Introduction of Alzheimer disease

  • What is Alzheimer disease?

     

    Alzheimer disease (AD), is a degenerative disease of the central nervous system. Its early clinical manifestations are mainly the impairment of memory and the decline of self-care ability, which eventually leads to cognitive impairment and loss, neurobehavioral abnormalities, mental state and complete loss of self-care ability. Clinical treatment of AD is mainly symptomatic, and there is no effective treatment to stop or delay the progress of the disease.

    Pathogenesis

    Since the first case of AD was reported in the early 20th century, the study of AD neuropathology has been deepening. In the mid-20th century, some scholars found that there were extensive senile plaques, neuron fiber tangles and neuron loss in the brain tissue of AD patients, which were also the main causes of amyloid cerebrovascular disease. Amyloid-beta (Aβ) is a product of hydrolysis of amyloid-beta precursor protein by endogenous protease. Its relative molecular weight is about 4.12KD. Studies have shown that amyloid precursor protein mutation is directly related to the occurrence of familial AD, which accounts for about 10% of the total number of AD patients. Sporadic AD is associated with head trauma, viral infection, environmental factors and other factors. However, most studies have shown that both familial and sporadic AD have similar pathological characteristics, that is, a large number of amyloid precursor proteins are secreted on the cell membrane, which are lysed by beta-secretase and gamma-secretase and release a large amount of soluble Aβ. When the body reaches a certain limit of its processing capacity, excess Aβ accumulate in the cerebral cortex, and around the cerebrovascular, the brain and the neurons. The dense deposition of Aβ in filamentous form leads to the emergence of neuroinflammatory senile classes, and its neurotoxicity is obvious, which is also the main reason for the occurrence and development of various clinical symptoms.

    Clinical manifestation

     

    The onset of the disease is slow or insidious, and patients and their families often can not tell when to get sick. Most of the patients were over 70 years old (male average 73 years old, female 75 years old). A few of the patients had rapid manifestation of symptoms after physical disease, fracture or mental stimulation. Females are more than males (3:1 for females and males). The main manifestations are the decline of cognitive function, mental symptoms and behavioral disorders, and the gradual decline of daily living ability. According to the deterioration of cognitive ability and physical function, it can be divided into three periods.

    The first stage (1-3 years)

    It is mild dementia. It is manifested by memory loss and forgetfulness of recent events; decreased judgment, patients can not analyze, think and judge events, and difficult to deal with complex problems; careless work or housework, unable to independently carry out shopping, economic affairs, and social difficulties; although they can still do some familiar daily work, they are confused with new things, and their emotions are weak. Indifference, occasional irritation, often doubtful; time orientation obstacles, the location and characters can be orientated, difficult to orientate the geographical location, complex structure of the visual space ability is poor; less vocabulary, naming difficulties.

    The second stage (2-10 years)

    Medium dementia. It is manifested by severe impairment of near and far memory, decline of visual space ability of simple structure, and obstacle of orientation of time and place; serious impairment in dealing with problems, identifying similarities and differences of things; inability to carry out outdoor activities independently, and need help in dressing, personal hygiene and maintaining personal appearance; inability to calculate; various neurological symptoms, such as aphasia and apraxia, appear. And blindness; emotional change from indifference to agitation, often moving, visible urinary incontinence.

    The third stage (8-12 years)

    It is a period of severe dementia. The patient is totally dependent on the caregiver, with severe memory loss and only fragments of memory; daily life can not take care of itself, incontinence of urine and urine, silence, rigidity of limbs, positive pyramidal signs, strong grip, groping and sucking primitive reflexes can be seen on physical examination. Ultimately coma, usually died of complications such as infection.

    Treatment

    Aβ is the core therapeutic substance of AD. Senile plaque deposited in the brain is the main pathological change of AD. Immunotherapy for Aβ, including active immunization (AB vaccine) and passive immunization (Aβ antibody), has been proved effective in AD animal models. The clinical trials of AD immunotherapy have failed at present. One of the main reasons for the failure is the occurrence of side effects. The specific mechanism is still unclear. Natural Aβ autoantibodies (NAbs-Aβ) are ubiquitous in human body. Studies have shown that NAbs-Aβ can antagonize the neurotoxicity of Aβ and protect AD. The key sites for the aggregation of Aβ and its toxic fragments are located in the middle of Aβ. Structural analysis of Aβ indicated that the amino terminal (N terminal) fibers of Aβ were exposed to the periphery of Aβ fibers, while the carboxyl terminal (C terminal) and middle segment were located at the core of Aβ fibers.

    Bapineuzumab

    Recombinant monoclonal antibody to Aβ. Bapineuzumab is a humanized monoclonal antibody that acts on the nervous system and may have potential therapeutic value for the treatment of Alzheimer's disease and possibly glaucoma.

    Crenezumab

    Recombinant monoclonal antibody to Aβ. Crenezumab is a humanized monoclonal antibody against human 1-40 and 1-42 Beta amyloid, which is being investigated as a treatment of Alzheimer's disease.

    Gantenerumab

    Recombinant monoclonal antibody to Aβ. Gantenerumab is a monoclonal antibody for the treatment of Alzheimer's disease. A phase I clinical trial has been conducted in 2006/07. Gantenerumab is currently being evaluated in a prodromal Alzheimer's disease population in the Scarlet Road study, a global phase II study of approximately 360 subjects in 100 centers in 15 countries.

    Although some progress has been made in the prevention and treatment of AD, it has not yet been proved which drug can terminate or reverse the process of AD. The treatment level is still only to improve symptoms or delay progress. Therefore, researchers from all over the world need to work together to bring more benefits to patients and their families who suffer from illness.