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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