Corticobasal degeneration

INTRODUCTION — Corticobasal degeneration (CBD) is a rare neurodegenerative disorder that poses significant challenges to clinical diagnosis and treatment. The classic description of CBD is that of a progressive asymmetric movement disorder characterized by various combinations of akinesia, rigidity, dystonia, focal myoclonus, ideomotor apraxia, and alien-limb phenomena. However, a wider range of clinical presentations is increasingly apparent, including onset with cognitive or behavioral abnormalities.

CBD is one of several neurodegenerative disorders related to accumulation of the cytoskeleton protein tau, or tauopathies; other tauopathies include Alzheimer disease (AD), progressive supranuclear palsy (PSP), and the tau subtype of frontotemporal lobar degeneration. CBD is also referred to as an atypical parkinsonian syndrome based on distinct yet overlapping features with Parkinson disease; other atypical parkinsonian disorders include PSP and multiple system atrophy.

This topic will review the clinical features, pathology, diagnosis, and management of CBD. Other atypical parkinsonian disorders are reviewed elsewhere. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis" and "Multiple system atrophy: Clinical features and diagnosis".)

HISTORY AND NOMENCLATURE

●First descriptions – The first description of CBD in 1967 reported the disorder in three patients who had an asymmetric, akinetic-rigid neurodegenerative syndrome with cerebral cortical dysfunction [1,2]. The original name given was "corticodentatonigral degeneration with neuronal achromasia," based upon its neuropathologic appearance. It would be another two decades before the next series of six patients was described [3]. However, as subsequent cases were evaluated, it became apparent that the dentate pathology was infrequent, and the nomenclature evolved to the more accurate terminology of corticobasal (ganglionic) degeneration [4,5].

●Clinical syndrome versus neuropathology – It is now recognized that pathologically proven CBD often begins as a cognitive or behavioral disturbance. Additionally, the characteristic cognitive and motor features are not specific to CBD, but may occur with other pathologically proven neurodegenerative disorders, including progressive supranuclear palsy (PSP), frontotemporal dementia, and Alzheimer disease (AD) [4,6-8]. This has prompted some experts to the use the term "corticobasal syndrome" (CBS) for cases with a clinical diagnosis, while reserving "CBD" for cases with neuropathologic confirmation.

●Tauopathy – A fundamental abnormality of the cytoskeletal protein tau is the underlying pathologic substrate, which has led to CBD being labeled as a tauopathy. Other tauopathies include AD, the tau subtype of frontotemporal lobar degeneration, and PSP [9,10]. The shared tau protein pathology may explain the overlap of clinical symptoms and the complex neuropathology present in these diseases.

EPIDEMIOLOGY — CBD is a rare disease with an estimated annual incidence less than 1 per 100,000 population and an estimated prevalence of approximately 2.3 per 100,000 population [11,12]. However, the precise incidence and prevalence of CBD remain unknown because of poor diagnostic accuracy due to the lack of validated and widely accepted diagnostic criteria, the absence of biomarkers, and the increasingly recognized clinical and neuropathologic heterogeneity of the disease [4,13].

The disease typically presents in the sixth to eighth decades of life with a mean age at onset of symptoms of 61 to 64 years [8,14,15]. The youngest reported case with pathologic confirmation had an onset of symptoms at 45 years of age [14], while the youngest reported case of clinically probable CBD had an onset of symptoms at age 28 years [16]. Some studies report an unequal sex distribution suggesting a predominance in females [14,17-19], but other reports have found no such sex preference [15].

The disease is considered to occur sporadically, although rare familial cases of CBD have been reported, leading to the possibility that there may be a genetic basis for at least a predisposition to the disorder [10]. There is limited evidence to suggest that environmental exposure to toxic or infectious agents plays a role in the pathophysiology of CBD. (See 'Pathology and pathophysiology' below.)

CLINICAL FEATURES — The classic description of CBD is that of a progressive asymmetric movement disorder with symptoms initially affecting one limb (upper or lower), including various combinations of akinesia and extreme rigidity, dystonia, focal myoclonus, ideomotor apraxia, and alien limb phenomena (table 1) [2,14,17,20]. However, most of the early reports describing the clinical features of CBD were retrospective case series from movement disorder centers that may have led to a referral bias and an overemphasis on the motor symptoms.

Variable features — CBD is a heterogeneous disorder that includes varied motor and cognitive phenotypes. This clinical heterogeneity has led to the use of the term "corticobasal syndrome" (CBS) for cases with a clinical diagnosis and "CBD" for cases with neuropathologic confirmation. In some cases the symptoms can be symmetric instead of the classic asymmetric presentation [21]. Furthermore, it has been found that cognitive impairment is a common manifestation of CBD and may be a presenting feature, while the parkinsonian motor features may emerge later as the disease progresses [15,22-24]. Important cognitive features of CBD include executive dysfunction, aphasia (including primary progressive aphasia), apraxia, behavioral change, and visuospatial dysfunction, with relatively preserved episodic memory. The heterogeneity is likely a reflection of the topographical variations in pathological changes in the brain [25].

In a systematic review of retrospective data from 210 cases of pathologically confirmed CBD, a final clinical diagnosis was available for 183 cases (87 percent), and multiple clinical phenotypes were associated with pathologically confirmed cases of CBD as follows [8]:

●CBS, 37 percent

●Progressive supranuclear palsy (PSP) syndrome, 23 percent

●Frontotemporal dementia, 14 percent

●Alzheimer-like dementia, 8 percent

●Aphasia, typically categorized as primary progressive aphasia or progressive nonfluent aphasia, 5 percent

●Mixed diagnoses involving the above phenotypes, 6 percent

●Parkinson disease, 4 percent

●Dementia with Lewy bodies, 1 percent

●Other, 1 percent

All of these phenotypes may also be associated with non-CBD pathologies, causing diagnostic challenges [8]. (See 'Diagnosis' below.)

Motor and gait involvement — In a systematic review that evaluated retrospective data from patients with pathologically confirmed CBD, the most common motor features (with frequency at presentation and during the entire course of disease) were the following [8]:

●Limb rigidity (57 and 85 percent)

●Bradykinesia or clumsy limb (48 and 76 percent)

●Postural instability (41 and 78 percent)

●Falls (36 and 75 percent)

●Abnormal gait (33 and 73 percent)

●Hyperreflexia (30 and 50 percent)

●Axial rigidity (27 and 69 percent)

●Tremor (20 and 39 percent)

●Limb dystonia (20 and 38 percent)

●Myoclonus (15 and 27 percent)

In many cases, motor symptoms begin in one limb. Rigidity can be profound with and without cogwheeling. Dystonia involves abnormal posturing of the hand (opened or closed) or foot (toe curling and foot inversion) that quickly becomes fixed. Along with apraxia (see 'Cortical dysfunction' below), the affected limb is rendered useless [26,27]. While axial rigidity, typical of PSP, is sometimes seen, the limb rigidity is notably more severe [14,28]. Symptoms ultimately progress to involve all four limbs.

The gait in CBD is variable but can be bradykinetic, short stepped, and shuffling, similar to the gait of typical Parkinson disease [29]. There is typically no arm swing in the affected upper limb, which is often flexed and held against the body. A wide based "frontal lobe" or freezing gait can also occur in this disorder [27,29]. One study found that freezing of gait occurred in 1 of 13 patients with CBD within three years, and in 3 of 12 patients within six years [30]. Rarely, CBD can present with gait freezing as primary progressive freezing gait [31]. Postural instability is considered a later feature as opposed to that seen in PSP. However, one study suggested that gait difficulty and a propensity to fall can be the earliest motor feature [24]. Occasionally, some patients can develop leg apraxia, making it impossible to walk.

Tremor is seen less frequently than in Parkinson disease [19] and is more often a rapid (6 to 8 hertz) postural/action tremor. There is also an irregularity and jerkiness to the tremor suggesting more of a myoclonic phenomenology. Nonetheless, the tremor is sometimes mistaken for the classic resting tremor of Parkinson disease early on [28,32].

The myoclonic activity seen in CBD is action- or reflex-induced rather than spontaneous [33] and can often be elicited by sensory or motor stimulation or action of the affected limb, such as by tapping the limb or testing deep tendon reflexes. The myoclonus is probably related to an enhanced, long-loop reflex with a pathway that is different from classic cortical reflex myoclonus [34].

Speech alterations — In a systematic review of patients with pathologically confirmed CBD, speech changes were noted at presentation in 23 percent of patients and during the entire course of disease in 53 percent [8]. Some earlier reports suggested that speech is ultimately affected in 90 percent or more of patients with CBD [14,35].

Dysarthria is prominent and often an early feature. Characteristics are mixed and varied. Approximately one-third of patients have the hypokinetic form, similar to the type seen in Parkinson disease, that is characterized by reduced volume, monotone pitch, fluctuating speech articulation, shallow inhalations, and a slow rate of speech punctuated with rapid burst [35]. Other less common forms include mixed dysarthrias with varied features of spasticity and pseudobulbar speech (as seen in PSP), strained strangulated voice with prolongation of sounds similar to spasmodic dysphonia, and hypernasality.

Apraxia of speech, a disorder of speech articulation, is characterized by effortful, halting speech and inconsistent speech sound distortions and errors. It can be a presenting symptom of CBD and overlaps with the nonfluent/agrammatic variant of primary progressive aphasia (naPPA; also called progressive nonfluent aphasia) [36-38]. (See 'Aphasia' below.)

Oculomotor dysfunction — Abnormal eye movements are noted at presentation in one-third of patients with CBD, and during the entire course of disease in 60 percent [8]. Pursuit eye movements in CBD are slow and saccadic with the appearance of several steps to reach a target [39]. Vertical saccades are usually normal or only mildly affected in CBD [40] as compared with PSP, where initial slowing of vertical saccades is followed by a limitation of saccadic range and eventually ophthalmoplegia. Initiation of saccades on demand may be impaired, although spontaneous saccades remain normal [41]. This represents a form of oculomotor apraxia. In a significant minority of CBD cases, oculomotor signs can mimic findings of PSP [7,15].

Cortical dysfunction — Cortical dysfunction is a defining feature of CBD, hence the name of the condition. In patients with pathologically confirmed CBD, the most common higher cortical features (with frequency at presentation and during the entire course of disease) are [8]:

●Cognitive impairment (52 and 70 percent)

●Behavioral changes (46 and 55 percent)

●Limb apraxia (45 and 81 percent)

●Aphasia (40 and 52 percent)

●Depression (26 and 51 percent)

●Cortical sensory loss (25 and 27 percent)

●Alien limb (22 and 30 percent)

Cognitive impairment — Cognitive decline is a prominent feature of CBD [13,42,43]. As an example, in a series of 13 autopsy-proven cases of CBD, dementia was the most common presentation [42]. Only 4 out of the 13 cases had an antemortem diagnosis of CBD, while 6 others were clinically diagnosed (incorrectly) as having Alzheimer disease (AD) [42].

Some CBD patients with cognitive symptoms never develop motor features. In such cases, pathological features may be greater in the temporal and less in perirolandic cortices than those with typical motor features [44].

Neuropsychological testing of patients with suspected CBD shows patterns distinctly different from those of patients diagnosed with AD [45]. In one study comparing 21 subjects who had CBD with 21 patients who had AD, those with CBD scored better in areas of verbal memory but showed more depression on the Geriatric Depression Scale, whereas patients with AD did better on tests of praxis and motor skills [45]. Both groups performed poorly on tests of attentional skills, as shown in the performance of speed of processing information and mental control. Another report found that learning disabilities could be overcome with verbal cueing in patients with CBD but not in those with AD, owing to the relatively preserved retention abilities in the former [46]. Some reports mention there may be mild impairment of episodic memory due to frontal lobe dysfunction resulting in poor encoding and retrieval [47].

In a study comparing the cognitive features of patients with a clinical diagnosis of CBD and PSP, ideomotor apraxia was significantly more frequent in those with CBD [48]. Executive function, though abnormal in both, was more severely impaired in those with PSP [48]. However, another study found that patients with CBD had a dysexecutive syndrome similar to that seen in PSP [46].

Behavioral change — Behavioral and neuropsychiatric manifestations of CBD may include depression, compulsive behavior, hypersexuality, hyperorality, unmotivated laughter, agitation, irritability, social withdrawal, and apathy [8,49-51].

Apraxia — Apraxia is a frequent manifestation of cortical dysfunction and is defined as difficulty performing learned and purposeful skilled movements despite having the desire to do so; it is not explained by deficits in comprehension or elemental motor or sensory function [52].

Various types of apraxia are observed in CBD, including ideomotor apraxia (inability to perform goal-directed movements; inability to imitate hand gestures and tool use, eg, pretending to brush one's teeth using the hand as the object) and ideational apraxia (inability to coordinate activities that require multiple sequential movements; loss of ability to conceptualize, plan, and execute the sequence of actions involved in the use of tools). With ideomotor apraxia, the most frequent type in CBD, unilateral damage to the dominant hemisphere and supplemental motor area can produce bilateral symptoms [33,53]. Ideational apraxias tend to occur in more advanced stages of CBD and in AD [33].

Apraxia may occur any time in the course of illness, including before the emergence of dystonia and myoclonus. In such cases, the apraxia alone may render the hand useless. Apraxia may also present after the onset of other motor symptoms and may then be difficult to detect because rigidity, dystonia, and myoclonus can themselves prevent the proper performance of skilled movements. The usual complaint of the patient is that the limb will not do what they want it to do. Apraxia is usually associated with cortical sensory loss such as agraphesthesia and astereognosis. Patients may complain of numbness and tingling, and examination may also demonstrate impaired two-point discrimination [10,39].

Other domains that may be involved include speech apraxia (see 'Speech alterations' above), buccofacial apraxia, eyelid opening apraxia, as well as oculomotor apraxia (see 'Oculomotor dysfunction' above) [54].

Aphasia — Language problems associated with CBD range from mild phonologic impairments to severe and progressive nonfluent aphasia, a type of aphasia often complicated by the coexistence of speech apraxia (see 'Speech alterations' above) that is sometimes observed in other tauopathies, including frontotemporal dementia and AD [15,22,36,55-57]. Logopenic and semantic variants of primary progressive aphasia can also be seen [58].

In patients with CBD, aphasia is usually noted earlier in those with cognitive-onset CBD compared with those who have motor-onset CBD and may be a presenting feature. However, aphasia typically develops with disease progression in patients with motor-onset CBD [56]. (See "Frontotemporal dementia: Clinical features and diagnosis", section on 'Primary progressive aphasia'.)

Alien limb phenomenon — Another manifestation of cortical dysfunction in CBD is the alien limb phenomena, which is seen in 30 to 50 percent of patients with CBD [8,14,59]. It can affect the arm or leg and is described as a feeling that the limb does not belong to the subject or that it has a will of its own. The limb moves outside of voluntary control with complex movements beyond simple levitation. It can appear to the observer that the limb is in constant motion, grabbing the other hand or other object. The patient indicates that they have no control. Although a striking feature when present, it is not pathognomonic for CBD, but should increase consideration for the diagnosis [19,60,61]. This phenomenon has also been associated with lesions in the mesial frontal lobe and genu as well as rostral body of callosum [62]. Interhemispheric inhibition through the transcallosal inhibitory pathways, which regulates the inhibition of contralateral motor cortex during the initiation of movement, is disrupted in these individuals [63].

Neuroimaging — In early stages of CBD, brain imaging with computed tomography (CT) and magnetic resonance imaging (MRI) may be normal [43]. As the disease progresses, abnormalities in the form of asymmetric cortical atrophy are observed in up to half of patients [64,65]. Focal atrophy predominantly involves the posterior frontal and parietal regions, along with dilatation of the lateral ventricles [66]. Atrophy of the corpus callosum is also detectable on imaging [48,66,67]. On T2-weighted images, there is signal hyperintensity of the atrophic cortex and underlying white matter [48] and, in some cases, minor signal hypointensity of the putamina and pallida, while the signal in the rest of the basal ganglia remains normal [66]. Voxel-based morphometry using MRI has shown atrophy predominantly involving the frontal lobes, basal ganglia, and brainstem [24]. (See 'Potential biomarkers' below.)

The use of striatal dopamine transporter imaging (DaTscan) and positron emission tomography (PET) in CBD and other parkinsonian syndromes is discussed separately. (See 'Potential biomarkers' below and "Diagnosis and differential diagnosis of Parkinson disease", section on 'DaTscan'.)

Electrophysiologic tests — Electrophysiologic tests in CBD are not diagnostic but can provide helpful information.

●Electroencephalography (EEG), normal at first, might show latent asymmetric slowing. Later in the course of the disease, EEG may show slowing in the delta and theta frequency, with occasional sharp waves that enhance with activation procedures such as hyperventilation and photic driving [68]. Myoclonic jerks show no preceding spike or sharp waves on back-averaged EEG testing [32,34].

●Electromyography might help to characterize the myoclonus of CBD, demonstrating the ultra-short-latency, stimulus-sensitive myoclonus typical of the disorder [27]. Electromyography reveals the short duration (25 to 50 msec) muscle discharges of simultaneously activated antagonist muscle pairs, occurring in clusters [32].

●Somatosensory evoked potentials, generally abnormal in CBD, rarely show enlargement of potentials and do not correlate with the presence of myoclonus [32,34]. (See "Symptomatic (secondary) myoclonus", section on 'Corticobasal degeneration'.)

PATHOLOGY AND PATHOPHYSIOLOGY — Due to the diagnostic uncertainty in life and the lack of biomarkers, the postmortem examination is necessary to make a definitive diagnosis of CBD. From the initial description of neuropathology [2], CBD was considered mainly as a distinct neurodegenerative disorder characterized by asymmetric frontoparietal atrophy with extensive neuronal loss, gliosis, and ballooned achromatic (ie, without staining) neurons. The descriptive pathologic terms "ballooned neurons" and "neuronal achromasia" eventually became synonymous with the disorder [17]. Today, a broader range of pathology has been established, and the overlap of many features with other neurodegenerative disorders such as frontotemporal dementia (including Pick disease), Alzheimer disease (AD), and progressive supranuclear palsy (PSP) is increasingly recognized to be related to a shared tau-related cytoskeletal pathology [4,13,69].

Typical autopsy findings in CBD on gross examination include an asymmetric frontoparietal cortical atrophy that is oftentimes localized to the perirolandic region [4,13,70]. A study comparing neuropathology between cases of CBD (n = 9) and PSP (n = 24) showed that gross brain atrophy was detectable in CBD irrespective of whether first symptoms were motor or cognitive [70]. Brain atrophy was progressive and, in contrast to PSP, was similar to that seen in other frontotemporal dementia tauopathies. There is also depigmentation and degeneration of the substantia nigra [4,13].

On microscopic examination, the cortex shows loss of neurons and gliosis [4,10,13,17,71]. The deeper layers of the involved cortex show achromatic ballooned neurons that are comprised of neurofilaments, with eccentrically located nuclei and almost complete loss of Nissl substance. Subcortical nuclei are affected variably, but the pars compacta of the substantia nigra usually shows uniformly severe loss of neurons [13]. Neurofibrillary tangles are found variably in the neurons of the cortex, striatum, globus pallidus, subthalamic nucleus, and brainstem [13], but are absent in the hippocampus, occipital cortex, and inferior and medial temporal cortex [17]. The distribution of subcortical neurofibrillary tangles in CBD is similar to that seen in PSP, but the strands have a more thread-like appearance in CBD, rather than the globose appearance typical of PSP [13]. Tau-positive astrocytic plaques (picture 1) are presently considered highly suggestive of CBD, as are tau inclusions in the glia [10,14]. These same astrocytic plaques, however, are reported in cases of PSP as well [13,72]. Tau-positive glial pathology and ballooned neurons have additionally been reported in Pick disease and PSP, but are considered diagnostic of CBD in the absence of numerous Pick bodies and globose neurofibrillary tangles [69]. Neuropil threads and basophilic inclusions are present in the substantia nigra and basal ganglia [14].

Tau is a protein that is expressed mainly in neurons [73]. It is involved in axonal transport and stabilization of neuronal microtubules. Abnormal phosphorylation of tau interferes with microtubule function, impairs axonal transport, and leads to tau aggregation into neurofibrillary tangles. Normal brain tau contains six isoforms that are generated by alternative messenger RNA splicing of a single tau gene on chromosome 17. Alternative splicing of exon 10 results in isoforms with either three repeats (3R) or four repeats (4R) of the tau microtubule binding domain. The normal ratio of 3R-tau and 4R-tau is approximately equal; disruption of the normal ratio is thought to lead to neurodegeneration [73]. Isoforms common to both CBD and PSP are aggregates of the 4R-tau that occur because of splicing of exon 10. By contrast, the 3R-tau form dominates in the aggregates of some other tau disorders, such as AD [10].

A sequential evaluation of aging-related tau astrogliopathy in 687 individuals, of which 40 cases had CBD and 97 cases had PSP, showed the presence of astrocytic plaque pathology following a particular pattern [74]. For CBD, this was sequenced under four stages as frontal and parietal cortex (stage 1), followed by temporal and occipital cortex (stage 2), and sequentially into the striatum and amygdala (stage 3), and finally to the brainstem (stage 4). By contrast, the study described the pattern in PSP as starting from striatum (stage 1), to fronto-parietal to temporal and then occipital areas (stage 2), followed by amygdala (stage 3), and finally to brainstem (stage 4).

As abnormally configured tau protein is a common neuropathological feature of CBD and PSP [9,10], it is suggested that the disorders may relate to abnormalities in the microtubule-associated protein tau (MAPT) gene. Although CBD and PSP are considered sporadic disorders, both are associated with a greater frequency of homozygosity for the H1 tau haplotype [75,76]. The H1 haplotype arose from an inversion of 900 kilobase pairs on chromosome 17q21 and contains the MAPT gene. The presence of particular single-nucleotide polymorphisms can help differentiate H1 from H2 and has been used to demonstrate the H1/H1 haplotype. Tau-associated pathology appears predominantly in the corpus callosum and parasagittal and paracentral gyri in CBD, as contrasted with PSP, where these findings are concentrated in subcortical regions [70]. In CBD, the tau histopathology correlates with areas of cortical atrophy.

TAR DNA-binding protein 43 (TDP-43) is also prominent in a subset of cases. In a study of 187 autopsy-confirmed CBD cases, TDP-43 pathology was found in 45 percent of specimens [77]. Cases with higher density of TDP-43 pathology were clinically similar to a PSP phenotype, including downward gaze palsy.

The uniqueness of CBD pathology and its distinction as a separate disease came into question with the advances in molecular biology demonstrating a link to the tau haplotype H1 that is associated with tau protein pathology in PSP [9]. As illustrated above, findings once thought unique to CBD have been increasingly recognized in other neurodegenerative disorders that display tau-associated pathology, particularly PSP [4,13,69]. These findings have led some experts to suggest that these two entities, expressed clinically as different phenotypes, are actually the same disease, or at least genetically linked. However, while both PSP and CBD are more frequently associated with homozygosity for the H1 tau haplotype [75,76], the H1 haplotype is also more common in patients with Parkinson disease compared with controls, even though tau accumulation and aggregation are not a part of its pathological picture [78], except in the late stages when dementia occurs and Alzheimer pathology is present in a significant minority of autopsied brains [79]. Therefore, the significance of the shared genetic associations among these disorders remains uncertain.

MAPT gene mutations lead to dysfunction of the membrane-associated 4R-tau and give rise to increased 4R-tau. Genome-wide association studies have shown genetic overlap with PSP and an association of CBD cases with single nucleotide polymorphisms in the MAPT H1 haplotype as well as in the myelin-associated oligodendrocyte basic protein (MOBP) gene [80,81].

Increased expression of C9orf72 may also play a role in some CBD cases. Intermediate-length C9orf72 repeats were significantly enriched in a study of autopsy-proven CBD [82]. Large C9orf72 repeat expansions, associated with amyotrophic lateral sclerosis and frontotemporal dementia, are known to decrease C9orf72 expression, but intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue.

A range of genetic alterations more commonly associated with other neurodegenerative disorders have been identified in patients with possible or probable corticobasal syndrome (CBS), as might be expected based on the variable neuropathologies associated with CBS [83]. In a systematic review of 40 publications on 58 such cases of CBS that also tested positive for a pathogenic variant in a previously described disease-causing gene, the most common variants were in granulin precursor (GRN; 48 percent), MAPT (16 percent), C9orf72 (10 percent), and prion protein (PRNP; 7 percent) [84]. Patients with GRN and C9orf72 variants manifested behavioral and cognitive symptoms that can be seen in frontotemporal dementia, such as visuospatial impairment, behavioral changes, and language alterations. Patients with MAPT and PRNP variants were more likely to manifest motor, oculomotor, and bulbar features. Variants were also identified in glucocerebrosidase (GBA), presenilin 1 (PSEN1), amyloid beta precursor protein (APP), TAR DNA binding protein (TARDBP), charged multivesicular body protein 2B (CHMP2B), leucine-rich repeat kinase 2 (LRRK2), and cytochrome P450 family 27 subfamily A member 1 (CYP27A1) [84].

DIAGNOSIS — The diagnosis of corticobasal syndrome (CBS) is made clinically, relying on the history and neurologic examination (see 'Diagnostic criteria' below). Neuropathologic assessment remains the gold standard for definitive diagnosis of CBD (see 'Pathology and pathophysiology' above).

Evaluation — The clinical diagnosis of CBS is challenging because of the wide variety of presentations, which include early behavioral or cognitive impairment in addition to the classic asymmetric akinetic-rigid motor syndrome with apraxia. Nevertheless, the classic asymmetric syndrome is relatively specific for the diagnosis, whereas the other phenotypes are less so. (See 'Clinical features' above.)

There are no established biologic markers for the disease. Routine blood, urine, and cerebrospinal fluid examinations are all unrevealing [17,18,43]. Structural and functional imaging studies can be employed but none is considered sensitive enough to reliably distinguish CBD from other atypical parkinsonian syndromes [18,85,86]. Structural brain imaging may be most helpful when done serially at 6- to 12-month intervals, as abnormalities become apparent over time [17]. Tests of olfaction can be a useful diagnostic tool, since olfactory dysfunction (hyposmia or anosmia) is common in Parkinson disease, rare in CBD and progressive supranuclear palsy (PSP), and mildly impaired in multiple system atrophy. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Olfactory testing'.)

One of the hallmarks of the CBD is poor or no responsiveness to levodopa therapy, a feature that is sometimes employed as a diagnostic screening tool for selected patients with suspected CBD who have prominent motor symptoms and appear clinically similar to Parkinson disease. The response to levodopa therapy can be tested by building up to carbidopa-levodopa 25/250 mg administered three times a day for at least two months. The response to levodopa is considered poor if the extrapyramidal features do not show marked improvement, or if the therapeutic effect is transient (ie, lasts less than a year). With little response, the drug should be tapered off gradually, although some patients may prefer to continue taking it if they notice deterioration of function during the tapering.

An excellent response to dopaminergic therapy is an important supportive feature for establishing the diagnosis of Parkinson disease, as discussed in detail elsewhere. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Response to dopaminergic therapy'.)

Antemortem versus postmortem diagnosis — The clinical diagnosis of CBS does not reliably predict the neuropathologic diagnosis of CBD. The challenge of making the correct antemortem diagnosis of CBD is illustrated by the following observations:

●In various autopsy series of patients with a clinical diagnosis of CBS, the final autopsy diagnoses are CBD (30 to 40 percent of cases), PSP (15 to 30 percent), Alzheimer disease (AD; 15 to 25 percent), and a variety of other pathologies (15 to 30 percent) [83,87].

●Another study found that the clinical diagnosis of CBS made by neurologists who were unaware of the neuropathologic diagnosis had a low sensitivity (35 percent) but a high specificity (>99 percent) for pathologically proven CBD [60].

●In a report of 21 cases with an antemortem clinical diagnosis of CBS, only 5 (23 percent) had pathologic confirmation of the diagnosis [7]. Conversely, among 19 cases with a pathologic diagnosis of CBD, a correct antemortem clinical diagnosis was made in 5 (26 percent).

●In a study of 19 cases of pathologically confirmed CBD from the United Kingdom brain bank, five had been diagnosed correctly in life, yielding a sensitivity of 26 percent, and four of these had received an alternative earlier diagnosis [7]. Eight were diagnosed with PSP. Of 21 cases with a clinical diagnosis of CBS, only five had CBD pathology, giving a positive predictive value of 24 percent. Six others had PSP. Forty-two percent of CBD cases presented clinically with a PSP phenotype and 29 percent of cases had PSP pathology.

These results suggest that the phenotype of CBS is nonspecific with respect to the underlying neuropathology, and that CBD is often misdiagnosed during life [24,88]. However, for most of the studies cited above, the experience of the practitioners who made the clinical diagnosis of CBS is uncertain. Unlike Parkinson disease, the accuracy of movement disorder specialist diagnoses in atypical parkinsonism has not been well studied. Thus, the generally poor performance for the antemortem diagnosis of CBS/CBD revealed in the available data may relate to inadequate recognition of the clinical features and the lack of truly discriminating clinical criteria.

Diagnostic criteria — A number of clinical and research criteria for CBD have been proposed, but none have been validated [8,18,89-91]. In a 2013 systematic review of pathologically confirmed cases of CBD, an expert panel identified different phenotypes associated with CBD pathology, and these phenotypes were used to create two sets of consensus criteria [8]. The first was clinical research criteria for probable sporadic CBD, designed to be more specific. The second was criteria for possible CBD, designed to be more inclusive and to emphasize clinical presentations consistent with CBD that may overlap with other tau-based pathologies.

The consensus phenotypes identified with CBD are as follows [8]:

●Probable CBS – Characterized by an asymmetric presentation and at least two of:

•Limb rigidity or akinesia

•Limb dystonia

•Limb myoclonus,

plus two of:

•Orobuccal or limb apraxia

•Cortical sensory deficit

•Alien limb phenomena (more than simple levitation)

●Possible CBS – May be symmetric and characterized by at least one of: limb rigidity or akinesia, limb dystonia, and limb myoclonus, plus one of: orobuccal or limb apraxia, cortical sensory deficit, and alien limb phenomena (more than simple levitation)

●Frontal behavioral-spatial syndrome (FBS) – Characterized by two of: executive dysfunction, behavioral or personality changes, and visuospatial deficits

●Nonfluent/agrammatic variant of primary progressive aphasia (naPPA) – Characterized by effortful, agrammatic speech plus at least one of:

•Impaired grammar/sentence comprehension with relatively preserved single-word comprehension

•Distorted speech production (apraxia of speech)

●PSP syndrome (PSPS) – Characterized by three of:

•Axial or symmetric limb rigidity or akinesia

•Postural instability or falls

•Urinary incontinence

•Behavioral changes

•Supranuclear vertical gaze palsy

•Decreased velocity of vertical saccades

The more specific clinical research criteria for probable sporadic CBD (table 2) are as follows [8]:

●Presentation with insidious onset and gradual progression

●A one-year minimum duration of symptoms

●Age ≥50 years at onset

●Permitted phenotypes are probable CBS, or FBS or naPPA plus at least one CBS feature (ie, limb rigidity or akinesia, limb dystonia, limb myoclonus, orobuccal or limb apraxia, cortical sensory deficit, or alien limb phenomena)

●Exclusions include a family history involving two or more relatives and/or a genetic mutation affecting tau (eg, MAPT gene)

The less restrictive clinical criteria for possible CBD (table 2) are the following [8]:

●Presentation with insidious onset and gradual progression

●A one-year minimum duration of symptoms

●No minimum age requirement

●Permitted phenotypes are:

•Possible CBS

•FBS or naPPA

•PSPS plus at least one CBS feature (ie, limb rigidity or akinesia, limb dystonia, limb myoclonus, orobuccal or limb apraxia, cortical sensory deficit, or alien limb phenomena)

●No exclusion for family history or genetic mutation affecting tau

Common exclusion criteria for both probable sporadic CBD and possible CBD are as follows [8]:

●Evidence of Lewy body disease (see "Clinical manifestations of Parkinson disease" and "Diagnosis and differential diagnosis of Parkinson disease" and "Clinical features and diagnosis of dementia with Lewy bodies"), such as classic 4 hertz Parkinson disease resting tremor, excellent and sustained levodopa response, or hallucinations

●Evidence of multiple system atrophy (see "Multiple system atrophy: Clinical features and diagnosis"), such as dysautonomia or prominent cerebellar signs

●Evidence of amyotrophic lateral sclerosis (see "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease"), such as the presence of both upper and lower motor neuron signs

●Semantic or logopenic variant of primary progressive aphasia (see "Frontotemporal dementia: Clinical features and diagnosis", section on 'Primary progressive aphasia')

●Structural lesion suggestive of a focal cause

●Granulin mutation or reduced plasma progranulin levels; TDP-43 mutations; fused in sarcoma (FUS) mutations (ie, genetic variants of frontotemporal dementia and amyotrophic lateral sclerosis)

●Evidence of AD, such as a low ratio of beta amyloid peptide 42 to tau in the cerebrospinal fluid or a positive amyloid positron emission tomography (PET) tracer study (see "Clinical features and diagnosis of Alzheimer disease"), or a genetic mutation suggesting AD, such as presenilin or amyloid precursor protein (see "Genetics of Alzheimer disease")

Proposed pathologic criteria for the diagnosis of CBD require the detection of characteristic tau-immunoreactive lesions in the neurons, glia, and cell processes of the cortex and striatum (caudate and putamen), particularly astrocytic plaques and thread-like lesions in both white matter and gray matter, in conjunction with neuronal loss in focal cortical regions and in the substantia nigra [92]. Supportive features include ballooned cortical neurons, cortical atrophy, and tau-positive oligodendroglial coiled bodies.

Potential biomarkers — There are no established biomarkers for the diagnosis of CBD. Functional imaging studies cannot reliably distinguish CBD from other atypical parkinsonian syndromes.

DaTscan (ie, striatal dopamine transporter imaging using 123I-FP-CIT single-photon emission computed tomography [SPECT]) is generally abnormal in CBD in a manner similar to Parkinson disease and other atypical parkinsonian syndromes such as multiple system atrophy and PSP. Compared with patients who had Parkinson disease, one study reported that FP-CIT binding reduction in patients with CBD was characterized by increased variability, more uniform reduction throughout the striatum (as opposed to greater putaminal loss in Parkinson disease), and greater hemispheric asymmetry [93]. However, this test cannot be used to definitively differentiate CBD from other atypical parkinsonian syndromes [94]. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'DaTscan'.)

SPECT scanning using 99mTc-hexamethylpropylene amine oxime (HMPAO), which measures blood flow through leukocyte labeling, shows regional reductions in HMPAO uptake in the medial frontal, temporoparietal, superior parietal, and lateral frontal regions of both hemispheres in CBD [95]. In addition, there is bilateral and symmetric reduction in thalamic blood flow in patients with CBD [95]. These results demonstrated a greater reduction in cerebral cortical blood flow and more asymmetry than those patients with Parkinson disease [95].

The PET finding most typical of CBD is asymmetric cerebral glucose hypometabolism most prominent in the posterior frontal, inferior parietal, and superior temporal regions, thalamus, and striatum of the more affected hemisphere [67,86,96-98]. There is also an asymmetric decrease in global cortical oxygen consumption [99]. In a small pilot study using PET, an automated algorithm, using multiple measures, distinguished patients with CBD (a tauopathy) from those with multiple system atrophy (a synucleinopathy) but not PSP (another tauopathy) based upon asymmetric variance in regional brain metabolism [100]. Of note, PSP and CBD can be hard to distinguish clinically and are closely related pathologically. The availability of PET imaging is generally limited to research centers. A European task force has endorsed use of 18-F fluorodeoxyglucose (FDG)-PET for assessing possible CBS pattern in patients with dementia [101].

Analysis of brain atrophy by magnetic resonance imaging (MRI) voxel-based morphometry is another method that may be useful to differentiate the underlying pathology of patients who present clinically with CBS. In a case-control study of 24 patients diagnosed on clinical grounds with CBS who had MRI during life and came to autopsy, a neuropathologic diagnosis of CBD was made in seven, AD in six, PSP in six, and frontotemporal lobe degeneration in five [102]. Focal atrophy detected on MRI by voxel-based morphometry in premotor and supplemental motor areas was suggestive of CBD or PSP, while more widespread atrophy was suggestive of frontotemporal lobe degeneration or AD. A subsequent study evaluated 18 patients with an autopsy diagnosis of CBD and 40 patients with known histopathology who presented with clinical CBS [24]. Anterior spread of atrophy from the perirolandic regions suggested that the underlying pathology was CBD, while brainstem and subcortical atrophy was more likely with PSP pathology, and posterior spread to temporoparietal cortex was more likely with Alzheimer pathology.

Imaging modalities that use tau-specific ligands have also been developed and studied in tauopathies, including CBD. One such agent is 18F-AV-1451, which has affinity to bind 3R- and 4R-tau, and has demonstrated binding to intra- and extraneuronal tangles with minimal binding to beta-amyloid, alpha-synuclein, or TDP-43 protein [103]. Although most studies have examined AD, there is some evidence of utility in CBD. Case reports have described a correlation with clinical symptomatology [104,105]. However, more evidence is needed before tau-based imaging is incorporated into clinical diagnosis.

Differential diagnosis — When presenting primarily with motor symptoms, CBD is most often misdiagnosed as either Parkinson disease (because of the asymmetric presentation of both disorders), PSP, or multiple system atrophy (predominant parkinsonism subtype) (table 3). (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Differential diagnosis'.)

Certain disorders associated with a predominant dementia, including AD, dementia with Lewy bodies, frontotemporal dementia, Pick disease, and PSP, can present rarely with focal myoclonus, apraxia, alien limb phenomena, focal or hemidystonia, or rigidity, making them difficult to distinguish from CBD with dementia. While some studies suggest that AD and CBD presenting as CBS can be differentiated by clinical features [106], neuropsychological testing, and imaging, the ability to make a correct diagnosis in life remains difficult [107]. (See "Clinical features and diagnosis of Alzheimer disease" and "Clinical features and diagnosis of dementia with Lewy bodies" and "Frontotemporal dementia: Clinical features and diagnosis".)

Patients presenting with a rapid progression of symptoms suggesting CBD with dementia as a feature should be evaluated for a prion disease, such as Creutzfeldt-Jakob disease. (See "Diseases of the central nervous system caused by prions" and "Creutzfeldt-Jakob disease".)

Features that suggest a synucleinopathy (eg, Parkinson disease, dementia with Lewy bodies, multiple system atrophy) rather than a tau disorder like CBD include rapid eye movement sleep behavior disorder and hyposmia. (See "Rapid eye movement sleep behavior disorder" and "Clinical manifestations of Parkinson disease" and "Diagnosis and differential diagnosis of Parkinson disease" and "Clinical features and diagnosis of dementia with Lewy bodies" and "Multiple system atrophy: Clinical features and diagnosis".)

MANAGEMENT — There are no neuroprotective treatments for CBD and no medications that provide significant symptomatic benefits as seen with levodopa in Parkinson disease. Treatment remains targeted at symptom amelioration and at best is not wholly effective [108]. Palliative and safety measures provide relatively little relief of symptoms but are important in overall management of the multiple stresses experienced by patient and caregiver.

Although patients with CBD are generally poorly responsive to levodopa, levodopa therapy may provide some degree of transient benefit for parkinsonism, which is commonly present in CBD [109]. A therapeutic trial is therefore suggested in patients with clinical parkinsonism. A typical regimen is carbidopa-levodopa up to 25/250 mg administered three times a day for at least two months. However, the benefit is at best modest and is seen in only a minority of patients with CBD [19]. At times the effect is demonstrated more clearly upon withdrawal of the drug.

In patients with little response, the drug should be tapered off gradually, although some patients may prefer to continue taking it if they notice deterioration of function during the tapering. Patients should be gradually (eg, slowly over one to two weeks) weaned off of any pharmacologic agent that proves to be ineffective, as side effects are frequent. Dopaminergic drugs should not be abruptly stopped because of the risk of parkinsonism-hyperpyrexia syndrome. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Parkinsonism-hyperpyrexia syndrome'.)

Alternative agents for parkinsonism, such as the dopamine receptor agonists, the monoamine oxidase type B (MAO-B) inhibitors selegiline or rasagiline, and dopamine-releasing agent amantadine, give an even less consistent response [19]. If patients do not respond to levodopa it is unlikely they will respond to these other agents.

Medications that can be used for management of tremor include propranolol, clonazepam, gabapentin, topiramate, and primidone. Baclofen and anticholinergics may be useful for rigidity and dystonia, and clonazepam is helpful in some cases for myoclonus. Patients should be monitored closely for adverse effects, which can be common in this age group. Botulinum toxin has been reported to provide some relief of dystonic spasms and pain in the limbs [17,19,43]. Unfortunately, the efficacy of these treatment agents is low [19].

Depression is common and should be recognized early so that appropriate treatment can be implemented. (See "Unipolar depression in adults: Assessment and diagnosis" and "Unipolar major depression in adults: Choosing initial treatment".)

For patients with cognitive dysfunction, it is reasonable to prescribe a cholinesterase inhibitor such as donepezil, rivastigmine, or galantamine. (See "Cholinesterase inhibitors in the treatment of dementia".)

Walking devices should be utilized for assistance in preventing falls, although upper limb apraxia may make their use impossible, and a wheelchair should be employed when balance is affected to the point of falling. Occupational therapy can be beneficial in assisting with devices for eating and grooming and other adaptive measures. Physical therapy may help some patients with dysfunction of balance and gait as well as range of motion and positioning of dystonic limbs. At least one report noted benefit from video game-based feedback in bilateral upper limbs [110]. Orthotic splinting may also reduce contractures and relieve pressure from tightly clenched fingers pressing into the palm.

Diet and nutrition are important aspects of care, especially because dysphagia is a common late symptom. Consultations from a dietician and a speech therapist can help manage both the risk of malnutrition and aspiration.

The care required for a patient with CBD can be very taxing for the family. Attention should be given to cues that the family is in distress, and referrals for respite care, in-home health assistance, hospice, and counseling should be made. Treatment is aimed at safety, symptom management, and patient and family supportive measures. (See "Palliative approach to Parkinson disease and parkinsonian disorders".)

PROGNOSIS — CBD is a neurodegenerative disease that progresses inexorably to death, but like other disorders in this category, the natural history can be quite variable among individual patients. In two reports with a total of 29 cases of pathologically confirmed CBD, the median survival was 5.5 and 7.9 years, respectively (range 2 to 12.5 years) [14,15]. The most common cause of death is from complications of immobility or dysphagia, such as pneumonia and sepsis [14].

SUMMARY AND RECOMMENDATIONS

●Corticobasal degeneration (CBD) often begins as a cognitive or behavioral disturbance. Because the cognitive and motor features considered characteristic of CBD are not specific to CBD, the term "corticobasal syndrome" (CBS) is used for cases with a clinical diagnosis, while "CBD" is reserved for cases with neuropathologic confirmation. (See 'History and nomenclature' above.)

●The classic description of CBD is that of a progressive asymmetric movement disorder with symptoms initially affecting one limb, including various combinations of akinesia and extreme rigidity, dystonia, focal myoclonus, ideomotor apraxia, and alien limb phenomenon (table 1). Cognitive impairment is also a common manifestation of CBD and may be a presenting feature. Important cognitive features of CBD include executive dysfunction, aphasia, apraxia, behavioral change, and visuospatial dysfunction, with relatively preserved episodic memory. (See 'Clinical features' above.)

●In early stages of CBD, brain imaging with computed tomography (CT) and magnetic resonance imaging (MRI) may be normal. As the disease progresses, abnormalities in the form of asymmetric cortical atrophy are observed in up to half of patients. Focal atrophy predominantly involves the posterior frontal and parietal regions, along with dilatation of the lateral ventricles. (See 'Neuroimaging' above.)

●Pathologically, CBD is characterized by asymmetric frontoparietal atrophy with extensive neuronal loss, gliosis, and ballooned, achromatic neurons. A fundamental abnormality of the cytoskeletal protein tau is the underlying pathologic substrate of CBD. Tau-positive astrocytic plaques are considered highly suggestive of CBD (picture 1), as are tau inclusions in the glia. (See 'Pathology and pathophysiology' above.)

●The diagnosis of CBS is made clinically (table 2). Neuropathologic assessment remains the gold standard for definitive diagnosis of CBD. The clinical diagnosis of CBS is often difficult because of the wide variety of reported presentations. There are no established biologic markers for CBD. (See 'Diagnosis' above.)

●When presenting primarily with motor symptoms, CBD is most often misdiagnosed as either Parkinson disease (because of the typical asymmetric presentation of both disorders), PSP, or multiple system atrophy (table 3). Certain disorders associated with predominant dementia, particularly Alzheimer disease (AD), dementia with Lewy bodies, and frontotemporal dementia (including Pick disease), can present rarely with focal myoclonus, apraxia, alien limb phenomena, and rigidity, making them difficult to distinguish from CBD with dementia. (See 'Differential diagnosis' above.)

●There are no neuroprotective treatments for CBD and no medications that provide significant symptomatic benefits. Treatment remains targeted at symptom amelioration but is not consistently effective. (See 'Management' above.)

●In patients with clinical parkinsonism, we suggest a therapeutic trial of levodopa (Grade 2C). The response can be tested using carbidopa-levodopa up to 25/250 mg administered three times a day for at least two months. With little response, the drug should be tapered off gradually, although some patients may prefer to continue taking it if they notice deterioration of function during the tapering. (See 'Management' above.)

●The median survival from onset of symptoms with CBD is 6 to 8 years and ranges from 2 to 13 years. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Deborah Walls, DNP, APRN-BC, who contributed to an earlier version of this topic review.