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Alzheimer's


Alzheimer's disease is the most common form of dementia that occurs in the elderly. Approximately 5-10% of the population over the age of 65 shows some sign of Alzheimer's disease. However, the disease is not restricted solely to the elderly. Some patients with early onset familial Alzheimer's disease (approximately 10% of all Alzheimer's disease sufferers) may have symptoms as early as the fifth decade of life.

Alzheimer's disease is characterized by a slow but progressive deterioration in cognitive performance. Typically confusion and forgetfulness (i.e., remembering recent events) are some of the early signs.

What is the cause of Alzheimer's disease?
The precise mechanisms, which cause Alzheimer's disease, are still unknown. However, there is now clear evidence that certain factors predispose individuals to Alzheimer's disease. That is to say that they are risk factors. It is now clear that heredity plays an important role in the pathogenesis of Alzheimer's disease.
A very small percentage of individuals are known to possess mutations in the gene encoding a protein known as the amyloid protein precursor or APP. These mutations are autosomal dominant and are localized on chromosome 21.

A larger percentage of patients suffer from a familial form of Alzheimer's disease associated with loci on chromosomes 14 or 1. The genes responsible for this form of Alzheimer's disease (presenilin-1 and presenilin-2, respectively) have recently been identified. They encode homologous proteins with multiple putative transmembrane domains. The physiological function of the presenilins is as yet unknown, although some early research suggests that the mutations in these genes may increase the rate at which the amyloid protein is produced from its precursor. Additionally, a C. elegans protein known as sel-12 has been identified, which shares amino acid sequence similarity to the presenilins. This protein is known to be involved in the facilitation of signaling by one or more members of the notch family of cell surface receptors.

The majority of Alzheimer's disease sufferers have the late-onset or sporadic form of the disease. It is now recognized that possession of one or two copies of the E4 allele of the apolipoprotein E gene (located on chromosome 19) is a risk factor for late-onset Alzheimer's disease.

Environmental risk factors may also play a major role. For example, there is evidence that head trauma could be a contributory factor. Although aluminium toxicity has not been ruled out as a contributory factor, there is as yet little strong evidence for a causal link.

The observation that cholinergic neurons in the basal forebrain are affected in Alzheimer's disease has led to the cholinergic hypothesis, which states that some of the cognitive changes, which occur result from a deficiency in cholinergic neurotransmission.

Biochemical Pathology of Alzheimer's disease

Amyloid plaques consist principally of a single building block, a polypeptide of 4 kDa referred to as the amyloid protein. The amyloid protein is derived from a much larger molecule known as the amyloid protein precursor or APP. APP has features of an integral transmembrane cell surface protein and is a common constituent of normal healthy cells. The precise mechanism whereby APP is cleaved to produce the amyloid protein is the subject of a considerable amount of research activity today.
However, cleavage of APP to produce the amyloid protein is only the first step in the production of amyloid plaques. There is evidence that proteins like apolipoprotein E may contribute to the aggregation of the amyloid protein to form the dense proteinaceous plaques, although this theory has not been completely established. Apolipoprotein E exists in three major allelic forms, termed apoE2, apoE3 and apoE4. Recent evidence suggests that individuals with the apoE4 allele have a slightly greater risk of getting Alzheimer's disease between the ages of 65-75.
Approximately 10% of all cases of Alzheimer's disease are inherited. This means that they are caused by mutations in specific genes. Mutations have been identified in the APP gene (very rare), and in genes known as presenilins (about 5% of all AD cases).

Some studies suggest that amyloid plaques (or strictly speaking, amyloid fibrils) are neurotoxic, and that this is the underlying reason for the neurodegeneration that is seen in Alzheimer's disease. Several theories have been proposed to explain why amyloid fibrils are neurotoxic. A large number of studies have shown that amyloid fibrils can disturb calcium homeostasis in cells. As calcium is important for neurotransmission (eg., the release of acetylcholine and other neurotransmitters) and for cell viability, such disturbances may be important for understanding disease pathogenesis. Other studies suggest that changes in oxidative metabolism result from the build-up of amyloid fibrils. Such a hypothesis may help to explain why anti-oxidants are beneficial. An inflammatory component to amyloid fibril toxicity also seems likely. Glial cells (both microglia and astrocytes) are commonly seen to invade neuritic plaques and may they be a source of APP or inflammatory cytokines, which influence APP production by neurons. Such a hypothesis may explain why anti-inflammatory drugs are beneficial.

Finally, it is worth noting that the production of plaques in the brain may not be a sufficient condition to cause Alzheimer's disease. Other factors may also be involved. There is evidence to suggest that diffuse plaques may have to mature into so-called neuritic plaques prior to the onset of clinical symptoms. A major debate rages over whether amyloid plaques are the cause of the neurodegeneration. It is quite possible that the plaques are simply an end-stage of amyloid fibril build-up. Alternatively, they may be a secondary feature of an underlying pathogenic mechanism. What seems very clear, however, is that the overproduction of forms of the amyloid protein which aggregate readily is sufficient to cause Alzheimer's disease. To date, all mutations in the presenilin and APP genes, which are pathogenic and which have been studied for their biochemical effects, have been shown to cause in increase in amyloid aggregation. As it is highly unlikely that all mutations would cause the same biochemical effect simply by chance alone, this indicates that amyloid aggregation is a necessary condition for disease pathogenesis.

Is there a treatment for Alzheimer's disease?

To date, there is no effective treatment for Alzheimer's disease. Research has suggested a number of possible approaches to treatment, but so far, none of these approaches has been clearly demonstrated to cause a significant improvement in the majority of Alzheimer's disease sufferers.

A partial list of therapeutic strategies is outlined below. Many of the approaches listed below are still in the basic research stage. For other strategies, drugs are being trialed. To date, only (Cognex) and Aricept, and Exelon (all cholinesterase inhibitors) have been approved for treatment by the US Food and Drug Administration. This list is by no means complete, and is not necessarily given in any particular order.
Cholinergic strategies
Acetylcholinesterase inhibitors (e.g., tacrine, Cognex, or Exelon)
M1 muscarinic receptor agonists
Neurotrophic factors (e.g., Nerve growth factor)
Inhibitors of oxidation (eg., vitamin E)
Metal chelating agents
Immunotropic drugs
Non-narcotic analgesics (eg., Ibuprofen)
Inhibitors of beta-A4 aggregation
Estrogen

How is Alzheimer's disease diagnosed?

"Diagnosing Alzheimer's Disease - Physician's Guidelines"

In the diagnosis of Alzheimer's Disease (AD), initial assessments are aimed at identifying the pathognomic features of the disease whilst excluding unrelated pathologies.

An eventual diagnosis of likely Alzheimer's Disease can be made after elimination of other forms of dementia and organic brain disorders.

N.B. Symptoms of Alzheimer's Disease are chronic, progressive and include:
- loss of recent memory, disorientation, inability to recall people, places, events; inability to remember everyday words, getting lost in familiar areas, wandering, aggressiveness, deterioration in personal habits/appearance.

Initially
1. History of stroke/MI/hypertension - eliminate multi-infarct dementia [TIAs, hypertension, focal neurological signs or symptoms and fluctuations in level of functioning suggest multi-infarct dementia, which is more likely in cigarette smokers]
2. Interview close family or carer:
- duration and course of symptoms? - carers main concerns (e.g. wandering, incontinence, aggressiveness)
- is patient becoming more forgetful?
- is there a change in behaviour and/or personality, or loss of skills or personal habits?
3. Carry out the Mini Mental State Examination (MMSE) (Non demented patients should score close to 30. Inconsistent responses to cognitive testing are common in depression, which does not cause problems with language (dysphasia) or parietal lobe symptoms such as disorders of motor skills (apraxia)]
4. Routine investigations to exclude other pathologies (Some of these may already have been undertaken by the patient's GP)
full blood count
gamma-glutamyl transferase
B12
syphilis serology (only if suspected due to patient's history)
folate
TSH
midstream urine
blood glucose
chest X-ray

After the initial procedures, the following investigations also should be made, although they do not necessarily have to be carried out in the order shown.

* If patient is depressed/delirious/psychotic (which may suggest pseudodementia)
give treatment where appropriate
Are dementia symptoms still present after therapy?
if not, patient probably does not have AD unless depression/deliriousness/psychosis were co-existent with dementia

* Investigate neurological signs if appropriate
exclude normal pressure hydrocephalus

Elimination of organic causes of dementia
These include:
Reversible - Intracranial processes and space-occupying lesions: tumour, sub-dural lesions, normal pressure hydrocephalus, general paralysis. Systemic disorders: cerebral anoxia, thyroid and parathyroid disorders, uraemia and liver disease, vitamin deficiencies, alcoholism, poisoning by drugs and chemicals, occult tumour.
Irreversible - Multi-infarct dementia, dementia of the Lewy body type, Pick's Disease, Jacob-Creutzfeld, Huntington's chorea, Parkinson's disease.
Most reversible causes can be eliminated after analyses of the patient's history, blood tests, chest X-ray and full physical examination.

Carry out suitable cognitive/global performance tests such as:
1. CAPE - Clifton Assessment Procedures for the Elderly
2. ADAS - Alzheimer's Disease Assessment Scale
3. CIBI - Clinical Interview Based Impression

1. A diagnosis of probable AD may be given at this point if:
2. patient has continued to show typical signs of dementia which show no remission
3. haematological investigations are normal or abnormalities can be explained
4. MMSE consistently <26 -
5. patient is not depressed/delirious/psychotic/pseudodemented or AD symptoms still show even after successful treatment of one or more of these
6. cognitive test results consistent with typical AD sufferer
7. multi-infarct dementia has been excluded as a cause

Finally
If diagnosis cannot be made at this stage consider CT scan - eliminate or confirm normal pressure hydrocephalus - are space occupying lesions present? (if so, this implies patient's symptoms are not caused by AD)
if CT shows either no abnormalities other than cortical atrophy and /or enlarges ventricles, symptoms are probably due to AD
PET/MRI scans may be considered in addition to CT where available and justifiable

The Mini Mental State Examination (MMSE)
This examination should only take about 10 minutes. It provides an assessment of the patient's mental state, and has become widely recognized as an initial test for a possible diagnosis of dementia.
ORIENTATION
1. What is the date/day/month/year/season? (Max. 5 pts) 2. Name the surgery (clinic) name road/town (area)/district/county (Max. 5 pts)
REGISTRATION
3. Name 3 objects, then ask the patient to name (Max. 3 pts) them. (Repeat this until the patient names all three, or has six trials to do so)
ATTENTION AND CALCULATION
4. Ask the patient to count backwards from 100 (Max. 5 pts) in 7's. Stop after 5 answers.
(alternatively ask the patient to spell "world" backwards)
RECALL
5. Ask for the 3 objects you named earlier to be (Max. 3 pts) repeated.
LANGUAGE
6. Naming: Show patient a wrist watch and a pencil and ask what they are. (Max. 2 pts)
7. Repetition: Ask the patient to repeat this sentence. "No ifs ands or buts" (Max. 1 pt)
8. Follow a command: Ask the patient to take a sheet of paper in their right hand, fold it, and put it on the floor. (Max. 3 pts)
9. Reading: Ask the patient to ready and obey the following:
CLOSE YOUR EYES (Max. 1 pt)
10. Give the patient a sentence to write, with a subject and a verb: e.g. The man was running for the bus. (Max. 1 pt) (correct grammar and punctuation are not necessary)
11. Draw two intersecting pentagons, each side about one inch
Ask the patient to copy it exactly. All to angles must be present and two must intersect to score one point. Tremor and rotation can be ignored. (Max. 1 pt)
Consider additional testing for a score of 26 or under.
* Certain authorities recommend a score of <23 for further follow up.
Reference: Folstein MF, Folstein SE, McHugh PR J.Psychiatr.Res. 1975. 12. 189-198

A special appreciation to Parke-Davis Research Lab for allowing us to use the information:
This publication was reproduced from a pamphlet supplied as a service to the Medical Profession by: Parke-Davis Research Laboratories, Chestnut Avenue, Lambert Court, Eastleigh, Hampshire S05 3ZQ. Telephone (0703) 620500.
Date of preparation, November 1993.

Source: Alzheimer Society of Ottawa-Carleton.


Information from the Alzheimer's Disease Institute
A special appreciation to ADI for supplying this information

About Alzheimer's disease
Alzheimer's disease is the most common cause of dementia. Dementia is a collective name for progressive degenerative brain syndromes, which affect memory, thinking, behavior and emotion. Symptoms may include:
loss of memory
difficulty in finding the right words or understanding what people are saying
difficulty in performing previously routine tasks
personality and mood changes

Dementia is not a normal part of aging. It knows no social, economic, ethnic or geographical boundaries. Although each person will experience dementia in their own way, eventually those affected are unable to care for themselves and need help with all aspects of daily life. There is currently no cure.

Causes of dementia
There are a number of diseases, which cause the symptoms of dementia as a result of the changes they have on the brain and the ultimate loss of nerve cells (neurons). The most common causes include:
Alzheimer's disease
Vascular (multi-infarct) dementia
Dementia with Lewy bodies
Fronto-temporal dementia (eg Pick's disease)
Alcohol-related dementia (including Korsakoff's syndrome)
AIDS-related dementia

It is not currently understood why people develop dementia but there are many factors, which have been suggested to have an effect on the risk of developing dementia. Some of these include; age, genes, education, and alcohol and head injury.

Alzheimer's disease
Alzheimer's disease is the most common cause of dementia and accounts for 50% - 60% of all cases. It destroys brain cells and nerves disrupting the transmitters which carry messages in the brain, particularly those responsible for storing memories. Alzheimer's disease was first described by Alois Alzheimer in 1906.

During the course of Alzheimer's disease, nerve cells die in particular regions of the brain. The brain shrinks as gaps develop in the temporal lobe and hippocampus, which are responsible for storing and retrieving new information. This in turn affects people's ability to remember, speak, think and make decisions. The production of certain chemicals in the brain, such as acetylcholine is also affected. It is not known what causes nerve cells to die but there are characteristic appearances of the brain after death. In particular, 'tangles' and 'plaques' made from protein fragments are observed under the microscope in damaged areas of brain. This confirms the diagnosis of Alzheimer's disease.

Symptoms
Typically, Alzheimer's disease begins with lapses of memory, difficulty in finding the right words for everyday objects or mood swings. As Alzheimer's progresses, the person may:
Routinely forget recent events, names and faces and have difficulty in understanding what is being said
Become confused when handling money or driving a car
Undergo personality changes, appearing to no longer care about those around them
Experience mood swings and burst into tears for no apparent reason, or become convinced that someone is trying to harm them

In advanced cases people may also:
Adopt unsettling behaviour like getting up in the middle of the night or wander off and become lost
Lose their inhibitions and sense of suitable behaviour, undress in public or make inappropriate sexual advances.

Finding help
There is a lot of help available for people with Alzheimer's disease and other dementias, caregivers and other interested parties on several different levels. Alzheimer associations exist in many countries around the world and many of these have branches or chapters throughout the country. Alzheimer associations provide information and support and can advise you of any services available in your area, as well as answer any specific questions you may have. Getting in touch with your Alzheimer association is one of the most important steps you can take.

Alzheimer's Association
919 N Michigan Avenue
Suite 1000
Chicago, Illinois 60611
United States of America
Tel: +1 312 335-8700
Fax: +1 312 335-1110
Email: info@alz.org


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