Parkinsonism and Related Disorders 68 (2019) 79–84

Contents lists available at ScienceDirect

Parkinsonism and Related Disorders
journal homepage: www.elsevier.com/locate/parkreldis

Cerebrovascular pathology presenting as corticobasal syndrome: An autopsy
case series of “vascular CBS”

T

Shunsuke Koga, Shanu F. Roemer, Koji Kasanuki1,2, Dennis W. Dickson∗
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA

ARTICLE INFO

ABSTRACT

Keywords:
Corticobasal syndrome (CBS)
Cerebrovascular pathology
Vascular parkinsonism
Corticospinal tract degeneration
Wallerian degeneration

Background: The corticobasal syndrome (CBS) is heterogeneous in terms of postmortem neuropathology. While
it has been previously studied with antemortem neuroimaging, clinicopathologic features of corticobasal syndrome associated with cerebrovascular pathology (vascular CBS) have yet to be reported.
Methods: To identify vascular CBS, we searched the database of the CurePSP Brain Bank for patients with a clinical
diagnosis of CBS who failed to meet neuropathologic criteria for corticobasal degeneration (CBD) or other neurodegenerative disease processes, but who had significant cerebrovascular pathology. Hemibrains were assessed macroscopically
and processed for histological assessment. Medical records were reviewed to characterize clinical features of vascular CBS.
Results: Of 217 patients with an antemortem diagnosis of CBS, we identified three patients with vascular CBS.
Multiple infarcts in the watershed regions (frontal lobe and motor cortex), periventricular white matter, thalamus,
and basal ganglia were observed in two patients. One patient had no cortical infarcts, but had multiple white
matter infarcts and corticospinal tract degeneration. All were clinically thought to have CBS based on progressive
asymmetric motor symptoms, including rigidity and apraxia, as well as cognitive impairment. Antemortem imaging studies showed findings of chronic cerebrovascular disease, with infarcts or white matter pathology.
Conclusions: This autopsy study of vascular CBS shows that, while rare, cerebrovascular pathology involving the
frontal lobe, white matter tracts, basal ganglia, thalamus, and corticospinal tract can underlie clinical features
suggestive of CBS. When neuroimaging suggests an alternative explanation, including chronic infarcts in critical
regions, caution is merited in considering CBD as the underlying pathology.

1. Introduction
Corticobasal syndrome (CBS) is characterized by progressive
asymmetric rigidity, apraxia, alien limb phenomena, myoclonus, cortical sensory loss, dystonia, and cognitive dysfunction [1,2]. The neuropathological substrate of CBS was once thought to be corticobasal
degeneration (CBD), but it is increasingly recognized that progressive
supranuclear palsy (PSP), Alzheimer's disease (AD), Lewy body disease
(LBD), and other neurodegenerative diseases can also present with CBS
[3,4]. In addition to neurodegenerative disorders, cerebrovascular pathology can also produce extrapyramidal signs or movement disorders
[5–9]. Compared to idiopathic Parkinson's disease, vascular parkinsonism is characterized by bilateral and symmetric lower limb-predominant parkinsonism and absence of resting tremor [5,8]. In rare
cases, vascular parkinsonism has presentations similar to PSP or multiple system atrophy (MSA) [10,11]. Patients with “vascular CBS” have

been reported based on MRI findings, but none of the cases were confirmed at autopsy [12–15]; therefore, it remains uncertain whether they
were devoid of neurodegenerative changes of corticobasal degeneration
(i.e., mixed CBD and vascular pathologies).
We herein describe three patients who clinically fulfilled diagnostic
criteria for CBS. All presented with insidious onset of asymmetric spasticity, apraxia, and bradykinesia. Previous strokes preceded the diagnosis
by several years and were clinically considered unrelated to CBS.
Neuropathologic analysis revealed cerebrovascular pathologies without
any other neurodegenerative processes, consistent with vascular CBS.
2. Materials and methods
2.1. Subjects
All patients included in this study were from the Cure PSP Brain

Corresponding author. Address: 4500 San Pablo Road, Jacksonville, FL 32224, USA.
E-mail address: dickson.dennis@mayo.edu (D.W. Dickson).
1
Department of Psychiatry, Juntendo School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113–8431, Japan.
2
Mental Clinic, Juntendo Tokyo Koto Geriatric Medical Center, 3-3-20 Shinsuna, Koto-ku, Tokyo, 136–0075, Japan.
∗

https://doi.org/10.1016/j.parkreldis.2019.09.001
Received 21 May 2019; Received in revised form 25 July 2019; Accepted 1 September 2019
1353-8020/ © 2019 Elsevier Ltd. All rights reserved.

Parkinsonism and Related Disorders 68 (2019) 79–84

S. Koga, et al.

Table 1
Clinical summary of vascular CBS patients.

Age at death
Sex
Disease duration, years
Clinical diagnosis
Evaluated physicians
Asymmetrical symptoms
Alien limb phenomena
Limb dystonia
Limb myoclonus
Limb apraxia
Cortical sensory loss
Hyperreflexia
Paresis/spasticity
Urinary incontinence
Pseudobulbar palsy
Cognitive impairment
Word finding difficulty
Medical history
Ischemic heart disease
Atrial fibrillation
Pacemaker/ICD
Hypertension
Dyslipidemia
Diabetes mellitus
Homocystinuria
Carotid artery stenosis
Peripheral vascular disease
Transient ischemic attack
Stroke
Anticoagulant therapy

CBS-1

CBS-2

CBS-3

69
M
12
CBS
2 Movement disorder specialists & 4 neurologists
L>R
+
+
+
+
–
+
+
+
NA
+
+

82
F
3
CBS
1 Movement disorder specialist & 3 neurologists
L>R
–
–
+
+
–
–
–
–
+
+
+

69
M
8
CBS
1 Neurologist
R >L
NA
NA
NA
+
–
+
+
NA
NA
+
+

–
–
–
–
+
+
+
–
–
+
+
–

+
+
+
+
+
+
–
–
+
+
+
–

+ (stents)
–
–
+
+
–
–
90%
+
–
+
Aspirin 81 mg/day

Abbreviations: CBS, corticobasal syndrome; ICD, implantable cardioverter defibrillator; L, left; NA, not available for review; R, right.

blue or Masson's trichrome stain and with immunohistochemistry for
CD68 (1:1000, KP-1, DAKO, Carpinteria, CA) and GFAP (1:5000, GA-5,
BioGenex, Fremont, CA).
For one case (CBS-2), 1-cm thickness coronal sections of frozen right
hemibrain were assessed macroscopically for infarcts and hemorrhages
because this patient had left-side predominant clinical symptoms, but the
formalin-fixed hemibrain was left side (i.e., presumably less affected side).

Bank at Mayo Clinic in Jacksonville, Florida, collected between 1998
and 2018. During this time frame, 217 patients had an antemortem
diagnosis of CBS. Patients having multiple differential diagnoses (e.g.,
CBS vs. PSP) were excluded. To identify vascular CBS, we searched the
database for patients without other major neurodegenerative disease
processes (e.g., AD, LBD, PSP, CBD, MSA, TDP-43 proteinopathy), but
with cerebrovascular disease. All brain autopsies were performed with
the consent of the legal next-of-kin or an individual with legal authority
to grant permission. De-identified studies using these autopsy samples
are considered exempt from human subject research by the Mayo Clinic
Institutional Review Board.

2.3. Clinical assessment
The following clinical information was derived from the medical
records, radiological reports, and brain bank questionnaires filled out by
a close family member as described previously [20]. This included sex,
age of onset, age at death, medical history, medication, imaging findings,
clinical symptoms, neurological signs, and final clinical diagnosis. Particular focus was on CBS features, including asymmetrical rigidity and
apraxia, myoclonus, cortical sensory loss, alien limb phenomena, pyramidal signs, and cognitive impairment. Given the retrospective nature
of the study, the quality of medical records was variable, and only information confirmed by two neurologists was included (SK, SFR). To
assess possible bias that might be related to clinical diagnosis, subspecialty and the number of physicians who evaluated patients (i.e.,
movement disorder specialist or general neurologist) were also noted.

2.2. Neuropathological assessment
Formalin-fixed hemibrains underwent systematic and standardized
sampling with neuropathologic evaluation by a neuropathologist (DWD).
The regions sampled for histopathology were the middle frontal gyrus,
superior temporal gyrus, inferior parietal gyrus, pre-and post-central
gyri, visual cortex, cingulate gyrus, anterior and posterior hippocampus,
amygdala, basal nucleus of Meynert, lentiform nucleus, hypothalamus,
thalamus at the level of the subthalamic nucleus, midbrain, pons, medulla, cerebellum, and cervical spinal cord. Paraffin-embedded 5-μm
thick sections mounted on glass slides were stained with hematoxylin
and eosin (H&E) or thioflavin S stains. Alzheimer-type pathology, including Braak neurofibrillary tangle stage and Thal amyloid phase, were
assessed as previously described [16–18]. Tau, Lewy-related, and TDP-43
pathology were assessed using immunohistochemistry for phospho-tau
(CP13, 1:1000, from Dr. Peter Davies, Feinstein Institute, North Shore
Hospital, NY), α-synuclein (NACP, 1:3000, Mayo Clinic antibody) [19]
and phospho-TDP-43 (pS409/410, 1:5000, Cosmo Bio, Tokyo, Japan),
respectively. Vascular pathologies, including infarcts, hemorrhages, ischemic gliosis, cribriform change, arteriosclerosis, atherosclerosis, and
cerebral amyloid angiopathy were assessed on H&E stained and thioflavin S stained sections. Select sections were processed with Luxol fast

3. Results
3.1. Clinical vignettes
Demographic and clinical features of vascular CBS patients are
summarized in Table 1.
3.1.1. CBS-1
This patient was a 69-year-old Caucasian man who had a medical
history of homocystinuria, dyslipidemia, diabetes mellitus, and migraine.
80

Parkinsonism and Related Disorders 68 (2019) 79–84

S. Koga, et al.

He did not receive any anticoagulant therapy, but was treated with vitamin B supplementations due to homocystinuria. At age 57, he complained of left foot drag, which his relatives had noticed for several
months before the patient noticed. He also had trouble dropping things
from his left hand. The symptoms steadily progressed, and he had numerous episodes of near falls. He also noticed trouble moving his left
hand. His left side became increasingly stiff, and gradually he lost the
ability to use his hand for any purposeful tasks. He complained of arm
and leg cramps, especially at night. He had also developed urinary urgency and later, urinary incontinence. On initial examination at age 60,
he had occasional word-finding difficulties, significant saccadic breakdown of smooth pursuit in both horizontal and vertical planes, left-sided
spastic catch, left-sided hyperreflexia, and extensive plantar response. No
bradykinesia or tremor was noted. Gait was spastic, with left hemiplegia
and foot-drop. His symptoms continued to progress over the next two
years. He complained that when yawning, his arm would elevate and
move spontaneously, even though he had difficulties lifting the arm
volitionally. He frequently lost track of where his left arm or leg was
located. On examination, a spastic-dystonic left hemiparesis and hyperreflexia with clonus were noted. There was substantial left-sided
apraxia. Cerebellar testing was unremarkable, but the evaluation was
limited on the left due to severe apraxia and dystonic weakness. His gait
was notable for increased dynamic tone and dystonic posture on the left
extremities. A brain MRI showed asymmetric right hemisphere atrophy
particularly in the frontal and temporal lobes, extending into parietal and
occipital lobes, with right lateral ventricle dilation. T2-weighted images
showed hyperintensities of the periventricular region suggestive of
gliosis, low signal changes in the right basal ganglia, right cerebral
peduncle, and right aspect of the pons. A clinical diagnosis of CBS was
made based on the combination of progressive spasticity, dystonia, and
apraxia.

3.1.3. CBS-3
This patient was a 69-year-old right-handed Caucasian man who
had a medical history of hypertension, hyperlipidemia, stroke at age 51,
severe peripheral and ischemic heart disease with two cardiac stents,
peripheral cyanosis, claudication, and colorectal cancer. His medications included aspirin 81 mg daily as an anticoagulant therapy. He
developed progressive right-sided weakness and stiffness, with occasional tremors at age 61. He also had slurring of speech, word-finding
difficulties, and short-term memory problems. He had progressive difficulty using utensils and required a wheelchair. He was treated with
carbidopa-levodopa at age 67, without response. At age 69, his neurological examination was notable for asymmetric rigidity (R > L),
lower muscle weakness (R > L), and a Babinski sign on the right. He
could follow simple, but not complex commands. He had word-finding
difficulties, perseveration, and frontal release signs. Carotid ultrasound
showed bilateral lesions, with 90% left internal carotid artery stenosis.
A brain MRI showed a chronic infarct in the left frontal lobe. An FDGPET scan showed focal left frontal hypoactivity, as well as diffuse left
cerebral hypoactivity, including decreased activity in the left basal
ganglia, thalamus, and the right cerebellum. Whole-body images
showed no evidence of tumor recurrence or metastasis. Based on his
progressive clinical symptoms and imaging studies, he was diagnosed
with CBS.
3.2. Pathological findings
Pathological findings, including the distribution of infarcts, are
summarized in Table 2. Arteriosclerotic small vessel disease was observed in two patients, particularly in arterioles of the basal ganglia.
Alzheimer-related pathology was insignificant, and tau, α-synuclein,
and TDP-43 pathology were not detected.
3.2.1. CBS-1
Macroscopically, the cerebral white matter had atrophy and discoloration, with gelatinous softening and partial cavitation. The white
matter pathology was most marked in the frontal and parietal lobe, but
also focally present in the temporal lobe and minimal in the occipital
lobe. In the most affected areas, the white matter ischemic damage was
so severe that it was nearly completely liquefied. The corpus callosum
and internal capsule, especially the anterior limb, were also affected
(Fig. 1A and B). There were dilated perivascular spaces, some cystic, in
the thalamus and putamen. Histologically, tissue rarefaction in frontal
white matter and internal capsule was associated with almost complete
myelinated fiber loss and dense fibrillary gliosis (Fig. 1C). There were
multiple foci of dystrophic calcification surrounded by lipid-laden
macrophages in most severely affected white matter (Fig. 1D–F). The
small vessels had arteriosclerotic hyalinosis, and some were completely
obliterated by collagenosis (Fig. 1E, G). The white matter lesions had
hypertrophic reactive astrocytes with GFAP (Fig. 1H). Similar changes
were present in the internal capsule. The posterior limb of the internal
capsule had severe degenerative changes with myelinated fiber loss,
gliosis, granular foamy axonal spheroids, and dystrophic calcification.
The cerebral peduncle, longitudinal fibers in the pontine base, medullary pyramid, and anterior corticospinal tract, but not lateral corticospinal tract, had severe atrophy with myelinated fiber loss and gliosis
(Fig. 1I) consistent with unilateral Wallerian degeneration.

3.1.2. CBS-2
This patient was an 82-year-old right-handed Caucasian woman
with a medical history of atrial fibrillation, hypertension, hyperlipidemia, diabetes mellitus, aortic atherosclerosis, congestive heart
failure, coronary artery disease, peripheral vascular disease, chronic
kidney failure, and obstructive sleep apnea. She had a pacemaker. She
underwent coronary artery bypass graft surgery and open-heart surgery with aortic valve replacement when she was 76 years of age.
After surgery, she developed continuous slurred speech, poor balance,
and neck stiffness. She was initially put on warfarin, but this was
discontinued due to gastrointestinal bleeding. She had progressive
worsening of gait and balance. She also had intermittent uncontrolled
facial movements. A year later, she was evaluated for a transient
episode of worsened slurred speech and left upper extremity weakness. A CT scan showed an old infarct in the left basal ganglia, but no
acute lesions. Her gait deteriorated, and she had falling episodes. At
age 81, she was referred to a movement disorder specialist due to
facial tics affecting eye, neck, jaw, and mouth. A diagnosis of CBS
seemed probable due to her cognitive impairment, marked asymmetric ideomotor apraxia in both upper extremities (L > R), rigidity
(L > R), bradykinesia, myoclonus, and possible eyelid apraxia or
blepharospasm. Additionally, she had neck rigidity, horizontal and upgaze nystagmus, pseudobulbar affect, as well as lower body negative
myoclonus. A clinical trial included levetiracetam for myoclonus and
baclofen for stiffness. A CT scan showed scattered deep white matter
hyperintensities consistent with small vessel disease, chronic lacunar
infarcts, and mild cerebral atrophy. Neuropsychological evaluation
showed rapidly progressive cognitive decline and significant decreases
in her Mini-Mental State Examination scores from 29/30 to 16/30 in
less than two years. She also had deficits in expressive language skills,
visuospatial construction, recall of verbal information, and frontal/
executive functions. These findings were considered supportive of a
neurodegenerative process, such as CBD.

3.2.2. CBS-2
Macroscopically, there were small infarcts in the motor cortex and
watershed region, as well as encephalomalacia in the left occipital pole
(Fig. 1J–L). Basal ganglia showed a cystic softening in the lateral caudate and putamen, with the involvement of the anterior limb of the
internal capsule (Fig. 1M). The right hemibrain had a large infarct in
the superior parietal lobe and multiple small infarcts in the visual
cortex and frontal watershed region. Microscopic examination revealed
multiple small infarcts of varying histologic age, including cystic
81

Parkinsonism and Related Disorders 68 (2019) 79–84

S. Koga, et al.

disease in cognition [21], as well as gait and balance [22–24]. All patients
met clinical criteria for CBS due to progressive asymmetric limb rigidity
and limb apraxia. The frequency of vascular CBS was only 1.4% (3/217)
in our cohort, but it might be under-represented due to selection bias.
To our knowledge, this is the first clinicopathological case series of
vascular CBS. Some studies described vascular CBS based on MRI findings without pathological confirmation, leaving open the possibility that
they had mixed vascular and degenerative pathologies [12,13]. Bhatia
et al. reported two patients who presented with a progressive asymmetric
syndrome of apraxia, rigidity, and dystonia [12]. They had chronic ischemic changes in the centrum semiovale and basal ganglia. One also
had an infarct in the right insular cortex, while the other had bilateral
infarcts in the pons. Subsequently, Kreisler et al. described five patients
with progressive asymmetric rigidity and apraxia suggestive of CBS [13].
All patients had chronic ischemic changes in centrum semiovale. Basal
ganglia were affected in four patients, and motor cortex was affected in
three patients. Neuroimaging studies highlight brain regions associated
with limb apraxia, a characteristic feature of CBS, to be frontal and
parietal lobes, as well as parieto-frontal association fibers [25–28]. The
thalamus and basal ganglia are also involved in a network of structures
underlying praxis [29], likely through connections with frontal and
parietal cortices [30]. Thus, patients with multiple infarcts in these brain
regions may present with limb apraxia that can be mistaken for CBS,
especially when signs and symptoms are asymmetric. In line with this,
our pathological analyses showed small vessel disease with multiple infarcts in watershed regions, primary motor cortex, deep white matter,
thalamus, and basal ganglia as the likely correlates of CBS.
Clinically silent small ischemic lesions in these anatomic regions may
lead to disability over time due to secondary Wallerian degeneration. A
study highlighting post-stroke upper limb spasticity showed that 33% of
patients developed spasticity three months after a stroke, and another
17% developed spasticity at even later stages [9]. Furthermore, half of
the patients with moderate spasticity progressed to severe spasticity [9].
This temporal profile resembles imaging studies of Wallerian degeneration [31]. Although early subtle changes may be evident using advanced
imaging techniques, such as diffuse tensor imaging, within a few weeks
after a stroke, Wallerian degeneration becomes obvious on routine T2weighted images several weeks to months after the initial stroke [32].
In this study, all patients had an insidious onset and a progressive
disease course. CBS-1 had multiple risk factors for cerebrovascular disease. Despite a lack of clinical history of hypertension, he had arteriosclerotic hyalinosis in small vessels. This finding is consistent with the
fact that histopathological findings of small vessel disease can be seen in
normotensive individuals and may imply other pathomechanism, such as
endothelial damage [33]. Moreover, his symptoms were first noted by his
relatives, suggestive of a clinically silent stroke. CBS-2 had asymmetric
atrophy and ventricular dilation with hyperintense signal changes possibly due to Wallerian degeneration. Despite severe peripheral and ischemic heart disease, usual anticoagulant therapy was not possible. CBS3 had onset of mild symptoms after open-heart surgery, a procedure with
an increased risk of stroke. He showed progressive decline until his
death, which was likely due to a combination of corticospinal Wallerian
degeneration and additional clinically silent ischemic lesions. He was not
eligible for anticoagulant therapy due to gastrointestinal bleeding. Although CBS-3 was not evaluated by a movement disorder neurologist, the
other two patients were followed and diagnosed by movement disorder
specialists. The clinical courses of these three patients suggest that
multiple risk factors for cerebrovascular disease in a setting of suboptimal anticoagulant therapy should be red flags for vascular CBS.
Severe white matter lesions and the clinical triad of dementia, gait
disturbance, and urinary incontinence in CBS-1 may raise a differential
diagnosis of Binswanger's disease [34]; however, it is not associated
with dystrophic calcification in white matter and is usually accompanied by multiple infarcts in the cerebral cortex and deep gray matter.
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is another consideration that can present with CBS [35], but HDLS is not

Table 2
Pathological features and infarct distribution in patients with vascular CBS.
Pathologic features

CBS-1

CBS-2

CBS-3

Brain weight, g
Braak neurofibrillary tangle stage
Thal amyloid phase
Lewy body
TDP-43 proteinopathy
Arteriosclerosis/atherosclerosis
Cerebral amyloid angiopathy
Infarct distribution
Frontal watershed region
Motor cortex
Midfrontal gyrus
Temporal lobe
Parietal lobe
Occipital lobe
Periventricular white matter
Leukoencephalomalacia
Caudate
Putamen
Internal capsule
Globus pallidus
Basal nucleus
Thalamus
Subthalamic nucleus
Hippocampus
Cerebellum
Wallerian degeneration
Internal capsule
Cerebral peduncle
Longitudinal fibers in the pontine base
Medullary pyramids
Lateral corticospinal tract
Anterior corticospinal tract

920
0
0
–
–
−/−
–
R
–
–
++*
++*
++*
+*
++
+
–
++
++
+
–
++
–
+
+
R
+
+
+
+
–
+

1160
I
0
–
–
+/+
–
L
++
++
+
–
–
++
+
+
++
++
++
–
–
+
–
–
+
L
+
+
–
–
NA
NA

1400
II
0
–
–
+/−
–
L
++
+
–
–
–
+
++
+
–
–
–
+
–
+
–
–
–
L
+
–
–
–
NA
NA

R**
++
–
–
–
++
++
–
–
–
–
–
–
–
–
–
–
–

+ indicates microinfarct and ++ indicates macroscopic infarct. * Infarcts in
the white matter in these regions. ** This hemibrain is a frozen sample and
assessed only macroscopically. Abbreviations: CBS, corticobasal syndrome; L,
left; NA, not available for review; R, right.

subacute-to-chronic lesions, as well as acute infarcts. The pathology
was especially marked in frontal lobe and watershed cortices (Fig. 1N
and O). The centrum semiovale and periventricular white matter had
marked rarefaction, loss of myelinated fibers, and perivascular collagenosis. There were cribriform changes and ischemic rarefaction, as
well as both small and large infarcts in the caudate, putamen, internal
capsule, and thalamus (Fig. 1P). The internal capsule and the corticopontine fibers of the cerebral peduncle showed advanced Wallerian
degeneration. The cerebellum had multiple small infarcts affecting
several folia in the hemisphere more than the vermis (Fig. 1Q).
3.2.3. CBS-3
Macroscopically, there were cortical infarcts in watershed regions
and softening in the subjacent white matter, as well as partially cystic
infarcts in the periventricular white matter in the left hemisphere
(Fig. 1R). Histologically, there were many microscopic cortical infarcts
of varying histologic age in the watershed region, motor cortex, and
visual cortex (Fig. 1S and T). There was also subcortical white matter
pathology and a large periventricular chronic infarct (Fig. 1U), with
Wallerian degeneration of adjacent fiber tracts, including descending
fibers in the internal capsule. The dorsal globus pallidus and anterior
thalamus had chronic microinfarcts.
4. Discussion
This study investigated three patients with “vascular CBS”, who
showed symptomatic small vessel disease with secondary corticospinal
Wallerian degeneration without evidence of neurodegenerative pathology. Although small vessel disease may be a nonspecific radiographic
finding, increasing evidence highlights the importance of small vessel
82

Parkinsonism and Related Disorders 68 (2019) 79–84

S. Koga, et al.

Fig. 1. Representative macroscopic and microscopic
findings from CBS-1 (A–I), CBS-2 (J–Q), and CBS-3
(R–U). (A) The periventricular white matter is atrophic
and nearly completely liquefied. A cystic infarct involves the putamen. (B) A white matter infarct in the
frontal lobe. (C) Luxol fast blue stain shows myelin
pallor in the white matter in the temporal lobe. (D)
There are multiple foci of dystrophic calcification (arrows). There are lipid-laden macrophages (arrow in E)
near the calcification, which are immunostained with
CD68 (F). The small vessels have arteriosclerotic hyalinosis (arrowhead in E) clearly demonstrated on the
Masson's trichrome stain (G). (H) The affected white
matter lesions have reactive astrocytes. (I) Luxol fast
blue stain reveals severe myelin loss in the entire cerebral peduncle. (J–O) CBS-2 has multiple infarcts in the
motor cortex (J, N), watershed region (K, O), and occipital lobe (L). (M, P) A large cystic infarct involves
caudate, putamen, and internal capsule. (Q) Multiple
infarcts in cerebellar folia affecting granular cell layers
and Purkinje cell layers. (R) CBS-3 has macroscopic infarcts in the watershed region (right arrow) and periventricular white matter (left arrow). (S–U) Cortical
microinfarcts with linear scarring from the watershed
region (S) and motor cortex (T), and a partially cystic
infarct with myelin rarefaction in the periventricular
white matter (U). D, E, N, P, Q, S, and T: hematoxylineosin stain; C, I, O, and U: Luxol fast blue stain; F: CD68immunostain; G: Masson's trichrome stain; H: GFAPimmunostain. Bars: C, D, I, Q, S, and T = 500 μm;
E = 50 μm; F, G, and H = 100 μm; N and O = 250 μm;
P = 3 mm; U = 1 mm. (For interpretation of the references to color in this figure legend, the reader is referred
to the Web version of this article.)

associated with the type of ischemic damage detected in this case and
often follows a frontotemporal distribution, without frank involvement
of cortex and deep gray matter nuclei.
A limitation of this study is that clinical information was not based on
standardized prospective or longitudinal clinical evaluations; therefore,
some clinical findings might have been missed. Correlations between
radiological and neuropathological findings were not evaluated in this
study. Another limitation is the procedure of freezing one half of the
brain and fixing the other half for neuropathology studies. Only the left
hemibrain was available for neuropathological assessment in CBS-2, although the right hemibrain was likely more affected due to her leftpredominant symptoms. To overcome this, the frozen right hemibrain
was also sampled and observed to have multiple infarcts in the neocortices, which correlate with her left-predominant motor symptoms.
The strength of our study was using autopsy-confirmed cases. A few
patients with vascular CBS have been described in the literature; however, because of the lack of pathological confirmation, underlying CBD
pathology cannot be completely excluded in these patients [12–15].
In summary, disruption of a network of structures underlying praxis,
including frontal and parietal cortices, thalamus, basal ganglia, and
white matter tracts between them, as well as corticospinal tract degeneration resulting from multiple infarcts can present with CBS. Our report
highlight that despite a substantial time lag between a stroke and unexplained spasticity, high-risk patients may suffer clinically silent strokes
and may warrant thromboembolic risk stratification and treatment.
Although our patients did not display symmetric lower body parkinsonism, suggestive of vascular parkinsonism [5], the presence of unexplained asymmetric spasticity and dystonia in the absence of cortical
sensory loss, bradykinesia or cogwheel rigidity may be red flags for
vascular CBS. Follow-up neuroimaging studies should be applied in highrisk patients even without acute neurological deficits or apparent stepwise progression. The correct diagnosis and management of vascular CBS
are important not only for clinical management but also for clinical research studies that do not have pathological confirmation.

Financial disclosures of all authors
Dr. Koga reports no disclosures.
Dr. Roemer reports no disclosures.
Dr. Kasanuki reports no disclosures.
Dr. Dickson receives support from the NIH (RF1 AG051504, R01
AG057181, P30 AG062677, and the Rainwater Charitable Foundation).
Dr. Dickson is an editorial board member of Acta Neuropathologica,
Annals of Neurology, Brain, Brain Pathology, and Neuropathology, and he
is editor of American Journal of Neurodegenerative Disease.
Author contributions
Shunsuke Koga: Conception and execution of the project; analysis
and interpretation of data, writing of the manuscript.
Shanu F. Roemer: Interpretation of data; review and critique,
writing of the manuscript.
Koji Kasanuki:Interpretation of data; review and critique.
Dennis W. Dickson: Conception and organization of the project;
interpretation of data; review and critique, data collection.
Acknowledgments
We would like to thank the patients and their families who donated
brains to help further the scientific understanding of neurodegeneration. The authors would also like to acknowledge Ariston L. Librero and
Virginia Phillips for histologic support, and Monica Castanedes-Casey
(Mayo Clinic, Jacksonville) for immunohistochemistry support. This
work is supported by NIH grant P50 NS072187, U54 NS100693, a Jaye
F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear
palsy research, and CBD Solutions Research Grant.
83

S. Koga, et al.

Parkinsonism and Related Disorders 68 (2019) 79–84

References

873–885.
[19] K. Gwinn-Hardy, N.D. Mehta, M. Farrer, D. Maraganore, M. Muenter, S.H. Yen,
J. Hardy, D.W. Dickson, Distinctive neuropathology revealed by alpha-synuclein
antibodies in hereditary parkinsonism and dementia linked to chromosome 4p, Acta
Neuropathol. 99 (6) (2000) 663–672.
[20] S. Koga, N. Kouri, R.L. Walton, M.T.W. Ebbert, K.A. Josephs, I. Litvan, N. GraffRadford, J.E. Ahlskog, R.J. Uitti, J.A. van Gerpen, B.F. Boeve, A. Parks, O.A. Ross,
D.W. Dickson, Corticobasal degeneration with TDP-43 pathology presenting with
progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype, Acta
Neuropathol. 136 (3) (2018) 389–404.
[21] E.L. Abner, P.T. Nelson, R.J. Kryscio, F.A. Schmitt, D.W. Fardo, R.L. Woltjer,
N.J. Cairns, L. Yu, H.H. Dodge, C. Xiong, K. Masaki, S.L. Tyas, D.A. Bennett,
J.A. Schneider, Z. Arvanitakis, Diabetes is associated with cerebrovascular but not
Alzheimer's disease neuropathology, Alzheimers Dement 12 (8) (2016) 882–889.
[22] S.H. Kreisel, C. Blahak, H. Bazner, D. Inzitari, L. Pantoni, A. Poggesi, H. Chabriat,
T. Erkinjuntti, F. Fazekas, J.M. Ferro, P. Langhorne, J. O'Brien, P. Scheltens,
M.C. Visser, L.O. Wahlund, G. Waldemar, A. Wallin, M.G. Hennerici, Deterioration
of gait and balance over time: the effects of age-related white matter change–the
LADIS study, Cerebrovasc. Dis. 35 (6) (2013) 544–553.
[23] P. Mahlknecht, S. Kiechl, B.R. Bloem, J. Willeit, C. Scherfler, A. Gasperi,
G. Rungger, W. Poewe, K. Seppi, Prevalence and burden of gait disorders in elderly
men and women aged 60-97 years: a population-based study, PLoS One 8 (7) (2013)
e69627.
[24] D. Pinter, S.J. Ritchie, F. Doubal, T. Gattringer, Z. Morris, M.E. Bastin, C.V.H.M. Del,
N.A. Royle, J. Corley, S. Munoz Maniega, A. Pattie, D.A. Dickie, J. Staals, A.J. Gow,
J.M. Starr, I.J. Deary, C. Enzinger, F. Fazekas, J. Wardlaw, Impact of small vessel
disease in the brain on gait and balance, Sci. Rep. 7 (2017) 41637.
[25] K.M. Heilman, E. Valenstein, Clinical Neuropsychology, fifth ed., Oxford University
Press, Oxford, 2012.
[26] K.Y. Haaland, D.L. Harrington, R.T. Knight, Neural representations of skilled
movement, Brain 123 (Pt 11) (2000) 2306–2313.
[27] D.A. Kareken, F. Unverzagt, K. Caldemeyer, M.R. Farlow, G.D. Hutchins, Functional
brain imaging in apraxia, Arch. Neurol. 55 (1) (1998) 107–113.
[28] B. Borroni, V. Garibotto, C. Agosti, S.M. Brambati, G. Bellelli, R. Gasparotti,
A. Padovani, D. Perani, White matter changes in corticobasal degeneration syndrome and correlation with limb apraxia, Arch. Neurol. 65 (6) (2008) 796–801.
[29] P.P. Pramstaller, C.D. Marsden, The basal ganglia and apraxia, Brain 119 (Pt 1)
(1996) 319–340.
[30] R.G. Gross, M. Grossman, Update on apraxia, Curr. Neurol. Neurosci. Rep. 8 (6)
(2008) 490–496.
[31] Y. Inoue, Y. Matsumura, T. Fukuda, Y. Nemoto, N. Shirahata, T. Suzuki,
M. Shakudo, S. Yawata, S. Tanaka, K. Takemoto, et al., MR imaging of Wallerian
degeneration in the brainstem: temporal relationships, AJNR Am. J. Neuroradiol.
11 (5) (1990) 897–902.
[32] M.J. Kuhn, D.J. Mikulis, D.M. Ayoub, B.E. Kosofsky, K.R. Davis, J.M. Taveras,
Wallerian degeneration after cerebral infarction: evaluation with sequential MR
imaging, Radiology 172 (1) (1989) 179–182.
[33] J.M. Wardlaw, C. Smith, M. Dichgans, Mechanisms of sporadic cerebral small vessel
disease: insights from neuroimaging, Lancet Neurol. 12 (5) (2013) 483–497.
[34] D.A. Bennett, R.S. Wilson, D.W. Gilley, J.H. Fox, Clinical diagnosis of Binswanger's
disease, J. Neurol. Neurosurg. Psychiatry 53 (11) (1990) 961–965.
[35] Y. Baba, B. Ghetti, M.C. Baker, R.J. Uitti, M.L. Hutton, K. Yamaguchi, T. Bird,
W. Lin, M.W. DeLucia, D.W. Dickson, Z.K. Wszolek, Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred, Acta Neuropathol. 111 (4) (2006) 300–311.

[1] N. Kouri, J.L. Whitwell, K.A. Josephs, R. Rademakers, D.W. Dickson, Corticobasal
degeneration: a pathologically distinct 4R tauopathy, Nat. Rev. Neurol. 7 (5) (2011)
263–272.
[2] M.J. Armstrong, I. Litvan, A.E. Lang, T.H. Bak, K.P. Bhatia, B. Borroni, A.L. Boxer,
D.W. Dickson, M. Grossman, M. Hallett, K.A. Josephs, A. Kertesz, S.E. Lee,
B.L. Miller, S.G. Reich, D.E. Riley, E. Tolosa, A.I. Troster, M. Vidailhet, W.J. Weiner,
Criteria for the diagnosis of corticobasal degeneration, Neurology 80 (5) (2013)
496–503.
[3] B.F. Boeve, A.E. Lang, I. Litvan, Corticobasal degeneration and its relationship to
progressive supranuclear palsy and frontotemporal dementia, Ann. Neurol. 54
(Suppl 5) (2003) S15–S19.
[4] K. Kasanuki, K.A. Josephs, T.J. Ferman, M.E. Murray, S. Koga, T. Konno, N. Sakae,
A. Parks, R.J. Uitti, J.A. Van Gerpen, N.R. Graff-Radford, Z.K. Wszolek,
D.W. Dickson, Diffuse Lewy body disease manifesting as corticobasal syndrome: a
rare form of Lewy body disease, Neurology 91 (3) (2018) e268–e279.
[5] P.M. FitzGerald, J. Jankovic, Lower body parkinsonism: evidence for vascular
etiology, Mov. Disord. 4 (3) (1989) 249–260.
[6] J. Winikates, J. Jankovic, Vascular progressive supranuclear palsy, J. Neural
Transm. Suppl. 42 (1994) 189–201.
[7] F. Alarcon, J.C. Zijlmans, G. Duenas, N. Cevallos, Post-stroke movement disorders:
report of 56 patients, J. Neurol. Neurosurg. Psychiatry 75 (11) (2004) 1568–1574.
[8] B. Thanvi, N. Lo, T. Robinson, Vascular parkinsonism–an important cause of parkinsonism in older people, Age Ageing 34 (2) (2005) 114–119.
[9] K.H. Kong, J. Lee, K.S. Chua, Occurrence and temporal evolution of upper limb
spasticity in stroke patients admitted to a rehabilitation unit, Arch. Phys. Med.
Rehabil. 93 (1) (2012) 143–148.
[10] K.A. Josephs, T. Ishizawa, Y. Tsuboi, N. Cookson, D.W. Dickson, A clinicopathological study of vascular progressive supranuclear palsy: a multi-infarct
disorder presenting as progressive supranuclear palsy, Arch. Neurol. 59 (10) (2002)
1597–1601.
[11] P.G. Glass, A.J. Lees, A. Bacellar, J. Zijlmans, R. Katzenschlager, L. SilveiraMoriyama, The clinical features of pathologically confirmed vascular parkinsonism,
J. Neurol. Neurosurg. Psychiatry 83 (10) (2012) 1027–1029.
[12] K.P. Bhatia, M.S. Lee, J.O. Rinne, T. Revesz, F. Scaravilli, L. Davies, C.D. Marsden,
Corticobasal degeneration look-alikes, Adv. Neurol. 82 (2000) 169–182.
[13] A. Kreisler, B. Mastain, F. Tison, G. Fenelon, A. Destee, [Multi-infarct disorder
presenting as corticobasal degeneration (DCB): vascular pseudo-corticobasal degeneration?], Rev. Neurol. (Paris) 163 (12) (2007) 1191–1199.
[14] Y.D. Kim, J.S. Kim, E.S. Lee, D.W. Yang, K.S. Lee, Y.I. Kim, Progressive "vascular"
corticobasal syndrome due to bilateral ischemic hemispheric lesions, Intern. Med.
48 (18) (2009) 1699–1702.
[15] Y. Miyaji, K. Koyama, T. Kurokawa, M. Mitomi, Y. Suzuki, Y. Kuroiwa, Vascular
corticobasal syndrome caused by unilateral internal carotid artery occlusion, J.
Stroke Cerebrovasc. Dis. 22 (7) (2013) 1193–1195.
[16] H. Braak, E. Braak, Neuropathological stageing of Alzheimer-related changes, Acta
Neuropathol. 82 (4) (1991) 239–259.
[17] D.R. Thal, U. Rub, M. Orantes, H. Braak, Phases of A beta-deposition in the human
brain and its relevance for the development of AD, Neurology 58 (12) (2002)
1791–1800.
[18] A.M. Liesinger, N.R. Graff-Radford, R. Duara, R.E. Carter, F.S. Hanna Al-Shaikh,
S. Koga, K.M. Hinkle, S.K. DiLello, M.F. Johnson, A. Aziz, N. Ertekin-Taner,
O.A. Ross, D.W. Dickson, M.E. Murray, Sex and age interact to determine clinicopathologic differences in Alzheimer's disease, Acta Neuropathol. 136 (6) (2018)

84