Alzheimer's disease

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Biochemistry
Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis.One of these fragments gives rise to fibrils of beta-amyloid, which for clumps that deposit outside neurons in dense formations known as senile plaques.
In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.
Publicat de health victorro la 04:54 0 comentarii
Etichete: Alzheimer, Biochemistry
Disease mechanism
Exactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology of AD is not known.The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.

Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response.
Publicat de health victorro la 04:53 0 comentarii
Etichete: Alzheimer, Disease, mechanism
Genetics

While the rare, early-onset form of Alzheimer's disease is mainly explained by mutations in three genes, the most common form has yet to be explained by a purely genetic model. The APOE gene is the strongest genetic risk factor for Alzheimer's discovered so far, but its presence is far from explaining all occurrences of the disease.

Less than 10% of AD cases occurring before 60 years of age are due to autosomal dominant (familial) mutations, which therefore represent less than 0.01% of all cases. These mutations have been discovered in three different genes: amyloid precursor protein (APP) and presenilins 1 and 2.Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta42, which is the main component of senile plaques.

Most cases of Alzheimer's disease do not exhibit familial inheritance, but genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). This gene is implicated in up to 50% of late-onset sporadic Alzheimer's cases.Geneticists agree that numerous other genes also act as risk factors or have protective effects that influence the development of late onset Alzheimer's disease. Over 400 genes have been tested for association with late-onset sporadic AD.One example is a variant of the reelin gene that may contribute to Alzheimer's risk in women.
Publicat de health victorro la 04:50 0 comentarii
Etichete: Alzheimer, Genetics
Diagnostic criteria
The National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) established the most commonly used diagnostic criteria for Alzheimer's disease.[84] These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation.[85] Eight cognitive domains are most commonly impaired in AD—memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association.[86][87]
Publicat de health victorro la 04:49 0 comentarii
Etichete: Alzheimer, Diagnostic criteria
Diagnostic tools
Neuropsychological tests such as the mini-mental state examination (MMSE), are widely used to evaluate the cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.[88][89] Neurological examination in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from standard dementia. Further neurological examinations are crucial in the differential diagnosis of AD and other diseases.[4] Interviews with family members are also utilised in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease, over time, of the person's mental function.[90] A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits.[91] Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.[92] Supplemental testing provides extra information on some features of the disease or is used to rule out other diagnoses. Blood tests can identify other causes for dementia than AD[4]—causes which may, in rare cases, be reversible.[93] Psychological tests for depression are employed, since depression can either be concurrent with AD or be the cause of cognitive impairment.[94][95]

When available as a diagnostic tool, SPECT and PET neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving mental status examination.[96]In a person already having dementia, SPECT appears to be superior in differentiating Alzheimer's disease from other possible causes, compared with the usual attempts employing mental testing and medical history analysis.[97] A new technique known as PiB PET has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a tracer that binds selectively to the Abeta deposits.[98] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.[99] Both advances have led to the proposal of new diagnostic criteria.[84][4]

• Added on: Mar 13th, 2009
• Country: Romania
• Language: English

• Author: rorac2009
• Listed in: Health Medicine
• Tags: biochemistry disease mechanism