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Cistanche is very good for Alzheimer's disease

1. Epidemiology

1. Prevalence and morbidity: AD is a common geriatric disease. There are some differences between domestic and foreign prevalence studies. Most studies report that the prevalence of AD in the elderly over 65 years old is 2% to 5%. The prevalence of AD in women is higher than that in men, and women are 1 to 2 times higher than men. Prevalence increases with age. A few researchers have conducted research on the incidence of dementia. Zhang Mingyuan and others in my country reported that the annual incidence of dementia among the elderly in the Shanghai community was 1.15% for those aged 65 and over, 1.54% for those aged 70 and over, and 1.54% for those aged 75 and over. 2.59% of those aged 80 and over, 3.54% of those aged 80 and over, and 3.23% of those aged 85 and over.

2. Risk factors: Age is significantly associated with AD prevalence, and the older the age, the higher the prevalence. In the elderly population over the age of 60, the prevalence approximately doubles for every 5-year increase in age. Female patients are about twice as likely as male patients. It is certain that AD is related to heredity, and most epidemiological studies suggest that family history of dementia is a risk factor for AD. Apolipoprotein E (Apo E) allele ε4 is an important risk factor for AD. The frequency of the Apo Eε4 allele was around 40% in autopsy-proven AD patients and around 16% in the normal control population. Brain trauma has been reported as a risk factor for AD, and severe brain trauma may be one of the causes of some AD. Those with a history of hypothyroidism have a high relative risk of developing AD. A history of depression, especially first-episode depression in old age, is a risk factor for AD. Low education level is associated with an increased prevalence of AD. The possible explanation is that early education and training promote the development of cortical synapses, increase the number of synapses and increase "brain reserve", thereby reducing the risk of dementia.

2.The etiology and pathogenesis

AD is a complex disease with multiple etiologies, and its pathogenesis has not been fully elucidated. Over the years, many advances have been made in the research on the etiology and pathogenesis of AD. The following are the main theories of etiology and pathogenesis.

1. Inheritance: Mutations in three autosomal dominant genes can cause familial AD. The APP gene mutation on chromosome 21 causes Aβ production and senile plaque formation, and the other two are the presenilin 1 and presenilin 2 genes (PS-1, PS-2). PS-1 is located on chromosome 14 and PS-2 is located on chromosome 1. The probability of detecting the above three gene mutations in familial AD patients is less than 10%, and the probability of detecting the above three gene mutations in sporadic AD patients is less than 1%. Apo E gene is an important risk gene for AD. The Apo E gene is located on chromosome 19 and encodes Apo E, a protein involved in lipid transport. In the brain, Apo E is produced by astrocytes, plays an important role in local lipid transport in brain tissue, and is closely related to the metabolism and repair of myelin after neuronal injury and degeneration. There are three common isoforms of Apo E, namely E2, E3 and E4, encoded by three dialleles ε2, ε3 and ε4, respectively. The frequency of the Apo Eε4 allele was significantly elevated in familial and sporadic AD. The frequency of Apo Eε4 allele in familial AD is the highest, about 50%. The Apo Eε4 in AD patients diagnosed by autopsy is also relatively high, and the frequency of sporadic AD ranges from 16% to 40%. Carrying the Apo Eε4 allele increases the risk of AD and advances the age of onset. The Apo Eε2 allele appears to have protective benefits, as carrying this gene reduces the risk and delays the age of onset. Apo E alleles with ε4/ε4 have the highest risk, with at least an 8-fold increase.

2. Senile plaques: Senile plaques are spherical tangles of neuron inflammation, which contain degenerated axons and dendrites, accompanied by astrocyte and microglial proliferation, and also contain a variety of proteases. The main component of senile plaques is amyloid beta (Aβ), a fragment of the amyloid precursor protein (APP). APP is a transmembrane protein encoded by the APP gene on chromosome 21, and its carboxy-terminus is located in the cell and its amino-terminus is located outside the cell. The cleavage site of normal APP metabolism is cleaved by α-secretase in the center of Aβ, so Aβ is not produced. Abnormal metabolism is that β-secretase first cuts APP at the amino-terminal 671st amino acid position, resulting in a soluble β-APP and a carboxyl-terminal fragment containing all Aβ; the latter is then cleaved by y-secretase to release 99 Carboxyl-terminal fragment of 1 amino acid and neurotoxic Aβ. Aβ is a heterogeneous polypeptide, among which Aβ polypeptides with 42 and 40 amino acids are the most toxic (Aβ42 and Aβ40). Aβ42 is the main component of senile plaques, and Aβ40 is mainly found in vascular lesions of AD. The neurotoxic effect of Aβ is the death of neurons through free radicals, stimulation of cell death programs, or stimulation of glial cells to produce inflammatory substances such as tumor necrosis factor.

3. Neurofibrillary tangles: Neurofibrillary tangles are insoluble protein deposits within neurons of the cortex and limbic system. Under the electron microscope, the proteins that make up the tangle are double-stranded helical filaments, and the main component is hyperphosphorylated tau protein. The molecular weight of tau protein is 50,000 to 60,000, and it is a microtubule-binding protein. The gene encoding this protein is located on the long arm of chromosome 17. Tau protein plays an important role in maintaining the stability of microtubules in neuronal axons, and microtubules are involved in the transport of substances within neurons. An important feature of the amino acid sequence of tau protein is the C-terminal three or four repeats, and these series constitute the microtubule-binding site. After hyperphosphorylation of tau protein, its binding function with microtubules is affected, and it is involved in the formation of neurofibrillary tangles. The phosphorylation mechanism of tau protein is still unclear. Abnormal activity of protein kinases and glutamatergic neurons may be related to hyperphosphorylation of tau protein.

4. Oxidative stress: The theory of oxidative stress is one of the pathogenesis of AD. The increase in protein sugar residues is called glycation, and protein glycation increases oxidative stress in cells. The major components of senile plaques and neurofibrillary tangles, Aβ and tau, are hyperglycated proteins. Neuronal DNA in susceptible cortical regions of AD was significantly damaged, and 8-hydroxyguanine concentrations, which reflect the level of oxidative stress, were elevated. In AD brain cells, the activities of enzymes involved in energy metabolism, such as pyruvate dehydrogenase, α-keto acid dehydrogenase, etc., are severely reduced. The severely deficient activity of these enzymes may be due to oxidative damage to the DNA encoding these enzymes.

5. Neurotransmitters: The cholinergic nervous system of AD has specific neurotransmitter defects. The cortex and hippocampus of AD patients have decreased choline acetyltransferase (ChAT), and the synthesis and release of acetylcholine by cholinergic neurons are significantly reduced. Decreased acetylcholine (ACh) is strongly associated not only with cognitive symptoms of dementia, but also with altered biological rhythms and delirium in patients. Glutamate is the main excitatory neurotransmitter in the human brain, and glutamate activates ionophilic receptors, causing influx of calcium and sodium ions. Excessive activation of ionophilic glutamate receptors plays an important role in the pathogenesis of AD. The main inhibitory neurotransmitter in the human brain is gamma aminobutyric acid (GABA), and in neurodegenerative diseases such as AD, the level of glutamate decarboxylase decreases and GABA binding sites are reduced. However, little is known about the role of the GABA system in the pathogenesis of AD. Norepinephrine and serotonin are the main monoaminergic neurotransmitters in the brain. The total and reuptake of norepinephrine in the brain of AD patients is reduced, the tyrosine hydroxylase that synthesizes norepinephrine is reduced, and the neurons in the locus coeruleus of the brainstem are lost. The degree of neuronal damage in the locus coeruleus and the degree of norepinephrine reduction were not related to the degree of cognitive decline, but were related to the affective symptoms of AD. Neurons in the raphe nucleus of AD patients are lost, and the concentrations of serotonin and its metabolites in cortex and cerebrospinal fluid are reduced. The changes of serotonin may be related to non-cognitive psychiatric symptoms of AD such as depression, aggressive behavior, etc. related.

At present, the more generally accepted ones are the amyloid cascade theory and the abnormal tau protein theory. In recent years, some scholars believe that the amyloid cascade theory is too simple to elucidate the pathological progression of AD, and put forward new theories, including the "dual channel hypothesis" and the "host response hypothesis", the former believes that the damage of common upstream molecular events leads to the increase of Aβ High and tau hyperphosphorylation, the latter of which is thought to contribute to multiple AD-related host responses due to etiological factors such as age-related factors. The mechanisms by which inflammation, oxidative stress, and hormonal changes can regulate Aβ and tau protein metabolism, leading to neuronal degeneration, remain to be elucidated.

Cistanche is very good for Alzheimer's disease

3. Clinical manifestations

AD usually has an insidious onset, and the course of the disease is continuous and progressive. The clinical manifestations can be divided into cognitive deficit symptoms and non-cognitive deficit psychoneurological symptoms, both of which will lead to the decline of social life function.

(1) Symptoms of cognitive impairment

Cognitive impairment in dementia usually includes memory impairment, agnosia, apraxia, and aphasia, and executive dysfunction due to these impairments in cognitive functions.

1. Memory loss: Memory impairment is a must for diagnosis. The memory impairment of dementia patients has the following characteristics: newly learned knowledge is difficult to recall; event memory is easily damaged, more easily damaged than far memory; recent memory loss is often the first symptom.

2. Language barriers: Although early patients have obvious memory impairments, their general social language skills are relatively maintained. After in-depth conversation, it will be found that the patient's language function impairment, mainly manifested as empty language content, repetition and repetition. Language impairment can be divided into three aspects, namely the ability to find words (word finding), sentence making and discourse (discourse) decline. Naming tests can reflect word finding skills. The patient may refer to the name by the purpose of the item, such as "writing" instead of "pen". The relationship and arrangement order of language words in sentences are related to syntactic knowledge. Syntactic knowledge is generally not easy to be damaged, if there is damage, it indicates that the degree of dementia is severe. When the degree of dementia is mild, it may be found that the patient's language and writing are relatively simple. Speaking ability refers to the organic combination of sentences to be spoken. The impairment of speech ability of people with dementia is usually obvious, they may use pronouns too much, and the reference relationship is not clear, and the language repeats more in conversation. In addition to the above-mentioned expressive language impairment, patients usually have difficulties in understanding language, including vocabulary and sentence comprehension, collectively referred to as cortical aphasia (aphasia).

3. Agnosia: refers to the difficulty in recognizing or distinguishing various sensory stimuli at the level of the cerebral cortex. This recognition difficulty is not caused by damage to peripheral sensory organs such as vision loss. Agnosia can be divided into visual agnosia, auditory agnosia and somatosensory agnosia. These three kinds of agnosia can show a variety of symptoms respectively. Visual agnosia is manifested as agnosia of objects or characters, colors, distances, and spatial environments. Visual agnosia is very easy to cause spatial orientation disorder. When the degree of visual agnosia is mild, the patient is easily disoriented in an unfamiliar environment, and when the degree is severe, it will also get lost in familiar places. Patients with visual agnosia have difficulty in reading, cannot distinguish objects through vision, and in severe cases cannot distinguish relatives, friends or even their own images, and patients eventually become "mind blind". Auditory agnosia is manifested as the disappearance or decrease of the directional response and psychological induction to the sound, the patient cannot recognize the meaning of the surrounding sound, and it is difficult to understand the meaning of speech, intonation and language. Somatosensory agnosia mainly refers to tactile agnosia. Patients with somatosensory agnosia have difficulty in distinguishing sensory stimuli on the body, and cannot analyze the intensity and nature of physical stimuli. In severe cases, patients cannot identify the items in their hands, and eventually do not know how to dress, wash their face, and comb their hair.

4. Apraxia: refers to normal sensation, muscle strength and coordinated movement, but unable to carry out purposeful activities, which can be divided into ideational apraxia, ideomotor apraxia and ideomotor apraxia. Motor apraxia. Conceptual apraxia refers to the patient's inability to execute commands. When the patient is asked to complete a certain action, he may do nothing or perform completely unrelated actions, and there may be imitative actions. The characteristic of ideomotor apraxia is the inability to imitate an action such as waving, salute, etc., and is related to the communication disorder between the parietal and frontal cortex. Motor apraxia refers to the inability to convert commands into purposeful movements, but the patient can clearly understand and describe the content of the commands. Asking patients to do some simple movements such as waving, salute, combing hair, etc. can easily find motor apraxia, and most of the mild to moderate dementia can complete simple and familiar movements. As the disease progresses, motor apraxia gradually affects the patient's ability to eat, dress, and other self-care abilities.

5. Executive dysfunction: Executive function refers to the inability to coordinate and orderly carry out various cognitive activities, which is related to the dysfunction of the frontal lobe and related cortical and subcortical pathways. Executive functions include higher-level cognitive functions such as motivation, abstract thinking, and the ability to organize, plan, and manage complex behaviors. Executive dysfunction manifests as a decline in daily work, learning and living abilities. Analyzing the similarities and differences of things, neuropsychological tests such as continuous subtraction, vocabulary fluency test, and wiring test can reflect the impairment of executive function.

(2) Mental and behavioral symptoms

The psychobehavioral symptoms of dementia are common in the middle and late stages of the disease. Patients with early symptoms such as anxiety and depression are mostly reluctant to expose. When the disease progresses to the point of being completely unable to take care of oneself and incontinence in basic life, the mental and behavioral symptoms will gradually subside and subside. Obvious psychobehavioral symptoms suggest a more severe degree of dementia or a more rapid progression of the disease. The mental and behavioral symptoms of dementia are diverse, including insomnia, anxiety, depression, hallucinations, delusions, etc., which can be roughly classified into neurosis, psychosis, personality changes, anxiety, depression, delirium and other symptom groups.

(3) Nervous system symptoms and signs

Mild to moderate patients often have no obvious neurological signs. A small number of patients have signs of extrapyramidal damage. Severe or advanced patients may appear primitive reflexes such as strong grip and sucking reflexes. The most obvious neurological signs in advanced patients are increased muscle tone, flexion stiffness of the extremities, and cortical stiffness.

For the convenience of clinical observation, according to the development of the disease, AD can be roughly divided into mild, moderate and severe.

1. Mild: recent memory impairment is mostly the first symptom of this disease, and therefore attracts the attention of family members and colleagues. The patient is prone to forgetting recent events, has difficulty learning new knowledge, and forgets appointments and business arrangements. After reading books and newspapers, I can remember very little, and I can't remember the names of new faces. Pay attention to difficulty concentrating, being easily distracted, forgetting what you are doing such as cooking, turning off the gas, etc. It is easy to get lost in unfamiliar places. Time orientation is often difficult to remember year, month, day and quarter. The computing power decreases, and it is difficult to complete 100 consecutive minus 7. Difficulty finding words, slow thinking, and thinking less clear and organized than before. Early patients have certain insight about their cognitive deficits, and may be accompanied by mild anxiety and depression. In terms of social functioning, patients are inattentive to work and household chores, and have difficulty dealing with complex life affairs, such as rationally managing money, shopping, and arranging and preparing meals. work ability

Decreased strength is often noticeable, incapable of performing familiar tasks from the past, and patients often avoid competition. Despite a variety of cognitive deficits, the patient can take care of himself completely in basic personal life such as eating, dressing, and washing. The patient may appear apathetic, withdrawn, and act more slowly than before, which at first glance may appear to be depression, but on closer inspection there is often no typical depressive symptoms such as depressed mood, negativity, and changes in appetite and sleep rhythms. The course of the disease lasts 3 to 5 years.

2. Moderate: As the dementia progresses, the memory impairment becomes more and more serious, and it becomes forgetful. Can not remember their address, forget the names of relatives, but generally can remember their own names. Distant memory impairment is becoming more and more obvious, with obvious forgetting of personal experience, unable to remember important personal life events, such as marriage date, work date, etc. In addition to time orientation, there are also obstacles to location orientation, and it is easy to get lost in familiar places, and even cannot find one's own room at home. The language function degenerates obviously, thinking becomes aimless, and the content is empty or redundant. Difficulty understanding spoken and written language. Significant impairment of concentration and calculation ability, unable to complete 20 consecutive minus 2. Because of impaired judgment, patients underestimate risk and give unrealistic assessments of their abilities. Due to agnosia, patients are gradually unable to recognize acquaintances and relatives, often regard their spouses as dead parents, and eventually do not recognize their own images in the mirror. Due to disuse, the patient cannot work at all, the patient cannot choose clothes according to the season, and it is difficult to complete various housework activities. Frequent incontinence. The mental and behavioral symptoms of patients at this stage are more prominent, often manifesting symptoms such as emotional instability, fear, agitation, hallucinations, delusional ideas, and sleep disturbances. A small number of patients are sleepy during the day and active at night. Most patients require specialized care. The course of the disease is about 3 years.

3. Severe: generally do not know their name and age, and do not know their relatives. Patients can only speak simple vocabulary, often only spontaneous language, speech is short, repetitive or stereotyped, or repeated a certain sound, and eventually can not speak at all. There are occasional verbal responses to pain stimuli. After the loss of language function, the patient gradually loses the ability to walk, and cannot stand by himself after sitting down. The patient can only stay in bed all day long. The mental and behavioral symptoms during this period gradually eased or disappeared. Most patients died of malnutrition, lung infection, bedsores, or other medical diseases within 2 years of entering this period. If the nursing and nutritional status are good, and there are no other serious physical diseases, they can still survive for a long time.

Cistanche is very good for Alzheimer's disease

4. Laboratory and auxiliary examination

1. Electroencephalographic physiology: The changes of EEG in the early stage of AD are mainly decreased amplitude and slowed α-section. A small number of AD patients have markedly reduced EEG alpha waves in the early stage, or even disappeared completely. With the progression of the disease, a wide range of irregular theta activity of medium amplitude can gradually appear, especially in the frontal and parietal lobes. Diffuse slow waves may appear in the late stage, but focal or paroxysmal abnormalities are rare. Typically, delta waves are superimposed on a background of common theta waves. Event related potentials (ERP) is an emerging technology of brain electrophysiology that has received more attention in recent years. Studies have shown that patients with mild cognitive impairment (MCI) with abnormal N400 or P600 have an 87% to 88% probability of developing dementia within 3 years.

2. Brain imaging examination: CT is very helpful for the diagnosis and differential diagnosis of AD. The prominent features of AD brain CT examination are cortical brain atrophy and ventriculomegaly, with widening of the sulcal fissure. Selective atrophy of the temporal lobe, especially the hippocampus, is an important pathological change in AD, and magnetic resonance imaging (MRI) can detect this change earlier than CT. The current neuroimaging technology can comprehensively evaluate the brain structure and function of AD patients from the perspectives of molecular, cellular, metabolic and microcirculation, and its role in the diagnosis of AD has been greatly changed. In 2011, the National Institute on Aging and Alzheimer's Association (NIA-AA) new criteria have officially included three imaging markers for the diagnosis or auxiliary diagnosis of AD, including amyloid PET imaging Positive, MRI showed atrophy of the medial temporal lobe and hippocampus, and FDG-PET showed decreased metabolism in the temporo-parietal lobe. Amyloid PET imaging can directly observe the distribution of Aβ deposition in AD brain in vivo through Aβ imaging agent, which has unique advantages for early diagnosis of AD, and is valuable for identifying MCI subtypes and evaluating disease prognosis. Magnetic resonance imaging includes structural magnetic resonance imaging (sMRI) and functional imaging (fMRI). The sMRI imaging markers in the new standard are beneficial for the diagnosis of AD dementia and MCI. The degree of brain atrophy it shows is significantly correlated with the results of cognitive assessment, which helps Monitor AD dementia progression. The glucose metabolism rate of the cerebral cortex determined by FDG-PET imaging mainly reflects the activity of nerves and synapses, so the detection of blood flow and metabolism can be used for early diagnosis and differential diagnosis of AD.

3. Cerebrospinal fluid examination: Routine examination of cerebrospinal fluid in AD patients generally has no obvious abnormality. The tau protein in the cerebrospinal fluid of AD patients is increased, and the Aβ42 is decreased, which has auxiliary diagnostic value. The specificity of detecting Aβ42 in cerebrospinal fluid (CSF) examination for the diagnosis of AD is greater than 90%, and the sensitivity is greater than 85%. The CSF total tau protein (T-tau) level of AD is significantly increased, about 3 times that of the normal control group, but the specificity is low, and it is increased in stroke, Creutzfeldt-Jakob disease and most neurodegenerative diseases high. Studies have found that phosphorylated tau protein (P-tau) is more specific for AD than T-tau. P-tau levels can be normal in depression, stroke, vascular dementia, and Parkinson's disease. Using high-sensitivity monoclonal antibody technology to detect the levels of phosphorylated P-Tau at various sites, such as threonine 181, 231 and serine 199, 235, 396 and other series of sites, can identify frontotemporal dementia, Lewy Dementia.

4. Neuropsychological tests: The neuropsychological deficits of AD may be more prominent in some aspects. Memory function is most severely impaired, and short-term memory is more susceptible to damage than some long-term memories. The language function is relatively preserved in the early stages of the disease, but language comprehension and naming abilities are more easily impaired than oral repetition and sentence making. The parietotemporal lobe is most severely damaged in AD, while primitive motor, sensory, and visual cortical structures remain relatively intact. These damage characteristics can explain the vulnerability of major higher cognitive functions such as language and visual space. AD also has obvious damage to the middle temporal lobe, including structures such as the hippocampus and parahippocampal gyrus, which may explain the memory impairment of AD. "Crystalline" cognitive function is closely related to experience and knowledge, and reasoning ability is a concrete manifestation. "Liquid" cognitive function refers to the basic cognitive function that has nothing to do with cognitive content. It is closely related to the speed and flexibility of absorbing and processing external information. It is mainly determined by genetics and can be reflected from the ability to concentrate and the flexibility of movements. The normal aging "crystal" cognitive function will not decline. After training, this function can be enhanced. Although the "liquid" cognitive function has decreased, the degree is mild and slow. On the contrary, the above two cognitive functions of AD patients Both decreased significantly, and the timing of "liquid" cognitive decline was significantly earlier.

5. Diagnosis and Differential Diagnosis

(1) Diagnosis

The diagnostic tool currently used in China is the ICD-10 classification of mental and behavioral disorders. The diagnosis of AD still relies on the exclusion method, that is, first judge whether there is dementia according to the cognitive impairment, and then comprehensively analyze the data of the medical history, course of the disease, physical examination, and auxiliary examination, and exclude dementia caused by various special causes before making AD The clinical diagnosis of AD depends on the pathological examination of brain tissue. Dementia patients cannot provide a complete and reliable medical history due to cognitive impairment, so in more cases, the medical history should be obtained from insiders, including relatives and caregivers. The next step is to perform a psychiatric and physical examination of the patient. Before the psychiatric examination, a brief standardized dementia screening tool is usually used to conduct a preliminary examination of the patient's cognitive function. , MMSE). The test is easy to administer and provides a brief overview of a patient's overall cognitive status, but this screening is not a substitute for a detailed psychiatric examination. The focus of psychiatric examination is to evaluate the patient's cognitive function status, with particular emphasis on detailed neurological examination of the patient during physical examination. Finally, laboratory tests for the diagnosis of dementia are performed. The routine auxiliary examination items for the diagnosis of AD should include routine examination of blood, urine, and feces, chest X-ray examination, serum calcium, phosphorus, sodium, potassium, liver and kidney function, syphilis screening, HIV screening, blood T3, T4 determination, Determination of blood vitamin B12 and folic acid, EEG, brain CT or MRI.

In 2011, the NIA-AA of the United States revised the AD diagnostic criteria, which divided the course of AD into three stages: asymptomatic AD (preclinical AD) and AD-induced mild cognitive impairment (mild cognitive impairment due to AD). To AD) and AD-induced dementia (dementia due to AD), there are different biological marker changes in different disease stages. Using molecular diagnostic technology, AD-related biomarkers can be detected in vivo, and the development and changes of AD can be assessed early to guide early clinical diagnosis and treatment.

Asymptomatic AD preclinical stages can be subdivided into three stages: under the interaction of age, genetics and environmental factors, abnormal Aβ metabolism and massive accumulation first appear; then synaptic dysfunction, glial cell activation, neurofibrillary tangles formation, Early neurodegeneration such as neuronal apoptosis; mild cognitive decline (less clinical symptoms than MCI) ensues.

Biomarker abnormalities are consistent with the AD pathophysiological cascade described above: first, decreased levels of Aβ42 in the CSF and increased deposition of Aβ tracer on positron emission tomography (PET) imaging; followed by markers of neuronal damage such as in the CSF. Elevated T-tau or P-tau protein, 18-fluorodeoxyglucose (FDG) PET imaging showed decreased metabolism in the temporoparietal region, and MRI showed atrophy of cortical structures in the medial temporal lobe, limbic lobe, and temporoparietal region. Preclinical diagnosis is based almost entirely on AD biomarkers. The NIA-AA criteria incorporate the above five biomarkers for clinical diagnosis. AD-induced MCI memory loss and other cognitive impairment manifestations, but daily life functions are not affected, it is a transitional state between normal aging and dementia, and has a high risk of transforming into AD dementia. Two types of biomarkers, Aβ accumulation and neuronal damage, are used in this period, which help to establish pathological changes related to AD clinical damage, especially the markers representing neuronal damage, which can indicate the possibility of MCI progressing to AD dementia.

The new criteria divide the period into three categories based on the presence or absence of the above markers: probable AD-induced MCI, probable AD-induced MCI, and unlikely AD-induced MCI, Aβ accumulation and neuronal damage markers If both of them are positive, it is likely to be caused by AD, and if one of the two is positive and the other cannot be detected and verified, it is likely to be caused by AD, and if both are negative, it is unlikely to be caused by AD. MCI, in order to improve MCI diagnostic accuracy. The dementia stage caused by AD refers to the clinical syndrome caused by the pathophysiological changes of AD. Based on the detection of biological markers, the potential AD pathological changes in dementia patients are determined, and this stage is divided into probable AD dementia, possible AD dementia and indeterminate AD dementia. All too likely AD dementia. The above five biomarkers can be used as auxiliary diagnostic indicators in dementia stage and MCI stage.

(2) Differential diagnosis

1. Vascular dementia: Vascular disease is the second cause of dementia. Brain imaging examination and Hachinski ischemic index score are helpful for the preliminary identification of vascular dementia and AD. The total score of Hachinski ischemia index score is 18 points, ≥ 7 points are likely to be vascular dementia; ≤ 4 points are likely to be non-vascular dementia, mainly AD; 5-6 points are likely to be mixed dementia. The detection of vascular lesions on CT or MRI can help confirm the diagnosis.

2. Frontotemporal dementia: Frontotemporal dementia is less common than AD, and its early manifestations are mainly behavioral and emotional changes or language impairment, while memory impairment is usually the first symptom of AD. Frontal and temporal lobe atrophy is characteristic of the frontotemporal lobe, whereas generalized brain atrophy and symmetrical enlargement of ventricles are more common in AD.

3. Progressive supranuclear palsy: Progressive palsy is characterized by eye movement disorder, subcortical dementia, usually accompanied by extrapyramidal symptoms, and is a typical subcortical dementia.

4. Depression: Senile depression can be manifested as pseudo-dementia, which is easily confused with AD. Depressive pseudodementia patients may have a history of affective disease, a clear onset time, obvious depressive symptoms, and cognitive deficits that do not show a progressive and comprehensive deterioration like AD. Orientation and understanding are usually good. Apart from mental retardation, there were no apparent behavioral deficits. Pre-morbid intelligence and personality were intact. In-depth examination revealed depression. Although the response was slow, the content was relevant and correct. Antidepressant therapy has a good effect.

5. Parkinson's disease: The first symptom of AD is cognitive decline, while the earliest manifestation of Parkinson's disease is extrapyramidal symptoms. Even with extrapyramidal symptoms, AD patients rarely have tremor, but up to 96% of Parkinson's patients have tremor.

6. Normal pressure hydrocephalus: In addition to dementia, this disease is often accompanied by urinary incontinence and ataxia gait disorder, and the brain pressure is not high. CT or MRI examination showed ventriculomegaly, but no obvious signs of cerebral cortical atrophy. Isotope pool scans showed a delay of more than 72 hours from the basal cistern to the convexity of the brain.

7. Brain tumors: Brain tumors with dementia as a prominent clinical manifestation are mainly found in frontal lobe, temporal lobe or corpus callosum tumors. In addition to the manifestations of dementia, signs of increased intracranial pressure are often seen. Cerebral angiography, CT or MRI examinations can clearly show brain tumors. tumor site.

6. Treatment

The etiology of this disease is unknown, and there is currently no effective treatment. The effective treatment methods are basically symptomatic treatment. Treatment of AD includes treatments for cognitive decline and non-cognitive psychiatric symptoms. Treatment options include physical therapy (primarily medication) and psychosocial and supportive care.

1. Treatment of cognitive impairment

(1) Cholinesterase inhibitors:

1) Donepezil: It inhibits acetylcholinesterase competitively and non-competitively, thereby increasing the ACh concentration in the synaptic cleft of brain cells. It is characterized by a long half-life of (103.8±40.6) hours, a high plasma protein binding rate (92.6%), and the steady-state plasma concentration can only be reached after 2 weeks. The drug is absorbed well after oral administration, and the peak time is (5.2±2.8) hours, and it can be administered once a day. Common adverse reactions include diarrhea, nausea, and sleep disturbance. About 50% of patients showed significant improvement in cognitive function. After drug discontinuation, patients' cognitive function levels decreased to placebo-treated levels within 3 to 6 weeks. The recommended starting dose of donepezil is 5 mg/d for 1 month

After the dose can be increased to 10mg/d. If it can be tolerated, the dose of 10 mg/d should be used as much as possible. The high dose can obtain better curative effect, but it is also prone to cholinergic adverse reactions.

2) Rivastigmine (rivastigmine): a carbamate, can inhibit both acetylcholinesterase and butyrylcholinesterase. Its half-life is about 10 hours, and the peak time is 0.5 to 2 hours. The recommended dose of the drug is 6 to 12 mg/d. Clinical trials have shown that the efficacy is related to the dose. When the daily dose is greater than 6 mg, the clinical efficacy is relatively positive, but when the high-dose treatment is used, the adverse reactions also increase accordingly.

3) Huperzine A (huperzine A): a cholinesterase inhibitor developed in China, an alkaloid extracted from the huperzine plant Melaleuca. The usual dose is 0.2 to 0.4 mg/d. Adverse reactions were relatively rare, including dizziness, anorexia, and bradycardia. Large doses can cause nausea and muscle tremors.

(2) Glutamate receptor antagonists - memantine: acting on the glutamate-glutamine system in the brain, it is a non-competitive N-methyl-D-aspartate (N-methyl-D-aspartate) with moderate affinity. N-methyl-D-aspartate, NMDA) antagonist. When glutamate is released in pathological excess, memantine reduces the neurotoxic effects of glutamate, and when glutamate is released too little, memantine hydrochloride improves the transmission of glutamate necessary for memory processes. The usage is 5 mg per day in the first week, 10 mg per day in the second week, 15 mg per day in the third week, and 20 mg per day in the fourth week. The maintenance dose is 10 mg each time, 2 times a day.

2. Treatment of psycho-behavioral symptoms

3. Psychosocial therapy

The main purpose of psychosocial therapy is to maintain the patient's cognitive and social life functions as much as possible, while ensuring the safety and comfort of the patient. The main content is to help the patient's family to decide whether the patient is hospitalized, home treatment or day care, etc.; to help the family to take appropriate measures to prevent the patient's suicide, impulsive aggression and "wandering" to ensure the patient's safety. Help family members with legal issues such as testamentary capacity and other capacity issues. An important aspect of social therapy is to inform the knowledge about the disease, including clinical manifestations, treatment methods, curative effects, development of the disease and prognosis, etc., so that family members can know what to do, and at the same time let family members or caregivers know the basic nursing principles.