1998 LECTURE SERIES

The Aging Brain: Distinguishing Normal and Pathological Memory Loss

Dr. Jelle Jolles
Maastricht Brain and Behavior Institute, Netherlands
May 13, 1998

There are several major topics I will cover. They all have to do with the difference between normal aging and pathological conditions.

There is a continuous change from birth to very high age, and we've known already for quite some time that biological aging starts in young adulthood when one is 25 to 35 years old. We know that young adults perform better in physical activities than older people. And as we all know, by far the majority of sportsmen and athletes are in their 20s. But what about brain function? Well, by far the majority of university professors, directors, politicians, and prime ministers are older than 20. Therefore, one might conclude that there is a difference between physical aging and brain aging.

We do know that brain volume decreases with age, especially after age 40. Then how come directors, politicians and other important people, as a rule, are older than 40? Does it have to do with increasing knowledge and increasing power?

The primary function of the brain is to help us adapt to a changing environment. The brain organizes all our bodily functions, so we react to threatening stimuli with changes in bodily function and changes in behavior. We will run away or fight. We hear people say something to us and react to them via verbal response. We hear and see the stimuli and react to some and disregard others. Our brain selects the relevant stimuli and regulates our behavior in an efficient manner.

Middle-aged men process information efficiently and, do not get in accidents. However, as we all know, this is not the case for many elderly. Something is wrong up there and memory problems are the consequence: The inability to cope with environmental demands in an appropriate perception and lack of attention to objects are functions that are not organized in a proper way. We know that some older people become anxious and do not go out again, because they are afraid that something may happen with which they cannot cope.

What are the cognitive problems that the older people suffer from? Of course, as we all know, the sensory problems. Also, it appears that many elderly are less efficient in finding solutions to everyday problems. They know that they know the problem and they know that they know the solution, but they can't find it in their brain.

Another quite serious problem has to do with selectivity. It is as though our brain is less able to perform two things at the same time. Such as listening to music and following a conversation.

Let me summarize what we know about the cognitive functions that deteriorate with age. Scientific research has shown that many cognitive functions deteriorate. Indeed, memory problems appear. Sensory functions decline, and we have less cognitive energy. But, above all, everything goes slower. We are slower in responding to the environment, slower in talking, slower in finding things in our memory. Problem solving goes down and many older people get another personality. Once, when they were younger, they were active and interested in many things. But with age, they become sometimes more conservative and also inflexible. Many elderly also experience mood problems. They become depressed or don't feel the energy anymore, which is needed to have an active lifestyle.

Is this general view on cognitive aging correct? No, it's not, because there are people who do not age in the way that I have described. Some elderly are aging successfully. They remain active up to a high age, only somewhat slower than they were, but competent for both regular and difficult mental tasks. But we do know more thanks to one example of a patient who has Alzheimer's Disease, a very serious pathological brain aging condition. She doesn't recognize her grandchildren and regards her 43-year-old daughter as her own mother. This is the most extreme example of pathological brain aging.

It's very important to know what determines the successful aging process, the usual aging process, and also what determines the pathological brain aging.

The successfully aging people do not appear to experience major problems in cognitive functioning. Now the major question which many people ask is, okay, successful aging, usual aging, pathological aging, but me, myself, I have memory problem. Does that mean that I will become demented? And what does it mean? How come? What can I do? Do I have to take pills to start brain jogging? Or what is it that I can do? Now these are many questions, and I'll ask these questions again and try to give some information with regard to scientific studies and their answers to these questions.

The first question is whether memory and related functions decline at the same rate. Does memory slowness and our problems with problem solving decline when you are 60, or when you are 70? I will describe some results from a very large study, from a strict aging study. It was a large population study, which means that we looked at many normal subjects, 1,940 healthy subjects, ages 25, 30, 35, etc., up to 80. We were very interested in the influences of education and health. I'll explain to you later why we were very interested in these health factors. To see whether particular factors might predict the development of pathological aging and what factors would predict the successful aging. The active recall from memory is compromised in the aging process, but passive recognition is not. This is what many elderly people experience. They know that they know it, but they just can't find it.

Another important aspect of memory and forgetting is the speed of processing information. We learn that the information processing speed of our brain is compromised with age, especially for complex tasks. This makes it easy to understand why many people experience mental problems already in their 40s. They are not able to cope with the busy life in which time is money. Already, at age 40, you are less able to do two things at a time. It costs more time and effort to shift your attention, and it costs more time to concentrate for a longer period of time. Up until now, I described performance, something that we, a psychologist or a doctor, test in you. We measure what the person does, but don't know yet what the person thinks or feels himself. What about subjective memory? What about subjective forgetfulness? What happens when you ask someone whether he or she considers him or herself forgetful? We did ask this question. We asked it to 4000 individuals, and we expected, of course, that old people have more forgetfulness then young people, and that especially this would be true for people age 60 and over. The results, however, were astonishing.

As for subjective forgetfulness, 30% of people age 25 to 35 say, yes, when you ask them, do you consider yourself forgetful? So one in every three subjects, age 25 to 35, thinks that he is forgetful. And this increases up to 50% in very old people. It is, of course, very interesting that the other 50% of the old people do not consider themselves forgetful. Fortunately, many older people are not forgetful. But, as a scientist, I want to know why. What is the reason that there is so much forgetfulness in young people? So we asked these 4,000 healthy people again to say what they regarded as the origin or cause of their memory problem. Young people say, "I am forgetful because life is so very busy. I am stressed and that's why I forget things." The older you become, the more you think that it is organic. "It is dementia."' "It is possibly physical illness." "It is possibly sleeping pills that I have used." So when you get older, there is another reason that you give to the forgetfulness.

In conclusion, the deterioration of memory already starts at age 30. There is subjective forgetfulness already in middle age, and slowness increases when complex functions are compromised. There's a borderline state between the normal aging and pathological aging.

In this sense, we have learned something new; that there are three aging patterns: successful, usual and pathological. Of course when people become demented, there should be a phase before that. And the important scientific and clinical question is "What determines the fact that someone experiences successful aging and others experience demented or pathological aging" So what factors influence these patterns? What influences the age-related decrement? We think health may be an important candidate. But we also think that education and psychosocial factors could also be of relevance.

As you know, when you're 60, 70, or 80, you may have a chronological age, and that is something that is similar for these people. But there are many other factors that are dissimilar. Take, for example, five regular, healthy, normal people, and look at the differences. The first is 70 and healthy, but 50 years ago, he had a heart operation. Second person is healthy, doesn't have forgetfulness, but has had a mild head injury in his youth. The third person used medication for the treatment of diabetes. The fourth is not sick, but he is lonely and his mood is somewhat depressed. The fifth has no formal education. So, there are five healthy individuals with a totally different history. History must have an influence on the age-related decline. But how? What factors?

Brain trauma is an important factor. We learn from the television and from cartoons that it is very funny to get a blow on your head. Our hero on the T.V. is always knocked unconscious several times, wakes up, smiles and eventually wins the fight and usually also wins a nice girl. However, reality is different. In our studies, we evaluated young and old people who considered themselves healthy. Half of them had suffered mild brain injury once in their life, and that may have been 2 years or 30 years ago. People who considered themselves healthy, but have had a blow on the head, are somewhat less in recalling the number of words. But especially when you are older. It is as though health and age interact with each other. Old people with head trauma have deteriorated more because of that interaction between head trauma and age. So the combination is important. As a scientist, I use a word for that, and the word is "vulnerability. We say that head trauma is a vulnerability factor for cognitive decline. It doesn't indicate that all people who have once had a small head injury will deteriorate. It gives you some extra chance.

Another example will be increased blood pressure. People with high blood pressure during the night have a problem with cognition. High blood pressure in the night gives lower memory and lower speed. Remember, again, that these were healthy subjects. Blood pressure changes seem to be able to influence the cognitive function. It could be that this problem causes their depth and sleep disturbance. This is a very important observation, because then you can show that sleep disturbances and memory problems over a day have a relation to one another.

We have evaluated many factors, which possibly influence cognition and memory with age. Prolonged periods of social drinking have an influence. They lead to less good memory performance. Note that I am not talking about alcoholics. I talk about social drinking, which means 25 to 35 glasses per week for men and 20 to 28 for women. Of course, many people can drink a lot and have very good memory. But, again, this alcohol use is some kind of a risk factor, a vulnerability factor.

The same applies to prolonged use of sleep medication and also for people approximately 70-years-old who have had an operation under general anesthesia. When you have an operation, it does not lead to memory problems. But combined with other things, it may give you an increased risk of the deterioration. The same applies to diabetes. There are several factors in the blood and that seem to be involved with memory and brain functioning, and chronic respiratory disease.

In conclusion, there are some health-related factors that do affect cognitive decline. When you are older, you are more vulnerable to the effect of health-related factors. Cognitive function may just be dependent on health rather than on age. Usually, the public, doctors, psychologists, and other scientists ascribed memory problems to age. And several years ago, our group was among the first to draw attention to the fact that the health-related problems might be least important. After all, we know already that the number of medical diagnosis increases with age. Also, the number of drugs that people use increases, and we can be very fortunate that there are good drugs to treat the medical things that happen when you are old. But yet there might be some side effects on memory. And it is good that science looks at these matters and tries to make better drugs and to treat medical conditions in such a way that memory problems will not be a consequence of that. But that is in the future.

This brings me now to a third major question. Given the importance of health, where lies the boundary between normal aging, usual aging, and dementia? One example includes a long series of investigations on similarities and differences between normal aging in elderly people with memory complaints and Alzheimer patients. Although memory problems in normal aging can be very handicapping, it is a huge difference from the pathological condition. We know that the quality of life of people with memory problems in age is somewhat less or maybe much less than they use to, but a memory problem in old age is not the same as Alzheimer's Disease. There is this large gap between the two.

I come now to a statement, a kind of theory as to this line between successful aging, to usual aging, and to pathological conditions. I spoke about the vulnerability factor. Well, age itself is such a vulnerability factor. Reduced health has been mentioned, but also prolonged periods of stress or psychological problems, particular psychosocial factors and lifestyle with increased health risk, heavy drinking, and also prolonged use of Benzodiazepens, or sleeping pills, is not good for your brain. It increases the risk, and that is a vulnerability factor.

Now the importance of the concept of vulnerability factors is that it says that the onset of real cognitive problems is shifted to lower age. When there are no risk factors, you will be experiencing successful aging. When you don't die from other causes such as cancer, infectious diseases, heart disease, etc., you may live to be 100, 110, 150-years-old. Only at the very late stage, say when you're 100, can a person get real cognitive problems. So in the final stage, there is deterioration, age-related. But the vulnerability factors shift this point to a lower age. So when you have early in your life events or the mild head trauma, you may not start with cognitive problems when you're 103, but instead when you are 93 or 83-year-old. At this moment, health is such that the chance that you die before that from another cause is somewhat bigger. You can also have these vulnerability effects at a later age that causes revolutionary shifts in your memory. But Alzheimer's Disease or real pathological aging does not have a cause. Also, in this case, the vulnerability factors can shift the onset of decline to lower age.

Fortunately, there are protecting factors. One important protecting factor is higher education. Other protective factors include having a high socioeconomic status, limited brain hazards, and a good lifestyle. Use it or lose it. All these are part of an active lifestyle. Open your ears and your eyes to get more stimulation. Unfortunately, this is not something that has been investigated in depth. I hope, as a scientist, that in the next ten years, we will be able to show that sensory activity will protect this cognitive decline. But this is in the future. In conclusion, there is a borderline between successful aging and pathological aging. The vulnerability factors and protecting factors may determine the position in that borderline. And one thing to mention about education as a possible factor is that we know for sure now, from many studies in the last years on education and dementia, and these studies generally show that dementia is less prevalent in people with higher education. The cause of that is not mentioned explicitly in many papers, but you heard my explanation for it.

I am a scientist. Scientists want to look in the brain. We always want to know why, what mechanisms are involved. And as a brain scientist, I want to look in the brain. I will give two experiments to show what we've found about brain mechanisms and its involvement in cognitive aging.

There is a real degeneration of brain tissue in Alzheimer's Disease. Now, what about people who have no dementia but have some memory problems or have some deterioration of memory function. We have hypothesized that the gross brain structure will be intact in these people, but that some very subtle changes in the structure within the brain, so, not on the outside, but inside in the brain, would be present. We hypothesized that particular areas that connect brain cells from the outer surface are involved. These areas under the cortex, under the outer surface of the brain, are called "subcortical white matter," because it is white in color. We tested the hypothesis that there's a relation between these very subtle changes in the white matter and memory dysfunction. We tested 1,000 healthy people, aged 60 and over, and in all these healthy people, we took a brain scan. We took computer scans of the brain, and then reconstructed it to see where in the brain there were changes. And also looked at cognitive functions. In conclusion, large-scale studies in otherwise healthy subjects show that compromised cognitive function may be related to the integrity of subcortical connecting fibers. For scientists, this is very important. But also, I think, eventually for the general public, because we may get better diagnostic tests with better ideas as to how to relate things, which happen in the brain to those that we measure on cognition.

The final topic refers to the question whether there is some kind of remedy for the cognitive problems that accompany aging, pharmacological treatment or something else. Can we do some psychotherapy or something? The question is thus, what is the remedy? Is there any remedy? Pills or brain jogging? Doctors have asked themselves whether or not we can use nicotine as a cognition enhancer. We have evaluated the potential beneficial affects of caffeine. And caffeine, indeed, is a drug, a psychoactive substance which is used the most in the world. And the psychoactive substance seems to be doing something on, our well being and possibly also memory. That's what we tested in this experiment. Nicotine improves your performance, but caffeine is still better. It's interesting that caffeine consumptions give you a better performance in memory tests. We have done quite some studies. We compared young people, middle-aged people and old people in the affect of caffeine on memory, and it turned out that, indeed, in middle-aged people, there was quite a substantial increase in memory performance. But it is very interesting to see that older people don't use so much caffeine. From 25 through 85 there's a rise in the caffeine consumption up to 45 years, and then it steadily decreases. When you look at individual cases, it is still more pronounced. So the possible beneficial affects of caffeine on cognitive function in elderly subjects is something that scientists should look about. But at this moment, of course, we know that caffeine also has other affects. We cannot advocate the statement that everybody should use caffeine. But this is something that, for pharmacological reasons, is interesting that these affects are there, so that pharmaceutical industries can find better drugs which may have actions like caffeine, but then without side effects.

We know from this type of experiment that pharmacological treatment bears some promise for the treatment of memory and other problems in the future. Another direction that we have been involved in the last few years is the use of hormones, especially the use of estrogen. Estrogen replacement therapy and other therapies with female hormones increases performance in elderly women. Again it is very important to do research in this pharmacological direction, because that could help many people in the future. But at this moment there are only a very limited number of drugs with proven activity on memory function in humans.

What about non-pharmacological treatments? These also could be relevant. For instance, psychoeducation. Give more knowledge to people as to what their good points and their bad points are. There's quite some evidence that vital functions, physical functions, and good mental functions are correlated, have some relation to each other.

The active lifestyle has been mentioned, however. I must admit that there have not been many experimental studies in this area. I expect that eventually a combination of pharmacological and non-pharmacological interventions may prove most effective.

In conclusion, caffeine has clear affects on cognition and energetic functions. The drugs with clearly proven affects in humans are not yet available, although there are drugs that can prevent the rapid deterioration of Alzheimer's Disease. In that respect, there has been great progress through the last few years, but drugs which can treat the cause of Alzheimer's Disease or the cause of memory dysfunction don't exist. We should be aware of that. That's one major reason, again, to keep doing research and be involved in this kind of work. Psychoeducation and non-pharmacological interventions may have relevance.