Early In Alzheimer Disease
Symptoms develop gradually, so for a while, many people continue to enjoy much of what they enjoyed before developing Alzheimer disease.
Symptoms usually begin subtly. People whose disease develops while they are still employed may not do as well in their jobs. In people who are retired and not very active, the changes may not be as noticeable.
The first and most noticeable symptom may be
Forgetting recent events because forming new memories is difficult
Sometimes changes in personality
Early in the disease, people become less able to use good judgment and think abstractly. Speech patterns may change slightly. People may use simpler words, a general word or many words rather than a specific word, or use words incorrectly. They may be unable to find the right word.
People with Alzheimer disease have difficulty interpreting visual and audio cues. Thus, they may become disoriented and confused. Such disorientation may make driving a car difficult. They may get lost on their way to the store. People may be able to function socially but may behave unusually. For example, they may forget the name of a recent visitor, and their emotions may change unpredictably and rapidly.
Many people with Alzheimer disease often have insomnia. They have trouble falling or staying asleep. Some people become confused about day and night.
At some point, psychotic behavior develops in many people with Alzheimer disease.
What Does Lewy Body Dementia Look Like
Lewy body dementia affects a persons ability to think and process information and it can negatively impact memory and alter personality. Though it shares aspects of other forms of dementia, there are distinct hallmarks of LBD. Lewy body dementia symptoms include:
- Fluctuating attention/alertness: These shifts can last hours or go on for days. The person may stare into space, appear lethargic or drowsy, and have hard-to-understand speech, appearing a lot like delirium. At other times, the person may have much more clarity of thought.
- Visual hallucinations: Often, these are very detailed hallucinations and visions of people or animals, and they can recur.
- Movement disorders: Parkinsons-like movement issues, such as muscle rigidity, tremors, falls, or a shuffling gait or way of walking, may occur.
Behavioural Consequences Of Cholinomimetic Drugs And Cholinergic Lesions
Many pharmacological studies have examined the effect of cholinomimetic drugs and cholinergic receptor antagonists on learning and memory tasks. The most commonly used model is based on the finding that scopolamine, a muscarinic receptor antagonist, induces amnesia in young healthy subjects comparable with that in old, untreated subjects. These deficits may be reversed by ChE inhibitors. Compounds that reverse these scopolamine induced deficits in experimental animals may be considered as potential drugs to treat cognitive impairment.
It is, however, difficult to separate reliably the effects on learning and memory processes from effects on other behavioural domains. For example, methylscopolamine is as active as scopolamine in several models of cognitive function, indicating that peripheral changes induced by these compounds indirectly influence performance in cognitive tasks. It is, therefore, very important to distinguish central versus peripheral effects of cholinminetic agents. Scopolamine induced impairment of performance may also be mediated by direct effects on sensorimotor function or motivation deficits.Further, it is likely that the scopolamine induced impairment in the performance of both experimental animals and humans in the delayed matching to position task is secondary to attentional deficits that are induced by the drug.
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Causes Of Alzheimer Disease
What causes Alzheimer disease is unknown, but genetic factors play a role: About 5 to 15% of cases run in families. Several specific gene abnormalities may be involved. Some of these abnormalities can be inherited when only one parent has the abnormal gene. That is, the abnormal gene is dominant. An affected parent has a 50% chance of passing on the abnormal gene to each child. About half of these children develop Alzheimer disease before age 65.
One gene abnormality affects apolipoprotein E the protein part of certain lipoproteins, which transport cholesterol through the bloodstream. There are three types of apo E:
Epsilon-4: People with the epsilon-4 type develop Alzheimer disease more commonly and at an earlier age than other people.
Epsilon-2: In contrast, people with the epsilon-2 type seem to be protected against Alzheimer disease.
Epsilon-3: People with the epsilon-3 type are neither protected nor more likely to develop the disease.
However, genetic testing for apo E type cannot determine whether a specific person will develop Alzheimer disease. Therefore, this testing is not routinely recommended.
Risk factors, such as high blood pressure, diabetes, high cholesterol levels, and smoking, can increase the risk of Alzheimer disease. Treating these risk factors as early as midlife can reduce the risk of mental decline in older age.
Acetylcholine And Myasthenia Gravis
Myasthenia gravis is an autoimmune condition that causes muscle weakness, especially after a person is active.
Myasthenia gravis causes the immune system to block or destroy acetylcholine receptors. Then, the muscles do not receive the neurotransmitter and cannot function normally. Specifically, without acetylcholine, muscles cannot contract.
Symptoms of myasthenia gravis can range from mild to severe. They may include:
- weakness in the arms, legs, hands, fingers, or neck
- drooping of one or both eyelids
- shortness of breath
- difficulty speaking
Many people with myasthenia gravis can lead regular lives. A variety of treatments can control symptoms.
AChE inhibitors that doctors prescribe to treat Alzheimers disease may also help relieve symptoms of myasthenia gravis. When these drugs slow the breakdown of acetylcholine, they improve neuromuscular connection and muscle strength.
An imbalance in levels of acetylcholine may have an effect in people with Parkinsons disease, too.
The body needs a balance of acetylcholine and dopamine, another chemical messenger, to control movements well.
Parkinsons disease is a neurodegenerative condition that causes involuntary movements, tremors, and difficulties with thinking and mood.
For this reason, some medications for Parkinsons disease block the action of acetylcholine. This allows dopamine levels to rebalance, which can help relieve some symptoms.
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When Theyve Done Their Job
Once a neurotransmitter has completed its task, it is no longer needed. There are three ways that communication with the neurotransmitter can be stopped.
The first is through a process called degradation. This process occurs when an enzyme comes in and changes the composition of the neurotransmitter. When this happens, the receptor no longer recognizes the neurotransmitter and therefore does not interact with it.
The second process is known as diffusion, when the neurotransmitter moves away from the receptor. The third is the reuptake process, which occurs when the neuron that released the neurotransmitter collects it and takes it back up its axon. ;
Behavior Disorders In Alzheimer Disease
Because people are less capable of controlling their behavior, they sometimes act inappropriately or disruptively . These actions are called behavior disorders.
Several effects of Alzheimer disease contribute to this behavior:
Because people with Alzheimer disease have forgotten the rules of proper behavior, they may act in socially inappropriate ways. When hot, they may undress in public. When they have sexual impulses, they may masturbate in public, use off-color or lewd language, or make sexual demands.
Because they have difficulty understanding what they see and hear, they may misinterpret an offer of help as a threat and may lash out. For example, when someone tries to help them undress, they may interpret it as an attack and try to protect themselves, sometimes by hitting.
Because their short-term memory is impaired, they cannot remember what they are told or have done. They repeat questions and conversations, demand constant attention, or ask for things they have already received. They may become agitated and upset when they do not get what they ask for.
Because they cannot express their needs clearly or at all, they may yell when in pain or wander when lonely or frightened. They may wander, yell, or call out when they cannot sleep.
Whether a particular behavior is considered disruptive depends on many factors, including how tolerant the caregiver is and what sort of situation the person with Alzheimer disease is living in.
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Later In Alzheimer Disease
As Alzheimer disease progresses, people have trouble remembering events in the past. They start to forget the names of friends and relatives. They may require help with eating, dressing, bathing, and going to the toilet. All sense of time and place is lost: People with Alzheimer disease may even get lost on their way to the bathroom at home. Their increasing confusion puts them at risk of wandering and falling.
Disruptive or inappropriate behavior, such as wandering, agitation, irritability, hostility, and physical aggression, is common.
Eventually, people with Alzheimer disease cannot walk or take care of their personal needs. They may be incontinent and unable to swallow, eat, or speak. These changes put them at risk of undernutrition, pneumonia, and pressure sores . Memory is completely lost.
Ultimately, coma and death, often due to infections, result.
Key Biological Processes In The Brain
Most neurons have three basic parts: a cell body, multiple dendrites, and an axon.
- The cell body contains the nucleus, which houses the genetic blueprint that directs and regulates the cells activities.
- Dendrites are branch-like structures that extend from the cell body and collect information from other neurons.
- The axon is a cable-like structure at the end of the cell body opposite the dendrites and transmits messages to other neurons.
The function and survival of neurons depend on several key biological processes:
Neurons are a major player in the central nervous system, but other cell types are also key to healthy brain function. In fact, glial cells are by far the most numerous cells in the brain, outnumbering neurons by about 10 to 1. These cells, which come in various formssuch as microglia, astrocytes, and oligodendrocytessurround and support the function and healthy of neurons. For example, microglia protect neurons from physical and chemical damage and are responsible for clearing foreign substances and cellular debris from the brain. To carry out these functions, glial cells often collaborate with blood vessels in the brain. Together, glial and blood vessel cells regulate the delicate balance within the brain to ensure that it functions at its best.
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Toxins Pesticides And Acetylcholine
Exposure to organophosphate pesticides or certain nerve agents used in warfare can cause levels of acetylcholine in the body to rise very high.
The Centers for Disease Control and Prevention say that these chemicals lead to a buildup of acetylcholine in the nervous system, causing symptoms of:
- respiratory arrest
A person can be exposed to these chemicals through the skin, through breathing, or through ingestion. In the United States, about 8,000 people a year are exposed to OPs.
Exposure is most likely to occur through contact with pesticides on crops including apples, grapes, spinach, cucumbers, and potatoes or through contact with household products such as ant and roach killers.
How Do Drugs Affect Neurotransmitters
Drugs can hinder neurons’ ability to send, receive, and process signals. In some cases, drugs such as heroin and marijuana can even act as neurotransmitters because they mimic the chemical structure of one. When those drugs are in the body and are seen as neurotransmitters, they can activate neurons.
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Drugs That Influence Neurotransmitters
Perhaps the greatest practical application for the discovery and detailed understanding of how neurotransmitters function has been the development of drugs that impact chemical transmission. These drugs are capable of changing the effects of neurotransmitters, which can alleviate the symptoms of some diseases.
- Agonists vs Antagonists: Some drugs are known as agonists and function by increasing the effects of specific neurotransmitters. Other drugs and referred to as antagonists and act to block the effects of neurotransmission.
- Direct vs Indirect Effects:These neuro-acting drugs can be further broken down based on whether they have a direct or indirect effect. Those that have a direct effect work by mimicking the neurotransmitters because they are very similar in chemical structure. Those that have an indirect impact work by acting on the synaptic receptors.
Drugs that can influence neurotransmission include medications used to treat illness including depression and anxiety, such as SSRIs, tricyclic antidepressants, and benzodiazepines.
Illicit drugs such as heroin, cocaine, and marijuana also have an effect on neurotransmission. Heroin acts as a direct-acting agonist, mimicking the brain’s natural opioids enough to stimulate their associated receptors. Cocaine is an example of an indirect-acting drug that influences the transmission of dopamine.
Introduction Of Gabaergic Neurotransmitter System
-aminobutyric acid is the principle inhibitory neurotransmitter in mammalian CNS. The inhibitory effect of GABA can be conferred through three distinct receptor subfamilies named GABAA, GABAB and GABAC receptors. Both GABAA and GABAC receptors are ligand-gated chloride channels, whereas GABAB receptors are G-protein coupled metabotropic receptors . In the vertebrate brain, GABAA receptors mediate the majority of fast inhibition in the brain. They are composed of five distinct subunits pentamerically assembled, forming a ligand-gated Cl ion channel. According to their gene identity, the identified GABAA receptor subunits are classified as 16, 13, 13, 13, , , and . In the mammalian brain, the most common combination of GABAA receptor contains two , two and one subunits. GABAC receptors are composed of 13 subunits, form homomeric or heteromeric channels, making them distinct from GABAA receptors in pharmacology and function . GABAA receptors are widely expressed in all the CNS, while GABAC receptors are highly enriched in retina. Since both GABAA and GABAC receptors are ligand-gated Cl channels, sometimes we also consider GABAC receptors as a minor subgroup in GABAA receptors . GABAB receptor is a metabotropic receptor coupling with Gi/o protein. It regulates neuronal activity by either opening the K+ channel or inhibiting Ca2+ channel via the Gi/o protein-dependent signaling cascade .
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How Neurotransmitters Work
In order for neurons to send messages throughout the body, they need to be able to communicate with one another to transmit signals. However, neurons are not simply connected to one another. At the end of each neuron is a tiny gap called a synapse and in order to communicate with the next cell, the signal needs to be able to cross this small space. This occurs through a process known as neurotransmission.
In most cases, a neurotransmitter is released from what’s known as the axon terminal after an;action potential;has reached the synapse, a place where neurons can transmit signals to each other.
When an electrical signal reaches the end of a neuron, it triggers the release of small sacs called vesicles that contain the neurotransmitters. These sacs spill their contents into the synapse, where the neurotransmitters then move across the gap toward the neighboring cells. These cells contain receptors where the neurotransmitters can bind and trigger changes in the cells.
After release, the neurotransmitter crosses the synaptic gap and attaches to the receptor site on the other neuron, either exciting or inhibiting the receiving neuron depending on what the neurotransmitter is.
Receptors and neurotransmitters act like a lock-and-key system. Just as it takes the right key to open a specific lock, a neurotransmitter will only bind to a specific receptor . If the neurotransmitter is able to work on the receptor site, it triggers changes in the receiving cell.
What Is Alzheimers Disease
Alzheimers disease is a slowly progressing and irreversible disease causing the degeneration of nerve cells in parts of the brain which are important for cognition and memory. It the most common cause of dementia, a general term for loss of memory and other mental abilities severe enough to interfere with daily life. Dementia is estimated to currently affect more than 48 million people worldwide.
Age is the largest risk factor for Alzheimers disease and to date, no available treatments are able to slow down or stop the progression of the disease. Due to increasing life expectancy, Alzheimers disease is viewed as one of the largest healthcare problems of this century, imposing a major economic burden on societies in the Western and developing world.
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What Happens To The Brain In Alzheimer’s Disease
The healthy human brain contains tens of billions of neuronsspecialized cells that process and transmit information via electrical and chemical signals. They send messages between different parts of the brain, and from the brain to the muscles and organs of the body. Alzheimers disease disrupts this communication among neurons, resulting in loss of function and cell death.
Implications Of Gabaergic Neurotransmission In Alzheimers Disease
- 1Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China
- 2Neurodegenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
- 3Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
- 4The Interdepartmental Program of Translational Biology and Molecular Medicine, Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA
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Correlation Of Metabolite Abundance And Measures Of Alzheimers Pathology
When examining the relationship between metabolite abundance and measures of pathology and cognitive performance several weak but significant correlations were observed. Of the 15 measured metabolites, all correlated with Braak and CERAD scores in all regions . Correlation analysis to investigate the relationship between metabolite abundance and cognitive performance showed that arginine, aspartate, aminobutanal and guanidobutanoate correlated with MMSE in all regions , GABA, aspartate, tyrosine, DOPA, ornithine, arginine, guanidobutanoate and aminobutanal correlated with Bentons visual retention index and guanidobutanoate correlated with the Boston naming score. Running Title: Neurotransmitter metabolism in Alzheimers brain
Current Status Of Neurotransmitters And Alzheimers Disease
Neurotransmitters play a large role in maintaining synaptic and cognitive functions in mammals, including humans, by sending signals across synapses . Neurotransmitters are usually stored in synaptic vesicles, beneath the membrane in the axon terminal, and are released into the synapse with the appropriate signal from neurons. The released neurotransmitters establish connections through the synaptic cleft and bind to their appropriate receptors.
Neurotransmitters with a known role in AD pathogenesis include acetylcholine, which is synthesized from serine; dopamine, from L-phenyl alanine/L-tyrosine; GABA, from glutamate, a by-product of decarboxylation; serotonin, from L-tryptophan; histaminergic, from L-histidine; and N-methyl-D-aspartate , from D-aspartic acid and arginine. Neurotransmitters without a significant role in AD pathogenesis include glutamate, glycine, norepinephrine, epinephrine, melatonin, gastrin, oxytocin, vasopressin, cholecystokinin, neuropeptide Y, and enkephalins. However, these neurotransmitters may have a role in causing oxidative stress, which is known to be involved in AD pathogenesis.
Neurotransmitters in a healthy synapse and an Alzheimers disease synapse.
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