Transcript Dementia Supischa Theerasasawat Eric Pfeiffer, M.D J. Wesson Ashford And Staff of National Institute on Aging.

Dementia
Supischa Theerasasawat
Eric Pfeiffer, M.D
J. Wesson Ashford
And
Staff of National Institute on Aging
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
Causes of Dementia
•
•
•
•
•
Alzheimer’s disease – 65%
Vascular Dementia – 10 %
Mixed AD and VaD – 10 %
Lewy Body Dementia – 5-10 %
Post-traumatic brain injury and postencephalitic dementia – 5-10 %
Alzheimer’s 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.
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
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. 1990;68:267-289.
Alzheimer’s Association. Available at: www.alz.org/hc/overview/stats.htm. Accessed 5/9/2001.
The Brain’s 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)
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
body’s internal clock
• Limbic system: controls emotions and instinctive behavior
(includes the hippocampus and parts of the cortex)
Slide 12
Neurotransmitter in AD
Acetylcholine
Glutamate
Acetylcholine Pathways
•
Two major cholinergic
projections within CNS
1. Ascending reticular activating
system
 Sleep-wake cycles
2. Cortical structures:
neocortex, hippocampus and
amygdala
 Learning and memory
function
Cholinergic deficit in AD
• Progressive loss of
cholinergic neurones
• Progressive decrease
in avaliable Ach
• Impairment in ADL,
behavior and cogniton
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.
The Glutamate Hypothesis of
Alzheimer’s 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. 1988;12:421-430.
N-Methyl-D-Aspartate Receptors
• Normal resting
membrane
potentials,
extracellular Mg2+
ions will block the
pore of NMDA
• 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.
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
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)
Atypical Early Features of AD
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
Slide 16
AD and the Brain
Beta-amyloid Plaques
1.
Amyloid precursor protein (APP) is the
precursor to amyloid plaque.
1. APP sticks through the neuron
membrane.
2.
3.
2. Enzymes cut the APP into fragments
of protein, including beta-amyloid.
3. Beta-amyloid fragments come together
in clumps to form plaques.
In AD, many of these clumps form,
disrupting the work of neurons. This
affects the hippocampus and other areas
of the cerebral cortex.
Slide 17
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.
Slide 18
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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