You’re Looking Very Well

by Lewis Wolpert

  Studies have revealed that separate brain regions that are involved in higher-order cognitive functions show less-coordinated activation with ageing. This reduced coordination of brain activity is associated with poor performance in several cognitive domains. Although neuronal loss is minimal in most regions of the normal ageing brain, changes in the connections between ageing neurons may contribute to altered brain function. More than 150 genes have been found to undergo age-dependent expression changes in the brain; some of these are more active with age in mice but less so with age in humans. The function of these genes and how they are turned on and off is not yet understood. Studies on mice have identified memory disturbances in the ageing brain as being due to certain genes associated with memory being turned off. There are also lower concentrations of neurotransmitters like dopamine, which has important roles in behaviour, cognition and voluntary movement. In the human brain, declining mitochondrial function may selectively affect neuronal populations with large energy demands, such as the neurons that degenerate in Alzheimer’s disease.

  With mental activities, there is usually a much less dramatic decline with age than with physical activities. It varies a great deal, but the old can still be very productive. Politicians can continue to be active until rather old, some might say too old. Roman emperors ruled until they were of extreme old age. Augustus, who lived until the age of 76, remained in office until his death and didn’t stop visiting the Senate on a regular basis until he was 74. Winston Churchill was still prime minister at the age of 80.

  Scientists usually do their best work when young, but there are important exceptions, such as Galileo writing Dialogues Concerning the New Sciences when he was 72. The physicist Max Planck wrote: ‘Scientific theories don’t change because old scientists change their minds; they change because old scientists die.’ It has been found that science professors in their 50s and 60s published almost twice as many papers each year as those in their early 30s. When he was 80, André Gide said that he did not detect any weakening of his intellectual powers but did not know what to turn them to.

  Writers, painters and sculptors do not lose their skills with age, and many have produced their finest works in the last fifteen or so years of a long life. At 97, Enrico Paoli, an Italian chess master, was the strongest active nonagenarian chess player in the world. He learnt chess when he was nine and started playing tournaments at 26. He won his last Italian championship title at the age of 60. Paoli was playing master-level chess at 96—in 2003 he played the international tournaments. Jose Raul Capablanca, the ‘Mozart of chess’, regarded Emanuel Lasker, who was world chess champion for 27 years, as the most dangerous player in the world in a single game, even as the latter neared 70. No other contemporary, he thought, surpassed him in his ability to evaluate a position and find the correct strategy.

  The decline of memory with age depends on the specific nature of the memory, as there are different types. For example a patient with a particular brain damage cannot recollect personal experiences, but can learn new motor skills and lists of words. This is an implicit memory and involves recall of motor and academic skills without conscious awareness of previous experiences. It is distinct from explicit memory, which involves recall of previous experiences and information. Explicit or episodic memory involves the memory of autobiographical events, including recent events, such as times, places and associated emotions and is the most common memory loss with age. As the length and complexity of sentences increases, older adults have more difficulty understanding and recalling them. Yet factual knowledge does not decrease with age, though spatial memory, such as the layout of a museum recently visited, does decline.

  It is common with old age to forget names of people or to lose a particular word—even though it is on the tip of the tongue. Usually the name or word is recalled later when one is thinking about something quite different. I have lost names, so too have many of my friends. I have also forgotten the faces of people whom I know quite well and have to ask them who they are when they greet me, and then I recall who they are. It is a bit embarrassing not to recall the name of someone you know when you meet them and need to introduce them to someone else. One also loses common objects, or as Edward Grey put it: ‘I am getting to an age when I can only enjoy the last sport left. It is called hunting for your spectacles.’

  Jonathan Swift, the author of Gulliver’s Travels, describes a familiar experience:

  That old vertigo in his head

  Will never leave him, till he’s dead:

  Besides, his memory decays,

  He recollects not what he says;

  He cannot call his friends to mind:

  He forgets the place where he last dined:

  Plies you with stories o’er and o’er,

  He told them fifty times before.

  Though there is no significant loss of knowledge with age, the elderly do not encode information into long-term memory as efficiently as the young. Forgetting to do something as one ages is common and worrying. Around 60 per cent of participants in a study of those aged 75 and older forgot to perform an action that they had previously been requested to carry out. A typical example of loss of a recent memory is the case of a distinguished but ageing TV presenter who went out to dinner on a Friday night. When he rang the hostess’s bell there was a delay, then she put her head out of an upper window and said hello. ‘Have I come on the wrong night?’ he asked. ‘No,’ she replied, ‘it was last Friday and you were here.’ All too familiar.

  * * *

  Complaints about memory are the most frequent cause for seeking medical advice about dementia. This is the result of episodic memory going wrong and leads to forgetting personal and family events and appointments; losing items round the house; repetitive questioning; inability to follow plots on TV or in films; forgetting past events and news items; and getting lost. The elderly have many more memories for events that occurred in adolescence and early adulthood than in midlife. Very few elderly show improved cognitive functioning in the evening, and unlike the young, their performance gets worse through the day. The herbal treatment ginkgo, used by the Chinese for thousands of years to overcome loss of memory in the old, has been shown to be totally ineffective. All the fuss over fish oil as a key brain food may be unjustified. A two-year study found there is no evidence that the supplements offer benefits for brain function in older people, contradicting previous surveys on the wonders of omega-3 fatty acids. But physical fitness contributed to more than 3 per cent of the differences in cognitive ability in old age after accounting for a participant’s test scores at age 11.

  About half of all lifetime cases of mental illness begin by age 14 but the chance of developing a mental disability increases as we age. The most common and serious one is dementia, an overall impairment in cognitive functioning sufficient to affect everyday activities, and there may be depression, hallucinations and delusions. The term dementia was introduced by Philippe Pinel in Paris in 1801; he also introduced the idea that people suffering from it should be treated with kindness—many patients at that time had actually been kept in chains—and he called this new principle ‘the moral treatment of insanity’. One of Pinel’s students, Dominique Esquirol, gave a very detailed and still valid description of dementia, pointing out, for example, that sufferers entertain perfect indifference to objects that were once most dear, and this includes relatives. They also often have a ridiculous passion. He carried out autopsies and noted abnormal convolutions in the brains of patients, but microscopic examinations of such brains had to wait for work on Alzheimer’s.

  While dementia is rare before 60, it increases with age and is present in 5 per cent of the over 65s and in 20 per cent of the over 80s. Dementia isn’t a specific disease, rather it describes a group of symptoms affecting intellectual and social abilities severely enough to interfere with daily functioning. Different types of dementia exist, depending on the cause. Low education and diabetes can contribute, and mental and physical activity help p
revent it. Alzheimer’s disease is the most common form of this disease, and is the cause in two thirds of cases of dementia. It increases the risk of dying by two to five times, and for those over 85 accounts for one third of deaths, though this is rarely on the death certificate. Staff who look after Alzheimer’s patients need to recognise it can be a terminal illness.

  Dementia and normal ageing may be on a continuum. Memory loss generally occurs in dementia, but memory loss alone doesn’t mean there is dementia. It can be difficult to distinguish between onset of Alzheimer’s and ordinary ageing relapses of memory and cognition. Dementia has many causes and some dementias, such as Alzheimer’s disease, occur on their own, not as a result of another disease. Some dementias, such as those caused by a reaction to medications or an infection, are reversible with treatment. Recent research shows that up to 80 per cent of people diagnosed with mild mental or cognitive impairment go on to develop much more debilitating dementia within just six years. As well as the personal devastation caused by cognitive decline, it is also the single biggest reason why older people lose independence and require 24-hour care.

  There are some 820,000 people in Britain with dementia, about half of whom suffer from Alzheimer’s disease. Generally Alzheimer’s is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer’s can occur much earlier. The disease in those in the 30 to 40 age group is rare, and even rarer are cases due to a genetic defect that results in it occurring in those as young as 16. There are estimates that there are over 20,000 younger people with dementia in the UK. The Alzheimer’s Society estimates that the disease costs Britain £17 billion a year. Families caring for patients save the government £6 billion a year. It is expected that a further one million people will develop dementia in the next 30 years, and it is projected that expenditure on long-term care services for older people with dementia is set to increase from about £4.6 billion in 1998 to £10.9 billion in 2031. It is claimed that 5.3 million Americans are living with the disease; a new case develops every 70 seconds. An estimated 27 million people worldwide had Alzheimer’s in 2006; this number may quadruple by 2050.

  Dementia causes problems with at least two brain functions, memory loss along with impaired judgement and language. Dementia can make an individual not just confused and unable to remember people and names, but also experience changes in personality and social behaviour. Some causes of dementia are treatable and even reversible, but early diagnosis is important so that treatment can begin before symptoms worsen. If the diagnosis is a dementia that will progressively deteriorate over time, such as Alzheimer’s disease, early diagnosis also gives a person time to plan for the future while he or she can still participate in making decisions. A quite simple test has been developed for detecting early stages of Alzheimer’s that would require further investigation. It is a two-page questionnaire, and has ten tests that include remembering a phrase, doing sums, identifying parts of a man’s suit, and drawing the time on a blank clock face. A quite different early diagnosis may be based on examining the fluid in the spine for the proteins that are responsible for the disease.

  The disease is named after Alois Alzheimer, who was born in 1864 in Germany and studied medicine. He then worked at the Municipal Mental Asylum in Frankfurt, and later moved with Emil Kraepelin to the Max Planck Institute in Munich. He died in 1915. His first patient with the disease that was eventually to carry his name was Auguste D., a 51-year-old woman. She presented with jealousy of her husband, paranoia, memory impairment and, towards the end of her life, loud screaming. On 3 November 1906 Alzheimer presented the results obtained from studying the structure of the cellular organisation of her brain which included several fibrils—amyloid protein—and numerous small abnormal foci due to cell death. It was his mentor Emil Kraepelin who gave the disease his name in the eighth edition of his textbook in 1910.

  At the early stages of Alzheimer’s disease the most commonly recognised symptom is memory loss, such as difficulty in remembering recently learned facts. Typically there is misplacing and losing objects and repeatedly asking the same questions. The sufferer has difficulty in finding words to complete a sentence and comprehension is poor, as is doing complex motor tasks. There are also non-cognitive symptoms—delusions, depression and anxiety, and verbal and physical aggression. Patients can be very difficult. One patient hit his wife, and did not understand the difference between night and day—he could go to bed and get up thirty times in a night. Median survival is about five years. Apathy can be observed at an early stage, and remains a most persistent symptom. Despite the loss of verbal language abilities, patients can often understand and return emotional signals. A remarkable finding is that facial asymmetry in men results in an increased mental decline in the years before death.

  Although it may not be easy, people with Alzheimer’s disease can live quite full and productive lives. Taking time to prepare for the challenges that come as the disease progresses will ease the difficult transitions. Well-known personalities such as Bernard Levin and Iris Murdoch had Alzheimer’s, and Terry Pratchett has a special form. He has problems recognising visual signals and can take minutes to tie a tie, but his talking is fluent, though his reading can be confused. Watching him and others with Alzheimer’s on a BBC TV programme, there was nothing in the way they talked or behaved which gave any indication of abnormality. But they could not remember what had happened recently, and one could not copy a geometrical design. Pratchett has said he ‘would eat a dead mole’s arse’ if it would cure him. He wants to be able to choose when to die. The TV journalist John Suchet has described the dementia of his wife, which started when she was 61. She now will pile dirty plates on top of clean ones, and repeatedly flush the toilet when not using it. Her memory is poor. Husbands and wives are six times more likely to get dementia if their spouse has it. This could be related to the stress of caring or living with someone in that condition.

  Andrea Gilleas describes in her book Keepers the severe problems of looking after a mother-in-law with Alzheimer’s. A recent play, Really Old, Like Forty Five by Tamsin Oglesby, takes place when Alzheimer’s has reached epidemic proportions. A family are trying to deal with an elderly lady member suffering from the disease. There are, unusually, comic elements like robot nurses, midway between cat and carer, and bizarre plans to help by government officials.

  Some cases of early-onset Alzheimer’s may be caused by a number of different gene mutations. These mutations cause the formation of abnormal amyloid, fibrous protein aggregates in the brain. One of the ways proteins can have severe negative effects is by becoming an amyloid. Many different proteins can do this, developing sticky elements which enable them to stick together and form sometimes deadly fibres. The amyloid appears to bind to the neurones with a prion protein that is associated with BSE and Creutzfeldt-Jacob disease. The amyloid accumulation interacts with a tau protein which gets into nerve cells and causes the formation of aggregates of particles, leading to the tangles which cause the death of nerve cells. Recent studies correlated levels of the tau and amyloid proteins in the cerebrospinal fluid with changes in cognition over time, and found that changes in these two protein levels may signal the onset of mild Alzheimer’s. This is a significant step forward in developing a test to help diagnose the early stages of Alzheimer’s disease.

  One predisposing genetic risk factor is related to the APOE genes that code for proteins that help carry cholesterol in the bloodstream. APOE comes in several different forms; APOE4 occurs in about 40 per cent of all people who develop late-onset Alzheimer’s and is present in about 25 to 30 per cent of the population. People with Alzheimer’s are more likely to have an APOE4 gene; however, many people with Alzheimer’s do not have it. There is concern that a genetic test for this gene could lead to excessive anxiety. This is particularly true of individuals whose parents have suffered from the disease. A study of such individuals tested for the APOE gene did not find any serious anxiety in those who tested positive, but no
ne suffered from anxiety or depression prior to the test. In addition, they were given counselling and followed up for a year. A surprising feature of the gene is that those who have it are more intelligent.

  There is no cure for Alzheimer’s, but a few drugs such as Aricept can improve memory a bit, and have general benefits including improving alertness and motivation for those in the early stages. It may take some months for there to be a noticeable improvement or slowing down of memory loss. Claims that the anti-histamine drug Dimedon had positive effects have now been shown to be wrong. Non-drug treatments include reality orientation with clocks, boards and newspapers; reminiscence therapy recalling past events like marriage; cognitive stimulation therapy like physical and mental games; and music therapy. There is evidence that exercise and a diet rich in fruit and vegetables lowers the risk of getting Alzheimer’s. A good education also lowers the risk.

  Dementia with Lewy bodies, which are abnormal aggregates of protein that develop inside nerve cells, is thought to be second only to Alzheimer’s disease as a cause of dementia. It is similar in some ways to both the dementia resulting from Alzheimer’s disease and the movement problems of Parkinson’s disease. While Alzheimer’s disease usually begins quite gradually, dementia with Lewy bodies often has a rapid or acute onset. Typically there are recurrent visual hallucinations, and Parkinsonian motor symptoms such as rigidity and the loss of spontaneous movement. These patients will often have a sleep behaviour disorder that involves acting out dreams, including thrashing or kicking during sleep. Patients may also suffer from depression. As with all forms of dementia, it is more prevalent in people over the age of 65. It gets is name from the protein clumps that develop in nerve cells and damage them and it overlaps clinically with both Alzheimer’s disease and Parkinson’s disease, but is more associated with the latter. The overlap in the presenting symptoms—cognitive, emotional, and motor—can make an accurate differential diagnosis difficult.