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