Corticobasal Degeneration

Etiology

CBD is primarily considered an idiopathic or sporadic neurodegenerative disorder, with familial cases being exceedingly rare.[2][5] Given the diagnostic difficulty, little is known about the disorder’s risk factors. The only well-established risk factor for CBD is advanced age.[2] No evidence links environmental exposures to toxic or infectious agents in its pathogenesis. At its core, CBD is driven by the pathological accumulation of hyperphosphorylated 4R tau protein, which disrupts microtubule stability, leading to neurodegeneration. Affected regions include the cerebral cortex and basal ganglia, correlating with the disease's hallmark motor and cognitive symptoms. This tau accumulation results in characteristic pathological findings such as astrocytic plaques, oligodendrocytic coiled bodies, and neurofibrillary tangles.

Genetic Basis

Mutations in the microtubule-associated protein tau (MAPT) gene are central to the pathogenesis of CBD due to their role in disrupting membrane-associated 4R tau function.[6] The extended MAPT tau haplotype (H1) and homozygosity for H1/H1 significantly increase in pathologically confirmed CBD cases, similar to progressive supranuclear palsy (PSP).[7] The MAPT H1c allele, a regulatory region likely enhancing 4R tau transcript production, is particularly prevalent in CBD and PSP.[8][9] In contrast, the H2 haplotype appears protective against CBD.[10] Results from genome-wide association studies have reinforced the associations at the MAPT locus between CBD and PSP.[8] Certain MAPT mutations—such as those in exon 10, intron 10, and exon 13—can mimic the clinical and pathological features of corticobasal syndrome and CBD.[11][12]

A genome-wide association study involving pathologically confirmed CBD also identified associations at single nucleotide polymorphisms in non-MAPT loci, including chromosome 17q21 (MAPT expression), chromosome 8p12 (lnc-KIF13B-1, a long noncoding ribonucleic acid), and chromosome 2p22 (SOS1). Notably, the study's results revealed a shared genetic risk at 3p22 involving myelin-associated oligodendrocyte basic protein (MOBP), highlighting its potential pathogenic significance given the oligodendrocyte and white matter involvement in tauopathies like CBD and PSP.[8] Further research confirmed overlapping genetic risk factors between CBD and PSP at other non-MAPT loci, including MOBP, NSF (linked to the H1 haplotype), epidermal growth factor receptor, glycine dehydrogenase, and CXC motif chemokine receptor 4. Additionally, the genetic overlap between CBD and frontotemporal dementia appears predominantly localized to the MAPT locus.[13]

Evidence of broader genetic pleiotropy has also emerged, linking CBD to immune-mediated diseases such as celiac disease, suggesting immune dysfunction may play a role in its pathogenesis.[14] Exome sequencing of 2 familial CBD cases identified mutations in Mg²⁺ transporter (MRS2) and zinc-finger and homeodomain protein 2 (ZHX2), both regulated by MIR4277.[15] These findings underscore the complexity of CBD genetics and emphasize the need for further studies to clarify the roles of these genes in the disease's pathophysiology.

Epidemiology

CBD is a neurodegenerative disorder characterized by complex pathological mechanisms and diverse clinical presentations, collectively referred to as clinicopathologic heterogeneity. This variability significantly hampers antemortem diagnosis and limits the ability to conduct robust epidemiological studies. Notably, CBD pathology is correctly predicted in only 25% to 56% of cases prior to autopsy.[16]

Due to its diagnostic challenges, studies often focus on the broader syndrome of CBS when assessing incidence and prevalence. Results from a meta-analysis showed the incidence of CBS ranges from 0.03 to 0.8 per 100,000 person-years and its prevalence from 0.83 to 25 per 100,000. Data were drawn from North America, Europe, Singapore, Japan, Sydney, Buenos Aires, and Egypt.[17] Additional estimates suggest an annual CBS incidence of less than 1 per 100,000 patients based on study results from Japan and Russia.[18][19] While earlier reports indicated an annual CBD incidence of 0.6 to 0.9 per 100,000, representing 4% to 6% of Parkinsonian syndromes, and a prevalence of 4.9 to 7.3 per 100,000, results from a large United Kingdom cross-sectional study involving 121,608 patients did not identify any confirmed cases of CBD.[20][21]

The disease typically has a late onset, with the youngest pathologically confirmed case reported at 42 and an average age of onset around 65.[22][23] An autopsy series from the CurePSP Brain Bank at the Mayo Clinic (Jacksonville, Florida) examined 76 cases of pathologically confirmed CBD. They found a mean age of death of 70 ± 8.7 years (range 46–89 years), with 53% of the cases being men. The estimated average disease duration was 6 ± 2.3 years.[2] While results from some studies have suggested a higher prevalence of CBD in women, others have not demonstrated significant sex differences.[22][24][25]

Pathophysiology

The pathophysiology of CBD is primarily driven by the accumulation of 4R hyperphosphorylated tau protein, which aggregates within neurons, astrocytes, and oligodendrocytes, leading to progressive neurodegeneration. Normally, tau protein is highly expressed in axons as it is required for microtubule stability and assembly.[26] However, hyperphosphorylation changes conformation and reduces its binding affinity for microtubules, impairing the latter's function. Dissociated tau has a higher propensity for multimerization, aggregation, and contributing to neurodegeneration.[4] The neurodegenerative process appears to spread in a prion-like manner across synapses, potentially explaining disease progression.[27]

The resultant tau inclusions disrupt neuronal function, contributing to synaptic dysfunction, axonal transport failure, and cell death. In support of this argument, results from a mouse-model-Alzheimer disease study showed that tau triggers N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxic signaling via targeting the postsynaptic Src kinase Fyn.[28] In addition, tau also disrupts synaptic function by accumulating in dendritic spines and reducing the count of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and NMDA receptors.[29]

Early pathological involvement is seen in the striatum and anterior frontal regions, with posterior spread over time. In advanced cases, widespread tau pathology affects the frontal, parietal, and temporal cortices, striatum, and corpus callosum.[30] Clinically, CBS is linked to perirolandic pathology. Still, other neurodegenerative diseases such as Alzheimer disease, PSP, Pick disease, Creutzfeldt-Jakob disease, and transactive response deoxyribonucleic acid binding protein-43 (TDP-43) proteinopathies can also underlie CBS.[31][32]

Beyond tauopathy, the neurodegenerative cascade in CBD involves mitochondrial dysfunction, impaired axonal transport, inflammation, and synaptic degeneration. Neuroinflammation is a key driver, with activated microglia and astrocytes releasing proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, and complement proteins. Microglia also facilitate tau propagation through endocytosis and exocytosis cycles.[1] Elevated levels of chitinase-3-like protein 1, a marker of astroglial neuroinflammation, have been observed in CBD and other tauopathies.[33]

White matter degeneration is another significant pathological feature, likely stemming from tau-mediated oligodendrocyte dysfunction, contributing to subcortical rarefaction and U-fiber loss. The asymmetric distribution of cortical and basal ganglia involvement correlates with the asymmetric clinical presentation of motor and cognitive deficits. Results from genetic studies have linked CBD to the H1 haplotype of the MAPT gene, which increases the risk of tau dysfunction and aggregation.

Additional genome-wide association study results have implicated myelin-associated oligodendrocyte basic protein and son of sevenless homolog 1, highlighting a potential role for white matter pathology and non-tau-mediated mechanisms. There is also emerging evidence of genetic overlap between CBD and immune-mediated diseases, suggesting a possible role for immune system dysregulation. Despite these advances, the precise triggers of tauopathy and the full extent of pathogenic pathways in CBD remain incompletely understood, underscoring the need for further research to facilitate targeted therapeutic development.

Histopathology

The histopathology of CBD is defined by distinct neuronal, glial, and axonal changes underpinned by hyperphosphorylated 4R tau protein deposition (see Image. Histopathologic Characteristics of Corticobasal Degeneration). These histologic features are essential for distinguishing CBD from other tauopathies, guided in part by the "Office of Rare Diseases Neuropathologic Criteria for CBD" (2002), which provides a standardized framework for diagnosis. At minimum, CBD diagnosis requires tau-positive neuronal and glial lesions in the cortex and striatum, particularly astrocytic plaques, thread-like lesions in white and gray matter, and focal neuronal loss in the cortex and substantia nigra.

Core Histopathological Features

• Astrocytic plaques
  • Astrocytic plaques are the hallmark lesion of CBD. These are formed by the deposition of hyperphosphorylated 4R tau within astrocytic processes, typically observed in the cortical gray matter and striatum. These plaques coexist with tau-laden dendritic neurites and oligodendroglial cytoplasmic tau tangles.[34][35] Tau deposition within glial cells contributes to widespread neuroinflammation and axonal dysfunction.
• Ballooned neurons
  • Ballooned neurons, or achromatic neurons, are a key histologic feature of CBD. These swollen neurons, predominantly found in the third, fifth, and sixth cortical layers, contain hyperphosphorylated tau aggregates.[36] Their distribution correlates with cortical atrophy and localized functional impairments, particularly in motor and sensory regions.
• White matter rarefaction
  • Subcortical white matter, including U-fibers, exhibits significant rarefaction in CBD.[37] This reflects widespread axonal degeneration and loss of connectivity between cortical and subcortical structures, contributing to the clinical manifestations of CBS.
• Thread-like lesions
  • Tau-positive thread-like lesions in white and gray matter are a defining feature of CBD. These thread-like structures are associated with disrupted neuronal processes and impaired synaptic connectivity.
• Neuronal loss and spongiosis
  • Neuronal loss is focal, most prominent in the substantia nigra and the affected cortical regions. Microvacuolization or laminar spongiosis may be present, particularly in the superficial cortical layers, although this finding can extend across all layers.

Subtypes of CBD Pathology

The distribution and severity of tau lesions allow for classification into 3 pathological subtypes:

• Typical CBD
  • Predominant involvement of the posterior frontoparietal or perisylvian cortex
• Basal ganglia-predominant CBD
  • Severe degeneration in the pallidum and subthalamic nucleus with milder cortical involvement
• PSP-like CBD
  • Severe brainstem and dentate nucleus degeneration, with variable cortical involvement

Tau Pathology in Clinical Variants

CBD manifests primarily as 2 clinical syndromes, CBS (CBD-CBS) and PSP-like syndrome (CBD-PSPS), each with distinct patterns of tau deposition:

• CBD-CBS
  • There is a greater tau burden in the primary motor and somatosensory cortex, subthalamic nucleus, putamen, and globus pallidus externa. Neuronal loss in the medial substantia nigra is less severe.
• CBD-PSPS
  • The tau burden is more extensive in the hippocampus, cerebellum, brainstem white matter tracts, and superior frontal cortex. Patients exhibit greater neuronal loss in the substantia nigra and more prominent tau pathology in limbic regions, such as the anterior thalamus and hippocampus.[38]

Prion-Like Tau Propagation

A prion-like spread of tau across synapses has been implicated in the pathogenesis of CBD. Misfolded tau aggregates propagate from cell to cell, seeding further tau pathology. This process exacerbates neurodegeneration and explains the progressive and asymmetric distribution of lesions.

Inflammatory and Synaptic Mechanisms

Several mechanisms mediate tau-induced neurodegeneration:

• Microtubule dysfunction
  • Hyperphosphorylated tau dissociates from microtubules, impairing their stability and assembly. The dissociated tau aggregates form neurotoxic filaments.
• Synaptic dysfunction
  • Tau disrupts synaptic function by targeting NMDA and AMPA receptors, leading to excitotoxicity and dendritic spine loss.
• Neuroinflammation
  • Tau activates microglia and astrocytes, triggering proinflammatory cytokines like tumor necrosis factor-α, IL-1β, and IL-6. Microglia may also mediate tau spread through cycles of endocytosis and exocytosis.

Additional Pathological Features in CBD-PSPS

Patients with CBD-PSPS often show additional pathologies, such as TDP-43 inclusions, particularly in the midbrain tegmentum.[39] These inclusions contribute to the more severe cognitive and behavioral impairments seen in this subtype compared to CBD-CBS.

Pathological Insights and Diagnosis

Immunohistochemical staining for hyperphosphorylated tau is crucial for diagnosing CBD. Astrocytic plaques, ballooned neurons, and tau-positive thread-like lesions distinguish CBD from other tauopathies. However, additional clinical or genetic data may be needed to differentiate CBD from frontotemporal dementia and Parkinsonism linked to chromosome 17.

History and Physical

History

CBD is a progressive neurodegenerative disorder with insidious onset, typically beginning in the sixth or seventh decade of life. The initial presentation varies among patients but often includes asymmetric motor dysfunction, cognitive impairment, or language deficits. The disease follows a relentlessly progressive course over several years, leading to severe disability.

In 2013, Armstrong et al and an international consortium of behavioral neurologists, neuropsychologists, and movement disorder specialists published updated clinical criteria for the diagnosis of CBD. These criteria were developed in response to the growing understanding of CBD and its clinicopathologic correlations based on 267 nonoverlapping pathologically confirmed CBD cases. From this effort, 4 distinct clinical phenotypes of CBD were identified:

• Probable and possible CBS
• Frontal-behavioral and spatial syndrome (FBS)
• A nonfluent agrammatic primary progressive aphasia syndrome (nfa-PPA)
• PSPS

Clinical Criteria for CBD

The clinical phenotypes were integrated to establish 2 overarching diagnostic categories: 

• Probable CBD
  • Requires an age of onset of more than 50 years
  • Excludes the presence of a family history or a known genetic mutation affecting tau protein
  • Diagnosis can only be made with:
    • Probable CBS, or
    • FBS or nfa-PPA, provided at least 1 CBS feature (i-vi) is present [16]
• Possible CBD
  • Does not require a specific age of onset
  • Allows for a positive family history or a known tau-protein mutation
  • Diagnosis can be made with:
    • Possible CBS, or
    • FBS or nfa-PPA, or
    • PSPS, provided at least 1 CBS feature (ii-vi) is present

Clinical Criteria for CBS

CBS is also divided into 2 overarching diagnostic categories: 

• Probable CBS
  • Characterized by an asymmetric presentation of at least 2 of the following:
    • Limb rigidity or akinesia
    • Limb dystonia
    • Limb myoclonus
      • Plus, at least 2 of:
        • Orobuccal or limb apraxia
        • Cortical sensory deficit
        • Alien limb phenomenon (must be more than simple levitation)
• Possible CBS
  • May present symmetrically and requires 1 of the following:
    • Limb rigidity or akinesia
    • Limb dystonia
    • Limb myoclonus
      • Plus, at least 1 of:
        • Orobuccal or limb apraxia
        • Cortical sensory deficit
        • Alien limb phenomenon (more than simple levitation)

Limitations of the Clinical Criteria

Study results have indicated that these diagnostic criteria lack specificity. No single clinical feature can reliably distinguish CBD from other neurodegenerative pathologies, such as Alzheimer disease (AD) or PSP, in patients presenting with CBS.[16][40] This diagnostic overlap underscores the complexity of CBD and its clinical mimics.

Pathologic Heterogeneity of CBS

To emphasize the variability of underlying pathology in CBS, a review of the Mayo Clinic Brain Bank until November 2021 of 345 brains from patients with an antemortem diagnosis of CBS recognized the underlying pathologic diagnoses to be of CBD (32%), PSP (31%), AD (20%), and others (17%), including diffuse Lewy body disease, frontotemporal lobar degeneration with TAR deoxyribonucleic acid-binding protein 43 (FTLD TDP), motor neuron disease, Pick disease, frontotemporal lobar degeneration with fused-in-sarcoma pathology (FTLD FUS), frontotemporal lobar degeneration with tau pathology (FTLD tau), Creutzfeldt-Jakobs disease, and cerebrovascular disease. CBS, regardless of the underlying pathology, has frontoparietal, as well as motor and premotor involvement.[37]

Physical

The physical examination of a patient with CBD reveals asymmetrical motor and cognitive impairments, as well as cortical sensory deficits and speech disturbances, which further distinguish CBD from other neurodegenerative disorders. The presentation can be highly variable, reflecting the heterogeneity of its underlying neuropathology. While asymmetrical rigidity, dystonia, myoclonus, and apraxia are hallmark features, some patients may present with predominant language dysfunction, cognitive impairment, or corticospinal signs. This variability often leads to diagnostic challenges and overlaps with other neurodegenerative disorders.

Clinical Features of CBD

The most common clinical presentation of CBD is corticobasal syndrome (CBS), a clinical syndrome characterized by cortical and extrapyramidal signs. The most common cortical signs are apraxia, cortical sensory deficits, and alien limb phenomenon, and the most common extrapyramidal signs are parkinsonism, dystonia, and myoclonus.[23] Common physical exam findings include: 

• Parkinsonian features and responsiveness to levodopa
  • Characteristically, parkinsonism in CBS is unilateral or asymmetric; however, symmetric CBD has been reported. This symmetric form of CBD is rare and typically associated with younger age at onset (median 61 vs 66, P < 0.05), less asymmetric cortical imaging findings, with a relative absence of other features of CBS such as myoclonus, dystonia, alien limb phenomenon, and limb apraxia.[41] Asymmetric limb rigidity and bradykinesia are likely the most common parkinsonian manifestations in pathologically proven CBD.[16][22] Limb rigidity may be lead-pipe in nature with or without cogwheeling and may have a coexistent component of dystonia and gegenhalten/paratonic rigidity in cases with predominant frontal lobe dysfunction.[16] As the disease progresses, limb rigidity involves all limbs.[22] Axial rigidity is less common in CBD as compared to other atypical parkinsonian disorders such as PSP.[22] This sign has been reported in about 27% of the cases at presentation and 69% at some point of disease evolution.[16]
  • Levodopa response can be moderate in a minority of patients; however, it is only transient. Levodopa-induced dyskinesias, akin to Parkinson disease (PD), have also been described.[42] Results from a study of 147 patients with CBD found that about one-fourth of the patients demonstrated at least moderate improvement in their parkinsonian symptoms attributable to levodopa; however, only 7 patients were autopsy-proven, and the retrospective nature of the study also limited the information on the magnitude or duration of the response.[24]
  • Tremor is less frequent in CBD than in PD and is phenotypically distinct from the PD's tremor.[24] Tremor has been described in about 39% of patients with CBD at some point in their disease course. This type of tremor usually combines resting, positional, and action tremor, irregular and sometimes resembling low-amplitude action myoclonus.[16]
• Gait difficulties, postural instability, and falls
  • Gait problems can present in about 73% of patients with CBD throughout their disease course.[16] Gait can present similarly to that in PD with features of bradykinesia, shuffling, and decreased arm swing; however, a wider-based gait with freezing has also been reported.[2] Freezing of gait tends to happen with increased disease duration, with an incidence of about 1 out of 13 patients within 3 years from disease onset and a 3-fold increase by 6 years.[43] Nonetheless, CBD should not typically present as a primary progressive freezing gait disorder.[44] Results from a study suggested that the frequency of falls and gait changes in patients with CBD-CBS are 29% and 36%, respectively, at first evaluation, but this seems to be an exception rather than a rule for the disease.[16] Apraxia can also manifest with gait abnormalities and falls.[2]
• Dystonia
  • According to large reviews of pathologically confirmed cases, dystonia appears to be present in about 40% of patients with CBD.[16][45] However, some study results have shown dystonia to be as frequent as in 90% to 100% of cases, perhaps due to referral bias and the inclusion of nonpathologically confirmed cases.[46][47]
  • Dystonia typically occurs within 2 years from disease onset and commonly affects the upper limb. Dystonia may evolve into hemidystonia or affect the other side, but it rarely starts in the leg.[45] Classic dystonic presentations are of adduction and flexion at the arm, forearm, wrist, and metacarpophalangeal joints with extension at interphalangeal joints, as opposed to flexion and internal rotation at the hip with flexion at the knee and inversion at the foot.[47] Interestingly, the onset of dystonia was later in the disease course in the cases with a "dementia" (frontotemporal dementia or Alzheimer disease) phenotype. The study also hinted at a possible association between dystonia and myoclonus as they almost cooccurred in their cases.[45]
• Myoclonus
  • Myoclonus has been estimated to be prevalent in about 27% of cases during the entire disease course.[16] Myoclonus has been described to be primarily focal, affecting the upper extremities and less so the face, more prominent in response to sensory stimulation and on voluntary action, ie, stimulus-induced, and at times to be superimposed with limb dystonia.[48][49][50][51] The known cortical pathology in CBD and the focal, predominantly distal, hypersynchronous jerks, with evidence of cortical hyperexcitability via magnetic brain stimulation in a study, suggest that the myoclonus in these patients is likely cortical in origin. Electrophysiologically, the myoclonus of CBD differs from cortical reflex myoclonus due to shorter latency of reflex jerks (40 ms vs 50 ms in hand muscles), absence of enlargement of cortical sensory evoked potentials, and lack of preceding cortical discharge in the back-averaged electroencephalogram before each jerk. These differences are hypothesized to arise from the enhanced direct sensory input to the motor cortex in CBD, as opposed to abnormal direct relays through the sensory cortex to the motor cortex or via cerebellar-thalamocortical projections in cortical reflex myoclonus. The specific electrophysiologic finding in favor of the above hypothesis is that the latency of reflex myoclonus in CBD is only 1 to 2 ms more than the sum of the afferent and efferent times to and from the cortex.[50]
• Bulbar symptoms
  • Results from a clinical study of 36 CBD patients (only 6 underwent neuropathological studies) revealed that dysarthria was present in 11% of patients early in the disease course, and the number rose to 70% at the 5-year follow-up.[52]
  • The median latencies of dysarthria and dysphagia were estimated to be around 40 months and 64 months, respectively, by a postmortem study of 13 patients with CBD in comparison to patients with PD and other APDs such as dementia with Lewy bodies, PSP, and multiple system atrophy. Similar to other parkinsonian disorders, survival decreases with the onset of dysphagia, with a median latency of 15 to 24 months. Therefore, early identification and treatment of dysphagia is fundamental to prevent or delay complications such as aspiration pneumonia and, in turn, potentially improve quality of life and increase survival time.[53]
• Apraxia
  • Apraxia is the clinical hallmark of CBS and presents at disease onset in about 45% of patients and later in the disease course in around 57% of patients.[16] Assessing praxis in the less affected limb may be helpful to avoid inaccurate assessment secondary to concomitant motor symptoms (like rigidity and dystonia) or involuntary movements (like myoclonus). Typically, it starts in the upper extremities and is of the ideomotor type (not knowing "how to do it"). However, the advanced stages of CBD can manifest ideational apraxia (not knowing "what to do"), which is less commonly seen otherwise in the disease.[54][55] The same applies to orobuccal apraxia, which tends to appear later in the disease course, although it can rarely be the initial manifestation of concurrent loss of speech output.[56] Ideomotor apraxia is associated with a decreased gray matter volume within the left supplementary motor area, premotor cortex, and caudate nucleus of patients with CBS.[57] In patients with CBS with more severe apraxia (usually a combination of ideomotor and ideational apraxia), there often is a global cognitive impairment and additional parietal or diffuse cortical damage.[54] The degree of apraxia appears independent of the side of motor impairment. Transitive and intransitive praxis seem to be equally impaired; however, praxis to imitating gestures seems to be worse impacted than to commands.[57]
• Aphasia
  • Language impairments are reported in about 53% of patients with CBD. They have been described with a broad spectrum ranging from mild abnormalities to severe progressive nonfluent aphasia, with some even progressing to complete mutism. Aphasia has primarily been found to be of anomic, Broca, or transcortical types but not receptive or Wernicke. These types are associated with left frontoparietal cortical damage and abnormalities within the subcortical white matter and corpus callosum.[16][25][58][59] Additionally, apraxia of speech, defined as problems with translating conscious speech plans into motor plans presenting with characteristic articulation and prosody errors, has been described in CBD as coexistent or independent from aphasia.[38]
  • Results from a retrospective study on 38 individuals with CBS established an association between aphasia and right-sided motor symptoms, further confirming that it stems from left hemispheric dysfunction. Such an association did not exist in patients with left-predominant motor presentation. Additionally, dysarthria did show such a preferential correlation.[60]
• Alien limb phenomenon
  • At the time of its initial description, the alien limb phenomenon was primarily thought of as a subjective difficulty in recognizing one's limb as one's own, especially in the absence of visual input.[61] Today, the alien limb implies one that carries "a will of its own" or "is foreign" together with an observable motor activity. Thus, it can be defined as an involuntary movement in the context of feeling estranged from the limb. The limb may perform meaningful acts without being guided by the patient's intention and may reach and grab objects with the inability to release grasped objects without intervention from the unaffected extremity; patients often express surprise and frustration at this errant limb and refer to it in the third person.[62][63][64] 
  • This phenomenon is present in about 30% of cases at any point during the disease course. The alien limb is usually localized to the corpus callosum alone, the corpus callosum and the dominant medial frontal cortex, or the posterior cortical/subcortical region. The consensus, however, is that the alien limb movements in CBD tend to be different than in patients with frontal lobe or corpus callosum lesions. Perseverative movements are less common, especially early in the disease's course. The alien limb is likely to drift, levitate, or assume odd postures similar to the patterns seen in parietal lesions. These movement patterns are presumed to stem from interactions between frontal lobe-mediated "avoidance" behaviors and parietal lobe-mediated "approach" behaviors. While frontal lobe damage may release parietal "approach" behaviors, parietal lobe injuries may release frontal "avoidance" behaviors, resulting in abnormal, everted, and overextended postures.[64][65] In line with this frontal-parietal lobe interaction, a bilateral asymmetric alien limb syndrome has also been reported in CBD, where 1 hand demonstrated tactile avoidance with levitation from presumed parietal dysfunction, and the other hand showed a continuous tactile pursuit of the examiner's hand from presumed frontal dysfunction.[66]
• Other
  • Apart from the well-established clinical phenotypes mentioned above, there are other potential manifestations of the disease:
    • AD-like amnestic phenotype [59][67] 
    • Conduction-type aphasia with prominent impairment in repetition [68] 
    • Posterior cortical atrophy with Balint syndrome triad of optic ataxia, oculomotor apraxia, and simultagnosia [69] 
    • Sleep disturbances including rapid eye movement, sleep behavior disorder, and insomnia [70] 
    • Neuropsychiatric complaints like apathy, depression, agitation, or impulsivity [71][72]
    • Autonomic dysfunction with urinary incontinence/constipation [71][73] 
    • Progressive oculovisual dysfunction [74] 
    • Frontal-type gait disorder [75]

Evaluation

There are no definitive laboratory tests for CBD, but a comprehensive workup is essential to rule out alternative diagnoses and identify supportive biomarkers.

Laboratory Tests

Blood Tests

Routine blood tests are typically unremarkable in CBD but are performed to exclude other causes of parkinsonism and cognitive impairment, including:

• Thyroid function tests 
  • To rule out hypothyroidism-related cognitive and motor dysfunction
• Vitamin B12, folate, and homocysteine levels
  • To assess for vitamin deficiencies contributing to neurodegenerative symptoms
• Syphilis and human immunodeficiency virus serology
  • To rule out infectious causes of dementia and movement disorders
• Autoimmune and paraneoplastic panels
  • In cases with atypical presentations to exclude autoimmune encephalitis and paraneoplastic syndromes
• Genetic testing
  • If there is a strong family history, testing for MAPT mutations or other tauopathies may be considered, though CBD is primarily sporadic.

Cerebrospinal Fluid Biomarkers

Cerebrospinal fluid (CSF) biomarkers have emerged as promising tools for diagnosing CBD, particularly for distinguishing it from other neurodegenerative disorders. Given the central role of tau pathology in CBD, recent research has focused on identifying isoform-specific tau species that reflect disease-specific neurodegeneration. Measuring soluble tau fragments in CSF can provide insights into the underlying pathological process, aiding in the early and accurate identification of CBD.

Results from a recent study on 4R isoform-specific tau species from microtubule-binding region (MTBR), ie, MTBR-tau₂₇₅ and MTBR-tau₂₈₂, showed that when normalized to total-tau, they increase in brain insoluble tau and decrease in the CSF soluble tau in primary tauopathies, especially CBD and FTLD-MAPT P301L. Interestingly, CSF MTBR-tau_275/t-tau and MTBR-tau₂₈₂/t-tau did not decrease in PSP and argyrophilc grain disease (AGD), the other 4R-tauopathies. This discrepancy originated from variability in the degree of neocortical pathology in PSP and AGD cases compared to CBD and FTLD-MAPT cases. This study, thus, proposes the potential role of CSF MTBR-tau₂₇₅ and MTBR-tau₂₈₂ as the first affirmative fluid disease biomarkers for primary tauopathies, especially CBD and FTLD-MAPT.[76]

CSF biomarkers for Alzheimer disease (AD), such as amyloid beta 42, total tau (t-tau), and phosphorylated tau, are crucial in ruling out AD in patients with overlapping clinical features. In a patient with predominantly cognitive symptoms, the possibility of underlying AD pathology should be considered first before considering other differentials like CBD, and this can be ascertained with the CSF levels of amyloid beta 42, t-tau, and p-tau with a sensitivity of 95% and specificity of 83%.[77] Additionally, neurofilament light chain (NfL) may be elevated in CBD, reflecting neurodegeneration.

Neuroimaging Studies

Radiographic imaging is critical for supporting the diagnosis of CBD and distinguishing it from other neurodegenerative conditions.

Magnetic Resonance Imaging 

Magnetic resonance imaging is a valuable tool in the evaluation of CBD, aiding in the exclusion of other neurodegenerative disorders and identifying characteristic atrophy patterns. Findings often include asymmetric cortical atrophy, particularly in the parietal and frontal lobes, and basal ganglia involvement (see Image. Corticobasal Degeneration on Magnetic Resonance Imaging). However, it is important to note that the imaging finding of asymmetric frontoparietal atrophy is more reflective of a clinical syndrome of CBS than an underlying CBD pathology. Advanced imaging techniques like diffusion tensor imaging and volumetric analysis may enhance diagnostic accuracy by detecting early structural and functional changes. However, MRI findings are often nonspecific, necessitating clinical correlation for definitive diagnosis.

A voxel-based morphometry study to analyze atrophy patterns found that patients with a clinical syndrome consistent with CBS exhibited perirolandic atrophy involving both the anterior and posterior central gyrus, regardless of the underlying pathology. In contrast, patients with pathologically confirmed CBD demonstrated atrophy in the perirolandic region and the dorsal prefrontal cortices, striatum, and brainstem.[78] Results from another study examining gray matter thinning in CBS patients revealed consistent involvement of the premotor cortex and insula in the dominant hemisphere and the supplementary motor area bilaterally. However, the distribution of atrophy varied based on the underlying pathology. Specifically, in CBD-CBS cases, gray matter loss extended from the premotor cortex into the inferior and superior posterior frontal lobes and supplementary motor area, a pattern closely resembling that observed in PSP-CBS, except for relative sparing of the inferior frontal lobe.[79]

Additionally, a correlation study using MRI volumetric and diffusion tensor imaging (DTI) in 47 patients (28 PSP and 19 CBD) indicated that 'brain volume' and 'white matter integrity' might serve as useful surrogate markers for tau pathology in 'subcortical/brainstem' and 'cortical' regions, respectively.[80] Results from another diffusion tensor imaging study involving 11 patients with probable CBD reported an increased apparent diffusion coefficient average in the motor thalamus and the precentral and postcentral gyri ipsilateral to the affected frontoparietal cortex, as well as in the bilateral supplementary motor area. Fractional anisotropy values were predominantly reduced in the precentral and supplementary motor areas, followed by the postcentral gyrus and cingulum.[81] However, a significant limitation of this study was the absence of pathological confirmation of CBD in these patients.

Positron Emission Tomography 

Positron emission tomography (PET) imaging is valuable in evaluating CBD, providing metabolic and molecular insights that complement clinical and structural findings. PET imaging utilizes radioligands to bind to in vivo targets to assist in quantitative visualization of functional processes. The most used radiotracer is [18F] fluorodeoxyglucose (FDG), which helps assess regional brain glucose metabolism. Over the past decade, various pathology-specific radiotracers, such as amyloid and tau tracers, have been developed to image tauopathies, especially AD, with a growing literature in 4R-tauopathies. 

Fluorodeoxyglucose-Positron Emission Tomography 

FDG-PET plays a crucial role in identifying regional differences in brain metabolism, which can aid in differentiating neurodegenerative disorders, particularly in the early stages when clinical distinctions between diseases remain challenging.[82] FDG-PET detects asymmetric cortical hypometabolism, particularly in the parietal and frontal lobes, aiding in differentiation from other neurodegenerative disorders. Results from a study identified and validated a distinct metabolic covariance pattern in 10 patients diagnosed with probable CBD. This pattern was characterized by asymmetric bilateral hypometabolism in the cerebrum, specifically involving the frontal and parietal cortices, thalamus, and caudate nucleus, with a relative increase in metabolism observed in the occipital regions. However, this study had notable limitations: (1) all participants exhibited the CBS phenotype, which includes asymmetric limb involvement and apraxia, meaning the identified metabolic pattern may not be representative of other CBD presentations; and (2) only 3 of the patients had a pathologically confirmed CBD diagnosis, raising the possibility that some may have had a different underlying pathology.[83]

Addressing these limitations, another study examined 29 CBS patients who underwent FDG-PET imaging and postmortem neuropathological evaluation. Of these, 14 were confirmed to have primary CBD pathology (CBD-CBS). Hypometabolism patterns varied across different underlying pathologies, but CBD-CBS patients demonstrated a more pronounced bilateral basal ganglia involvement. Notably, the primary motor cortex was the only common hypometabolic region among all groups. Based on these results, the study suggested that FDG-PET could be valuable for differentiating pathological diagnoses in patients with CBS.[84] Further research is needed to determine its applicability in CBD cases that do not present with the CBS phenotype.

Tau PET Imaging

Tau PET imaging has emerged as a promising technique for assessing tau pathology in neurodegenerative diseases. Among the first-generation tracers, [18F]AV-1451 (flortaucipir) demonstrated increased uptake in the bilateral premotor and motor cortices and globus pallidus in patients with CBD patients compared to controls. Additionally, there was a trend toward greater globus pallidus uptake in patients with CBD compared to PSP, suggesting potential utility in differentiating tauopathies. However, [18F]AV-1451 has significant limitations, including poor specificity for 4R tau, the dominant tau isoform in CBD, as it preferentially binds to the mixed 3R/4R paired helical tau filaments found in AD.[85][86] Furthermore, off-target binding remains a challenge, particularly due to the tracer's high affinity for monoamine oxidase-B (MAO-B), complicating interpretation.[87] Results from another study investigating antemortem tau PET imaging in relation to postmortem autopsy findings demonstrated that while [18F]AV-1451 reliably identified advanced Braak tau pathology in AD, it failed to detect early-stage neurofibrillary tangle pathology and was unable to differentiate non-AD tauopathies, including CBD.[88]

To overcome these limitations, second-generation tau tracers have been developed. [18F]PM-PBB3 (also known as [18F]-APN-1607) has shown greater efficacy in binding to and tracking the accumulation of 4R tau over time, particularly in carriers of MAPT mutations.[89] Results from a case study involving a patient with auditory agnosia and dysprosody, [18F]PM-PBB3 uptake was observed in the occipital cortex, asymmetrical neocortex, subcortical regions, basal ganglia, thalamus, and midbrain. Based on this distribution, the authors suspected underlying CBD pathology; however, the absence of pathological confirmation limited definitive conclusions.[90]

Another promising tracer, [18F]PI-2620, has shown asymmetric pallidal uptake in patients with CBD, distinguishing it from patterns observed in PD and PSP.[91] A study examining patients with CBS provided results demonstrating that there was preferential uptake in the dorsolateral prefrontal cortex and basal ganglia contralateral to the clinically affected side, irrespective of beta-amyloid status. This suggests that [18F]PI-2620 may be valuable in assessing underlying pathology and tracking disease progression in CBS.[92]

Despite the advances in tau PET imaging, significant challenges remain, particularly concerning off-target binding and inconsistencies between antemortem imaging and postmortem pathological findings. Although second-generation tracers like [18F]PM-PBB3 and [18F]PI-2620 have shown improvements in reducing off-target binding in the basal ganglia, cerebral white matter, and monoamine oxidases-A/B, they have introduced new binding artifacts in regions such as the skull and meninges. Furthermore, the specificity of these tracers for 4R tau requires further validation through larger-scale studies.[85] 

Other Diagnostic Tests

Other diagnostic tests can aid in differentiating CBD from other neurodegenerative conditions. Dopamine transporter imaging (eg, DaTscan/SPECT) may reveal asymmetric striatal dopamine transporter loss; however, this finding is nonspecific and can also be observed in other parkinsonian syndromes. Electromyography and nerve conduction studies are often performed to exclude mimicking conditions such as motor neuron disease. Additionally, neuropsychological testing assesses cognitive function in patients with CBD, identifying deficits that vary based on disease phenotype. Common findings include executive dysfunction, apraxia, nonfluent aphasia, and visuospatial impairments.

Treatment / Management

Symptomatic Management

The treatment framework below is largely derived from the CurePSP Centers of Care consensus on best practices in PSP and CBS clinical management.[71] However, given the large clinical heterogeneity in the disease presentation and individual disease manifestations, a tailored care plan must be synthesized for individuals with CBD with the help of an interprofessional team including neurologists, psychotherapists, speech therapists, psychiatrists, ophthalmologists, sleep specialists, occupational therapists, physical therapists, and palliative care physicians.(B3)

A levodopa trial should be conducted for parkinsonism. An adequate trial would entail titrating it over a month to 900 to 1200 mg daily in 3 divided doses and maintaining the maximum tolerated dose for at least a month. If there is no response or the emergence of adverse events like dyskinesias, the medication must be tapered slowly over at least 2 weeks. Abrupt discontinuation can cause parkinsonism-hyperpyrexia syndrome. Other dopaminergic agents like monoamine oxidases-B inhibitors or catecholamine O-methyltransferase inhibitors are even less likely to provide benefits than levodopa.

Constipation and urinary disturbances may become prominent as a part of possible autonomic dysfunction in CBD. Constipation may respond to increased physical activity, adequate hydration, fiber supplementation, and pharmacologic therapy with stool softeners or osmotic laxatives. Stimulant laxatives should only be used short-term. Medications like guanylate cyclase c agonists (linaclotide) and selective 5-hydroxytryptamine receptor 4 agonists (prucalopride) may need to be prescribed in refractory cases of constipation.

Urinary dysfunction may be targeted with the use of alpha-receptor antagonists (tamsulosin, terazosin, doxazosin, alfuzosin, silodosin), 5-alpha reductase inhibitors (finasteride, dutasteride), beta-3 adrenoceptor agonists (mirabegron, vibegron), and selective M3 antimuscarinic anticholinergics (darifenacin, solifenacin); however, nonselective antimuscarinic agents (oxybutynin, tolterodine, fesoterodine) should be avoided given central anticholinergic side effects. Botulinum toxin injections may need to be considered for refractory overactive bladder. Polypharmacy can be avoided using nonpharmacologic measures like condom catheters for men, clean intermittent urinary catheterization, and transtibial nerve stimulation.

Melatonin can manage sleep disturbances like insomnia and rapid eye movement sleep behavior disorder; however, low-dose clonazepam may be necessary if melatonin fails. Given cognitive side effects, other benzodiazepines, benzodiazepine receptor agonists, and tricyclic antidepressants must be avoided. Stimulants, if used for excessive daytime somnolence, must be restricted to low doses.

As bulbar symptoms progress, sialorrhea and dysphagia may become more troublesome. Botulinum toxin is the first-line therapy for sialorrhea. Sublingual atropine drops are not recommended due to central anticholinergic adverse events, and oral glycopyrrolate, if used, should be monitored for the same reason. In cases of dysphagia, an early referral to speech-language pathology should be placed. Conservative measures with small bites and sips, multiple swallows, and thickened liquid consistencies can be helpful; however, percutaneous gastrostomy tube placement may become necessary in severe cases, necessitating timely goals-of-care discussions by the treating physician.

Apraxia of speech and nonfluent aphasia are best managed by intense, repetitive exercises and using gestures, nonspeech modalities, and pacing methods with the help of a trained speech pathologist. Transcranial magnetic stimulation to the cerebellar region and transcranial direct current stimulation to the dorsolateral prefrontal region are potential experimental treatments for speech apraxia and aphasia, respectively. Limb apraxia warrants occupational therapy with interventions like gestural training, bimanual or bipedal tasks, mirror therapy, repetitive facilitation exercises, or video game-based rehabilitation.

If focal, botulinum toxin is the best treatment for dystonia. Other pharmacologic therapies include baclofen and clonazepam. Baclofen can be started at 5 mg daily and titrated to a maximum dose of 10 mg 3 times a day, while clonazepam is usually started at 0.25 mg daily and titrated to no more than 3 mg per day. Occupational therapy with an evaluation for orthoses may be beneficial for dystonia.

Pharmacologic management of cognitive impairment with cholinesterase inhibitors should be reserved for amnestic deficits. Caregiver and family education, establishment and maintenance of a daily routine, occupational therapy, external memory aids (eg, calendars, daily planners), technology (eg, mobile devices), and lifestyle modifications may be beneficial nonpharmacologic measures. Behavioral symptoms of apathy can be managed with a trial of methylphenidate or modafinil; depression and other mood disorders may respond to selective serotonin reuptake inhibitors (SSRIs). Impulsivity, if present, may need reduction of levodopa, mood stabilizers, a trial of SSRIs, or mediations used for attention deficit hyperactivity disorder like atomoxetine. Progressive eyelid and visual dysfunction may lead to blepharospasms, decreased blinks, reduced tear production, diplopia, saccadic slowing, and hypometria. Botulinum toxin for blepharospasm, artificial tears for dry eyes, binocular prisms for gaze limitation, environmental modifications, and referral to an ophthalmologist or a neurooptometrist may all prove helpful in the symptomatic management of ocular and visual dysfunction.

Targeted Tau Therapy

With the recent landmark United States Food and Drug Administration approval of drugs targeting amyloid pathology, there has been an increased interest in developing monoclonal antibodies targeting intracranial pathologies such as amyloid beta and tau.[93][94] However, a similar breakthrough has not yet been achieved with the advent of tau-directed therapies.[95] Therefore, it has become more pertinent than ever to develop disease-specific biomarkers to help predict the pathology in the antemortem diagnosis of neurodegenerative diseases with increased sensitivity and specificity and monitor the quantitative effect of the treatment over time.(A1)

Clinical trials in developing a disease-modifying therapy for 4R-tauopathies either focus on reducing the toxic gain of function caused by pathologic tau aggregates or restoring a loss of normal tau function.[96] Toxic gain of function may be mitigated by reducing tau gene expression, preventing posttranslational modifications that promote tau aggregation, or clearing tau aggregates mostly via an immunologic mechanism. Loss-of-function restoration strategies focus on microtubule stabilization.[97]

An immunoglobulin G4 monoclonal antibody, gosuranemab, against the N-terminal region of tau reduced both full-length tau and extracellular tau fragments in cell culture and animal models; however, its results showed a failure in demonstrating efficacy in the phase 2 PASSPORT study in PSP-Richardson syndrome (PSP-RS) patients.[98] As a result, a parallel basket study, TauBasket, examined other 4R-tauopathies like CBD, nonfluent variant primary progressive aphasia, traumatic encephalopathy, and frontotemporal lobar degeneration-MAPT was terminated due to futility analysis results from PASSPORT.[97] A major controversy in the use of monoclonal antibodies surrounds the appropriate tau protein epitope target, and it continues to be a matter of ongoing investigation. A transgenic mice model showed that antibodies targeting the tau's middomain region suppressed tau aggregation, whereas N-terminal antibodies did not.[99] A tau middomain monoclonal antibody, UCB0107, completed phase 1 studies in health controls, and an open-label extension study is ongoing.[97]

A microtubule stabilizer, TPI 287, was evaluated in AD and 4R-tauopathies, PSP, and CBS; however, it showed a dose-related worsening in cognitive outcomes in the 4R-tauopathy arm, preventing further development.[100] Most other trials have primarily been conducted in individuals with PSP-RS. Neuroprotective drugs (riluzole, rasagaline), tau phosphorylation inhibitors (glycogen synthase kinase-3 beta inhibitors like lithium, valproate, tideglusib), and tau acetylation inhibitors (salsalate) in PSP-RS have largely produced discouraging results. (A1)

Other prospective potential agents in various stages of clinical trials are tau transcription factor inhibitors (NCT04253132), tau aggregation inhibitors (AZP2006), and O-GlcNAcase inhibitors (hypothesized to help with tau hyperphosphorylation from transgenic mice studies).[97] There has been a recent interest in tau-targeted antisense oligonucleotides (ASOs) in 4R-tauopathies given an ASO-mediated 50% reduction in tau translation and prevention of neuronal loss in transgenic mouse models.[101] MAPTRx, a tau-targeting ASO, was found to be safe and showed a dose-dependent reduction in the total-tau CSF concentration in mild AD in a phase 1 randomized trial, and phase 2 of this drug is ongoing.[102] Encouraging results will potentially expand clinical trials for these agents in 4R-tauopathies. 

Differential Diagnosis

The most common clinical presentation of CBD, CBS, can have varying underlying pathologies other than CBD itself. These underlying pathologies can be PSP, AD, PD, diffuse Lewy body disease, Pick disease, Creutzfeldt-Jakob disease, cerebrovascular disease, motor neuron disease, frontotemporal lobar degeneration (FTLD)-TDP, FTLD-tau, or FTLD-FUS.[37][103] Patients with CBD who have cognitive predominant symptoms are more likely to have comorbid underlying AGD, a medial temporal tauopathy, when compared to CBD with CBS (73% vs 35%).[104]

Prognosis

Results from a study analyzing the natural history and survival of patients with confirmed CBD showed a median survival time from symptom onset of 7.9 years with a standard deviation of 0.7 years and a range of 2.5 to 12.5 years. After the first clinic visit, median survival was 4.9 years with a standard deviation of 0.7 years and a range of 0.8 to 10 years. Frontal syndrome, early bilateral bradykinesia, or 2 parkinsonian symptoms (tremor, bradykinesia, and rigidity) predicted a shorter survival.[22]

Complications

Patients with CBD are likely to accumulate progressive disability with disturbances in speech and language, swallowing, cognition, behavior, gait and posture stability, oculovisual functions, sleep, and possibly autonomic symptoms, eg, urinary dysfunction and constipation.[71]