| disease | Alzheimer's Disease (AD) |
| alias | AD, Alzheimer's Disease, Alzheimer's Disease |
Alzheimer's disease is a chronic degenerative brain disorder. The cause of the disease remains unknown, characterized by distinctive neuropathological and neurochemical changes. It often begins gradually, with onset possible in the presenile period, but the incidence is higher in the senile period. The type that begins before the age of 65 often has a family history of dementia, progresses more rapidly, and exhibits significant temporal and parietal lobe damage, including aphasia and apraxia, with more pyramidal tract symptoms. AD can last for 20 years, with the early or grade I stage lasting 9 years, the intermediate stage [second stage] or grade II lasting 5 years, and the deterioration stage lasting 6 years, placing a heavy burden and suffering on individuals, families, and the nervous system. According to statistics: there are 2 to 4 million AD patients in the United States, 17 to 25 million worldwide, and large-scale surveys in China are still lacking. According to the latest urban census results, the prevalence of AD is higher than that of vascular dementia. In Western countries, AD is the fourth leading cause of death after heart disease, cancer, and stroke.
bubble_chart Etiology
The cause of the disease is unknown, and in recent years, a significant amount of research abroad has focused on genetics, immunology, viral infections, neurotransmitters, and neuroendocrinology, indicating that many factors are related to the disease's mechanism and cause.
1. Genetic factors
AD has familial aggregation, with 40% of patients having a positive family history, showing autosomal dominant inheritance and polygenic inheritance. Some propose the genetic theory (or gene theory), suggesting that, like Down syndrome, there is an amyloid gene on the 21st pair of chromosomes. Family history investigations of delayed-onset AD show that individuals with two apoE4 genes have an 8 times higher risk of developing delayed-onset AD than those with two apoE3 genes, while those with the apoE2 allele have an even lower risk. Some scholars (Corder) point out that up to 75% of delayed-onset AD patients are related to apoE to some extent.
2. Environmental factors(1) Aluminum accumulation: The aluminum concentration in certain brain regions of AD can be 10 to 30 times that of a normal brain, with aluminum deposits in the core of senile plaques (SP). Aluminum selectively distributes in neurons containing neurofibrillary tangles (NFT), and after binding to chromosomes in the nucleus, it affects gene expression. Aluminum is also involved in the formation of senile plaques and neurofibrillary tangles. Hence, some scholars propose the "aluminum toxicity theory."
(2) Viral infections: It has been found that many viral infectious diseases can cause structural changes similar to AD's neurofibrillary tangles and senile plaques in morphology, such as Scrapie, Kuru disease, Creutzfeldt-Jacob disease (C-J disease), etc. All of these have dementia symptoms in their clinical manifestations.
(3) Immune system dysfunction: The prevalence of AD significantly increases with age in the elderly, and aging is related to the decline of the immune system and the increase in autoimmune diseases. Moreover, the markers in AD's senile plaques are similar to immunoglobulin chains, suggesting that the deposition of antigen-antibody complexes forms amyloid cores, which may lead to neurodegeneration and the formation of senile plaques.
(4) Neurotransmitter theory: Neuropharmacological studies of AD confirm that the activity of acetylcholine transferase in the cerebral cortex and hippocampus of AD patients is reduced, directly affecting the synthesis of acetylcholine and the function of the cholinergic system, as well as the reduction of 5-HT and substance P.
(5) Normal aging: Neurofibrillary tangles and senile plaques can also be seen in normal brain tissue, but in smaller quantities. In AD, these damages exceed a certain "threshold" level.
In summary, in the complex study of AD's causes, age-related changes and genetic factors are relatively clear. The presence of a large number of NFTs and SPs is characteristic.
The significant changes in the brains of AD patients are characterized by generalized brain atrophy, particularly pronounced in regions associated with higher-order cognitive functions such as the hippocampus and corresponding cortical areas, with enlarged ventricles and widened sulci. There is a dramatic and noticeable reduction or disappearance of neurons and synapses in the central nervous system. Ganglion cells undergo widespread degeneration, exhibiting shrinkage, vacuolization, and lipid deposition, accompanied by the typical and characteristic diffuse senile plaques (SP) predominantly in the frontal lobe, often occurring between the ages of 50 and 60 without obvious triggers, and neurofibrillary tangles (NFT).
Characteristics of SP:
1. Contains amyloid fibers, showing a positive reaction to amyloid;
2. Immunohistochemical examination confirms the presence of IgG within SP, which normally reacts with antiserum.
bubble_chart Clinical Manifestations
This disease is more common in women than in men (approximately 1.5 to 2:1). It usually develops slowly, making it difficult to determine the onset of the disease. By the time dementia becomes apparent and medical attention is sought, it is often more than 1 to 2.5 years after the onset. According to Yang Desen's data, 70.6% of cases have a disease duration of less than 5 years, while 29.4% have a duration of more than 5 years.
Initially, there is often an accelerated deterioration of aging, with a short-term appearance of slowed, sticky, and rigid thinking, increased self-centeredness, difficulty controlling emotions, lack of concentration, verbosity, and carelessness in tasks. Within a few years, malignant forgetfulness appears, progressing from occasional forgetfulness to frequent forgetfulness, from forgetting recent events to forgetting distant events, and from forgetting details of events to forgetting the events themselves. Immediate recall is severely impaired, with events that occurred just hours or even minutes ago being impossible to recall, leading to a shortened memory span. Eventually, it can become so severe that even one's name, birthday, and family members are completely forgotten, as if living in childhood, often accompanied by a decline in calculation ability.
At the same time as memory impairment, disorientation may occur. For example, after going out, one may not recognize the way home; after using the toilet, one may not find the hospital bed.
Difficulty in association, reduced comprehension, and poor judgment. Initially, it manifests as a complete lack of planning and creativity in work, and later, even familiar tasks cannot be completed. For example, a renowned chef may no longer be able to control the heat and seasoning, resulting in dishes that are either raw or burnt, too bland or too salty, and inedible. In severe cases, even others' speech cannot be understood, and when told to undress, one may open their mouth, and when told to extend their hand, one may stand still for a long time.
2. Behavioral Changes
Behavior initially becomes childish and clumsy, often involving ineffective labor, followed by aimless labor. For example, rummaging through cabinets, misplacing items, being busy without knowing what one is doing; hoarding waste, treating it as treasure, fearing theft; neglecting personal hygiene habits, not washing dirty clothes, not rinsing in the morning, sometimes exhibiting irrational and disruptive public behavior, affecting public order. There may also be a gradual reduction in movement, sitting in a corner, motionless as a wooden chicken. In the advanced stage, there is complete inability to move, bedridden, incontinence, and total inability to manage daily life, resembling a vegetative state. According to statistics, 60% generally die within 6 months of admission, and 80% die within 18 months of admission, with the main cause of death being secondary infections.
3. Emotional Disorders
Initially, emotions may be more childish, or exhibit childlike euphoria, and be easily irritable. Later, facial expressions become stiff, and emotions become dull.
4. Focal Symptoms
During the course of the disease, focal symptoms may occasionally appear. For example, damage to the neocortex most commonly and earliest results in nominal aphasia, but other forms of aphasia, as well as various apraxias, agnosias, and acalculias, may also occur, eventually leading to a complete loss of cognitive ability.
5. Changes in Appearance
Patients with senile dementia often appear aged, with a senile appearance, white hair, tooth loss, sunken mouth, and arcus senilis in the cornea. Pupillary light reflex may occasionally be sluggish. Sensory organ function declines, physiological reflexes are sluggish, the body is bent, walking is unsteady, gait is shuffling, weight loss occurs, muscles atrophy from disuse, there is involuntary head shaking, slurred speech, drooling, finger tremors, and difficulty in writing.
Most scholars classify this disease into four types based on clinical symptoms: ① Simple type: The most common, primarily characterized by the aforementioned dementia symptoms. ② Depressive type: Often manifests as excessive concern about one's own body and low mood. ③ Manic-grandiose type or early-onset type (prsyophrenia): Initially characterized by lengthy, boastful speech and excited mood, often accompanied by confabulation and grandiosity, but in the advanced stage, it may shift to impoverished and repetitive content, eventually only able to utter monotonous and incomprehensible words. ④ Hallucinatory-delusional type: Paxa л bcknn states that more than half of the patients with this disease have various delusions, the most common being delusions of loss secondary to memory deficits, followed by delusions of jealousy, hypochondria, influence, persecution, grandiosity, and litigation. Most delusions are not fixed, with impoverished and fragmented content, but still somewhat close to reality.
bubble_chart Auxiliary Examination
1. Laboratory tests often show no significant changes.
2. The electroencephalogram (EEG) may reveal non-specific diffuse slow waves, with slowed α-wave rhythm and reduced amplitude; in severe cases, bilateral synchronous sharp waves at 0.5 c/s may be observed. Cerebral blood flow imaging shows reduced local cerebral blood flow in the cerebral cortex and a decreased cerebral oxygen metabolic rate.
3. CT scans or MRI often show varying degrees of ventricular enlargement, cortical atrophy, and widening of the cerebral sulci.
The diagnosis of AD must first recognize the clinical symptoms of AD, inquire in detail about the medical history, and then conduct a careful mental state and neurological examination.
1. The diagnostic criteria established in China in 1993 are as follows: (1) Dementia confirmed by intelligence testing; (2) At least two cognitive dysfunctions; (3) Progressive worsening of memory and cognitive impairments; (4) No disturbance of consciousness; (5) Onset between 40 and 90 years of age; (6) No other physical or brain diseases can explain the above conditions.
Supporting conditions: (1) Progressive worsening of aphasia, apraxia, agnosia; (2) Impairments in daily life and behavior; (3) Similar patients in the family; (4) Normal cerebrospinal fluid, no specific changes in EEG, CT shows brain atrophy, and it is progressively worsening.
The pathological diagnostic indicators for AD are relatively clear: (1) <60歲痴呆者，腦活栓組織中應有大量SP(≧15個/10個低倍視野)和NFT；⑵> For dementia patients aged 70, only SP is seen in brain tissue without NFT, and there must be a large number of SPs; (3) Only NFT in brain tissue only meets the diagnosis of boxing dementia, not dementia; (4) If there is no SP or NFT in the brain tissue of dementia patients, other causes should be considered.
2. DSM-IV (1994) diagnostic criteria
3. WHO's ICD-10 (1992) diagnostic criteria
The standards set by the National Institute of Neurological Disorders and Stroke (NINDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA) in the United States stipulate that based on symptoms, scales, and neuroimaging findings, it can only be diagnosed as "possible Alzheimer's disease," and confirmation depends on brain tissue biopsy. This is difficult for patients and their families to accept in China, and there are more difficulties in the early diagnosis of AD.
Currently, the United States has developed double-label immunohistochemistry to detect NFT; stereoisomer biology technology to calculate the number of neurons and tau quantity. Some units in China have started measuring phosphorylated neurofilament (PNF)/PHF values in cerebrospinal fluid.
In any case, the clinical misdiagnosis rate of dementia is still high (>15%), especially in early diagnosis, which is quite difficult. CT/MRI has diagnostic value. Positron emission tomography (PET) research and application are receiving attention.
bubble_chart Treatment Measures
There is no definitive, highly effective, or curative method yet. The drugs for treating AD are mainly divided into two categories:
1. Enhancing the function of the cholinergic system in the brain, primarily cholinesterase inhibitors and M-cholinergic receptor agonists.
2. Neuroprotective agents acting on the neurotransmitter system to delay the degeneration process of brain neurons. Theoretically, blocking the formation of β-amyloid protein (ABP), inhibiting the neurotoxicity of ABP, and protecting or repairing neurons can achieve the goal of preventing and treating AD.
Currently, only two drugs for treating AD have been approved by the US FDA: tacrine, approved in September 1993, and E-2020 (donepezil), approved in March 1997, both of which are cholinesterase inhibitors.
Others:
① Aluminum chelating agents, such as deferoxamine, can reduce aluminum absorption and brain tissue aluminum concentration, with good tolerance, and there is some clinical and experimental evidence.
② Non-steroidal (NSAIDs) and steroidal anti-inflammatory drugs Yaodui have shown some alleviation of symptoms in some patients and are one of the candidate treatment strategies.
③ The use of sex hormones, supporters believe that estrogen replacement therapy after menopause in elderly women has a certain effect on senile dementia.
④ Brain metabolism-improving drugs: such as ginkgo leaf extract, which can improve neuronal metabolism and have a positive impact on neurotransmitters; a large amount of piracetam can delay the progression of AD and improve naming and remote memory.
⑤ Calcium ion antagonists: such as nimodipine, recent studies have shown that calcium overload and imbalance in calcium homeostasis caused by various reasons are the final common pathway leading to cell death.
⑥ Gene therapy: using recombinant technology to replace defective genes with normal genes to achieve the goal of curing genetic defects, which is not yet achievable. Exogenous nerve growth factor can effectively prevent damage to the central cholinergic system and improve animal learning and memory; there has been a first report of using nerve growth factor to treat AD; one month after intracerebral injection, serial word memory improved, but other cognitive functions did not change.
⑦ Chinese medicine Chinese medicinals treatment: there have been records since ancient times, generally from the perspective of brain, heart, kidney, and other zang-fu organs and qi, blood, phlegm, stasis, fire, and depression as the mechanism of disease. In recent years, Japan has studied AD using Angelica and Peony Powder, Uncaria Powder, and Coptis Detoxification Decoction from the perspective of depression, wind, heat, and toxicity, believing that they have a certain effect on improving learning and memory in AD.
⑧ Acupuncture and moxibustion therapy: already under exploration. Scalp acupuncture targets bilateral language areas and dizziness hearing areas; ear acupuncture targets heart, brain, and subcortical and endocrine points; body acupuncture targets Fenglong, Jian Shi, Dazhui, Shenshu, philtrum, Neiguan, Fengchi, and other points, generally emphasizing the selection of points based on pattern identification.
Vascular dementia has a rapid onset and progresses in a stepwise manner. It is characterized by non-global intellectual impairment, significant memory impairment, emotional lability, and minimal personality changes, with notable focal brain signs. There is often a history of hypertension and stroke. CT or MRI scans reveal multiple cerebral infarcts with a total volume exceeding 50ml, or multiple lacunar infarcts, predominantly located in the thalamus and frontal-temporal lobes, or manifestations of subcortical arteriosclerotic encephalopathy. Brain electrical activity mapping shows asymmetric diffuse slow-wave power enhancement on both sides, with normal α-wave power. The activity of GuZu-SOD in cerebrospinal fluid is not elevated, and cholinesterase activity is not reduced, which distinguishes it from senile dementia.
Normal pressure hydrocephalus: Dementia progresses relatively quickly, with no increase in intracranial pressure, gait ataxia in the lower limbs, unsteady walking, and urinary incontinence. CT or MRI shows significant ventricular enlargement with minimal cortical atrophy.
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