Corticobasal degeneration (CBD) is a rare neurodegenerative disease involving the cerebral cortex and the basal ganglia. CBD symptoms typically begin in people from 50 to 70 years of age, and typical survival before death is eight years. It is characterized by marked disorders in movement and cognition, and is classified as one of the Parkinson plus syndromes. Diagnosis is difficult, as symptoms are often similar to those of other disorders, such as Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and a definitive diagnosis of CBD can only be made upon neuropathologic examination.
Signs and symptoms Because CBD is progressive, a standard set of diagnostic criteria can be used, which is centred on the disease's evolution. Included in these fundamental features are problems with cortical processing, dysfunction of the basal ganglia, and a sudden and detrimental onset. Psychiatric and cognitive dysfunctions, although present in CBD, are much less prevalent and lack establishment as common indicators of the presence of the disease.
Although corticobasal degeneration has a plethora of symptoms, some are more prevalent than others. In a study of 147 patients with CBD, it was found that all of them had at least one Parkinsonian sign, 95% having two and 93% had some higher order dysfunction (cognitive impairments like acalculia, sensory loss, dementia, neglect, etc.). In a separate study of 14 patients recorded three years after the onset of symptoms, many patients had high numbers of motor symptoms: 71% had bradykinesia (slow movements), 64% showed apraxia, 43% reported limb dystonia, and although more cognitive 36% had dementia. In another study of 36, over half had a useless/alien arm and 27% had a gait impediment. From this, it can be seen why CBD is hard to diagnose. Even if it can be distinguished as different from one of the other similar diseases, the varying combinations of symptoms create a difficult path to diagnosis.
Motor and associated cortical dysfunctions Some of the most prevalent symptom types in people exhibiting CBD pertain to identifiable movement disorders and problems with cortical processing. These symptoms are initial indicators of the presence of the disease. Each of the associated movement complications typically appears asymmetrically and the symptoms are not observed uniformly throughout the body. For example, a person exhibiting an alien hand syndrome (explained later) in one hand, will not correspondingly display the same symptom in the other hand. Predominant movement disorders and cortical dysfunctions associated with CBD include:
Parkinsonism Alien hand syndrome Apraxia (ideomotor apraxia and limb-kinetic apraxia) Aphasia
Parkinsonism The presence of parkinsonism as a clinical symptom of CBD is largely responsible for complications in developing unique diagnostic criteria for the disease. Other such diseases in which parkinsonism forms an integral diagnostic characteristic are Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Parkinsonism in CBD is largely present in an extremity such as the arm, and is always asymmetric. It has been suggested that the non-dominant arm is involved more often. Common associated movement dysfunctions that comprise parkinsonism are rigidity, bradykinesia, and gait disorder, with limb rigidity forming the most typical manifestation of parkinsonism in CBD. Despite being relatively indistinct, this rigidity can lead to disturbances in gait and correlated movements. Bradykinesia in CBD occurs when there is notable slowing in the completion of certain movements in the limbs. In an associated study, it was determined that, three years following first diagnosis, 71% of persons with CBD demonstrate the presence of bradykinesia.
Alien hand syndrome Alien hand syndrome has been shown to be prevalent in roughly 60% of people diagnosed with CBD. This disorder involves the failure of an individual to control the movements of their hand, which results from the sensation that the limb is "foreign". The movements of the alien limb are a reaction to external stimuli and do not occur sporadically or without stimulation. The presence of an alien limb has a distinct appearance in CBD, in which the diagnosed individual may have a "tactile mitgehen". This mitgehen (German, meaning "to go with") is relatively specific to CBD, and involves the active following of an experimenter's hand by the subject's hand when both hands are in direct contact. Another, rarer form of alien hand syndrome has been noted in CBD, in which an individual's hand displays an avoidance response to external stimuli. Additionally, sensory impairment, revealed through limb numbness or the sensation of prickling, may also concurrently arise with alien hand syndrome, as both symptoms are indicative of cortical dysfunction. Like most of the movement disorders, alien hand syndrome also presents asymmetrically in those diagnosed with CBD.
Apraxia Ideomotor apraxia (IMA), although clearly present in CBD, often manifests atypically due to the additional presence of bradykinesia and rigidity in those individuals exhibiting the disorders. The IMA symptom in CBD is characterized by the inability to repeat or mimic particular movements (whether significant or random) both with or without the implementation of objects. This form of IMA is present in the hands and arms, while IMA in the lower extremities may cause problems with walking. Those with CBD that exhibit IMA may appear to have trouble initiating walking, as the foot may appear to be fixed to floor. This can cause stumbling and difficulties in maintaining balance. IMA is associated with deterioration in the premotor cortex, parietal association areas, connecting white matter tracts, thalamus, and basal ganglia. Some individuals with CBD exhibit limb-kinetic apraxia, which involves dysfunction of finer motor movements often performed by the hands and fingers.
Aphasia One or more of the following problems occurs in approximately half of the people with CBD. The symptoms are usually progressive, and can result in a complete loss of the ability to communicate. The presence or absence of these symptoms can help a neurologist make a more accurate diagnosis. Aphasia can be accompanied by dysarthria, Apraxia of speech, and cognitive problems. Aphasia is defined as difficulty with: speaking, understanding language, reading, and writing.
Aphasia can result in difficulty understanding more complex sentences, difficulty understanding articles or books, being unable to say specific words, using non-words and not recognizing it, long pauses trying to speak, abandoning speaking attempts, and difficulty spelling. Dysarthria is defined as weakness of the muscles associated with speaking including the mouth, throat, and breathing muscles. This results in slurred speech, speech that is too slow or too fast, and distorted or missing sounds in words. Apraxia of speech is defined as a disruption in the brain's ability to plan the movements needed to say words, resulting in difficulty initiating speech, errors in the sounds themselves, and errors sequencing the sounds or syllables in words. Apraxia causes long pauses trying to start speaking, an inability to start a word, oral groping, and mixed up sounds in words. Cognitive problems include but are not limited to memory loss, difficulty organizing thoughts, impulsivity, difficulty doing calculations, or difficulty planning, prioritizing, or self monitoring.
Another related problem is swallowing difficulty, called dysphagia. Dysphagia is diagnosed by x-ray or endoscopy of the throat while swallowing. Swallowing problems can progressively worsen, which compromises nutrition, hydration, and pulmonary health. Dysphagia can cause aspiration pneumonia, which is the leading cause of death in people with Parkinson's and PD+Plus disorders doi:10.1038/s41598-021-86011-w. Treatment for these problems can be addressed in speech and language therapy by a speech-language pathologist.
Psychiatric and cognitive disorders Psychiatric problems associated with CBD often present as a result of the debilitating symptoms of the disease. Prominent psychiatric and cognitive conditions cited in individuals with CBD include dementia, depression, and irritability, with dementia forming a key feature that sometimes leads to the misdiagnosis of CBD as another cognitive disorder such as Alzheimer's disease (AD). Frontotemporal dementia can be an early feature.
Molecular features Neuropathological findings associated with CBD include the presence of astrocytic abnormalities within the brain and improper accumulation of the protein tau (referred to as tauopathy).
Astroglial inclusions Postmortem histological examination of the brains of individuals diagnosed with CBD reveal unique characteristics involving the astrocytes in localized regions. The typical procedure used in the identification of these astroglial inclusions is the Gallyas-Braak staining method. This process involves exposing tissue samples to a silver staining material which marks for abnormalities in the tau protein and astroglial inclusions. Astroglial inclusions in CBD are identified as astrocytic plaques, which present as annular displays of blurry outgrowths from the astrocyte. A recent study indicated that produces a high density of astrocytic plaques in the anterior portion of the frontal lobe and in the premotor area of the cerebral cortex.
Tauopathy The protein tau is an important microtubule-associated protein (MAP), and is typically found in neuronal axons. However, malfunctioning of the development of the protein can result in unnatural, high-level expression in astrocytes and glial cells. As a consequence, this is often responsible for the astrocytic plaques prominently noted in histological CBD examinations. Although they are understood to play a significant role in neurodegenerative diseases such as CBD, their precise effect remains a mystery.
In recent years corticobasal degeneration has come to be understood as a tauopathy. This is believed due to the most common indicator of CBD being a faulty tau protein. Tau proteins are integral in keeping microtubules stable; defective cells create four microtubule-binding repeats with increased affinity in binding with microtubules. Because of this increased affinity, they form insoluble fibers (also called "paired helical filaments"). Microtubules themselves keep the cell and cytoskeletal structure stable. Thus, when tau proteins create unnatural configurations, microtubules become unstable, which eventually leads to cell death.
Diagnosis New diagnostic criteria known as the Armstrong criteria were proposed in 2013, although the accuracy of these is limited and further research is needed.
Recent findings in clinicopathology have made it possible to distinguish CBD from Parkinson's and increase the accuracy of diagnosis, using developments in MRI and nuclear medicine.
Criteria Insidious onset and gradual progression Lasts 1 year or more Meets one of the four subtypes: Possible CBS FBS or NAV PSPS plus at least one CBS feature other than limb rigidity or akinesia No Exclusion criteria present More likely if onset is after age 50 More likely if no family history (2 or more relatives) More likely if no genetic mutation affecting T (e.g., MAPT)
Possible corticobasal syndrome subtype Symptoms may be symmetric or asymmetric.
One or more of: limb rigidity or akinesia limb dystonia limb myoclonus, plus one of: orobuccal or limb apraxia cortical sensory deficit alien limb phenomena (more than simple levitation) More likely (probable sporadic CBS) if: Asymmetric presentation Onset after age 50 No family history (2 or more relatives) No genetic mutation affecting T (e.g. MAPT) plus two of: limb rigidity or akinesia limb dystonia limb myoclonus plus two of: