【Concept】.
Alzheimer’s disease (AD) is a degenerative disease of the central nervous system that occurs in old age and pre-mature aging, and is the most common type of dementia in old age. It starts clinically insidiously, with early manifestations of memory loss, and progresses with overall cognitive decline and progressive decline in activities of daily living, which may be accompanied by various psychiatric symptoms and behavioral disturbances. The etiology and pathogenesis of the disease remain unclear. The pathology is characterized by neuroinflammatory plaques, neurogenic fiber tangles, neuronal loss and amyloid angiopathy. Zhou Aihong, Department of Neurology, Xuanwu Hospital, Capital Medical University
[Epidemiology
AD is the most common type of dementia in old age, accounting for 50-60% of all patients with dementia in old age. the prevalence of AD in people aged 65 years and above is about 4%, and increases about 1-fold for each 5-year increase in age between 65 and 90 years, increasing to 23% in the group aged 85 years and above.
The main risk factors for AD are advanced age, female gender and genetic factors. In recent years, many studies have suggested that vascular risk factors such as high-fat diet, morbid obesity, hypertension, diabetes, and hyperlipidemia also increase the risk of AD. High education level, active social activities, and regular exercise may be protective factors.
Pathogenesis]
The exact pathogenesis of AD is unclear and is thought to be the result of a combination of aging, genetic and environmental factors. There are several theories, among which the amyloid cascade hypothesis is the more influential one.
The amyloid cascade hypothesis is that β amyloid peptide is a normal product in the brain, and there are three main types of Aβ: Aβ1-40, Aβ1-42 and Aβ1-43. A series of pathological processes eventually lead to a decrease in neurons and abnormal transmitters, resulting in clinical cognitive and behavioral symptoms.
2. abnormal tau protein phosphorylation hypothesis tau protein is a microtubule-associated protein that maintains cytoskeleton stability by binding to microtubules. tau protein is abnormally hyperphosphorylated in the brain of AD patients, and the hyperphosphorylated tau protein aggregates to form double-stranded helical filaments, which form the main component of neurogenic fiber tangles and produce neurotoxicity. On the other hand, the reduction of normal tau protein leads to microtubule collapse, which aborts or disrupts axoplasmic transport, leading to axonal degeneration and neuronal death.
3. Genetic hypothesis Based on the age of onset, AD can be divided into early-onset AD (<65 years) (early-onset Alzheimer's disease, EOAD) and late-onset AD (≥65 years) (late-onset Alzheimer's disease FAD is mostly early-onset, accounting for about 10% of all AD cases. FAD is mostly early onset, accounting for about 10% of all AD, and is inherited in an autosomal dominant fashion. Three mutations have been identified that can cause FAD: APP gene, presenilin 1 (PS1) gene and presenilin 2 (PS2) gene mutation. The apolipoprotein E (ApoE) ε4 genotype (ApoEε4) is a predisposition gene for late onset familial AD and disseminated AD.
4. neurotransmitter hypothesis There are abnormalities of various neurotransmitters in the brain of AD patients, such as excitatory amino acids, norepinephrine, 5-hydroxytryptamine, and dopamine.
5. Other factors and hypotheses About the pathogenesis of AD, there are other hypotheses, such as oxidative stress hypothesis and microcirculatory disorder hypothesis, but all these factors are related to Aβ, or lead to increased Aβ, or participate in Aβ cascade reaction, which support the amyloid cascade hypothesis from different sides.
Clinical presentation】
AD often develops between 40 and 90 years of age, especially in old age (after 65 years of age), with some onset in the pre-geriatric period (early-onset AD). The clinical onset is insidious and continues to progress, with situational memory impairment as an early and prominent manifestation. In the advanced stage of the disease, gait abnormalities and convulsions can occur. Eventually, the patient becomes bedridden.
1. Cognitive dysfunction Cognitive dysfunction is the core symptom of AD.
(1) Memory impairment The prominent symptom in the early stage of AD patients is situational memory impairment. Patients cannot recall the recent events, often forget where things were placed, or even forget the last meal they ate.
(2) Disorientation Disorder Early in the course of the disease, patients can develop temporal disorientation, they do not know the current year, season, month and day of the week. In the mild to moderate stage, the patient has disorientation in location and can easily get lost. In the severe stage, the patient is lost indoors and cannot recognize his or her loved ones or even himself or herself.
(3) Executive dysfunction Patients with AD have abnormal executive function at an early stage, with reduced motivation, rigid and stereotyped thinking, inability to adapt to new environments, and reduced problem-solving ability.
(4) Aphasia Early AD patients can develop language disorders, hollow language, and obvious writing difficulties. As the disease progresses, reading and writing ability further decreases, and spoken language lacks substance and logic. In severe cases, stereotyped language appears, and in the final stage, patients become silent.
2. Decreased ability to perform daily activities The cognitive dysfunction described above leads to a decrease in the patient’s ability to perform daily activities. In mild AD, patients have difficulties in complex daily activities such as working, independent shopping, independent travel, cooking, etc. In moderate AD, patients’ basic daily activities deteriorate and they are unable to take care of themselves completely. In severe cases, patients need help with eating and bowel movements.
Behavioral and psychiatric symptoms are common in AD patients, among which apathy, depression, agitation and sleep abnormalities are the most common. Mood changes and emotional indifference usually occur early in the disease. In the middle and late stages of the disease, other psychiatric symptoms such as sleep abnormalities, hallucinations and delusions, and behavioral symptoms such as hyperactivity, wandering and aggression are also common.
4. Neurological signs There are no focal neurological signs in the early stage of AD, but if focal signs are present, the diagnosis of AD should be suspected. The neurological signs often appear in the late stage of the disease, which are balance disorder, gait abnormality, increased muscle tone, myoclonus and so on. Patients eventually lose the ability to stand and walk completely and become bedridden for a long time.
Ancillary tests
1. Routine blood, urine and biochemical examination AD patients have normal routine blood, urine and biochemical examination. Blood, urine and biochemical examinations have two purposes: (1) to exclude other causes of dementia, such as liver and kidney insufficiency, VB12 deficiency, etc.; (2) to determine whether the patient has complications and to guide treatment, such as anemia, electrolyte disorders, infection, etc.
2. Cerebrospinal fluid examination Routine cerebrospinal fluid examination is normal in patients with AD. Specific biochemical indexes can detect the decrease of Aβ42, increase of total tau protein and abnormal phosphorylated tau protein, which have auxiliary diagnostic value.
3. structural imaging examination Early stage brain atrophy mainly in hippocampus and medial temporal lobe, and late stage extensive brain atrophy mainly in temporal lobe, parietal lobe and anterior frontal lobe gray matter atrophy. ct examination is economical and convenient, but MRI is more sensitive.
4. Genetic testing Genetic examination should be performed to identify mutated genes in AD families with autosomal dominant inheritance. The examination of mutated genes in the non-diseased members of the family can help predict the future development of the disease.
Diagnosis and differential diagnosis
The diagnosis of AD can be made with a clinically probable diagnosis of cognitive decompensation caused by other diseases, excluding hippocampal and temporal lobe atrophy.
AD should be differentiated from other causes of dementia, and AD with combined hallucinations, depression, and psychotic behavioral symptoms should be differentiated from delirium, depressive evidence, and schizophrenia. Mild AD should also be differentiated from benign amnesia.
Mild AD should be distinguished from benign amnesia, and benign amnesia should be distinguished from early AD to relieve the elderly of the burden of thought.
Table 1 Differentiation between mild AD and benign amnesia
Mild AD
Benign amnesia
Memory impairment
Severe, suggesting no help
Likely to recall afterwards, suggesting help
Memory checks are more normal than normal or significantly less than before
Memory checks are often normal
Memory impairment has a definite impact on life
Generally does not affect life
Other cognitive functions
Have other cognitive impairments such as orientation, visuospatial function, etc.
Other cognitive functions are normal
Daily ability
Decreased than before
Can live normally and independently
Emotional personality
May change significantly
No significant change
Progression
Continued progression over several years
Often remains stable
2. Differentiation of AD from other causes of dementia Dementia is a syndrome with multiple causes that can lead to dementia, and different types of dementia should be differentiated because of different treatments and prognoses.
(1) Vascular dementia often starts relatively suddenly (in days to weeks), has a fluctuating course, is often accompanied by signs of stroke such as hemiparesis of the limbs, and often has a clear stroke lesion on head CT or MRI. However, it is important to note that subcortical small vessel dementia is relatively insidious and progresses slowly, sometimes making it difficult to distinguish from AD.
(2) Frontotemporal lobar degeneration Frontotemporal lobar degeneration is a relatively uncommon degenerative brain disease that often occurs in the early stages of aging, with behavioral personality changes (frontotemporal dementia) or language impairment (progressive nonfluent aphasia and semantic dementia) as early and prominent manifestations, while memory, orientation and visuospatial function are relatively preserved in the early stages.
(3) Lewy body dementia The 3 core symptoms of Lewy body dementia are fluctuating cognitive impairment, Parkinson’s syndrome, and distinctive visual hallucinations. In addition, patients are hypersensitive to antipsychotic drugs. In contrast, patients with AD have persistent cognitive impairment, and hallucinations and Parkinson’s symptoms appear late in the disease and can be differentiated.
AD should also be differentiated from other subcortical dementias (e.g. Parkinson’s disease, Huntington’s disease, hepatomegaly and progressive supranuclear palsy), and care should be taken to exclude prion disease and other infectious encephalopathies, normal cranial pressure hydrocephalus, metabolic and toxic dementias.
Treatment
The aim of AD treatment is to slow down the progress of the disease, improve the quality of life of patients, and reduce the burden of family members. The principles of treatment are: ① early prevention and treatment Early identification of AD and treatment at the early stage of the disease; ② long-term treatment AD is a chronic and continuously progressive disease, which requires long-term regular medication; ③ regular follow-up Evaluation of drug efficacy and side effects, evaluation of disease progression, and adjustment of drugs and treatment plans; ④ strengthening care Patients mostly die from complications, therefore, it is important to strengthen daily care and prevent and treat complications. The treatment of AD includes the following aspects.
1. Improving cognition and living ability Including both pharmacological and non-pharmacological aspects.
(1) Non-pharmacological measures Some studies suggest that brain activity and cognitive exercise may be able to improve the cognitive function of patients or slow down the decline of cognitive function. Patients should be allowed to perform certain activities as much as possible, such as reading books, newspapers, puzzles, etc. The ability of patients to exist should be maintained as much as possible, and caregivers should not do everything on their behalf.
(2) Drug therapy Currently, there are 2 types of drugs for the treatment of AD: cholinesterase inhibitors (donepezil, carboplatin, and the domestic drug Shisanine A) and excitatory amino acid receptor antagonists (memantine hydrochloride). The overall selection principle is: ① mild AD patients preferred cholinesterase inhibitors, if one is not effective, can switch to another, if both are ineffective, can switch to or add excitatory amino acid receptor antagonists; ② moderate patients can be preferred to either of the two types of drugs, if a cholinesterase inhibitor is not effective, can switch to other cholinesterase inhibitors or add excitatory amino acid receptor antagonists; ③ severe patients preferred excitatory amino acid (3) Excitatory amino acid receptor antagonists are preferred in severe patients. ④ Also, the contraindications of both classes of drugs should be noted, and patients with contraindications or relative contraindications to one drug may prefer the other drug. In addition, meperidine hydrochloride has a certain ameliorative effect on agitation in patients with AD, and may be considered preferable for patients who are old and frail and have significant psycho-behavioral symptoms.
Other medications include: ① Mental stimulants Pyrrolidone drugs such as piracetam, aniracetam (also known as aniracetam) and olacetam; ② Ergot alkaloids Dihydroergot alkaloids, ergot bromelain; ③ Ginkgo biloba extract. These drugs may be effective and can be tried clinically, but the results of studies are inconsistent.
2. Control of psychiatric and behavioral symptoms Includes 2 means, pharmacological and non-pharmacological
Psychiatric and behavioral symptoms are common in patients with dementia, increasing the mortality rate of patients and the burden of caregivers. Timely and effective control of psychiatric and behavioral symptoms can improve the quality of life of patients and their families. At present, there are two main approaches to improve psycho-behavioral treatment, non-pharmacological and pharmacological.
(1) Non-pharmacological treatment mainly includes psychological interventions for patients and caregivers, and is the preferred treatment method for improving psychiatric behavior. The caregiver should respect the patient and speak kindly, while maintaining a safe and relatively quiet environment to avoid inducing psychobehavioral symptoms in the patient. Before non-pharmacological treatment, the patient’s behavioral and emotional changes need to be analyzed to determine the causes or triggers for correct and targeted treatment. After treatment, treatment effects should be examined and symptoms reassessed to guide the next step of treatment.
(2) Pharmacological treatment
Depression Selective 5hydroxytryptamine reuptake inhibitors are currently used more often in the elderly. Such drugs include fluoxetine (Prozac), paroxetine (Sertraline), citalopram, sertraline, etc.
Anxiety Benzodiazepines are effective in improving anxiety (e.g., Valium, Lola, etc.), but because long-term use of these drugs can lead to drug resistance and dependence, clinical application of these drugs for anxiety treatment should choose short-acting preparations, and the longest course of treatment should not exceed 4 weeks or intermittent application. After that, stop the use of tranquilizers. For panic disorder or panic, selective 5HT reuptake inhibitors can be tried.
Psychotic symptoms such as hallucinations, delusions, agitation, and aggression
Meperidine hydrochloride has been shown to improve symptoms of agitation, aggression, and restlessness and can be added first. Selective 5-HT receptor reuptake inhibitors are useful for improving mood. When the above drugs are ineffective, new atypical antipsychotics such as quetiapine, olanzapine and risperidone can be used, but the side effects of the drugs should be explained to the family. The following principles should be noted: (1) start at low doses; (2) increase the dose slowly; (3) increase the dose at slightly longer intervals; (4) use the smallest effective dose as much as possible; (5) alleviate the disease, but do not seek complete control; (6) pay attention to drug interactions; (7) individualize the treatment.
3. Treatment of complications In the late stage of AD, patients cannot feed themselves, have unstable gait, and end up in bed. Malnutrition, falls, fractures, pulmonary or urinary tract infections, and decubitus ulcers often occur at this stage, and care should be strengthened to prevent these complications from occurring, and targeted treatment measures should be taken if complications occur.