Corticobasal Degeneration (CBD) is a type of tauopathy (a general term for neurodegenerative diseases primarily caused by accumulation of tau protein) characterized by abnormal deposition of 4-repeat (4R) tau protein in different cell types and regions of the brain. It is a rare disease in which neuronal loss and atrophy progress in multiple brain regions, presenting a variety of clinical features including motor symptoms, cortical dysfunction, and eye movement abnormalities.
CBD was first reported by Rebeiz et al. in 1968. They described three patients with a progressive neurological disease characterized by impaired motor control and abnormal postures, naming it “corticodentatonigral degeneration with neuronal achromasia.” Pathologically, it was characterized by asymmetric neuronal loss in the frontoparietal lobes and substantia nigra. For about 20 years thereafter, the disease was rarely reported. Six similar cases were reported in 1985, and in 1989 Gibb et al. proposed the name “Corticobasal Degeneration (CBD).”
The typical age of onset for CBD is in the 50s to 70s. The youngest pathologically confirmed case was 45 years old. Some reports suggest a female predominance, while others report no sex difference, so no consensus has been reached. Most cases are sporadic, but rare familial cases have been reported. Due to significant phenotypic overlap with other neurological diseases, the true incidence and prevalence are unknown.
In a series of 21 CBD autopsy cases, the clinical phenotypes included progressive supranuclear palsy syndrome (PSPS) as the most common (10 cases), followed by corticobasal syndrome (CBS) in 4 cases, frontal behavioral-spatial syndrome (FBS) in 2 cases, nonfluent/agrammatic variant primary progressive aphasia (naPPA) in 1 case, and other types in 4 cases, demonstrating a variety of clinical presentations1).
Typical age of onset is in the 50s to 70s. The youngest pathologically confirmed case was 45 years old. Due to significant clinical overlap with other neurological diseases, the exact incidence is unknown.
In the early stages of CBD, patients often notice difficulty using one hand or leg and slowness of movement. Gait instability and a tendency to fall also appear. Cognitive decline or behavioral changes may precede motor symptoms. Visuospatial impairment (difficulty judging the position of objects) can be an initial symptom.
CBD presents with various combinations of motor and cortical symptoms.
Key Features
Limb rigidity: Unilateral predominant hypertonia. Poorly responsive to levodopa.
Bradykinesia: Slowness of movement and fine motor impairment. Characteristically asymmetric.
Postural instability: Increased risk of falls.
Limb apraxia: Inability to perform intended movements correctly.
Aphasia: Reduced fluency of speech and grammatical impairment.
Relatively rare features
Myoclonus: Sudden muscle contractions.
Limb dystonia: Fixed abnormal postures.
Alien hand sign: Involuntary movements of the hand against the patient’s will.
Cortical sensory loss: Impaired touch and position sense.
Pyramidal tract signs: Upper motor neuron signs such as hyperreflexia.
Ophthalmic signs are not essential for the diagnosis of CBD but are often present.
In one case of pathologically confirmed CBD, vertical saccade limitation and horizontal saccade slowing have been reported3).
In CBD, ocular signs such as gaze apraxia, vertical supranuclear gaze palsy, apraxia of eyelid opening, and visuospatial cognitive impairment may be observed. Although these are not essential for diagnosis, it is important for ophthalmologists to recognize CBD for early detection.
The exact cause of CBD is unknown, but increased phosphorylation of tau protein and impaired vesicle transport are suggested to be involved.
Several susceptibility loci associated with the risk of developing CBD have been identified.
Genome-wide association studies (GWAS) have identified 17 variants in 14 genes common to CBD, PSP, and frontotemporal dementia (FTD), highlighting genetic pleiotropy 2). Combinations of these variants may determine disease-specific patterns of brain vulnerability.
Currently, the only known risk factor is aging. There is no evidence that environmental factors cause CBD, but geographic mapping of tauopathies suggests that specific environments may contribute to disease onset.
A definitive diagnosis of CBD is only possible through postmortem pathological examination. Antemortem diagnosis is difficult, and the misdiagnosis rate is high.
The Armstrong criteria (2013) define the following four clinical phenotypes:
Among cases presenting with CBS phenotype, less than 50% are due to CBD. It has been reported that approximately 42% of pathologically confirmed CBD cases were clinically diagnosed as PSP during life3).
| Imaging modality | Key findings |
|---|---|
| MRI | Asymmetric frontoparietal atrophy |
| FDG-PET | Frontoparietal hypometabolism |
| Tau PET | Visualization of tau accumulation |
On MRI, focal atrophy in the premotor cortex suggests CBD or PSP, while a pattern of widespread atrophy suggests Alzheimer’s disease (AD) or FTLD. Tau PET (e.g., [18F]flortaucipir) is useful for visualizing tau accumulation in the brain, but uptake is variable and not seen in all cases. Tau PET with Florzolotau (18F) has been reported to be useful for estimating 4R tauopathy 6).
Because CBD has a highly diverse clinical spectrum, differentiation from the following diseases is important.
Currently, a definitive diagnosis of CBD is only possible through postmortem pathological examination. During life, clinical diagnosis based on imaging tests such as MRI and tau PET, along with clinical criteria, is performed, but it is known to have a high misdiagnosis rate.
Currently, there is no disease-modifying therapy (curative treatment) for CBD. Management focuses on symptomatic and supportive care.
The following rehabilitation should be initiated from the time of diagnosis.
Currently, there is no fundamental treatment for CBD. The effects of symptomatic therapies including levodopa are limited, and supportive therapies such as physical therapy, occupational therapy, and speech therapy are the mainstay of management. Clinical trials of tau-targeted therapies are ongoing, and future progress is expected.
The prognosis of CBD is poor. The disease duration is typically 6–7 years, with a range of 2–12.5 years reported. Patients with concurrent dementia have shorter survival. The most common causes of death are sepsis and aspiration pneumonia.
Dysfunction of tau protein plays a major role in the development of CBD. The H1 haplotype of the MAPT gene, particularly the H1c subhaplotype, produces dysfunctional 4R tau or increases the expression level of 4R tau. Post-translational modifications of 4R tau, especially hyperphosphorylation, are thought to cause neurodegeneration.
Hyperphosphorylated 4R tau forms tau filaments and deposits in various cell types such as neurons, microglia, and astroglia. Stronger microglial activation correlates with a definitive diagnosis of CBD, but a direct causal relationship between microglial activation and neurodegeneration has not been established.
The spread of pathological tau in the brain involves a mechanism called “tau seeding.” Pathological tau species incorporate normal tau, leading to the formation of tau aggregates. Aggregated tau is released and taken up by other cells, inducing new aggregation, a “prion-like” cell-to-cell propagation. There is a hypothesis that tau accumulation in astrocytes precedes that in neurons.
Mimuro et al. (2024) examined 21 autopsy-confirmed CBD brains and found argyrophilic grains and neurofibrillary tangles (NFT) in all cases. β-amyloid deposition was present in 71.4%, Lewy body pathology in 14.3%, and LATE (limbic-predominant age-related TDP-43 encephalopathy) in 23.8% 1). CBD brains may share similar cellular vulnerability with age-related multiple proteinopathies.
Both CBD and PSP are 4R tauopathies, but they can be distinguished pathologically. CBD is characterized by astrocytic plaques, whereas PSP is specific for tufted astrocytes.
Zhao et al. (2022) used digital pathology image analysis to quantify subcortical tau burden and showed that the tau pallido-claustral ratio (tau-PC ratio) with a cutoff of 1.5 can differentiate PSP from CBD with high accuracy 5). In CBD, tau accumulates heavily in both the globus pallidus and claustrum, whereas in PSP, tau accumulation predominates along the globus pallidus-substantia nigra-subthalamic nucleus axis.
Clinical trials of potential tau-lowering therapies are ongoing. These treatments are expected to be applied to CBD and at least slow disease progression. However, improving the accuracy of antemortem diagnosis of CBD and optimizing the timing of treatment initiation are prerequisites for practical use.
Nakamura et al. (2023) reported that in CBS cases, tau PET with Florzolotau (18F) showed marked ligand uptake in the brainstem, subthalamic nucleus, basal ganglia, and bilateral frontal subcortical areas, and was useful for presuming 4R tauopathy as the underlying pathology 6). Tau PET may contribute to improving the accuracy of antemortem diagnosis.
Zhao et al. (2022) proposed an automated tau quantification protocol using QuPath software and showed that differentiation between PSP and CBD is possible even from limited brain sampling 5). A coronal section at the level of the subthalamic nucleus is useful as a “core” slice.
Rini et al. (2021) reported cases showing pathological features of both CBD and PSP, and identified multiple pleiotropic risk variants by whole-genome analysis 2). In the future, a weighted genetic risk score (GRS) of known variants may be applied to screen clinically challenging cases.
Yoo et al. (2021) reported an autopsy-confirmed case in which CBD became apparent after a pontine infarction 4). Based on the cortico-basal ganglia-cerebellar connectome model, they suggested that the acute infarction may have clinically unmasked a latent abnormal network of CBD. Atypical parkinsonism appearing after stroke should include latent CBD in the differential diagnosis.
