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Dr. Harriett Butchko
Introduction
We’re living longer, but there is
an ironic price to pay for our longevity -- the incidence
of certain age-related diseases is rising. As life expectancy
increases, the incidence of neurodegenerative diseases
such as Alzheimer’s disease (AD) also is growing.
Because there is such a high incidence
of AD in the U.S., the question may be asked whether
there are other neurodegenerative diseases with some
symptoms similar to AD that might be misdiagnosed as
Alzheimer’s. This paper will specifically examine
the likelihood that sporadic Creutzfeldt-Jakob disease
(CJD) may be misdiagnosed as Alzheimer’s.
Overview of neurodegenerative diseases
There are a number of neurodegenerative
diseases, but, other than Alzheimer’s disease,
which affects 15,000 people per million population,
most are unfamiliar and rare. Creutzfeldt-Jakob Disease
(CJD) is the rarest of all, affecting only one person
per million population. Other neurodegenerative diseases
include Parkinson’s disease (3,600 cases per million
population); Frontotemporal dementia (140/million);
Huntingdon’s disease (folk singer Woody Guthrie
is the most famous victim of this disease which occurs
at a rate of 110/million); Amyotrophic lateral sclerosis
(also called Lou Gehrig’s disease, has an incidence
of 70/million); Progressive supranuclear palsy (50/million);
Spinocellerebellar ataxias (40/million); and Pick’s
disease (20/million).
According to Nobel Laureate Dr. Stanley
Prusiner, the common characteristic of virtually all
neurodegenerative diseases is abnormal processing of
proteins in the brain. “Misprocessed proteins
often accumulate because the cellular mechanisms for
removing them are ineffective. The particular protein
that is improperly processed determines the malfunction
of distinct sets of neurons and thus the clinical manifestations
of the disease.”
All of the neurodegenerative diseases,
including CJD, occur sporadically or are genetically
inherited. However, CJD differs from the other neurodegenerative
diseases in one important respect: it also is transmissible.
Alzheimer’s disease background
Alzheimer’s disease is the most
common neurodegenerative disorder in the U.S. According
to the Alzheimer’s Association, an estimated 4.5
million Americans suffer from AD and, because increasing
age is the greatest risk factor, the number of AD victims
is expected to continue to increase as the population
ages. AD affects one out of every 10 people over age
65, and the risk of AD doubles every five years after
age 65. Nearly half of all 85-year-old individuals are
affected. In addition, rare, inherited forms of AD can
strike individuals who are in their 30s and 40s.
AD is the leading cause of dementia (conditions
that gradually destroy brain cells) in the elderly,
accounting for 50-75 percent of all cases of dementia.
In addition, according to the National Center for Health
Statistics, Alzheimer’s is the eighth leading
cause of death in the United States. An individual with
AD will live, on average, 7-10 years after the onset
of clinical symptoms but may live as long as 20 years.
Creutzfeldt-Jakob disease background
Another neurodegenerative disease (but
a very rare one) called Creutzfeldt-Jakob disease (CJD)
has received, perhaps, more public attention in recent
years than Alzheimer’s. CJD was first diagnosed
in the 1920s, tends to occur sporadically (with no known
cause), and affects approximately one in one million
people annually throughout the world. Like AD, increasing
age is a risk factor for CJD. The mean age at death
in the U.S. for CJD is 68 years, and incidence among
individuals aged 60 to 74 is about five cases per million
population annually. Cases have been recorded in patients
as young as 17 years and as old as 83 years. CJD is
invariably fatal with mean illness duration of five
months; death occurs within 12 months of illness in
80 percent of patients.
CJD has been thrust into public attention
because of a similar sounding, but separate and distinct,
disease called variant CJD (vCJD), first diagnosed in
the United Kingdom (UK) in 1996. Variant CJD has been
linked to consuming beef products contaminated with
central nervous system tissue from cattle infected with
Bovine Spongiform Encephalopathy (BSE, often called
mad cow disease). Because of the similarity of names,
there is substantial public confusion about CJD and
vCJD in terms of incidence and causes. Worldwide, there
have been (as of March 2005) a total of 166 cases of
vCJD with 93 percent of those occurring in the UK. The
United States has not had an indigenous case of variant
CJD. The only diagnosed case of vCJD in the U.S. was
a woman who had lived most of her life in the UK.
Disease mechanisms
Unfortunately, due to the difficulties
in studying diseases associated with the brain, the
disease processes for neurodegenerative diseases are
not yet fully understood. However, much is known about
the pathological effects of these diseases on the brain.
Alzheimer’s destroys the nerve cells
that process, store and retrieve information in the
brain. This nerve cell destruction is thought to be
the result of accumulation of amyloid plaques and neurofibrillary
tangles. Amyloid is a general term for protein fragments
that the body produces normally. In a healthy brain,
these protein fragments would be broken down and eliminated.
In AD patients, the fragments accumulate to form hard,
insoluble plaques. Neurofibrillary tangles are insoluble
twisted strands of a protein called tau protein that
form inside brain cells. Scientists do not yet know
whether the plaques or tangles cause AD or are a byproduct
of some other process.
CJD also destroys nerve cells in the brain.
However, while extensive amyloid plaque accumulation
is the prominent feature of Alzheimer’s, only
about 10% of CJD cases exhibit amyloid plaque. CJD is
characterized as a prion disease because it is caused
by an infectious protein particle known as a prion.
Prions are the only known pathogens that are devoid
of nucleic acid (prions contain no DNA or RNA). Unlike
Alzheimer’s disease, which is not transmissible,
CJD can be transmitted through exposure to the pathogenic
form of the prion protein molecule that causes it.
CJD causes cell death through accumulation of an abnormal
form of cellular prion protein. All mammals produce
normal cellular prion protein (PrP) in cells of the
central nervous system and other tissues. This normal
protein can change its shape into an abnormal, misfolded
form called a prion, which is pathogenic and can destroy
nerve cells. Scientists believe that when abnormal prion
protein comes in contact with normal prion protein,
the normal protein alters its structure to become like
the abnormal protein. The accumulation of abnormal PrP
in brain cells results in altered function and eventual
cell death or loss of cell function. Scientists do not
know what factors trigger this conversion. Some believe
the abnormal PrP itself causes the conversion, while
others believe a virus-like entity may be involved.
Symptoms
While there are some similarities in the
symptoms of AD and CJD, an experienced clinician usually
can distinguish between the diseases. Once AD begins,
it progresses relatively slowly. The first symptom may
be mild forgetfulness, which may include difficulty
remembering recent events, activities, the names of
familiar people or things and inability to solve simple
math problems. As the disease progresses, more serious
symptoms emerge such as difficulty in speaking, understanding,
reading, or writing. Later, people with AD may become
anxious or aggressive, or wander away from home. Late
in the disease, motor and sensory abnormalities and
gait disturbances may occur.
CJD symptoms typically consist of a rapidly
progressive dementia, visual abnormalities, or cerebellar
dysfunction including muscle incoordination and gait
and speech abnormalities. During the course of the disease,
most patients develop motor dysfunction with abnormal
reflexes, spasticity, tremors and rigidity; some patients
may also show behavioral changes with agitation, depression
or confusion. These symptoms often progress very rapidly,
and patients develop a state of akinetic mutism (inability
to talk or carry out purposeful behavior even though
the eyes are open) during the terminal stages of the
illness. Myoclonus (muscle contractions in the form
of "jerks" or twitches) is the most constant
physical sign and is present in more than 80 percent
of CJD patients.
Diagnosis
A definitive diagnosis of both AD and
CJD requires an autopsy and examination of brain tissue.
However, a trained clinician can diagnose either disease
with a high degree of accuracy. The Alzheimer’s
Association notes that diagnostic tools and criteria
make it possible for physicians to diagnose AD with
an accuracy of 90 percent. Diagnostic tools used by
physicians include tests of memory, problem solving,
attention, counting, and language; medical tests such
as tests of blood and urine; and brain scans.
In the case of CJD, certain diagnostic
tests are indicative of the disease. Specifically, periodic
short wave complexes on an EEG, certain signals on an
MRI and the presence of a protein called 14-3-3 in cerebrospinal
fluid are, in conjunction with the clinical picture,
considered to be diagnostic of CJD.
Dr. Richard Johnson, Eisenhower Professor
of Neurology and Neuroscience at Johns Hopkins University
School of Medicine, feels it is unlikely that CJD would
be misdiagnosed as Alzheimer’s disease. Dr. Johnson
has said that Johns Hopkins had reviewed all its case
files on Alzheimer’s and CJD and found no misdiagnoses.
Dr. Johnson said, “There has, in the entire program
here, never been a case of Creutzfeldt-Jakob disease
misdiagnosed. And I don't think it would be in most
institutions, certainly at the present day, where when
a patient has that rapid a course, has other movement
disorders that are routinely seen in Creutzfeldt-Jakob
disease, you're not going to call that Alzheimer's disease.
It's not going to be missed.”
Conclusion
In nearly all cases, the differences between
the clinical presentations of Alzheimer’s disease
and CJD will be sufficient to clearly distinguish these
two neurodegenerative diseases. Nevertheless, because
some early CJD symptoms may be similar to those of AD,
it is possible for some misdiagnoses to occur early
in the course of the disease. However, the incidence
of such misdiagnoses is likely to be very small and,
given the slow progression of AD versus the rapid progression
of CJD, most of those early misdiagnoses likely would
be quickly corrected.
References and further reading
Alzheimer’s Association. www.alz.org
Belay, ED, Maddox, RA, Gambetti, P. and
Schonberger, LB. Monitoring the occurrence of emerging
forms of Creutzfeldt-Jakob disease in the United States.
Neurology 60:176-181, 2003.
Cashman, NR. A prion primer. Can Med Assoc
J. 157(10): 1381-1385, 1997.
Creutzfeldt-Jakob Disease Foundation,
Inc. www.cjdfoundation.org.
Cummings, JL and Cole, G. Alzheimer Disease.
JAMA. 287(18): 2335-2338, 2002.
Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob
Disease in the United States: 1979-1998. JAMA 284: 2322-2323,
2000.
Johnson, R. Interview. National Public Radio Morning
Edition, January 13, 2004.
Johnson, RT and Gibbs, CJ, Jr. Creutzfeldt-Jakob
disease and related transmissible spongiform encephalopathies.
NEJM. 339(27): 1994-2004, 1998.
National Center for Health Statistics.
www.cdc.gov/nchs/fastats/lcod.htm.
National Institute on Aging/Alzheimer’s
Disease Education & Referral Center. www.alzheimers.org.
Prusiner, SB. Shattuck lecture –
neurodegenerative diseases and prions. NEJM. 344(20):
1516-1526, 2001.
Trevitt, CR and Singh, PN. Variant Creutzfeldt-Jakob
disease: pathology, epidemiology, and public health
implications. AJCN 78(suppl): 651S-666S, 2003.
Dr. Harriett Butchko is a physician
with postgraduate training in neurology and is a Principal
in the Foods and Chemicals Practice of Exponent, Inc.,
an international scientific consulting firm.
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