Is the Pathology of Corticobasal Syndrome Predictable in Life?
Bhaskara P. Shelley, MBBS, MD, DM, (Neuro),1John R. Hodges, MD, FRCP, FMedSci,1,2*
Christopher M. Kipps, FRACP,1John H. Xuereb, FRCP, MD, FRCPath,3and Thomas H. Bak, MD,4
1Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
2Prince of Wales Medical Research Institute, Barker Street, Randwick, New South Wales, Australia
3Department of Pathology (Molecular Histopathology Division), University of Cambridge, Addenbrooke’s Hospital,
4Human Cognitive Neuroscience, University of Edinburgh, Edinburgh, UK
Abstract: Corticobasal syndrome (CBS) has been associated
with a heterogeneous spectrum of pathologies with an
increasing number of reports of Alzheimer’s type pathology.
There is, however, no means of predicting pathology of CBS
in vivo at present. We compared the clinical features of
patients presenting with CBS who have either pathologic
changes of classic corticobasal degeneration (CBD) or Alz-
heimer’s disease (AD) at post-mortem to identify predictors
of the specific pathological processes in life. Twelve patients
with CBS were followed prospectively; six had AD and six
had classic CBD neuropathology. After review of the pre-
senting clinical features, we identified nine potential predic-
tor variables, compared their frequency in the two groups,
and performed a discriminant function analysis. Initial epi-
sodic memory complaints and poor performance on the com-
bined orientation-memory subtest of the Addenbrooke’s
Cognitive Examination (ACE) reliably predicted AD pathol-
ogy while varying combinations of early frontal-lobe type
behavioral symptoms, nonfluent language disturbance, oro-
buccal apraxia, and utilization behavior predicted CBD pa-
thology ante-mortem. CBS is frequently associated with
Alzheimer’s disease pathology. Early episodic memory
impairment versus early behavioral symptomatology appears
to best predict AD or CBD pathology in life. ? 2009
Movement Disorder Society
Key words: corticobasal syndrome; corticobasal degenera-
tion; Alzheimer’s disease; pathology; behavior; nonfluent
aphasia; utilization behavior
The syndrome of Corticobasal Degeneration (CBD)
is of considerable interest to movement disorder spe-
cialists and behavioral neurologists. Although initially
described as a distinctive levodopa-resistant, asymmet-
ric, akinetic-rigid syndrome associated with prominent
apraxia, cortical sensory loss, focal reflex myoclonus,
and alien limb phenomena,1it has become increasingly
clear that cognitive and behavioral features are also
extremely common with considerable overlap between
CBD, progressive supranuclear palsy (PSP), and fron-
totemporal dementia (FTD) syndromes.2–4
As originally conceived, CBD was also considered a
distinct pathologic disorder characterized by cortical
degeneration with swollen ‘achromatic’ neurons, neu-
ronal loss in the substantia nigra and extensive neuro-
nal and glial cytoplasmic tau-positive inclusions. More
recently, however, there is growing evidence that
patients with clinically classic CBD have alternative
pathologies5–12including AD, PSP, and FTD leading
some investigators to propose the label of Corticobasal
Syndrome (CBS).13–15Recent advances in molecular
and genetic research have shown that mutations, muta-
tions of the microtubule associated protein tau (MAPt)
and progranulin gene in association with ubiquitinated
neuronal cytoplasmic inclusions occur in CBD with
It is unclear from the current literature, however,
whether there are any systematic differences between
patients with and without corticobasal degeneration pa-
thology. A very recent clinco-pathological study of
patients with classic tau inclusion CBD emphasized early
language dysfunction, executive and socio-behavioral
Potential conflict of interest: None reported.
Received 7 May 2008; Revised 16 November 2008; Accepted 2
Published online 16 June 2009 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.22558
*Correspondence to: Professor John Hodges, Federation Fellow
and Professor of Cognitive Neurology, Prince of Wales Medical
Research Institute, Barker Street, Randwick, Sydney NSW 2031,
Australia. E-mail: email@example.com
Vol. 24, No. 11, 2009, pp. 1593–1599
? 2009 Movement Disorder Society
changes, and the relative preservation of episodic
memory.18We reviewed our series of 12 clinically-
diagnosed and prospectively-assessed patients with
CBS that came to post mortem. Six had pathologi-
cally-confirmed classic CBD while the remaining six
cases had AD pathology. The primary aim of this
study was to investigate whether any clinical predictor
variables could identify which specific pathology
caused the CBS ante-mortem.
SUBJECTS AND METHODS
Twelve consecutive cases diagnosed clinically with
CBS between 1997 and 2004 were followed up at reg-
ular intervals in the Disorders of Movement and Cog-
nition Clinic. All patients underwent neurological ex-
amination, neuroimaging studies that (structural and
functional) and standard neuropsychological assess-
ments, including the Addenbrooke’s Cognitive Exami-
nation (ACE)19and were prospectively followed up
until death every 6 months.
Since the establishment of the DMC every effort
was made to follow-up any patient with CBS and to
enrol them into the Brain Bank. All patients were
referred by other consultant neurologists with a puta-
tive diagnosis of CBS. After review of the database,
we found only three other cases who were lost to fol-
low-up. The 12 reported here represent therefore the
majority (12 of 15) of those seen over a 7-year period.
All 12 patients fulfilled the diagnostic criteria for
CBS and had been assessed by one of the two behav-
ioral neurologists (JRH and THB). The following
essential core diagnostic criteria were used: (1) asym-
metrical presentation, (2) akinetic-rigid syndrome, (3)
ideomotor apraxia, and (4) signs of frontal-executive
dysfunction. Apraxia was systematically assessed by
asking subjects to first copy a series of meaningless
gestures, then to mime to command meaningful ges-
tures and finally to copy the examiner performing tran-
sitive movements.20The supportive criteria included
(1) insidious onset and gradual progression (2) lack of
sustained response to dopaminergic treatment (3) myo-
clonus, (4) dystonia, (5) alien hand syndrome, (6) cort-
ical sensory loss tested by two-point discrimination,
graphaesia or tactile object recognition, (7) visuospatial
deficits, and (8) progressive nonfluent aphasia.20The
diagnosis of CBS was based on the presence of at least
three essential and four supportive features.
The medical records, clinical and neuroimaging in-
formation were reviewed by a behavioral neurologist
(BPS) blind to the neuropathology results. Particular
attention was paid to the first clinical assessment, date
of diagnosis, and onset of first symptom as reported by
the family. ‘‘Early’’ features were defined as clinical
symptoms apparent during the initial third of the dis-
ease duration, ‘‘Late’’ as features that represented the
patient’s state towards the end of disease progression,
and ‘‘Mid’’ as features that were evident in the mid-
phase of the disease process.
All 12 cases had undergone neuropathological exam-
ination by the same senior neuropathologist (JHX)
without access to clinical information other than age
and date of death. The routine procedure for brain col-
lection and preparation is discussed elsewhere.21In
brief, the cerebral hemispheres were bisected and the
left cerebral hemisphere and attached half of the mid-
brain was fixed in 10% buffered formalin while the
right cerebral hemisphere, right hemi-brainstem and
the left cerebellar hemisphere were snap frozen.
Tissue blocks were taken from the frontal (Brod-
mann area 6/46), temporal (area 21/ 22), parietal (area
39/40), occipital (area 17/18), and anterior cingulate
(area 24) cortex, as well as from anterior medial tem-
poral lobe, posterior medial temporal lobe, midbrain
(substantia nigra), pons, medulla oblongata (hypo-
glossal nucleus), and cerebellum.
Sections from all regions were stained with haema-
toxylin, eosin and immunohistochemical techniques for
the assessment of neurodegenerative changes using
current diagnostic protocols.22–25In addition to the
application of Braak staging for Alzheimer-type pathol-
ogy,26other specific lesions sought were Pick bodies,
Pick cells, glial tau pathology, cytoplasmic ubiquitin-
positive tau-negative inclusions, intranuclear ubiquitin
inclusions, ubiquitinated neurites, neurofilament inclu-
sions, Lewy bodies, and bA4 peptide deposition in the
neuropil and in blood vessels.
Each case was placed in a diagnostic category based
on the occurrence of specific microscopic lesions. A
diagnosis of Alzheimer’s disease (AD) was made in
six cases on the basis of Braak Stage 4 or greater pa-
thology26which required the presence of both neuritic
plaques and neurofibrillary tangles, with the involve-
ment of isocortex. The remaining six patients displayed
ballooned neurons, tau-positive neuronal and glial
inclusions, threads and grains, and nigral degeneration
that were consistent with the standard criteria for the
diagnosis of CBD.24
1594 B.P. SHELLEY ET AL.
Movement Disorders, Vol. 24, No. 11, 2009
Demographic variables were analyzed with unpaired
Whitney U tests) were used for analysis of median sur-
vival times from onset and presentation.
On the basis of review of the literature, and our clin-
ical experience, we identified nine potential variables
that might predict AD or CBD pathology ante-mortem,
and compared the frequency in both groups. These
nine clinical variables were (1) initial episodic memory
complaints, (2) early visuospatial features, (3) promi-
nent nonfluent language impairment, such as distorted
articulation and /or phonological errors in speech (4)
frontal-lobe type behavioral alterations, such as person-
ality changes, disinhibition, apathy, emotional blunting
and loss of insight (5) recent change in eating behav-
ior, (6) presence of utilization behavior, (7) oculomotor
apraxia, (8) orobuccal apraxia, and (9) the combined
hypothesized that initial episodic memory complaints
and the ACE-OM combined subtest scores would best
discriminate AD from CBD, while the other variables
would be predictors of CBD pathology.
Dichotomous clinical variables indicating the pres-
ence or absence of individual features were analyzed
to calculate Likelihood Ratios (SPSS 12.0.1, Apache
Software Foundation). Statistical significance was set
at a threshold of 0.01.
For the purpose of this analysis, a feature was
regarded as present if it appeared at any stage in the
clinical course. Follow-up discriminant analysis was
done to identify the most important variables contribut-
ing to group separation.
Table 1 summarizes the demographic, cognitive, and
survival data. The male to female ratio was 2:4 in AD
and 4:2 in the CBD group. At presentation patients
with CBD were comparatively younger than the AD
group by about 4 years; but this difference was not sig-
nificant, (t (10) 5 1.24, P 5 0.20). In the CBS-AD
group, median survival time from symptom onset was
12 years (SD 4.5; range: 5–13], and 8 years from diag-
nosis (SD 4.3; range: 1–11]. These indices were shorter
in the classic CBD group: median survival times from
onset and diagnosis were 5 years (SD 2.8; range, 4–11]
and 3.5 years (SD 2.1; range, 3–8] years, respectively.
Although, the disease duration of CBD was ?7 years
shorter than in the AD group, the difference was not
significant, (t (10) 5 1.24, P 5 0.24). There was no
family history of dementia and/or movement disorder
in any of the patients in our series.
The clinical details of each patient are summarized
in Table 2. Six features were distributed significantly
differently across the groups. Four features, namely
frontal type behavioral symptoms (LR 5 10.9, P <
0.001), initial nonfluent language impairment (LR 5
7.6, P < 0.01), utilization behavior (LR 5 7.6, P <
0.01) and orobuccal apraxia (LR 7.6, P < 0.01 ) were
more frequent in the CBD group, whereas two fea-
tures: initial episodic memory complaints (LR 5 10.9,
P < 0.001) and the ACE combined orientation-mem-
ory subscore (LR 5 10.9, P < 0.001 ) were more
commonly represented in the AD group. Alterations in
eating behavior, early abnormalities of visuospatial
function, and oculomotor apraxia were not distributed
differently across the subgroups (all P > 0.05).
In a confirmatory discriminant analysis with the nine
pre-specified predictor variables entered in step-wise
fashion (Table 3), and neuropathological diagnosis as
the classification variable, a single discriminant func-
tion was identified (v25 17.289, df 5 2, P < 0.001).
Examination of the structure matrix showed that two
variables loaded strongly on this function and contrib-
uted maximally to group separation: the orientation-
memory subtest of the ACE (F to remove 5 9.643,
Wilks k 5 0.286, P < 0.001) and the presence of fron-
tal-lobe type behavioral change (F to remove 5 9.643,
Wilks k 5 0.286, P < 0.001).
Case 9: CBS with Alzheimer’s Pathology
This 70-year-old right handed woman presented with
a 3-year history of intermittent right upper limb myo-
TABLE 1. Summary of demographic and cognitive data
Mean SDMean SD
Age at symptom
Time to presentation
Survival from diagnosisa
MMSE (n 5 12)
ACE (n 5 10)
69.5 188.8.131.52 0.24 (ns)
8 4.3 3.5 2.8 0.49 (ns)
aMedian survival in years.
SD, standard deviation; ns, not significant; MMSE, mini mental
state examination; ACE, Addenbrooke’s cognitive examination; O-M
total, Combined orientation and memory subscore of the ACE.
1595 PATHOLOGY OF CORTICOBASAL SYNDROME
Movement Disorders, Vol. 24, No. 11, 2009
clonic jerks. In addition, and noted that her right upper
limb ‘‘won’t do what I want it to do’’, she had diffi-
culty in writing, dressing, fastening buttons, and using
cutlery. Approximately 18 months after the onset of
these motor problems, she developed impairment of
episodic memory and difficulty with calculations and
word finding. Family and past medical history were
upper limb ideomotor dyspraxia worse for meaningless
gestures but also affecting miming of transitive ges-
tures, and mild extrapyramidal rigidity, bilateral asym-
metric (right > left) spontaneous myoclonic finger
jerks, right left disorientation, bilateral agraphaesthesia,
and severe dysgraphia. Her right hand adopted awk-
ward positions while walking. Bedside cognitive exam-
ination showed abnormalities in attention, orientation,
anterograde memory and particularly visuo-construc-
memory impairment, reduced verbal fluency, dyscalcu-
lia, visuo-constructive impairment, and poor executive
TABLE 2. Cumulative clinical features of the 12 cases of corticobasal syndrome
Clinico-pathologic case series
123456789 10 1112
Age of onset (yr)
Duration of illness (yr)
Most affected side
Symptom onset to diagnosis (yr)
Survival time from disease
Survival time from diagnosis (yr)
Insidious onset; gradual
Cerebral cortical features
Alien hand phenomenonb
Cortical sensory lossb
Frontal release signs
Cognitive and behavioural features
Initial episodic memory
Language impairment (NFA)b
Personality and behaviour
Visual spatial deficitsb
Signs of frontal-executive
Change in food preference
Initial ACE total score
MRI atrophy pattern
3 1113 1113
NAL>R genBil FT Bil FP, L T
Early, initial dominant feature; [Early], presenting symptom; Mid, features seen in the middle 1/3rd of the illness; Late, features appearing during the
last 1/3rd of the illness; – 5 features not present or not stated in case record; P, present; FP, frontoparietal; TP, temporo-parietal; Bil, bilateral; L, left; R,
right; NA, no available data; ACE, Addenbrooke cognitive examination; MMSE, mini mental state examination.
aDissociated laterality: dyspraxia on the left; extrapyramidal signs on the right.
bDiagnostic features of proposed criteria [Ref. 20].
1596 B.P. SHELLEY ET AL.
Movement Disorders, Vol. 24, No. 11, 2009
functions. There was a moderate degree of cortical at-
rophy on MRI, most marked posteriorly, and particu-
larly on the left, with SPECT showing left fronto-tem-
poral parietal perfusion deficits.
Over the next 3 years, the dyspraxic extrapyramidal
and memory components worsened. Two years post
presentation, she scored 15 and 50 on the MMSE and
ACE. Neurological examination showed delayed sacca-
dic initiation with normal range of eye movements,
severe bilateral upper limb apraxia, rigidity, and cog-
wheeling (right more than the left), positive frontal
release reflexes (pout, palmomental and glabellar), but
preserved gait and balance. After 6 years, she was bed-
bound and mute.
The whole brain weighed 920 g. The left hemisphere
showed severe cerebral gyral atrophy and sulcal widen-
ing, with an emphasis on frontal and anterior parietal
lobes. Coronal slices of the left hemisphere confirmed
the moderately severe degree cortical and the medial
temporal lobe atrophy. Transverse section through the
hemi-brainstem showed mild pallor of the substantia
nigra and moderate pallor of the locus coeruleus. Mi-
croscopic examination showed very extensive (Braak
stage V) Alzheimer-type pathology in all cortical
In summary, although she had the typical hallmarks
of CBS as evidenced by a constellation of extreme
dyspraxia in conjunction with pronounced extrapyrami-
dal signs, the impressive early deficit in episodic mem-
ory and absence of language or behavioral changes
were indicators of the underlying AD pathology.
All 12 patients were assessed by a behavioral neu-
rologist with extensive experience of neurodegenera-
tive disorders and diagnosed in life as having classic
CBS which is not traditionally regarded as a present-
ing feature of Alzheimer’s disease. Moreover, all 12
fulfilled strict diagnostic criteria yet half had Alzhei-
mer’s disease and not CBD. Despite significant pro-
gress, current clinical classifications do not accurately
predict the underlying specific pathological process.
Our study takes this area forward by identifying a set
of clinical and cognitive variables which may help to
determine the pathological substrate of CBS in vivo.
Furthermore, we have also added to growing aware-
ness of the overlap between clinical features of CBD
and AD, in terms of its atypical phenotypic look-alike
features reminiscent of CBD.
Two independent predictors were found to distin-
guish accurately between AD and CBD: initial episodic
memory complaints for the AD group, and frontal-lobe
type behavioral symptomatology in the CBD group.
No CBD patient had early episodic memory complaints
whereas none of the patients with AD had frontal-lobe
type behavioral changes. Moreover, three other clinical
variables: (1) initial nonfluent language impairment,
(2) orobuccal apraxia, and (3) presence of utilization
behavior showed significant associations with CBD pa-
thology during life. In contrast, alterations in eating
behavior, initial visuospatial features and oculomotor
apraxia were not reliable distinguishing features.
The combined orientation-memory subtest score of
the ACE19was found to be abnormal in all patients in
the CBS-AD group in keeping with their early episodic
memory complaints. The relatively preserved episodic
memory functioning in CBD is in accordance with a
recent finding that such patients perform better on the
memory subtest of the Dementia Rating Scale (DRS)
than those with AD.27Memory impairment in classic
CBD has been ascribed to the poor use of strategic
processes in encoding and retrieval, arising from exec-
utive dysfunction or disruption of frontal-subcortical
circuits.27Supportive evidence for this assertion comes
from a recent autopsy study correlating the relative
preservation of episodic memory in pathologically con-
firmed CBD with mild or absent neuronal loss and less
tau-immunoreactivity in the hippocampus and temporal
lobe.18We assume that the early episodic memory
impairment reflects involvement of the medial tempo-
ral lobe in the CBS-AD group.
In our cohort of patients with CBD, the frontal-lobe
type behavioral disturbance typically included a combi-
nation of apathy, irritability, socially inappropriate dis-
behavior, and the lack of insight. Other neuropsychiat-
ric disturbances included depression, agitation, aggres-
TABLE 3. Analysis of predictor variables
Predictor variable LR
Initial episodic memory
Initial visuospatial presentation
Initial nonfluent language impairment
Frontal-lobe type behavior
ACE OM subtest score
LR, likelihood ratio.
1597 PATHOLOGY OF CORTICOBASAL SYNDROME
Movement Disorders, Vol. 24, No. 11, 2009
sion, anxiety, intractable shouting, and outbursts of
rage. Such neuropsychiatric and behavioral alterations,
and particularly apathy, mood disturbance, disinhibition
and obsessive-compulsive symptoms have reported.28–30
Recently, behavioral disturbance was described in 22%
of 36 pathologically confirmed cases of CBD.31Our
work suggests that the presence of such behavioral fea-
tures is one of the most important discriminators of
CBD pathology from AD pathology during life, and
confirms the importance of carefully documenting be-
havioral features in the clinical assessment of such
Most of the classic CBD cases had forced grasping
and/or utilization behavior which tended to occur early
in the clinical course. No patient with AD pathology
manifested frontal motor phenomena. Furthermore,
several investigators have documented frontal involve-
ment by neuropsychological evidence of dysexecutive
abnormalities in CBD.32,33Even brief bedside assess-
ment, using verbal letter and category fluency, has
been reported to be useful and sensitive in detecting
the signs of frontal dysexecutive dysfunction in
patients with CBD.27,34
Initial features of nonfluent aphasia with disrupted
articulation, and/or phonological speech errors were
also predictors of CBD pathology, and supports the
growing evidence for an overlap between CBD and
primary progressive aphasia.21,35
review highlighted that of 42 studies (399 patients),
34% of clinically diagnosed CBD and 44% with patho-
logically confirmed CBD had associated aphasia.36
Recent work investigating the neural associations of
speech production disorder in progressive nonfluent
aphasia highlighted the role of the left anterior insular
cortex, frontal operculum, and inferior frontal gyrus
(BA 44/47).37Language dysfunction was also docu-
mented to be an early feature in the autopsy-confirmed
CBD series which correlated with tau pathology in the
frontal gray matter and white matter.18Non-fluency is
reported to be the result of a combination of varying
degrees of speech apraxia and syntactic processing def-
icits; it is of interest therefore that the majority of
patients with a nonfluent presentation also had early,
prominent oro-bucco-facial apraxia. Apraxia of speech
(AOS) is typically misclassified as dysarthria but is im-
portant to recognize as it has implications for manage-
ment and prediction of pathology because it has been
strongly associated with underlying tau pathology.38It
would be of interest for future investigations to assess
the relative contributions of motor articulatory deficits
and higher-order language processing such as syntactic
processing in CBD.
The presence of orobuccal apraxia also distinguished
the two groups (CBD > AD), and may also be useful
in differentiating CBD from idiopathic Parkinson’s dis-
ease and other atypical parkinsonian syndromes where
it is typically absent. The presence of orobuccal
apraxia is related to the simultaneous pathological
involvement of parietal lobule and supplementary
motor area.39The fact that both nonfluent aphasia
apraxia of speech and orobuccal apraxia are more com-
mon in CBD than CBS-AD reflects the more asymmet-
ric distribution of pathology in the CBD group.
Asymmetrical extrapyramidal symptoms are recog-
nized as one of the hallmarks of CBD20but were also
present in all six patients with CBS-AD. Extra pyramidal
signs such as akinesia and rigidity are known to occur in
late stages of AD,40but are not generally accepted as a
presenting feature of AD. Another typical motor feature
of CBD, the flexed, dystonic unilateral upper limb pos-
ture, was observed only in two of our cases. Although
previous autopsy-confirmed CBD series have emphasized
an asymmetry of extrapyramidal features, rigidity, brady-
kinesia, apraxia, and a ‘‘useless arm’’ as hallmarks of
CBD, our study did not document these clinical features
as distinguishing CBD from AD.5,28,41,42
One rather surprising finding was the absence of al-
ternative pathologies that have been reported in associ-
ation with CBS, notably PSP and FTLD with ubiqui-
tin/TDP-43 positive inclusions and FTLD with tau-pos-
itive Pick bodies.3,5,13,16,17
pathology in our cohort was also higher than in other
growing number of case reports of CBS associated with
AD pathology.5,12These differences probably reflect
variation in the patterns of ascertainment and referral.
Our Disorders of Movement and Cognition Clinic was
established to evaluate and manage patients with com-
plex syndromes involving aspects of cognition and
motor control: of 17 patients evaluated over a 7 year
period, 12 were followed to death and are reported
here. It is quite likely that other clinics evaluating fewer
such patients would have a higher prevalence of non-
AD pathology. Nevertheless, all of our patients fulfilled
strict criteria for CBS and had prominent apraxia as an
early or presenting feature as shown in Table 2.
In conclusion, current diagnostic criteria for CBS do
not distinguish between cases with classic CBD pathol-
ogy and clinically similar cases of AD. Our findings of
prominent nonfluent language dysfunction, early be-
havioral abnormalities emphasize a predominantly
frontal and parietal distribution of disease in addition
to the basal ganglia in CBD, but with less involvement
of the medial temporal lobe structures. We have identi-
The prevalence of AD
although there is a
1598 B.P. SHELLEY ET AL.
Movement Disorders, Vol. 24, No. 11, 2009
fied a pattern of clinical predictor variables that appear Download full-text
to be good candidates to discriminate CBD from AD
related CBS in vivo; this needs further validation in a
larger prospectively assessed cohort.
Author Roles: B. Shelley, C. Kipps: data analysis,
drafting of manuscript. T. Bak, J. R. Hodges: Clinical
diagnosis and followup, neurological examination, neu-
ropsychological and neuropsychiatric assessment, edit-
ing of manuscript. J. Xurueb: neuropathological diag-
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