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Neuropsych Conditions: Alzheimer's Disease

AHAF Pictures: Normal brain Brain with Alzheimer's Amyloid plaques/Neurofibrillary tangles Brain changes with short movie

Websites: The Alzheimer's Association, American Health Assistance Foundation

UC Davis Information
Alzheimer's disease is a progressive, irreversible neurological disorder that attacks the brain and results in memory loss, confusion, impaired judgment, and personality changes. It is the most common cause of severe intellectual impairment in older individuals and is a primary reason for the placement of the elderly in nursing homes. More than 5000,000 Californians are affected by this illness. At present it is not known what causes Alzheimer's disease or how to prevent or care it. However, there is often much that can be done to reduce the symptoms, improve functioning, and aid the family in caring for the patient at home.

Dementia is a term used to refer to a group of symptoms that are the result of the deterioration of mental functions, such as thinking, remembering, and judgment and that is severe enough to hinder everyday activities and social relationships. Alzheimer's disease is one of the many kinds of dementia. It is important to note that, although Alzheimer's is the most common form of dementia, not all dementia is Alzheimer's.

Amyloid Plaques

In AD, plaques develop first in areas of the brain used for memory and other cognitive functions. They consist of largely insoluble (cannot be dissolved) deposits of beta-amyloid - a protein fragment snipped from a larger protein called amyloid precursor protein (APP) - intermingled with portions of neurons and with non-nerve cells such as microglia (cells that surround and digest damaged cells or foreign substances that cause inflammation) and astrocytes (glial cells that serve to support and nourish neurons). Plaques are found in the spaces between the brain's nerve cells. Although researchers still do not know whether amyloid plaques themselves cause AD or whether they are a by-product of the AD process, there is evidence that amyloid deposition may be a central process in the disease. Certainly, changes in the structure of the APP protein can cause AD, as shown in one inherited form of AD, which is caused by mutations in the gene that contains instructions for making the APP protein. Recent work has revealed much about the nature of beta-amyloid and the ways in which it may be toxic to neurons, the processes by which plaques form and are deposited in the brain, and ways in which the numbers of plaques can be reduced.

Neurofibrillary Tangles

The second hallmark of AD consists of abnormal collections of twisted threads found inside nerve cells. The chief component of these tangles is one form of a protein called tau. In the central nervous system, tau proteins are best known for their ability to bind and help stabilize microtubules, which are one constituent of the cell's internal support structure, or skeleton.

In healthy neurons, microtubules form structures like train tracks, which guide nutrients and molecules from the bodies of the cells down to the ends of the axon. Tau normally holds together the "railroad ties" or connector pieces of the microtubule tracks. However, in AD tau is changed chemically, and this altered tau twists into paired helical filaments - two threads of tau wound around each other. These filaments aggregate to form neurofibrillary tangles. When this happens, the tau no longer holds the railroad tracks together and the microtubules fall apart. This collapse of the transport system first may result in malfunctions in communication between nerve cells and later may lead to neuronal death that contributes to the development of dementia. Recent research has shed much light on this abnormal aggregation of tau protein and on the role that certain genetic mutations play in changing tau's structure and contributing to neurodegeneration.

TAU

One major diagnostic feature of AD is the formation of neurofibrillary tangles in susceptible nerve cells in the brains of persons with AD. Tangles are composed of tau-containing paired helical filaments. Since the discovery in 1998 that mutations in the tau gene cause FTDP-17, scientists have rapidly initiated experiments to try to understand how changes in the structure of tau or how altered levels of specific forms of tau could result in the abnormal production of paired helical filaments and death of neurons in this disease. Finding out how changes in tau structure cause paired helical filaments and neuron death in FTDP-17 will help scientists to understand the similar process in AD brains.

Two types of transgenic mice have been used to examine how tau is involved in this process. One type of mouse, created by scientists at the University of Pennsylvania School of Medicine, overproduced one of the six forms of human tau (Ishihara et al., 1999). The mice showed aggregation of tau resulting in loss of microtubules in the neurons as well as degeneration of axons. The mice had pathology similar to that seen in FTDP-17 and the amyotrophic lateral sclerosis/Parkinsonism-dementia complex of Guam. These findings suggest that these neurodegenerative diseases can result from altered expression of normal forms of tau.

A second type of transgenic mouse was created with one form of the human tau gene containing the most common human mutation causing FTDP-17 (Lewis et al., 2000). Investigators at the Mayo Clinic, Jacksonville, Florida, found that this mouse had problems with walking and other movements and had behavioral deficits. The investigators found a direct relationship between the level of expression of the mutated gene, the number of neurofibrillary tangles, and the age of the mouse. This mouse model confirms the hypothesis that neuron loss can and does result from a mutation of the tau gene.

Diagnostic Tests

A diagnosis of dementia requires a medical history; physical examination, including neurological examination); and appropriate laboratory tests.

Taking a thorough medical history involves gathering information about the onset, duration, and progression of symptoms; any possible risk factors for dementia, such as a family history of the disorder or other neurological disease; history of stroke; and alcohol or other drug (prescription or over-the-counter) use.

The American Psychiatric Association has established two generally accepted criteria for the diagnosis of dementia: (1) erosion of recent and remote memory and (2) impairment of one or more of the following functions:

Language
misuse of words or inability to remember and use words correctly (i.e., aphasia)

Motor activity
unable to perform motor activities even though physical ability remains intact (i.e., apraxia)

Recognition
unable to recognize objects, even though sensory function is intact (i.e., agnosia)

Executive function
unable to plan, organize, think abstractly

Symptoms often develop gradually and show a progressive deterioration in function.

Differential Diagnosis

Delirium The physician must distinguish between delirium and dementia. Delirium is a transient, acute mental disturbance that manifests as disorganized thinking and a decreased ability to pay attention to the external world. Delirium is often caused by infectious disease, brain tumor, poisoning, drug or alcohol intoxication or withdrawal, seizures, head trauma, and metabolic disorders. It is important to treat underlying conditions promptly, as they may be life-threatening or progressive if left untreated. Symptoms of delirium include the following:

• Disorientation as to person, place, and time
• Memory impairment
• Rambling, irrelevant, incoherent speech
• Reduced level of consciousness

Neuropsychological tests (see List) are administered to assess difficulties in attention span, perception, memory, problem solving, and social and language skills. Responses to these tests may provide diagnostic clues.

Blood tests may be ordered if the history and physical examination indicates an infectious, metabolic, or toxic condition. The results help the physician rule out Alzheimer’s and help determine an effective treatment plan.

• B12, folate, thiamine levels (vitamin deficiency)
• Blood glucose (hypoglycemia)
• Complete blood count (anemia)
• Drug screen (drug toxicity)
• Electrolytes (hypercalcemia, hypermagnamesia, hypernatremia)
• Liver function (liver disease)
• Lumbar puncture (normal-pressure hydrocephalus, encephalitis, meningitis)
• Thyroid function (hypothyroidism)
• VDRLT (syphilis and HIV infection)

An analysis of DNA in the blood sample may reveal the ApoE4 gene, which is found in about one-third of Alzheimer’s disease patients.

Electroencephalography (EEG) traces brain wave activity. Some central nervous system disorders cause distinct changes in brain wave activity. Alzheimer’s disease generally reveals "slow" waves.

An EEG can help distinguish a severely depressed or delirious patient whose brain waves are normal from a patient with a degenerative neurological disease.

Imaging tests (MRI scan or PET scan) can detect structural, or physical, changes in the brain caused by stroke, blood clots, tumors, head injury, or hydrocephalus.

Alzheimer's Disease Medications Fact Sheet (From ADEAR)
Download this fact sheet as a PDF

Five prescription drugs currently are approved by the U.S. Food and Drug Administration to treat people who have been diagnosed with Alzheimer's disease (AD). Treating the symptoms of AD can provide patients with comfort, dignity, and independence for a longer period of time and can encourage and assist their caregivers as well. It is important to understand that none of these medications stops the disease itself.

Treatment for Mild to Moderate AD
Four of these medications are called cholinesterase inhibitors. These drugs are prescribed for the treatment of mild to moderate AD. They may help delay or prevent symptoms from becoming worse for a limited time and may help control some behavioral symptoms. The medications are: Reminyl® (galantamine), Exelon® (rivastigmine), Aricept® (donepezil), and Cognex® (tacrine). Scientists do not yet fully understand how cholinesterase inhibitors work to treat AD, but current research indicates that they prevent the breakdown of acetylcholine, a brain chemical believed to be important for memory and thinking. As AD progresses, the brain produces less and less acetylcholine; therefore, cholinesterase inhibitors may eventually lose their effect.
No published study directly compares these drugs. Because all four work in a similar way, it is not expected that switching from one of these drugs to another will produce significantly different results. However, an AD patient may respond better to one drug than another. Cognex® (tacrine) is no longer actively marketed by the manufacturer.

Treatment for Moderate to Severe AD
The fifth approved medication, known as Namenda® (memantine), is an N-methyl D-aspartate (NMDA) antagonist. It is prescribed for the treatment of moderate to severe AD. Studies have shown that the main effect of Namenda® is to delay progression of some of the symptoms of moderate to severe AD. The medication may allow patients to maintain certain daily functions a little longer. For example, Namenda® may help a patient in the later stages of AD maintain his or her ability to go to the bathroom independently for several more months, a benefit for both patients and caregivers.

Namenda® is believed to work by regulating glutamate, another important brain chemical that, when produced in excessive amounts, may lead to brain cell death. Because NMDA antagonists work very differently from cholinesterase inhibitors, the two types of drugs can be prescribed in combination.

Dosage and Side Effects
Doctors usually start patients at low drug doses and gradually increase the dosage based on how well a patient tolerates the drug. There is some evidence that certain patients may benefit from higher doses of the cholinesterase inhibitor medications. However, the higher the dose, the more likely are side effects. The recommended effective dosage of Namenda® is 20 mg/day after the patient has successfully tolerated lower doses. Some additional differences among these medications are summarized in the table on the other side.

Patients may be drug sensitive in other ways, and they should be monitored when a drug is started. Report any unusual symptoms to the prescribing doctor right away. It is important to follow the doctor's instructions when taking any medication, including vitamins and herbal supplements. Also, let the doctor know before adding or changing any medications.
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