Theft or hypochondria

Introduction Alzheimer's disease dementia can have a persecution of delusions, theft or suspected delusions. Dementia in Alzheimer's disease is a progressive degenerative neurological degenerative disease. Clinically, it is characterized by memory impairment, aphasia, misuse, loss of recognition, visual spatial impairment, executive dysfunction, and personality and behavioral changes such as personality dementia. The etiology has not been known so far. In the past, people who were 65 years old were called presenile dementia; after 65 years old, they were called senile dementia. The main pathological changes of this disease are cerebral cortical atrophy, neurofibrosis and degeneration of cerebral nerve cells and senile plaques, which are common diseases in old age.

Cause

(1) Causes of the disease

From the existing epidemiological data, AD may be a heterogeneous group of diseases that occur under a variety of factors, including biological and psychosocial factors. Although AD neuropathology, especially molecular biology research, has made great progress, which lays a foundation for the study of pathophysiology and etiology of AD, it is still in the exploratory stage, and the etiology of AD is far from being elucidated. Epidemiological studies have analyzed the risk factors for AD, providing clues for finding the cause, but the risk factors are not the cause. From the current research, there are more than 30 possible factors and hypotheses of AD, such as family history, female, head trauma, low education level, thyroid disease, too high or too low maternal age, and viral infection. The discussion of different aspects of the same issue may be correct and not mutually exclusive. From the current research, there may be different reasons for AD. The following factors are related to the pathogenesis of this disease:

Family history

Most epidemiological studies suggest that family history is a risk factor for AD. In some patients, members of the family members who suffer from the same disease are higher than the general population, and the risk of congenital disease is also increased. Further genetic studies have confirmed that the disease may be caused by autosomal dominant genes. Recently, through gene mapping studies, it was found that the pathogenic gene of amyloid in the brain is located on chromosome 21. It can be seen that dementia is related to heredity, but it is hard to be sure how big the genetic effect is. Due to the late onset of AD, there are no reports of twins based on the general population. The same prevalence reported in a small number of elderly single-ovary twins (MT) studies is not very high. Most reports suggest that there is a family aggregation phenomenon in AD, and the relationship between AD and the positive family history of first-degree relatives is also quite positive.

According to available data, in eight case-control studies, AD was associated with a history of dementia in first-degree relatives, and no association was found in the other. A reanalysis of 11 case-control studies in Europe showed that if at least one first-degree relative had dementia, the risk of dementia increased more than three-fold. The study of the distribution frequency of apolipoprotein E (Apo E) genotype in the population further supports the pathogenesis of genetic factors on AD. The Apo E allele 4 has been shown to be an important risk factor for AD. The frequency of the Apo E 4 gene was significantly increased in both familial and sporadic AD. The frequency of Apo E 4 gene in autopsy-recognized AD patients is about 40%, compared with about 16% in normal control population, and the risk of AD with an 4 allele is two to three times that of the general population. The risk of carrying two 4 alleles is about eight times that of the general population. It is now clear that the Apo E4 allele is not a necessary factor in the pathogenesis of AD, and its predictive effect on the pathogenesis of AD remains to be confirmed by prospective studies. The author's analysis may be associated with the collection of late-onset AD, suggesting that family aggregation may be an important risk factor for early-onset AD. However, this interpretation of positive results should be cautious, and family aggregation is not a true genetic factor. Thus, genetic factors are not the only factor in the pathogenesis of AD.

2. Some physical diseases

Such as thyroid disease, immune system diseases, epilepsy, migraine, etc., have been studied as a risk factor for AD. In patients with a history of hypothyroidism, the relative risk of developing AD is 2.3. There was a history of seizures before the onset of AD (relative risk was 1.6). The history of migraine or severe headache has nothing to do with AD. Many studies have found that the history of depression, especially the history of depression in the elderly, is a risk factor for AD. A recent case-control study suggests that other functional disorders such as schizophrenia and paranoid psychosis are associated with depression. A comparison of early history of central nervous system infections, such as encephalitis, meningitis, herpes virus infection, and history of exposure to livestock, and animal history of eating animals have failed to demonstrate that these factors are associated with AD. Chemicals that have been studied as risk factors for AD include heavy metal salts, organic solvents, pesticides, and pharmaceuticals. The role of aluminum has been a concern because animal experiments have shown that aluminum salts have an impact on learning and memory; epidemiological studies suggest that the prevalence of dementia is related to the amount of aluminum in drinking water. According to preliminary results of a study on the prevalence of dementia in France, Michel et al. reported that aluminum was a risk factor for AD, but further analysis denied this result. Flaten et al. (1990) reported that aluminum in drinking water is associated with dementia. Since then, several studies have failed to confirm that aluminum is a risk factor for AD. Case-control studies of people with a history of heavy metal exposure, including exposure to aluminum, did not find any heavy metals associated with AD. It may be due to the accumulation of neurotoxins such as aluminum or silicon in the body, which accelerates the aging process. However, although aluminum is a neurotoxic substance, it has not been considered as a risk factor for AD in the existing studies. It has been reported that smoking is not a risk factor for AD, but instead protects AD. And some authors did not find the relationship between the two. Smokers suffering from less AD may be due to their short life expectancy and they will die if they are old.

3. Education level

There are more and more reports about the low level of education and the increased prevalence of dementia. Shanghai reported that the prevalence of dementia and AD was 6.9%, and that school age was 1.2% more than 6 years. A recent Italian epidemiological survey has similar findings. However, in a Japanese case-control study, no association was found between education levels and dementia and/or dementia subtypes. There is no reasonable explanation for this. Some scholars believe that this is caused by systematic errors. Since most epidemiological studies use a two-stage screening test, a diagnostic test is performed on patients who are positive for screening, so that people with low illiteracy or low education may have low scores in the screening test and easy to enter the diagnosis. The stage of sexual examination is diagnosed as dementia, which increases the prevalence, and in fact these people may not have cognitive decline at all. It is believed that this is due to the biological characteristics of illiterate itself, not to education, and that education is related to the socio-economic situation, further complicating this issue. However, Zhang Mingyuan et al. (1990) used different screening cut-off values according to the different educational levels of screening subjects during screening to avoid such systematic errors. As a result, the prevalence of dementia was still high in low-educational people. Several studies have confirmed this result since then. The low level of education and the etiology of AD are still unclear. The possible explanation is that early education and training promoted the development of cortical synapses, increased the number of synapses and increased the brain reserve, thus delaying dementia. Diagnostic time. This hypothesis is supported by some clinical observations. For example, patients with high levels of AD can retain some cognitive functions even in advanced stages, and their duration from diagnosis to death is relatively short. Low levels of education have a similar relationship with vascular dementia and other secondary dementias.

4. Head trauma

Head trauma refers to head trauma with conscious disturbance, and brain trauma has been reported as a risk factor for AD. Of the 12 case-control studies, 3 were found to be significantly associated; 4 AD had more traumatic history than the control group, but there was no statistical significance, and the other 5 did not find any association. However, a recent follow-up study of a severe brain injury has attracted more interest. Robert et al. followed the average follow-up of patients with severe traumatic brain injury for 25 years. As a result, approximately one-third of patients had amyloid-like deposition similar to AD in brain tissue. Clinical and epidemiological studies suggest that severe brain injury may be one of the causes of certain AD. According to current data, head trauma may be a risk factor for AD, but it is not certain.

5. Mother childbearing age is too high or too low (greater than 40 years old or younger than 20 years old)

Due to Down's syndrome (DS), it may be a risk factor for AD, and DS risk increases with the increase of maternal age. There were 9 case-control studies, some of which were found to be related, some found to be different but not statistically significant, or none of them were found at all, and some were considered to be only risk factors for some sporadic AD.

6. Other

Progressive failure of the immune system, impaired detoxification of the body and lentivirus infection, as well as social and psychological factors such as widowhood, solitary, economic difficulties, and life bumps can be the cause of the disease.

(two) pathogenesis

Genetic factor

DS has similar pathological changes in AD. If DS has an AD rate of about 100% in adults, it is known that the DS pathogenic gene is located on chromosome 21, which is of great interest to AD genetics research. However, the study of AD genetics is difficult. Most researchers have found that the risk of AD in patients with family members is about 3-4 times higher than that of the general population. St. George-Hyslop et al (1989) reviewed the research data of AD family and found that family members are at risk of AD, 14.4% for parents and 3.8% to 13.9% for siblings. Using life-time statistical analysis, the risk of AD in first-degree relatives of FAD was as high as 50%, while that in the control group was only 10%. These data support some early onset FAD, which is a group of age-related dominant autosomal dominant inheritance; There is a female-only family, which is rare to rule out X-linked inheritance, and most sporadic cases may be the result of interactions between genetic susceptibility and environmental factors.

The twin study is an important method of clinical genetics research. Kallman (1956) studied 108 pairs of twins with the same disease rate, 42.8% for single-oval twins and 8% for twin-oval twins. Due to the large age difference between the occurrence of certain single-oval and twin-oval twins, twins with different diseases may be the same afterwards. Therefore, the incidence of monozygotic and twin twins is estimated to be close to about 40%, that is, one of the twins has AD, and the other has a 40% chance of developing AD, but the sibling may be much later. .

The development of molecular genetics technology has provided broad prospects for the etiology of AD. The genetic degree points associated with AD are currently known to have at least four of them: the early-onset AD loci are located on chromosomes #1, 14, and chromosome 1, respectively. Corresponding possible pathogenic genes are the APP, S182 and STM-2 genes. The delayed-type AD locus is located on chromosome 19, and the possible pathogenic gene is the apolipoprotein E (Apo E) gene. It suggests the heterogeneity of AD inheritance, that is, different DNA changes lead to the same clinical manifestations, or genotypes are different and the phenotypes are the same, as follows:

(1) Early-onset AD: Most of the new data comes from rare early-onset, studies with AD family history or DS patients. Considerable progress has been made in the study of disease genes associated with AD, and mutations in three genes have been found to be associated with early-onset familial autosomal dominant AD. The APP gene mutation on chromosome 21 is adjacent to the beta amyloid sequence. APP is a transmembrane protein located on the cell membrane, Golgi complex and vesicles, and the amyloid beta is partially located in the membrane and partially outside the membrane. In cell culture and transgenic mice, mutated APP expression resulted in increased beta amyloid production and reduced APPM production. Elevated amyloid beta promotes the formation of senile plaques and is associated with its toxicity. In the neuronal transmutation caused by APP mutation, the decrease of SAPP level may play an important role, because SAPP can promote the survival of neurons and increase their plasticity, and also protect neurons from excitotoxic substances and oxidative damage. Most early-onset familial AD is not caused by APP mutations. The other two related to early-onset familial AD are the presenilin 1 and presenilin 2 genes (PS1, PS2). PS-1 is located on chromosome 14, and PS-2 is located on chromosome 1. PS-1 and PS-2 expression are also transmembrane proteins that are located on the endoplasmic reticulum of brain neurons. Cell cultures expressing presenilin and transgenic mice have found that presenilin mutations increase beta amyloid production and increase neuronal sensitivity to metabolic and oxidative damage. Pathogenic activity caused by mutations in the presenilin gene may include disturbance of Ca2 regulation in the endoplasmic reticulum.

1 early-onset AD chromosome 21 locus and APP gene: St.George-Hyslop et al. (1987) 48 cases and 54 cases in 8 generations, 20 cases in 6 cases and 4 autosomal dominant in 23 cases Genetically high-fat FAD families were analyzed by linkage with the 2l chromosome DNA probe. The early-type AD locus was found to be located in chromosome 21q11.2-21q22.2 of chromosome 21. Schellenberg (1991) measured the long arm of chromosome 21, the lod score, log of the odd of linkage was only in some early-onset AD, while D21S13, D21S16 and D21S110 showed small positive values, and the rest were negative. value. It is suggested that some subgroups of early-onset AD are linked to chromosome 2l, and some of the localizations are not fully understood.

The A4 of SP is composed of 39-43 amino acids, which is encoded by APP gene. The linkage analysis also locates this gene in the 21q11.2-21q22.2 region, suggesting that APP gene may be involved in the pathogenesis of AD. The APP gene contains 18 exons. During transcription, the splicers APP770, APP751 and APP695 encoding 770, 751 and 695 amino acids are generated by alternative splicing of the 7th, 8th and 15th exons. The beta amyloid is the 16 and 17 exons of the APP gene.

Mutation refers to a mutation in a gene sequence, and structural changes result in abnormalities in function, affecting the quality and quantity of the protein it expresses. Some of the mutations are partial or total deletion of the gene, and some are due to the insertion of the foreign DNA sequence, the insertion occurs in the exon, and the genetic code changes, resulting in a large change in the protein sequence. The earliest discovered APP gene mutation occurred in the 693th codon of exon 17, corresponding to the 22nd amino acid of amyloid, from glutamate to glutamine. Later, in the second early-type AD family, a mutation in the codon 717 from valine to glycine was found. The above APP gene mutations are located in the A4 region or adjacent regions, suggesting that this gene mutation may be related to the formation of A4 and the pathogenesis of AD. However, the 21st chromosome APP gene mutation was only found in 2% to 3% of a few patients with FAD, and most of the FAD and late-onset AD did not see this mutation.

Chromosome 214 locus and AD3, S182 genes: Since the discovery of some early-type AD family APP mutations in 1991, scientists have been working hard to find other related genes in AD. Using a short tandem repeat polymorphism marker linkage analysis, it was found that another pathogenic locus of some early-onset AD was located in the 14q24.3 region of the long arm of chromosome 14. The logarithm of the linkage advantage obtained by the nine families is Z=9.01 (Z>3 is chained). So far, 11 early families have found that early-type AD is linked to chromosome 14. Related genes (AD3 and S182, different investigators may use different names for the same gene) have been cloned and are autosomal dominant genes whose mutations may be the cause of 70% to 80% of early-onset AD.

Chromosome 31 locus and STM2 or E5-1 gene: Sequence analysis of the entire coding region of STM2 gene of chromosome 1 was performed on 4 patients with VG (Valga German) family. The result was a mutation in 141 codon, nucleoside The acid is mutated by AT (AACATC), ie, N141 I. This gene is called the STM2 or E5-1 gene. Both STM2/E5-1 and the S182 gene located on chromosome 14 encode transmembrane proteins, all of which are autosomal dominant. In the molecular structure, there is high homology in the site of mutation, which may belong to a gene family, so the AD gene of chromosome 14 is called Presenilin-2 (PS-2) gene S182. % to 80% of early-onset AD is caused by mutation of this gene. The AD gene on chromosome 1 is called the Presenilin-2 (PS-2) gene, and STM2/E5-1 is associated with a small subgroup of VG in early-onset AD. The discovery of presenilin is a major breakthrough in the field of AD research in recent years and has become a hot spot in AD research.

(2) Late-onset AD: chromosome 19 locus and apolipoprotein (Apo E) gene. In the more common sporadic late-onset AD, Apo E gene (Apo E4) is a current molecular biology and molecular genetics study. Hot spot. Apo E is known to be a plasma protein associated with blood lipids and is a risk factor for hyperlipidemia and arteriosclerosis. Apo E is involved in lipid metabolism in the brain and may play a part in the regeneration of peripheral and central nervous system injuries.

In the genetic study of late-onset AD, Apo E gene was found to be an important risk gene for late-onset AD. The Apo E gene is located at the 19q13.2 site on chromosome 19, and the encoded Apo E is a lipid transport-related protein with a relative molecular mass of 34×103, consisting of 299 amino acids, and is rich in arginine. It is one of the components of low density lipoprotein particles. In the brain, Apo E is produced by astrocytes and plays an important role in the local lipid transport of brain tissue, especially after neuronal damage and degeneration, the metabolism and repair of myelin phospholipids. Apo E has three common subtypes, E2, E3 and E4, which are encoded by three complex alleles 2, 3 and 4, respectively. The difference in the Apo E 3 protein subtypes differs only in the amino acids at positions 112 and 158. This difference is due to the single base polymorphism of the Apo E gene at these two codon positions. Although the distribution frequencies of Apo E alleles are different in different populations, 3 is the most common, followed by 4, and 2 is less common. The frequency distribution of the Apo E allele in normal whites was: 2, 8%; 3, 78%; 4, 149%. According to reports, the distribution in the normal Han population is: 2, 4%; 3, 83%; 4, 13%. Numerous studies have confirmed that the frequency of the Apo E4 allele is significantly elevated in familial and sporadic AD. The frequency of Apo E4 allele was the highest in familial AD, about 50%. The Apo E4 of AD patients diagnosed by autopsy was also high, and the frequency of sporadic AD was 24%-40%. Further studies have shown that the Apo E4 allele is significantly associated with late-onset AD. The risk of using AD with the Apo E4 allele is increased and the age of onset is advanced. Interestingly, the Apo E2 allele appears to have a protective effect, and carrying this gene reduces the risk of disease and delays the onset of onset. The Apo E allele genotype 4/4 has the highest risk of disease, which can be increased by 4-8 times. The risk of 2/3 individuals is less than that of 3/3 individuals, and the 2/4 and 3/3 individuals are sick. There is no significant difference in risk. The 4 allele is only a risk factor. Carrying the 4 allele does not necessarily mean that AD is caused. Many AD patients do not have the 4 allele. In addition, many individuals with 4/4 genotype have no dementia even when they reach the age of seniority. evidence of. Therefore, there may be multiple genes or other factors that contribute to the onset of AD.

It has recently been discovered that the alpha-1 antichymotrypsin (ACT) gene can affect the risk associated with the Apo E gene. The Apo E genotype was 4/4, and the risk of ACT genotype A/A individuals was significantly increased. It has also been previously found that the Apo E genotype can affect the age of onset of AD patients with APP mutations, and the age of onset of the 4/4 genotype is significantly advanced. The mechanism by which Apo E affects the pathogenesis of AD is not certain. In the laboratory, Apo E binds to both tau and amyloid beta. It was hypothesized that Apo E binds to amyloid beta to promote senile plaque formation and affect beta amyloid metabolism, while Apo EII prevents hyperphosphorylation of tau to avoid NFT formation. So far, several genes have been found to be involved in the pathogenesis of AD. This genetic heterogeneity of the etiology of AD suggests that AD may not be a disease, perhaps a collection of multiple diseases. There are many so-called risk genes associated with late-onset AD disease, such as ACT gene, angiotensin-converting enzyme gene (ACE), 2-macroglobulin gene (a2M), 5-HT transporter gene, mitochondrial gene, etc. The role of these genes has not yet been elucidated.

Mutations in the tau protein gene can cause familial frontotemporal dementia, but so far, AD has not been found to have a tau protein mutation. Creutzfeldt-Jacob disease (CJD), or human spongiform encephalopathy, is a rare form of dementia. The annual incidence of CJD is about one in a million, which can be divided into hereditary and acquired, and hereditary CJD accounts for 5% to 10%. 70% of hereditary CJD is caused by a 100 K point mutation in the PRNP gene.

The above shows that Apo E4 has the highest frequency in Nigeria, followed by Sudan, and the Chinese population (Beijing) has the lowest frequency of 4.

About 2/3 of AD patients have at least one Apo E4 allele, and two patients with genetically two Apo E4 alleles have the possibility of developing AD with two Apo E3 or Apo E2 alleles. 8 times. A quarter of the world's population is estimated to be heterozygous Apo E4 allele. The other 2% to 3% of the population are homozygous, and the risk of developing AD in homozygous population is as high as 90%. The Apo F4 gene not only helps predict who may have AD, but also has a dose effect, which is manifested by the age of onset. Corder et al. (1994) reported a group of delayed-type AD pedigrees with an additional copy of the 4 gene. The age of onset of AD is 7 to 9 years earlier. The average age of onset of the 4 gene was 84.3 years, 75% for one E4 gene, and 68.4 years for two patients.

Apo E gene was detected in 1000 elderly people (mean age 85 years) with multiple medical diseases. The frequency of Apo E4 gene was significantly correlated with the decrease in MMSE cognitive test scores. The relative risk of cognitive test scores was significantly affected by the Apo E4 gene dose. Although Apo E is a risk factor for hyperlipidemia and arteriosclerosis, the Apo E4 gene dose does not increase the relative risk of cerebrovascular disease, whereas the risk of dementia with cerebrovascular disease with Apo E4 allele increases. The authors also observed the effect of Aoo E gene on cognitive decline in some patients. Those with Apo E4 allele were found to have a much lower MMSE score than those without Apo E4 at 6 months of follow-up.

However, some centenarians with the Apo E4 gene have no dementia, and about 40% of AD patients do not have the 4 allele. In addition, there was no AD in the monitoring of Apo E4 containing genes for 20 years. Therefore, according to current data, Apo E4 gene may be only a risk factor for AD and not the cause of AD. Like polygenic diseases such as coronary heart disease and tumors, environmental factors may trigger a trigger in gene activation or mutation.

In summary, available data indicate that the early-onset AD loci are located on chromosomes 21, 14, and 1, respectively, and the corresponding genes are APP (related to the formation of A4), S182 (presenilin-1, 70% to 80% of early-onset AD) Gene mutations caused) and STM2/E5-1 (presenilin-2 is associated with VG early-onset AD). The delayed-type AD locus is located on chromosome 19 and the corresponding gene is Apo E. In summary, AD has genetic heterogeneity, indicating that AD cannot be a single gene inheritance, but may be a genetic and environmental factor interaction, is a multi-gene disorder. Genetic transmission cannot explain most cases of AD in the general population.

2. Cytoskeleton and synapse

Both neuronal cells and glial cells of senile dementia have structural changes. These changes include nerve cell death, dendritic contraction and swelling, synapse reduction, and glial cell responses. Cellular signaling pathways that control cell growth and activity also change. The cytoskeleton contains many different sizes of polymers and protein components. The polymer is divided into microfilaments (6 nm in diameter) composed of actin; medium filaments (10-15 nm in diameter) consisting of one or more special filament proteins, which are different in different cells (eg in neurons) Neurofilament protein and glial fibrin in astrocytes; microtubules (25 nm in diameter) composed of tubulin. In addition to the filamentous proteins that form the cytoskeleton, the cells also have proteins that bind to the cytoskeleton, which regulate the polymerization and depolymerization of neurofilament proteins. Neurons express several microtubule-bound proteins (MAP) that are distributed in different parts of a complex cellular structure. For example, MAP-2 is present in dendrites and not in axons, and tau is present in axons. Not in the dendrites.

During normal aging, there is no significant change in the protein content of the cytoskeleton (such as microtubules, actin, and neurofilament proteins), but the cytoskeletal arrangement and post-translational modifications of the cytoskeletal proteins have changed, for example, some brains. The phosphorylation level of the tau protein is increased, especially in areas related to learning and memory (such as the hippocampus and forebrain base). In addition, in some neurons, hydrolysis of calcium-regulated cytoskeletal proteins such as MAP-2 and spectrin increases, and glial fibrillary acidic protein increases. Multiple types of analysis of different synapses in rodents and humans have revealed that the number of synapses in certain brain regions is reduced during aging, but increased synaptic volume can compensate for this reduction, and synapses can have reconstruction".

An important neuropathological change in AD, NFT, is the deposition of insoluble proteins in neurons in the cortical and limbic systems. Under an electron microscope, the entangled protein is a double-stranded helix (PHF). The PHF is laterally tightly coupled and highly insoluble. The main component of the double helix is the highly phosphorylated tau protein. The tau protein has a relative molecular mass of 50,000 to 60,000 and is a microtubule-binding protein. The gene encoding this protein is located on the long arm of chromosome 17. The tau protein plays an important role in maintaining the stability of microtubules in neuronal axons, which are involved in the transport of substances in the neuron. An important feature of the amino acid sequence of the tau protein is the C-terminal 3 or 4 repeat sequences, which form the microtubule binding site. After hyperphosphorylation of tau protein, its binding function to microtubules is affected, which is involved in the formation of NFT, neuronal thread and senile plaques. It is not yet clear how the tau protein is phosphorylated and how it is tightly bound laterally to be highly insoluble. Abnormal activity of protein kinase C and glutamatergic neurons may be associated with hyperphosphorylation of tau.

NFT is a filamentous accumulation of tau protein formed in the degenerated neuronal cytoplasm. The number of microtubules in tangled neurons is reduced, and the configuration of microtubule-binding proteins such as MAP-2 and tau is often changed in cells. The tau protein is hyperphosphorylated in NFT, possibly due to a decrease in dephosphorylation or a direct oxidation of lipids and a covalent bond modification of a peroxidation product such as 4-hydroxynonenal due to changes in phosphorylase activity.

Synapse reduction is one of the characteristics of AD. Whether synaptic reduction occurs before cell death is inconclusive, but it is certainly associated with neuronal degeneration and death. There is increasing evidence that excitatory poisoning in synapses can lead to synaptic degradation, which may trigger the death of neuronal cells. The accumulation of glutamate receptors in the postsynaptic membrane of the spinal cord dendrites is markedly increased, indicating a large amount of Ca2 influx in normal physiological synaptic transmission. Biochemical changes associated with aging (such as increased energy and oxidation levels of neurons) and biochemical changes associated with disease (such as amyloid in AD) can make synapses susceptible to excitotoxicity.

3. Central nervous system neurotransmitters

In order to explore the pathogenesis of AD, the central nervous system of AD patients was studied in depth. Ach (acetylcholine) acts as a neurotransmitter in certain neurons of the brain and spinal cord. The cholinergic neuronal pathway of basal forebrain neurons is linked to a wide range of cortical regions and hippocampus. These cholinergic neurons are closely related to learning and memory. Since the 1990s, the concentration of neurotransmitters, the number of receptors, and neurotransmitter synthase in AD brain have become the focus of AD research. It has been well established that many important neurotransmitters or temperament are widely lost, especially in the cerebral cortex and hippocampus. It is generally believed that the core symptom memory loss of AD is caused by the loss of acetylcholine, which is the hypothesis of AD choline function. According to:

Degeneration and loss of extensive nbM cholinergic neurons in patients with 1AD;

2 In hundreds of patients with confirmed AD, the level of acetylcholine and its synthase choline acetyltransferase (ChAT) in the brain is low, and in some brain regions, ChAT can be reduced to 30% of the normal level. ChAT is located in cholinergic neurons and is regarded as a marker of cholinergic neurons. ChAT activity is decreased, indicating that cholinergic neurons are lost. Although ChAT activity decreases with age, the decrease in AD is most significant. It has been reported that ChAT reduction is highly correlated with cholinergic neuron loss, and is also associated with prenatal cognitive function and brain pathological changes in AD patients. Other transmitters are also reduced, but no correlation is found;

3 scopolamine and atropine are both muscarinic cholinergic receptor antagonists, which can cause memory and cognitive decline in normal young people, similar to memory loss in AD patients;

4 cholinesterase inhibitor physostigmine or muscarinic receptor agonist arecoline can reverse the memory loss caused by scopolamine;

5 Injury of rodent nbM with excitatory neurotoxin can cause low cholinergic dysfunction in animals, manifested as learning and memory impairment. At present, the use of drugs to promote neurotransmission to compensate for the lack of transmitter function has made great progress in the treatment of Parkinson's disease. Therefore, it is desirable to discover neurotransmitter defects in AD in order to find an effective treatment.

The earliest discovered is that the AD cholinergic neuron system has specific neurotransmitter defects. Reduced choline acetyltransferase (ChAT) in the cortex and hippocampus. ChAT is contained in the presynaptic sputum of cholinergic neurons in the nucleus of the forebrain. The nucleus of the forebrain is mainly composed of the Meynert basal ganglia and the septal nucleus. These neuronal damage reduced ChAT, resulting in a decrease in Ach synthesis in the cortex and hippocampus. Ach is closely related to near memory, and memory impairment is the main clinical manifestation of AD. Interestingly, AD only had castive cholinergic neurons damaged, and cholinergic neurons in the basal ganglia and spinal cord were unaffected. The cholinergic receptors in the human cerebral cortex are mainly M1 receptors, accounting for about 80%. The number of M1 receptors in AD is almost normal, and a few studies have found that M2 receptors in AD are reduced and are associated with the degree of damage to cholinergic neurons. Normal M1 receptor numbers suggest that cholinergic transmitter defects in AD may be modulated by compensatory mechanisms. Some people think that the results of the receptor number may not be reliable, because even if the receptor is normal, if the second messenger in the cell cannot activate the G protein, the information cannot be transmitted to the cell, and the neurons cannot be activated effectively.

The cholinergic transmitter system of AD patients is very damaging, choline transport, Ach synthesis and release are reduced, and the binding of cholinergic M receptor to GTP effector protein is reduced, especially the M receptor agonist activates cortical nerve. The ability of the GrP-binding protein in the cell membrane is decreased. Increased levels of membrane lipid peroxidation in neurons can result in impaired cholinergic signaling, as exposure of cultured cortical neurons to beta amyloid, Fe2, and the lipid peroxidation product 4-hydroxynonenal results in cholinergic The binding ability of the M receptor to the GTP-binding protein Gqll is impaired.

Oxidative stress causes dopamine dysfunction, and oxygen free radicals play a major role in the pathogenesis of Parkinson's disease, but the role of oxidative stress in dopamine signaling changes remains unclear. Age-related damage is present in the binding of dopamine receptors to GTP effector proteins. Most of the AD patients had no obvious dopaminergic neuron loss in the nigrostriatal system. A few studies have found that the metabolites of dopamine in the cerebrospinal fluid of AD patients are reduced.

Norepinephrine and 5-HT are the major monoaminergic neurotransmitters in the brain. Norepinephrine neurons are mainly located in the blue spot, and 5-HT neurons are located in the middle nucleus. Both neurons are widely projected into the cerebral cortex. There are several subtypes of norepinephrine receptors, each of which binds to a GTP-binding protein. There are also several subtypes of 5-HT receptors, some of which bind to GTP and some of which constitute ligand ion channels. The total amount of norepinephrine and reuptake in the brain of AD patients decreased, the TH of synthetic norepinephrine decreased, and the neurons in the blue spot of brain stem were lost. Interestingly, the loss of blue-spotted neurons is limited to neurons that project to the forebrain, while neurons that project to the cerebellum and spinal cord are normal and have no pathological changes in AD. The extent of damage to the blue-spotted neurons and the degree of norepinephrine reduction are not related to the extent of cognitive decline, but are associated with the emotional symptoms of AD. Neurons in the interstitial nucleus of AD patients are depleted, and the concentrations of 5-HT and its metabolic products in the cortex and cerebrospinal fluid are reduced. Changes in 5-HT may be associated with non-cognitive psychotic symptoms of AD, such as depression and aggressive behavior.

Glutamate is the major excitatory neurotransmitter in the human brain. Glutamate activates the ionotropic receptor, causing Ca2 and Na influx. Over-activation of the ionic glutamate receptor plays an important role in the pathogenesis of stroke, AD, Parkinson's disease and Huntington's disease. As the age increases, the level of glutamate ionotropic receptors decreases, possibly due to the degradation of related neurons. The role of glutamatergic neurotransmission in neuronal death, age-related, and disease-related brain deficits is not well understood. The major inhibitory neurotransmitter in the human brain is gamma aminobutyric acid (GABA). In neurodegenerative diseases such as AD, glutamate decarboxylase levels decrease and GABA binding sites decrease. The mechanism of action of the GABA system in various dementias is currently poorly understood.

Vascular lesion

Like other organs, blood vessels in the brain are prone to atherosclerosis, making blood vessels prone to occlusion and rupture, leading to stroke. This is the most important pathogenesis of vascular dementia (VD). The most common consequences of cerebrovascular disease are neuronal loss and cognitive impairment. Decreased cerebral perfusion plays an important role in cognitive decline. Among the main causes of senile dementia, VD ranks second. As the age increases, cerebral blood flow decreases, while the metabolic rate of oxygen and glucose decreases. Microvascular structural changes in brain aging include curl thickening of the basement membrane and intima of the vessel wall, and the like. Biochemical factors of vascular changes may include damage and inflammatory response of endothelial cells by oxidized low density lipoprotein (LDL). Damage to endothelial cells affects the function of glucose transport, which allows macrophages to easily cross the blood-brain barrier. When the age increases, the function of the blood-brain barrier is weakened, including capillary wall thinning and a decrease in the number of mitochondria in endothelial cells, and the important transport function of endothelial cells is impaired. This damage in the brain of AD patients is more serious. Vascular destruction, especially the destruction of brain microvessels, can lead to neuronal damage and cognitive impairment. Apolipoprotein E (Apo E) polymorphism is associated with increased risk of AD and arteriosclerosis, and the risk of both diseases is elevated in the 4 allele, with the 2 allele. Then the risk is reduced. This association suggests that vascular lesion changes play an important role in the neurodegenerative process of AD.

5. Amyloid

Pathological features of AD Age-related plaques are spherical tangles following neuronal inflammation, which include degenerating axons and dendrites, accompanied by astrocytes and microglia. In addition, it also contains a variety of proteases. The center of senile plaques is amyloid beta, a fragment of beta amyloid precursor protein (APP) containing 39 to 43 amino acids. Immature senile plaques are seen in many brain regions, and immature senile plaques have only amyloid beta, but no neuroinflammatory response. APP is a transmembrane protein with the tail located in the cell and the rest mostly outside the cell. Normal APP metabolism is that the site near the cell membrane is cleaved by -secrtetase, and the restriction site is located in the center of the amyloid beta fragment, so the normal metabolic pathway does not produce amyloid beta. Only a relatively long APP fragment, called soluble APP (sAPP), is produced, which has a cellular nutrient effect. In addition, there are two enzyme cleavage sites, namely -secretase and -secretase sites. The site is located outside the a site, and the gamma site is located in the cell membrane inside the alpha site. These two sites were digested to form a -amyloid of 39 to 43 amino acids. However, it is not yet possible to explain all AD cases with the above mechanism. There are three possible mechanisms for the conversion of APP metabolism to beta amyloid:

1 Some familial AD changes the structure of APP protein due to mutation of APP gene;

When the 2APP gene is normal, it may be related to various factors. For example, an APP fragment containing amyloid is found in lysozyme, so amyloid may be secreted by cleavage of peptidase and protease in lysosome;

As a result of more than 3 types of injury, a variety of experimental injuries such as damage to the cortical neurons at the base of the forebrain can increase APP synthesis in mice. Diffuse age spots can be seen in severe human brain injury. An increase in oxidative stress or impaired energy metabolism in neurons alters the hydrolysis process of APP, promoting beta amyloid and fiber formation. The accumulation of amyloid beta in the brain of AD patients is roughly parallel to the severity of neuronal cell decline and cognitive impairment.

Beta amyloid deposition is toxic to neurons, killing neurons by free radicals, stimulating cell death programs, or stimulating glial cells to produce toxic substances such as tumor necrosis factor. Cell culture has shown that amyloid beta is neurotoxic, making neurons vulnerable to metabolism, excitatory substances and oxidants. The propensity of amyloid beta to form fibers is related to its neurotoxic effects. Substances that prevent fiber formation, such as Congo red dyes, block the toxic effects of amyloid beta. Neuronal damage caused by amyloid beta includes peroxidation of lipids in the membrane, resulting in a toxic acetaldehyde called 4-hydroxynonenal. 4-hydroxynonenal is capable of covalent modification of certain membrane proteins involved in maintaining the dynamic balance of membranes and their energy metabolism such as Na-K pumps, Ca2-ATPases, glucose transporters, and glutamate transporters. Oxidative stress induced by amyloid beta in neurons not only leads to increased intracellular Ca2 concentration, mitochondrial dysfunction and apoptosis (a form of cell death characterized by cell shrinkage, nuclear condensation, DNA fragment formation), Will cause changes in the cytoskeleton. These changes are similar to those seen in the NFT. Antioxidants such as vitamin E and glutathione prevent apoptosis and NFT.

Certain neurotrophic factors (cell signaling proteins produced in the brain) protect cells from beta amyloid by inducing expression of an antioxidant enzyme gene. In addition to participating in neurodegenerative processes, beta amyloid also impairs the signaling pathways of neurotransmitters. Beta amyloid not only impairs the binding of the acetylcholine M receptor to the guanine effector protein, but also inhibits the production of acetylcholine. Amyloid beta can damage the cerebral blood vessels and cause insufficient nutrient transport in the brain parenchyma. There is a large amount of beta amyloid deposition in the cerebral blood vessels of AD patients. Amyloid beta also impairs glucose transport in endothelial cells, reducing the barrier function of these cells. Amyloid beta induces oxidative stress in endothelial cells, causing cell degeneration and death, and also promotes inflammatory processes in the brain.

Due to the development of transgenic technology, transgenic technology can now be used to study the effects of gene product overexpression or gene mutation. Pathological changes in certain types of AD have now been demonstrated in animal models. Incorporating familial AD APP variant genes into mice by transgenic technology, the human brain can produce beta amyloid deposition, neuroinflammatory senile plaques, synapse reduction, astrocytes and microglia, neuronal degeneration and neurons Programmed necrosis.

Some scholars have used -amyloid antibody as an ELISA test to detect a variety of heteropeptide fragments, including 27 to 43 amino acid residues, from the cerebrospinal fluid of AD patients, starting with aspartic acid. Nakamura et al found that -amyloid levels were significantly increased in cerebrospinal fluid of patients with early-onset AD (mean 59 years), while late-onset AD was not significantly different from normal controls, and beta amyloid was associated with early-onset AD. Motter et al. used amyloid 42 as the same index to detect the cerebrospinal fluid of 37 cases of AD. The content of amyloid 42 was significantly lower than that of the control group and other patients with nervous system diseases, but the tau protein was significantly increased, and the total amyloid protein was not. Significant differences.

There are two most prominent advances in the study of amyloid beta, one of which has been the isolation of beta and gamma secretase, providing a chemical basis for the development of drugs that may inhibit the formation of this enzyme and senile plaques. Inhibitors of these two secretases are under development and it is possible to prevent the formation of senile plaques with beta and gamma secretase inhibitors in the future. The second is that the beta amyloid "vaccine" used to combat senile plaques has been successfully tested in animals. Inoculation of APP transgenic mice with beta amyloid "vaccine" can prevent or reduce the formation of senile plaques. At present, the beta amyloid "vaccine" has entered the stage of clinical trials. It is a great pity that a small number of volunteers who were inoculated with the beta amyloid "vaccine" developed an "encephalitis-like reaction" and the experiment had to be temporarily stopped in order to analyze the cause. It is believed that if these two new therapies are successful, the prevention and treatment effects of AD will be greatly improved.

6. Lipids, nucleic acids and free radicals

Some dementia patients, especially AD patients, have increased accumulation of insoluble proteins in the brain, and cytoskeletal tau and amyloid beta are the two most closely related substances. The lipid content in neuronal cells is relatively high, especially in myeloid cells such as oligodendrocytes, so roughly half of the brain's net weight is composed of lipids. The reduction of myelin lipids in the brain of AD patients, including cerebroside phosphate, phosphorylcholine, phosphoethanolamine, and sphingomyelin, is gradually reduced, while intracellular destructive lipids are increased. The accumulation of destructive cell membrane lipids is manifested by an increase in lipofuscin particles in the neurons.

The levels of DNA and RNA in the brain of AD patients are reduced. Although RNA levels in the Meynert basal ganglia, several regions of the cerebral cortex, and some brain nucleus decreased, RNA levels in the hippocampus were elevated. The level of oxidation of a protein is usually measured using the protein carbonyl group. Brain tissue studies have found that levels of protein oxidation and elevated carbonyl groups are elevated in susceptible brain regions of patients with AD and Parkinson's disease, especially in degenerated neurons. The increase in protein sugar residues is called glycation, and protein saccharification increases the oxidative stress of cells. The beta amyloid and tau proteins in the main components of senile plaques and NFT are two hyperglycosylated proteins.

In neurodegenerative diseases, progressive and extensive oxidation of mitochondrial DNA occurs. DNA damage in the hippocampus and susceptible cortical regions of striatal and AD patients with HD has been demonstrated, particularly with elevated levels of 8-hydroxyguanine. This DNA damage may be caused by several reactive oxygen molecules with hydroxyl hydroxide radicals and peroxynitrate roots. The cause of mitochondrial DNA damage is that most of the free radicals are produced in the mitochondria. Cell culture assays have found that mitochondrial DNA damage leads to electron transfer failure in mitochondria and reduces ATP production, and also impairs mitochondrial calcium barrier function, increasing neuronal sensitivity to excitotoxic substances and metabolic damage.

Free radicals are molecules with asymmetric electrons in the outer orbit of the nucleus. In living organisms, various oxygen-carrying molecules are the main species of free radicals. Oxygen free radicals in cells are mainly derived from mitochondria because superoxide anion radicals (O2-) are produced during electron transport in the mitochondria. Superoxide dismutase (MnSODt and Cu-Zn-SOD) converts O2- to hydrogen peroxide (H2O), which is then converted to O2-H by Fenton reaction under the catalysis of Fe2 and Cu2. Peroxynitrite (0N00-) is derived from the interaction of nitrous oxide (NO2-) and O2-. The main factor that stimulates NO production is an increase in Ca2 levels, which binds to calmodulin and activates NO synthase. Although O2-H and ONOO- can cause direct damage to proteins and DNA, the main form of their destruction of cells is to attack fatty acids on the cell membrane and initiate the lipid peroxidation process.

Oxygen free radicals derived from mitochondria play a major role in the gradual oxidative damage of cells. Brain energy and metabolic damage can lead to increased production of oxygen free radicals. Limiting calorie intake seems to reduce the production of mitochondrial oxygen free radicals. Rats were fed a calorie-restricted diet (30% to 40% reduction in calories) and found to have reduced cellular oxidative stress (eg, reduced oxidation of proteins, lipids, and DNA) in many non-neurological tissues. Recent studies have found that oxidative stress is also reduced in the brains of rodents fed a calorie-restricted diet. In the presence of neurodegenerative diseases, in addition to the damage of oxygen free radicals, some factors that cause oxidative stress also play an important role. For example, the continuous production and accumulation of amyloid beta in AD patients is a key factor in the increase of neuronal oxidative stress. Cell culture confirmed that beta amyloid can cause lipid peroxidation in neuronal membranes, which can destroy neurons and cause neuronal death.

7. Mitochondria and energy metabolism

The abnormal metabolism of neurons in dementia is increased, and it is more serious in dementia caused by neurodegenerative diseases. In brain cells of AD patients, the activity of enzymes in several energy metabolism processes is severely reduced. Among the three enzymes involved in mitochondrial oxidative metabolism are pyruvate dehydrogenase complex, -ketoacid dehydrogenase complex and cytochrome C oxide.DNAADAD()ATP

N-4-(MPTP)ADC-ADADDNAADADAD(4-hydroxynoncnal)

8.

LCa2 NCa2 TCa2 10-8mol()()AD

Ca2 Ca2 Ca2 Ca2 Ca2 ATPCa2 ADCa2 (Fe2 )()Ca2

9.

AD--()(AD)AD17-AD

10.

(NGF)(bFGF)(BDNF)(IGF)ADbFGFbFGFBDNFMPTP(PD)bFGFsAPP(AD)Ca2

AD

11. Other

(1)NFTSPGarruto(1994)NFTstauADtautauAD

(2)AD-(Creutzfeldt-Jacob)ADAD

(3)1059AD87OR1.8(95%32.7)19881990126ICD-10 ADLogistic

(4)ADAD;AD

(5)(excitoxins)N MDA(N-methyl-D-aspartate)Cl-

AD

an examination

Related inspection

CT

70(7375)(31)(1988)363656

CT

Memory impairment

AD(3min3)

24

2.

AD()

3.

()AD(Boston Naming Test)MMSEWernicke

4.()()

(Prosopaghosia)

5.

ADAD?80?82?ADMMSE3

6.

7.

EEGREM

8.(catastrophic reaction)

9.(Sundowner syndromeSundowning)

()

10.Klüver-Bucy(KBS)

70%KBS()

11.Capgras

30%10%13%40%50%

12. Clinical manifestations of AD in each phase

(1)1(13);;;;;EEG;CT/MRI;PET/SPECT/

(2)2(210);;;;;;;EEG;CT/MRI;PET/SPECT/

(3)3(812);;EEG;CT/MRI;PET/SPECT/

AD()

AD

EEG

AD85%90%

WHOICDAPADSMCMACCMD(NINCDS)AD(ADRDA)AD(probable)(possible)(definite)ICD-10AD

Attached: CCMD-2-R diagnostic criteria.

1. Alzheimer's disease (Alzheimer's disease) (290; F00)

(1) Meet the criteria for brain organic disorders.

(2) The onset is slow, and the progressively worsened dementia is the main clinical symptom. Although the disease development can be temporarily paused, it is irreversible.

(3) The following diseases should be excluded:

1 Dementia caused by other brain diseases such as cerebrovascular disease.

2 pseudo-dementia caused by mental disorders such as depression.

2.(290.1;F00.0)

65

(Alzheimer)(290.0.290.2;F00.1)

65

3. Alzheimer's disease (Alzheimer's disease), atypical or mixed type (290.8; F00.2) meets the diagnostic criteria for Alzheimer's disease, but the clinical symptoms are not typical, or combined with cerebrovascular disease.

4. Alzheimer's disease (Alzheimer's disease), other types (290.8; F00.9) meet the diagnostic criteria for Alzheimer's disease, but do not fully meet the diagnostic criteria of the above type 3.

Differential diagnosis

It is estimated that more than 60 diseases can develop clinical symptoms similar to dementia, some of which are treatable or reversible, so differential diagnosis is of great significance.

1.AD;AD

2.(Benign Senescent ForgetfulnessBSF)(age-associated memory impairmentAAMI);ADAAMIAAMI

AAMI diagnostic criteria:

(1) At least 50 years of age.

(2)()

(3) Psychological test evidence of memory loss, such as the recognized standardized test operation is at least one standard deviation lower than the average of young people.

(4) The total intellectual function is not degraded.

(5) No evidence of dementia.

(6)1h(Crook TBartus RTFerris SH1986)

3.(VD)AD

4. Pick up disease.

5. Creutzfelt-Jacob disease.

6.(PD)1/3PDMynertPDPDAD

7.LewyNFTsADADPDLewy

ADChATPDPDLewyChATPDLewyChAT

8.(normal pressure hydrocephalusNPH)60

9.

10.Reding(1985)27%

;

PD;

;

()

(dementia syndrome of depressionDSD)

The identification of DSD and AD is as follows:

(1) In contrast to primary dementia, the onset of DSD and the interval between treatments are shorter.

(2) DSD has a history of affective disorders in the past.

(3) DSD patients have more depression and delusions than AD.

(4) The behavioral decline of AD patients is consistent with the degree of cognitive impairment.

(5) DSD sleep disorders are more serious, often wake up early.

(6) DSD self-knowledge is saved, and the memory test scores are often improved under encouragement or prompting.

(7) Patients with AD have characteristic speech deficits, which may be associated with dyslexic disease, and DSD.

(8)DSD/

(9)DSDPETAD

The outcome of DSD has not been determined. It has been reported that 44 patients with DSD recovered their pre-cognitive levels after treatment. After 8 years of follow-up, 89% had AD.

11.AD;00.02

12.(1990)160DSM--RAD56%(90/160)38(24%)35(22%)191093217(11%)87543

70(7375)(31)(1988)363656

CT

1.AD(3min3)

24

2.AD()

3.()AD(Boston Naming Test)MMSEWernicke

4.()()(Prosopaghosia)

5.ADAD?80?82?ADMMSE3

6.

7.EEGREM

8.(catastrophic reaction)

9.(Sundowner syndromeSundowning) ()

10.Klüver-Bucy(KBS) 70%KBS()

11.Capgras30%10%13%40%50%

12.AD

(1)1(13);;;;;EEG;CT/MRI;PET/SPECT/

(2)2(210);;;;;;;EEG;CT/MRI;PET/SPECT/

(3)3(812);;EEG;CT/MRI;PET/SPECT/

AD()

ADEEG

AD85%90%

WHOICDAPADSMCMACCMD(NINCDS)AD(ADRDA)AD(probable)(possible)(definite)ICD-10AD

Attached: CCMD-2-R diagnostic criteria.

1. Alzheimer's disease (Alzheimer's disease) (290; F00)

(1) Meet the criteria for brain organic disorders.

(2) The onset is slow, and the progressively worsened dementia is the main clinical symptom. Although the disease development can be temporarily paused, it is irreversible.

(3) The following diseases should be excluded:

1 Dementia caused by other brain diseases such as cerebrovascular disease.

2 pseudo-dementia caused by mental disorders such as depression.

2.(290.1;F00.0)

65

(Alzheimer)(290.0.290.2;F00.1)

65

3. Alzheimer's disease (Alzheimer's disease), atypical or mixed type (290.8; F00.2) meets the diagnostic criteria for Alzheimer's disease, but the clinical symptoms are not typical, or combined with cerebrovascular disease.

4. Alzheimer's disease (Alzheimer's disease), other types (290.8; F00.9) meet the diagnostic criteria for Alzheimer's disease, but do not fully meet the diagnostic criteria of the above type 3.

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