1. Cognitive impairment: attention and concentration, memory, language, visuospatial skills, orientation, calculation, application, executive function and other dysfunction.
2. Behavioral abnormalities: delusions, hallucinations, misconceptions and other psychotic symptoms; Depression, anxiety, euphoria, apathy, insomnia and other psychological symptoms; Roaming, agitation, disastrous reaction, complaint, disinhibition, intrusion, disobedience and other abnormal behaviors.
3. Impaired daily living ability: basic living ability such as taking medicine, going to the toilet, dressing, eating, dressing, walking and bathing; Ability to make phone calls, shop, cook, do housework, wash clothes, take or drive transport, finance and other tools.
The risk factors of ad include uncontrollable factors (pathogenic genes and risk genes) and controllable factors (hypercholesterolemia, obesity, hypertension, diabetes, depression, nerve injury, vascular injury, inflammation, smoking, excessive drinking, unhealthy diet, etc.).
Risk factors exist in people's life. Different life stages (early life stage, middle life stage, and late life stage) have different important risk factors.
In all cases, about 40% of patients were associated with 12 controllable risk factors. Studies have shown that controlling risk factors may help prevent dementia. Based on the impact of risk factors on patients, the recommended interventions for decision makers and individuals include: Keep the systolic blood pressure below 130 mmHg after 40 years old; Encourage the use of hearing aids to compensate for hearing loss and reduce hearing loss through ear protection; Prevent head injury; The weekly alcohol intake shall not exceed 21 units (one unit of alcohol is equal to 10ml or 8g of pure alcohol); Quit smoking and support others to quit smoking; Reduce exposure to air pollution and second-hand smoke; Provide primary and secondary education for all children; Reducing obesity and its associated diabetes; Keep exercising from middle age, if possible, to old age.
In July 2020, in view of the urgent need to treat AD, the world's famous scholars in this field conducted a systematic review and meta-analysis of the existing research evidence, formulated the world's first international guideline for evidence-based prevention of AD, and put forward 21 suggestions in four aspects, believing that ad can be prevented.
1. Treatment principle The treatment of ad should follow four principles: comprehensive treatment, early intervention, standardized treatment, and combination of drug and non drug treatment.
(1) Comprehensive treatment principle: pay full attention to ABC syndrome [ABC syndrome refers to people with clinical manifestations such as cognitive decline (c), behavior (b) and activity (a)], improve patients' cognitive dysfunction, control patients' mental and behavioral abnormalities, improve patients' daily living ability, and bring greater clinical benefits to AD patients.
(2) Early intervention principle: active intervention in the risk factors of AD, such as prevention and treatment of depression, smoking cessation, avoidance of hearing loss, stabilization of blood pressure, and adjustment of blood sugar, is of great significance to reduce and delay the occurrence of AD.
(3) Standard treatment principle: select reasonable drugs for treatment. All drugs should start at low dose and gradually increase to the recommended effective dose or maintenance dose; The drugs to improve cognition should be sufficient, sufficient treatment, or even combined; Antipsychotics are generally used in small doses and for short periods.
(4) The principle of combination of drug and non drug therapy: as an effective supplement to drug therapy, non drug therapy can play a certain role in the management of ABC syndrome; Some non drug treatments can even delay the progression of AD.
2. Therapeutic drugs Drugs commonly used in clinical treatment of AD: Drugs for core symptoms: donepezil, kabalatin, galantamine, shishanjian a, memantine; Inhibitory drugs: risperidone, olanzapine and quetiapine; Excitatory drugs: nicergoline, olacetam, piracetam, etc.
In a long-term cohort study on ad, the enrolled patients were AD patients in the dementia registration system. They all started to receive acetylcholinesterase inhibitors (Chels) within 3 months after diagnosis. A total of 11652 patients used drugs, and 5826 non users served as controls. The results showed that the MMSE score of the treatment group was increased by 0.13 every year, especially when the dose of donepezil was more than 7.5mg. In a meta-analysis, from the randomized, double-blind, parallel, placebo-controlled trials of memantine in the treatment of dementia, the studies with delayed release of 20mg or 28mg and follow-up time of 6-7 months were selected, and the mild and moderate to severe AD patients were analyzed respectively.
The analysis results show that memantine has a definite effect on the overall clinical, cognitive function, daily living ability and mental and behavioral symptoms of moderate to severe AD patients. At present, AD drug treatment can not completely reverse the pathological process of cognitive impairment, and its treatment objectives mainly focus on improving cognitive function, delaying disease progression, improving daily living ability, prolonging the survival period of patients, and reducing the care burden of caregivers.
3. Current situation of drug research and development At present, the research and development of ad drugs are divided into three categories: biological agents for disease correction therapy, small molecule drugs for disease correction therapy, and small molecule drugs for relieving symptoms.
There were 132 drugs in clinical trials in 2019, and 96 drugs can be classified as disease modifying therapy; Of which 38 (40%) were β As the main target or one of the targets, tau is the second representative target of disease correction therapy (accounting for 18%). Ad has a high failure rate in drug research and development, and it is difficult to make good progress in new drug research and development without breaking through the inherent mode of "one drug, one target". The pathogenesis of ad is complex.
Before neurodegeneration, the processes that change with age include inflammation, autophagy damage, vascular dysfunction, synaptic loss, mitochondrial and metabolic dysfunction, and epigenetic changes. These processes provide a variety of targets for AD drug development.
At present, more and more attention has been paid to the relationship between inflammation and ad, and drugs targeting inflammation have become one of the research hotspots. The results of phase III clinical study of manna Turner in China show that manna turner can significantly and continuously improve the cognitive function of AD patients, and has the dual effects of symptom improvement and potential course change. Manna turner can cross the blood-brain barrier and directly target a β， It can effectively reduce neuroinflammation and remodel the imbalance of intestinal flora.
From this perspective, manna Turner broke through the R & D pattern of "one drug and one target" in AD, and systematically responded to the complex disease mechanism of AD (inhibition of a β Reduce neuroinflammation, and balance the intestinal flora). Synaptic dysfunction is closely related to cognitive impairment in AD, and drug research targeting synaptic plasticity and neuroprotection is also a hotspot. In addition, metabolic disorder and energy imbalance are also part of the pathological mechanism of AD. At the same time, potential anti ad drugs targeting vascular factors are also one of the research hotspots.
4. Non drug intervention Healthy diet: Mediterranean diet, Deshu diet (DASH diet); Sports: aerobics, aerobics, square dancing; Physical therapy: transcranial magnetic stimulation, transcranial pulse stimulation; Cognitive training: memory, reasoning, processing speed training; Social activities: complex work, elderly community; Psychological intervention: validation and nostalgia therapy.
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