Welcome to the Oxford University Department Psychiatry podcast series. I'm Nicholas Onoda, and today we have with us Professor Clausen, my dear professor at MIT for more than a decade. The reasons have been focussed in AIDS related changes of mood and memory function in the elderly. Could you tell us more about it? Yes, thanks. Thanks, Nikitas. If you say for more than two decades, that really makes me think my feeling is that I have to reinvent myself every five years or so.
I arrived here about 10 years ago and then I was carrying along an interest in effect as old as a particular depression because it took on the chin old age psychiatry. I spent the first five years looking at brain changes in people with depression who were in the age range of 60 to 80 years. I got a bit frustrated with that because if you concentrate on patients, you probably have to do case control studies.
So the numbers of people you examined is always limited and equally you have to find controls, which means that the results you find can be determined by the selection of controls as much as by the patients you are focussing on. For the last five years, I've done something completely different. I managed to get some money to image 800 people who have been followed up previously. They're part of Whitehall two cohort, which has been around since nineteen eighty five.
So they've just been followed up for about 30 years now. We are selecting a subgroup randomly from the remaining 6000 7000 participants. So give them a detailed neuropsychological, Bachi. We assess them psychiatrically. That is, we screened them for any kind of psychiatric condition. They do an MRI scan which covers things like brain structure, grey matter structure, white matter integrity, but also connectivity.
That is to what extent various parts of the brain work together where people are at rest. The idea is to look at, first of all, the quality of brain structure and function in people who are now on average are about 70 years old. And then to see whether we can derive the abnormalities in this group from any factors in the past.
So I'm thinking about risk factors for common psychiatric conditions such as depression and dementia, which are essentially the same as the kind of risk factor we have identified for cardiovascular disease that is vascular risk, risk of stroke as metabolic syndrome and markers of chronic stress or unhealthy ageing. We are just about finishing the collection of these scans.
We have something like 30 subjects off the 800, but we've looked at the first five and there's some interesting results emerging. The risk factors that are generally thought to be important for old age depression and for dementia already have an effect on brain structure and function in people who are ostensibly completely normal. So they have brain changes without being diagnosed with any specific psychiatric disease.
But also we find that the degree to which these brain changes can be detected already predicts, for example, that neuropsychological function. We also look at specific risk factors. One of our most important factors at the moment is alcohol, and that is alcohol consumption over the last 20 years. And we found some association between relatively heavy but normal drinking and brain changes, particularly in the hippocampus.
So that number of really interesting results coming out and the number of subjects we have acquired allows us to control of all sorts of things that may confound the results in a like age, sex, specific, general diseases, etc. And the other aspect which we're also able to investigate is to what extent, what factors are associated with resilience and resilience would be good performance on tests or successful life without any psychiatric diagnosis in the presence of brain changes.
So that's the overall programme. And I hope that over the next five years we'll get some interesting results published. So how does our brain change as we age? Well, that's that's a very wired question. I guess the accessible answer would be let's not look at the brain, but look at mental function. And we know that as we get older, actually quite early on in life, let's say in people's 40s, we already are as a group.
If you look at a large number of people, we would be climbing in certain functions. So people have divided mental performance or IQ into crystallised and fluid forms. Fluid are the ones that are changeable, particularly with age, and they have something to do with the speed of processing, with executive function, with reasoning, etc. Whereas other aspects like language related performance tends to be relatively stable over life.
So there clearly is something happening. It's not necessarily all bad. If you give complex task to young people and then to old people, you sometimes find that they perform equally well, but they get to the same targets with different strategies. Younger people tend to be quicker in their responses, in many of the components of their tasks.
But overall, planning tends to be a bit more haphazard, whereas older people tend to be more strategic about solving a task and may move slower but arrive at the end at roughly the same time. So that implies already that there is a degree of plasticity or at least a degree of compensating for certain difficulties, for example, a slower response. I think that is really the fascinating thing about brain ageing. But there are changes that are not necessarily negative.
I mean, it is true that with age, brains shrink. As you get changes, you get scars in the white matter and the other changes that suggests that there is some degeneration taking place. But at the same time, the brain restructures itself and seems to compensate for such changes quite effectively, obviously up to a certain point. Thinking outside the box, how would you describe the five year old child, what Alzheimer of diseases to start with?
I probably wouldn't give a five year old child, in fact, anybody a lecture about Alzheimer's disease. I think the way to explain psychiatric illness to somebody who hasn't experienced it first hand is to go to start from their own experience and to follow a process in which you ask them, for example, you know, have you noticed something different about granddad or granny? And then the child may actually come up already with some very pertinent observation of and he can use those observations,
put them into context and explain what's happening. So I wouldn't confront anybody, never mind a child with an explanation as such, but they would try to find out how they experience this other person's illness and then build on that and help with categorising certain things.
So, for example, if somebody is irritable or somebody doesn't remember something which is perceived as neglectful or deliberate, I may be able to say, look, you know, she or he actually cannot remember from time to time what what happened. So you have to just repeat again what you said before. It's not built well on their part. It's not that they don't like you or whatever. You just have to be aware that if you tell them something, it won't be there maybe half an hour later.
Apart from medication, what useful advice would you give to a friend that was only diagnosed with Alzheimer's disease? OK. I mean, that's a difficult one. I guess I would try to include advice that I would give patients so I would make sure that they have thought of the future. They have considered things like power of attorney. And I would maybe voice my concern if they were driving and I felt that was unsafe. So there may be some practical things that would need dealing with.
But on the other hand, I would just suggest that the best thing to do is to enjoy life as much as possible and not be put off by the condition. I think it's in the nature of Alzheimer's disease that certainly after a while, people are not aware of the extent of their difficulties. So it's often not difficult to get people to focus on the positive side of life because they don't have to ruminate about the future and about the possible consequences of their illness.
Although we have seen so many promising treatments. One of the headlines that have been so many setbacks in real life. What's the reason behind this? Well, I think the most obvious reason is that the brain is very complicated conditions that affect the brain and to be very diverse. So what we see as one entity that has dementia or even Alzheimer's disease may actually be composed of a whole range of different conditions.
Or in fact, it may be that it may be the end stage or the outcome of a whole number of different processes and diverse processes that may be related to simple things like vascular function that may, of course, include the position of substances like amyloid, etc. But I don't think there's any evidence that we found a unique mechanism which causes Alzheimer's disease, apart from possibly in a number of a very small number of families with a dominant gene who tend to develop the disease.
So I think it's a multifactorial, multi causal condition. That final common pathway, which would be losing brain cells and losing brain function, is so distant from the original causes that it is very hard to find a mechanistic treatment that's going to help everybody. You know, we obviously can boost certain aspects of brain function while the brain is still intact.
You know, I think there will not be a single treatment. I doubt that, for instance, removing amyloid from the brain is going to solve the issue. I think it's more complex than that because we don't really understand how the brain works. But I doubt that there's going to be a single treatment that's going to be effective for the majority of patients. At this point, I'd like to pose a different question. It's a common belief that successful researchers have never faced failure.
Is that true? Well, yes and no. It depends on how you define failure if failure is catastrophic because. Well, imagine that it's going to make it impossible for you to ever pick yourself up and carry on. But on the other hand, think not well guarded secret. But in order to be a researcher, you have to put up with a lot of frustration and with a lot of negative results. By design, you're really trying to disprove clever ideas you have.
And if you're successful, of course, you've been quite scientific, but on the other hand, not very successful in actually generating new knowledge in the negative sense that you say, well, this or that cannot be explained by the explanation I originally thought would be adequate. And if you go down to everyday practise, the same applies to your outputs or talking about anything from grant applications to submitted papers, I think you really have to get a lot of money.
If you could show me a researcher who didn't have lots of rejections at that level in return, I think in order to be a researcher, you have to be able to put up with the the nature of the job is that you have to have an unreasonable sense of confidence that whatever you're doing is worthwhile to be able to put up with the continuous frustration that comes your way in terms of rejections of grant applications, of papers, of negative outcomes, of studies, etc.
So to that extent, I would imagine if you had suffered a catastrophic failure or loss in your life, you may not be able to do that. But on the other hand, failure is the bread and butter of research. So in that context, the answer is no. What advice would you give to people who want to get involved? OK, well, there are obviously different levels. I think everybody who relies on research to correct their actions really needs to understand what conclusions you can draw from research.
So from that point of view, you may be good enough to read textbooks and read reviews and think about it, but to do a bit of research and get your hands dirty, as it were, may be helpful, really, to understand to what extent you can rely on research results and how you can interpret results to guide your practise later. On the other hand, if you want to become a pro, you know somebody who does research for a living. I think it's first of all that there are two aspects to it.
One is that you cannot be guided alone by the content of the research. Let's say you're interested in schizophrenia. That's not enough. You have to have a method that is of a certain sophistication and that goes beyond just thinking hard about a certain condition. And in psychiatry, that means becoming an expert in a particular method, whether that is pathology or whether it is biochemistry or pharmacology or electrophysiology or even the physics of imaging in order to add useful knowledge.
I think the time of just getting to knowledge by introspection and psychiatry is over. So one advice is learn the trades, learn the methods that will be applicable to the topic of interest, and that is likely to lead to to new results. And the other advice is do what is enjoyable for you. This you're not going to be able to live with doing something you find boring or irrelevant for decades.
You have to be excited by the topic of your research. And, you know, in other words, don't do it if you don't enjoy it in order to sustain research. In spite of the failures I mentioned earlier, you have to get something out of dealing with the topic and whether it is the satisfaction of getting a result out of that analysis or whether you actually have a very specific interest in a particular condition and you hope to help people with this condition,
there has to be a motivation of that kind to to keep. You're going to find out that. Thank you for your. Thank you.