DEMENTIA AND ALZHEIMER'S DISEASE
Dr. Mathew Abraham, M.D. (Gen. Med), D.M.(neuro)
Consultant Neurologist
Indira Gandhi Co-op. Hospital, Cochin
Dr. Radhika warrier M.D (Gen. Med)
Senior Registrar, Dept. of Neurology
Indira Gandhi Co-op. Hospital, Cochin
 India is slowly ageing. As a poor, under developed country at the time  of developed country at the time of independence, our life expectancy was only 40 years, with a very high birth rate. This result in a pyramidal demographic pattern, in which children constituted the broad base, while the apex of the pyramid was made up of a small number of aged people. As health parameters  have improved, this pyramid has become smaller at the base, acquired a broader middle and a higher apex, which would reflect the present day birth rate which is lower, a broader, economically active young and middle aged population, and a larger number of ageing people, which is growing even larger as we advance (Life expectancy in India for males is 57.7 years and of Female is of 58.1 years; in USA for males is 73 and of female of 79. In Kerala, life expectancy for males is 66.8 and of female is 72.3). About 8% of the present national population falls in this aged category (over 60 years). Of these, only 33% fall in the "young-old" group of between 60 and 65, while the majority constitutes the "old-old" (above 65 years)
 As a person gross older, there is a process of natural dying of various cells, and a  slow erosion of one's faculties, physical & mental. In fact, from the moment of our birth, there is a biological death clock that starts ticking. This determines the rate of natural growth and dying out, and is programmed into the genetic code of each cell. How this dying out process is calibrated and set is still a great mystery, except that genetic factors are primarily responsible .Environmental and toxic factors also have a role in this process. The brain cells are no exception to this, and with age, they too gradually undergo a process of natural ageing & death. However, the rate at which this process occurs is never severe enough to affect the person'd daily mental and thinking faculties so that he is never incapacitated in his routine day to day activities.
 Occasionally, however, this process of brain cell attrition and death may occur faster than usual, resulting in the impairment of one's faculties, severe enough to be detrimental to one's daily activities. This is condition of DEMENTIA. This abnormal brain-cell death may be the result of identifiable disease or toxic factors (multiple strokes, alcohol abuse syphilis or AIDS), inherited diseases (like Huntington's chorea) or disease of as yet unknown causes (like Alzheimer's Disease).
 As one grows older, the chance of developing dementia becomes higher. This is understandable as the dementia process seems to be a result of accelerated ageing (due to multiple causes). Between the ages of 60 and 65, (the young old), the chances of developing dementia are about 5%. This increases by 5% for every 5 years of advancing age, so that by 80 years of age, a person has a 20% chance of being demented. It is estimated that by the 2011 census, 10% of India's Population will be above 60. This gives us an idea of the magnitude of the imminent problem.
 In Kerala, this is going to be bigger. Because our local health statistics are better than the national averages, by 2011, 13% of our population in Kerala will be above 60. Moreover, this state has more women than men, and the women live longer than men. This is going to produce the unique problem of having a large number of elderly widows in this state. Social changes will also be adding to the problem. The break up of the joint family system has been fairly rapid and so the support of the elderly has become increasingly the responsibility of the children. Large number of our work force are employed outside the state or in the gulf, leaving many elderly parents back home to fend for themselves. It is thus not difficult to understand why the establishment of old age homes is going to be a future growth industry in Kerala.
What, than, is Dementia ?
 Dementia is the gradually progressive, acquired loss of cognitive faculties of the brain, in multiple domains of functions, in an alert, fully-conscious patient. Each of these terms requires a little elucidation. Cognition is the ability to act reasonably & logically in a given set of circumstances and it is the loss of this logical, deductive process that occurs in dementia, Moreover, normal brain functioning involves various domains - memory, logical thinking & planning, abstract thinking, visuospatial integration, and the processing of various incoming stimuli in the visual, tactile and auditory areas. Dementia results in the loss of more than one of these realms.
 One more condition requires definition at this stage - Pseudodementia. This, as the name implies is a false loss of brain function resulting from a state of anxiety and depression. Faculties appears slower or more confused than normal, and memory appears to be slowly fading. However this is an eminently treatable condition, and the early and correct identification of the anxious, depressed state can bring about a full and very rewarding recovery of function.
The symptoms of Dementia and Alzheimer's
 Very often the first symptoms are noticed by a patients immediate family members or a colleague in the office. The patient appears to be a little confused or is not as sharp as usual. He may forget where he kept his keys or his files. He may be slow in taking decisions, and sometimes his judgment may be affected. He may lose his way in familiar surroundings. More often, than not, the deterioration of mental faculties may appear or become obvious after a high fever or serious illness, but a careful history would clarify that this was a pre existing, ongoing process that was made obvious by the acute illness. Sometimes the patient loses his insight into the illness. He is unaware or the fact that he is demanding, and it is the relatives who bring this to the attention of the doctor.
 Broadly, the clinical symptoms of dementia and Alzheimer's disease can be grouped under the following.
1) Memory Disturbances : Would be the hallmark of a dementing process and is a very early symptoms. The pattern of memory loss is also fairly characteristics, in that, remote and distant memory is fairly well preserved, while very recent memory is impaired to various degrees. The patient may not remember what he had for lunch that day (or whether he had lunch at all) but paradoxically, is able to relate minute details of his childhood. Such a peculiar memory loss often results in the relatives assuming that the patients "acting" a memory loss, When in reality, it often holds the key to the true dementing process. This is in contrast to all forms of memory, recent and past may appear to be equally affected.
2) Language Disturbances : Are also very common early occurence. This may be found in the inability of the patient to express himself clearly, choose the right word or have difficulty in naming people and objects. Often the understanding of spoken speech is affected, resulting in the confused babbling and jargon. A formerly fluent and silver-tongued speaker may soon ba at a loss for words. The problem may gradually deteriorate till he becomes totally mute.
3) Apraxias and Agnosias : Apraxias is the inability to execute a particular action (In response to a command) in the presence of normal power, sensation and co-ordination. Such a patient would be unable to follow a command (e.g. Touch your right ear) although he may later be seen doing the same thing spontaneously. Agnosia is the inability to comprehend the meaning of an incoming sensory signal, so an object cannot be identified on sight, or the spoken word cannot be understood.
Essentially aparexias and agnosias result from faulty processing and transmission of information in various parts of the brain.
4) Visuospatial Disorientation : The ability to integrate in space is a function predominantly done in the non-dominant Right side of the brain. When this area is affected, patients have a peculiar difficulty in finding their way in familiar surroundings. Drawings become difficult to copy and 3 dimensional depictions are very difficult to visualize. Dressing may become a problem as the patient loses his ability to button a shirt properly or pleat a sari.
5) Behavioural problems : These are some of the most distressing symptoms in dementia. The patient may become agitated and aggressive and very easily provoked in to bouts of temper and even violence. There may be mood changes, swinging from mania to depression. Crying spells may occur, interspersed with facetious and inappropriate laugher. Fixed ideas and obsessions may become a problem. patients can develop ideas of persecution, with paranoid feelings. Hallucinations and illusions may occur with the patient reacting to these ideas. Some patients develop megalo-mania, with ideas of overconfidence and over ambition. This may be lead to erroneous judgments in their financial and personal affairs. They may get into indiscrete sexual escapades, leading to shocking scandals and social ostracization.
 The behavioural aberrations of dementia probably constitute the most stressful dilemmas that the families and caregivers face.
6) Bladder and Bowel Incontinence: With the damage to certain frontal areas of the brain the patients loss control over bowel and bladder functions. They may pass urine or bowels in inappropriate locations. Moreover, having lost insight into their actions, they are not bothered about these indiscretions, which only adds to the embarrassment of the family.
7) Gait Disturbance : Patients develop a short shuffling gait with hesitancy about what to do with their feet and where to place them, This usually gets worse with tome, and eventually the patient become bedridden.
 The above - mentioned symptoms form a spectrum of the disease. An individual patient may start with any of the above symptoms, depending on which part of his brain is affected first, but over time, many of the other symptoms appear. Moreover, there are variations between patients as to which symptoms will be the predominant one, although disturbances of memory always constitute a major problem.
The role of the Doctor - the Clinical Approach to Dementia
 Very often, it is the relative who brings the patient to the doctor, indicating that he is "losing his memory" From the history and examination, the doctor essentially determines whether the deterioration in faculties is needed a cognitive decline and whether it involves multiple domains i.e., is it a case of true dementia?.
 Since there are a few cases of reverisible dementia, which are secondary to specific diseases, the next step of the diagnosis is to identify whether the patient has a treatable or reversible dementia or not. This he may do by a series of tests, which include routine blood tests, specific tests for vitamine B 12 deficiancy, syphlis, hypothyroidism, or liver or kidney disease. A CT or MRI scan may be ordered to rule out treatable conditions like a brain tumor, subdural heamatoma, (A clot outside the brain) or a normal pressure hydrocephalus. ie collection of fluid inside the brain The early identification of these conditions is vital, as any delay in diagnosis will render these irreversible. A specific mention has to be made here about the possibility of the condition being a case od pseudo dementia. Appropriate treatment with anti anxiety and anti depressant drugs would help get such a person back to his pre morbid, normal state.
 It is only after the treatable causes of dementia have been ruled out, that the doctor considers the possibility of an untreatable dementia like Alzheimer's disease. This essentially means that Alzheimer's is a diagnosis of exclusion, since this constitutes, up to now an untreatable, irreversible, slowly progressive condition - a death sentence. 
 Even with a diagnosis of Alzheimer's it is worth the while of the doctor to periodically review the diagnosis, to keep searching for an alternative that might be treatable.
 What happens in Alzheimer's disease ?
 Essentially there is a premature ageing and accelerated cell death, that is restricted to the brain cells, while the body remains healthy. This results in a shrinking or atrophy of the brain with intercellular connections being snapped. it effectively short circuits the electrical activity of the brain at various places, resulting in distorted and aberrant neuronal transmission, which in turn produces misinterpretions of incoming sensory signals and outgoing verbal and motor commands. This is what leads to a decline in the patients mental faculties.  
 Pathologically the brain gets seeded with senile plaques-small discs of an amyloid protein, that are surrounded by the remnants of nerve cells called neurofibrillary tangles. This happens in even the normally aging brain, but in Alzheimer's the process is far more intense and widespread, resulting in the disruption of neuronal circuits.
 There are also alterations in the specific messenger chemicals of the brain (Neurotransmitters). A significant decline has been detected in the chemical messenger - Acetylcholine, because of the specific deficiency in a catalytic enzyme, Choline Acetyle Transferase. Other neuro transmitters like Adrenaline and Serotonine are also deranged, but no specific causative link could be attributed to them so far. The identification of the deficiency of Acetycholine has offered a possible clue to a method of treatment of Alzheimer's. Drugs like Tacrine and Rivastigmine reduce the breakdown of Acetylcholine, thus helping to sustain its level for longer periods. This has offered some promise in slowing down the relentless progression of the disease.
 What triggers off these abnormal changes remains a mystery
 A small proportion of patients with Alzheimer's have a similar condition affecting close relatives- the inherited variety of the disease. The aberration here has been identified to be located on some chromosomes (1 and 14) or due to aberrant lipoproteins. This genetic pre disposition However does not explain the cause in the vast majority of patients with Alzheimer's. Since the specific causative factors remain in the realm of conjuncture, a large number of possible culprits have been implicated viruses, toxins, increased aluminum in the cells. None of these have conclusively been held responsible for causing Alzheimer's disease.
What is new in AD
 A lot of new discoveries have been made in the field of AAAD in the last decade. These involve the areas of genetics, pathophysiology and therapeutics.
 As mentioned before AD is usually a sporadic disease. However in a small percentage of patients, there is a familial incidence. It has long been known that some of the pathological changes in the brain resemble the changes seen in Down's syndrome and this was a clue to the possibility that the abnormality lay in the chromosome 21, where the Down's defect was. The defect in the gene here results in the formation of abnormal amounts of BAP which is also slightly different in composition from the normal BAP. This gets deposited in the brain to form senile plaques.
 Subsequently abnormal genes have been found in other chromosomes. An abnormality in chromosome 14 results in the formation of Presenellin 1, while another abnormality in chromosome 1 results in Presenellin 2. Both these forms result in inherited AD with different characteristic age of onset and rates of progression. On the other view, an abnormality in Chromosome 19 results in the formation of the E4 allele of the Apolipoprotien. This produces an increased risks of Alzheimer's disease, though it does not invariably lead to AD in all cases.
The recent unraveling of the genetic code has now allowed us a method of possibly understanding the exact sequence of the abnormal genes, and the  way these gene products (proteins) go on to produce AD. This method allow us to modify and correct the genetic abnormality in the future or block the deleterious affects of the gene products by genetic engineering. this is an area of great promise
 New understanding of the pathological process and possible avenues of treatment.
 As mentioned before, AD results mainly in the deposition of abnormal amounts of beta Amyloid protein which form the core of the characteristic senile plagues. It has now been found that the BAP is cleaved from a mother protein, Amyloid precursor protein by a scissor enzyme Gamma Secretes. This is a normal process that occurs in all cells, but in AD this phenomenon is exaggerated. Moreover, the cleavage takes place at a different site, resulting in the formation of an abnormality long BAP containing 42 aminoacids ( as compared to the normal sequence of 40 aminoacids) The abnormal BAP tends to elicit an immune response from surrounding lymphocytes resulting in the release of prostaglandins that can also damage innocent cells nearby. Specific inhibitors of Gamma secretes would offer a method of reducing the abnormal formation of BAP.
 The normal neuron has a cytoskeleton that consists of parallel rows of protein strands that are held in place like the sleepers of a railway track by special protein molecules called tau and ubiquity. In AD some damage occurs to the protein, resulting in their inability to hold the cytoskeleton in place. this lead to a distortion of the cytoskeleton, malformation of neurofibrillary tangles and neuronal malfunctioning.
 It is still controversial what initiates the process. There has been a feirce debate between the Baptists (scientists who support the fact that abnormal deposition of altered BAP is the primary process) and the Tauist (who claim that the formation of neurofibrillary tangle occurs first). Some progress has been made in the resolution of this controversy because of the development of special genetically modified stains of Labmice. One strain has an abnormality that mimic human AD in that there are usually large amount of BAP deposit in their brains. Recently a vaccine has developed that seems to halt deposition of BAP in these mice, and even reverse the process. Human trails are presently under way and this offers promise for essential control and cure of AD
 Similary strains of mice has been developed that mimic the formation of neurofibrillary tangles. Once again cross breading of the two strains has led to the presents of both BAP and neurofibrillary tangles, providing an animal model of the disease. This is great stride in experimental work, providing a platform where AD can be experimentally studied and newer drugs can be tride out in before being extended to man.
 Derangement of various neurotransmitter systems especially Acetylcholin is a hallmark of the disease. Tremendous  advance has been made in the understanding of the basic mechanism of neurotransmitter function, and specific method of correcting the malfunctioning in various diseases. So far, the mainstay of drug treatment of AD has been the cholinesterase inhibitors which prolong the effect of the depleted acctyl-choline, partially reversing the malfunctioning. Newer and better ChE inhibitors have been developed, which have more specific action and fever side effects. Rivastigmine, Galantamine are some drugs that shows promise. Other drugs like special prostaglandin inhibitors( Cox - 2 inhibitors) may block the effects of the immune reactions elecited by abnormal deposition of BAP. This would probably control the damage to normal cells in AD. Similary, some newly discovered Nerve growth factors may help in restoring some of the damaged synapses and even replication of new cells to replace the dead or dying once of AD.
 Eventually, the promise of complete cure lies in the understanding of the basic genetic defect that results in the formation of abnormal proteins. The recent discoveries of the human genetic sequence will go a long way in the unravelling of these mysteries and would result in total cure of AD in the not so distant future.
Approach to management of Alzeimer's disease
 Since the disease remains untreatable, no specific drug can help cure the malady. The patient is best looked after at home, in surroundings that he is most familiar with, among people he knowns for long.
 Putting demented patients in an unfamiliar environment will only increase their confusion. Hospitalization should be reserved for any acute medical or surgical condition that requires attention. What is important to remember is that any sudden deterioration in cognition requires an intensive search for an infection or the possibility of trauma, being a cause. Depression is often a problem and the use of the new antidepressants like Fluoxetine may specifically help here, in turn reducing the confusion and irritability.
 Aggressive behaviour is quite common and caregivers need special training in handling these situations, learning to defuse them and avoiding provoking patients into violence. Often drugs may be needed to control the behavioural disturbances.
 Sexual aggression is an aspect that has not been given enough attention. For the caregivers, it is often the most taxing and stressful of all the problems associated with Alzheimer's. Sleeping in a different room might help but occasionally specific tranquillizers are needed to curb this problem.
 Since the pathology of Alzheimer's involves the specific deficiency of Acetylcholine, drug treatment involves using agents that reduce the breakdown of this neurotransmitter. Tacrine and Rivastigmine are two drugs which have shown some promise. They probably help in decelerating the down hill course of the disease, without reversing the process. Whether they help would depend on what stage the therapy is started. At present these drugs are not easy to get and are very expensive, beyond the reach of most people.
The caregiver and Alzheimer's
 It often falls upon the closest family members to look after a patient with Alzheimer's. This is even more relevent in this country as we do not have a system of organized old age homes or centers where demented patients are specially cared for.
 Being a caregiver for a demented patient is one of the most stressful situations one can ever imagine. It is indeed a tragedy to see a person you may have loved and respected disintegrate before your very eyes. There is no emotional return for the caregiver, for him to keep the association going- it is progressively a one-way affair. It can be very demanding on one's time, patience and physical resources. It can be a very depressing experience.
 There are a number of ways by which the burden can be reduced. Properly educating the caregiver, in all the aspects of dementia, along with special training in handling the specific situations one may encounter, will certainly help them cope better. Proper organization of one's time and resources can reduce the physical and mental stress. Having two or three members in the household who can take turns in care giving will also aid the process. This is becoming increasingly difficult in these days of unclear families, and often help has to be sought from outside. Taking a break from these chores helps to relieve some of the stress. The support of organizations like the Alzheimer's Society also is very useful in these situations. It help the caregiver interact with others who can share their experience and ideas about coping. The common bond of having to go through a similar trauma can be emotionally very supportive.
The role of the Alzheimer's Society and other NGO's in dementia
 Specified organization like the Alzheimer's Society help to bring similarly affected people and their relatives together. Meeting of affected people with professionals in the field helps them keep abreast of the latest on the subject. As mentioned above, caregivers find a forum to exchange ideas, clarify doubts and share experiences. special training programmes for caregivers help improve their coping skills physically and emotionally which does a lot to relieve stress and depression.
 Most all these societies help spread information and awareness of these diseases, and in turn, help exert the might of public opinion on Governmental policies for the aged.
What of the future?
 As of now, Alzheimer's remains a death sentence. But with the enormous amount of research going on throughout the world, especially in the last "Decade of the brain", important insights have occured into the pathophysiology of the disease. Some progress has been made in producing effective drugs. We need a few serendipitous discoveries for that all important break through, for a cure.
 Today, the situation may still appear grim and hopeless. But then, this was the case with smallpox and polio, not so long ago. Small pox has been eradicated worldwide, and polio will become a footnote in history in a few years from now. If such dreaded diseases could be effectively conquered, surely there is hope yet for the unfortunate victims of Alzheimer's disease.