Acta Neuropathol (1997) 94 : 416–424

© Springer-Verlag 1997

R E G U L A R PA P E R

Kuniaki Tsuchiya · Kenji Ikeda · Toshiki Uchihara ·
Tatsuro Oda · Hiroyuki Shimada

Distribution of cerebral cortical lesions in corticobasal degeneration:
a clinicopathological study of five autopsy cases in Japan

Received: 3 February 1997 / Revised: 14 April 1997 / Accepted: 2 May 1997

Abstract We investigated five Japanese patients with autopsy-proven corticobasal degeneration (CBD) both clinically and pathologically, and examined the distribution of
their cerebral cortical lesions in hemisphere specimens.
The lesions were classified into three categories (slight,
moderate and severe). Only two of our patients had clinical features considered to be typical of CBD. Severe lesions were present in the posterior portions of the frontal
lobe, anterior to the precentral gyrus in two patients with the
clinical diagnosis of CBD. By comparison, in two patients
with clinically diagnosed frontal Pick’s disease, and one
with the clinical diagnosis of progressive supranuclear palsy
(PSP), severe lesions were seen in the anterior portions of
the frontal lobe. The primary motor area of all five had
mostly slight to moderate lesions. We postulate that the
clinical features of CBD have a much wider spectrum than
previously believed. Our data also indicate that the lesion
responsible for limb-kinetic apraxia in CBD is in the premotor cortex. We suggest that when the anterior portions
of the frontal lobe are damaged, the clinical picture mimics those of Pick’s disease and PSP. In addition, we consider that focal cerebral atrophy of CBD is multicentric.
Key words Cerebral cortical lesion · Clinicopathological
correlation · Corticobasal degeneration · Pick’s disease ·
Progressive supranuclear palsy

K. Tsuchiya (Y) · H. Shimada
Department of Pathology, Tokyo Medical College,
6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160, Japan
Tel.: 81-3-3351-6141; Fax: 81-3-3354-3780
K. Tsuchiya · K. Ikeda
Department of Neuropathology,
Tokyo Institute of Psychiatry, Tokyo, Japan
T. Uchihara
Department of Neurology,
Tokyo Medical and Dental University, Tokyo, Japan
T. Oda
Department of Psychiatry,
National Shimofusa Sanatorium, Chiba, Japan

Introduction
Corticobasal degeneration (CBD), first described by Rebeitz et al. [20, 21] as corticodentatonigral degeneration
with neuronal achromasia, is a progressive neurodegenerative disorder that affects the cortical and subcortical systems [8, 22]. The main clinical characteristics of CBD are
apraxia, cortical sensory loss, alien limb, dementia, oculomotor abnormalities, dysarthria, postural instability, akinesia, rigidity, and pyramidal signs. The major neuropathological hallmarks of the disease are a characteristic cortical degenerative process with many ballooned
neurons, and neuronal loss with gliosis in the substantia
nigra [12]. Recently it has been suggested that there is
clinical heterogeneity in CBD [3]. It has become increasingly apparent that there is pathological heterogeneity of
disorders with similar clinical phenotype. For example,
frontotemporal dementia has been described to be due to
CBD, Pick’s disease, motor neuron disease-type dementia, dementia of frontal type, and Alzheimer’s disease [11].
The distinctive cerebral cortical features of CBD is limbkinetic apraxia [7, 13], generally believed to be due to a
lesion in the paracentral region [13]. The cerebral lesions
of CBD are considered to be conspicuous in the precentral
and postcentral gyri, hence the limb-kinetic apraxia has
been attributed to lesions of these gyri.
The purpose of this report is to describe clinical and
pathological findings on five Japanese patients with autopsy-proven CBD, and to delineate the multiplicity of
clinical features of this disorder. We also provide a detailed distribution of the cerebral cortical lesions of CBD
based on histological examination, and consider that the
lesion responsible for limb-kinetic apraxia is present in
the premotor cortex. In addition, we also address the clinicopathological correlation between the clinical signs that
mimic Pick’s disease [19, 27] and progressive supranuclear palsy (PSP) [26], and the presence of moderate to
severe lesions in the anterior portion of the frontal lobe.
To our knowledge, no similar study has been performed
before.

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Materials and methods
Cases
The present investigation was carried out on five autopsy cases
whose clinical records and tissue specimens are stored in the Department of Neuropathology, Tokyo Institute of Psychiatry (case 1,
no. 94084; case 2, no. 92008; case 3, no. 91053; case 4, no. 95029;
case 5, no. 93013).
After fixation in formalin, the brains of cases 1, 2, 3 and 5 were
sectioned in the coronal plane, and that of case 4, in the horizontal
plane. Cerebral hemispheric blocks including the frontal lobe, parietal lobe, temporal lobe, occipital lobe, striatum, pallidum, subthalamic nucleus, thalamus, amygdala, and hippocampus were
taken in both hemispheres. For case 1, nine cerebral hemispheric
blocks were taken; for case 2, five; for case 3, seven; for case 4,
five; and for case 5, four. Additional tissue blocks were taken from
the midbrain including substantia nigra, brain stem, and cerebellum. The brains were embedded in paraffin and cut to a thickness
of 10 µm. The sections were stained with hematoxylin-eosin (H & E),
and by the Klüver-Barrera (KB), Holzer, Bodian, and modified Gallyas-Braak methods [1, 4, 10].
The neuropathological diagnosis of CBD in the five cases was
made on the basis of the findings described in the Results section,
which included many astrocytic plaques [6] in the cerebral cortex
and the widespread presence of argyrophilic threads [9] in the central nervous system. The neuropathological features of all five are
fundamentally consistent with the pathological criteria of CBD of
Feany and Dickson [6] and the recently proposed NINDS criteria
[14].
The clinicopathological findings on cases 1, 2, 3, and 5 have
been reported previously by Tsuchiya et al. [28], Oda et al. [16],
Mitani et al. [15], and Oda et al. [17], respectively. The neuropathological characteristic of case 3, including abnormal cytoskeletal pathology peculiar to CBD was also described by Uchihara et al. [29]. The clinical and pathological features of case 4 are
described in this report.
Case 4

Fig. 1a, b Neuropathological findings on case 4. a Ballooned neuron in the frontal cortex. H & E stain. b Astrocytic plaque and
many argyrophilic threads in the frontal cortex. Modified GallyasBraak stain. a × 150, b × 225

Clinical course
The patient was in good health until August 1989, when at the age
of 58 years she developed abnormal behavior. There was no family history of neurological disease with dementia and parkinsonism. Two months later, lack of spontaneity became apparent. At
the age of 59, iteration appeared, such as buying the same type of
food every day in large quantities. She could not do any housework after March 1991. Change in taste such as smoking appeared
in May 1991. She was bed-ridden after 1992, and died in March
1993, at the age of 62 years. During the course of her illness, limbkinetic apraxia and parkinsonism, including muscular rigidity and
akinesia were not observed. The total duration of the illness was 3
years and 7 months, and the clinical diagnosis was frontal Pick’s
disease.
Neuropathological findings
The weight of the brain was 987 g. The macroscopic examination
revealed atrophy of the bilateral frontal lobes. The atrophy of the
gyri orbitales was more marked on the right than on the left. The
histological examination disclosed neuronal loss with astrocytosis,
status spongiosus, and numerous ballooned neurons in the cerebral
cortex of the frontal lobes (Fig. 1a). Neuronal loss with astrocytosis was evident in the striatum, pallidum, thalamus, substantia nigra, and dentate nucleus. There were corticobasal inclusions in the
substantia nigra. Neither Pick bodies nor senile plaques were seen
in the cerebral cortex or the hippocampus. Modified Gallyas-Braak
method showed many argyrophilic threads in the central nervous

system, and numerous astrocytic plaques in the cerebral cortex
(Fig. 1b).
Classification of cerebral cortical lesions
The lesions identified by light microscopy were classified into
three categories: slight, slight neuronal loss and gliosis of the superficial layers; moderate, obvious neuronal loss with gliosis of the
second and third layers, often accompanied by status spongiosus
and relative preservation of the neurons of the fifth and sixth layers; or severe, pronounced neuronal loss with gliosis of the second
to sixth layers (Fig. 2). The primary motor area, including Betz
cells, was identified on the hemisphere specimens of the five cases.
The data obtained for each patient are depicted schematically in
Figs. 3–7.

Results
Clinical features
The main clinical information on the five patients is summarized in Table 1. There were two males and three females. None of them were related. None of patients included in this study had a family history of neurological

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Fig. 2 Neuronal loss and gliosis in the frontal cortex (a, b from
case 5; c, d from case 3; e, f from case 1). a Severe: Pronounced
neuronal loss of the second to sixth layers. H & E stain. b Severe:
Prominent gliosis of the cerebral cortex with marked fibrillary
gliosis of the white matter. Holzer stain. c Moderate: Obvious neuronal loss of the second and third layers accompanied by status
spongiosis and relative preservation of neurons of the fifth and
sixth layers. H & E stain. d Moderate: Obvious gliosis of the cerebral cortex with slight fibrillary gliosis of the white matter. Holzer
stain. e Slight: Slight neuronal loss of the superficial layers. H & E
stain. f Slight: Slight gliosis of the superficial layers. Holzer stain.
a–f × 21

Table 1 Summary of clinical
and pathological features
(M male, F female, + present,
– absent, CBD corticobasal
degeneration, PSP progressive
supranuclear palsy)

disease with dementia and parkinsonism. The age at onset
of symptoms varied between fifth and seventh decades of
life, with the average being 63.6 years. The duration of
the disease ranged from 25 months in case 1 to 8 years in
case 2; the mean duration was 4 years and 11 months.
Only cases 1 and 3 showed limb-kinetic apraxia as the initial sign; the other three showed psychiatric signs, including delusion of persecution and abnormal behavior. Dementia was noted in all patients. Oculomotor abnormalities were evident in cases 1, 2, and 3. Vertical gaze palsy
was observed in three patients. In case 2, who was diag-

Case

1

2

3

4

5

Sex
Heredity
Age at death (years)
Duration of the disease

M
–
67
2 years
1 month
Limb-kinetic
apraxia
+
+
+
+

F
–
53
8 years

F
–
62
3 years
7 months
Abnormal
behavior
–
+
+
–

F
–
69
7 years

Delusion of
persecution
–
+
+
+

M
–
67
3 years
10 months
Limb-kinetic
apraxia
+
–
+
+

Abnormal
behavior
–
+
+
–

+
Tremor
+
CBD

+
Tremor
+
PSP

+
Tremor
+
CBD

1370
+

1050
–

1040
+

–
–
–
Pick’s disease
(frontal type)
987
+

+
–
+
Pick’s disease
(frontal type)
940
–

Initial signs
Limb-kinetic apraxia
Personality changes
Dementia
Oculomotor
abnormalities
Muscular rigidity
Involuntary movements
Pyramidal sign
Clinical diagnosis
Brain weight (g)
Asymmetric atrophy
of the cerebrum

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Fig. 3 Distribution of cerebral
cortical lesions of case 1. The
lesions are classified into three
categories: slight (
), moderate (
), severe (
). Normal cerebral cortex is also depicted (
). The primary motor areas are between the arrows. The right side of the
brain is on the right of the photograph

nosed as having PSP, downward gaze palsy was evident.
Muscular rigidity was evident in four cases. The clinical
diagnosis of two patients was CBD, that of one, PSP and
that of the remaining two, frontal Pick’s disease.

stantia nigra, and dentate nucleus of all five. Corticobasal
inclusions in the substantia nigra was also present in the
five cases. Staining by the modified Gallyas-Braak method
revealed the widespread presence of argyrophilic threads
in the central nervous system and many astrocytic plaques
in the cerebral cortex of the five patients.

Neuropathological findings
The weight of the patients’ brain ranged from 940 to 1370 g
(average: 1077 g) (Table 1). Neuronal loss with many ballooned neurons and gliosis was evident in the cerebral
cortex of all cases; asymmetric atrophy of the cerebrum
was obvious in three (Table 1). Loss of neurons with gliosis was found in the striatum, pallidum, thalamus, sub-

Distribution of cerebral cortical lesions
The data obtained are schematized in Figs. 3–7. In case 1,
whose initial sign was limb-kinetic apraxia and who was
clinically diagnosed as having CBD, we found severe lesions in the posterior portions of the frontal lobe, includ-

420

Clinicopathological correlations
Only the two patients who presented limb-kinetic apraxia
as initial sign, followed by parkinsonism and dementia,
were clinically diagnosed as having CBD. Both had severe lesions chiefly in the posterior portions of the frontal
lobe, including the premotor area, anterior to the precentral gyrus. By contrast, in the three other patients, moderate to severe lesions were evident in the anterior portions
of the lobus frontalis.
The clinical and pathological data indicated above suggest that the lesion responsible for limb-kinetic apraxia in
CBD is present in the premotor area. Our results also lead
us to believe that when the anterior regions of the frontal
lobe are damaged, the resulting clinical picture mimics
those of frontal Pick’s disease and PSP, and that when the
main damage is in the posterior portions of this lobe, the
clinical picture is typical of CBD.

Discussion

Fig. 4 Distribution of cerebral cortical lesions of case 2. For details see Fig. 3

ing the premotor area, anterior to the precentral gyrus
(area 6 after Broadmann) (Fig. 3C, D). His primary motor
area had slight to moderate lesions (Fig. 3E–H). Moderate
lesions were seen in the anterior portions of the frontal
lobe of case 2, who exhibited delusion of persecution as
the initial sign and was diagnosed as having PSP (Fig.
4A–C). The primary motor area of this patient showed
slight lesions (Fig. 4C, D). Case 3, who presented limb-kinetic apraxia as initial sign and was clinically diagnosed
as CBD, had severe lesions in the posterior portions of the
frontal lobe and in the anterior portions of the parietal
lobe (areas 1–7 after Broadmann) (Fig. 5C–G). The lesions in the primary motor area of this patient were mostly
moderate (Fig. 5C–F). Obvious severe lesions were found
in the anterior portions of the frontal lobe of case 4, whose
initial sign was abnormal behavior and whose clinical diagnosis was frontal Pick’s disease (areas 6, 8, 9, and
44–46 after Broadmann) (Fig. 6A–D); the lesions in the
primary motor area were slight to moderate (Fig. 6A, B).
Case 5, who had the same initial sign and clinical diagnosis as case 4, had severe lesions in the anterior portions of
the frontal lobe (areas 6, 8, 9, and 45–47 after Broadmann) (Fig. 7A–C). The lesions in the primary motor area
of this patient were slight to moderate (Fig. 7D).

The characteristic clinical features of CBD were thought
to be asymmetric motor disturbance with cortical sensory
loss and apraxia without marked cognitive dysfunction,
supranuclear gaze palsies, parkinsonism, and involuntary
movements [12]. However, despite these criteria, it is very
difficult to make a clinical diagnosis of CBD. For instance, of the three autopsy cases of CBD reported by
Gibb et al. [8], no definite clinical diagnosis could be
made for one, and PSP was suspected in the other two.
Moreover, an autopsy case of PSP that was clinically diagnosed as CBD has been reported recently [25]. Even
though Rebeiz et al. [20, 21] indicate in their original report that mental ability was surprisingly intact until the late
stages of the disease, several autopsy cases of CBD presenting initially with dementia have been recorded [3, 5,
18, 23, 30]. Paulus and Selim [18] reported an atypical
autopsy case of CBD; the patient had a 2-year history of
progressive forgetfulness, apathy, sexual recklessness,
episodic depression, and difficulty in walking. The gross
examination of the patient’s brain revealed mild atrophy
of the cerebrum with frontal accentuation, and the histological examination disclosed pathological changes typical of CBD, including globular inclusions positive for tau
protein in the neurons of the upper cortical layers. Of the
three autopsy cases reported by Wakabayashi et al. [30],
one presented with memory impairment and difficulty in
carrying out housework as initial symptoms at the age of
71. This patient died 6 years later; the gross examination
revealed marked atrophy of the frontal lobe, mainly on the
left, with the histology being compatible with CBD, including positive tau pathology in the neurons of the cerebral cortex. In a clinical study of 36 cases, Rinne et al.
[23] described one patient with neuropathologically confirmed CBD who presented with gait difficulties and falls
as the initial signs, followed by a profound behavioral syndrome with personality changes, bulimia, impulsiveness
and frontal lobe release signs. More recently, Brown et al.

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Fig. 5 Distribution of cerebral
cortical lesions of case 3. For
details see Fig. 3

[5] reported on two families in which 15 individuals developed progressive dementia with features of frontal lobe
dysfunction, including personality changes and stereotyped behavior. The postmortem examination of two patients from separate families disclosed lobar atrophy of
the frontotemporal cortex with many swollen neurons and
neuronal loss, as well as neuronal loss with gliosis in the
pallidum and substantia nigra. Immunohistochemically,
the swollen neurons of the two patients showed positive
reaction with an antibody to tau protein. The authors indicated that on clinical assessment, the families had many
features of Pick’s disease, but that the pathological examination revealed hallmarks suggestive of CBD. In regard
to the multiplicity of clinical features of the disease, the
study by Feany and Dickson [6], who examined 11 patients with autopsy-proven CBD, is particularly interesting. They state that few cases have clinical features generally considered to be typical of CBD, and suggest that

most patients meeting the neuropathological criteria for
the disorder would not be diagnosed ante mortem.
Based on our data, and on the atypical autopsy cases
referred to above, we postulate that the clinical features of
CBD have a much wider spectrum than previously believed.
It has been reported that the focal atrophy in CBD was
confined to the frontal and/or parietal lobes. Of the three
cases described by Rebeiz et al. [20, 21], the most striking
abnormality was in the superomedial frontoparietal cortex
with asymmetry in two of them. The Betz cells in the precentral cortex of one patient appeared normal with a good
complement of Nissl granules [21]. In another study on
neuropathologically verified CBD, the gross examination
disclosed very marked atrophy of the precentral and postcentral gyri, and the microscopic examination of the precentral gyrus revealed severe neuronal loss with gliosis
and absence of Betz cells [24]. On the other hand, the

422
Fig. 6 Distribution of cerebral
cortical lesions of case 4. For
details see Fig. 3

macroscopical brain examination of the three cases of
Gibb et al. [8] disclosed atrophy of the superior parietal
region with slight accentuation of the left in one patient,
mild atrophy of the posterior frontal and parietal region in
another, and mild atrophy of the frontal region in the third.
From the previous data [8, 20, 21, 24] it is evident that
the distribution of cerebral cortical lesions in CBD has
been determined mainly by macroscopic examination.
Hence, our study on the distribution of such lesions based
on the detailed microscopic examination of hemisphere
specimens provides information not available heretofore.

From our results it is obvious that the lesions do not predominate in the paracentral region, and that the most severe lesions of CBD are mainly in the frontal lobe. By
comparison, the primary motor area of the CBD patients
exhibited mostly slight to moderate damage.
The lesion responsible for limb-kinetic apraxia has until now been a matter of discussion. Limb-kinetic apraxia
has been most commonly attributed to alterations of frontal or rolandic areas from the proposal by Liepmann [13].
The lesion responsible for limb-kinetic apraxia has also
been attributed to the premotor area by some researchers

423

eron et al. [3], in which extensive deposition of abnormal
tau in the neurons was evident. The patient had had an
isolated speech disturbance for 5 years before developing
the more typical motor features of CBD. The neuropathological examination showed atrophy of the left posterior
frontal lobe. Wakabayashi et al. [30] also described a variant case of CBD with positive tau pathology, who presented motor aphasia as the initial sign at the age of 67.
The patient died at age 73, and the neuropathological examination revealed marked atrophy of the frontal, precentral, and parasylvian gyri, with the histology being compatible with CBD.
Based on our results on the distribution of cerebral cortical lesions in CBD, and on the atypical autopsy cases
who had primary progressive aphasia [2, 3, 30], we consider that focal cerebral atrophy of CBD is multicentric.
We can assume that the “atrophic center” is present in the
anterior and posterior portions of the frontal lobe and in
the parasylvian region, including the first temporal gyrus.
In addition, we also believe that when the lesion starts in
the anterior portion of the lobus frontalis, the clinical features of CBD mimic those of PSP or frontal Pick’s disease, and that when these features present with primary
progressive aphasia, the lesion begins in the parasylvian
region including the first temporal gyrus.
Fig. 7 Distribution of cerebral cortical lesions of case 5. For details see Fig. 3

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deep gray matter showed positive reaction with anti-tau.
An atypical autopsy case of CBD was described by Berg-

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