Alzheimer

• The underlying cause of Alzheimer's disease is unknown. Scientists have discovered some things but still do not have the whole picture.
• Neuronal degeneration in Alzheimer's disease

  1. Degeneration occurs in the hippocampus early

  2. Degeneration of neurons in the cerebral cortex later

  3. Subsequent decline in cerebral volume
• Hippocampus


  Serves an important role in memory, central to speech, perception, reasoning, and other higher functions
• As hippocampal neurons degenerate


  Short-term memory begins to fail
• As cortical neurons degenerate

  Patients begin having difficulty with language followed by complete loss of speech, bladder and bowel control and ability for self-care followed by death
• In patients with advanced Alzheimer's disease, levels of acetylcholine are 90% below normal
• Acetylcholine


  An important transmitter in the hippocampus and cerebral cortex, critical to forming memories
• Cholinergic function can be normal in patients that have only mild Alzheimer's disease, so loss of cholinergic function cannot explain the cognitive deficits that occur early in the disease process
• Neuritic plaques


  Spherical bodies composed of beta-amyloid (a protein fragment) surrounded by neuron remnants, seen mainly in the hippocampus and cerebral cortex
• Beta-amyloid is present in high levels and may actually contribute to the neuronal injury
• An accumulation of beta-amyloid begins early in the Alzheimer's disease process, perhaps even 10 to 20 years prior to the first symptoms
• Treatments directed against beta-amyloid are being developed because of the central role that beta-amyloid appears to play
• Neurofibrillary tangles


  Form inside of neurons when the orderly arrangement of microtubules becomes disrupted due to production of an abnormal form of tau protein
• Apolipoprotein E4


  Plays a role in cholesterol transport, and may contribute to Alzheimer's disease
• Individuals with one or two copies of the gene that codes for apoE4 are at increased risk for Alzheimer's disease, however many people with Alzheimer's disease do not have the gene for apoE4
• Endoplasmic Reticulum-associated binding protein

  Found to be present in high concentrations in patients with Alzheimer's disease

  Enhances the neurotoxic effects of beta-amyloid
• Major risk factors for Alzheimer's disease

  • Advancing age
  • Family history
  • Being female
  • Head injury
  • Low education level
  • Production of the apolipoprotein E4
  • High levels of homocysteine
  • Low levels of folic acid
  • Estrogen and progesterone therapy
  • Nicotine in cigarette smoke
  • Sedentary lifestyle
• Symptoms of Alzheimer's disease

  1. Progress from mild to moderate to severe

  2. Early disease: memory loss and confusion, impaired judgment, personality changes

  3. As disease progresses: difficulty with self-care, wandering, pacing, agitation, screaming, sundowning

  4. Final stages: unable to recognize family members or communicate
• The progressive symptoms of Alzheimer's disease typically begin after the age of 65 but may appear as early as 40 years old, and the life expectancy from symptom onset may be 20 years or more, but is usually four to eight years
• Goal of Alzheimer's disease treatment

  To improve the symptoms and reverse the cognitive decline, but currently available drugs cannot do this
• Drugs now in use may slow the loss of memory and cognition and prolong independent function, but for some patients even these modest goals are unlikely
• Drugs approved for the treatment of Alzheimer's dementia

  • Three cholinesterase inhibitors: donepezil, galantamine, rivastigmine
  • Memantine
• Cholinesterase inhibitors


  Approved for mild to moderate Alzheimer's disease, may delay or slow the progression of the disease but will not stop it, improvements are modest and short-lasting
• Donepezil


  A CYP2D6 and CYP3A4 substrate,

  highly protein bound with a prolonged plasma half-life,

  takes about 15 days to achieve a steady state

  Cholinesterase inhibitor

  reversible inhibition
• Rivastigmine


  Causes irreversible inhibition of acetylcholinesterase,

  has the same adverse effects as donepezil and galantamine

  no significant drug interactions
• Galantamine


  Prepared by extraction from daffodil bulbs, has the same adverse effects and drug interactions as donepezil
• Memantine indication


  Indicated only for moderate to severe Alzheimer's disease,

  has modest benefits,

  can slow the decline in function and improve symptoms,

  when taken with donepezil- less decline in cognitive function than donepezil alone
• Memantine adverse effects


  • well tolerated
  • dizziness, heaache, confusion
  • diarrhea/constipation
• Aducanumab was just approved for the treatment of Alzheimer's disease under accelerated approval, and drug companies are required to conduct post-approval studies to verify the drug's clinical benefit
• Aducanumab


  monoclonal antibody

  For mild to moderate Alzheimer's disease, not severe,

  has been shown to decrease amyloid plaque - reduce clinical decline,

  Expensive

  FDA could remove it from the market
• Spasticity


  A group of movement disorders of central nervous system origin, characterized by heightened muscle tone, spasm, and loss of dexterity,

  most common causes are multiple sclerosis and cerebral palsy
• Drugs used to treat spasticity

  • Baclofen
  • Diazepam
  • Tizanidine
  • Dantrolene
• Muscle spasm


  An involuntary contraction of a muscle or muscle group, often painful and decreases the ability to function,

  Causes: epilepsy, hypocalcemia, pain syndromes, and trauma
• Treatment for acute muscle spasm

  1. Physical measures like immobilization, cold compresses, whirlpool baths, physical therapy

  2. Drug therapy with analgesics, NSAIDs, and centrally acting muscle relaxants
• Centrally acting muscle relaxants

  cyclobenzaprine,

  chlorzoxazone,

  diazepam metaxalone,

  tizanidine,

  methocarbamol,

  orphenadrine,
• Metaxalone is the least sedating out of the group of centrally acting muscle relaxants
• Tizanidine


  Can cause hypotension and hallucinations, should be tapered when discontinuing
• Carisoprodol


  Can be hazardous to patients predisposed to intermittent porphyria
• What elevated plasma levels are associated with increased risk for AD?

  Homocysteine
• How can Homocysteine be lowered?

  eating foods/supplements rich in folic acid, B6, and B12