龄相关性痴呆都是多因素导致的，实际上很难提炼出每种因素导致的VCI特征。不同类型的VCI特点存在很多重叠。但是，与非血管性痴呆相比，VCI确实有一些更常见特征。很显然，VCI更常伴有卒中或卒中所致局灶症状，更常存在步态障碍，步态更缓慢或更易跌倒。另外，VCI的认知障碍程度可能存在差异，患者更易出现执行功能障碍及注意力问题。有些VCI患者短期情景记忆不错，但其注意力及思维敏捷性降低。我认为不能根据这些诊断VCI，还需依靠神经影像学检查。与阿尔茨海默病的退行性病变相比，我们在发现血管病变方面做的更好。临床实践中，当发现白质高信号、微出血及小梗死等脑小血管病变标志时，需积极控制危险因素并进行卒中二级预防以预防未来事件发生。与尚无有效治疗的阿尔茨海默病相比，我们在预防小血管病未来事件方面做得较好。

　　Dr Greenberg: When we are talking about differences， the overlap is very high. We generally understand that most age-related dementia is multifactorial， which makes it very hard to tease apart separate characteristics and in any case， there is a lot of overlap. But there are some features that are more common in VCI than in non-vascular dementia. Clearly， the presence of stroke or focal symptoms from stroke is more common for obvious reasons. There is probably more gait impairment in people with VCI with a tendency for a slower gait or more falls. Some cognitive differences are differences by degree which makes it hard to base a diagnosis on. There tends to be more executive dysfunction and attention problems in people with VCI. Some VCI patient’s short-term episodic memory is quite good but they remain impaired due to loss of attention and mental agility. But I don’t think we can rely on these to make a diagnosis. Really diagnoses are made by neuroimaging. We are much better at seeing the vascular lesions that we are not seeing in the degenerative lesions of Alzheimer’s disease， i.e. the markers of white matter hyperintensity， microbleeds and small infarcts. From a practical standpoint， when we see those markers we try to follow all the steps of risk factor control and secondary stroke prevention to prevent future events. We are probably better at doing that than we are preventing Alzheimer’s changes where we don’t have a treatment.

　　《国际循环》：VCI与阿尔茨海默病的认知损害模式与诊断标准有哪些不同？

　　International Circulation: What are the differences between VCI and Alzheimer’s in the patterns and diagnostic criteria of cognitive impairment?

　　Greenberg教授：阿尔茨海默病的诊断非常困难，主要根据临床表现判断。一般来说，若患者出现经典的进行性痴呆，且无其他致病因素时，可诊断为阿尔茨海默病。我们现在知道，血管因素在其发病中也发挥了重要作用，阿尔茨海默病与VCI的很多特征存在重叠，很多患者可能符合阿尔茨海默病诊断的同时也符合VCI诊断。Tau成像可能是目前诊断阿尔茨海默病特异性最好的方法，随着淀粉样蛋白成像及Tau成像等新兴技术发展，阿尔茨海默病的诊断也在不断进步。虽然Tau成像发展处于初步阶段，尚未被任何国家用于临床，但未来5~10年，我们可能会有不错的成像技术帮助我们更加了解阿尔茨海默病的病理变化。

　　Dr Greenberg: Alzheimer’s diagnosis is very hard from the standpoint that it is mostly made on clinical grounds. The classical Alzheimer’s diagnosis is made where someone has the classic progressive dementia and the absence of other causative factors. Now that we know there is often a vascular contribution， there is a very large overlap zone， so many people may meet the criteria for possible Alzheimer’s disease and also possible VCI. This creates this large overlap group in the middle. There are some people with relatively pure disease at each extreme. Alzheimer’s diagnosis is also an area that is undergoing growth with amyloid imaging and through exciting new techniques like tau imaging which is perhaps the most specific marker for Alzheimer’ disease. That is still in the early stages and is not in clinical use in any country but is an area where if we have this discussion again in five or ten years， there may be good imaging techniques to say specifically how much Alzheimer’s pathology is present.