Chapter 12: Degenerative Disorders

In this Chapter…

• Alzheimer’s Disease
• Amyotrophic Lateral Sclerosis (ALS)
• Huntington’s Disease
• Parkinson’s Disease

Alzheimer’s Disease

• Earliest symptoms of Alzheimer’s disease include:   * Forgetfulness   * Disorientation as to time or place   * Difficulty with:     * Concentration     * Calculations     * Language     * Judgment
• As the disease progresses, severe behavioral disturbances can occur   * The individual may even become psychotic
• The individual also becomes incapable of self-care and bedridden in the final stages   * Usually death occurs from pneumonia or another complication of immobility
• A diagnosis of possible Alzheimer’s disease can be made with less than 80% accuracy in earliest stages   * As the disease progresses, the accuracy of the diagnosis exceeds 90%
• The diagnosis depends on   * Medical history   * Physical & neurological examinations   * Psychological testing   * Lab tests   * Brain imaging studies     * New brain imaging strategies show promise in enabling doctors to visualize Alzheimer’s   * The final confirmation of the diagnosis requires examination of brain tissue     * The brain tissue is usually obtained through an autopsy
• The causes and mechanisms for brain abnormalities in Alzheimer’s disease are still not fully understood
• Reductions occur in the markers for many neurotransmitters that allow cells to communicate with others   * These neurotransmitters inlcude acetylcholine, somatostatin, monoamine neurotransmitters, and glutamate
• The damage to neural systems for attention, memory, learning, and higher cognitive abilities are believed to cause clinical symptoms   * Brain tissue of deceased Alzheimer’s patients shows abnormal accumulations of beta-amyloid     * $Beta-amyloid:$ a small fibrillar peptide that accumulates in the spaces around synapses in Alzheimer’s patients       * These accumulations are called neuritic plaques   * $Neurofibrillary tangles$: a modified, aggregated form of the protein tau in the cell bodies of neurons   * Neuritic plaques and neurofibrillary tangles form in brain regions important for memory and intellectual function   * A mildly radioactive chemical marker can show amyloid plaques and tau tangles in living people
• $Early-onset Alzheimer’s:$ a rare, dominantly inherited disorder that causes the onset of Alzheimer’s in an individual’s 40s or 50s instead of past 65   * The gene encoding the Amyloid Precursor Protein (APP) is on Chromosome 21   * Early-onset Alzheimer’s is related to mutations in the genes for presenilin 1 and 2     * Presenilin 1 and 2 are proteins involved in the process of generating beta-amyloid from APP   * Genes for Early-onset Alzheimer’s causes the beta-amyloid plaques to accumulate earlier
• $Apolipoprotein E (ApoE):$ influences one’s susceptibility to Alzheimer’s disease later in life   * Exists in 3 forms   * The epsilon 4 form of ApoE is most clearly associated with increased risk for Alzheimer’s disease

Latest Research and Treatments

• Current treatments do not modify the course of the disease   * They only offer temporary mitigation of some symptoms including agitation, anxiety, unpredictable behavior, sleep disturbances, and depression   * 4 of the current treatments prevent the breakdown of acetylcholine     * The last available one regulates glutamate
• Mice carrying mutant genes develop abnormalities and some of the microscopic changes in tissue structure that occur in humans   * Mice models don’t work for all diseases
• $Beta and gamma secretases:$ enzymes that cut the amyloid peptide and release it from neurons into the space around synapses
• $Alpha secretases:$ break up beta-amyloid peptides and prevent amyloid accumulation
• Anti-amyloid therapies aim to remove existing beta-amyloid or decrease the production of new beta-amyloid
• Cognitive activity, physical activity, and heart-healthy diets all lower the risk for Alzheimer’s disease   * Obesity, high blood pressure, high cholesterol, metabolic syndrome, and diabetes raise the risk

Amyotrophic Lateral Sclerosis (ALS)

• ALS is also called Lou Gehrig’s disease
• ALS affects neurons that control voluntary muscle movements   * Motor neurons in the brain and spinal cord begin to disintegrate   * The muscles weaken and deteriorate from lack of stimulation
• The first signs of progressive paralysis are seen in the hands and feet or in muscles of speech and swallowing
• Early symptoms include:   * Weakness in legs   * Difficulty walking   * Clumsiness of hands when washing and dressing   * Slurred speech
• Almost all the muscles under voluntary control are affected   * However, the mind and senses are still intact
• Death is usually caused by respiratory failure or pneumonia
• Over 90% of ALS is sporadic   * Potential causes include:     * An excess amount of glutamate     * Oxygen in a dangerous form (oxidative distress)     * Environmental factors     * Autoimmune response
• The other 5-10% of ALS is familial and linked to a genetic defect   * A mutation in the gene that codes for the enzyme superoxide dismutase might be a cause of ALS

Huntington’s Disease (HD)

• The disease slowly progresses over a 10 to 20 year period   * HD doesn’t allow the individual to walk, think, talk, and reason
• Symptoms start between 30 and 50 years of age
• HD Affects basal ganglia and cerebral cortex
• Initial symptoms include:   * Involuntary jerking of limbs, torso, facial muscles   * Mood swings   * Depression   * Irritability   * Slurred speech   * Clumsiness
• Symptoms as the disease progresses   * Difficulty swallowing   * Unsteady gait   * Loss of balance   * Impaired reasoning   * Memory problems
• Death can occur by pneumonia, heart failure, or other complications
• Diagnosis of HD is made by a detailed clinical exam and examining the family history   * Predictive testing is only for adults   * Children under the age of 18 may be tested to confirm the diagnosis of juvenile-onset Huntington’s
• The mutation for HD is an expanded triplet repeat   * Essentially, a sequence is repeated is repeated more often than needed     * This abnormal gene codes for an abnormal version of a protein called huntingtin       * The normal function of this protein is still unknown     * This protein is widely distributed in the brain and appears to be associated with proteins involved in transcription       * HD may be caused by the gain of a new and toxic function among these proteins

Parkinson’s Disease

• Individuals with Parkinson’s disease only start showing symptoms over the age of 50   * Age is the only known risk factor for the development of the disorder
• Parkinson’s disease is characterized by:   * Slowness of movement   * Muscular rigidity   * Walking   * Balance impairment   * Many patients develop resting tremors as well
• It may also cause changes in non-motor functions of the brain
• Parkinson’s disease is caused by the loss of dopamine-producing cells of the substantia nigra pars compacta in the midbrain   * 40% of these cells must be lost before symptoms occur     * This suggests that the brain has a way of temporarily warding off symptoms
• Continued loss of cells leads to reaching the threshold where the brain can no longer recover
• It is believed that both genetic and environmental factors contribute to the injury and loss of cells in Parkinson’s disease
• Cases of early-onset Parkinson’s disease may be inherited

Treatment Breakthroughs and the need for more research

• $Levodopa$: a drug discovered in the 1960s that is converted to dopamine in the brain
• Other drugs either boost the effect of dopamine by inhibiting breakdown or extend the length of dopamine-like effects   * This is because of their ability to bind and act on similar brain regions for longer periods of time   * One example of this is the use of carbidopa with levodopa     * Carbidopa helps prevent the breakdown of levodopa in the bloodstream
• Dopamine replacement therapy doesn’t cure the disease or slow its progression   * It is not optimal for treating non-motor aspects of disease   * It also becomes less effective over time
• MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine) was accidentally discovered by drug synthesizers in the late 1970’s   * Drug addicts who injected MPTP-contaminated drugs developed Parkinson’s   * MPTP is converted to a substance in the brain that destroys dopamine-producing neurons   * Specific regions in the basal ganglia become abnormally active
• $Pallidotomy:$ surgical deactivation or destruction of overactive structures that greatly reduces symptoms   * The structures that are operated on are the pallidum and subthalamic nucleus
• Other treatments include   * Chronic deep-brain stimulation   * Replacement therapy using stem cells is being tried   * Gene transfer of trophic factors is being studied in animal models and tested in clinical trials

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