What Is Familial Alzheimer's Disease?

Alzheimer's disease (AD) is a progressive, progressive, degenerative neurological disease that is occult. Clinically, it is characterized by generalized dementia such as memory impairment, aphasia, apraxia, apraxia, impaired visual spatial skills, executive dysfunction, and personality and behavior changes. The etiology is unknown. Those who develop disease before 65 years old are called Alzheimer's disease; those who develop disease after 65 years old are called Alzheimer's disease.

Basic Information

nickname: Alzheimer's disease
English name: Alzheimer disease, AD
Visiting department: Neurology

Multiple groups: Over 70 years of age
Common causes: unknown
Common symptoms: Decreased cognitive function, behavioral disorders, and gradual decline in living ability

Causes of Alzheimer's disease

The disease may be a heterogeneous group of diseases that develops under the influence of multiple factors, including biological and psychosocial factors. From the current research, there are more than 30 possible factors and hypotheses for the disease, such as family history, females, head trauma, low education level, thyroid disease, too high or low reproductive age, and viral infection. The following factors are related to the onset of the disease:

Family history

Most epidemiological studies suggest that family history is a risk factor for the disease. The family members of some patients suffer from the same disease more than the general population. In addition, the risk of congenital stupidity is also increased. Further genetic studies have confirmed that the disease may be caused by an autosomal dominant gene. Recently, through gene mapping studies, the pathological genes of amyloid in the brain were found on the 21st pair of chromosomes. It is obvious that dementia is genetically related.

Congenital stupidity (DS) has similar pathological changes to the disease. If DS is alive, it will occur in about 100% of adults. The disease-causing gene of DS is known to be located on chromosome 21, which has caused great interest in the genetic research of the disease. However, the genetic research of the disease is difficult, and most researchers have found that family members' risk of developing the disease is about 3 to 4 times higher than that of the general population. St. George-Hyslop et al. (1989) reviewed the research data of the family of the disease and found that the risk of family members suffering from the disease was 14.4% for parents; 3.8% to 13.9% for siblings. Using statistical analysis of longevity, the first-degree relatives of FAD have a 50% risk of the disease, compared with only 10% in the control group. These data support some early-onset FAD, which is a group of dominant autosomal dominant inheritance associated with age; There is an article in the literature of female-only affected families, which rarely excludes X-linked inheritance, and most sporadic cases may be the result of interactions between genetic susceptibility and environmental factors.

At least four genetic degree points related to AD are currently known: early-onset AD loci are located on chromosomes 21, 14, and 1, respectively. The corresponding possible pathogenic genes are APP, S182 and STM-2 genes. The late-type AD locus is located on chromosome 19, and the possible pathogenic gene is the apolipoprotein E (APOE) gene.

2. Some physical diseases

Such as thyroid disease, immune system disease, epilepsy, etc., have been studied as risk factors for the disease. People with a history of hypothyroidism have a higher relative risk of developing the disease. Before the onset of the disease, there was more history of seizures. A history of migraine or severe headache has nothing to do with the disease. Many studies have found that a history of depression, especially senile depression, is a risk factor for the disease. A recent case-control study suggests that in addition to depression, other functional mental disorders such as schizophrenia and paranoid psychosis are also relevant. Chemical substances that have been studied as risk factors for the disease include heavy metal salts, organic solvents, pesticides, and drugs. The role of aluminum has been of concern because animal experiments have shown that aluminum salts have an effect on learning and memory; epidemiological studies suggest that the prevalence of dementia is related to the amount of aluminum in drinking water. Accumulation of neurotoxins such as aluminum or silicon in the body may accelerate the aging process.

3. Head injury

Head trauma refers to head trauma with conscious disturbance. Brain trauma has been reported as a risk factor for this disease. Clinical and epidemiological studies suggest that severe traumatic brain injury may be one of the causes of some of the disease.

4. Other

Progressive failure of the immune system, weakening of the body's detoxification function and lentiviral infection, as well as socio-psychological factors such as widowed, solitary living, economic difficulties, and life bumps can become the cause of the disease.

Clinical manifestations of Alzheimer's disease

The onset of the disease is slow or insidious, and patients and family members often cannot tell when it is onset. It is more common in the elderly over the age of 70 (males are 73 years old and females are 75 years old). A small number of patients have rapid symptoms after physical illness, fracture or mental stimulation. There are more women than men (female: male 3: 1). The main manifestations are cognitive decline, mental symptoms and behavioral disorders, and a gradual decline in daily living ability. Divided into three periods according to the deterioration of cognitive ability and physical function.

The first stage (1 to 3 years)

For mild dementia. It is manifested as memory loss and outstanding forgetfulness of recent events; decreased judgment ability, patients cannot analyze, think, and judge events, and it is difficult to handle complex issues; work or housework cartoons are inadvertent, and they cannot independently carry out shopping, economic affairs, etc., and social difficulties; Although I am still able to do some familiar daily work, I still feel confused about new things, indifferent emotions, occasionally irritating, and often suspicious; when I have a time disorientation obstacle, I can orient the places and people I am in , Difficult to orientate the geographical location, poor visual spatial ability of complex structures; less vocabulary, difficult to name.

The second stage (2 to 10 years)

For moderate dementia. It is manifested as severe impairment of near and far memory, reduced visual space ability of simple structure, and obstruction of time and place; severe damage in handling problems and identifying similarities and differences between things; unable to perform outdoor activities independently, in clothing, personal You need help with hygiene and maintaining your personal appearance; you can't calculate; various neurological symptoms can be seen, aphasia, apraxia, and ignorance can be seen; the emotion changes from indifference to irritability, often walking, and urinary incontinence.

The third stage (8-12 years)

For severe dementia. The patient has completely relied on the caregiver, severe memory loss, only the memory of the fragments; daily life can not take care of himself, incontinence of urine, stiff limbs, stiff limbs, positive cone tract signs on physical examination, strong primitives such as strong grip, fumble and sucking reflection. Eventually, he was unconscious and died of complications such as infection.

Alzheimer's disease test

Neuropsychological test

Mini Mental Scale (MMSE): Concise in content, short in measurement time, easy to be accepted by the elderly, it is the most common scale for clinically measuring the degree of intellectual impairment in this disease. The total score of this scale is related to the level of cultural education. If illiteracy is 17 points; primary school level 20 points; secondary school level 22 points; college level 23 points, it indicates that cognitive impairment exists. Further detailed neuropsychological tests should be performed including assessment of cognitive functions such as memory, executive function, language, use, and visual spatial ability. For example, the cognitive component of the AD Rating Scale (ADAS-cog) is a set of 11-item cognitive ability tests designed to detect changes in the severity of AD, but it is mainly used in clinical trials.

Daily life assessment: For example, the Daily Life Assessment (ADL) scale can be used to assess the degree of impaired daily life of patients. The scale has two parts: one is the physical life self-care ability scale, which measures the patient's ability to take care of his own life (such as dressing, undressing, combing hair, and brushing teeth, etc.); the second is the tool use ability scale, which measures the use of patients Ability to use everyday tools (such as making phone calls, taking a bus, cooking by yourself, etc.). The latter is more susceptible to cognitive decline in the early stages of the disease.

Assessment of behavioral and psychiatric symptoms (BPSD): including the Alzheimer's Behavioral and Pathological Rating Scale (BEHAVE-AD), neuropsychiatric symptoms questionnaire (NPI), and Cohen-Mansfield agitation questionnaire (CMAI), etc. The baseline assessment of the information provided not only reveals the presence or absence of symptoms, but also evaluates the frequency, severity, and burden of the caregiver. Repeated assessments can also monitor the effect of treatment. The Cornell Dementia Depression Scale (CSDD) focuses on assessing the dementia and depressive performance of dementia. The 15-item depression scale can be used to evaluate depression symptoms in AD. CSDD is more sensitive and specific, but has nothing to do with the severity of dementia.

2. Hematology test

It is mainly used to detect the presence of concomitant diseases or complications, find potential risk factors, and exclude dementia caused by other causes. Including blood routine, blood glucose, blood electrolytes including blood calcium, kidney function and liver function, vitamin B ₁ ₂ , folic acid level, thyroxine and other indicators. Serum tests for syphilis, human immunodeficiency virus, and Borrelia burgdorferi should be performed in high-risk groups or those with clinical symptoms.

3. Neuroimaging

Structural imaging: specific imaging findings used to rule out other underlying diseases and discover AD.

Head CT (thin-layer scan) and MRI (coronary) examinations can show obvious atrophy of the cerebral cortex, especially the hippocampus and medial temporal lobe, supporting the clinical diagnosis of AD. Compared with CT, MRI can detect changes in subcortical blood vessels (such as key site infarction) and suggest special diseases (such as multiple sclerosis, progressive supranuclear palsy, multiple system atrophy, cortical basal degeneration, prion diseases, Temporal dementia, etc.) are more sensitive to changes.

Functional neuroimaging: such as positron scanning (PET) and single photon emission computed tomography (SPECT) can improve the reliability of dementia diagnosis.

18F-deoxyribose glucose positron scan (18FDG-PET) can show reduced glucose metabolism in the temporal parietal and superior temporal / posterior temporal regions, posterior cingulate cortex, and anterior wedge, revealing specific abnormal changes in AD. Early AD shows reduced frontal lobe metabolism. 18FDG-PET has a sensitivity of 93% and a specificity of 63% for the diagnosis of AD pathology, and has become a practical tool, especially for the differential diagnosis of AD and other dementias.

PET imaging of amyloid is a very promising technique, but it has not yet been routinely applied.

4. Electroencephalogram (EEG)

The EEG of AD is characterized by decreasing alpha waves, increasing theta waves, and decreasing average frequency. But 14% of patients had normal EEG in the early stages of the disease. EEG is used in the differential diagnosis of AD and can provide early evidence of prion disease or suggest possible toxic-metabolic abnormalities, transient epilepsy amnesia, or other epilepsy disorders.

5. Cerebrospinal fluid test

Cerebrospinal fluid cell count, protein, glucose, and protein electrophoresis analysis: suspected vasculitis, infection, or demyelinating disease should be tested. Patients with rapidly progressing dementia should undergo a 14-3-3 protein test to help diagnose prion disease.

Cerebrospinal fluid beta amyloid and Tau protein detection: The level of beta amyloid (A42) in the cerebrospinal fluid of AD patients is reduced (the content of A42 in the cerebrospinal fluid is reduced due to the deposition of A42 in the brain). . Studies have shown that the sensitivity of A42 diagnosis is 86% and the specificity is 90%; the sensitivity of total Tau protein diagnosis is 81% and the specificity is 90%; the sensitivity of phosphorylated Tau protein is 80% and the specificity is 92%; Compared with the control, the sensitivity of diagnosis of AD can reach 85% to 94%, and the specificity is 83% to 100%. These markers can be used to support the diagnosis of AD, but the specificity of identifying AD from other dementias is low (39% to 90%). At present, there is no uniform detection and sample processing method.

6. Genetic testing

Can provide a reference for diagnosis. The amyloid precursor protein gene (APP) and presenilin 1, 2 (PS1, PS2) mutations accounted for 50% of familial early-onset AD. The detection of apolipoprotein APOE4 gene can be used as a reference for sporadic AD.

Alzheimer's disease diagnosis

Diagnostic criteria set by the National Institute of Neurological and Speech Disorders AD and Related Diseases Association (NINCDS-ADRDA). Possible diagnostic criteria for AD: A plus one or more supporting features B, C, D or E.

Core diagnostic criteria:

A. Early and significant episodic memory impairment, including the following characteristics

1. Patient or informed person complained of slow progressive memory loss over 6 months.

2. The test found objective evidence of severe episodic memory impairment: mainly memory impairment, which could not be significantly improved or returned to normal by suggestion or recognition tests.

3. At the onset or progression of AD, episodic memory impairment can be independent or related to other cognitive function changes.

Supporting features:

B. Atrophy of the middle temporal gyrus

Use visual scores for qualitative assessment (refer to the age-specific norms of specific populations), or quantitative volume measurement of the region of interest (refer to the age-specific norms of specific populations). Magnetic resonance imaging shows that the hippocampus, entorhinal cortex, and amygdala decrease in volume.

C. Abnormal cerebrospinal fluid biomarkers

-amyloid 1-42 (A1-42) concentration decreased, total Tau protein concentration increased, or phosphorylated Tau protein concentration increased, or a combination of the three.

Biomarkers discovered and verified in the future.

D. Specific imaging of PET functional neuroimaging

Decreased glucose metabolism in bilateral temporal and parietal lobe.

Other validated ligands, including Pittsburgh Complex B or 1- {6-[(2-18F-fluoroethyl) -methylamino] -2-naphthyl} -ethylenemalondicyanide (18F-FDDNP) .

E. There is a clear AD-associated autosomal dominant mutation in the immediate family.

Exclusion criteria:

History: Sudden onset; early symptoms: gait disorder, seizures, behavior changes.

Clinical manifestations: focal neurological manifestations, including hemiplegia, sensory loss, visual field defect; early extrapyramidal symptoms.

Other medical diseases are severe enough to cause memory and related symptoms: non-AD dementia, severe depression, cerebrovascular disease, poisoning and metabolic abnormalities, which require special examination. FLAIR or T2 signal abnormalities in MRI of the midtemporal gyrus consistent with infectious or vascular injury.

Criteria for the diagnosis of AD:

AD can be confirmed if you have the following manifestations: both clinical and histopathological (brain biopsy or autopsy) evidence, consistent with NIA-Reagan's AD autopsy diagnosis criteria. Both criteria must be met at the same time.

Evidence of AD diagnosis both clinically and genetically (mutation of chromosome 1, 14, or 21); both criteria must be met.

Alzheimer's disease treatment

1. The purpose of symptomatic treatment is to control the associated psychopathological symptoms

(1) Anxiolytics If you have symptoms of anxiety, agitation, and insomnia, you can consider using short-acting benzodiazepines, such as alprazolam, oxazepam (noroxydrine), and laurazepam (rolla ) And triazolam (Hellas). The dose should be small and not suitable for long-term application. Be alert to side effects such as excessive sedation, lethargy, slurred speech, ataxia, and unstable gait. Increasing daytime activity is sometimes more effective than taking sleeping pills. At the same time, other physical diseases, such as infection, trauma, urinary retention, and constipation, which can induce or aggravate the patient's anxiety and insomnia, should be dealt with in a timely manner.

(2) About 20% to 50% of patients with AD have antidepressant symptoms. Depressive symptoms that last for a short period of time should be relieved by persuasion, psychological treatment, social support, and environmental improvement. Antidepressants can be added if necessary. Nortriptyline and desipramine have less side effects. Doxepin (doxepine) and maprotiline are also available. In recent years, some new antidepressants have been introduced in our country, such as serotonin reuptake inhibitors (SSRI), paroxetine (Silote), fluoxetine (Yuker, Baiyoujie), orally; sertraline (Zolo Re), oral. Anticholinergic and cardiovascular side effects of these drugs are generally lighter than tricyclics. However, fluoxetine has a long half-life and should be used with caution in the elderly.

(3) Antipsychotics can help control patients' behavioral disorders, agitation, aggression, hallucinations and delusions. However, a small dose should be used and the drug should be discontinued in time to prevent toxic side effects. Consider low-dose perphenazine orally. The low blood pressure and extrapyramidal side effects of thioridazine are lighter than those of chlorpromazine, and it is helpful to the common anxiety and agitation of elderly patients. It is one of the commonly used antipsychotic drugs in the elderly, but it is easy to cause changes in the electrocardiogram. It is appropriate to monitor ECG . Haloperidol has a milder effect on sedation and orthostatic hypotension, but has the disadvantage of easily causing extrapyramidal reactions.

In recent years, some atypical antipsychotic drugs such as risperidone and olanzapine are commonly used in clinical practice, with good curative effect. It has fewer cardiovascular and extrapyramidal side effects and is suitable for elderly patients.

2. Nootropics or drugs that improve cognitive function

The goal is to improve cognitive function and delay disease progression. The research and development of this kind of medicine is still in the ascendant, new drugs are emerging one after another, and there has been some improvement in cognitive function and behavior, and the cognitive function score has also improved. According to the pharmacological effects of nootropic drugs, they can be divided into drugs that act on neurotransmitters, cerebral vasodilators, and brain metabolism-promoting drugs.

(1) Drugs that act on neurotransmitters Cholinergic system block can cause memory and learning loss, similar to amnesia in normal elderly. If the central cholinergic activity is strengthened, it can improve the learning and memory ability of the elderly. Therefore, changes in the cholinergic system are closely related to the degree of cognitive impairment in AD, the so-called cholinergic hypothesis. The purpose of pseudocholine therapy is to promote and maintain the function of residual cholinergic neurons. These drugs are mainly used in the treatment of AD.

(2) Activating drugs for brain metabolism These drugs have many and complicated effects. They are mainly to expand cerebral blood vessels, increase the use of oxygen, glucose, amino acids and phospholipids by cerebral cortical cells, promote the recovery of brain cells, and improve functional brain cells. So as to achieve the purpose of improving memory.

Prognosis of Alzheimer's disease

Because of the many factors involved in the onset of disease, it must not be treated with drugs alone. Clinical meticulous and scientific nursing plays a vital role in patient behavior correction and memory recovery. For those who are bedridden for a long time, pay attention to bowel movements, and regularly turn over and rub back to prevent pressure ulcers. Patients with excitement should be accompanied by their families to avoid accidents. Pay attention to the patient's diet and provide assistance or nasal feeding to those who cannot or cannot eat. Strengthen the training of patients' living ability and memory.