Alzheimer's Disease


Alzheimer's Disease
Alzheimer's disease is a degenerative disease of brain tissue that causes progressive and irreversible loss of mental functions. It is the leading cause of dementia among the elderly, affecting approximately 24 million people throughout the world.

The process responsible for the neurodegenerative disease is still poorly understood: it is due to the formation of amyloid plaques and tau protein aggregates forming the neurofibrillary degeneration. The cortical atrophy resulting in a key first time the internal temporal lobe (including the hippocampus) and the frontal cortex associations and temporo-parietal at a later stage.

The exact cause is still unknown, but it is assumed that environmental and genetic factors contribute to it. Mutations in at least four genes that predispose to Alzheimer's disease have been identified. They are particularly involved in familial cases early onset, which represent less than 5% of patients with Alzheimer's disease. For the so-called sporadic form of Alzheimer's disease, an increasing number of susceptibility genes (such as ApoE) have been identified.

Until the 1960's, it was assumed that the disease was rare, but later we realized that in many cases, what we took for normal aspects of senescence was a result of this disease.

The first symptom is loss of memory of recent events (amnesia), which manifests itself initially by minor distractions which gradually increases with disease progression, while the oldest memories are relatively preserved. Thereafter, cognitive deficits extend the areas of language (aphasia), the organization of movements (apraxia), visual recognition (Agnosie) and executive functions (such as decision-making and planning) . These symptoms reflect a particular disease process of degeneration up to the frontal lobes of the brain. These psychological changes affect human qualities essential and for this reason the disease is sometimes described as a disease in which the victims suffered the loss of qualities that form the essence of human existence.

Alois Alzheimer (1864-1915) is a psychiatrist and a German neuropathologist from the early twentieth century who studied the brains of people with dementia, through a new technique colouring aniline and impregnations silver.

In 1906, Alois Alzheimer described for the first time the anatomical changes observed in the brain of a patient of 51 years, Auguste D. Achievement of dementia, it also presented hallucinations and disturbances of orientation. In 1911, Alzheimer discovered a case similar to that of Auguste D.

It is the psychiatrist Emil Kraepelin who suggested that the disease is named after Alzheimer's, named after its discoverer.

There are usually a form of "sporadic" by far the most common in the elderly, and a "familial", starting more précocément.

Alzheimer's disease says more than half of all cases of dementia in the elderly. The prevalence of the disease increases sharply with age.

In Belgium, the prevalence of dementia is estimated at 5 to 10% after 65 years and nearly 20% beyond 80 years.

In France, the study "PAQUID" (1988-2001) showed that 17.8% of people over 75 years are suffering from Alzheimer's disease or a related syndrome. According to a departmental assessment of 2004, approximately 860 000 people are affected by Alzheimer's disease in France. A figure could reach 1.3 million in 2020 and 2.1 million in 2040. The number of new cases is about 225 000 per year.

The prevalence of the disease increases if there is a history of trauma or cranial vascular disease. This increase can be explained by a lysis neuronal symptomatologiquement making the disease earlier.

The plaques (or amyloid plaques)
It is extracellular lesions of Alzheimer's disease. These plates are the accumulation of a peptide and abnormal nerve 42 amino acids, peptide A β42, the most amyloïdogène beta-peptide amyloïde.Ce, normally of 40 amino acids, comes from a bad cleavage of the protein (APP Amyloïd Precursor Protein). This would participate in the massive entry of calcium into the neuron and activate microglia (inflammatory reaction), leading to inevitable death of the neuron by necrosis or apoptosis. These plates are mainly located in the neocortex and the hippocampus.

The neurofibrillary degeneration
These cell injury secondary to the accumulation of tau protein (protein association with microtubules that are part of the cytoskeleton) hyperphosphorylée responsible for the formation of filaments matched. When the tau protein is hyperphosphorylée, it will comply with a pair of helical filaments, and then aggregate to train neurodégénérescences fibrillar. The substances necessary for the proper functioning of neuron could therefore no longer be sent to cell body and the neuron will die.

Forms Genetic
Less than 1% patients have a disease of purely genetic origin. This form is characterized by:

* The appearance of signs before age 60;
* An autosomal dominant (half of each generation is reached).

Two genes are involved:

* A mutation in the APP gene on chromosome 21 that encodes a precursor of amyloid protein (five changes in the codon 717 are known);
* A PSEN1 gene mutation on chromosome 14 (many mutations which are mutations false sense).

Genetic predisposition
The so-called sporadic forms, ie non-family, also include a genetic predisposition:

* Is the existence, discovered in 1993, the APOE4 is the 4 allele of the gene apolipoprotein E which is significantly linked to increased risk of Alzheimer's disease. But the presence of the APOE4 is neither necessary nor sufficient to develop the disease;
* The gene for apolipoprotein E is present in three forms allelic: APOE2, APOE3, and APOE4. The first is found in 51% of the population, the second meeting in 80% of the population and the third is found in 15% of the population;
* The presence of the APOE4 in the form heterozygous increases by 2 the risk of Alzheimer's disease;
* The presence of the APOE4 in the form homozygous increases by 11 the risk of Alzheimer's disease.

The apolipoprotein E intervene in the mechanisms of neuronal repair.

The cellular mechanisms underlying the neuronal degeneration
There are two levels of mechanisms: intra-and extracellular.
In both levels, there is an accumulation of proteins which leads to a malfunction of the cell. In the intracellular mechanisms, the accumulation called neurofibrilles. In the extracellular mechanisms, it is called amyloid plaques.

The middle intracellular
In microtubules, protein Tau placed on a perpendicular and allow the rigidity of microtubules for axonal transport.

From time to time, subject to a normal proteins Tau stand out. They are replaced and degraded rapidly.
But in a subject suffering from Alzheimer's disease, protein Tau become detached from the microtubules, and fall in the intracellular environment. They are not all degraded and will therefore aggregate. That will train neurofibrilles. The neurofibrilles too large block the functioning of the neuron and do not allow proper axonal transport. The neurofibrilles compress the neuron and cause neuronal death.

There are several explanations for the posting of Tau proteins:

* Phosphorylation: this allows the functionality of the protein. The protein Tau is very little phosphorylated and when it is very phosphorylated, it can not focus on the microtubules. Thus, the proteins that stand out and accumulate in forming neurofibrilles. In this explanation, the cause of the increase in phosphorylation is unknown.
* Cuts proteolytiques of tau proteins, which seem to intervene early and way would be a landmark event concomiant the hyperphosphorylation of these proteins.
* Genetic factors: Like all proteins, there is a gene that encodes the protein Tau. The gene may have different alleles in September. These seven alleles can be classified into two categories:
o those three grounds R
o those four grounds R.

Tau proteins derived alleles in three grounds have a fixation R less important than proteins derived alleles for four reasons.

The middle extracellular
In the mid extracellular protein at stake is the protein amyloid. It is a membrane protein (located on the cell membrane). This protein is detached from the membrane and enters the extracellular environment. It is then recovered and then deteriorated.

In patients with Alzheimer's disease, the degradation is not complete and a fragment, called β-amyloid, rest and can not be degraded. These fragments eventually aggregate and form amyloid plaques. In accumulate in the extracellular environment, these plates compress neurons. This phenomenon leads to a malfunction, which may be followed by the neuronal death.

The plaques will liberate H2O2. This application will show two OH molecules called free radicals. The molecules will therefore involve their free electron. The membrane will be "holes", which will leave penetrate other free radicals which will tackle the DNA of neuron. The functions of the cell will be destroyed. It will therefore be no more genetic information.

The cause of the accumulation also appears with normal aging, but accumulation at the base of Alzheimer's is not known.

The only factor is a genetic factor. This is another protein to act with this process of formation of amyloid plaques. It's called apolipoprotein E. this protein depends on an allele that can be of three kinds: E2, E3 and E4.
The alleles E2 and E3 are specific to the human species. They come from a mutation E4. The allele is the most common allele E3 (70%), followed by E4 allele (20%) followed by the E2 allele (10%).
The E4 allele is associated with the formation of amyloid plaques. This allele would inhibit the growth neuritique (training axons and dendrites). This growth allows the neuronal plasticity. This phenomenon is very important for the functioning of the central nervous system. The E4 allele is therefore associated with diseases of neuronal dysfunction. The allele E3 promotes neuronal plasticity, but not as much as the E2 allele. It is for this reason that the E2 allele is associated with longevity.

The emergence of the disease
In order to study the disease, mice transgenic (genetically modified) are used. In some mice, the gene encoding the protein is mutated Tau. Among others, the gene encoding the protein amyloid, who is transferred. Some mice will undergo mutations in two genes.

The mice that had a mutation in the gene encoding protein Tau show an outbreak little pronounced. The mice that had a mutation in the gene encoding the protein amyloid behave like healthy mice. Mice who have suffered mutations in both genes show a disease exacerbated, well defined.

This does not happen necessarily the same way in humans, but it shows that the amyloid plaques potentiate the disease. The neurofibrilles first appear, and when the amyloid plaques appear, the disease is triggered.

The disease presents as a disturbance of memory or behaviour, evolving gradually into dementia. The cognitive disorders can be more carefully assessed by a standardized examination (form). The mood disorders are often associated. At a late stage is an alteration of the overall state dependency with up to one malnutrition and even death.

Early detection of Alzheimer's disease is a major element for better treatment and better support for patients and their entourage.

The value of early detection of Alzheimer's disease may allow sufferers to receive treatment earlier. According to a research team french, new criteria, from a combination of memory tests, brain imaging data and biomarkers, that could detect Alzheimer's disease at an early stage, early symptoms, " with a rate of diagnostic certainty over 90%."

Risk factors
* Age essentially (over 65)
* Family history of Alzheimer's disease, or the existence of specific mutations (presenilin, APP),
* Personal history of depression, head injury, a concept of exposure to aluminium (although these notions are controversial)
* Isoform 4 of the apolipoprotein (rarely sought)
* A diet low in polyunsaturated fatty acids omega-3 and rich in saturated fatty acids.

Criteria DSM-IV
The criteria of the DSM-IV based on:

The installation of intellectual wearing a partial or complete:

* Memory: amnesia of recent and old,
* Disorder of executive functions (ie to organize and carry out a complex task, such as leaf out its tax return)
* Language disorders (aphasia amnesiac) characterised by "omission of the word"
* Disturbance of praxie: apraxia (ie realisation of gestures complex: for example, use the washing machine),
* A Agnosie (disorders of recognition): For example, road signs, then faces.

These disorders have an impact socio-professional.

Their evolution is a gradual and irreversible (continuing decline ...).

These signs can not be explained by other causes: neither organic (tumor, infectious, toxic) or psychological (depression, schizophrenia), and outside an acute confusion.

Assessment Tools
All these disorders (amnesia troubles, executive functions, aphasia, Agnosie, apraxia) can be evaluated by a psychometric test: MMSE (Mini Mental State Evaluation, or test Folstein), established on a scale of 30 points: a score below 24 out of 30 is suspect of dementia.
This result should be interpreted according to the socio-economic level of the patient (a high level can improve the score and therefore distort the test), as it will ensure that no confusion before its completion.

A neuropsychological evaluation can be done, evaluation, which includes many psychometric tests, including:

* Also a MMSE (Mini Mental State Assessment Test or Folstein)
* A test called the clock (explores praxie)
* A test reminder (explores memory).

and other explorations.

Further testing

* The brain scan or MRI can show cortical atrophy (particularly hippocampal), but (cortical atrophy or sub-cortical) is seen in other diseases of the elderly. These examinations can also eliminate other causes: cancer, stroke, intra-cerebral hematoma or sub-dural, ethyl encephalopathy ... There are indications, however, are being evaluated to try to make an early diagnosis (including reducing the size of the hippocampus).
* The tomography positron emission is a recent review, allowing the analysis of certain radioactive tracers injected into the body. There is a fairly sharp decrease metabolism of several parts of the brain (temporal lobe, parietal and posterior), with good sensitivity and specificity. The decrease in activity in the hippocampus would indicate promising.
* The strength in the cerebrospinal fluid of the t-tau protein, protein phosphorylated tau and amyloid beta peptide of 42 amino acids allows, as imaging, a diagnosis consistent assistance, these strengths are routinely available in some Hospitals edge.
* The dosages of vitamin B12 and vitamin B9 (folate), and a review thyroid (TSH) are routinely made, because vitamin B12 and B9 or hypothyroidism can be causes of dementia (dementia curable).

Diagnosis of Certainty
Only an autopsy can be diagnosed with certainty of Alzheimer's disease with consideration anatomical pathology of the brain. In practice, the diagnosis of Alzheimer's disease is likely therefore essentially in a person showing signs of dementia appear progressive and for which other causes have been eliminated.

Diagnostics differentials
* The initial stage of the disease, a benign forgetfulness associated with age, a slight cognitive impairment or mild cognitive impairment (MCI),
* Other forms of dementia original degenerative
* Dementia called secondary (an organic),
* Anxiety disorders, depression: hence the interest of a test anxiolytic treatment and / or antidepressant during a sufficient time, the persistence of the table confirm that this is indeed a dementia.

If this assessment and this test test are negative, we say that the diagnosis of Alzheimer's disease is likely; diagnosis could not be certain that after a biopsy with histological examination of the brain. There is no diagnostic certainty of life.

Researchers are trying to create a vaccine that would prevent this madness. This line of research remains promising.

Although there is no real way to protect themselves from Alzheimer's disease, certain individuals are less likely to develop the disease than others, and it is usually due to their past: people with monitoring many studies have had more time to develop their memory, and are therefore less likely to suffer from the disease [ref. desired]. A diet rich in vitamins C and E would also be protective.

Nowadays, much sooner detect Alzheimer's becomes possible. A programme of artificial intelligence, born of a collaboration between two laboratories french (ESPCI-Paris-Lyon ISC) and the Japanese institute RIKEN, has learned to distinguish the warning signs of mild cognitive impairment from those moving towards this disease. The error rate is 7%.

It would be possible to divide by 2 the risk of developing Alzheimer's disease maintaining a simple cognitive activity as read a newspaper, play chess or checkers, visiting libraries, etc.. This reduction in risk is due to cognitive activities current elderly. Those practiced in the past would have no influence on the cognitive decline associated with age.

According to research presented at the 4th International Scientific Symposium on Tea and Human Health held in Washington DC in January 2008, "green tea have a direct impact on brain function, because it contributes to the preservation these functions and to repair damaged cells. " These scientific note that consumption of tea reduces the risk of developing dementia and other neurodegenerative diseases such as Parkinson's and Alzheimer's.

Currently, there is no treatment curing Alzheimer's disease, or even to stop its progress, but there are some medications that can delay the progression of the disease. They can mitigate the loss of memory, problems of language and reasoning, or simply slow down at least ostensibly disease progression. These drugs are not permanent and are not always effective, what was the source of controversy, including their economic justification. Nevertheless, even the bodies of expertise tougher recognize their interest.

There is another type of treatment, non-drug, namely a re-education: some courses allow the patient and his family to live on a daily basis with the disease, while others réhabituent patients to live independently. The occupational therapy aimed at stimulating the attention of patients, also have some effectiveness.

Salaries symptomatic
They change on a non-specific behavior of the patient without addressing the disease itself. The psychotropic are used to reduce anxiety, aggressiveness or states of agitation of patients. The anticholinergics, neuroleptics and benzodiazepines a long half-life should be avoided because of their side effects in these patients very fragile.

The cure for Alzheimer's disease by a vaccine would be feasible, according to studies. The health check vaccinated patients showed a statistical improvement in their cognitive functions.

The idea is not new: in 1999, Dale Schenk, an American researcher, introduced in the journal Nature a method for getting rid of the disease in mice. By immunizing against A-beta peptide transgenic mice that overexpress it comes to preventing the emergence of deposits among young animals and to limit and even reduce their extension in individuals older.

A first clinical trial phase one in humans led to England is a success, the 80 patients treated well bear vaccination and a quarter of them produce many antibodies. However, the subsequent monitoring is more mixed: while intracerebral amyloid deposits are less important, no effect on the intellectual deterioration has been proved.

Other treatments
A number of drugs, tested for other diseases, were suspected at one time or another, to protect against Alzheimer's disease. They are particularly some statins, some anti-oxidants (vitamin E), some anti-inflammatories. These observational studies, whose initial goal was not to treat dementia, in essence include many biases and need to be confirmed. The first results are disappointing.

Social consequences
A patient is a family who needs help. The family includes children, siblings, nieces and nephews ... In referring to the number currently estimated at 800 000 patients in France and considering an average of 3 family around a sick, more than 2 400 000 people who are concerned more or less directly by Alzheimer's disease. It is a major problem for society.

In Western countries, the family has limited resources to provide time for the patient support they need so more and more continues as the evolution of the disease. Yet, in 70% of cases, the family that supports the patient and allows him to remain at home.

It was aware of the considerable contribution of these caregivers "natural" and professionals realize that the "Help the caregivers' is probably one of the ways to meet this enormous public health challenge.

Demographically, the age group most affected (80 years and older) is currently growing. So we have to improve without delay the system of care for people affected by Alzheimer's disease, and especially their families.

Information, training, groups, respite opportunities (receptions day, or for specific periods) are the main means to enable relatives to relax and cope with their tasks efficiently and humanely.

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