Transcript Alzheimer’s disease Paul R. Earl Facultad de Ciencias Biológicas Universidad Autónoma de Nuevo León San Nicolás, NL, Mexico.

Alzheimer’s disease
Paul R. Earl
Facultad de Ciencias Biológicas
Universidad Autónoma de Nuevo León
San Nicolás, NL, Mexico
A German doctor Alois Alzheimer (1864-1915) in
1907 published on a degenerative attack on the
nerve cells of the cerebral cortex—a brain
disorder—in Z Psychiatrie Psychisch-Gerichtlich
Medizine 64: 146-148 that became known as
Alzheimer’s 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 brain’s chemical
messengers—mainly acetylcholine.
Alois Alzheimer
AD’s 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
wandering—are 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.
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, Parkinson’s and
Huntington’s 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.
The key to dementia is age (??) !
Alzheimer’s 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
Parkinson’s disease, dementia of
Huntington’s disease, dementia of Pick’s
disease, frontal lobe dementia and others.
Apathy is a major feature of both
depression and AD.
Symptoms in AD might be:
1/ 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.
Sometimes AD is a Family Disease
Genetic factors appear to play a significant
role in the pathogenesis of Alzheimer’s
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.
Treatment notes
The 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.
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.
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.
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.
DRUG NAMES
Namenda (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.
Dementia With Lewy Bodies
Dementia 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
Parkinson’s disease and AD. LB contain deposits
of the protein alpha-synuclein that is also linked
to Parkinson’s 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.
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 patient’s 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.
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.
An amyloid plaque stained with Congo
Red on the left and neorofibrillary
protein on the right.
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.
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.
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: 622631 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.
Histopathology
Histopathologic 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 ßamyloid. Thus, the generation of ßamyloid peptide is increasingly regarded
as the AD central pathologic event.
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/Amyloid1.htm
which is the Boston University Amyloid
Treatment and Research Program.
Older Americans Act
The 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.
What successful management
strategies are available ?
Successful patient management aims to
minimize behavioral disturbances, maximize functioning and independence, and
foster a safe and secure environment.
Several principles are recommended:
1/ 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 sleep
hygiene. Medicate only as a last resort.
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.
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.
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 following:
1/ physician knowledge about diagnosis and
treatment, and the skills required to assess patients;
2/ attitudes and beliefs about dementia held by the
public and medical professionals;
3/ fiscal barriers, including access, insurance
coverage, and reimbursement and managed care
issues;
4/ demographic and socioeconomic factors, including
race, ethnicity, and culture;
5/ disease complexity and the dependence on
specialists to diagnose and treat.
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--affect 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 endstage 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?
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.