How Does Alzheimer’s Disease Affect The Central Nervous System

Physical Changes To Expect

Which symptoms you have and when they appear are different for everyone.

Some people have physical problems before serious memory loss.

In one study, people who walked slowly and had poor balance were more likely to be diagnosed with Alzheimer’s disease in the following 6 years.

Some of the changes you might experience are:

• Loss of balance or coordination
• Stiff muscles

Acetylcholine Storage In Vesicles

ACh that is synthesized in the cytoplasm of cholinergic neurons is transported into synaptic vesicles by VAChT, which is located in the synaptic vesicle membrane . The gene encoding VAChT has been cloned and hydrophobic analysis indicates that the protein has twelve transmembrane domains . Each molecule of ACh transported by VAChT is in exchange for two vesicular protons, which leads to the fulfill of synaptic vesicles with the neurotransmitter . The vesicular transporter activity can be blocked by vesamicol, which is a non-competitive inhibitor .

VAChT carboxyl-terminus has many motifs important for cellular trafficking and for its localization to synaptic vesicle membranes . Interestingly, PKC can phosphorylate VAChT and regulate its vesicular localization . A VAChT knockdown mouse model, expressing about 68% less VAChT protein, shows major neuromuscular deficits. This data highlights the importance of the transporter to the peripheral nervous system. Furthermore, cognitive impairment can take place even due to a mild decrease in VAChT protein expression .

Molecular And Cellular Mechanisms Of Toxicity And Cancer

activity of the Na+K+ATPase, which is a target of the oxidative stress of the neuron, and this oxidative stress is a consequence of Alzheimers. .The Aluminum is related to Alzheimer. Elevated levels of Aluminum in the brain can be a consequence of the Alzheimer disease. When you have the Alzheimer disease, the hematoencephalic barriers efficacy is reduced, and Aluminum gets in the brain easily . High level of Aluminum in the brain causes the formation of neurofibrilar tangles

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How Are Cns Problems Treated

If the side effects of medications include nervous system problems, they usually go away if you stop taking the drugs. This may take as long as several months.

People with CNS problems may have problems with taking their medications on schedule They may need extra help remembering to take their medications.

Several other neurological problems are emerging in people, even those taking antiviral medications. This includes conditions related to immune reconstitution inflammatory syndrome .

Acetylcholine Release And Inactivation

When cholinergic neurons are depolarized, ACh is exocytosed from synaptic vesicles and released into the synaptic cleft, where it can activate both muscarinic and nicotinic receptors. ACh present at the synaptic cleft is rapidly inactivated by the enzyme acetylcholinesterase , releasing choline and acetate . Cholinergic neurons secrete AChE into the synaptic cleft, where the enzyme is normally associated with the plasma membrane . Neurotransmitters other than ACh are normally reuptaken into the presynaptic neuron and then inactivated by specific enzymes. Thus, the mechanism of ACh inactivation is unique. Each molecule of AChE can hydrolyze 5000 molecules of ACh per second, which makes AChE one of the most kinetically efficient enzymes known . It has been demonstrated that AChE, in addition to metabolizing ACh, has a number of non-classical actions. For a review on non-classical actions of AChE, see .

AChE gene can generate multiple protein products due to mRNA splicing . These distinct transcripts exhibit unique expression in the various tissues, as well as different patterns of plasma membrane association . The main AChE transcript is expressed in muscles and brain. Other transcripts of AChE are expressed in developing blood cells .

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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.

Neurodevelopmental Disorders And Mental Illness

Mental illnesses are nervous system disorders that result in problems with thinking, mood, or relating with other people. These disorders are severe enough to affect a persons quality of life and often make it difficult for people to perform the routine tasks of daily living. Debilitating mental disorders plague approximately 12.5 million Americans at an annual cost of more than $300 billion. There are several types of mental disorders including schizophrenia, major depression, bipolar disorder, anxiety disorders, post-traumatic stress disorder, and many others. The American Psychiatric Association publishes the Diagnostic and Statistical Manual of Mental Disorders , which describes the symptoms required for a patient to be diagnosed with a particular mental disorder. Each newly-released version of the DSM contains different symptoms and classifications as researchers learn more about these disorders, their causes, and how they relate to each other. A more detailed discussion of two mental illnesses, schizophrenia and major depression, is given below.

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Patient Description And Samples

CSF and sera originated from a sample collection of patients who gave their informed consent from Montpellier neurological and Clinical Research Memory Centers for cognitive or behavioral disorders . This study was ethically approved under the number 12.128Ter by the Comité consultatif sur le traitement de linformation en matière de recherche .

Patients were selected based for AD on the clinical criteria established in 1984 by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association . MCI patients were selected following the Petersen MCI diagnosis criteria with a concern regarding a change in cognition, impairment in one or more cognitive domains, preservation of independence in functional abilities without dementia. Mini-mental state examination values illustrating differences in cognition of the different clinical groups are provided in Table 1.

Table 1. Demographic and CSF biomarkers in the population.

For the microarrays approach, a total of 49 serum samples were analyzed. Sera originated from control subjects , AD , or MCI patients. Among these MCI patients, 10 showed biological characteristics of AD. Of note, the time between the collection of the samples and their analysis was not significantly different between groups .We also analyzed the CSF of 20 of these 49 patients .

Targeted Quantification Of Tricarboxylic Acid Cycle Intermediates Tryptophan Breakdown Products And Other Amino Acids And Acylcarnitines

Absolute quantification was performed using the 6495 QqQ mass spectrometer interfaced with the 1290 UHPLC, operated in the dMRM mode. In brief, aliquots of calibrators, plasma, or CSF were extracted by the addition of internal standard mixtures after which the sample was directly injected for LC-MS/MS analysis . Stable isotope-labeled analogues were used as internal standards to determine the response factor while correcting for extraction yield and matrix effect. Data processing was done using MassHunter Quantitative Analysis.

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More Information About Alzheimer Disease

The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

• Alzheimer’s Association: This web site provides information about Alzheimer disease, including statistics, causes, risk factors, and symptoms. It also provides resources for support, including information about daily care of people with Alzheimer disease, care for the caregiver, and support groups.

• The Alzheimer’s Society: This web site provides a guide to dementia , a guide for caregivers, and information about types of dementia, symptoms, diagnosis, treatments, risk factors, and prevention.

• Institute of Neurological Disorders and Stroke Alzheimer’s Disease Information Page: This web site defines Alzheimer disease and provides information about treatment, prognosis, and available clinical trials and links to other organizations focused on Alzheimer disease.

Zinc Finger Transcription Factors And Gene Regulation

Zinc is responsible for the DNA-binding ability of many transcription factors through a unique ability to form molecules known as zinc finger proteins. These ubiquitously expressed proteins directly regulate gene expression. They also appear to interface with RNA and function to facilitate protein-protein interactions. While several classes of ZnF proteins are known to exist, by far the most common form is the classical ZnF, consisting of 2 cysteine and 2 histidine or 1 cysteine and 3 histidine residues centralized around a zinc ion with a short b-hairpin and an a-helix incorporated into the structure. The conformation of ZnFs centers around the coordinated zinc ion and provides the molecule with the potential to form a finger-like structure that is capable of binding tightly with specific DNA sequence domains .

Other zinc finger transcription factors that are clearly involved in neuronal function include the thyroid hormone receptor that plays a role in neuronal growth and development, and both retinoic acid receptors and vitamin D receptors that participate in neuronal differentiation.

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What Are Vascular Issues

Many people with Alzheimers disease also have other changes to their brain, including vascular issues. If there is any kind of vascular issue, like a mini-stroke or hardening of the arteries, this can lead to a breakdown of the blood-brain barrier, leaving the brain vulnerable to harm. If the blood-brain barrier is compromised in someone with Alzheimers disease, glucose doesnt properly reach the brain, which stops it from getting rid of beta-amyloid and tau proteins, both of which are toxic to the brain in excess amounts.2 This, in turn, causes more inflammation, which contributes to vascular problems and the cycle continues.

Medical research is focused on identifying changes to the brain early and discovering new treatments to stop progression of Alzheimers disease.

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What Happens To The Brain In Alzheimers Disease

People with AD gradually suffer memory loss and a decline in thinking abilities, as well as major personality changes. These losses in cognitive function are accompanied by changes in the brain, including the build-up of amyloid plaques and tau-containing neurofibrillary tangles, which result in the death of brain cells and the breakdown of the connections between them.

Amyloid plaques and neurofibrillary tangles are the primary hallmarks of Alzheimers disease. Plaques are dense deposits of protein and cellular material outside and around the brains nerve cells. Tangles are twisted fibers that build up inside the nerve cells. Scientists have known about plaques and tangles since 1906, when a German physician, Dr. Alois Alzheimer, first identified them in the brain of woman who had died after suffering paranoid delusions and psychosis. Intensive research efforts of the last two decades have revealed much about their composition, how they form, and their possible roles in the development of Alzheimers disease. The deposition of amyloid in the form of plaques is thought by many scientists to trigger the cascade of events leading to Alzheimers pathology. Amyloid now is believed to be a critical target for eventual treatment. The best evidence that amyloid causes the disease comes from the genetic studies in which mutations of APP, PS1, PS2 and APOE e4 all facilitate amyloid accumulation.

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Insight Into Ways Organ Systems Outside The Brain May Affect Alzheimer’s Disease

Date:

IOS Press

Summary:

A new study provides insights into the way A-beta in the peripheral blood stream affects A-beta clearance in the brain. Scientists found that when circulating A-beta levels in the blood stream of rats were elevated, known amounts of radioactively tagged A-beta were swept from the brain more slowly.

In Alzheimer’s disease the brain accumulates a molecule called A-beta that can be quite toxic to brain cells. Many researchers believe that finding ways to clear A-beta may be a key to treatment or prevention of Alzheimer’s disease.

A new study provides new insights into the way A-beta in the peripheral blood stream affects A-beta clearance in the brain. Scientists from the University of Washington in Seattle, VA Puget Sound Health Care System, and the University of Hong Kong found that when circulating A-beta levels in the blood stream of rats were elevated, known amounts of radioactively tagged A-beta were swept from the brain more slowly.

These findings directly demonstrate something researchers have proposed for several years nowthat freely circulating A-beta concentrations outside the brain can regulate A-beta clearance rates inside the central nervous system.

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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.

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Loss Of Neuronal Connections And Cell Death

In Alzheimers disease, as neurons are injured and die throughout the brain, connections between networks of neurons may break down, and many brain regions begin to shrink. By the final stages of Alzheimers, this processcalled brain atrophyis widespread, causing significant loss of brain volume.

Learn more about Alzheimer’s disease from MedlinePlus.

Diagnosis Of Alzheimer Disease

Alzheimer disease is suspected when the following are present:

• The diagnosis of dementia has been confirmed.

• Usually, the most noticeable symptom, particularly in the beginning, is forgetting recent events or not being able to form new memories.

• Memory and other mental functions have gradually deteriorated and are continuing to deteriorate.

• The dementia began after age 40 and usually after age 65.

• Doctors have ruled out other brain disorders that could be causing the problems.

Some symptoms can help doctors distinguish Alzheimer disease from other dementias. For example, visual hallucinations are more common and occur earlier in dementia with Lewy bodies than in Alzheimer disease. Also, people with Alzheimer disease are often better-groomed and neater than people with other dementias.

Information from additional tests helps doctors make the diagnosis of Alzheimer disease and exclude other types and causes of dementia.

Analysis of cerebrospinal fluid , obtained during a spinal tap, and positron emission tomography may be used to help diagnose Alzheimer disease. If CSF analysis detects a low level of beta-amyloid and if PET scans show amyloid deposits or tau deposits in the brain, the diagnosis is more likely to be Alzheimer disease. However, these tests are not routinely available.

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Safety And Supportive Measures

Creating a safe and supportive environment can be very helpful.

Generally, the environment should be bright, cheerful, safe, stable, and designed to help with orientation. Some stimulation, such as a radio or television, is helpful, but excessive stimulation should be avoided.

Structure and routine help people with Alzheimer disease stay oriented and give them a sense of security and stability. Any change in surroundings, routines, or caregivers should be explained to people clearly and simply.

Following a daily routine for tasks such as bathing, eating, and sleeping helps people with Alzheimer disease remember. Following a regular routine at bedtime may help them sleep better.

Activities scheduled on a regular basis can help people feel independent and needed by focusing their attention on pleasurable or useful tasks. Such activities should include physical and mental activities. Activities should be broken down in small parts or simplified as the dementia worsens.

Microglia And Brain Development

Microglia are the endogenous immune cells of the central nervous system. Over the past decade, the ontogeny of microglial cells has been controversial. Their developmental progression has gone through several interesting iterations leading to our current understanding of how these peripherally derived cells come to reside in the central nervous system . During development, myeloid precursors travel to the brain and then differentiate into microglia . These tissue-specific macrophages make their way to the brain through the circulation from the embryonic yolk sac . They grow concurrently with neurons, before the development of astrocytes and oligodendrocytes, participating in key neurodevelopmental events such as neurogenesis, synaptic pruning, and thus the development and remodeling of neuronal circuits. There is evidence that microglia need to adapt to their quickly changing environment and modify their functions as needed . It seems logical, then, that aberrant or impaired microglial activation during development would be implicated in CNS disease later on in life.

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