51

Journal of Alzheimer’s Disease 40 (2014) 51–55
DOI 10.3233/JAD-131676
IOS Press

Short Communication

Lateralized Cortical Involvement and
Contralateral Parkinsonism without Basal
Ganglia Involvement in Two Autopsy Cases
of Corticobasal Syndrome-Alzheimer’s
Disease
Taku Hommaa,d,e,∗ , Hideki Takuboc , Kazushi Takahashib , Shiro Matsubarab , Manabu Takahashid ,
Nobuaki Funatad,f , Yoko Mochizukia,h , Toshio Mizutania , Takashi Komoria
and Toshiki Uchiharaa,g
a Department of Pathology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
b Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
c Department of Neurology, Ebara Hospital, Tokyo, Japan
d Department of Pathology, Ebara Hospital, Tokyo, Japan
e Department of Pathology, Saitama Medical University, Saitama, Japan
f Department of Pathology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
g Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute for Medical Science, Tokyo, Japan
h Department of Neurology, Tokyo Metropolitan Kita Medical and Rehabilitation Center, Tokyo, Japan

Accepted 30 October 2013

Abstract. Corticobasal syndrome (CBS) is characterized by lateralized motor disturbance due to levodopa nonresponsive
parkinsonism and progressive apraxia. Although CBS is neuropathologically heterogeneous, it remains unclear whether the
clinical features of all CBS cases are the same. We report two autopsy cases diagnosed clinically as CBS and pathologically as
Alzheimer’s disease characterized by lateralized cerebral cortical degeneration and absence of significant nigrostriatial lesions.
Cerebral cortical degeneration in both cases was contralateral to their motor disturbances. Thus, nigrostriatial lesions and
contralateral cerebral cortical lesions can cause motor disturbances in CBS, necessitating the need for bedside examination in
patients with CBS.
Keywords: Alzheimer’s disease, cerebral cortex, corticobasal syndrome, parkinsonism, striatonigral system

INTRODUCTION
∗ Correspondence to: Taku Homma, MD, PhD, Department of

Pathology, Tokyo Metropolitan Neurological Hospital, 2-6-1
Musashi-dai, Fuchu, Tokyo 183-0042, Japan. Tel.: +81 42 323 5110;
Fax: +81 42 322 6219; E-mail: homma.taku@gmail.com.

Corticobasal syndrome (CBS) is a clinical diagnostic term, pointing to a lateralized motor disturbance
caused by a mixture of levodopa nonresponsive
parkinsonism and progressive apraxia [1]. In addition

ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

52

T. Homma et al. / Lateralized Cortical Lesion as a Cause of Contralateral Parkinsonism of CBS-AD

to corticobasal degeneration, pathologically featured
by deposition of a four-repeat tau, the underlying
cytopathologies of CBS are heterogeneous [2, 3] and
include Alzheimer’s disease (AD) [2]. We describe
two autopsy-verified AD cases that were clinically
diagnosed as CBS based on such lateralized motor disturbance. Nigrostriatal degeneration was, at most, mild
without laterality, whereas neurofibrillary degeneration around the pericentral area was more pronounced
in the neocortex contralateral to the motor disturbances.

CASE REPORTS
Patient 1 (Pt1) [4] (67-year-old right-handed male)
presented with gait disturbance and postural instability. Neurological examination revealed mask-like
face, lead-pipe rigidity of the right upper limb, micrographia, and small voice; however, hallucination,
personality change, and dementia were absent. Two
years later, his short-term memory was slightly disturbed. Brain magnetic resonance imaging (MRI)
performed three years after symptom onset showed
bilateral cerebral atrophy, which was most prominent
at the medial temporal region, including the hippocampus. Limb-kinetic apraxia and nonfluent aphasia
supervened five years after symptom onset. Follow-up
MRI showed left-side-dominant cerebral atrophy with
progressive atrophy of the hippocampus and parahippocampus. Rigidity involving his trunk and extremities
was more pronounced on the right side. At 74 years,
he died of septicemia due to pneumonia.
Patient 2 (Pt2) [5] (60-year-old male) presented with
gait disturbance and difficulty in dressing. Neurological examination revealed left-side-dominant lead-pipe
rigidity of the trunk and extremities; upper limb
myoclonus was observed seven years after symptom
onset. Brain MRI revealed right-side-dominant cerebral atrophy. Nine years after symptom onset, he died
of pneumonia and acute pancreatitis. Levodopa was not
effective throughout the disease course in both cases.
The fixed brain of Pt1 weighed 1090 g. External macroscopic examination revealed mild
fronto–temporo–parietal atrophy without laterality (Fig. 1a). After serial coronal slicing, left-sided
atrophy involving anterior medial temporal structures
such as the amygdala and hippocampus was evident.
The substantia nigra (SN) and locus coeruleus
(LC) were relatively preserved. Microscopically,
numerous neurofibrillary tangles (NFTs) and senile
plaques (SPs) were observed in the cerebral cor-

tices, corresponding to Braak NFT stage VI and
Braak SP stage C [6, 7] by Gallyas–Braak staining,
Methenamin–Bodian staining, and both AT8 and
amyloid-␤ (A␤) immunohistochemistries, in addition
to laminar necrosis in the entorhinal cortex, which
were compatible with a histological diagnosis of
advanced AD. Remarkable neuronal loss and gliosis
were limited to the temporal medial region, including the amygdaloid nuclei, hippocampi, entorhinal
cortices, and precentral gyri, where neurofibrillary
changes were more robust in the left (Fig. 1b) than
the right (Fig. 1c) side (Table 1). SN was median part
predominantly affected by slight neuronal loss and
gliosis without laterality (Table 1, Fig. 1d). The LC
and subcortical gray matter, including the caudate
nuclei, putamen (Fig. 1e), and globus pallidus, were
all free from neuronal loss and gliosis (Table 1).
The fixed brain of Pt2 weighed 1037 g. Cerebral atrophy was more prominent in the right side,
especially in the right parietal lobe and post- and
precentral gyri (Fig. 1f). After coronal slicing, rightsided atrophy became more evident in the occipital
lobe and right pericentral gyrus. The temporal medial
region, including amygdaloid nuclei, hippocampi, and
entorhinal cortices, showed atrophy without laterality. Mild depigmentation was observed in the SN and
LC. Microscopically, numerous NFTs and SPs were
observed in the cerebral cortices, corresponding to
Braak NFT stage VI and Braak SP stage C [6, 7] by
Gallyas–Braak staining, Methenamin–Bodian staining, and both AT8 and A␤ immunohistochemistries,
in addition to laminar necrosis in the entorhinal cortex
and both superior and inferior parietal lobules, which
were compatible with AD. However, NFTs were more
abundant in the right parietal area (Fig. 1h) than the
left counterpart (Fig. 1g, Table 1). In Pt2, remarkable
neuronal loss and gliosis affected the temporal medial
regions, including amygdaloid nuclei, hippocampi,
and entorhinal cortices, and the right-side-dominant
pericentral regions and cerebral cortices of the parietal
lobe (Fig. 1g and h) (Table 1). In the SN, mild neuronal
loss and gliosis were median to lateral part predominantly noted, without laterality (Table 1, Fig. 1i). The
LC and subcortical gray matter, including the caudate, putamen (Fig. 1j), and globus pallidus, showed
mild-to-no-gliosis; no remarkable neuronal loss was
observed in those nuclei (Table 1).
By phosphorylated ␣-synuclein immunohistochemistory, several Lewy bodies were observed only
in the amygdalaoid nuclei of Pt1, whereas none were
observed in Pt2. There was neither astrocytic plaques
nor tufted astrocytes in both cases.

T. Homma et al. / Lateralized Cortical Lesion as a Cause of Contralateral Parkinsonism of CBS-AD

53

Fig. 1. Macroscopic and microscopic symmetry of cortical lesions. a) Symmetrical cerebrum with mild fronto–temporo–parietal atrophy. b,
c) Compared with the right side (c), the left precentral cortex (b) was affected by numerous NFTs (Gallyas–Braak). d, e) The substantia nigra
(d) and putamen (e) were well preserved (H&E). f) Marked cerebral atrophy with right-side laterality, which was most prominent in the right
occipital lobe and the right pericentral sulcus region. g, h) Compared with the left side (g), the right precentral cortex (h) was affected by
numerous NFTs (Gallyas–Braak). i, j) The substantia nigra (i) and putamen (j) were well preserved (H&E).

In the present report, semiquantitative analyses for
neuronal loss and gliosis in the peri-sylvian fissure
region, basal ganglia, and substantia nigra were performed. In addition, the average number (/mm2 ) of
both NFTs and SPs per 10 fields (200 power fields)
was calculated. These data are described in Table 1.

DISCUSSION
The prevalence of AD pathology in CBS patients
is estimated to be 5.2–50% in prospective [2, 8–10]
and 17.6–23.8% in retrospective [8, 11, 12] studies.
However, this overall prevalence does not clarify the
relation between AD pathology and this characteristic mixture of ipsilateral parkinsonism and apraxia.
Either parkinsonism or apraxia could be independently
manifested in AD [13, 14]. In accordance with the
conventional framework of neurology, parkinsonism
is ascribed to nigrostriatal lesions possibly with
tau deposition [13], and apraxia is usually ascribed
to cortical lesions [14] in AD. On the other hand,
extrapyramidal features in the absence of significant
nigral lesion have been reported in AD patients [2, 4, 5,
10, 15–20]. Among them, some exhibited extranigral
lesions in the basal ganglia [2, 19], which may explain
the extrapyramidal symptoms [2]. Even after exclud-

ing AD cases with significant lesions in the SN or basal
ganglia, there still remain some autopsy-verified AD
patients who developed some motor disturbance [2, 4,
5, 15, 17, 18, 20] with more or less extrapyramidal features. It is also being recognized that extrapyramidal
symptoms in CBS are not necessarily accompanied
by a reduced uptake of FP-CIT in the nigrostriatal
system by FP-CIT single photon emission computed
tomography (SPECT) [21, 22]. These cliniconeuropathological and SPECT results suggest that the
so-called extrapyramidal features may be evident even
in the absence of functional or pathological involvement of the nigrostriatal system, as confirmed here.
Motor disturbances in AD patients without significant
lesions in the SN or basal ganglia are lateralized
frequently [2, 4, 5, 15, 17]. In such cases, the cortical
asymmetry represented by macroscopic atrophy or
NFT abundance is always contralateral to the motor
disturbance, with extrapyramidal and apraxic features
[2, 4, 5, 15, 17]. It is plausible that this unique mixture
of extrapyramidal and apraxic features originates in
the contralateral cortex, at least in CBS-AD patients.
This is one of the potential explanations as to why two
apparently distinct manifestations, extrapyramidal
and apraxic features, develop ipsilaterally.
Because lateralized cortical lesions not accompanied by basal ganglia lesions may develop in

54

T. Homma et al. / Lateralized Cortical Lesion as a Cause of Contralateral Parkinsonism of CBS-AD
Table 1
Clinico-pathological characteristics of two CBS-AD cases
Case 1

Case 2

Male
67
7
Rt side-dominant
Gait disturbance
Postural instability
Lead pipe rigidity
Myoclonus
+ (short-term memory)
Hand-finger apraxia
Lt side-dominant cerebral atrophy, including
hippocampus and parahippocampus
–

Male
60
9
Lt side-dominant
Gait disturbance
Postural instability
Lead pipe rigidity
Myoclonus
–
Dressing apraxia
Rt side-dominant cerebral atrophy

Clinical features
Gender
Age at onset
Duration of illness
Parkinsonism

Dementia
Apraxia
Brain MRI
Effect of L-dopa
Pathological features

Left

Brain weight (g)
Macroscopical cerebral atrophy
Braak NFT stage [6, 7]
Braak SP stage [6]
Laminar necrosis
Peri-sylvian region

Basal ganglia

Substantia nigra

–
Right

Left

1090
Lt = Rt
VI
C
ER
PreMo
Neuronal loss
Gliosis
NFT (/mm2 )
SP (/mm2 )
Mo
Neuronal loss
Gliosis
NFT (/mm2 )
SP (/mm2 )
Se
Neuronal loss
Gliosis
NFT (/mm2 )
SP (/mm2 )
Caud
Neuronal loss
Gliosis
NFT (/mm2 )
SP (/mm2 )
Put
Neuronal loss
Gliosis
NFT (/mm2 )
SP (/mm2 )
GP (e/i)
Neuronal loss
Gliosis
NFT (/mm2 )
SP (/mm2 )
Neuronal loss
Gliosis
NFT (/mm2 )
SP (/mm2 )

Right
1037
Lt < Rt
VI
C
Occ, ER

–
–
54
17

–
–
55
14

+
+
125
12

++
++
137
14

+
+
88
20

±
±
36
16

+
+
79
22

++
++
97
19

–
–
27
9

–
–
28
10

+
++
118
21

+++
+++
59
23

–
–
2
NA

–
–
1
0

–
+
2
0

–
+
4
0

–
–
1
NA

–
–
2
0

–
+
2
2

–
+
2
0

–/–
–/–
0/0
NA
±
±
10
NA

–/–
–/–
0/0
0/0
±
±
7
NA

–/–
–/–
0/0
0/0
+
+
6
NA

–/–
–/–
0/0
0/0
+
+
10
NA

Lt, left; Rt, right; PreMo, premotor cortex; Mo, motor cortex; Se, sensory cortex; Caud, caudate nucleus; Put, putamen; GP, globus pallidus;
NFT, neurofibrillary tangle; SP, senile plaque; e, external segment; i, internal segment; ER, entorhinal cortex; Occ, occipital cortex. Degrees of
neuronal loss and gliosis are described as follows: −, none; ±, slight; +, mild; ++, moderate; +++, severe.

T. Homma et al. / Lateralized Cortical Lesion as a Cause of Contralateral Parkinsonism of CBS-AD

contralateral CBS in situations other than AD [2,
20, 23], this clinical presentation is not unique to
AD. However, it remains to be clarified by autopsy
whether an isolated cortical lesion due to cerebral
infarction may mimic CBS, although there is one clinical investigation in which anterior cerebral artery
territory infarction was described as the cause of
CBS [24]. Awareness of CBS with or without basal
ganglia lesions will challenge the conventional framework of clinical neurology if these apparently different
pathological conditions cannot be distinguished. CBS
patients should be reexamined at the bedside while
keeping this awareness in mind to allow clinical distinction of these conditions in the future.

[8]

[9]

[10]

[11]

[12]

ACKNOWLEDGMENTS

[13]

The authors thank Mr. Mitsuhiro Ikeda, Mrs. Yoshie
Ishizaka, Mrs. Nao Hiraishi, and Mrs. Yoko Suzuki
at the Tokyo Metropolitan Neurological Hospital, and
Ms. Aya Kimura, Ms. Azusa Matsuo, and Ms. Wakana
Isa at the Ebara Hospital for their excellent technical
assistance.
Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2011).

[14]

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