Dementia

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Dementia
Supischa Theerasasawat Eric Pfeiffer, M.D J.
Wesson Ashford And Staff of National Institute on
Aging
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DEMENTIA DEFINITION
A clinical syndrome, due to loss of brain cells,
characterized by memory loss and other cognitive
impairments, to the extent that the individual is
showing impaired social or occupational
functioning
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Causes of Dementia

• Alzheimers disease 65
• Vascular Dementia 10
• Mixed AD and VaD 10
• Lewy Body Dementia 5-10
• Post-traumatic brain injury and post-encephalitic
  dementia 5-10

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Alzheimers Disease What it is

• A disease in which brain cells die prematurely
  and progressively, leaving the individual with
  impaired memory capacity, decision-making
  capacity, and eventually self-care capacity.

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What it does continued

• It lasts anywhere from two to twenty-two years
• It affects ten percent of all older people
• At age 65 only one percent have the disease
• At age75 this has gone up to ten percent
• At age 85 this has gone up to 35 percent
• At age 90 it is nearly fifty percent

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Prevalence and Impact of AD

• AD is the most common cause of dementia in people
  65 years and older
• Affects 10 of people over the age of 65 and 50
  of people over the age of 85
• Approximately 4 million dementia patients in the
  United States
• Annual treatment costs 100 billion
• AD is the fourth leading cause of death in the
  United States
• The overwhelming majority of patients live at
  home and are cared for by family and friends

Evans DA. Milbank Q. 199068267-289.
Alzheimers Association. Available at
www.alz.org/hc/overview/stats.htm. Accessed
5/9/2001.
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• The Brains Vital Statistics
• Adult weight about 3 pounds
• Adult size a medium
  cauliflower
• Number of neurons 100,000,000,000 (100
  billion)
• Number of synapses (the gap between
  neurons) 100,000,000,000,000 (100
  trillion)

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Inside the Human Brain
Other Crucial Parts

• Hippocampus where short-term memories are
  converted to long-term memories
• Thalamus receives sensory and limbic information
  and sends to cerebral cortex
• Hypothalamus monitors certain activities and
  controls bodys internal clock
• Limbic system controls emotions and instinctive
  behavior (includes the hippocampus and parts of
  the cortex)

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Neurotransmitter in AD

• Acetylcholine
• Glutamate

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Acetylcholine Pathways

• Two major cholinergic projections within CNS
• Ascending reticular activating system
• Sleep-wake cycles
• Cortical structures neocortex, hippocampus and
  amygdala
• Learning and memory function

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Cholinergic deficit in AD

• Progressive loss of cholinergic neurones
• Progressive decrease in avaliable Ach
• Impairment in ADL, behavior and cogniton

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Glutamate pathways

• Glutamate is the fast excitatory neurotransmitter
  in regions associated with cognition and memory.
• Cortical and subcortical structures that
  contained glutaminergic receptors are
  structurally damage in AD.
• Glutamate acts as an excitotoxin causing neuronal
  death when excessive levels are chronically
  released.

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The Glutamate Hypothesis of Alzheimers Disease

• Glutamatergic Neurotransmission
• Normal glutamate stimulates 70 of excitatory
  synapses (physiological)
• Abnormal glutamate stimulation can cause neuronal
  toxicity and may impair learning (pathological)
• Rationale for NMDA Antagonists
• Normalization of glutamatergic neurotransmission
  may maintain or improve cognition and prevent
  neurotoxicity

NMDA N-methyl-D-aspartate Source Greenamyre
JT. Prog Neuropsychopharmacol Biol Psychiatry.
198812421-430.
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N-Methyl-D-Aspartate Receptors

• Normal resting membrane potentials, extracellular
  Mg2 ions will block the pore of NMDA

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• Blockade of NMDA receptors can produce amnesia
  and hallucination.
• Excessive activation of NMDA receptors can lead
  to massive Ca2 influx and trigger irreversible
  process leading to cell death.

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Pathways for excitotoxicity in AD
Energy deficiency Decrease in membrane
potential Decrease glutamate uptake Increase
glutamate release Glutamate levels NMDA
receptor activation Increased Ca2
influx Excitotoxicity
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Clinical AD

• Impaired of short-term memory, unable to use cues
• Relative preservation of remote memory
• Mild difficulty with word-finding
• Visuospatial involvement
• Reduced ability to plan, judge, and organize
• Relatively preserved social behavior (apathy)

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Atypical Early Features of AD
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AD and the Brain
Plaques and Tangles The Hallmarks of AD The
brains of people with AD have an abundance of two
abnormal structures

• beta-amyloid plaques, which are dense deposits of
  protein and cellular material that accumulate
  outside and around nerve cells
• neurofibrillary tangles, which are twisted fibers
  that build up inside the nerve cell

An actual AD plaque
An actual AD tangle
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AD and the Brain
Beta-amyloid Plaques Amyloid precursor protein
(APP) is the precursor to amyloid plaque. 1.
APP sticks through the neuron membrane. 2.
Enzymes cut the APP into fragments of protein,
including beta-amyloid. 3. Beta-amyloid
fragments come together in clumps to form
plaques.
1.
2.
In AD, many of these clumps form, disrupting the
work of neurons. This affects the hippocampus and
other areas of the cerebral cortex.
3.
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AD and the Brain
Neurofibrillary Tangles
Neurons have an internal support structure partly
made up of microtubules. A protein called tau
helps stabilize microtubules. In AD, tau changes,
causing microtubules to collapse, and tau
proteins clump together to form neurofibrillary
tangles.
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AD Research the Search for Causes
Studies at the Cellular and Molecular Level

• Oxidative damage from free radical molecules can
  injure neurons.

• Homocysteine, an amino acid, is a risk factor for
  heart disease. A study shows that an elevated
  level of homocysteine is associated with
  increased risk of AD.
• Scientists are also looking at inflammation in
  certain regions of the brain and strokes as risk
  factors for AD.

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