Transcript History of AD

Pathology and Treatment
By Fiona
Nicholson
Alzheimer’s Disease Overview
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History of AD
Diagnosis of AD
Stages
Risk Factors
Physiology
Treatment
Auguste D.
History of AD
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Alzheimer’s disease was
characterized by Dr. Alois Alzheimer
in 1906 after performing an autopsy
on his patient, Mrs. Auguste D. who
was thought to have “amnesiac
writing disorder.”
Dr. Alzheimer noted “peculiar
formations” (amyloid plaques) and
“dense bundles” (neurofibrillary
tangles).
During the autopsy, a substance was
noted that was later characterized as
the beta-amyloid protein.
Dr. Alois Alzheimer
How common is Alzheimer’s?
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Out of all the
neurogenerative diseases,
Alzheimer’s has the highest
prevalence at 1.450/100,000
The incidence and
prevalence of this disease
increases with age; between
the ages of 65-69, the
prevalence is 1.53%, and
between the ages of 80-85,
the prevalence increases to
25-30% of the population
Diagnosis of AD
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No direct confirmatory test exists
Diagnosis of AD is based on careful clinical
assessment which can include medical interviews
Laboratory tests are conducted to eliminate the
possibility of other diseases that can mimic the AD
Neuropsychological tests are conducted to assess
the cognitive symptoms
Brain scans can show the progression of AD and
how the disease influences brain activity
Stages of Alzheimer’s Disease
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Stage 1: No impairment
No memory problems are evident to a health care professional during an interview
Stage 2: Very mild cognitive decline
Patients may feel they have memory lapses (such as forgetting keys), but these are
not evident during a medical interview
Stage 3: Mild cognitive decline
Friends, family, and coworkers notice memory decline, and the decline is measurable
in a clinical setting. Examples are decreased ability to remember names when
introduced to new people, losing or misplacing a valuable object, and reading a
passage and retaining little information
Stage 4: Moderate cognitive decline (early to mid stage AD)
AD is able to be diagnosed at this stage, and decreased cognitive ability is very
evident in the following areas: decreased ability to recall information about recent
occasion, decreased ability to perform mental arithmetic, impaired ability to pay pills
and manage finances, reduced memory of personal history. Patients may seem
withdrawn in complex situations
Stages of Alzheimer’s Disease
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Stage 5: Moderately severe cognitive decline (moderate or mid-stage AD)
Major deficits in memory and difficulty in cognitive function; AD patients
require some assistance with daily activities. Patients may not be able to
recall their phone number or current address and can be confused about
what day or the week or what season it is. Patients maintain knowledge
about themselves, such as their name and the names of close family
members.
Stage 6: Severe cognitive decline (moderately severe AD)
Memory deficits worsen and personality changes are evident. Patients tend
to lose awareness of recent events, cannot recollect personality history
accurately, need help with everyday activities, and can wander and become
lost.
Stage 7: Very severe cognitive decline (severe or late-stage AD)
Patients lose the ability to respond to the environment, lose the ability to
speak, and lose control over their movement.
Risk Factors for AD
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Age
Genetics
Lifestyle
Head trauma
Clinical depression
Down’s syndrome
Environmental toxins
What causes AD?
According to Goodman and Gilman, AD is “characterized by
marked atrophy of the cerebral cortex and loss of cortical
and subcortical neurons.” (p. 538)
Areas of the brain affected:
Physiology of AD
2 Hallmarks of Alzheimer’s Disease
1. Amyloid Plaques
2. Neurofibrillary
tangles
Amyloid Plaques
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Found in the spaces
between nerve cells
Composed of an
insoluble protein peptide
called beta-amyloid,
other proteins, and
remnants of other brain
cells (neurons, non-nerve
cells, and glial cells)
Plaques develop in the
brain in many people as
they age, but in AD
patients, plaques develop
in the cognitive areas.
Neurofibrillary Tangles
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Tangles develop
inside nerve cells
Abnormal collections
of twisted protein
fibers
Protein threads are
composed of the
hyperphosphorylate
d tau protein
Healthy Neuron
Neuron with AD
Shrinkage
of cerebral
cortex
Enlarged
ventricles
Shrinkage of
hippocampus
Three Hypotheses Concerning
AD Development
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Amyloid Cascade Hypothesis
Tau Hypothesis
Cholinergic Hypothesis
Amyloid Cascade Hypothesis
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The initiating event that leads to the formation of
plaques is an excess of Αβ peptides.
Patients with missense mutations in the APP, Presenilin
1, and Presenilin 2 genes (“Alzheimer’s genes”) are prone
to overproduction.
Patients without AD genes start to overproduce Αβ
peptides from a failure of metabolism.
The response to the excess of Αβ peptides involves an
inflammatory response and free radical formation.
This toxic cascade, induced by amyloid accumulation,
eventually leads to the organization into plaques.
Tau Hypothesis
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In healthy neurons, Tau normally has a certain
amount of phosphate molecules attached, and
binds to microtubules and stabilizes them.
In an AD neuron, tau is hyperphosphorylated
which disengages the protein from the
microtubules.
The resulting detached tau proteins group
together and form tangles. The microtubules
disintegrate, which leads to the collapse of the
neuron’s transport system.
Cholinergic Hypothesis
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Acetylcholine biosynthesis is reduced in the
presence of plaques and tangles.
Because less of a neurotransmitter
(acetylcholine) is synthesized, this leads to a
loss of neurons.
Thus, even more brain cells are lost than
usual, which can lead to AD.
There is no cure for
Alzheimer’s disease!
The following treatments can alleviate
symptoms or slow the progression of
the disease.
Treatment
1. Symptomatic Treatments:
a) Acetylcholinesterase Inhibitors
b) NMDA-receptor Antagonists
2. Disease-modifying Treatments:
a) Inhibition of amyloid formation
b) Inhibition of abeta aggregation
c) Tau phosphorylation inhibitors
3. Other Therapies:
a) Gingko biloba
b) Estrogen therapy for women
c) Anti-inflammatory drugs: aspirin
4. Life Style Changes
a) Stress control
b) Monitor Diet
c) Cognitive Stimulation
5. Psychotic Treatments:
a) Antidepressants
b) Anti-anxiety medicine
c) Antipsychotics
1a) Acetylcholinesterase Inhibitors
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“Smart drugs”
Decrease the rate that Ach is
broken down, therefore
increasing Ach concentration
Treatment with these drugs
does not cure Alzheimer’s, but
they do help to alleviate
symptoms
These drugs have to be able to
cross the blood brain barrier
sufficiently
More beneficial in early stages
of Alzheimer’s versus later
stages
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Disadvantages:
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With long term use, these drugs
increase the overall level of Ach in
the body which causes
gastrointestinal side effects
bradycardia, hypotension,
hypersecretion,
bronchoconstriction, GIT
hypermotility, and decrease
intraocular pressure.
Acetylcholinesterase Inhibitor
Examples
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Tacrine
1st drug to be approved for
treatment of Alzheimer’s in
1993
No longer clinically used
because of its extremely
toxicity
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Donepezil (Aricept)
No definitive proof exists that
this drug slows down the
progression of Alzheimer’s,
but studies show benefits in
behavior and cognition
Acetylcholinesterase Inhibitor
Examples
Galantamine (Razadyne)
 Treatment for mild to
moderate Alzheimer’s
 Extracted from daffodils or
snow-drop bulbs
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Rivastigmine (Exelon)
significant treatment effects on
the cognitive (thinking and
memory), functional (activities
of daily living) and behavioral
problems have been observed
Treatment for mild to
moderate dementia
1b) NMDA Receptor Antagonists
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Hypofunction of the NMDA receptor is thought
to contribute to memory deficits associated with
old age.
Memantine (Axura)
•Targets the cholinergic
system
•Acts as an noncompetitive
antagonist at the 5HT3
receptor
2) Disease-modifying Treatments:
Used to treat moderate to severe forms of AD
a) Inhibition of amyloid formation
to inhibit the toxic cascade that leads to amyloid
formation
b) Inhibition of abeta aggregation
to inhibit the overproduction of the abeta peptide
c) Tau phosphorylation inhibitors
to prevent hyperphosphorylation of Tau proteins and
maintain microtubules
3a) Other Therapies: Ginkgo Biloba
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Ginkgo biloba is thought to
improve thinking, learning,
and memory in AD patients
Ginkgo has antioxidant
properties and increases
Ginkgo is used preventively
because it is thought to
delay the onset of AD in
patients that are at higher
risk
4. Life Style Changes
a) Stress control
b) Monitor Diet
c) Cognitive Stimulation
d) Social and Visual Stimulation
5. Psychotic Treatments
Applicable in later stages of AD
a) Antidepressants
b) Anti-anxiety medicine
c) Antipsychotics
Noteworthy Cases of AD
Ronald Reagan
Rita Hayworth
Charlton Heston