Transcript L2_Alzheimers

Dr.Wael Mansy, Ph.D.
Department of Clinical Pharmacy
College of Pharmacy / King Saud University
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Cognition refers to all the processes by which the sensory input is
transformed, reduced, elaborated, stored, recovered, and used.
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It involves the perception of sensory input and the ability to learn and
manipulate new information, recognize familiar objects and recollect past
experiences, solve problems, think abstractly, and make judgments.
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Dementia is a syndrome of deterioration in cognitive function severe
enough to interfere with occupational or social performance.
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It is a common and disabling disorder in the elderly and is becoming a
growing public health problem because of rapidly increasing numbers of
elderly people in the developed countries of the world.
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DEMENTIA
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Dementia or non-normative cognitive decline can be caused by
any disorder that permanently damages large association areas of
the cerebral hemispheres or subcortical areas subserving memory
and learning.
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The essential feature of dementia is impairment of short- and
long-term memory, which is associated with deficits in abstract
thinking, impaired judgment and other higher cortical functions,
or personality change.
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The disturbance should be sufficiently severe as to interfere
significantly with work or social activities.
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Common causes of dementia:
1. Alzheimer disease
2. vascular dementia
3. frontotemporal dementia
4. Creutzfeldt-Jakob disease
5. Wernicke-Korsakoff syndrome
6. Huntington chorea.
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Alzheimers
1. Dementia of the Alzheimer type occurs in middle or late
life and accounts for 60% to 80% of all cases of
dementia.
2. The disorder affects more than 4.5 million Americans
and may be the fourth leading cause of death in the
USA.
3. In 2006, there were 26.6 million sufferers worldwide.
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Alzheimers
4. The risk for development of Alzheimer disease increases
with age, and it is estimated that almost 50% of
individuals 85 years of age and older live with this illness,
which affects almost twice as many women as men.
5. It is projected that, unless a cure or prevention is
developed, there will be 14 million Americans with
Alzheimer disease by the year 2050, (1 in 85 people
globally ).
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
Alzheimer's disease (AD), also known as Senile Dementia of the Alzheimer
Type (SDAT) or simply Alzheimer’s is the most common form of dementia.

This incurable, degenerative, terminal disease was first described by a
German psychiatrist and neuropathologist Alois Alzheimer in 1906 .

Alzheimer's disease (AD) is a slowly progressive disease of the brain that is
characterized by impairment of memory and eventually by disturbances in
reasoning, planning, language, and perception.

Many scientists believe that Alzheimer's disease results from an increase in
the production or accumulation of a specific protein (beta-amyloid protein)
in the brain that leads to nerve cell death.
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 The pathophysiologic aspects of Alzheimer disease involve
neuropathologic and neurotransmitter changes.
 Alzheimer disease is characterized by cortical atrophy and loss
of neurons, particularly in the parietal and temporal lobes .
 With significant atrophy, there is ventricular enlargement (i.e.,
hydrocephalus) from the loss of brain tissue.
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Stages of Alzheimer's disease

The major microscopic features are the presence
of neuritic (senile) plaques, neurofibrillary tangles, and
amyloid angiopathy.

The neuritic plaques are patches or flat areas
composed of clusters of degenerating nerve terminals
arranged around a central amyloid core.
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The dominant component of the amyloid core is
amyloid beta (Aβ), a peptide derived from the
proteolysis of a larger membranes panning amyloid
precursor protein (APP).
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There is increasing evidence that Aβ is
the critical molecule in the pathogenesis
of Alzheimer disease.

Full-length APP has an intracellular
region, a membrane-spanning sequence, and an extracellular region.

The normal degradation of APP involves cleavage in the middle of the Aβ
domain by a proteolytic α-secretase enzyme, with the release of two soluble
nonamyloidogenic pieces.
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
However, APP can also be cleaved at either end of the Aβ
domain, leading to the release of intact and highly amyloidogenic
Aβ that accumulates in senile plaques as amyloid fibrils.

There are at least three distinct forms of secretase enzymes (α-,
β-, γ- secretase). Evidence suggests that cleavage by the β- and γ-
secretase leads to the generation of Aβ.
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The neurofibrillary tangles, found in the cytoplasm of abnormal
neurons, consist of fibrous proteins that are wound around each
other in a helical fashion. These tangles are resistant to chemical or
enzymatic breakdown, and they persist in brain tissue long after the
neuron in which they arose has died and disappeared.

A major component of the paired helical filaments is an
abnormally hyperphosphorylated form of the protein tau, an axonal
microtubule-associated protein that enhances microtubule assembly.
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 Some plaques and tangles can be found in the brains of older
persons who do not show cognitive impairment. The number and
distribution of the plaques and tangles appear to contribute to the
intellectual deterioration that occurs with Alzheimer disease.
 In persons with Alzheimer disease, the plaques and tangles and
associated neuronal loss and glial reaction are evident earliest in
the entorhinal cortex, then spread through the hippocampal
formation and isocortex, and then extend to the neocortex.
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Alzheimer
disease
has
been
associated with a decrease in the level of choline acetyltransferase
activity in the cortex and hippocampus. This enzyme is required
for the synthesis of acetylcholine, a neurotransmitter that is
associated with memory.
 The reduction in choline acetyltransferase is quantitatively
related to the numbers of neuritic plaques and severity of
dementia.
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 It is likely that Alzheimer disease is caused by several factors that interact
differently in different persons.
 Progress on the genetics of inherited early-onset Alzheimer disease shows
mutations in at least three genes , which can cause Alzheimer disease in certain
families:
1. the APP gene on chromosome 21: a gene which is associated with an
autosomal dominant form of early-onset Alzheimer disease, and can be
tested clinically.
2. presenilin-1 (PS1), a gene on chromosome 14;
3. and presenilin-2 (PS2), a gene on chromosome
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 Persons with Down syndrome develop the pathologic changes of Alzheimer
disease and a comparable decline in cognitive functioning at a relatively young age.
 Virtually all persons with Down syndrome exihibit the pathologic features of
Alzheimer disease as they age. PS1 and PS2, both intracellular proteins, are
components of γ-secretase and possibly part of a multiprotein complex containing
the proteolytic site for breakdown of Aβ.
 A fourth gene, an allele (_4) of the apolipoprotein E (ApoE) gene found on
chromosome 19, increases the risk of Alzheimer disease and lowers the age of
onset.
 ApoE can bind Aβ and is present in plaques, but how this allele increases the
risk of Alzheimer disease has not been established.
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 Although age is the greatest
, additional factors have been
identified as adding to the risks for development of Alzheimer
disease. These include:
1. head trauma
2. inflammatory factors
3.oxidative stress.
 Education has been identified as a
, with
suggestions that education can increase synaptic density.
 Other studies have looked at exercise as a possible
in maintaining hippocampal health.
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Microscopy image of a neurofibrillary
tangle, conformed by hyperphosphorylated tau protein.
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 Alzheimer-type dementia follows an insidious and progressive course, with
an average survival of 8 to 10 years after diagnosis.
 The hallmark symptoms are loss of short-term memory and denial of such
memory loss, with eventual disorientation, impaired abstract thinking, apraxias,
and changes in personality and affect.
 Various stages of the disease have been recognized, ranging from four to the
more nuanced seven stages identified by the Alzheimer Association.
 All are characterized by progressive degenerative changes.
 The initial change is subtle, characterized by short-term memory loss that
often is difficult to differentiate from the normal forgetfulness that occurs in the
elderly, and usually is reported by caregivers and denied by the patient.
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 Although most elderly persons have trouble retrieving from
memory incidental information and proper names,
 Persons with Alzheimer disease randomly forget important and
unimportant details. They forget where things are placed, get lost
easily, and have trouble remembering appointments and performing
novel tasks.
 Mild changes in personality, such as lack of spontaneity, social
withdrawal, and loss of a previous sense of humor, occur during this
stage.
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 As the disease progresses, the person with Alzheimer disease
enters the moderate stage. This stage may last several years and
is marked by a more global impairment of cognitive functioning.
 During this stage, there are changes in higher cortical
functioning needed for language, spatial relationships, and
problem solving.
 Depression may occur in persons who are aware of their
deficits.
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 There is extreme confusion, disorientation, lack of insight, and inability to carry
out the activities of daily living.
 Personal hygiene is neglected, and language becomes impaired because of
difficulty in remembering and retrieving words.
 Behavioral changes can include agitation, sleep problems, restlessness and
wandering, aggression, and suspiciousness.
 Some persons may become hostile and abusive toward family members. Persons
who enter this stage become unable to live alone and should be assisted in making
decisions about supervised placement with family members or friends or in a
community-based facility. Severe Alzheimer disease is the last stage of the disease.
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 It is characterized by a loss of ability to respond to the environment.
Individuals in this stage require total care, and spend most of their time
bedridden. Death can occur as a result of complications related to chronic
debilitation. There is extreme confusion, disorientation, lack of insight, and
inability to carry out the activities of daily living.
 Personal hygiene is neglected, and language becomes impaired because of
difficulty in remembering and retrieving words.
 Behavioral changes can include agitation, sleep problems, restlessness
and wandering, aggression, and suspiciousness.
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 Some persons may become hostile and abusive toward family
members. Persons who enter this stage become unable to live alone
and should be assisted in making decisions about supervised
placement with family members or friends or in a community-based
facility. Severe Alzheimer disease is the last stage of the disease.
 It is characterized by a loss of ability to respond to the
environment. Individuals in this stage require total care, and spend
most of their time bedridden. Death can occur as a result of
complications related to chronic debilitation.
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