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Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia.

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Corticobasal Degeneration and Its
Relationship to Progressive Supranuclear
Palsy and Frontotemporal Dementia
Bradley F. Boeve, MD,1 Anthony E. Lang, MD,2 and Irene Litvan, MD3
In 1967, J. J. Rebeiz, E. H. Kolodny, and E. P. Richardson described three patients with a progressive
asymmetrical akinetic-rigid syndrome and apraxia and
labeled these cases corticodentatonigral degeneration
with neuronal achromasia.1 They recognized the resemblance of the pathology to Pick’s disease, particularly the neuronal achromasia, also called Pick cells. Although there were few additional reports for the next
20 years, interest in this disorder has increased significantly since the early 1990s, when it was renamed corticobasal degeneration (CBD). The core clinical features that have been considered characteristic of the
disorder include progressive asymmetrical rigidity and
apraxia, with other findings suggesting additional cortical (eg, alien limb phenomena, cortical sensory loss,
myoclonus) and basal ganglionic (eg, bradykinesia, dystonia, tremor) dysfunction.
Recently the relationships of CBD to progressive supranuclear palsy (PSP) and frontotemporal dementia
(FTD) have been recognized, which include clinical,
pathological, biochemical, and genetic features.
The terminology relating to CBD is confusing not
only because several terms have been applied to the disorder, such as corticonigral degeneration, corticobasal
ganglionic degeneration,2 as well as CBD,3 but also because the constellation of clinical features may be seen
with pathology other than CBD. Others have suggested syndromic terms such as corticobasal syndrome,
corticobasal degeneration syndrome4, and progressive
asymmetrical rigidity and apraxia syndrome.5 There are
reasonable arguments for and against each of the syndromic terms, and although consensus on the terminology has not been established, some now use the
term corticobasal syndrome. In this review, we use the
term corticobasal syndrome (CBS) to characterize the
constellation of clinical features initially considered the
defining characteristics of corticobasal degeneration
From the 1Division of Behavioral Neurology, Department of Neurology, and Alzheimer’s Disease Research Center, Mayo Clinic,
Rochester, MN; 2Division of Neurology, Department of Medicine,
University of Toronto, Toronto, Ontario, Canada; and 3Department of Neurology, University of Louisville School of Medicine,
Louisville, KY.
and reserve use of the term corticobasal degeneration
(CBD) for the histopathological disorder.
Clinical Features of the Corticobasal Syndrome
Progressive Asymmetrical Rigidity and Apraxia
The core clinical features are progressive asymmetrical
rigidity and apraxia.2,5 Symptoms typically begin in
one limb (no predilection for the right or left side has
been observed). Patients describe their limb difficulties
as “clumsiness,” “incoordination,” or “stiffness.” On
examination, the limb is mildly to severely rigid and
sometimes adopts a dystonic posture. Features of both
rigidity (ie, velocity-independent increased tone) and
spasticity (ie, velocity-dependent increased tone) can be
present in the affected limbs. Alternating motion rates
are markedly reduced. The affected limb often becomes
profoundly apraxic.6 Although the clumsiness and
breakdown of complex coordinated movements may
represent limb kinetic apraxia, it is difficult to completely distinguish this from the effects of basal ganglia
dysfunction, including rigidity, bradykinesia, and dystonia; when these latter features are well developed, it
may even be impossible to adequately assess for the
presence of ideomotor and ideational apraxia. The
spread of limb involvement and rate of progression are
variable. The most common scenario is progressive
asymmetrical rigidity and apraxia in one of the upper
limbs for at least 2 years, then involvement of either
the ipsilateral lower limb or the contralateral upper
limb, eventually leading to severe generalized disability
several years later.
Alien Limb Phenomenon
There is debate regarding what constitutes alien limb
behavior, with definitions ranging from true alien limb
behavior to pseudoathetosis due to cortical sensory loss
Address correspondence to Dr Boeve, Department of Neurology,
Mayo Clinic, 2001 1st St. S.W., Rochester, MN 55905.
E-mail: bboeve@mayo.edu
Published online Jun 23, 2003, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.10570
© 2003 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
S15
to simple levitation of a limb. Patients often describe
their affected limb as “alien,” “uncontrollable,” or
“having a mind of its own,” and they often label the
limb “it” when describing the limb’s behavior. The
movements are spontaneous, minimally affected by
mental effort, and sometimes requiring restraint by the
contralateral limb. This phenomenon often lasts a few
months to a few years before progressive rigidity or
dystonia supercedes.
may occur. Initially, dystonia may be evident only during walking or reaching. In those with symptoms beginning in a lower limb, the foot is often tonically inverted, and ambulation is severely limited. Pain often
but not always accompanies dystonia. Some have argued that dystonia results from striatal damage, although the completely dystonic arm may represent severe degeneration of motor (including premotor)
cortex.
Cortical Sensory Loss
Cortical sensory loss is often manifested symptomatically as “numbness” or “tingling.” Impaired joint position sense, impaired two-point discrimination, agraphethesia, and astereognosis in the setting of intact
primary sensory modalities are all evidence of cortical
sensory loss. Many patients with “numbness” in one
hand undergo unsuccessful carpal tunnel release
surgery.
Tremor
Tremor is another common presenting feature, and patients typically describe the affected extremity as
“jerky.” A postural and action tremor often evolves to a
more jerky tremor and then to myoclonus. Because
tremor typically coexists with rigidity, it can lead to the
incorrect diagnosis of Parkinson’s disease. Unlike the
tremor of Parkinson’s disease, which is most prominent
at rest and dampens with action, the tremor is amplified with activity and minimal at rest. A classic 4 to
6Hz parkinsonian rest tremor is rarely, if ever, evident
in this disorder.
Myoclonus
Myoclonus, if present, usually begins distally in one
upper limb and may spread proximally. The frequency
and amplitude of myoclonic jerks typically increase
with tactile stimulation (ie, stimulus-sensitive myoclonus) and action (ie, action myoclonus). Recent electrophysiological studies suggest that the myoclonus in this
disorder results from enhanced direct sensory input to
cortical motor areas. Typically, a peripheral stimulus
that induces myoclonic jerks is not associated with an
enhanced somatosensory-evoked potential, and the latency from stimulus to jerk is brief, just sufficient to
have reached the cortex and returned to the periphery
(ie, ⬇40 milliseconds in the upper limb). These features are distinct from most other forms of cortical reflex myoclonus (which is associated with enhanced
somatosensory-evoked potential and a longer stimulusto-jerk latency).7
Mirror Movements
Mirror movements are present if the opposite limb involuntary performs the same activity as the one being
examined. Mirror movements are often suppressible,
but when the individual is distracted and rechallenged
with the same maneuver several minutes later, the mirror movements will recur. Patients also frequently demonstrate overflow movements on the same side of the
body, whereby attempted movement in an arm or leg
causes additional movement in the ipsilateral limb, including elevation, mirroring, and the like.
Dystonia
Dystonic posturing of a limb is a common early manifestation, usually affecting one upper limb. Frequently,
the posturing of the hand takes on a “fisted” appearance, although hyperextension of one or more fingers
S16
Annals of Neurology
Vol 54 (suppl 5)
2003
Lack of L-Dopa Response
There are no published cases in which a significant and
sustained clinical improvement has occurred with
8
L-dopa therapy. Many regard the lack of objective improvement during therapy with 1,000mg of daily
L-dopa (divided doses, on an empty stomach) as a diagnostic feature of the disorder (realizing that other
akinetic-rigid syndromes fail to respond to L-dopa as
well).
Dementia
Clinically significant dementia was not considered a
typical early finding in patients with the CBS, but impairment in one or more cognitive domains is often
present. Neuropsychological testing typically indicates
impairment in attention/concentration, executive functions, verbal fluency, language, and visuospatial functioning,9 all of which may be overshadowed by the
more predominant limb rigidity and apraxia features.
Learning and memory are minimally affected early in
the illness. Lately, more typical frontotemporal dementia has been described in cases of the CBS4 and also in
cases of CBD pathology without the CBS. Although
the pathology of CBD may be the commonest cause of
the CBS, some studies have found that it presents
more commonly as a dementia.4,10 Dementia of the
frontal lobe type is common in CBD, but this feature
is certainly not specific for CBD. Aphasia (which is
typically nonfluent),4,11 and hemineglect are frequent
lateralized cognitive features. Apraxia of speech and/or
nonverbal oral apraxia is quite common; in fact, one
published case presented with speech apraxia and did
not develop other “typical” features until at least 5
years later.12 Although rarely symptomatic, patients often demonstrate constructional dyspraxia on drawing
tasks, particularly if the parietal lobe of the nondominant hemisphere is sufficiently affected.
Neuropsychiatric Features
Depression, apathy, and “frontal” behavioral disturbances can occur in the CBS.13 Visual hallucinations
and delusions have not been described. The presence of
visual hallucinations in the setting of cognitive impairment and/or parkinsonism may therefore favor a diagnosis of Lewy body disease rather than the CBS.14
Ocular Motor Apraxia
Ocular motor apraxia occurs to some degree in almost
every patient. This includes difficulty initiating saccades and voluntary gaze, but pursuit and optokinetic
nystagmus are typically preserved. Patients may develop
supranuclear gaze paresis that can be indistinguishable
from that seen in progressive supranuclear palsy (PSP),
but this is usually a late feature. Eyelid opening/closing
apraxia is also frequent.
Other Findings
Several other less specific findings may also occur.
Frontal release signs, hypokinetic dysarthria, asymmetrical hyperreflexia, and/or extensor toe responses also
occur with some frequency. Postural instability is very
common later in the disease and may be related to gait
apraxia, bilateral lower-limb parkinsonism, or dystonia.
If balance problems are present at an early stage, they
are usually secondary to lower-limb involvement at onset. Appendicular ataxia, chorea, and blepharospasm
are infrequent manifestations. Dysphagia begins insidiously in the latter stages of the disease, in contrast to
what usually occurs in PSP, and as in that disorder
eventually leads to aspiration pneumonia and death in
most instances.
Laboratory Findings in the Corticobasal
Syndrome
Neuropsychological Findings
Neuropsychometric testing typically shows impairment
in those domains subserved by frontal/frontostriatal
and parietal cognitive networks: attention/concentration, executive functions, verbal fluency, praxis, language, and visuospatial functioning.9 The profile of
impairment depends in part on which cerebral hemisphere is maximally affected. Performance on tests of
learning and memory tends to be mildly impaired if
impaired at all in the early years. Alternate diagnoses,
particularly Alzheimer’s disease, should be considered if
performance on delayed recall and recognition measures is markedly abnormal.
Electrophysiological Findings
The electrophysiological aspects of the myoclonus in
cases of presumed CBD have been described briefly
above,7 including the short reflex latency and reduced
inhibition following magnetic stimulation over the cortex.15 Although we know of at least one patient with
pathologically proven CBD that had a longer latency
more typical of cortical reflex myoclonus, other patients with the CBS with a long latency form of reflex
myoclonus that we have studied have demonstrated
other pathologies at postmortem (eg, Pick’s disease,
Alzheimer’s disease, and motor neuron inclusion body
dementia).
Structural Neuroimaging Findings
The purpose of performing a computed tomography or
magnetic resonance imaging scan of the brain is to exclude a structural lesion such as a tumor, abscess, hematoma, or infarct. In the absence of these lesions,
some findings can be supportive of the diagnosis of the
CBS, such as asymmetrical cortical atrophy, especially
frontoparietal, with the more prominent atrophy existing contralateral to the side most severely affected clinically. Asymmetrical atrophy in the basal ganglia, lateral ventricles, and cerebral peduncles may be present.
Other reported magnetic resonance imaging findings
for the CBS include atrophy of the middle or posterior
segment of the corpus callosum, signal changes in the
putamen, and hyperintense subcortical signal changes
in motor ⫾ somatosensory cortex.16
Functional Neuroimaging Findings
Asymmetrical hypoperfusion on single-photon emission computed tomography and asymmetrical hypometabolism on positron emission tomography involving
the parietofrontal cortex ⫾ basal ganglia have been reported. Imaging of the nigrostriatal dopamine system
typically demonstrates a reduction of striatal tracer uptake that is greater contralateral to the clinically most
affected side. Unlike the experience of patients with
Parkinson’s disease, in those with CBD, uptake in the
caudate is generally reduced to the same extent as in
the putamen. However, these findings are not specific
for CBD pathology.17
In summary, although neuroimaging findings, the
electrophysiological findings in myoclonus, association
of a specific tau haplotype, and increased cerebrospinal
fluid tau have been investigated, there are no antemortem biological markers identified to date that definitively distinguish CBD from other causes of the CBS.
The proposed criteria for the clinical diagnosis of the
CBS are shown in the Table. These criteria are similar
to those previously suggested for the antemortem diagnosis of CBD. Consensus criteria for the pathological
diagnosis of CBD have recently been published.18
Boeve et al: PSP, CBD, and FTD
S17
Table. Proposed Criteria for the Diagnosis of the Corticobasal Syndrome
Core features
Insidious onset and progressive course
No identifiable cause (eg, tumor, infarct)
Cortical dysfunction as reflected by at least one of the following:
Focal or asymmetrical ideomotor apraxia
Alien limb phenomenon
Cortical sensory loss
Visual or sensory hemineglect
Constructional apraxia
Focal or asymmetric myoclonus
Apraxia of speech/nonfluent aphasia
Extrapyramidal dysfunction as reflected by at least one of the following:
Focal or asymmetrical appendicular rigidity lacking prominent and sustained L-dopa response
Focal or asymmetrical appendicular dystonia
Supportive investigations
Variable degrees of focal or lateralized cognitive dysfunction, with relative preservation of learning and memory, on neuropsychometric testing
Focal or asymmetric atrophy on computed tomography or magnetic resonance imaging, typically maximal in parietofrontal
cortex
Focal or asymmetric hypoperfusion on single-photon emission computed tomography and positron emission tomography,
typically maximal in parietofrontal cortex ⫹/⫺ basal ganglia ⫹/⫺ thalamus
Clinicopathological Heterogeneity
Although the early literature on CBD suggested it was
a distinct clinicopathological entity, the evolving experience at several academic centers indicates that considerable clinical and pathological heterogeneity exists in
the CBS and CBD. An updated review of this heterogeneity from one institution19 indicates that the underlying pathology in 32 autopsied cases of the CBS was
as follows: CBD, 18; Alzheimer’s disease, 3; Pick’s disease, 2; PSP, 6; dementia lacking distinctive histology,
2; and Creutzfeldt–Jakob disease, 3. Others found dementia with Lewy bodies20 and motor neuron inclusion body dementia.21 Furthermore, CBD can present
clinically as the CBS, dementia (not otherwise specified; the commonest presentation in one series),10 a
progressive aphasia syndrome,12,22,23 frontotemporal
dementia,10,22,24 posterior cortical atrophy (with some
or all features of the Balint’s syndrome),25 and progressive speech apraxia.12 Some patients often present with
one of these focal cortical degeneration syndromes and
subsequently develop features overlapping with one or
more syndromes.4 Hence, it is now clear that in the
CBS, as in the other focal/asymmetrical cortical degeneration syndromes, the clinical presentation and progression of symptoms reflect the topographic distribution of histopathology more so than the specific
underlying histology. Furthermore, CBD has a variable
pattern of cerebral cortical pathology, and the topographic distribution of pathology dictates the clinical
presentation. However, the commonality of some of
the histological entities contributes to the understanding of the nosology of CBS-CBD and lessens the emphasis on heterogeneity.
S18
Annals of Neurology
Vol 54 (suppl 5)
2003
Corticobasal Degeneration and Progressive
Supranuclear Palsy: Distinct Disorders
or Variants of the Same
Pathophysiological Process?
The similarities between CBD and PSP suggest they
may be variants of the same pathophysiological process.
The prominent tau pathology, association with the H1
tau haplotype,26 presence of four-repeat tau isoforms,
and overlapping clinical features are all arguments for
shared pathophysiology. Although it has been argued
by some that CBD and PSP should be incorporated
into the concept of the Pick complex, this deposition
of four-repeat tau contrasts with the predominant
three-repeat tau in Pick’s disease, thus aligning CBD
more closely to PSP as well as to FTDP-17, or chromosome 17–linked FTD with parkinsonism.27 Yet recent evidence suggests that four-repeat tau also occurs
in Pick’s disease. The differences in clinical presentations and pathological features of CBD and PSP warrant further study.27,28
Future Directions
Clearly, with the CBS no more than 60% sensitive and
specific for the disease CBD, further research in improving the antemortem diagnosis of CBD may be
fruitful. No consensus yet exists for the diagnosis of the
CBS; the criteria proposed in this article can form the
basis for future refinement. Further characterization of
the natural history of patients with the CBS (ie, clinical, laboratory, neuropsychological, radiological features) is also important, because this information is
necessary to design future drug trials, particularly if
agents active against tau pathophysiology are devel-
oped. Debate continues about whether CBD and PSP
are variants of the same pathophysiological process or
distinctly separate disorders, and this warrants clarification. Additional studies on the rare kindreds with the
clinical features of the CBS and/or pathological features of CBD, whether associated with mutations in
tau (ie, FTDP-17) or not, may offer key insights.
This research was supported by grants from the National Institute
on Aging (AG06786, AG16574, AG17216 to B.F.B.), National
Parkinson Foundation (A.E.L.), and Austin Community Foundation (I.L.).
We thank our many colleagues for their ongoing support and collaborations in CBD research. We also extend our appreciation to
our patients and their families for participating in research on CBD.
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Boeve et al: PSP, CBD, and FTD
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