Alzheimers disease Paul R' Earl Facultad de Ciencias Biolgicas Universidad Autnoma de Nuevo Len San

1
Alzheimers diseasePaul R. EarlFacultad
de Ciencias BiológicasUniversidad Autónoma de
Nuevo LeónSan Nicolás, NL, Mexico
2
A German doctor Alois Alzheimer (1864-1915) in
1907 published on a degenerative attack on the
nerve cells of the cerebral cortexa brain
disorderin Z Psychiatrie Psychisch-Gerichtlich
Medizine 64 146-148 that became known as
Alzheimers disease (AD). Possibly 5 million
people over 65 have AD in the US, and the number
of AD cases may triple by 2050. It is a
progressive disease of the brain that is
characterized by loss of memory and a disturbance
in at least one other thinking function (for
example, language or perception of reality). Loss
of nerve cells in strategic brain areas, in turn,
causes deficits in the neurotransmitters, which
are the brains chemical messengersmainly
acetylcholine.
3
ADs gradual, yet relentless attack on memory is
the major sign and the earliest. Symptoms extend
to other cognitive deficits in language, object
recognition and executive functioning. Psychosis,
agitation, depression and wanderingare common.
Incidentally, the German word for madness is Der
Wandersinn. AD is a
neurodegenerative disease that begins with an
insidious and progressive course and great
clinical variability, ending by 10 years.
Alois Alzheimer
4
A reduced amount of acetylcholine is thought to
cause the loss of memory. Reduced cerebral blood
flow might also be involved in AD. Nevertheless,
amyloid disequilibria with plaque formation and
the death of neurons seem still more important as
causes of dementia and death. The other causes
of dementia that must be ruled out include
cerebrovascular, Parkinsons and Huntingtons
diseases, subdural hematoma, normal-pressure
hydrocephalus, brain tumor and systemic
conditions, e.g., hypothyroidism, vitamin B12
E, folic acid deficiency, niacin deficiency,
hypercalcemia, neurosyphilis, HIV infection and
toxicities. The factors of diseases can be
summarized as 1/ too little, 2/ too much or 3/
the wrong kind.
5
The key to dementia is age (??)
!Alzheimers disease, remote from normal
ageing, is the most prevalent form of dementia,
and billions of dollars in costs that are rising
as the elderly population proportionally takes up
more of the population. Regardless, many of the
issues raised also pertain to other forms of
dementia such as multiinfarct dementia, dementia
of Parkinsons disease, dementia of Huntingtons
disease, dementia of Picks disease, frontal lobe
dementia and others.Apathy is a major feature of
both depression and AD.
6
Symptoms in AD might be1/ Apathy, 2/
Wandering, 3/ Depression,
4/ Aggression, 5/
Delerium,
6/ Hallucination and 7/ Mania.
Over 90 years of age
means over 30 AD and possibly 50 .The public
views forgetfulness or "senility" as a normal
part of aging, and this is not so.
7
Sometimes AD is a Family DiseaseGenetic factors
appear to play a significant role in the
pathogenesis of Alzheimers disease. In its
familial form, AD is caused by mutations in
chromosomes 1, 14 21, and 1 and is transmitted
in an autosomal dominant mode. Each of these
mutations appears results in the overproduction
of the B amyloid protein found in neuritic
plaques. Onset of the familial form is usually
early. However, the familial form accounts for
less than 5 of AD.
8
Treatment notesThe primary goals of treatment
are to improve quality of life and maximize
functional performance by enhancing cognition
mood and behavior.
The expensive hardship is the loss of
independence so that the patient at some point
with need nursing care. Appropriate drugs that
are mainly cholinesterase inhibitors can keep the
patient funtional longer.
9
AD begins slowly. At first, the only symptom may
be mild forgetfulness,which can be confused with
agerelated memory change. Most people with mild
forgetfulness do not have AD. In the early stage
of AD, people may have trouble remembering recent
events, activities, or the names of familiar
people or things. They may not be able to solve
simple math problems. These difficulties are
often not serious enough to cause alarm.
Although early and late stage AD could even be
different diseases, the constellation of
symptoms, age differences at the onset of AD and
so forth are not sufficiently clear. Research
funding, especially in the third world, for AD is
poor. Additional tests including of course
genetic ones may allow better estimates of rate
of decline.
10
Cholinesterase inhibitors improve central
cholinergic neurotransmission. Take Donepezil as
an example. It produces improved cognitive
effects, e. g., enchanced memory, orientation,
language and reasoning over periods of 12-24
weeks without hepatotoxicity. The recommended
starting dose of 5 mg/day, increased to 10 mg/day
after 1 month. The higher dose, while more
efficacious, has a greater tendency to cause
cholinergic adverse effects, e. g., nausea,
diarrhea and insomnia if increased too rapidly,
and such effects may worsen behavior.
11
The fifth approved medication, known as Namenda,
Axura and Ebixa (memantine), is an N-methyl
D-aspartate (NMDA) antagonist for the treatment
of moderate to severe AD. The medication may
allow patients to maintain daily functions a
little longer. For example, Memantine may help a
patient in the later stages of AD maintain his or
her ability to go to the bathroom independently
for several more months, a benefit for both
patients and caregivers. Memantine is believed to
work by regulating glutamate, another important
brain chemical that, when produced in excessive
amounts, may lead to brain cell death.
12
DRUG NAMESNamenda (memantine). Blocks the toxic
effects associated with excess glutamate and
regulates glutamate EFFECTS include
activation.Reminyl (galantamine). Prevents the
breakdown of acetylcholine and stimulates
nicotinic receptors to release more acetylcholine
in the brain.Exelon (rivastigmine). Prevents the
breakdown of acetylcholine and butyrylcholine (a
brain chemical similar to acetylcholine) in the
brain.Aricept (donepezil). Prevents the
breakdown of acetylcholine in the brain.
13
Dementia With Lewy BodiesDementia with Lewy
bodies (LB) is the second most frequent cause of
degen-erative dementia in elderly adults. LBD is
a neurodegenerative disorder associated with
abnormal structures found in the brain sometimes
associated with Parkinsons disease and AD. LB
contain deposits of the protein alpha-synuclein
that is also linked to Parkinsons disease and
multiple system atrophy. Symptoms can range from
traditional Parkinsonian effects, such as loss of
spontaneous movement (bradykinesia), rigidity
(muscles feel stiff and resist movement), tremor
and shuffling gait to effects similar to those of
AD such as acute confusion, loss of memory, and
some loss of cognition.
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How prevalent is AD ?AD affects an estimated 4
million people in the US. It causes anguish to
millions more caregivers and family members, who
must cope with the patients steady irreversible
decline in cognition, functioning and behavior.
AD might reach 14 million by the year 2040.
Patients and caregivers often mistake early
symptoms for normal aging changes, and physicians
may fail to recognize the initial signs of
dementia or misdiagnose them. Regardless, AD and
aging are not similar. For example, the cognitive
changes of aging as a slowing of information
processing are benign, while dementia is
progressive and disabling.
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What is the impact on society ?When the costs
of medical and longterm care, home care and lost
productivity for caregivers are totaled, the
direct dollar expenditure and indirect costs like
family care approach 100 billion each year.
Medicare, Medicaid and private insurance bear
much of the direct cost, but families who care
for patients assume the largest portion of
expenses.
16
An amyloid plaque stained with Congo Red on the
left and neorofibrillary protein on the right.
17
What are the different forms of dementia and how
can they be recognized ?AD lasts about 10 years
with a range of 3-20. Memory impairment is
present in the earliest stages. Patients have
difficulty learning and retaining new
information. Older memories are lost. Aphasia,
apraxia, disorientation, visuospatial
dysfunction, and impaired judgment and executive
functioning set in. Functional impairment like
getting lost occur.
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The presence of delirium or depression may
confound dementia recognition. Delirium is an
acquired impairment of attention, alertness and
perception. Like dementia, delirium is
characterized by cognitive impairment. It can be
distinguished by its acute onset, marked
fluctuations in cognitive impairment over the
course of a day, disruptions in consciousness and
attention, and alterations in the sleep cycle.
Hallucinations and visual illusions are common. A
general medical condition, such as infection or
metabolic disturbance or drug side effects
typically causes delirium. Delirium and dementia
often coexist, particularly in a hospital
setting. Also, dementia is a risk factor for
delirium.
19
Three tests will greatly aid in discriminating
the status of the patient. They are
1/ Measurement of functional
activities in older adults in the community. J
Gerontol 1982, 37 323-329, 2/ Assessment of
behavioral problems in dementia The revised
memory and behavior problems checklist. Psychol
Aging 1992, 7 622-631 and 3/ Mini-Mental
State A practical method for grading the
cognitive state of patients for the clinician. J
Psychiatr Res 1975, 12 189-198. See also
Accuracy of clinical diagnosis of Alzheimer
disease and clinical features of patients with
non-Alzheimer neuropathology. Alzheimer Dis Assoc
Disord. 1996, 10 180-188.
20
HistopathologyHistopathologic changes include
neuritic plaques, neurofibrillary tangles,
synaptic loss, hippocampal granulovacuolar
degeneration and B amyloid angiopathy. ß-amyloid
deposition and neurofibrillary tangle formation
are two histopathologic features of Alzheimer
disease. Most of the genetic risk factors are
related to ß- amyloid. Thus, the generation of
ß-amyloid peptide is increasingly regarded as the
AD central pathologic event.
21
Apolipoprotein E (ApoE) as a major genetic risk
factor in AD. ApoE is a normal protein, which
transports cholesterol in the circulatory system
(www.alzheimers.org). There are three versions of
the ApoE gene ApoE2, ApoE3 and ApoE4. Every
person inherits one version of the gene from each
parent, and ApoE3 is the most common gene of the
three and found in more than half of the
population. See http//amyloid.bu.edu/amyloid/Amyl
oid1.htm which is the Boston University Amyloid
Treatment and Research Program.
22
Older Americans ActThe Older Americans Act was
originally signed into law by President Johnson
in July 14, 1965 (PDF). In addition to creating
the Administration on Aging, it authorized grants
to States for community planning and services
programs, as well as for research, demonstration
and training projects in the field of aging.
Later amendments as in to the Act added grants to
Area Agencies on Aging for local needs
identification, planning and funding of services,
including but not limited to nutrition programs
in the community as well as for those who are
homebound. Programs are to serve Native American
elders.
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What successful management strategies are
available ?Successful patient management aims to
minimize behavioral disturbances, maxi-mize
functioning and independence, and foster a safe
and secure environment. Several principles are
recommended1/ Schedule regular patient
surveillance and health maintenance visits every
3 to 6 months. Evaluate medications periodically,
and consider initiating drug-free periods. Check
for sleep disturbances and provide guidance on
proper sleephygiene. Medicate only as a last
resort.
24
What specialized staff and facilities are
available to the community ?Geriatricians,
geriatric psychiatrists, psychologists, or
neurologists should be consulted when the
presentation or history is atypical or complex,
especially when cases are younger than 60 years.
Geriatric psychiatrists and psychologists can
provide behavioral management, especially for
agitation, psychosis or violent behavior.
Management of suicidal behavior or treatment of
major depression, and individual or family
therapy for patients and caregivers deserves
attention. Functional evaluation to make a
determination about institutionalization or
hospitalization may be crucial.
25
Several specialized services are available in the
US, including adult day care and respite care.
Skilled nursing care provided by the home health
agencies. Help lines of the Alzheimer's
Association and outreach services, as offered by
area agencies on aging and councils on aging,
agencies mandated and funded under the federal
Older Americans Act. Aging services also can
recommend handypersons and homemakers, friendly
visitor or companion programs, and housing and
legal assistance. Meals-on-wheels arranges food
services for the homebound, while senior citizens
centers, church and community groups, and
hospitals offer transportation options.
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What are the most promising research areas ?What
barriers contribute to the delivery of inadequate
or untimely medical services in primary care
settings?Areas of investigation might include
the following1/ physician knowledge about
diagnosis and treatment, and the skills required
to assess patients2/ attitudes and beliefs
about dementia held by the public and medical
professionals3/ fiscal barriers, including
access, insurance coverage, and reimbursement and
managed care issues4/ demographic and
socioeconomic factors, including race, ethnicity,
and culture5/ disease complexity and the
dependence on specialists to diagnose and treat.
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How do different health delivery systems
influence the course of illness, care settings
and impact on the family? How do different
disease management models--for instance, primary
care vs specialist vs collaborative psychiatric
vs medical managed care vs fee-for-service--affec
t diagnosis, treatment and outcome? Which quality
indicators are most useful? What are the best
ways to maintain the safety and independence of
AD patients? When should patients stop driving,
living alone or participating in other
potentially hazardous activities? What level of
care is appropriate and humane for patients with
severe end-stage AD? In light of any advance
directives that terminal patients may have
prepared, is symptomatic treatment warranted?
Should life be extended and, if so, for how long?
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Whenever possible, health services and outcomes
research should be conducted in diverse
community populations. Most studies of dementia
to date have been conducted in academic or other
unrepresentative settings. Differences in the
quality and level of care in diverse geographic
regions and populations and subgroups should be
studied. Minorities in particular face very
different treatment and management issues. The
use of "natural populations" in controlled
community settings offers more practical answers
to these questions.