Clinical manifestations

Presentation and course

Corticobasal degeneration is a neurodegenerative disorder within the category of tauopathies, a heterogenous group of dementias and movement disorders unified by neuropathological evidence of intracellular filament accumulation composed of microtubule-associated tau protein (110; 124; 31).

Certain characteristics help to guide the clinician to a likely diagnosis of corticobasal degeneration rather than other parkinsonian disorders. First, patients are markedly asymmetric in their motor dysfunction with both parkinsonian (primarily rigidity and akinesia) and cortical features (19). Patients have remarkable difficulty using the involved body side because of superimposed ideational and ideomotor dyspraxia (231; 26).

and cortical sensory loss (Case records of Massachusetts General Hospital 1985; Gibb et al 1988). Using the De Renzi ideomotor apraxia test, Soliveri and colleagues (190) compared limb apraxia in patients with corticobasal degeneration (N = 24) and progressive supranuclear palsy (N = 25). They found that “awkwardness errors,” conceptually appropriate but clumsily executed actions because of fine finger motility, were the most common apraxic error in patients with corticobasal degeneration, followed by spatial errors, characterized by incorrect orientation or trajectory of the arm, hand, and digits in space or in relation to the body. Sequence errors, incorrect sequences of actions, or inappropriate repetition of movements were least impaired in corticobasal degeneration. The order of impairment was reversed in patients with progressive supranuclear palsy. Overall, apraxia was more frequent and more severe in patients with corticobasal degeneration as compared to those with progressive supranuclear palsy. Orofacial, limb, and truncal dyspraxia can occur (148; 152). In a study of 44 consecutive patients with corticobasal degeneration, 23% had a prior history of immobilization or trauma of the limb affected with apraxia (62). This suggests the possibility that limb apraxia and dystonia in patients with corticobasal degeneration may represent a form of peripherally-induced movement disorder (219; 88).

Revised clinical criteria have been proposed to update the National Institute of Neurological Disorders and Stroke (NINDS) criteria (07), but unfortunately they do not improve the specificity of diagnosis (02). In their review of 267 cases of corticobasal degeneration, the most common clinical features noted anytime during the clinical course were limb rigidity (85%), bradykinesia or clumsy limb (76%), postural instability (78%), falls (75%), abnormal gait (73%), and axial rigidity (69%). Less commonly seen, but present, were tremor (39%), limb dystonia (38%), and myoclonus (27%). Higher cortical features present in more than 5 cases included general cognitive impairment (70%), behavioral changes (55%), limb apraxia (57%), aphasia (52%), depression (51%), cortical sensory loss (27%), and alien limb (30%). When examining 210 cases with available neuropathology, authors were able to categorize the corticobasal degeneration into 5 subtypes that comprised 87.1% of cases: corticobasal syndrome (37.1%), progressive supranuclear palsy syndrome (23.3%), frontotemporal dementia (13.8%), Alzheimer disease-like dementia (8.1%), and aphasia (typically categorized as primary progressive aphasia or progressive nonfluent aphasia, 4.8%). An additional 5.7% were mixed diagnoses involving these phenotypes. Parkinson disease was diagnosed in 3.8% of patients. Two patients were diagnosed with dementia with Lewy bodies, and 3 patients received other diagnoses. Two patients received no syndromic diagnosis. In another series of 147 clinically diagnosed corticobasal degeneration subjects, Kompoliti and colleagues reported parkinsonian signs in 100% of subjects, other movement disorders such as myoclonus or dystonia in 89%, and higher cortical dysfunction in 93%. The most common parkinsonian sign was rigidity (92%), followed by bradykinesia (80%), gait disorder (80%), and tremor (55%) (102). Ocular motor signs, including supranuclear gaze palsy, simultanagnosia, oculomotor apraxia, optic ataxia, and Balint sign can occur (130). Nocturnal movement disorders include periodic limb movements during sleep (85). Urinary symptoms are likewise common (177).

Although rest tremor rarely occurs in this condition, postural and action tremor and dystonic spasms often with superimposed jerks are common (29).

Dystonia occurs in over half the subjects with corticobasal degeneration referred to movement disorder centers (219). In a clinical pathological study, dystonia was present in 37.5% of 296 cases of corticobasal degeneration (196). Facial dystonia, lingual dystonia, orofacial dyspraxia, dysarthria, and pseudobulbar affect can impair communication (153; 208; 60). Dystonic contraction of the procerus muscle can cause vertical wrinkling of the glabellar region and the bridge of the nose (187). Myoclonus may also predominate as the most problematic movement disorder (206; 25; 69).

Although pathologically there are significant differences, clinically, it may be impossible to distinguish corticobasal degeneration from several other neurodegenerative dementias. There are reports with radiological support of cases of supranuclear palsy masking as corticobasal degeneration and vice versa (135). The absence of hallucinations may help distinguish corticobasal degeneration from other parkinsonian syndromes. However, rarely, patients can have dual pathology involving tau as well as Lewy bodies, resulting in symptoms of corticobasal degeneration as well that of dementia with Lewy bodies (143). Geda and colleagues found that 22% of corticobasal degeneration subjects had depression, compulsive behavior, and frontal lobe-type behavioral alterations, which are also commonly observed in other neurodegenerative dementias (55). Although tau pathology is a common biological substrate for corticobasal degeneration and progressive supranuclear palsy, a study highlighted that corticobasal degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) pathology may present with symptoms similar to that of progressive supranuclear palsy (101). Similarly, a clinico-pathologic subtype of Alzheimer disease was reported to have symptoms similar to that of corticobasal degeneration (178). Considering certain overlaps in the clinical profile of the 2 tauopathies, ie, progressive supranuclear palsy and corticobasal degeneration, there have been debates whether to classify these 2 tauopathies as 2 distinct disorders or not (79; 115).

Corticobasal degeneration can present with language and speech alterations, particularly primary progressive aphasia. There are 3 types of primary progressive aphasia: 1) progressive nonfluent aphasia, characterized by effortful speech with agrammatism and speech apraxia; 2) semantic primary progressive aphasia, which involves fluent speech with loss of word and object meaning; and 3) logopenic progressive aphasia, characterized by word-finding pauses, moderate anomia, and impaired repetition of sentences (137). In 1 study of 10 patients with primary progressive aphasia who were followed prospectively until they became nonfluent or mute, Kertesz and Munoz found that all had evidence of frontotemporal dementia at autopsy, but 4 also had features of corticobasal degeneration (97). Subsequently, published reports have highlighted the emergence of corticobasal degeneration (15; 98) or a mixed-pathology in patients who initially present with primary progressive aphasia (37). A longitudinal study compared the clinical and neuroimaging characteristics of patients with nonfluent/agrammatic primary progressive aphasia who were later autopsy-proven to have underlying progressive supranuclear palsy or corticobasal degeneration (179). This study by Santos and colleagues revealed that the presence of severe dysarthria and greater white matter than gray matter atrophy at presentation and the appearance of adverse brainstem anatomical and clinical signs at follow-up were typical of progressive supranuclear palsy (179). Other abnormalities of speech in corticobasal degeneration include orobuccal apraxia and a flat, aprosodic speech. Some patients can present with a foreign accent (123). A variety of speech and language abnormalities have been described in patients with corticobasal degeneration (158).

In some families, neurodegenerative tauopathies may be inherited as autosomal-dominant disorders with variable clinicopathological phenotypes (92). One study describes a patient with clinically typical and autopsy-proven corticobasal degeneration. Her mother was diagnosed with Parkinson disease, but autopsy showed corticobasal degeneration pathology as in the index patient. The sister of the index patient had the clinical symptoms of primary progressive aphasia, but no pathology was available. This family suggests that corticobasal degeneration, progressive supranuclear palsy, and primary progressive aphasia may be overlapping diseases with a common pathological basis rather than distinct entities.

The most affected limb can be so dysfunctional that patients find they have little control as it spontaneously floats upward or moves as if no longer attached to the patient's body ("alien limb" phenomenon) (43; 63). Alien limb can be seen as a motor or sensory-based phenomenon (11). Although the alien hand phenomenon is common (observed in 50% to 60% patients), rarely, patients may also develop alien leg phenomenon (63; 151). In a cohort of 150 patients with alien limb phenomenon studied by Graff-Radford and colleagues, 108 patients had a diagnosis of corticobasal degeneration (63). The median time from the onset of the disease to the onset of alien limb phenomenon was 12 months.

On neuropsychological testing, patients with corticobasal degeneration show a mild global cognitive decline, a dysexecutive syndrome similar to that seen in progressive supranuclear palsy, and explicit learning deficits (162; 65). This profile is often distinct from Alzheimer disease, but clinical dementia can be the primary feature that brings patients for neurologic evaluation (38). Among 64 detailed case reports reviewed, 20 showed dementia at some stage of the illness, yielding an incidence of 31% (173). This is close to an earlier estimate of 43% (172). Disinhibition, perseveration, and hemispatial neglect are alternate neuropsychological effects that can impair social, professional, and artistic functions (100). In 1 series of autopsy-proven cases of corticobasal degeneration, dementia was the most frequent clinical presentation (67). Semantic memory deficits are particularly marked for numbers (72). Sensory symptoms, unusual in most parkinsonian syndromes, can occur in approximately one third of patients and can be the presenting symptom resembling primary progressive aphasia (173; 49; 64; 174). Approximately 15% of patients develop dysphasic signs (172; 173; 94). There are cases of corticobasal degeneration presenting with other cortical findings, such as progressive apraxic agraphia or acalculia, in addition to many patterns of cognitive dysfunction (154; 156; 150).

Table 1. Major and Minor Symptoms of Corticobasal Degeneration

Prognosis and complications

Corticobasal degeneration inevitably progresses slowly and is invariably fatal. The progression typically is faster than that of typical idiopathic Parkinson disease. In 1 series of pathologically proven cases, dysarthria occurred 40 months after disease onset and dysphagia at a median of 64 months, in contrast to 84 months and 130 months in Parkinson disease (139). Medications do not appear to affect the natural progression of the neurodegenerative process, and the disease usually progresses to death within 6 to 9 years (59; 226). In 1 series, early bilateral bradykinesia and frontal lobe dysfunction were among the features associated with shorter survival (223). In a study that compared the clinical characteristics of symmetric corticobasal degeneration (no difference between right- and left-sided cortical or extrapyramidal signs or symptoms) and typical cases of corticobasal degeneration, it was revealed that patients with symmetric features had a younger age at disease onset as well as death (74).

Clinical vignette

A 57-year-old librarian described an 8-month history of left-sided hand and leg incoordination. Specifically dating the onset of difficulty was challenging, but she experienced increasing slowness and loss of agility in the left hand when she performed tasks such as dressing, sorting cards, or typing. Often, the left hand cramped, and over the previous month she noted that the whole hand or index fingers occasionally moved by themselves. The left leg also cramped and inverted after she walked more than 200 feet. She felt her right side was unaffected, and her thinking was normal, although she was easily startled. She experienced general body jerks when reading quietly at night. She stumbled but had no falls.

Clinical findings. The patient had a masked face and slight impairment of vertical conjugate gaze. She had parkinsonian signs of rigidity and bradykinesia bilaterally; they were more severe on the left. The left hand and foot had dystonic posture. When the patient closed her eyes and outstretched her hands, the left hand drifted upward, and the fingers wiggled; "They've a mind of their own," she commented. There were intermittent myoclonic jerks of all extremities. Primary sensory modalities were normal, but she had astereognosis in the left hand and could not imitate hammering or saluting to a verbal command with the left hand. Her gait was shuffling, and to a postural threat, she took 3 steps backwards.

Diagnostic tests. Lab tests, including thyroid functions, were normal. MR scan showed cerebral atrophy, particularly of the right parietal region. SPECT scan showed asymmetric uptake of DaTSCAN, especially in the right basal ganglia.

Clinical course. She received carbidopa and levodopa at 25 and 100 mg 3 times per day; there were no signs of benefit. Dopamine agonists only resulted in nausea and dizziness secondary to hypotension. The hand cramp became more troublesome, and she received focal botulinum toxin injections, with relief of pain and spasm. Gait deteriorated with increased falls, and she eventually became wheelchair dependent. The right upper extremity became markedly bradykinetic and rigid in a flexed position. Myoclonus increased and was rhythmic at times, but no seizures developed. Clonazepam abated the myoclonus, but only low doses were used because of sedation. The patient died 5 years after onset.

Biological basis

Etiology and pathogenesis

Corticobasal degeneration falls into a category of diseases called tauopathies (79). Tau is a protein that was originally implicated in disease in 1997 (193), followed by the discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Subsequently, tau pathology was implicated in other pathologically similar diseases, such as Alzheimer disease, Pick disease, and progressive supranuclear palsy (172; 89). The pathological process can involve different tau isoforms such as 3R-tau, 4R-tau, or mixed 3R-/4R-tau isoforms. Corticobasal degeneration has been recognized as a 4R-taupathy (79). Familial cases of corticobasal degeneration or families with both corticobasal degeneration and frontotemporal dementia have been linked to mutations of chromosome 17 (176). In addition, although the microtuble-associated protein tau gene (MAPT) has been associated with autosomal dominant forms of dementia, it may be a factor in sporadic corticobasal degeneration. A case of a 41-year-old gentleman with the corticobasal degeneration phenotype was found to have G389R mutation in the MAPT gene (175). The clinical features of corticobasal degeneration, including primary progressive aphasia, have been described in 2 cases with LRRK2 G2019S mutation (32).

Familial cases of clinical corticobasal degeneration are exceptional, but 2 brothers with typical clinical findings of clinical corticobasal degeneration have been identified (52). A kindred with some members having clinically suspected corticobasal degeneration and others with frontotemporal dementia suggest that common underlying etiologies may have different clinical phenotypes (21). A genome-wide association study reported that corticobasal degeneration and progressive supranuclear palsy share a common genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein) (105).

Other genetic etiologies continue to be explored with the use of whole genome sequencing, but no etiology has yet been determined. The association of C9orf72 intermediate repeats with corticobasal degeneration further expands the landscape of neurodegenerative disorders, such as Huntington disease associated with intermediate repeat expansion (27; 180). Pathologically, corticobasal degeneration has distinctive features that include prominent frontoparietal cortical atrophy and degeneration of the substantia nigra pars compacta. When atrophy is diffuse, other diseases must be considered, such as frontotemporal lobar degeneration or Alzheimer disease, but focal atrophy suggests corticobasal degeneration (224). Pallidal, striatal, and amygdalar lesions can also occur (211). Although the clinical presentation is usually asymmetric, pathological changes and cortical atrophy at death may be symmetric or asymmetric with typically prominent atrophy of the precentral gyrus (34). Microscopically, the traditional hallmark sign is the presence of swollen achromatic cells (ballooned neurons) that resemble those seen in Pick disease (168; 59). A set of minimal neuropathologic consensus criteria was established in 2002 for corticobasal degeneration by the Office of Rare Diseases. These are: cortical and striatal tau-positive neuronal and glial lesions, especially astrocytic plaques and thread-like lesions in both gray and white matter, as well as neuronal loss in focal cortical regions and in the substantia nigra (41). The report also details the technical methods to establish these pathological findings, including the use of specific stains. This set of criteria does not place emphasis on the traditional ballooned neurons or on the clinical features of corticobasal degeneration. Corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia can be distinguished pathologically, but variants of frontotemporal dementia may be more difficult to distinguish (90).

Several other features also can occur in corticobasal degeneration. In contrast to the eosinophilic Lewy bodies that typify Parkinson disease, basophilic nigral inclusions can occur in corticobasal degeneration. Alpha B crystallin, a protein identified in several neurodegenerative disorders, can be seen in ballooned neurons in corticobasal degeneration (121). Ballooned and tau positive neurons cluster in a distinctive pattern with larger ballooned neuron clusters in the lower cortical laminae and larger tau positive neuron clusters in the upper laminae (09). Other reported pathologic findings in corticobasal degeneration include loss of Betz cells associated with prominent astrocytosis and presence of ballooned neurons in the fifth layer of the primary motor cortex (212), and neuropil threads and neuronal inclusions in cervical spinal cord (87).

Studies of tau protein demonstrate that corticobasal degeneration shares a common genetic background with progressive supranuclear palsy (10). Both share the same tau H1 haplotype (82). This finding suggests a similar genomic cause and introduces the concept that these 2 conditions may be phenotypically distinct prototypes of a single biological disorder. Overrepresentation of the H1/H1 genotype has been identified in corticobasal degeneration, progressive supranuclear palsy, and primary progressive aphasia (189). Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene have identified a candidate region between exon 1 and intron 9 that may account for variable phenotypic presentations (164).

The nonamyloid cortical plaques are actually collections of abnormal tau in the distal processes of astrocytes. In addition to the glial pathology that includes tau-positive cytoplasmic inclusions in oligodendrocytes, neuronal alterations involve tau-positive inclusions in multiple cortical cell groups (47; 192). The tau in corticobasal degeneration is hyperphosphorylated (201) and forms unusual twisted filaments that share some features with the paired helical filaments of Alzheimer disease but have distinct ultrastructural differences (107; 166; 228). In contrast with Alzheimer disease, tau immunoreactivity does not uniformly co-localize with Bodian-positive neurofibrillary tangles, suggesting that in corticobasal degeneration, the tau molecule is less liable to form argyrophilic fibrils in neocortical neurons (213). Amino-terminally cleaved tau fragments may distinguish corticobasal degeneration from progressive supranuclear palsy so that, despite the identical compositions of tau isoforms, different proteolytic processing takes place in the 2 disorders (05). In a series of pathologically proven corticobasal degeneration cases, the 2 disorders shared the same accumulation of aggregates containing the 4-repeat isoforms of tau (06; 82). Furthermore, studies of the Ras/MEK/ERK pathway of tau phosphorylation demonstrate that MAPK-P immunoreactivity is found in large numbers of tau-positive glial cells in both conditions (48). In familial dementia with swollen achromatic neurons and corticobasal inclusion bodies (a condition closely resembling corticobasal degeneration), a silent mutation in exon 10 of tau has been identified, suggesting that this region may be of interest to the study of corticobasal degeneration (183; 194). The R406 missense mutation in exon 13 does not appear to bear any relationship to corticobasal degeneration (76). Exon 10 has been an area of focus for corticobasal degeneration and progressive supranuclear palsy (183). The degenerative process is marked in several other areas including locus ceruleus, globus pallidus, red nucleus, and the lateral thalamic and cerebellar nuclei, the corpus callosum, and cerebral white matter (227). Cases exist with features of both corticobasal degeneration and progressive supranuclear palsy and these underscore the heterogeneity of both disorders outside the classic archetypes (221; 44; 95). Tau pathology in the cerebellar cortex involves primarily the Purkinje cells and Bergmann glia, similar to patterns seen in progressive supranuclear palsy (160).

Given the pathology, it is not surprising that with further use of genetics in corticobasal degeneration that tau associated genes are being discovered as potential underlying etiologies of the disease. In a cohort of 109 autopsy confirmed cases of corticobasal degeneration, microtubule-associated protein tau gene (MAPT) mutations were found in 4.6% of corticobasal degeneration patients compared to 1.2% of controls (103). More novel mutations seem to be identified as time and more samples are studied (01).

Advances in biological understanding of corticobasal degeneration have been impeded by the lack of a transgenic animal model to mimic the tauopathy of corticobasal degeneration involving both glia and neurons. The first glial tau accumulation model has been generated in transgenic mice (77). Subsequently, several experimental approaches in animal models have attempted to reduce the tau-burden in neurodegeneration (188; 127).

Studies on pathophysiology have included analysis of cortical disinhibition with transcranial magnetic stimulation (50). Corticobasal degeneration subjects demonstrate enlarged motor evoked potentials obtained in the cortex related to the clinical symptoms involving the hand, suggesting altered cortical excitability and altered transcollosal function (210). Burrell and colleagues revealed that nearly 25% of the patients may have relatively unexcitable motor evoked potential, and for the patients with an excitable cortex, 40% had a reduced resting motor threshold (26). Motor control studies have linked kinematic measures, specifically greater "quality of movement coefficient" to the presence of limb apraxia in corticobasal degeneration. These findings suggest disruption of frontoparietal circuits related to grasping and manipulation together with defective cortical inhibition. In 1 review, neurophysiological abnormalities in corticobasal degeneration are explained in detail (141).

Some cases suggest a possible role of the TAR-DNA-binding protein 43 (TDP-43). This nuclear protein is typically involved in transcriptional repression and splicing but is found in inclusions in a range of neurodegenerative disease including amyotrophic lateral sclerosis, Alzheimer disease, and frontotemporal lobar degeneration (222). It has been found in over 15% of corticobasal degeneration cases (216). Another potential etiology is a mutation along the same pathway that results in abnormal tau phosphorylation, specifically progranulin mutation (195; 200). Progranulin is a widely expressed growth factor that plays a role in development, wound repair, and inflammation. It has been linked to tumorigenesis, but its role in neurons is yet to be determined (54).

Epidemiology

No community-based information is available, but disease registries have been used to estimate the prevalence of corticobasal degeneration (205). One tertiary care center found 1 corticobasal degeneration patient for every 6.7 patients with progressive supranuclear palsy (83). A multicenter survey found a higher ratio of 1:2.5 in Japan, resulting in a prevalence estimate for corticobasal degeneration of 1.93 per 100,000 (138). Based on referral series, corticobasal degeneration appears to be a disorder of late middle age or later life. The mean age of onset is 60 to 65 years of age (171). The youngest age of onset in a pathologically verified case was 45 years (223), but another group reported a patient with an onset of symptoms at the age of 28 years (40). There is a mild predominance of men. No geographic predominance or ethnic clustering has been reported.

Differential diagnosis

Although early reports suggested that corticobasal degeneration was a clinically distinct disorder, additional studies have shown that prototypic signs of corticobasal degeneration, including progressive asymmetric rigidity and apraxia, can develop in the context of other histopathological diagnoses like progressive supranuclear palsy, Pick disease, Creutzfeldt-Jakob disease, Alzheimer disease, progressive multifocal leukoencephalopathy, Fahr disease, motor neuron disease-inclusion dementia, neurosyphilis, and sporadic spinocerebellar ataxia type 8 (20; 66; 218; 109; 119; 16; 12). Conversely, intellectual impairment, supranuclear gaze palsies, and pyramidal signs that ordinarily suggest other parkinsonism-plus syndromes can occur in corticobasal degeneration, and these features are problematic from the perspective of differential diagnosis (170). Ocular problems are reminiscent of progressive supranuclear palsy, whereas pyramidal signs, weakness, and Babinski signs, when apparent, may suggest multiple system atrophy. If dementia predominates, the picture might suggest focal Alzheimer disease or Pick disease. Focal parietal lobe Pick disease can present with all the typical features of corticobasal degeneration including parkinsonism, myoclonus, and asymmetric dyspraxia (111; 134). When myoclonus predominates, Creutzfeldt-Jakob disease and other disorders with secondary myoclonus should be considered (125; 99). Other non-Alzheimer dementias, such as dementia with Lewy bodies, primary progressive aphasia, semantic dementia, frontotemporal dementia, and familial forms of frontal lobe dementia, must also be considered in cases where cognitive decline predominates (23; 155; 96; 132; 72). Voxel-based MRI analyses that measure cortical atrophy across different regions have been applied to separate corticobasal degeneration cases presenting as dementia from other dementing illnesses (70). MR-based volumetry models have been developed to help differentiate progressive supranuclear palsy from corticobasal degeneration (68). In a study using cases confirmed with autopsy-based diagnosis, however, neither cortical atrophy, corpus callosum atrophy, or subcortical and periventricular white matter signal changes showed any finding specific to corticobasal degeneration (91). Although apraxia, alien limb, or arm levitation are often hallmarks of corticobasal degeneration, such findings can occur in progressive nuclear palsy, Alzheimer disease, Pick disease, and Creutzfeldt-Jakob disease (14; 20). In comparison with progressive supranuclear palsy, however, apraxic errors in corticobasal degeneration are more frequent and severe, involving both transitive and intransitive tasks (159). In 1 study comparing progressive supranuclear palsy and corticobasal degeneration subjects with dyspraxia, corticobasal degeneration-related dyspraxia was most pronounced for distal movements (191). Electrophysiologically, the myoclonus in corticobasal degeneration is associated with enhanced long-loop responses without enlarged somatosensory potentials (28). This pattern is distinct from that of classical cortical reflex myoclonus. Other causes of alien hand syndrome, especially of the nondominant hand, include processes that affect the middle portion of the corpus callosum (57). The time course of the disease may also help distinguish it from other slower progressive disorders. Corticobasal degeneration typically advances more quickly than idiopathic Parkinson disease, but on a similar time course as progressive supranuclear palsy.

One set of authors attempted to identify differences in corticobasal degeneration presenting with corticobasal syndrome (n = 11) or Richardson syndrome (n = 15) with respect to demographic, clinical, and neuropathological features (104). Corticobasal degeneration cases were also compared with patients with pathologically proven progressive supranuclear palsy with Richardson syndrome (n = 15). Cases with corticobasal degeneration, regardless of presentation, shared histopathological and tau biochemical characteristics, but they had differing densities of tau pathology in neuroanatomical regions that correlated with their clinical presentation. In particular, those with corticobasal syndrome had greater tau pathology in the primary motor and somatosensory cortices and putamen, whereas those with Richardson syndrome had greater tau pathology in limbic and hindbrain structures. Compared with progressive supranuclear palsy, patients with corticobasal degeneration and Richardson syndrome had less neuronal loss in the subthalamic nucleus, but more severe neuronal loss in the medial substantia nigra and greater atrophy of the anterior corpus callosum. Clinically, they had more cognitive impairment and frontal behavioral dysfunction. The results of this study suggest that Richardson syndrome can be a clinicopathological presentation of corticobasal degeneration. Unfortunately, this study does not help clinicians to differentiate progressive supranuclear palsy from corticobasal degeneration.

Corticobasal degeneration can be a difficult diagnosis to make clinically, and low sensitivity of current clinical diagnostic criteria suggests that it is underdiagnosed. False negative misdiagnoses occur primarily with progressive supranuclear palsy, multi-infarct parkinsonism, multiple system atrophy, and both Alzheimer and Pick diseases (118). Although there are reports of rapidly progressive, fulminant corticobasal degeneration, it is prudent to rule out transmissible spongiform encephalopathy (Creutzfeldt-Jakob disease) in patients with such disease progression (217; 144; Rodriguez-Porcel et al 2016; 209). Because it shares the characteristics of predominant asymmetry with Parkinson disease, corticobasal degeneration should be kept in mind in the differential diagnosis of this more common entity (165). Differential diagnosis is further complicated by the description of new, atypical corticobasal degeneration variants (146; 203). With the increasing trend toward subspecialty services, groups working with demented patients and those working with movement disorders need to be particularly sensitive to this disorder. In 1 study, the authors compared 3 published diagnostic criteria for clinically diagnosed corticobasal syndrome in a group of 40 consecutive patients (22 men, mean age 67 years) with focal cortical syndrome characterized by apraxia and parkinsonism, and found that 30 patients (75%) satisfied all 3 criteria (129). They proposed their own diagnostic criteria (“Cambridge criteria”), which include not only the motor and sensory features but also cognitive features, especially speech and language impairment, frontal executive dysfunction, and visuospatial deficits. Considering the fact that there are overlaps in the clinical features of the neurodegenerative dementias, thorough motor examination of patients with dementia is essential (13).

There are few studies with pathological confirmation to help determine the best method of diagnosing corticobasal degeneration. In a study examining cognitive testing to help differentiate corticobasal degeneration from Alzheimer disease, initial episodic memory complaints and poor performance on the combined orientation-memory subtest of the Addenbrooke's Cognitive Examination reliably predicted Alzheimer disease pathology whereas varying combinations of early frontal-lobe type behavioral symptoms, nonfluent language disturbance, orobuccal apraxia, and utilization behavior predicted corticobasal degeneration pathology (186).

Diagnostic workup

The diagnosis of corticobasal degeneration is primarily a clinical one, but other studies used in many parkinsonian disorders may be considered based on clinical findings. CT or MR imaging may show signs of generalized cerebral or focal parasagittal and parietal atrophy. One study assessed the use of routine MRI for separating Parkinson disease and other parkinsonian syndromes including corticobasal degeneration with a "cortical score" derived from assessment of atrophy in several regions; corticobasal degeneration and progressive supranuclear palsy could be distinguished from multiple system atrophy by "positive predictive values of greater than 90%.” Without such regionally based calculations, the final accuracy of diagnosing corticobasal degeneration by standard MR remains limited (229). Another study compared corticobasal degeneration patients with progressive supranuclear palsy and age-matched controls. There was a disproportionate, asymmetric (left> right) pattern of brain atrophy that involved the bilateral premotor cortex, superior parietal lobules, and striatum (22). A voxel-wise metaanalysis of the studies using voxel-based morphometry revealed that there is characteristic pattern of grey matter atrophy in patients with atypical parkinsonian disorders (230). In this study, compared to multiple system atrophy and progressive supranuclear palsy, patients with corticobasal degeneration had significantly reduced volume of the superior parietal lobule.

White matter hyperintensities on T2-weighted images have also been reported and may involve the primary motor cortex and supplementary motor cortex as an index of demyelination or gliosis (42; 225). Single photon emission computed tomography scans have been used to differentiate patients with clinically diagnosed corticobasal degeneration from those with progressive supranuclear palsy. The “eye of the tiger” sign, with prominent low signal intensity throughout the globus pallidus, except for an anteromedial area of high signal intensity, has been reported on axial T2 weighted MR in 1 case (136). Further comparisons in atypical parkinsonism demonstrated reduced size and increased ADC measurements disproportionately involving the lateral thalamus (75).

PET scans show alterations of cortical metabolism as well as striatal dopamine function, most marked in the cortex and subcortex contralateral to the more severely affected limbs (182; 181; 46; 17; 45; 81; 36). Glucose hypometabolism usually is most marked in the parietal lobe and thalamus but may focus on the frontal lobe and striatum (204). The pattern of cortical deficits in glucose utilization in corticobasal degeneration is distinct from that seen in progressive supranuclear palsy. In comparing the 2 conditions, Nagahama and colleagues demonstrated that corticobasal degeneration was associated with significantly lower glucose metabolism in the inferior parietal, sensorimotor, bilateral temporal cortex, and striatum (142). Metabolic differences in the midbrain, anterior cingulated, and orbitofrontal regions can also be useful in distinguishing progressive supranuclear palsy from corticobasal degeneration (53). In a study measuring brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in 7 patients with corticobasal syndrome, there was decreased acetylcholinesterase activity in the paracentral region and frontal, parietal, and occipital cortices (78).

Asymmetry of metabolic activity in the parietal lobe contralateral to limb apraxia can also be documented by PET scans (46; 45; 86). Hypometabolism of the superior parietal lobule and supplementary motor cortex among subjects with visuoimitative upper limb apraxia in corticobasal degeneration further suggests direct involvement of parietofrontal neural networks (157). 11C-(R)-PK11195, a marker of peripheral benzodiazepine binding sites, has been used as a PET ligand to assess microglial activation. In a small series of patients with corticobasal degeneration, increased binding occurred in the nigra, pons, basal ganglia, and cortical regions known to have neuropathological changes in corticobasal degeneration (56). The limitation of the PET studies is the unavailability of diagnostic certainty as the aforementioned studies were cross-sectional in nature. Considering the fact that several areas of the brain were reported to have hypometabolism of glucose, it seems localization of abnormal protein characterizes the symptoms more than the nature of the protein deposition itself (145; 03).

SPECT imaging is becoming more widely available and asymmetry was initially used to distinguish measures of cerebral blood flow. In 2005, Kreisler and colleagues compared SPECT in corticobasal degeneration to subjects with Parkinson disease and found asymmetric and reduced cerebral blood flow indices in medial frontal, lateral frontal, and parietal regions (106). More recent SPECT utilizes dopamine transporter imaging as a functional measure. In a retrospective analysis of dopamine transporter (DAT) SPECT studies in 2 patients with a pathologically confirmed corticobasal syndrome, baseline scans at 1.5 years after symptom onset revealed only mild abnormalities (reduced uptake in 1 putamen). Follow-up scans at 4.5 years (case 1) and 5 years (case 2) after symptom onset showed a marked decline of striatal DAT binding. In both cases, there was a 37% binding reduction from the age-expected striatal binding value. Therefore, patients with corticobasal degeneration may have delayed neuronal loss in the substantia nigra and follow-up DAT imaging may be of value in patients with possible corticobasal degeneration and a normal baseline scan (163). In a study on 34 patients with corticobasal degeneration, using FDG PET and DAT SPECT, Mille and colleagues revealed asymmetric cortical and subcortical hypometabolism, symmetrically reduced metabolism in the thalamus, and slightly asymmetric reduction in DAT (131). In the same study, the D2/3 receptors seemed to have preserved function.

Functional magnetic resonance scan performed during motor activity can also demonstrate asymmetrically decreased activity in the parietal lobe during both simple and complex sequences (214). The technique has also been applied to the study of the dementia associated with corticobasal degeneration (184). Diffusion tensor imaging has also been used to identify alterations in white matter involving the corpus callosum and corticospinal tract (18). Although the aforementioned studies based on functional and molecular imaging provide valuable insights into the neural networks associated with corticobasal degeneration, results of these studies represent comparison of groups of patients. Hence, utility of these modalities of investigation for individual patients still remains debatable at present.

Somatosensory evoked potentials may demonstrate prolongation of N20 latencies after median nerve stimulation on the dyspraxic side (147; 202). EEG may show signs of nonspecific slowing, more prominent on the side contralateral to the more affected limbs (114; 117; 207; 24). In a report of 2 early cases of corticobasal degeneration, detailed electrophysiological studies failed to identify giant somatosensory evoked potentials or cortical spikes preceding myoclonus jerks (122). Several lines of evidence indicate the probable existence of a subcortical network underlying the myoclonus in corticobasal degeneration (197).

Cerebrospinal fluid analysis remains a research tool, but may help in the future for differentiating corticobasal degeneration from other conditions. Homovanillic acid, the CSF metabolite of dopamine, is not abnormally diminished in the early phases of corticobasal degeneration in contrast to some cases of early Parkinson disease (93). Of particular interest is the identification of cerebrospinal fluid tau protein and alterations reported in corticobasal degeneration and progressive supranuclear palsy, which both offer the potential for future in vivo biological markers that focus on these or similar products (133). Tau values in corticobasal degeneration are significantly higher than seen in progressive supranuclear palsy, and tau assays provide diagnostic sensitivity of 82% and diagnostic specificity of 80% (215). Although potential biomarkers for Parkinson disease and Alzheimer disease are getting closer, CSF analysis for corticobasal degeneration remains, excluding it from other conditions rather than a specific test to evaluate for corticobasal degeneration (71).

Systematic neuropsychological studies of corticobasal degeneration are few in number. Five patients showed impairment of praxis and “frontal-type behaviors” with relative preservation of intellect (17). Fifteen patients subjected to extensive neuropsychological tests showed global cognitive deterioration, a “dysexecutive syndrome,” learning deficits without retention difficulties, dynamic motor disorders, and asymmetric limb apraxia (162). In the largest group studied to date, 21 patients showed more severe deficits of praxis and motor programming than patients with Alzheimer disease (128). However, the patients with corticobasal degeneration also exhibited more evidence of depression, and the effects of a “pseudodementia” could not be discounted. A detailed study of apraxia in corticobasal degeneration showed that the ideomotor type was the most common (113). One patient followed with sequential neuropsychological testing showed not only impairment of praxis and global cognitive function, but also unilateral visual inattention and obsessive-compulsive features (169). Patterns of apraxia deficits may help differentiate cases of corticobasal degeneration from those with progressive supranuclear palsy (39). Another 4 pathologically confirmed cases suggested that early stage corticobasal degeneration may present with self-centered behaviors, such as frontotemporal dementia, apathy with and without auditory hallucination, and aggressive behaviors with delusion and visual hallucination prior to the onset of motor manifestations (84).

Of course, the ultimate diagnostic tool is the use of clinicopathological examination. When 17 patients with corticobasal syndrome were examined in 1 study, 4 clinical syndromes or subtypes emerged: progressive nonfluent aphasia (n = 5), behavioral variant frontotemporal dementia (n = 5), executive motor (n = 7), and posterior cortical atrophy (n = 1) (112). Behavioral or cognitive problems were the initial symptoms in 15 of 18 patients; less than half exhibited early motor findings. Compared to controls, corticobasal syndrome patients showed atrophy in dorsal prefrontal and perirolandic cortex, striatum, and brainstem (p < 0.001 uncorrected). Notably, frontal lobe involvement was characteristic of corticobasal syndrome, and frontal, not parietal or basal ganglia, symptoms dominated early stage disease in many patients.

Management

There are no therapeutic avenues that fully control the symptoms of corticobasal degeneration or reduce the progression of the underlying neurodegeneration. Symptomatic treatment of the individual motor symptoms (parkinsonism, dystonia, myoclonus) and nonmotor symptoms (cognitive impairment, behavioral symptoms) remains the cornerstone of the management of patients with corticobasal degeneration. Parkinsonian features may be abated partially by dopaminergic drugs such as levodopa or dopamine agonists. In the largest published treatment series, Kompoliti gathered 147 cases of clinical corticobasal degeneration and found that antiparkinsonian drugs induced some clinical benefit in 24% of treated subjects and that levodopa was the most effective agent (102). In a retrospective study on pathologically proven cases of corticobasal degeneration, levodopa had resulted in mild-to-moderate improvement (116). Side effects of levodopa, like dyskinesia, are not typical but can occur (51). In addition, the acute levodopa challenge that has been useful in distinguishing patients with idiopathic Parkinson disease from those with atypical parkinsonian disorders including corticobasal degeneration tends to have more side effects (nausea, dizziness, headache) in the latter (220).

For myoclonus, both levetiracetam and clonazepam have been reported to be beneficial (33; 108). Major side effects of these medications include mood changes and somnolence. For the symptomatic treatment of dystonia, botulinum toxin may be helpful. Botulinum toxin selectively injected into dystonic limbs was locally useful, especially when the fist becomes forcibly clenched and functionally useless (102; 35; 140). Because depression is a frequent accompaniment, its signs must be identified and symptoms treated (73). In 1 study, depression occurred in 73%, apathy in 40%, irritability in 20%, and agitation in 20% of corticobasal degeneration subjects. Irritability was significantly associated with other signs of disinhibition (120). In a study, 42% of 68 patients with corticobasal degeneration had depressive symptoms during the initial visit, whereas the prevalence increased to 55% when all the visits were considered. Selective serotonin reuptake inhibitors (SSRIs) are effective in ameliorating the depressive symptoms (126). Tricyclic antidepressants should be avoided in view of their disabling anticholinergic side-effects.

Emerging therapies may be considered in the future, including low-frequency repetitive transcranial magnetic stimulation (rTMS). rTMS improved the unified Parkinson disease rating scale (UPDRS) and quality of life after 3 months of therapeutic interventions, and there was no significant deterioration in cognitive functions (185). Additionally, consistent with other neurodegenerative diseases, maintaining and encouraging physical activity may improve functional outcomes (198). Apathy may be observed in patients with corticobasal degeneration, and the presence of apathy is associated with a greater caregiver burden (08).

Several therapeutic approaches targeting the potential underlying biological processes are being attempted to reduce the progression of the pathology. These approaches include reduction of abnormal post-translational modifications, blocking of transcellular spread of tau, stabilization of microtubules and neuroprotection, and enhancement of tau degradation (149).

There are excellent reviews of pharmacological, diet, and other symptomatic therapies for corticobasal degeneration (108; 126).

Special considerations

Pregnancy

Not applicable. Age of disease onset is usually in the sixth or seventh decade of life.

Anesthesia

No specific issues are necessary, but delirium is common for patients with parkinsonism and acute medical issues or postsurgically.