The incidence and prevalence of Alzheimer’s disease (AD) is rapidly rising along with the silver wave of population aging sweeping the world, with one additional case of dementia in the world every seven seconds and 4.6 million new cases of AD each year. The number of people with AD worldwide has exceeded 36 million and will reach 115 million by 2050. 2010 saw a global cost of over $600 billion for people with AD, accounting for 1% of GNP, and will increase by 85% by 2030. The number of AD patients in the United States has reached 5 million, with the fourth highest prevalence rate and the fifth highest death rate in the disease rankings. AD is a serious disabling disease in which the knowledge and skills acquired through lifelong struggle gradually decline or are lost. Severe mental decline and language impairment lead to communication difficulties, inability to care for themselves, and “relentless” torment of loved ones and caregivers due to abnormal mental behavior. At present, there is no specific treatment for clinically diagnosed AD, especially for moderate to severe AD. Therefore, the early diagnosis and intervention of dementia has become a hot topic for scholars from different countries in recent years.
The prerequisite for early intervention is early diagnosis, i.e. early detection of preclinical phase AD (PCAD) with mild symptoms, especially those with AD pathological changes in the brain but no clinical symptoms.
In the World AD Report 2011, written by Pauline et al. on behalf of the International Dementia Association after a systematic and comprehensive review of relevant evidence, it was suggested that early diagnosis of AD can be achieved and that early diagnosis and intervention can significantly improve the cognitive function of AD patients, delay their admission to medical and nursing facilities, and that the cost of early diagnosis is significantly less than the cost of subsequent anti-dementia medication. In 2010, the National Institute on Aging and the AD Consortium recommended new diagnostic definitions and criteria, proposing a three-stage diagnostic framework for AD: dementia phase, mildly symptomatic dementia phase, and early intervention.
phase), pre.dementia phase with mild symptoms (pre.dementia phase), and asymptomatic PCAD. speding et M
o classify PCAD into 3 phases: phase 1 with only brain amyloid deposits and no clinical symptoms; phase 2 with brain amyloid deposits and evidence of associated neurodegeneration; and phase 3 with brain amyloid deposits and neuronal damage, plus mild cognitive and behavioral decline. There is evidence of pathophysiological changes in the brain years or even more than 10 years before the onset of clinical symptoms in AD. Such a long preclinical period provides a time window to intervene in the development of the disease. The authors emphasize that the PCAD criteria were proposed for research purposes only. according to Llado and Sdnchez-Valler, PCAD also includes (1) individuals carrying one or more ApoE alleles that contribute to increased risk factors for AD dementia with positive biomarkers of AD pathology and (2) individuals carrying autosomal mutated genes with positive pre-symptomatic biomarkers that eventually develop dementia. patients who eventually develop dementia.
Current research on PCAD has focused on exploring evidence of abnormalities in cerebrospinal fluid biomarkers such as β-amyloid (AB) and tau proteins, brain volume changes, and Aβ imaging and genetic abnormalities. Excessive deposition of extracellular senile plaques centered on Aβ1-42 in the brain tissue of patients resulted in reduced Aβ1-42 concentrations in the cerebrospinal fluid. Hyperphosphorylation of intracellular tau protein resulted in a significant increase in neurogenic fiber tangles, cerebrospinal fluid total tau (t-tau) protein and phosphorylated tau (p-tau) protein levels. The most direct and reliable method to confirm the alteration of both is brain tissue biopsy, but it is more difficult to perform widely in the clinic. Because the cerebrospinal fluid is directly linked to the extracellular space of the CNS, biological changes in the brain are reflected in the cerebrospinal fluid, so detection of Aβ and tau proteins in the cerebrospinal fluid, for example, can more objectively reflect pathophysiological changes in brain tissue.
Nghiem reported that the use of MRI to measure volumetric changes in the brain such as hippocampal atrophy and cortical thinning can predict dementia up to 10 years in advance, and PET plus Pittsburgh complex B (PIB) can show the number of A13 plaques in brain tissue and predict dementia. Clinical symptoms combined with imaging and cerebrospinal fluid markers can increase the correct diagnosis of AD by more than 80%. For ApoE
susceptibility gene, APP gene, PSl and PS2 gene kites can detect and predict AD, but their expression levels vary between AD subtypes.
Xiong et al. used MRI and PIB techniques to detect Aβ, tau protein, and ApoE susceptibility genes in the cerebrospinal fluid of 269 volunteers aged 45-75 years with normal cognitive function and found that AB1-42 was decreased in volunteers with a family history of AD, and ApoE
e4 alleles were increased, and there was a significant age correlation. There were ApoE
Vidoni et al. showed the relationship between midlife body mass index (BMI) and cognitive function and found a significantly higher rate of mild cognitive impairment (MCI) in those with lower BMI compared to those with higher BMI, with a significantly higher rate of brain Aβ spot signal (85%) in the former compared to the latter (48%). The former had significantly higher brain Aβ spot signal (85%) compared to the latter (48%), and other biomarker abnormalities were also more significant. Similar changes were found in people without cognitive impairment. In recent years, the basic and clinical research on AD in China has been very successful, and the research on early diagnosis of AD has also started.
Since PCAD patients have no clinical symptoms of dementia or only mild cognitive and behavioral decline, early diagnosis is particularly difficult clinically and mainly relies on laboratory diagnosis.
At present, the detection of AB42, t-tau, P-tau and subtypes p-taul81, 199 and other phosphorylation specific sites in cerebrospinal fluid of AD patients is mostly limited to some large research institutions in developed countries, and the diagnostic kits are still in the research stage, with sensitivity and specificity to be improved, and the market rate is extremely low because of their high price. Research on more convenient biomarkers of blood, urine and other body fluids has just started. There is also a lack of laboratory tests for AD-specific biomarkers for clinical diagnosis in China, and there is almost a gap for cerebrospinal fluid biomarkers such as Aβ, tau protein assays and PIB technique for Aβ imaging. However the specificity of these diagnostic markers has also been questioned. Some studies have shown that abnormalities of Aβ1-42 and tau can also be found in the cerebrospinal fluid of normally aging elderly people without AD, and PIB shows an increase in brain AB spots and MRI shows a decrease in brain volume, etc. Thus, the level of these biomarkers does not yet provide full information for the diagnosis of AD, nor can it be certain that people with such changes will necessarily develop dementia. Therefore, scientific definition of the boundary between normal and abnormal levels of these markers and identification of one or several specific diagnostic markers for different subtypes of dementia still require multicenter, large sample and long-term longitudinal prospective studies.
At present, most hospitals diagnose AD mainly based on clinical symptoms and neuropsychological scales, and most scales are less sensitive to mild dementia, which would miss most patients with mild AD and MCI and make it more difficult to detect PCAD. e.g., MMSE can identify healthy elderly with dementia but not healthy elderly with MCI, Montreal Cognitive Assessment Scale has a higher sensitivity to MCI with a sensitivity of The sensitivity of the Montreal Cognitive Assessment Scale for MCI is higher, with a sensitivity of 92.4%, significantly better than that of the MMSE at 24.2%, but its sensitivity and specificity for diagnosing PCAD still needs to be studied.
At present, the knowledge of dementia is not widely spread in China, and the public and even some medical personnel have low knowledge and high misunderstanding of dementia, resulting in low consultation and treatment rates of dementia patients. In medical institutions, except for some physicians in neurology, psychiatry and geriatrics, most of them lack knowledge about dementia and are not familiar with the clinical characteristics and differentiation points of AD and other types of dementia in old age, and they do not know how to use neuropsychological scales and corresponding auxiliary examinations correctly.
Early diagnosis of AD has a long way to go. Early diagnosis and intervention can benefit AD patients more, so the prologue of research on early diagnosis of AD has been opened. As the world’s largest ear-entry country and the country with the largest number of dementia patients, we should do something in exploring the early diagnosis of AD.
1. Research on early diagnosis of AD should be jointly conducted by multidisciplinary experts and multicenter organized by the academia with government funding and taking advantage of national resources and talents. First of all, we should research on AD diagnostic specific cognitive markers (cognitive
For example, we should focus on biomarkers such as Aβ, tau protein and its subtypes in cerebrospinal fluid and blood, and develop specific diagnostic kits; conduct brain imaging studies such as AB imaging of brain tissue; carry out research on specific susceptibility genes; encourage the creation of neuropsychological scales and localization of foreign scales to determine the neurological and psychological characteristics of different subtypes of PCAD and MCI. Psychological characteristics of different subtypes of PCAD and MCI. At the same time, basic and clinical research based on different etiologies and pathogenesis should be encouraged and funded.
2. With reference to the cohort studies such as the King’s Island Project in Sweden, the Rotterdam Study in the Netherlands and the Cache Valley Study in the United States, we should establish research bases in urban neighborhoods and villages across the country in a systematic manner to prospectively, in large samples and over a long period of time, observe and study the incidence, prevalence, risk factors (such as hypertension, vascular events, diabetes, BMI, lipid abnormalities, genetic factors, diet and lifestyle, etc.), the effect of drug treatment and regression, etc., it is possible to find some diagnostic clues of PCAD from the clinical perspective.
3. Establish a nationwide network of AD expert diagnostic research centers and provincial sub-centers with the participation of basic and clinical multidisciplinary experts, and develop a national near-term and long-term plan for basic research and clinical prevention and treatment of AD dementia. Add a PCAD research program and develop a PCAD research strategy based on the currently published Chinese Guidelines for the Diagnosis and Treatment of Dementia and Cognitive Disorders.
4. Strengthen the promotion and popularization of dementia science knowledge with the help of media to increase the public’s awareness of dementia. Hold various professional training courses to raise the awareness of relevant specialties in general hospitals and primary medical personnel to pay attention to dementia as they do to hypertension and diabetes, etc., and to have basic skills for diagnosis and intervention of dementia, MCI and PCAD.