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Update on CBGD
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Corticobasal degeneration (CBD), also known as corticobasal ganglionic degeneration (CBGD), was first described in the late 1960’s 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 1980’s and 1990’s. 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 Parkinson’s 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 Alzheimer’s disease (AD), Pick’s 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 Alzheimer’s disease, Pick’s 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 Alzheimer’s disease that influence amyloid, which is an abnormal protein in Alzheimer’s disease but not CBD, Pick’s disease, or PSP, may not be effective for the non-Alzheimer’s disorders).
How will a disease-altering or preventative treatment for CBD be developed? Let’s 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, Alzheimer’s disease, Parkinson’s disease, etc., is/are being conducted, and consider participating in research. If you can’t 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 Alzheimer’s Association chapter-the staffs at the national and local offices of the Alzheimer’s 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, I’d 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 (I’m 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 illness—this 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.