Prof. James Vickers
Dementia is a term that we use to refer to a change in functioning from previous levels. The domains that are affected by dementia include your higher cognitive abilities, personality and behaviour. There are many dozens of diseases that will actually cause dementia, and most of these are associated with advanced ageing, although some, particularly with a high genetic predisposition, can occur at much younger ages.
The four major neurodegenerative diseases that cause dementia are Alzheimer’s Disease, Lewy Body Disease, Frontotemporal Dementia and Vascular Dementia. And sometimes these occur singularly and they can also occur in combination. And it’s these four that we’ll focus on in the presentation today.
The major cause of dementia is Alzheimer’s Disease, and this probably accounts for around 50% to 60% of cases. We know that Alzheimer’s Disease is characterised by specific pathological changes that occur inside the brain, and these were originally described by Alois Alzheimer at the beginning of the 20th century. The three changes include those that happen at the macroscopic level, which involves shrinkage or atrophy of the brain, and this can affect particular structures of the cerebral cortex, including the frontal lobe, temporal lobe and parietal lobe. The other two pathological changes occur at the microscopic level, and these are neurofibrillary tangles and amyloid plaques. Amyloid plaques are spherical structures that occur between nerve cells and are comprised of a protein known as A-beta. Now A-beta is a normal protein that you would find in all of our brains, but in Alzheimer’s Disease, it undergoes an abnormal transformation. It forms small fibrils that accumulate together to form plaques, and where plaques form in the brain, they cause damage to nerve cells, particularly the processes of nerve cells, the axons, the dendrites, as well as synaptic connections between those nerve cells. The other major microscopic change that occurs inside the brains of people with Alzheimer’s Disease is the neurofibrillary tangle. Now, within all nerve cells there’s a fine meshwork of filamentous proteins that we refer to as the cytoskeleton. When a nerve cell is affected by Alzheimer’s Disease, this cytoskeleton collapses and is replaced by the neurofibrillary tangle. The main protein that comprises this tangle is an altered form of a normal brain protein we refer to as tau. Now, tangles probably take many years to actually develop within nerve cells, and they seem to follow the initial development of plaques within the brain. They are also very insoluble structures, which means they don’t dissolve very easily. So when a nerve cell dies, usually the tangle is left behind, and we refer to this as a tombstone or ghost tangle. There are new imaging technologies that are being developed for Alzheimer’s Disease that might help us visualise these amyloid plaques and neurofibrillary tangles inside the brains of people while they’re alive. If we combine the data from these new studies with that which has been derived from pathological studies, we now appreciate that there’s a particular sequence of pathological change that occurs inside the brain with Alzheimer’s Disease. It seems likely then that plaques may occur many years, sometimes as many as ten to fifteen years, before you develop overt symptomatology. The plaques appear to precede the neurofibrillary tangles and the neurofibrillary tangles themselves are more closely linked with the loss of synaptic connections between nerve cells, which lead to the pattern of symptoms. In this regard, Alzheimer’s Disease is a degenerative and progressive disorder in that the disease develops from one stage to the next - from a clinical silent period, where plaques develop inside the brain, through to the initial stages of the disease, which can be insidious and often difficult to detect, then through to the progressive deterioration in higher cognitive functions. One of the early cognitive functions that seems to be affected by Alzheimer’s Disease is short-term memory and the ability to form new memories.
导致认知的主要原因是阿尔茨海默病，可能约占50％至60％的病例。我们知道，阿尔茨海默病的特征是在脑内发生特定的病理性变化，这些特征最初在20世纪初由Alois Alzheimer所描述。这三种变化包括在宏观水平发生的改变，其涉及脑的收缩或萎缩，并且影响包括额叶，颞叶和顶叶在内的大脑皮质的特定结构。其他两种病理性改变发生在微观水平，它们是神经原纤维缠结和淀粉样斑块。淀粉样的蛋白斑块是存在于神经细胞之间的球形结构，并由称为A-beta的蛋白质所构成。在我们所有正常的大脑中，A-beta是一种正常的蛋白质。但在阿尔茨海默病患者的大脑中，这种蛋白发生异常的转变。它形成小的原纤维，进而这些原纤维聚集在一起形成斑块，并且这些在脑中形成的斑块对神经细胞，特别是神经轴突和树突以及这些神经细胞之间的突触连接造成损害。在阿尔茨海默病患者脑内发生的另外一个主要的微观变化是神经原纤维缠结。在所有的神经细胞中都有一个由丝状蛋白构成的细丝网络，我们目前称之为细胞骨架。当神经细胞受阿尔茨海默症影响时，该细胞骨架塌陷并被神经原纤维缠结所替代。构成该缠结的主要蛋白质是一种正常脑蛋白的改变形式，我们称为tau蛋白。缠结可能需要许多年才真正在神经细胞内发展，并且它们似乎在脑内的最初的斑块的发展之后形成。它们也是非常不溶的结构，这意味着它们非常不易溶解。因此，当神经细胞死亡时，通常会留下缠结，我们将其称为墓碑或幽灵缠结。有一些为阿尔茨海默病而正在开发的新的成像技术，可能会帮助我们活体观察人类大脑内的这些淀粉样斑块和神经原纤维缠结。如果我们将来自这些新研究的数据与来自病理学研究的数据相结合，现在我们会认识到在阿尔茨海默氏病患者的脑内发生了特定的病理变化序列。斑块似看起来似乎在症状出现之前已经存在了许多年，有时多达十至十五年。斑块似乎出现在神经原纤维缠结之前，并且神经原纤维缠结本身与神经细胞之间的突触连接的丧失更紧密地相关，从而导致症状的产生。在这方面，阿尔茨海默病是一种退行性和进行性疾病，其中疾病从一个阶段发展到下一个阶段 - 从斑块在脑内发展的临床沉默期，直到疾病发生的初始阶段，这个过程可能是隐蔽的并且经常难以检测的，然后进入更高的认知功能逐渐恶化时期。似乎受阿尔茨海默病影响的早期认知功能之一是短期记忆和形成新的记忆的能力。
In Alzheimer’s Disease, we know that particular brain regions are vulnerable to degeneration, and even within those brain regions, certain nerve cells are particularly susceptible. One of the structures of the brain that’s affected early in the disease is the medial temporal lobe, and as this degenerates, you may see some symptoms, such as an inability to form new memories and difficulties generally in short-term memory. But then the disease progresses to other brain regions, to other lobes of the cerebral cortex, and as this occurs you will see difficulties in other higher cognitive areas, as well as behaviour and personality, and this might include planning ability, logical thinking, orientation in space and time, as well as language.
The speed of progression, as well as the age of onset, of Alzheimer’s Disease does vary between individuals. We don’t really understand why this is the case, but it’s likely mainly due to genetic predisposition, but other lifestyle factors may well play a role.
In Alzheimer’s Disease, there are likely to be a range of genetic risk factors that contribute to your relative risk of developing this condition. The best known one, and the one that has the most impact on your risk, is the apolipoprotein E gene. Now, this comes in three variations – Epsilon II, Epsilon III and Epsilon IV. You inherit one version of this gene from each of your parents. Essentially, the more of the Epsilon IV version of this gene you have, the higher risk you have of developing dementia as you get older. In less than 5% of cases, there’s a much stronger genetic predisposition and we often refer to this as familial forms of Alzheimer’s Disease. We know of three genes that carry a range of mutations that can cause familial Alzheimer’s Disease. One of these is the amyloid precursor protein gene, and we know that this is then linked potentially to the production of amyloid beta that forms the plaques in Alzheimer’s Disease.
在阿尔茨海默病中，可能存在一系列遗传风险因素，这些因素会促进您发展这种疾病的相对风险。最著名的一个，对你的风险影响最大的是载脂蛋白E基因。现在，这有三种基因变异 - Epsilon II，Epsilon III和Epsilon IV。你每个人从各自的父母继承这个基因的一个版本。基本上，你如果拥有更多的Epsilon IV版本的基因， 等你变老时你就有更高的发展为老年认知症的风险。在不到5％的病例中，有更强的遗传倾向，我们经常将其称为家族型阿尔茨海默病。我们知道三个携带一系列可导致家族性阿尔茨海默病的突变的基因。其中之一是淀粉样蛋白前体蛋白基因，并且我们知道这可能与在阿尔茨海默病中形成斑块的淀粉样蛋白β的产生有关。
Another cause of dementia is Lewy Body Disease. Now, this is known by a variety of terms, including diffuse Lewy Body Disease, Dementia of the Lewy Body Type and Alzheimer’s Disease with Lewy Bodies. The cardinal pathological feature of Lewy Body Disease is the presence of an abnormal proteinaceous inclusion inside nerve cells called the Lewy Body. Now, the Lewy Body is a spherical structure made up of proteins, fine filaments and lipids. It also occurs as the main pathological feature of Parkinson’s Disease, and we think that Parkinson’s Disease and Lewy Body Disease are related to each other. Some of the clinical features of Lewy Body Disease may well include motor problems that you see in Parkinson’s Disease, such as tremor. Similarly, if you have Parkinson’s Disease for a long period of time, you may then develop cognitive issues that are very similar to what we see in Lewy Body Disease. Inside the brains of people with Lewy Body Disease, you’ll often also see amyloid plaques, and this probably speaks to some kind of interrelationship between Lewy Body Disease and also Alzheimer’s Disease.
Another cause of dementia is Frontotemporal Dementia, and this is really a spectrum of different diseases. Broadly, they’re characterised by dramatic shrinkage, or atrophy, of brain regions, such as the frontal lobe, and the frontal sections of the temporal lobe. The symptomatology of the disease broadly follows the damage to these cortical areas – for example, with frontal lobe damage, comes changes in personality and behaviour, as well as higher cognitive skills, such as planning and judgement. With damage to the temporal lobe, there’s often problems with language and speech production.
认知症的另一个原因是额颞叶痴呆，这其实是一系列不同的疾病。广泛地讲，它们的特征是脑部的急剧收缩或萎缩，例如额叶和颞叶的正面部分。疾病的症状学大致广泛存在于对这些皮质区域的损伤 - 例如，伴随额叶损伤，发生个性和行为上的变化，以及更高的认知技能，例如规划和判断能力。由于颞叶损伤，语言的产生常常出现问题。
Of all of the conditions that cause dementia, frontotemporal dementia probably has the strongest genetic predisposition. So around about 30% to 40% of cases of frontotemporal dementia are likely linked to particular genetic mutations. And because of this genetic predisposition, these cases tend to have a relatively early onset.
Vascular dementia is sometimes known as multi-infarct dementia, and this involves an interruption to the normal blood flow into the brain. In most cases of vascular dementia, this involves damage and disruption to the small blood vessels that penetrate through the brain, particularly in the white matter tracks underlying the cerebral cortex. In other cases of vascular dementia, there might be a series of small strokes occurring in different regions of the brain. Vascular pathology is actually quite common with advanced ageing and this vascular disease can coexist with other forms of dementia, such as Alzheimer’s Disease.
These different forms of dementia are the focus of intense study globally. We are trying to understand the sequence of pathological changes that lead to dementia. In many cases, this is probably largely attributed to advanced ageing, as well as your genetic predisposition, but we’re also interested in how more modifiable risk factors may play out in terms of the disease pathology. Ultimately, we’re interested in therapeutic agents that might modify disease progression, so might have an effect on the specific pathological hallmarks, or it might be that we can look at interventions that might improve on your relative resilience to these dementing disorders.