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(CBD), also known as corticobasal ganglionic degeneration (CBGD), was
first described in the late 1960s by Drs. Rebeiz, Kolodny, and Richardson.
Following a lengthy period with no additional reports, several more patients
were identified and their symptoms and autopsy findings were described
in the 1980s and 1990s. Patients typically have symptoms reflecting
dysfunction in the cerebral cortex (thus the term cortical
or cortico-) and basal ganglia (thus the terms basal
or basal ganglionic), and symptoms are usually worse on one
side of the body. Specifically, cortical dysfunction is manifested as
poor coordination of the arms or legs (apraxia), tendency for the arm
to act as if it has a mind of its own (alien limb phenomenon),
numbness or odd sensations (cortical sensory loss), poor comprehension
and/or expression of language (aphasia), and quick jerks (myoclonus).
Slowness of movement (bradykinesia), stiffness in a limb (rigidity), fixed
muscle contractions such as when the fingers curl into a fist (dystonia),
and tremor are presumed to reflect basal ganglia dysfunction. Some patients
develop memory impairment and/or personality/behavioral changes. Problems
with walking eventually occur in almost all. In our studies the duration
of illness from onset of symptoms to death has ranged from 3-13 years.
The vast majority of patients do not appear to have any family history
of dementia or parkinsonism, although there are rare cases in whom a hereditary
process may be at play. The cause of CBD is not yet known.
This illness is frustrating
to patients, their families, and the physicians who care for them. Since
insight and memory tends to be preserved throughout most of their illness,
depression is common and should be treated when it evolves. Physical,
occupational, and speech therapy can be helpful although as the illness
progresses third party payers tend to not reimburse for these services,
unfortunately. Medications provide little benefit, but agents such as
Sinemet are worth trying. All sleep disorders such as sleep apnea and
restless legs syndrome should be evaluated and treated as improvement
in quality of life for patients and their loved ones can occur.
I realize I have
not painted a pleasant picture to those suffering from this illness and
their loved ones, but I must be honest in what research thus far has taught
us. The frustration over misdiagnosis is problematic for patients and
families as many are diagnosed with Parkinsons disease or a stroke.
Misdiagnosis for clinicians and researchers adds to the confusion regarding
CBD, as our research has recently shown that only half of those diagnosed
in life with CBD are actually found to have CBD when brain tissue is examined
after death (by autopsy). Other disorders that can appear identical to
CBD during life (also known as CBD mimickers) include Alzheimers
disease (AD), Picks disease, progressive supranuclear palsy (PSP),
nonspecific degenerative changes, and rarely Creutzfeldt-Jakob disease.
Thus a definitive diagnosis of CBD requires examination of tissue after
death. The high misdiagnosis rate makes research on patients suffering
from presumed CBD during life difficult to interpret.
However, recent research is shedding light on CBD. When brain tissue is
prepared appropriately and examined by an experienced neuropathologist,
the prominent abnormalities in a protein called tau as well
as other findings helps establish the diagnosis of CBD. The functions
of tau in nerve cells are complex and not fully understood, but it is
clear that tau is required to bind to structures called microtubules for
normal functioning to occur in brain cells (neurons). When something goes
wrong in tau functioning, neurons eventually die. As more neurons die,
symptoms progressively worsen, and usually focal atrophy in the brain
becomes apparent on a CT scan or MRI scan. SPECT and PET scans can show
abnormalities when CT and MRI scans are rather normal.
Therefore, abnormalities in tau protein are now thought to be the critical
factor in the pathogenesis of CBD. Interestingly, tau dysfunction also
is critical in the pathogenesis of Alzheimers disease, Picks
disease, and progressive supranuclear palsy. It is highly possible that
a treatment for one of these disorders involving tau processing will be
beneficial for some or all of the others (although treatments for Alzheimers
disease that influence amyloid, which is an abnormal protein in Alzheimers
disease but not CBD, Picks disease, or PSP, may not be effective
for the non-Alzheimers disorders).
How will a disease-altering or preventative treatment for CBD be developed?
Lets consider what has already occurred in Alzheimer disease, where
the identification of genes has led to major breakthroughs in our understanding
of the pathogenesis of AD. Approximately 5-10% of patients with AD have
a hereditary form in which roughly half of the members of each generation
of a family develop AD. Three such genes have been identified through
1999 (and there are several more not yet identified). Mutations in which
a single error in the DNA has occurred in these different genes all act
to increase levels of a form of amyloid in the brain, which form structures
known as amyloid or neuritic plaques. It is believed that these plaques
somehow cause neurons to die and neurofibrillary tangles to develop (neurofibrillary
tangles consist of abnormal tau, but this abnormal form of tau is different
from that in CBD). Scientists have placed these genes into mice so that
they develop amyloid plaques and thus they appear to develop Alzheimer-type
changes. Developing strains of mice with abnormal human genes offers great
opportunities to test various medicines to see if any prevent or delay
the development of disease. This line of research has already led to one
major discovery in AD (the vaccine against amyloid) and many more discoveries
are likely to follow.
A similar approach
is being applied to tau-related disorders. There are members of several
families around the world who have developed what is called frontotemporal
dementia and parkinsonism or FTDP, in which abnormal tau is found
in the brain tissue of those who have granted permission for autopsy.
The findings are quite similar to CBD. Scientists from various institutions
around the world pooled their efforts and identified several mutations
in the tau gene that cause this illness (as of early 2000, there is no
genetic test available for clinical use, but this may become available
in the future). Clearly, there are other genetic and probably environmental
factors involved in the pathogenesis of CBD, but strains of mice carrying
the abnormal tau gene are being developed, and research with a variety
of medicines will begin soon. Most researchers are quite optimistic that
preventative and/or disease-altering medicines will be developed, but
when this will occur, what side-effects will be present with treatment,
and how costly treatment will be, are not yet known.
This is where patients and their families can contribute to CBD research.
Talk to your local physicians to help identify a nearby institution where
research on CBD, Alzheimers disease, Parkinsons disease, etc.,
is/are being conducted, and consider participating in research. If you
cant find anyone or any institution nearby, keep searching. It is
clear that research involving biologic tissue such as blood
samples, cerebrospinal fluid samples, autopsied brain tissue, all have
enormous potential for advancing knowledge in this area. Considering whether
to grant permission for eventual autopsy is not a pleasant issue to ponder,
but this is one of the most important aspects of research in CBD and other
disorders. Tell your legislators your thoughts on continuing adequate
funding for neurodegenerative disorders research. Get involved in your
local Alzheimers Association chapter-the staffs at the national
and local offices of the Alzheimers Association are dedicated individuals
who want to help. Let others know what has and has not worked in your
journey with this illness. And maintain emotional and spiritual support
for all those affected by CBD.
I strongly commend all those individuals have supported the Rare Dementia
Registry and provided their words of wisdom in this monograph. Personally,
Id like to thank Alan McIlvaine, Theresa Roberts, and Darcy Croissant
for their assistance to me and my colleagues who are actively involved
in research on CBD (Im sure my friend and colleague Dr. Caselli
shares these thanks), as well as for their perseverance in the fight against
this illness. Do not underestimate what impact highly motivated individuals
can make in the fight against any illnessthis superb monograph exemplifies
what can be developed by dedicated and caring individuals.
Please realize that many gifted scientists from around the world are devoted
to finding the cause of and cure for corticobasal degeneration. Through
the Rare Dementia Registry we will keep you abreast of significant advances
in CBD research.
Thanks to all who
strive to optimize quality of life for those confronting this illness.
Brad Boeve, MD
Thanks to Dr. Boeve for the foregoing information.