3
Grey Cells:
the anatomy of the ageing brain
The dark interior of the red-brick building at number 37 on Madrid’s sunny Avenida del Doctor Arce is home to the Cajal Institute, a neuroscience research centre set up early in the 20th century. It is named after its first director, Nobel Prize winner Santiago Ramón y Cajal, famous for his precise drawings of brain cells (neurons) and the methods he developed to accurately reproduce the cell structure. He was also a pioneer when it came to understanding what happens to neurons as we age.
Cajal’s oak desk still stands in the Institute’s library. Here, he did his painstaking work, producing countless anatomical drawings. It is quite an experience to see the originals: not only was Cajal a scientific genius, but he also had artistic talent. He was able to depict the neurons and their dendrites (branch-like projections) in such detail because he used chemical substances to colour brain tissue so that its structure was clearly visible under the microscope. Cajal used thin slices of tissue from the brains of cadavers, along with colouring agents developed shortly before by the Italian doctor and scientist Camilo Golgi.
Through his accurate observations, Cajal disproved the prevailing theory (which Golgi also subscribed to) that the brain consists of a network of cells connected by threads, like a spider’s web. Cajal discovered that the dendrites of nerve cells do not touch, but are separated by a tiny gap known as the synaptic cleft. Neurons communicate with one another not through a physical connection but through chemical messengers (neurotransmitters), which traverse the gap between neurons and attach themselves to receptors in the neuron’s cell wall, like a key in a lock. This is how they transmit signals, and each substance has its own receptor.
FIGURE 10. Drawing of neurons by Nobel Prize winner and neuroscientist Santiago Ramón y Cajal (1852–1934).
Cajal’s important discoveries led to much greater knowledge about how the brain works. Communication between neurons is the basis for functions such as memory, concentration, and thinking skills. If we want to know what changes in our brains as we get older, Cajal’s drawings show us the main elements of that process. Figure 10 is one of his drawings. The black dots are the neurons, or ‘control centres’. The dendrites are the tiny projections emerging from the neuron wall. The longer threads are called axons: they carry signals from one neuron to another. Figure 11 shows a simplified version of two neurons that are in contact with each other.
FIGURE 11. Neurons and their dendrites.
As figure 11 clearly shows, a neuron has one long projection (the axon), and lots of dendrites. Axons are enclosed in a fatty sheath, known as myelin, which increases the speed at which signals are transmitted. The areas of the brain where many axons come together are known as ‘white matter’, because of the colour of the myelin layer. ‘Grey matter’ is mainly at the outer edge of the brain, the cerebral cortex, where the cell bodies of the neurons are. White and grey matter are clearly visible on an MRI scan.
As I explained, neurons use neurotransmitters to send signals to other neurons. The neurotransmitters either increase or reduce the chance that the neuron in question ‘depolarises’, which means that an electrical signal is transmitted from the cell nucleus to the end of the axon. That process can activate another neuron, and then another, eventually forming a full circuit. A circuit consists of groups of neurons (hundreds of thousands of them), sometimes from different areas of the brain, which are connected to one another and work together, for instance when we speak or read. Cajal demonstrated that neurons form the building blocks of our brains and are the basis for all brain activity. The brain has around 100 billion neurons distributed over four large areas: the frontal, temporal, parietal, and occipital lobes (see figure 12).
FIGURE 12. The brain is divided into four lobes: the frontal, temporal, parietal, and occipital lobes.
So what happens in our brains as we grow older? We know of course that something changes, since our mental capacities change, as we saw before, and our mental capacities are inextricably bound up with brain anatomy and function. But what exactly changes? Do neurons die? Does the form or composition of the neuron cell nucleus change? Or is it to do with the projections (some might say the ‘wiring’) or the fatty sheath around the axons, which normally speeds up brain activity? And which area of the brain suffers the most because of those changes? There are enough questions here to warrant a closer look at the anatomy of the brain. But before we do that, we have to know more about general ageing processes in our bodies.
CHANGES AT CELL LEVEL
Brain cells are subject to the same ageing process as other cells in the body. Many studies have shown that the activity of the insulin hormone is vital to that process. This is because insulin is an essential part of our metabolism, the process that converts the food we eat into energy. After many years, this process results in the wear and tear that accompanies ageing. Insulin works through a chain reaction involving other substances in our bodies, including hormones related to insulin. This is known as the glucose–insulin system. People whose glucose–insulin system is not highly active tend to live longer. Its activity is related to how many calories you consume — in other words, people who eat little, but consume a healthy portion of food every day, live longer. This idea is not new: it was proposed as far back as the 2nd century CE by the Greek physician Galen as an effective prescription for a longer life. The 16th-century writer Alvise Cornaro was also a firm believer in the theory. Since then, countless studies have confirmed this view, although most of them used animal subjects such as mice. Reduced calorie intake is also a feature of the Okinawa diet, which I will discuss later.
Thus, eating less means you can live a longer and healthier life. For some people, this is an automatic process: they are genetically programmed to eat in moderation. Although it’s not entirely clear how eating less leads to a longer life, biologists believe that when times are hard and an organism gets very little food, a physiological reaction is launched. This protects cells through reduced activity in the insulin-signalling pathways and so increases survival chances. Or to put it another way: a slower metabolic rate means less wear and tear.[1]
Connected to this is another mechanism that plays an important role in ageing: oxidative stress. This occurs when chemically reactive molecules containing oxygen are produced in greater amounts than normal, which can result in cell damage. Some of these molecules are free radicals, a natural by-product of breathing — that is, we all have them.
Oxidative stress is a cumulative process associated with ageing, and it is particularly harmful to DNA, the genetic information contained in the cell. Although it was long thought that oxidative stress is always harmful to the cells, it now seems likely that a degree of stress can do no harm — only very high levels are damaging. Eating a lot increases the metabolic rate and therefore oxidative stress, while eating just a little has a protective effect.
There are many other things that influence the ageing of our cells besides the glucose–insulin system and oxidative stress. One example is the mitochondrial damage that builds up over the years. Mitochondria are structures essential to cells, including neurons, because they play an important role in metabolism. Another influential factor is the weakening of our lungs and hearts as we age. As our blood vessels become harder and thinner, fewer nutrients and less oxygen reach the brain. This can lead to hypoxaemia — reduced blood oxygen levels — or, in the worst-case scenario, anoxia, which is a complete lack of oxygen. This can result in cell damage and even cell death, and may lead directly to reduced brain function.
A BRAIN AGED 115
Only 20 years ago, scientists thought that as we grew older our brain cells started to die, a process that began at birth and sped up after the age of 70. New research has shown, however, that most brain cells remain reasonably intact until we die (as long as there is no brain disease present). This was certainly the case with 115-year-old Hendrikje van Andel, whose brain was studied by neuropathologists at the University Medical Centre Groningen (UMCG) immediately after her death.
Reaching the age of 100 is a special event for anyone who lives that long, but particularly for Hendrikje. When she was born in 1890, she weighed only 1.6 kilograms and her chances of survival were low. As a child, her health was poor: she became ill after her first day at school, and her parents decided that she should stay at home. Her father was a teacher and he home-schooled her; she went on to become a teacher herself.
Until the age of 105, Hendrikje lived independently. After that, her sight deteriorated so much that she had to move to a retirement home. But mentally she was still alert. She listened to the radio every day and knew what was going on in politics and sport. At the age of 82, not knowing how long she would live, she had decided to donate her body to medical science after her death. When she was 111, she contacted UMCG to ask them whether such an old and fragile body was still useful to them. So the scientists decided to pay her a visit. They explained to her that her body was of great significance for research and asked if she was prepared to undergo a number of cognitive tests. She was glad to be able to do something for science, and undertook two sets of neuropsychological tests: once when she was 112, and then again when she was nearly 114. These showed that she had an exceptionally good memory for her age — in fact, she could recall stories slightly better than the average 70-year-old. She was also able to focus her attention and recognise objects by touch. The second set of tests showed that she had slightly more difficulty with questions that called on her working memory and with reasoning, but she had no clear cognitive disorders and no sign of Alzheimer’s. This was confirmed by the post-mortem examination. Hendrikje’s brain tissue was remarkably intact — unlike in people with Alzheimer’s, there was little build-up of protein and there was hardly any sign of shrunken or dead neurons. Nor was there any significant hardening of the arteries. In fact, the cause of her death had nothing to do with her brain: she died of undiagnosed stomach cancer.
DNA research has since shown that genetics probably played an important role in keeping her brain healthy as she grew older: she proved to have the ‘good’ variant of a whole series of genes that are linked to Alzheimer’s. Her mother lived to the age of 100, which also indicates an inherited element. According to the researchers in Groningen, the case of Hendrikje van Andel shows that reaching an extremely advanced age is not automatically accompanied by substantial deterioration in the brain or by brain disease. Nevertheless, changes take place even in the brains of healthy people as they grow older.
CHANGES IN THE BRAIN THAT ACCOMPANY AGEING
Generally speaking, the weight and volume of the brain diminish as we move into old age. The brain grows continuously from infancy until about the age of 21. For much of the previous century, you weren’t treated as an adult until you reached the age of 21; and in terms of neuroscience, you might say that 21 was a less random choice of age for adulthood than 18. Between the ages of 20 and 50, brain volume remains fairly constant, although this depends on the individual. After that, it gradually begins to decline (a total of about 10 per cent), and around the 80th year of life you see a substantial reduction in volume. Areas such as the frontal cortex and the hippocampus (figure 13) are more affected by ageing than other parts of the brain. This can be seen in the reduced volume of grey and white matter and in the level of activity in these areas. The frontal cortex is involved in planning and looking ahead, in working memory, and in organising and monitoring our behaviour, while the hippocampus is essential to our long-term memory, particularly information storage (though the frontal cortex, in its turn, is instrumental in retrieving that stored information). So one answer to the question of why older people are more forgetful could be that their hippocampus has shrunk slightly, which means they find it more difficult to retain information.
FIGURE 13. Location of the hippocampus in the brain.
Large-scale studies using MRI scans to measure brain volume show that the frontal parts of the brain shrink more than the areas at the back. Some of these studies compared a group of older people (aged 60 to 80) with a younger group (20 to 40). This is not an ideal method, since other differences between the groups besides age may play a role. Older people may have different lifestyles, social contacts, or eating habits, all of which could influence the results. From a scientific point of view, a more convincing result can be obtained by studying the same group of people over a number of years, subjecting them to MRI scans every ten years or so, and tracking changes in their brains. This is known as longitudinal research.
The American neurologist Susan Resnick, who is the principal investigator on the Baltimore Longitudinal Study of Ageing, did just such a study. For four years, she followed 92 people whose ages varied from 59 to 85 and measured their brain volume using MRI scans. After the first year, the only thing she found was an enlargement of the ventricles, the cavities in our brains that are filled with cerebrospinal fluid. This is an indication that the brain tissue has shrunk slightly, which is inevitable given that everything still has to fit within the cranium (the upper bony structure of the skull). After two years and four years, however, Resnick found a reduction in the volume of both grey and white matter. The reduction in grey matter was mainly visible in the frontal and parietal lobes and, to a lesser extent, in the parts of the temporal lobe essential to the storage of information (the hippocampus is also in the temporal lobe). The back part of the brain, the occipital cortex, was the least affected.
In contrast, the reduction in white matter was spread over the entire brain. The reduction in white matter is a sign of a decrease in myelin, the fatty sheath surrounding the axons that increases the speed at which signals are transmitted. This could of course be the underlying reason for the diminished processing speed in older people that I described earlier. MRI studies have in fact shown that older people whose white-matter tracts (the ‘wiring’ of our brains) are no longer intact respond more slowly in neuropsychological tests such as the digit symbol substitution test discussed in chapter 1.[2]
Other studies focused exclusively on changes in white matter as people aged. A common finding in all these studies was that minor damage to white matter, known as white-matter changes, can be seen from around the age of 50. On an MRI scan, these show up as small, bright white spots. The older a person is, the more of these minor injuries can be seen. Although they aren’t necessarily serious, they do have a relationship to diminished cognitive function. This was demonstrated in a study carried out by the University of Edinburgh. People with an average age of 78 were invited to participate in a study involving MRI scans of their brains. The unusual feature of this study was that researchers had access to test results of the subjects’ mental capacities (such as memory and concentration) at age 11. In 1932, the subjects had taken part in a large-scale regional study, the Scottish Mental Survey, which included tests of reasoning, speed of processing, and memory. After undergoing a brain scan, the same people, now aged 78, took a number of tests measuring cognitive function. The crucial question was what would be a better predictor of their current mental capacities: the test results from when they were children, or the white-matter changes visible now? The answer was remarkable: they were equally good predictors. About 14 per cent of their current performance could be explained on the basis of their childhood scores, while another 14 per cent could be explained by white-matter changes. In other words, if you scored well as a child, there was a greater chance that you would do the same at age 78. But white-matter changes can affect the picture. If you have them, you perform less well on memory and speed-of-processing tests. The individual differences were interesting. If Gareth had a better memory than Mary in 1932, that might well be reversed 67 years later if he had more white-matter damage.
A final point: it is not just the volume of the brain that shrinks; its weight decreases too. On average, the brain becomes 5 to 10 per cent lighter between the ages of 50 and 80. The furrows (sulci) in the cerebral cortex widen, while the ridges (gyri), which contain the grey matter, become narrower. If brain cells do not die in huge numbers as we age, how can the brain’s volume and weight decrease? It’s likely that this is partly the result of certain brain cells shrinking. Some of the dendrites die off, but not the neurons themselves or the axons. There is also a decrease in the number of synapses, where the passage of signals from one neuron to another occurs.
REDUCED GROWTH IN BRAIN CELLS
Scientists are just like the rest of us: they too can have fixed ideas that they find difficult to shake off. One such idea in neuroscience was the belief that the mature brain no longer produced new cells — that no new neurons were generated once you reached adulthood; they simply died in greater numbers. People were so convinced of this that any indications that new brain cells could be produced was simply disregarded. In the last 20 years, however, the evidence for neurogenesis (the growth of new neurons) has become so overwhelming that no one can ignore it anymore. Neurogenesis primarily takes place in the hippocampus, the structure that is so important to learning and memory. Thousands of neurons are produced on a daily basis in this area, though admittedly most of them die again within a few weeks. The chance that a neuron will survive is linked to learning processes. When you learn something new, such as a foreign language or how to play the flute, it is highly likely that some of the new cells will be used for this. New cells make it easier to learn something new.
Recently, an interesting hypothesis emerged, arguing that ageing in the brain is largely caused by a reduction in neurogenesis. Is there any evidence for this intriguing supposition? There is certainly evidence for the claim that neurogenesis slows down in the older brain — in fact, it diminishes by 80 per cent. Older brains also contain fewer stem cells (cells that are capable of changing into another type of cell). The question is whether this is connected to poorer mental performance, a link that has been shown in mice. In one study, substances naturally produced in the bodies of older mice were injected into younger mice, causing neurogenesis to slow down.[3] Consequently, the younger mice were less able to find their way through a maze. Research into growth factors in our bodies that promote neurogenesis show that these factors also improve mental capacities in older people. The effectiveness of these growth factors has therefore not diminished — they still play a part in creating new cells or repairing damaged cells — but they have decreased in number. We’ll return to this later.
THE PASA PATTERN
For the non-specialist, the titles of research articles are usually fairly dry and boring. But now and again there’s a little bit of humour. Take for example the article published in 2008 by an American research group led by neuropsychologist Roberto Cabeza — it was entitled ‘Qué PASA? The posterior–anterior shift in aging’. Of course, you have to know that in Spanish-speaking countries, que pasa is almost invariably used as an opening remark when people meet. A good English translation would be ‘What’s up?’ So what’s up with brain activity in older people? As the title of the article shows, PASA stands for the posterior–anterior shift in ageing, the phenomenon by which less activity in the back of the brain is seen in older people than in their younger peers, while there is correspondingly more activity in the front of the brain. In the last 15 years, functional MRI studies into ageing have established clear changes in brain activity. The numerous results that have been published constantly refer to PASA, the shift from the back to the front of the brain in older people who are performing a task well. In one of the studies, people aged around 70 performed a memory task using words and an observational task using pictures. These are two very different tasks: the first mainly activates the frontal and temporal lobes; the second, the occipital areas at the back. A shift in brain activity towards the front of the brain could be clearly seen in older people.
But what does this mean? The results of a number of studies show that what is happening is a type of compensation. Certain areas of the brain are called upon to compensate as much as possible for a declining ability to perform tasks involving memory, concentration, and co-ordination of thought and action. Cabeza’s research shows that in older people undergoing tests while in the MRI scanner, a more noticeable PASA pattern correlates with better performance. In other words, the anterior part of the brain, which we learned earlier is the most affected by ageing in terms of the structure and function of brain tissue, has to draw on all its resources in order to perform well. Calling more on this area helps older people to get the most out of their brains. In many, this process is automatic and unconscious, but it is quite possible that training our mental skills could reinforce this pattern.
PASA is not the only resource older people can draw on. There is another change that is often observed in the older population: a reduction in the asymmetry of brain activity.[4] ‘Asymmetry’ here means that one side (or hemisphere) of the brain is more active than the other. In the performance of language tasks, for instance, the left side is usually more active than the right. But when listening to emotional music, the right side is more active in most people. Dozens of studies have shown that a reduction in this asymmetry occurs as we age, and this more bilateral pattern of activity mostly takes place in the frontal lobe. Researchers have demonstrated that in younger people, it is primarily the right hemisphere that is active during the performance of visual-attention tasks, while in older subjects both are active. Conversely, younger people performing language tasks (word-based tasks involving working memory) largely called upon the left hemisphere, while in older people the left side was less active and the right side more. Is using the hemispheres more equally also a case of compensation, or is it a more general effect that occurs in ageing — in other words, that the different parts of the brain concern themselves less with specific tasks and are more generally active? More specifically, could an area that in younger people is primarily involved in language processing contribute to visual attention in older people? Smaller areas would thus be less active in specialised tasks, spreading the pattern of activity more generally over the entire brain.
FIGURE 14. Older people use the right and left hemispheres more equally (see arrows). The right hemisphere contributes to working memory and the left to focusing attention on visual stimuli (e.g. pictures that may appear in different places on a screen).
Research results point to the existence of compensation: older people who do not display a shift towards greater bilateral activity in the two sides of the brain perform less well in memory tasks than those whose brains show evidence of reduced asymmetry. One study in particular produced clear evidence of this phenomenon. On the basis of brain activity during the recall of information acquired earlier, it distinguished three groups: first, young adults in whom the right frontal cortex was largely activated; second, older people showing the same pattern of activity; and third, older people whose right frontal cortex was less active, but whose left frontal cortex was more strongly activated (that is, who showed reduced asymmetry). Which of the two groups of seniors performed the best? You might imagine it to be the group showing the same pattern as the young adults, who, as expected, performed well. But that was not the case. The group of older people displaying reduced asymmetry performed better than the group showing the same pattern as the young adults. This is strong evidence for reduced symmetry being a form of compensation. More research is needed into compensation, but it is perfectly possible that it involves a reorganisation of neural networks that results in parts of the brain ‘co-operating’ better with each other.
A TIDY BRAIN
Why do the cognitive skills of some older people continue to be superior to those of others of the same age? At 77, Dutch politician Frits Bolkestein wrote The Intellectual Temptation, thought by some critics to be his finest book. Yet there are others in their late seventies who cannot concentrate sufficiently to even read such a book.
To explain this striking difference between people of the same generation, researchers came up with the ‘cognitive reserve’ hypothesis, according to which our brains have some degree of reserve capacity. Both genetic and environmental factors affect its size. How can we describe this reserve capacity? It is divided into structural capacity and functional capacity. The first is dependent on the amount of intact brain tissue and connections between different areas of the brain (that is, brain structure); the second, with the way different areas of the brain function (that is, brain activity).
A simple example illustrates the difference between the two. Imagine you have a shed full of all kinds of objects and belongings. You decide to put some of them in your attic because the shed has reached full capacity. The attic is your reserve capacity. It is structural because it is a physical space: your reserve capacity is dependent on extra physical structure. But what you could also do is rearrange the objects in the shed to create more space. My wife points this out this every year when I’m packing the car for our summer holidays. So this is comparable to functional reserve capacity — a different strategy for arranging things releases existing space for other uses. Do older people who still function well in cognitive terms have functional reserve capacity? Indeed they do. Making greater use of the areas at the front of the brain (the PASA effect) and of both hemispheres is an example of this. With regard to structural reserve capacity, an undamaged hippocampus can expand that capacity, while the accumulation of protein that accompanies ageing will reduce it. What is also important is whether neurogenesis is taking place. Thus, if you want to keep your cognitive functions in good shape, you need to do something about your brain’s reserve capacity. Later on, we’ll look at whether that’s possible; and if so, how.
IMPORTANT INSIGHTS