Corticobasal degeneration.

160

Corticobasal Degeneration Ana M. Grijalvo-Perez, MD1

Irene Litvan, MD, FAAN1

1 Department of Neurosciences, University of California, San Diego,

La Jolla, California

Address for correspondence Irene Litvan, MD, Department of Neurosciences, University of California, San Diego, 8950 Villa La Jolla Drive, Suite C112, La Jolla, CA 92037 (e-mail: [email protected]).

Abstract Keywords

► corticobasal degeneration ► corticobasal syndrome ► nonfluent progressive aphasia ► frontotemporal dementia ► progressive supranuclear palsy ► tauopathy ► atypical parkinsonian syndromes ► neurodegeneration

Among the atypical parkinsonian syndromes, corticobasal degeneration (CBD) is probably the most challenging disorder to diagnose antemortem. It can present with multiple phenotypes, none of them specific enough to lead to an unequivocal diagnosis. Alternatively, multiple other neurodegenerative disorders with a different underlying pathology, such as Alzheimer disease (AD), can mimic its clinical course. The ultimate etiology of CBD is unknown; however, current neuropathological and genetic evidence support a role for microtubule-associated protein tau. The classic clinical presentation is corticobasal syndrome, which typically presents as an asymmetric parkinsonism with a variable combination of ideomotor apraxia, rigidity, myoclonus, and dystonia, often associated with the presence of an alien limb phenomenon. Recently, a new set of diagnostic criteria has been developed, but still definite diagnosis requires autopsy confirmation. At the present time, no disease modifying therapies are available, but extensive research is being conducted.

Corticobasal degeneration is a rare, progressive neurodegenerative disorder with distinct pathological features and multiple phenotypic presentations that can also occur in other conditions.1–4 This clinical heterogeneity and lack of specificity of CBD pose a significant diagnostic challenge even to movement disorder specialists.1,5 It shares with other disorders, such as Alzheimer disease (AD), Pick disease, and progressive supranuclear palsy (PSP), the presence of tau pathology.2,6 Specifically, in the case of both PSP and CBD, there is accumulation of four-repeat (4R tau) isoforms. This shared tau pathology may explain the complex clinical overlap manifested between these disorders.1,5–7 The classic clinical presentation of corticobasal degeneration, namely, corticobasal syndrome (CBS), was initially described by Rebeiz and collaborators in 1967.8,9 In that seminal article, they described the neuropathological find-

Issue Theme Atypical Parkinsonian Disorders; Guest Editors, Yvette Bordelon, MD, PhD, and Carlos PorteraCailliau, MD, PhD

ings of three individuals presenting in late adult life at the Massachusetts General Hospital with a similar progressive course of an asymmetric, akineto-rigid syndrome with higher cortical dysfunction of unknown etiology. The authors considered it as a single clinicopathological entity and described it as “corticodentatonigral degeneration with neuronal achromasia” based upon its neuropathological hallmark appearance. The disease as a whole, however, remained neglected for almost two decades until 1985 when the next series of six patients were reported.10 The current term corticobasal degeneration (also known as corticobasal ganglionic degeneration) was coined a few years later by Marsden and collaborators in 1989,11 when it became apparent that dentate pathology was infrequent in CBD. Since its original description, it has become evident that CBD is not a single clinicopathological entity.1 Furthermore,

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1381734. ISSN 0271-8235.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Semin Neurol 2014;34:160–173.

several phenotypes in addition to CBS, which was the classic phenotype described by Rebeiz et al, have emerged to correlate with CBD pathology on postmortem evaluation.1,2,5,7 These include frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and Richardson syndrome (the most common clinical presentation of PSP).1,3 In addition, we understand that CBS is a syndrome that has several underlying pathological correlates other than CBD. Examples of pathologies that have been described in CBS patients include AD, PSP, tau or TDP-43 frontotemporal lobar degeneration (FTLDTDP), and less commonly, Creutzfeldt-Jakob disease (CJD).4,7,12–14 Given the complexity of clinical phenotypes associated with the pathological diagnosis of CBD, an international consortium of behavioral neurologists, neuropsychologists, and movement disorder specialists recently developed a new set of criteria for the diagnosis of CBD that will be examined in detail later in this review.1 Finally, being able to correctly predict CBD pathology has become more than merely academic interest owing to a growing number of new tau-directed therapies currently undergoing clinical trials. Along this line, efforts are being made to develop biomarkers that can distinguish this distinct 4R tauopathy from other non-tau neurodegenerative disorders.3

Epidemiology Incidence and Prevalence Studies looking at the diagnostic accuracy displayed by clinicians when evaluating several neuropathological diagnoses including CBD suggest that this disorder is markedly underdiagnosed.15 Despite various clinical diagnostic criteria, it is estimated that the pathology of CBD is predicted prior to autopsy in only 25 to 56% of cases.1 Given the challenges presented by antemortem diagnosis of CBD,1 it is not surprising that the precise incidence and prevalence of CBD is unknown.6 Compared with other atypical parkinsonian disorders (APDs), little is known about the incidence of CBD because there are no population-based epidemiologic studies available.3 Only case reports or case series from specialized movement disorder clinics are reported in the literature, offering crude estimates of its incidence.6,16 One large movement disorders clinic case series reported that CBS constitutes 0.9% of their patients with parkinsonism.17 Based upon an estimate of the frequency of CBS among other APDs on the basis of Russian and Japanese studies, the estimate of the incidence of CBS is less than 1 per 100,000 patients per year.16,18,19 However, this number could be an overestimation of the true incidence of CBD presenting with a CBS phenotype as the underlying pathology of CBS is varied.7,12 On the other hand, there are no estimates of the other phenotypic presentations of CBD.1,3

Sex and Age Distribution The age of onset of CBS is typically late adulthood, commonly between the fifth to seventh decades of life.3,16 The youngest case with a pathologic confirmation of CBD reported onset of

Grijalvo-Perez, Litvan

symptoms at age 45.20 Meanwhile the youngest case of CBS, but without pathological confirmation of CBD, was recently moved from age 4021 to age 28.22 In an autopsy series of 76 cases of pathologically confirmed CBD from the CurePSP Brain Bank at the Mayo clinic in Jacksonville, Florida, the mean age at death was 70.0 8.7 years (range: 46–89 years), with 53% men.4 In the same series, the disease duration for CBD was estimated as 6.0 2.3 years. Patients with CBD survive 7 to 9 years, with shorter survival in patients presenting with dementia than in those with classic CBS.23 Regarding gender distribution, some authors have suggested a predominance in women,20,24,25 whereas other reports have failed to show any gender difference.26

Environmental Risk Factors Little is known about risk factors for APDs in general, and this applies for CBD in particular. This is not surprising in light of the diagnostic difficulties presented by this disorder. In fact, currently the only known risk factor for both CBD and PSP is advanced age.6 At this point, there is no evidence to suggest that environmental exposure to toxic or infectious agents plays a role in the pathophysiology of CBD.

Pathophysiology Neuropathological Features Pathological criteria for a diagnosis of CBD have been formulated by a working group supported by the Office of Rare Diseases of the National Institutes of Health and subsequently validated by and independent group of neuropathologists.2 According to this criteria, the minimal pathologic features for CBD are cortical and striatal tau-positive neuronal and glial lesions. In particular, this refers to astrocytic plaques and thread-like processes in gray and white matter in a characteristic distribution.2 Additionally, non-tau pathological features, such as “achromatic” or “ballooned” cortical neurons, are considered an important, but not essential histological feature of CBD, as previously described by Rebeiz,9 because this finding lacks diagnostic specificity.2,27 In cases in which ballooned neurons are difficult to detect, immunostaining for phospho-neurofilament or α-β-crystallin may prove useful. Additionally, other methods to evaluate for Alzheimer-type and Lewy body pathology are necessary to rule out other causes of dementia and parkinsonism, depending on the clinical presentation.2 The combination of this criteria provides good differentiation of CBD from other pathologies, with the exception of frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), in which case additional clinical and genetic information is required for diagnosis.2

Pathogenesis Tau pathology is considered to be the main contributing factor in CBD. Compared with other tauopathies such as AD, CBD, PSP, and many variants of FTDP have predominantly 4R hyperphosphorylated tau pathology. This refers to the presence of 4 repeats in the tau microtubule binding domain, Seminars in Neurology

Vol. 34

No. 2/2014

161


Corticobasal Degeneration



as compared with an equimolar distribution of 3R and 4R isoforms in AD.28 Even though the ultimate cause that leads tau to become hyperphosphorylated is currently unknown, some studies support a role for microglia signaling in the setting of neuroinflammation in the pathogenesis of sporadic tauopathies.29,30 However, further work is needed to determine whether this mechanism may lead to new strategies for the treatment of tauopathies.28 In regards to the connection between tau deposition and neurodegeneration, some recent studies have localized taumediated dysfunction to the synapse.31,32 Ittner et al showed that tau plays a role in targeting fyn kinase to postsynaptic compartments triggering excitotoxic signaling via N-methylD-aspartate (NMDA) receptors.31 In addition, tau has been found to accumulate in dendritic spines disrupting synaptic function by reducing the numbers of postsynaptic α-amino3-hydroxi-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors.32 Ultimately, a common approach to gain understanding about the pathogenesis of a specific disorder is to develop an animal model. Although to date no specific animal models for CBD have been established, lines of transgenic mice mimicking some features of human tauopathies have been produced.28 Specifically, transgenic mice (JNPL3), which develop neurofibrillary degeneration and express four-repeat human tau with the P301L missense mutation have been developed.28 Phenotypically, this line of mice exhibits most prominently limb dystonia, a motor feature commonly seen in patients with CBS, as well as with a reduction in grooming, weight, and vocalization.28 The importance of this model is that it links neurofibrillary pathology to neuronal loss, allowing crucial events in tauinduced neurodegeneration to be studied. Moreover, it offers a system in which the relationship of neurofibrillary degeneration to other pathologies, particularly, Aβ production, can be examined. Finally, it provides a model in which therapies can be assessed.28

Genetic Basis Corticobasal degeneration and PSP have been found to share a similar genetic basis with a higher frequency of the microtubule-associated protein tau (MAPT) H1 haplotype (and the specific H1c subhaplotype) than what is found in healthy controls.33,34 In addition, patients with mutations within the MAPT gene located on chromosome 17q21.3 can display clinical and pathological features associated with CBD.35,36 Additional genetic bases other than MAPT have been recently elucidated based on genome-wide association (GWA) studies for PSP.37 Höglinger et al, recently described in one such study new PSP susceptibility genes, such as STX6, which encodes syntaxin 6, a SNARE-class complex protein that is implicated in endoplasmic reticulum (ER) stressmediated pathogenesis in PSP as well as other tauopathies such as AD.37,38 Other candidate susceptibility genes from that GWA study include MOBP, which encodes a myelin protein produced in oligodendrocytes and EIF2AK3, a gene Seminars in Neurology

Vol. 34

No. 2/2014

that encodes PERK a component of the ER unfolded protein response (UPR).37 When excess unfolded proteins accumulate in the ER, PERK is activated; this leads to inhibition of protein synthesis, allowing the ER to clear misfolded proteins. However, the mechanism by why such a system contributes to PSP pathogenesis is unclear. In addition, it is unclear if the results found in such GWA for PSP and other tauopathies such as AD similarly apply for CBD. Therefore, despite the major advances in our understanding of the genetics of CBD, further studies are needed to reveal its genetic background.39 Finally, CBD is a sporadic disorder, and accordingly, most patients report no family history. However, limited numbers of familial CBD-like cases have been described in the literature. Overall they seem to be the exception rather than the rule.28 Familial CBS may be associated with a different non-tau spectrum of pathology such as granulin mutations (GRN)40,41 and FTLD-TDP. On the other hand, a recent exome sequencing study in two familial cases of CBD showed mutations leading to possible structural changes in MRS2 and ZHX2 genes, which appear to have the same upstream regulator miR-4277. The role of the MRS2 and ZHX2 gene products in CBD should be further investigated.42 Linkage disequilibrium studies suggest that progressive supranuclear palsy (PSP) is an autosomal recessive condition that maps to a polymorphism in the tau gene. These results provide evidence that homozygous mutations in the tau gene may cause PSP. Recently, a missense mutation in exon 13 of one tau allele (R406W) was found in a single family with an atypical clinicopathologic form of dominantly inherited PSP. The authors report that the R406W mutation is lacking in 25 unrelated individuals with PSP and in 6 unrelated individuals with CBD.43

Biochemical Features As previously mentioned, in CBD there is an aberrant pattern of hyperphosphorylated MAPT. This protein is required for microtubule assembly and stability, and accordingly is highly expressed in axons.44 Hyperphosphorylation of tau changes its conformation, reducing its binding affinity for microtubules with subsequent loss of proper microtubule function. It also favors aggregation and inclusion because dissociated tau has a greater propensity for multimerization, which in turn leads to neurodegeneration.45 Although PSP and CBD are both 4R tauopathies, biochemical analysis has shown differences in the tau protein cleavage fragments associated with each disorder. Namely, the detergent-insoluble cleaved tau fragments from CBD patients migrate as two bands (a doublet of around 37 kDa), whereas those from patients with PSP migrate as a single band of 33 kDa.3 Such disparities in tau proteolysis might be related to the different pathological hallmarks that occur in patients with CBD and PSP. However, except for the difference in size of those fragments, the biochemical properties of tau are similar in the brains of patients with CBD and PSP.


162

Clinical Course: Signs and Symptoms Corticobasal syndrome, the classic clinical presentation of CBD pathology as initially described by Rebeiz, is characterized by 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 phenomena.9 However, we now understand that CBD pathology can present in the setting of multiple other clinical syndromes other than CBS.28 From a recent systematic review of 267 nonoverlapping pathologically confirmed cases of CBD collected from the literature as well as brain banks, four syndromes manifesting CBD pathology have emerged that capture over 85% of all presentations.1 These include CBD-CBS (probable and possible based on new diagnostic criteria, see ►Table 1), CBD-frontal behavioral-spatial syndrome (FBS), CBD-naPPA (categorized as nonfluent/agrammatic variant of primary progressive aphasia) and CBD-PSP (Richardson syndromelike). Other less common phenotypes associated with CBD pathology include posterior cortical atrophy (PCA) and dementia with features similar to AD.1,28 In this article, we will focus mostly in the clinical course, signs and symptoms of the most common phenotypic presentation of CBD—CBS—and will discuss the other clinical presentations in a review of the most recent diagnostic criteria proposed for CBD (►Table 1).1


the literature.48,49 Patients with CBD may exhibit some transient degree of levodopa response.50 One study evaluating treatment outcome in 147 patients with CBS found some benefit in about one quarter of the patients; however, this effect was noted to be modest.24 Interestingly, it is rare for CBD patients to develop levodopa-induced dyskinesias, but it has been reported in some autopsy-proven cases.51 Of note, symmetric onset parkinsonism has been described in pathologically confirmed CBD cases from the Mayo Clinic Rochester database.52 This presentation, named S-CBD, seems to be fairly rare and typically is associated with less asymmetric cortical findings on imaging and younger age at onset (median 61 vs. 66 years, p < 0.05). In addition, other typical features of CBS, such as myoclonus, alien limb phenomenon, dystonia and limb apraxia, tend to be absent in S-CBD.52

Tremor Tremor is less frequently seen in CBD compared with PD. To be precise, it has been described to be present in 39% of patients at any point during their disease course.1 It typically manifests as a combination of resting, postural, and action tremors. In general, tremor is poorly characterized in CBD and at times is difficult to separate from low-amplitude myoclonus, but for the most part, seems to be distinct from the typical resting tremor seen in PD.24

Gait Abnormalities, Falls, and Postural Instability Motor Features Parkinsonism and Levodopa Responsiveness Classically, the motor features of CBD emerged from descriptions in which the predominant phenotype was consistent with a CBS presentation.1 Namely, patients manifest asymmetric onset parkinsonism with absent or transient levodopa responsiveness.46 Asymmetric limb rigidity (85%) and bradykinesia (76%) were the most common parkinsonian manifestations in a recent review of pathologically proven CBD cases.1,20 Such findings were frequently reported already at disease onset in 57% of patients, in the case of limb rigidity and in about half the cases for bradykinesia.1 Interestingly, among parkinsonian syndromes, with rare exceptions, only PD presents with such asymmetry.47 With regard to the characteristics of limb rigidity, it is often described as severe, but has rarely been properly described in CBD.1 It may be lead-pipe parkinsonian rigidity with/without superimposed cogwheeling, and at times with possibly a component of dystonia and gegenhalten/paratonic rigidity in cases that exhibit a more prominent pattern of frontal lobe dysfunction.1 Over time, limb rigidity evolves to involve all limbs.20 Axial rigidity can be found in CBD, but not as frequently or severely as in other APDs such as PSP.20 It has been reported to be present in 27% of the cases at presentation and 69% at some time during the disease course.1 Lack of or limited dopamine responsiveness in CBD has been extensively reported,24,47 and forms part of several of the different sets of inclusion criteria for a diagnosis of CBD in

Gait abnormalities in CBD are variable and can be present in up to 73% of patients throughout their disease course. 1 At times, the gait is characterized as bradykinetic and shuffling similar to that seen in PD, with typically decreased arm swing in the affected upper limb. A wider-based gait with prominent freezing has also been described in CBD.23,48 One study found that freezing of gait can happen in 1 out of 13 patients within 3 years from disease onset, with a threefold increase at 6 years.53 On the other hand, it is rare for CBD to present as a primary progressive freezing gait disorder (PPFG).54 One study described gait difficulties and a tendency to fall as possibly the earliest motor feature of CBD,55 but this seems to be uncommon at presentation.1 Occasionally, gait difficulties are secondary to leg apraxia, leading to falls and making ambulation difficult if not impossible.

Dystonia It is considered one of the classical features of CBD and accordingly is one of the inclusion criteria in all sets of clinical diagnostic criteria for CBD.1 Recently, a study was published reviewing the presence of dystonia in over 400 pathologically proven CBD cases.56 Authors found that dystonia was present in only 37.5% of the 296 cases with adequate information, and that the majority of those presented as CBS in 54% of cases.56 Similar numbers were subsequently reported in a recent study on diagnostic criteria for CBD based on an expert panel and pathologically confirmed cases.1 Other studies, however, report a higher frequency of dystonia, probably due to a Seminars in Neurology

Vol. 34

No. 2/2014

163





Table 1 Clinical phenotypes associated with corticobasal degeneration Syndrome

Features

Probable corticobasal syndrome

Asymmetric presentation of 2 of the following: (a) Limb rigidity or akinesia (b) Limb dystonia (c) Limb myoclonus Plus 2 of the following: (d) Orobuccal or limb apraxia (e) Cortical sensory deficit (f) Alien limb phenomena (more than simple levitation)

Possible corticobasal syndrome

May be asymmetric with 1 of the following: (a) Limb rigidity or akinesia (b) Limb dystonia (c) Limb myoclonus Plus 1 of the following: d. Orobuccal or limb apraxia e. Cortical sensory deficit f. Alien limb phenomena (more than simple levitation)

Frontal behavioral-spatial syndrome (FBS)

2 of the following: Executive dysfunction Behavioral or personality changes Visuospatial deficits

Nonfluent/agrammatic variant of primary progressive aphasia (naPPA)

Effortful, agrammatic speech plus at least 1 of the following: Impaired grammar/sentence comprehension with relatively preserved single-word comprehension Groping, distorted speech production (apraxia of speech)

Progressive supranuclear palsy syndrome (PSPS)

3 of the following: Axial or symmetric limb rigidity or akinesia Postural instability or falls Urinary incontinence Behavioral changes Supranuclear vertical gaze palsy or decreased velocity of vertical saccades

Source: Adapted with permission from Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013;80:496–503. © 2013 American Academy of Neurology. http://www.neurology.org/content/80/5/496.full

combination of referral bias and mixed populations of clinically and pathologically proven cases.57,58 Dystonia in CBS typically occurs within 2 years from disease onset, affecting most commonly the upper limb, and then may evolve to hemidystonia or also affect the other side, but rarely starting on the leg.56 The classic distribution of dystonia includes adduction and flexion of the arm, forearm, wrist, and metacarpophalangeal joints with extension of interphalangeal joints, whereas in the leg, the hip can be flexed and internally rotated, associated with flexion of the knee and foot inversion.57 Remarkably, it was noted that the onset of dystonia seemed to happen at later stages during the disease course in those cases presenting with a “dementia” (FTD or AD) phenotype. They also shared a distinct distribution, affecting predominantly the cervical region as well as the face.56 With regard to Seminars in Neurology

Vol. 34

No. 2/2014

other phenotypes (in addition to CBS) associated with dystonia, the authors found that 15% had FTD, and 10.7% presented as PSP, in which case blepharospasm and axial dystonia were the most frequent distributions. 56 Another interesting finding of that study was that dystonia and myoclonus almost co-occurred in their cases, suggesting a possible association.56

Myoclonus It has been described in several case series to be present in 55% to 93% of all patients with CBS.21,24,59 However, in a recent compilation of brain bank and published cases it was found to be much less prevalent than previously reported, with an incidence of 27% during the entire disease course.1 In CBD, myoclonus is most commonly described in the upper extremities, less so in the face and at times superimposed


164


Dysarthria/Dysphagia Dysarthria has been described as one of the initial symptoms of CBD in multiple case reports. For instance, a clinical study of 36 CBS patients, some with confirmed CBD pathology, found that it was present in 11% of patients early in the disease course,21 and to a much larger extent in 70% of patients at 5-year follow-up.21 A postmortem study of 13 CBD patients compared with other patients with PD as well as other APDs, such as DLB, PSP, and MSA, found that the latency from disease onset to development of dysarthria is different among those disorders.64 Namely, the median dysarthria latencies were shorter for PSP and MSA (24 months each), intermediate for CBD and DLB (40 and 42 months, respectively), and much longer for PD (84 months).64 On the other hand, median dysphagia latencies were also shorter for APD, that is, 42 months for PSP, similar for DLB (43 months), intermediate for CBD (64 months) and MSA (67 months), and much longer, about double for PD (130 months).64 To summarize, latency to onset of dysarthria and or dysphagia early in the disease course helps to discriminate APDs from idiopathic PD, but is not a reliable feature to distinguish among the APDs.64 Of note, survival time after onset of a complaint of dysphagia is poor and overall similar among all parkinsonian disorders, with a median latency of 15 to 24 months. Because latency to a complaint of dysphagia highly correlates with total survival time, early evaluation and adequate treatment of patients with dysphagia is fundamental to prevent or delay complications such as aspiration pneumonia, which in turn may improve quality of life and increase survival time. 64

165

Upper Motor Neuron Features Upper motor neuron signs such as hyperreflexia or extensor plantar responses (Babinski sign) have been described in CBD cases, and from a review of confirmed CBD cases they can be as common as in 50% of the patients during their disease course.1 However, they are not specific and have been described in other APDs, so they are not a helpful sign to guide diagnosis, but may point to localization of pathology particularly when present asymmetrically.

Eye-Movement Abnormalities Abnormal eye movements have been described in 33% CBD patients at onset and up to 60% of cases during the entire disease course, based on a compilation of 209 confirmed CBD cases.1 Compared with PSP patients, who typically have decreased saccade velocity but relatively preserved latency throughout the disease course,65 patients with CBS display preserved horizontal saccade velocity, but increased horizontal latency of reflexive visually guided saccades.66,67 This finding is more pronounced ipsilateral to the side with more prominent apraxia.65 The correlation between saccadic impairments and apraxia has been attributed to result from posterior parietal cortex dysfunction.66,68 Although vertical saccade impairment is the major criterion in PSP, some CBD patients might show slow vertical saccades later in the disease but typically with less severity.65 In addition, square-wave jerks are most commonly seen in PSP patients rather than in CBD patients throughout the entire disease course.65 With regard to the antisaccade task, namely, the ability to make saccades away from a visual target, this test has been associated with executive dysfunction in several neurodegenerative conditions.69 Antisaccade latency is also abnormal in CBS patients,70 but a higher percentage of errors have been described in PSP compared with CBS cases.65 Overall, based on all the different patterns of eye movement abnormalities, repetitive electro-oculographic (EOG) recordings may help distinguish patients with CBD from those with PSP.65

Higher Cortical Features Apraxia Apraxia is one of the core inclusion criteria in all including the most recent CBD diagnostic criteria.1,48,59,71,72 It has been described to occur at any point in time during the course of illness, presenting at disease onset in 45% of patients and as high as 57% later during the disease course, based on a recent compilation of CBD patients.1 It typically starts in the upper extremities and less frequently the orofacial region. At times, because of the combination of motor manifestations of CBD such as akinetic limb rigidity, dystonia, and the presence of involuntary movements such as myoclonus, evaluation for apraxia may be challenging, but can be accomplished by assessment of praxis in the less affected limb.73 Ideomotor apraxia (IMA), which is characterized by “not knowing how to do it” (compared with not knowing “what to Seminars in Neurology

Vol. 34

No. 2/2014


with limb dystonia.20,56 Myoclonus in CBD seems to display distinct clinical and electrophysiological characteristics.1,60 Namely, it tends to be focal, that is, confined to a single limb (typically the arm) and is more prominent on voluntary action61 or in response to sensory stimulation; it therefore has been labeled “stimulus-sensitive myoclonus.”60,62,63 In regard to its electrophysiological characteristics, in contrast to the recognized forms of cortical reflex myoclonus, the myoclonus of CBD is not associated with enlargement of the secondary component of the cortical somatosensory evoked potential (SEP) or back-averaged electroencephalographic (EEG) spikes preceding each myoclonic jerk.60 In addition, it exhibits a shorter latency in CBS patients (40 ms in hand muscles compared with 50 ms, which is the typical latency).1,60,62 The combination of focal, predominantly distal, hypersynchronous jerks, evidence of enhanced cortical excitability, together with the known cortical pathology suggests that the myoclonus in CBD patients may be cortical in origin.60 Given its shorter latency, one possibility is that it may represent enhancement of a direct sensory input to the motor cortex.63 In contrast, the more widely recognized variety of cortical reflex myoclonus may involve abnormal relays through sensory cortex to motor cortex, either directly or via cerebellarthalamo-cortical projections.60




do,” which is the hallmark of ideational apraxia) is the most common form of apraxia seen in CBD.74,75 Ideational apraxia, on the other hand, tends to occur more in AD, but can also manifest in advanced stages of CBD.73 The same applies for buccofacial apraxia, which tends to occur late in the course of CBD, although it rarely may be the initial manifestation together with loss of speech output.76 Overall, IMA is thought to be associated with decreased gray matter volume in the left supplementary motor area, premotor cortex, and caudate nucleus of patients with CBS.77 In subgroups of CBS patients with more severe apraxia (typically a combination of ideomotor and ideational apraxia), this correlates with global cognitive impairment and additional parietal or more diffuse cortical damage.74 Interestingly, the overall degree of apraxia has been shown to be independent of the side of motor impairment.77 Praxis to imitation of gestures (vs. command) seems to be particularly impaired in patients with CBS, while there is about equal impairment in transitive (tool-related) and intransitive praxis.77 As a general rule, systematic assessment for apraxia facilitates the differential diagnosis between patients with CBS and those with PSP.78

Language Disturbances Language abnormalities are a common and frequently presenting feature described in CBD patients with a broad spectrum, ranging from mild impairments to severe progressive nonfluent aphasia.1,79 Some aphasic patients with CBD may progress to complete mutism.1,26,80 In a study of 15 patients with CBS,81 the authors described the presence of aphasia in up to 53% of patients. Similar numbers have also been reported in a more recent compilation.1 The classification of types of aphasia seen in those patients included anomic, Broca, and transcortical motor aphasias, but not receptive aphasias such as Wernicke.81 These findings were associated primarily with left frontal and parietal cortical damage as well as subcortical white matter and corpus callosum abnormalities.81 In addition, apraxia of speech, defined as difficulty in translating conscious speech plans into motor plans resulting in characteristic articulation and prosody errors, has also been described in CBD, coexisting or independent from aphasia.55,82

Alien Limb Phenomena One of the most striking signs occasionally associated with CBD is the “alien limb” phenomenon, most typically manifested as an alien hand syndrome.83 This is usually described as involuntary and purposeful hand movements, with a feeling of foreignness of the involved limb, commonly associated with a failure to recognize ownership of the limb in the absence of visual clues.83,84 The affected limb is often described by patients as having “a will of its own,” or in other words, a loss of the sense of agency associated with the purposeful movement of the limb but typically retaining a sense of ownership of the limb. That is, patients feel that they have no control over the movements of the “alien” hand, but that instead the hand has the

Seminars in Neurology

Vol. 34

No. 2/2014

capability of acting autonomously, i.e., independent of their voluntary control. Such phenomena have captivated the imagination of both neuroscientists and the public alike. In Stanley Kubrick’s movie Dr. Strangelove, its main character displays this bizarre movement disorder. In the movie, his right hand seems to be driven by a will of its own, at times raising into a Nazi salute and other times seemingly grabbing at his own throat. Interestingly, alien limbs are not pathognomonic of CBD, but rather occur in a variety of other disorders, including strokes involving the genu or anterior rostrum of the corpus callosum and the contralateral frontomedial cortical and subcortical regions, as well as in other rare neurodegenerative conditions such as CJD.85 Concerning the presence of alien limbs in CBD, this phenomenon is well recognized.21,59,86 A description of an alien limb was already present in the original 1968 article by Rebeiz and collaborators9 that characterized CBD as a clinicopathological entity. A variety of phenomena has been described to constitute alien limb manifestations, yet what behaviors truly constitute alien limb phenomena remains a matter of debate.1,14,84 There are few studies reviewing the semiology of alien limb phenomena in CBD despite its presence being included in multiple of the previous CBD criteria.49,71,72 Terms used to describe the different phenomenology include dissociation from one’s own limb, magnetic apraxia,87 intermanual conflict, enabling synkinesis, grasping, impulsive hand groping, intermanual conflict, and purposeless wandering of the limb.1 Overall, the consensus is that the alien limb movement abnormalities seen in CBD may differ from those seen in patients with lesions in the frontal lobes or corpus callosum. In CBD, perseverative movements are less common, particularly early in the course of the disease.83 The alien limb is more likely to drift or levitate and assume odd postures. Similar patterns of movement can occur with parietal lesions.83 On the other hand, in patients with CBD that have frontal dysfunction, rather than levitation they can demonstrate continuous tactile pursuit of the examiner’s hand (also described as “tactile mitgehen”).86 In regard to the prevalence of this phenomenon in patients with CBD, it has been described to be present in about onethird of the cases at any point during the disease course.1 However, the true prevalence is not known because there is a possibility that this may have been underreported in prior case series.

Cortical Somatosensory Loss This has been described in approximately a quarter of a recent group of CBD cases, but this is possibly underreported because it was only described in less than half of all cases.1,20 When present, it can be associated with limb apraxia. Agraphesthesia, extinction, and astereognosis have been described in patients with CBD and correlate with parietal lobe pathology.47


166

Visuospatial Phenomena Complex cortical visuospatial phenomena, such as visual neglect/agnosia, simultagnosia, and optic ataxia such as those seen in Balint syndrome, have been described as a rare phenotypic variant of CBD.20,88 This pattern of progressive cortical dysfunctions has been termed PCA, a clinical syndrome that is more typically seen as a manifestation of AD rather than CBD pathology.89

Cognitive Impairment/Behavioral Changes Cognitive impairment is a common finding in CBD based on a recent compilation of 209 brain bank and published cases.1 In that case series it was present at onset in 50% of patients and up to 70% later during the disease course. In particular, executive dysfunction associated with behavioral changes seems to be common in CBD. In fact, one of the phenotypic presentations of CBD includes FBS, a variant of FTD with multiple behavioral abnormalities. These include personality changes such as irritability, disinhibition, hypersexuality, apathy, and bizarre or antisocial behaviors. Changes in behavior overall were present in about half of the patients at any point during the disease course.1 In addition, prominent memory impairment that frequently leads to a diagnosis of AD can be a manifestation of CBD. On the other hand, visuospatial dysfunction and acalculia are uncommon in CBD.26 Given the presence of a characteristic pattern of cortical and subcortical neuropathological lesions in CBD, it has been predicted that these patients may have a specific cognitive profile. One such study looked at performance in an extensive battery of neuropsychological tests of 15 patients with CBS compared with age- and education-matched controls. It also compared them with patients with AD and PSP, matched for degree of dementia and depression, and found that such characteristic profiles exist.90 In brief, patients with CBS have a dysexecutive syndrome which is similar to that of PSP patients, but more severe than in classic AD. In addition, compared with AD, PSP, and CBS patients seem to share a similar pattern of difficulties with memory retrieval without consolidation deficits that improve using semantic cues, whereas in AD cued recall is also impaired. On the other hand, patients with CBS have asymmetric praxis disorders, as previously stated, which are not typically seen in AD and PSP cases. In summary, neuropsychological testing of suspected CBD patients may provide help to distinguish this condition clinically from other neurodegenerative diseases.90

Neuropsychiatric Features Neuropsychiatric disturbances are common in patients with CBD. These features were characterized in a group of 15 pathologically confirmed patients with CBD as well as 34 patients with PSP that presented to the National Institutes of Neurological Disorders and Stroke (NINDS) for outpatient evaluation.91 Both PSP and CBD patients were administered the neuropsychiatric inventory (NPI), which is a well-established tool to evaluate for behavioral abnormalities such as apathy, irritability, and depression among others.92 The study found that most CBD patients (87%) manifest some form of


psychiatric comorbidity.91 Among these, depression is the most common phenomenon (73%) and has actually been described as being more frequent and severe in patients with CBD compared with PSP patients.91,93 This finding was followed by apathy (40%), irritability (20%), and agitation to a similar degree.91 Less commonly, patients reported anxiety, disinhibition, delusions, or aberrant motor behavior such as pacing. Conversely, patients with PSP exhibited significantly more apathy, approximately a twofold increase compared with CBS patients.91 On the other hand, this study noted the presence of differences in terms of neuropsychiatric profile based on the hemispheric predominance of patients’ motor manifestations. Specifically, patients with CBD with left motor symptoms had higher disinhibition, apathy, and irritability, and lower depression scores than those with right motor symptoms, but these differences were not found to be statistically significant.91 Interestingly, the combination of higher depression and irritability with low apathy scale scores correctly discriminated patients with CBD from patients with PSP and controls 88% of the time, suggesting that CBD patients express a distinct neuropsychiatric profile.93 Accordingly, neuropsychiatric symptoms should be assessed in all patients with CBD to enhance symptom detection and improve management.93 Finally, it becomes evident from some studies reviewing the clinical course of patients with CBD that depression at times may precede onset of motor symptomatology, which has also been described to be the case in other basal ganglia disorders, such as PD and Huntington disease.94,95 This suggests that understanding the early neuropsychiatric manifestations in parkinsonian disorders may shed some light into the pathogenesis of conditions such as CBD, and hopefully lead to better management for patients with this disorder.91,93

Studies Positron Emission Tomography Studies with 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET) in CBS patients show decreased glucose uptake suggestive of hypometabolism in multiple cortical and subcortical regions. These include frontal, temporal, sensorimotor, and parietal association cortices, as well as in the caudate nucleus, lenticular nucleus, and thalamus.96,97 In addition, studies using striatal fluorodopa uptake measured with PET have shown diminished uptake in both the caudate and putamen. These abnormalities tend to be asymmetric with greater involvement contralateral to the most affected side of the body.96 Furthermore, a recent study found distinct patterns of glucose hypometabolism on (18F-FDG) PET among patients with CBS compared with PD, MSA, DLB, and normal pressure hydrocephalus (NPH), suggesting that PET may play a role in the differential diagnosis of challenging cases of APD.98 More recently, advances in amyloid (Pittsburgh compound B [PiB]) PET imaging will hopefully help to differentiate CBD from other pathologies such as AD, which prior to the advent Seminars in Neurology

Vol. 34

No. 2/2014

167





of this imaging technique could only be confirmed postmortem.99

Magnetic Resonance Imaging Several attempts have been made using diverse magnetic resonance imaging (MRI) findings with the goal of discriminating between the different APDs. Voxel-based morphometry (VBM) studies looking at patterns of selective gray matter loss among individuals are yielding encouraging results.28 For instance, a study comparing VBM in autopsy proven cases of PSP and CBD showed that the pattern of cortical atrophy in CBD patients as a whole where very different from that seen in PSP.100 Namely, all patients with CBD displayed posterior lateral and medial frontal cortical atrophy regardless of the various clinical presentations.100 In addition, another striking difference between them was the lack of brainstem atrophy in CBD compared with PSP.100 Otherwise, differences in atrophy patterns elsewhere in the brain noted in that study seem to reflect the differences expected depending on the particular clinical syndrome with underlying CBD pathology: Patients with CBD manifested clinically as PCA in addition to posterior frontal gray matter loss displayed substantial atrophy in posterior frontal regions of the brain compared with patients with FBS, who display marked prefrontal atrophy.100 Recently, a three-dimensional MRI-based volumetric study showed the possibility of differentiating PSP from CBD antemortem.101 The authors found a significant reduction in average brain, brainstem, midbrain, and frontal gray matter volumes in patients with PSP, whereas patients with CBD showed atrophy of the parietal cortex and corpus callosum. Based on that model, the authors claim they can correctly predict the diagnosis in 95% of controls as well as in 76% of all PSP patients and 83% of all CBD patients.101 In addition, using proton magnetic resonance spectroscopic imaging (1H-MRSI) in vivo in CBD patients, Tedeschi et al described a marked reduction in N-acetylaspartate (NAA)/ creatine ratio compared with controls in the centrum semiovale, as well as a significantly reduced NAA/choline ratio in the lentiform nucleus and parietal cortex.102 Moreover, in the parietal cortex of CBD patients, NAA/Cho was significantly reduced contralateral to the most affected side. These results suggest that this technique may help in the diagnostic evaluation of CBD patients.102

AD, naPPA, and semantic dementia were followed over time and contrasted on diffusion-tensor imaging (DTI) with control subjects. At follow-up, all patients with naPPA had evolved into either CBD or PSP and showed diffuse white matter abnormalities involving the entire cerebrum.104 By contrast, patients with AD or semantic dementia on DTI showed more limited areas of abnormality centered around the posterior cingulate and rostral temporal lobes, respectively.104 Fractional anisotropy scores were consistently the most sensitive metric in this study, and overall from this study it is suggested that DTI can have an important role as a diagnostic marker for CBD.104 Interestingly, a recent study using volumetric T1-MRI and DTI found that CBD and PSP patients display a reduction in thalamic size, particularly involving the lateral thalamus as well as increased ADC measurements, consistent with selective neurodegeneration and atrophy in this region.105 Such findings were not seen in patients with idiopathic PD, suggesting that this may be a specific marker of tau-related pathology.105

Evoked Potentials In an electrophysiological study of patients with a clinical diagnosis of CBD, it was found that 3 out of 13 patients had abnormal SEP asymmetry.106 In addition, three other patients were found to have extremely high N20 amplitudes in the affected side. However, similar asymmetric abnormalities have been described before in patients with other APDs such as MSA or PSP. Therefore, such electrophysiological techniques have low specificity for differentiating CBD from other parkinsonian disorders at an early stage of the disease.106

Neuropsychological Testing As previously described, CBS as well as all the remaining phenotypical variants of CBD can manifest with a complex array of cognitive and neuropsychiatric disturbances.1,90,107 Accordingly, a comprehensive neuropsychological evaluation by an expert team including assessment of language, visuospatial, executive function, and memory among others is indicated in all patients with suspected CBD.90 As previously stated, cognitive impairment is a common finding in CBD and can be seen in over 50% of patients at time of presentation.1

Single Photon Emission Computerized Tomography

Identification of Potential Biomarkers

Most recently, the first study looking at dopamine D2 receptor single photon emission computerized tomography (SPECT) using (123)I-IBZM SPECT was performed in autopsy proven CBD patients.103 Unfortunately, that study showed variable findings in terms of loss of postsynaptic striatal neurons, suggesting that this technique is of limited practical value in the diagnostic workup of patients with suspected CBD.103

Although presently there are no specific cerebrospinal fluid (CSF) biomarkers in the case of CBD and related tauopathies, a considerable amount of research is being conducted in this direction because such markers could improve enormously our premortem diagnostic accuracy for these challenging patients.1,28 Among the studied candidates, CSF tau levels have been studied extensively, particularly in the case of AD, but also in series of patients with PSP and CBD.108–110 Some of those studies have found a significant increase in CSF tau in patients with CBD compared with both healthy controls and PSP cases,108 whereas others described no notable difference.110 More recently, some promising studies are being conducted measuring not only total CSF tau, but also levels of

Diffusion-Tensor Imaging A recent study reported that CBD and PSP might be recognizable at a single subject level with the use of diffusion tensor imaging.104 In this study, patients with a clinical diagnosis of Seminars in Neurology

Vol. 34

No. 2/2014


168

tau fragments and tau hyperphosphorylation patterns with the goal of finding a more specific biomarker.111,112 However, even with the assessment of more complex CSF phosphorylated tau profiles, the differential diagnosis of tauopathies continues to impose a significant challenge. Namely, a substantial group of patients with CBD, DLB, FTLD, and vascular dementia exhibit a CSF biomarker profile that overlaps with AD, requiring further autopsy confirmation in the future.112 Alternatively, multiple types of tau ligands are currently being developed to use with PET imaging as a biomarker for AD and other related tauopathies. One such class of ligands, namely, phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums (PBBs) were recently described to be of clinical use for detection of tau-deposition both in an animal model of AD as well as in a subject diagnosed with CBS.113


Taking into consideration these four clinical phenotypes, plus other specific aspects such as disease presentation, duration of symptoms, age at onset, presence of family history, and known genetic mutations, led to the development of two sets of diagnostic classifications for CBD (►Table 2)1 (1) clinical research criteria for probable CBD (cr-CBD), which are set to be more specific, maximizing the probability of diagnosing classic CBD without inclusion of other pathologies; and (2) possible CBD criteria (pCBD), which were designed as less restrictive and therefore potentially yielding more false-positive diagnoses, but still with the goal of identifying only tau pathology (►Table 2).1 For more details about the diagnostic as well as exclusion criteria for both the clinical research and possible CBD criteria, see ►Table 2.1

Treatment Diagnostic Criteria New diagnostic criteria have been recently developed to reflect all the recognized clinical phenotypes or syndromes that can present with CBD pathology.1 These newly proposed diagnostic criteria include two levels of clinical confidence, namely probable and possible CBS. Thus, the consensus phenotypes thought to be most representative of CBD can be divided into four variants: probable and possible CBS, FBS, naPPA, and PSP (for more details see ►Table 1).

Unfortunately, current pharmacological therapies for CBD are usually of limited clinical benefit.47 At present, no diseasemodifying agents are available and symptomatic therapies are typically largely ineffective.24 In regards to symptomatic therapies, it is reasonable to do a trial of levodopa, although parkinsonism in CBD typically exhibits at best a limited response. A proper trial should include levodopa treatment for at least 1 month with the maximum tolerated dose (typically, 900–1200 mg/d).1

Table 2 Diagnostic criteria for corticobasal degenerationa Clinical research criteria for probable sporadic CBD (cr-CBD)

Clinical criteria for possible CBD (p-CBD)

Presentation

Insidious onset and gradual progression

Insidious onset and gradual progression

Minimum duration, y

1 year symptoms

1 year symptoms

Age at onset, y

50

No minimum

Exclusion

Permitted

Permitted phenotypes

Probable CBS or FBS or NAV plus at least one CBS feature (a–f)c

Possible CBS or FBS or NAV or PSPS plus at least one CBS feature (b–f)c

Genetic mutation affecting tau (e.g., MAPT)

Exclusion

Permitted

Family history

b

Abbreviations: CBD, corticobasal degeneration; CBS, corticobasal syndrome; FBS, frontal behavioral-spatial syndrome; NAV, nonfluent/agrammatic variant of primary progressive aphasia; PSPS, progressive supranuclear palsy syndrome. Source: Adapted with permission from Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013;80:496–503. © 2013 American Academy of Neurology. http://www.neurology.org/content/80/5/496.full. a Exclusion criteria for both clinical research criteria for probable sporadic CBD and possible CBD: (1) Evidence of Lewy body disease—classic 4-Hz Parkinson disease resting tremor, excellent and sustained levodopa responsiveness, or hallucinations; (2) evidence of multiple system atrophy— dysautonomia or prominent cerebellar signs; (3) evidence of amyotrophic lateral sclerosis—presence of both upper and lower motor neuron signs; (4) semantic- or logopenic-variant primary progressive aphasia; (5) structural lesion suggestive of a focal cause; (6) granulin mutation or reduced plasma progranulin levels, TDP-43 mutations, FUS mutations; (7) evidence of Alzheimer disease (excluding some cases of CBD with coexisting amyloid pathology)—cerebrospinal fluid profile strongly suggestive of AD such as low CSF Aβ42/tau ratio or positive 11C-Pittsburgh compound B positron emission tomography (amyloid imaging), or genetic mutation suggesting AD (e.g., presenilin, amyloid precursor protein).1 b Two or more relatives. c See ►Table 1 for details about phenotypes. Seminars in Neurology

Vol. 34

No. 2/2014

169





The most useful symptomatic therapies are those aiming at treatment of myoclonus and dystonia. Specifically for myoclonus, different drugs such as valproic acid, clonazepam, and levetiracetam have been tried with good effect. In regards to dystonia, chemodenervation with botulinum toxin can improve the patient’s quality of life because it can decrease hand contractures that can contribute to pain or difficult hygiene, although in most instances, they would not lead to a gain of function in view of usual concurrent apraxia. In addition, patients with CBD benefit enormously from supportive services such as physical, speech, and occupational therapy, usually to a higher degree than pharmacologic approaches. Ideally, a multidisciplinary team familiar with the care of patients with APDs should be involved to ensure providing the best care for these patients. Finally, the ultimate therapeutic goal is to develop disease-modifying therapies. This will require future development of specific treatments targeted at decreasing the pathological substrate of CBD, namely 4R-tau. A multistep approach is fundamental, and several strategies have been addressed to counteract for the loss of tau function. To date, although some research studies are promising there are no Food and Drug Administration approved or established pharmacological treatment options for tauopathies. Some examples of the different approaches include using microtubule-stabilizing agents, reducing tau hyperphosphorylation through inhibition of kinases, increasing intracellular tau degradation by targeting proteins of the ubiquitin proteasome complex and decreasing tau aggregation by using blocking agents of protein–protein interactions.114 Thus far, three compounds have progressed to human clinical trials: methylene blue,115 lithium chloride,116 and an octapeptide (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) known as NAP.117 In addition, a novel approach is the use of anti-tau antibodies as a scavenger tool, which in in vitro models of certain tauopathies such as AD is yielding promising results.118 Additionally, transgenic animal models harboring MAPT mutations and representing key features of the neuropathology seen in human tauopathies are being developed, and will eventually become excellent tools for future drug discovery.28

5 Kouri N, Murray ME, Hassan A, et al. Neuropathological features

6

7

8

9

10

11 12

13

14

15 16 17

18

19

20

21

References 1 Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis

of corticobasal degeneration. Neurology 2013;80(5): 496–503 2 Dickson DW, Bergeron C, Chin SS, et al; Office of Rare Diseases of the National Institutes of Health. Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 2002;61(11):935–946 3 Kouri N, Whitwell JL, Josephs KA, Rademakers R, Dickson DW. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 2011;7(5):263–272 4 Dickson DH, Hauw J-J, Agid Y, Litvan I. Progressive supranuclear palsy and corticobasal degeneration. In Dickson DW, Weller RO, eds. Neurodegeneration. 2nd ed. Hoboken, NJ: Wiley/Blackwell; 2011


Vol. 34

No. 2/2014

22

23

24

25 26

of corticobasal degeneration presenting as corticobasal syndrome or Richardson syndrome. Brain 2011;134(Pt 11): 3264–3275 Dickson DW. Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol 1999;246(Suppl 2):II6–II15 Boeve BF. The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: implications for further study. J Mol Neurosci 2011;45(3):350–353 Rebeiz JJ, Kolodny EH, Richardson EP Jr. Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans Am Neurol Assoc 1967;92:23–26 Rebeiz JJ, Kolodny EH, Richardson EP Jr. Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 1968; 18(1):20–33 Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 38-1985. A 66-year-old man with progressive neurologic deterioration. N Engl J Med 1985; 313(12):739–748 Gibb WR, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain 1989;112(Pt 5):1171–1192 Chand P, Grafman J, Dickson D, Ishizawa K, Litvan I. Alzheimer’s disease presenting as corticobasal syndrome. Mov Disord 2006; 21(11):2018–2022 Lang AE, Bergeron C, Pollanen MS, Ashby P. Parietal Pick’s disease mimicking cortical-basal ganglionic degeneration. Neurology 1994;44(8):1436–1440 Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 2003;54(Suppl 5):S15–S19 Litvan I. Progressive supranuclear palsy and corticobasal degeneration. Baillieres Clin Neurol 1997;6(1):167–185 Togasaki DM, Tanner CM. Epidemiologic aspects. Adv Neurol 2000;82:53–59 Stacy M, Jankovic J. Differential diagnosis of Parkinson’s disease and the parkinsonism plus syndromes. Neurol Clin 1992;10(2): 341–359 Winter Y, Bezdolnyy Y, Katunina E, et al. Incidence of Parkinson’s disease and atypical parkinsonism: Russian population-based study. Mov Disord 2010;25(3):349–356 Osaki Y, Morita Y, Kuwahara T, Miyano I, Doi Y. Prevalence of Parkinson’s disease and atypical parkinsonian syndromes in a rural Japanese district. Acta Neurol Scand 2011;124(3): 182–187 Wenning GK, Litvan I, Jankovic J, et al. Natural history and survival of 14 patients with corticobasal degeneration confirmed at postmortem examination. J Neurol Neurosurg Psychiatry 1998; 64(2):184–189 Rinne JO, Lee MS, Thompson PD, Marsden CD. Corticobasal degeneration. A clinical study of 36 cases. Brain 1994;117(Pt 5):1183–1196 DePold Hohler A, Ransom BR, Chun MR, Tröster AI, Samii A. The youngest reported case of corticobasal degeneration. Parkinsonism Relat Disord 2003;10(1):47–50 Litvan I, Grimes DA, Lang AE. Phenotypes and prognosis: clinicopathologic studies of corticobasal degeneration. Adv Neurol 2000;82:183–196 Kompoliti K, Goetz CG, Boeve BF, et al. Clinical presentation and pharmacological therapy in corticobasal degeneration. Arch Neurol 1998;55(7):957–961 Watts RMS, Richardson EP. Corticobasal ganglionic degenereration. Oxford: Butterworth-Heinemann; 1994 Murray R, Neumann M, Forman MS, et al. Cognitive and motor assessment in autopsy-proven corticobasal degeneration. Neurology 2007;68(16):1274–1283


170


28

29

30

31

32

33

34

35

36

37

38

39 40

41

42

43

44

45

46 47

ballooned neurons in cortical degeneration with neuronal achromasia. Clin Neuropathol 1992;11(1):28–35 Lewis J, McGowan E, Rockwood J, et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 2000;25(4): 402–405 Ishizawa K, Dickson DW. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol 2001;60(6): 647–657 Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 2010;68(1):19–31 Ittner LM, Ke YD, Delerue F, et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 2010;142(3):387–397 Hoover BR, Reed MN, Su J, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010;68(6):1067–1081 Baker M, Litvan I, Houlden H, et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 1999;8(4):711–715 Houlden H, Baker M, Morris HR, et al. Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 2001;56(12):1702–1706 Bugiani O, Murrell JR, Giaccone G, et al. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 1999;58(6): 667–677 Spillantini MG, Yoshida H, Rizzini C, et al. A novel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies. Ann Neurol 2000;48(6): 939–943 Höglinger GU, Melhem NM, Dickson DW, et al; PSP Genetics Study Group. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 2011; 43(7):699–705 Unterberger U, Höftberger R, Gelpi E, Flicker H, Budka H, Voigtländer T. Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo. J Neuropathol Exp Neurol 2006;65(4):348–357 Wenning GK, Litvan I, Tolosa E. Milestones in atypical and secondary parkinsonisms. Mov Disord 2011;26(6):1083–1095 Spina S, Murrell JR, Huey ED, et al. Corticobasal syndrome associated with the A9D Progranulin mutation. J Neuropathol Exp Neurol 2007;66(10):892–900 Masellis M, Momeni P, Meschino W, et al. Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain 2006;129(Pt 11):3115–3123 Fekete R, Bainbridge M, Baizabal-Carvallo JF, et al. Exome sequencing in familial corticobasal degeneration. Parkinsonism Relat Disord 2013;19(11):1049–1052 Higgins JJ, Litvan I, Nee LE, Loveless JM. A lack of the R406W tau mutation in progressive supranuclear palsy and corticobasal degeneration. Neurology 1999;52(2):404–406 Witman GB, Cleveland DW, Weingarten MD, Kirschner MW. Tubulin requires tau for growth onto microtubule initiating sites. Proc Natl Acad Sci U S A 1976;73(11):4070–4074 Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 1986;261(13): 6084–6089 Fahn SJJ, Hallett M. Principles and Practice of Movement Disorders. 2nd ed. Amsterdam: Elsevier; 2011 Reich SG, Grill SE. Corticobasal degeneration. Curr Treat Options Neurol 2009;11(3):179–185

171

48 Kumar RBC, Pollanen M, Lang AE. Corticobasal Degeneration. 3rd

ed. Baltimore: Lippincott Williams & Wilkins 49 Stover NP, Watts RL. Corticobasal degeneration. Semin Neurol

2001;21(1):49–58 50 Constantinescu R, Richard I, Kurlan R. Levodopa responsiveness in

51

52

53

54 55

56

57 58

59 60

61

62 63

64

65

66 67

68 69

70

71 72

disorders with parkinsonism: a review of the literature. Mov Disord 2007;22(15):2141–2148, quiz 2295 Frucht S, Fahn S, Chin S, Dhawan V, Eidelberg D. Levodopainduced dyskinesias in autopsy-proven cortical-basal ganglionic degeneration. Mov Disord 2000;15(2):340–343 Hassan A, Whitwell JL, Boeve BF, et al. Symmetric corticobasal degeneration (S-CBD). Parkinsonism Relat Disord 2010;16(3): 208–214 Müller J, Seppi K, Stefanova N, Poewe W, Litvan I, Wenning GK. Freezing of gait in postmortem-confirmed atypical parkinsonism. Mov Disord 2002;17(5):1041–1045 Factor SA, Higgins DS, Qian J. Primary progressive freezing gait: a syndrome with many causes. Neurology 2006;66(3):411–414 Lee SE, Rabinovici GD, Mayo MC, et al. Clinicopathological correlations in corticobasal degeneration. Ann Neurol 2011;70(2): 327–340 Stamelou M, Alonso-Canovas A, Bhatia KP. Dystonia in corticobasal degeneration: a review of the literature on 404 pathologically proven cases. Mov Disord 2012;27(6):696–702 Vanek ZF, Jankovic J. Dystonia in corticobasal degeneration. Adv Neurol 2000;82:61–67 Godeiro-Junior C, Felício AC, Barsottini OG, et al. Clinical features of dystonia in atypical parkinsonism. Arq Neuropsiquiatr 2008; 66(4):800–804 Riley DE, Lang AE, Lewis A, et al. Cortical-basal ganglionic degeneration. Neurology 1990;40(8):1203–1212 Thompson PD, Day BL, Rothwell JC, Brown P, Britton TC, Marsden CD. The myoclonus in corticobasal degeneration. Evidence for two forms of cortical reflex myoclonus. Brain 1994;117(Pt 5): 1197–1207 Ling H, O’Sullivan SS, Holton JL, et al. Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 2010; 133(Pt 7):2045–2057 Chen R, Ashby P, Lang AE. Stimulus-sensitive myoclonus in akinetic-rigid syndromes. Brain 1992;115(Pt 6):1875–1888 Thompson PD, Shibasaki H. Myoclonus in corticobasal degeneration and other neurodegenerations. Adv Neurol 2000; 82:69–81 Müller J, Wenning GK, Verny M, et al. Progression of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders. Arch Neurol 2001;58(2):259–264 Rivaud-Péchoux S, Vidailhet M, Gallouedec G, Litvan I, Gaymard B, Pierrot-Deseilligny C. Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy. Neurology 2000;54(5):1029–1032 Vidailhet M, Rivaud-Péchoux S. Eye movement disorders in corticobasal degeneration. Adv Neurol 2000;82:161–167 Boxer AL, Garbutt S, Seeley WW, et al. Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer disease. Arch Neurol 2012;69(4):509–517 Vidailhet M, Rivaud S, Gouider-Khouja N, et al. Eye movements in parkinsonian syndromes. Ann Neurol 1994;35(4):420–426 Heuer HW, Mirsky JB, Kong EL, et al. Antisaccade task reflects cortical involvement in mild cognitive impairment. Neurology 2013;81(14):1235–1243 Rivaud-Péchoux S, Vidailhet M, Brandel JP, Gaymard B. Mixing pro- and antisaccades in patients with parkinsonian syndromes. Brain 2007;130(Pt 1):256–264 Lang AERD, Bergeron C. Cortical-Basal Ganglionic Degeneration. Philadelphia: WB Saunders; 1994 Bak TH, Hodges JR. Corticobasal degeneration: clinical aspects. Handb Clin Neurol 2008;89:509–521


Vol. 34

No. 2/2014


27 Smith TW, Lippa CF, de Girolami U. Immunocytochemical study of




73 Leiguarda R, Merello M, Balej J. Apraxia in corticobasal degener-

96 Blin J, Vidailhet MJ, Pillon B, Dubois B, Feve JR, Agid Y. Corticobasal

ation. Adv Neurol 2000;82:103–121 Leiguarda R, Lees AJ, Merello M, Starkstein S, Marsden CD. The nature of apraxia in corticobasal degeneration. J Neurol Neurosurg Psychiatry 1994;57(4):455–459 Zadikoff C, Lang AE. Apraxia in movement disorders. Brain 2005; 128(Pt 7):1480–1497 Lang AE. Cortical basal ganglionic degeneration presenting with “progressive loss of speech output and orofacial dyspraxia.”. J Neurol Neurosurg Psychiatry 1992;55(11):1101 Huey ED, Pardini M, Cavanagh A, et al. Association of ideomotor apraxia with frontal gray matter volume loss in corticobasal syndrome. Arch Neurol 2009;66(10):1274–1280 Pharr V, Uttl B, Stark M, Litvan I, Fantie B, Grafman J. Comparison of apraxia in corticobasal degeneration and progressive supranuclear palsy. Neurology 2001;56(7):957–963 Black SE. Aphasia in corticobasal degeneration. Adv Neurol 2000; 82:123–133 Grimes DA, Lang AE, Bergeron CB. Dementia as the most common presentation of cortical-basal ganglionic degeneration. Neurology 1999;53(9):1969–1974 Frattali CM, Grafman J, Patronas N, Makhlouf F, Litvan I. Language disturbances in corticobasal degeneration. Neurology 2000; 54(4):990–992 Josephs KA, Duffy JR, Strand EA, et al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 2006;129(Pt 6):1385–1398 Biran I, Chatterjee A. Alien hand syndrome. Arch Neurol 2004; 61(2):292–294 Carrilho PE, Caramelli P, Cardoso F, Barbosa ER, Buchpiguel CA, Nitrini R. Involuntary hand levitation associated with parietal damage: another alien hand syndrome. Arq Neuropsiquiatr 2001; 59(3-A):521–525 Brainin M, Seiser A, Matz K. The mirror world of motor inhibition: the alien hand syndrome in chronic stroke. J Neurol Neurosurg Psychiatry 2008;79(3):246–252 Fitzgerald DB, Drago V, Jeong Y, Chang YL, White KD, Heilman KM. Asymmetrical alien hands in corticobasal degeneration. Mov Disord 2007;22(4):581–584 Denny-Brown D. The nature of apraxia. J Nerv Ment Dis 1958; 126(1):9–32 Rajagopal R, Bateman R, Van Stavern GP. Visual involvement in corticobasal syndrome. J Neuroophthalmol 2012;32(4): 338–340 Tang-Wai DF, Josephs KA, Boeve BF, Dickson DW, Parisi JE, Petersen RC. Pathologically confirmed corticobasal degeneration presenting with visuospatial dysfunction. Neurology 2003;61(8): 1134–1135 Pillon B, Blin J, Vidailhet M, et al. The neuropsychological pattern of corticobasal degeneration: comparison with progressive supranuclear palsy and Alzheimer’s disease. Neurology 1995; 45(8):1477–1483 Litvan I, Cummings JL, Mega M. Neuropsychiatric features of corticobasal degeneration. J Neurol Neurosurg Psychiatry 1998; 65(5):717–721 Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997; 48(5, Suppl 6): S10–S16 Cummings JL, Litvan I. Neuropsychiatric aspects of corticobasal degeneration. Adv Neurol 2000;82:147–152 Cummings JL, Diaz C, Levy M, Binetti G, Litvan I. Neuropsychiatric Syndromes in Neurodegenerative Disease: Frequency and Signficance. Semin Clin Neuropsychiatry 1996;1(4): 241–247 Santamaría J, Tolosa E, Valles A. Parkinson’s disease with depression: a possible subgroup of idiopathic parkinsonism. Neurology 1986;36(8):1130–1133

degeneration: decreased and asymmetrical glucose consumption as studied with PET. Mov Disord 1992;7(4):348–354 Juh R, Pae CU, Kim TS, Lee CU, Choe B, Suh T. Cerebral glucose metabolism in corticobasal degeneration comparison with progressive supranuclear palsy using statistical mapping analysis. Neurosci Lett 2005;383(1-2):22–27 Zhao P, Zhang B, Gao S. 18F-FDG PET study on the idiopathic Parkinson’s disease from several parkinsonian-plus syndromes. Parkinsonism Relat Disord 2012;18(Suppl 1):S60–S62 Vandenberghe R, Adamczuk K, Van Laere K. The interest of amyloid PET imaging in the diagnosis of Alzheimer’s disease. Curr Opin Neurol 2013;26(6):646–655 Josephs KA, Whitwell JL, Dickson DW, et al. Voxel-based morphometry in autopsy proven PSP and CBD. Neurobiol Aging 2008; 29(2):280–289 Gröschel K, Hauser TK, Luft A, et al. Magnetic resonance imagingbased volumetry differentiates progressive supranuclear palsy from corticobasal degeneration. Neuroimage 2004;21(2): 714–724 Tedeschi G, Litvan I, Bonavita S, et al. Proton magnetic resonance spectroscopic imaging in progressive supranuclear palsy, Parkinson’s disease and corticobasal degeneration. Brain 1997;120(Pt 9):1541–1552 Pirker S, Perju-Dumbrava L, Kovacs GG, Traub-Weidinger T, Asenbaum S, Pirker W. Dopamine D2 receptor SPECT in corticobasal syndrome and autopsy-confirmed corticobasal degeneration. Parkinsonism Relat Disord 2013;19(2):222–226 Sajjadi SA, Acosta-Cabronero J, Patterson K, Diaz-de-Grenu LZ, Williams GB, Nestor PJ. Diffusion tensor magnetic resonance imaging for single subject diagnosis in neurodegenerative diseases. Brain 2013;136(Pt 7):2253–2261 Hess CP, Christine CW, Apple AC, Dillon WP, Aminoff MJ. Changes in the Thalamus in Atypical Parkinsonism Detected Using Shape Analysis and Diffusion Tensor Imaging. AJNR Am J Neuroradiol 2013 van de Wassenberg WJ, van der Hoeven JH, Leenders KL, Maurits NM. 128-channel somatosensory evoked potentials in the differential diagnosis of parkinsonian disorders. Parkinsonism Relat Disord 2009;15(8):564–571 Bruns MB, Josephs KA. Neuropsychiatry of corticobasal degeneration and progressive supranuclear palsy. Int Rev Psychiatry 2013;25(2):197–209 Urakami K, Mori M, Wada K, et al. A comparison of tau protein in cerebrospinal fluid between corticobasal degeneration and progressive supranuclear palsy. Neurosci Lett 1999;259(2): 127–129 Mitani K, Furiya Y, Uchihara T, et al. Increased CSF tau protein in corticobasal degeneration. J Neurol 1998;245(1):44–46 Arai H, Morikawa Y, Higuchi M, et al. Cerebrospinal fluid tau levels in neurodegenerative diseases with distinct tau-related pathology. Biochem Biophys Res Commun 1997;236(2):262–264 Portelius E, Hansson SF, Tran AJ, et al. Characterization of tau in cerebrospinal fluid using mass spectrometry. J Proteome Res 2008;7(5):2114–2120 Schoonenboom NS, Reesink FE, Verwey NA, et al. Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Neurology 2012;78(1):47–54 Maruyama M, Shimada H, Suhara T, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 2013;79(6): 1094–1108 Ludolph AC, Kassubek J, Landwehrmeyer BG, et al; Reisensburg Working Group for Tauopathies With Parkinsonism. Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options. Eur J Neurol 2009; 16(3):297–309

74

75 76

77

78

79 80

81

82

83 84

85

86

87 88

89

90

91

92

93 94

95


Vol. 34

No. 2/2014

97

98

99

100

101

102

103

104

105

106

107

108

109 110

111

112

113

114


172



117 Brunden KR, Ballatore C, Crowe A, Smith AB III, Lee VM, Troja-

tive inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci U S A 1996;93(20): 11213–11218 116 Pérez M, Hernández F, Lim F, Díaz-Nido J, Avila J. Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J Alzheimers Dis 2003;5(4):301–308

nowski JQ. Tau-directed drug discovery for Alzheimer’s disease and related tauopathies: a focus on tau assembly inhibitors. Exp Neurol 2010;223(2):304–310 118 Yanamandra K, Kfoury N, Jiang H, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 2013;80(2):402–414


115 Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR. Selec-

173


Vol. 34

No. 2/2014

Copyright of Seminars in Neurology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

Fulminant corticobasal degeneration: Agrypnia excitata in corticobasal syndrome.

Diagnosis and treatment of corticobasal degeneration.

Key emerging issues in progressive supranuclear palsy and corticobasal degeneration.

A disease-specific metabolic brain network associated with corticobasal degeneration.

Neuroleptic malignant syndrome in a patient with corticobasal degeneration.

Semantic Corticobasal Dementia: Challenging Nosology in Frontotemporal Lobe Degeneration.

Suppression of myoclonus in corticobasal degeneration by levetiracetam.

Astrocytic inclusions in progressive supranuclear palsy and corticobasal degeneration.

Levodopa-responsive depression associated with corticobasal degeneration: a case report.

Disentangling the neural correlates of corticobasal syndrome and corticobasal degeneration with systematic and quantitative ALE meta-analyses.

computed tomography in a patient with corticobasal degeneration.

Neuroleptic malignant syndrome in an elderly patient with normal pressure hydrocephalus overlapping corticobasal degeneration.

In vivo decreased dopamine transporter uptake in corticobasal degeneration presenting with primary progressive aphasia without parkinsonism.

Pathological features of preclinical or early clinical stages of corticobasal degeneration: a comparison with advanced cases.

Corticobasal degeneration: clinical characteristics and multidisciplinary therapeutic approach in 26 patients.

Corticobasal degeneration: decreased and asymmetrical glucose consumption as studied with PET.

Apraxia in anti-glutamic acid decarboxylase-associated stiff person syndrome: link to corticobasal degeneration?

Concomitant accumulation of α-synuclein and TDP-43 in a patient with corticobasal degeneration.

Progression of Microstructural Degeneration in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Longitudinal Diffusion Tensor Imaging Study.

An autopsied case of corticobasal degeneration showing severe cerebral atrophy over a protracted disease course of 16 years.

Ultrastructural differences in pretangles between Alzheimer disease and corticobasal degeneration revealed by comparative light and electron microscopy.

Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration.

Managing Advanced Progressive Supranuclear Palsy and Corticobasal Degeneration in a Palliative Care Unit: Admission Triggers and Outcomes.

Corticobasal syndrome: Five new things.