July 11, 2022
Years published: 1994, 1997, 2000, 2002, 2012, 2022
NORD gratefully acknowledges Abigail Feda and Meghan Schmitt, NORD Editorial Interns from the University of Notre Dame, Joseph Farris, PhD, Professor of Biology, Saginaw Valley State University, and Jee Bang, MD, Assistant Professor of Neurology, Assistant Professor of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Division of Movement Disorders, Clinical Director, Johns Hopkins Huntington Disease Center, Co-Director, Movement Disorders Fellowship Program,
Co-Principal Investigator, LBDA Research Center of Excellence, for assistance in the preparation of this report.
Corticobasal degeneration (CBD) is a rare progressive neurological disorder characterized by cell loss and deterioration of specific areas of the brain. Affected individuals often experience movement disorders initially in one limb that might spread to both the arms and legs. Symptoms include muscle rigidity and the inability to perform purposeful or voluntary movements (apraxia). Affected individuals may have sufficient muscle power for manual tasks but struggle to direct their movements appropriately. Although CBD was historically described as a motor disease, it is now recognized that cognitive and behavioral symptoms are also associated with CBD and often come before the motor symptoms. Initial signs typically appear in people ages 60-70, and may include language difficulties, poor coordination and issues with memory. The exact cause of CBD is unknown; however, it may be linked to the accumulation of the tau protein in the brain.
Because signs and symptoms associated with CBD are frequently caused by other neurodegenerative disorders, researchers use the term “corticobasal syndrome” to indicate the clinical diagnosis. “Corticobasal degeneration” is diagnosed after a patient dies and an autopsy reveals the necessary criteria of brain pathway abnormalities specific to CBD. This is an important distinction because less than half (35-50%) of patients presenting with symptoms of of corticobasal syndrome during life have CBD at autopsy.
The symptoms, progression, severity and presentation of CBD can vary greatly from one person to another. It is important to note that affected individuals may not have all of the symptoms discussed below. Patients should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
In many patients, the first sign of CBD is trouble with movement of the limbs. The muscles of affected individuals may stiffen or shake, primarily in the limbs (progressive extrapyramidal muscle rigidity). Individuals are often unable to make voluntary, purposeful movements with the affected limb (apraxia). Affected individuals have sufficient muscle power for manual tasks but have difficulty directing their movements appropriately. Difficulties with the affected limb can worsen over time. People with CBD may first become aware of the disorder when they have difficulty coordinating movements in the performance of manual tasks such as buttoning a shirt, combing their hair or gesturing with their hands. Affected individuals often describe their actions as stiff, clumsy or uncoordinated. Some patients may be unaware of the movement or unable to control the movement of a limb (alien limb syndrome). Some individuals may experience a loss of discriminative sensation in one or two areas of the body. Symptoms typically begin on one side of the body (unilateral) but usually progress over time to affect both sides and all four limbs. Arms are usually affected before the legs, but in rare cases, legs may show symptoms first.
Additional symptoms of CBD may include shaking while in particular positions (postural tremor) or while performing a task (action tremor) and/or exaggerated slowness of movements (bradykinesia) or lack of movement (akinesia). The combination of movement abnormalities including limb rigidity, rest tremor and bradykinesia/akinesia. is known as parkinsonism. Sudden, brief involuntary muscle spasms causing jerky movements (myoclonus) may also occur. In some patients, involuntary muscle contractions can force certain part(s) of the body into abnormal, sometimes painful movements and positions (dystonia). Affected individuals often experience focal dystonia, where only one area such as the leg, neck or arm, has involuntary muscle spasms. Affected individuals may also develop contractures, a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. Oftentimes balance is affected as well (postural instability). For example, affected individuals may have trouble resuming walking when slightly unstabilized.
CBD may also cause speech and language abnormalities including difficulties understanding or expressing language (aphasia), difficulty saying what they want to say despite knowing the right words (apraxia of speech) and speech difficulties due to problems with the muscles that enable speech (dysarthria). Additional symptoms that may occur include difficulty swallowing (dysphagia), an inability to control eyelid blinking and/or an uncoordinated walk (ataxic gait). Eventually, affected individuals may be unable to walk without assistance.
Individuals with CBD can develop a more global loss of intellectual abilities (dementia), usually later in the course of the disease. Affected individuals may also exhibit memory loss, impulsiveness, disinhibition, apathy, irritability, reduced attention span and obsessive-compulsive behaviors. In some patients, the signs and symptoms of dementia may even precede the development of motor symptoms. Initial cognitive symptoms include a non-fluent, progressive aphasia and impairments in executive function.
For many years, CBD was thought to be a neurological condition primarily associated with movement disorders. In recent years, researchers have noted that cognitive and behavioral abnormalities occur more frequently than initially believed. As CBD progresses, affected individuals may become unable to communicate effectively. Eventually, affected individuals may become bedridden and susceptible to life-threatening complications such as pneumonia, bacterial infections, blood infection (sepsis) or blockage of one or more of the main arteries of the lungs, usually due to blood clots (pulmonary embolism).
The exact, underlying cause of CBD is unknown. Researchers believe that multiple different factors contribute to the development of the disorder, such as environmental changes and aging.
The symptoms of CBD develop due to the progressive deterioration of brain tissue. Nerve cell loss occurs in specific areas, leading to atrophy or shrinkage in specific lobes of the brain. The severity and type of symptoms depend on the area of the brain affected by the disease. The cerebral cortex and basal ganglia are the two areas most typically affected, although other parts of the brain may become involved. The cerebral cortex is the outer layer of nerve tissue surrounding the brain (cerebral hemispheres) called the grey matter. The cerebral cortex is involved with higher brain functions including voluntary movement, memory, learning and coordination of sensory information. The basal ganglia is a cluster of nerve cells involved with motor and learning functions.
Researchers have determined that a protein called tau plays a role in the development of CBD. Tau is a specific type of protein normally found in brain cells. The function of tau within nerve cells is complex and not fully understood, although it is believed to be associated with healthy brain function as it contributes to transportation of nutrients (microtubule stability). In CBD, abnormal levels of tau accumulate in certain brain cells, eventually causing their deterioration. These tau proteins are also hyperphosphorylated, meaning that extra phosphate groups are attached to the protein, which destabilizes nutrient transportation.
The exact role that tau plays in the development of CBD is not fully understood, and abnormalities involving tau are also seen in other neurodegenerative brain disorders including Alzheimer’s disease, progressive supranuclear palsy, Niemann-Pick disease type C and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). These disorders collectively are referred to as “tauopathies.”
Because CBD occurs randomly, it is considered to be a non-inherited illness. However, a genetic basis may exist given that there are rare familial cases. Some research has found links between CBD and a tau gene variant. Researchers have discovered that the H1 haplotype of MAPT, a tau gene, is present in people with CBD at a higher frequency than in controls. However, not all CBD patients have the tau gene variant, and not all people with the gene variant develop CBD.
CBD typically occurs in older populations. No confirmed cases of CBD have been reported in individuals under 40. People between the ages of 50-70 are susceptible, with the average age of CBD onset being 64. Some studies have suggested the disease is slightly more prevalent among women. The disorder is estimated to affect 5 people per 100,000 in the general population, with approximately 1 new case per year per 100,000 people. CBD also represents 4–6% of patients with parkinsonism. However, cases may go undiagnosed or misdiagnosed making it difficult to determine the true frequency of CBD in the general population.
The definitive diagnosis for CBD can only be confirmed after a patient’s death during autopsy. However, CBD is suspected if characteristic neurologic symptoms occur in a slowly progressive course in the absence of a stroke, tumor or other structural lesion. Distinguishing CBD from other, similar neurodegenerative disorders is difficult, so patients with similar signs and symptoms are diagnosed with “corticobasal syndrome” (as opposed to the definitive diagnosis of “corticobasal degeneration”) during clinical care. One of the most common misdiagnoses of CBD is progressive supranuclear palsy (PSP). During autopsy, PSP and CBD can be differentiated by the location of accumulated tau proteins. In general, CBD mostly affects in the white matter and cortical regions while PSP shows more effects in the deep grey matter regions. There are no specific tests for a diagnosis of CBD, but researchers are currently looking to see if positron emission photography (PET scans) or single-photon emission computerized tomography (SPECT scans) can uncover changes related to the disorder. A clinical diagnosis is made based upon a thorough neurological exam involving a variety of specialized tests.
Clinical Testing and Work-Up
Imaging techniques such as computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to rule out other conditions or reveal brain tissue degeneration within the cerebral cortex and basal ganglia. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures including the brain. An MRI uses magnetic field pulses to produce cross-sectional images of organs and bodily tissues such as the brain.
While there is no specific treatment for slowing the progression of CBD, there are treatments available for managing symptoms. Specific symptoms are dependent on the individual, but most cases prove resistant to such therapy.
Affected individuals may be treated with certain drugs for movement symptoms such as levodopa and similar medications that are normally used to treat Parkinson’s disease. These drugs are generally ineffective but may help with the slowness or stiffness some individuals experience. Muscle spasms (myoclonus) may be controlled with medications such as clonazepam, however, benzodiazepines should be used sparingly as they may have undesired side effects in these patients. Botulinum toxin (Botox) has been used to treat contractures and pain but does not restore the ability to control movements. Baclofen is another drug that may be used to treat muscle rigidity. Medications called cholinesterase inhibitors may be prescribed to manage memory problems and other symptoms. These include medications such as donepezil, rivastigmine and galantamine.
Physical therapy may be beneficial in maintaining the mobility and range of motion of stiffened, rigid joints and prevent muscle tightening (contractures). Occupational therapy is beneficial in assessing the safety of an affected individual’s home and in determining what adaptive medical equipment may increase a person’s independence. Speech therapy may be beneficial in treating individuals whose speech and language abnormalities are associated with CBD. Affected individuals may need devices such as a cane or walker to assist in walking.
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