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Progressive supranuclear palsy phenotype mimicking synucleinopathies
Kateřina Menšíkováa,⁎, Radoslav Matějb, Lucie Tučkovác, Robert Rusinad, Jiří Ehrmannc, Petr Kaňovskýa
aDepartment of Neurology, Palacky University Medical School, Olomouc, Czech Republic
bDepartment of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic
cDepartment of Pathology, Palacky University Medical School, Olomouc, Czech Republic
dDepartment of Neurology, Thomayer Hospital, Prague, Czech Republic
a b s t r a c ta r t i c l ei n f o
Received 21 November 2012
Received in revised form 18 February 2013
Accepted 12 March 2013
Available online 13 April 2013
Multiple system atrophy
Dementia with Lewy bodies
Progressive supranuclear palsy
Background: Atypical parkinsonian syndromes are currently divided into two groups based on their patholog-
ical appearance: synucleinopathies and tauopathies. Based on recent clinico-pathological studies it is increas-
ingly clear, that some pathological characteristics are shared by both groups.
Study objective: To describe two pathologically proven cases of tauopathy manifesting in vivo in two typical
synucleinopathy phenotypes: multiple system atrophy and dementia with Lewy bodies.
Patients and methods: There were 67-year-old woman with a phenotype of multiple system atrophy and a
70-year-old man with a phenotype of dementia with Lewy bodies. The clinical diagnosis was based on the
commonly used clinical diagnostic criteria. A detailed neuropathological examination of the brain was
conducted post-mortem in both cases.
Results: The overall pathological picture corresponded with a rare combination of two neurodegenerative
stage of Alzheimer's disease.
Conclusion: The interesting feature in both our cases was the presence of dual pathology: diffuse tauopathy and
Alzheimer's pathology. We believe, that our two unique cases should serve as an evidence that tauopathies such
as CBS and PSP might mimic practically anything from the family of atypical parkinsonian syndromes, particu-
larly when another concomitant neurodegenerative disease is present.
© 2013 Elsevier B.V. All rights reserved.
Atypical parkinsonian syndromes are currently divided into two
groups based on their pathological appearance: synucleinopathies and
tauopathies. The group of synucleinopathies consists of Parkinson's
disease (PD), Parkinson's disease dementia (PDD), dementia with
Lewy bodies (DLB), and multiple system atrophy in both parkinsonian
and cerebellar forms (MSA-P, MSA-C). The group of tauopathies is
formed by progressive supranuclear palsy (PSP) in all three pheno-
types: Richardson's syndrome (RS), PSP-parkinsonism (PSP-P), and
pure akinesia with gait freezing(PAGF); corticobasal degeneration syn-
dromes (CBS) are also tauopathies. Some pathological characteristics
are shared by both groups [1,2].
The clinical differential diagnosis of atypical parkinsonism is usually
difficult. There is an arbitrary difference between the clinical courses of
PDD and DLBD, based on the clinical diagnostic criteria [3,4]. Neverthe-
er, as are PSP and CBS [5,6], furthermore, that PSP might manifest as a
CBS phenotype, and, finally, that CBS can mimic any of the others .
Their phenotypes and pathological substrates are usually intermixed
in a large clinico-pathological series [8–10]. On the other hand, the
misdiagnosis between PSP and MSA or DLB is rarely reported, probably
due to thepresence of unique characteristicsin thephenotypesof these
disorders. However, even this diagnostic challenge may appear. To doc-
ument that, we present two pathologically proven cases of tauopathy
manifesting in vivo in two “typical” synucleinopathy phenotypes: MSA
2. Case 1
A 67-year-old woman first noticed impaired stability when walking
with a tendency to fall in all directions at the age of 60. These problems
had lasted 3 years when the patient was admitted to in-patient ward.
Except for the postural instability, the neurological examination was
normal; there were no signs of rigidity, bradykinesia, tremor or any
other extrapyramidal features. ENT examination also did not show
any significant abnormality. The brain MRI results were near-normal,
and the brain stem auditory evoked potentials were registered with
normal responses. An X-ray of the cervical spine revealed advanced de-
generative changes, leading to a diagnosis of probable initial cervical
myelopathy. The patient was referred to the department of rehabilita-
tion medicine. Over the next six months, the impaired stability wors-
ened, and gait initiation disorder and impaired articulation appeared.
Journal of the Neurological Sciences 329 (2013) 34–37
⁎ Corresponding author. Tel.: +420 588443430.
E-mail address: email@example.com (K. Menšíková).
0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/jns
Author's personal copy
The patient had a mild ataxia with intention tremor of both the upper
and lower limbs, and increased elementary postural reflexes were
present as a first sign of rigidity. Over the next 3 months, the impaired
was referred to the in-patient ward of a tertiary movement disorders
centre and examined in detail. Parkinsonian syndrome with rigidity,
bradykinesia and hypokinesia, shuffling gait with bilateral reduced
arm swing, and positive pull-test were present; brisk tendon reflexes
examination revealed a mild cognitive impairment (mild constructive
apraxia and a disorder of visuo-spatial orientation); the mini-mental
state examination (MMSE) score was 27 points, the overall results did
not meet the DSM-IV criteria for dementia. Brain MRI showed mild
non-specific white matter abnormalities in both hemispheres (Fig. 1).
The DaTSCAN examination did not reveal any significant abnormality.
The bedside Thompson test revealed orthostatic hypotension; the
head-up tilt (HUT) test was positive, and a urodynamic study showed
an apparent detrusor hyperreflexia. The biochemical, microbiological,
and immunological examinations of blood serum and cerebrospinal
fluid were normal. Neurophysiological examinations (electroencepha-
lographic study, nerve conduction studies, electromyography, and mul-
timodal evoked potentials) did not show any significant abnormality. A
diagnosis of probable MSA-P was made based on the clinical diagnostic
criteria published in 1999 , and L-DOPA treatment was initiated;
this did not improve the patient's symptoms. Over the next 12 months,
the gait progressively worsened and the falls became more frequent.
The patient's ability to walk and stand required the use of walkers;
within the next 6 months she required a wheelchair. Over the next
12 months, the rigidity and postural instability further progressed,
followed by the development of severe dystonic contractions of both
the upper and lower limbs bilaterally; anterocollis also appeared.
Dystonia was treated with botulinum toxin type A; however, only
mild improvement was achieved. Severe dysphagia, which appeared
3 months later, required a percutaneous endoscopic gastrostomy with
tube feeding. As a result of the overall disease progression (mainly of
the rigidity, postural instability, and dystonia) the patient gradually
became immobile and bedridden; nevertheless, her cognition was still
fairly good (MMSE score 26). The patient died due to bronchopneumo-
nia after (approximately) 7 years of the disease course.
3. Case 2
A70-year-oldmalewithhistory of ischaemic heartdisease, hyperten-
with falls, together with visual hallucinations, and dysarthria. His wife
reported at the time of consultation recent increasing personality
changes, with agitation, social disinhibition, and dressing apraxia, at
the same time, he developed paranoid delusions and emotional incon-
tinence with spasmodic laughter. The condition progressively wors-
ened; however, considerable fluctuations in the disease course were
observed by the patient's family.
cies in answeringeven simple questions. Parkinsonian features included
hypomimia and mild symmetric rigidity with marked akinesia but no
tremor. Slowed hypometric oculomotor saccades (usually present in
DLB), dysarthria, hyperreflexia, and slurred gait completed the clinical
presentation. There was also positive evidence from spouse and family
that the patient suffered from REM-sleep behavioural disorder (RBD).
A neuropsychological assessment revealed alterations in episodic
and visual memory in both memorization and retrieval (free recall 2/
10 items; recognition 12/20; very restricted learning curve 3-2-2-1
from a list of 10 words). Visuospatial functions were impaired with al-
tionate and without a clear conception, and important details were
reduced verbal fluency, with deficits in conceptualization, problem
etition and comprehension were preserved. The patient had no signs of
depression. The MMSE score was 20. MRI scans revealed slight sym-
metric cerebellar atrophy and rare, small, nonspecific (probably post-
ischaemic) white matter lesions (Fig. 2). The DaTSCAN examination
revealed only non-significant reduction of tracer uptake bilaterally.
Total tau, phosphotau, and beta-amyloid levels in the cerebrospinal
up to 750 mg daily and donepezil 10 mg daily. Over the following
months, the cognitive performance partially improved (MMSE raised
to 22) and behaviouraland psychotic symptomsregressed,but akinesia
with rigidity increased, and falls became more frequent. The falls
described by the patient's family were such as those seen in postural
instability with gait disorder or orthostatic hypotension; there were
no signs or descriptions of sudden, unexpected falls typical for PSP.
Subsequently, patient's gait considerably worsened, and urinary
incontinence developed. The previously reported fluctuating course
changed into a more steady progression. About 16 months after the
initial assessment, the patient was bedridden with severe rigidity de-
spite 1000 mg L-DOPA daily, and memory and cognitive performance
re-emerged, and so memantinewas added. Nevertheless, the patient's
condition continued to worsen and he died from terminal broncho-
pneumonia 1 year later, i.e., 6 years after the initial signs manifested.
A detailed neuropathological examination of the brain was
conducted in both cases. Formalin-fixed, paraffin-embedded blocks
from the following regions were examined: frontal, temporal, parietal
and occipital cortices, hippocampus and parahippocampal region, basal
ganglia, brain stem at the level of substantia nigra, oblongata at the
5 μm-thick sections of formalin-fixed and paraffin-embedded tissue
Fig. 1. Case 1: Sagittal T1-weighted MRI showing the normal shape of the brain stem
and rare small nonspecific (probably post-ischaemic) white matter lesions.
K. Menšíková et al. / Journal of the Neurological Sciences 329 (2013) 34–37
Author's personal copy
were incubated with primary antibodies against the following antigens:
α-synuclein (1:5000, Signet, Dedham, MA, USA, 4D6); tau AT8 (1:200,
tau, 4-repeat isoform DR4 (1:200, Upstate Biotechnology, Lake Placid,
NY, USA, 1E1/A6); β-amyloid peptide (1:100, Dako, Glostrup, Denmark,
The immunohistochemical examination excluded clinical diagnoses
of synucleinopathy in both cases. Prominent positivities were seen in
reaction to the hyperphosphorylated form of tau protein (clone AT8)
and the isoform of tau protein DR3 and DR4. In response to the
monoclonal antibody against tau protein (clone AT8) there were evi-
dent numerous pretangles and tangles in the hippocampus and
parahippocampal region; further there were “tufted” astrocytes, glial
and cytoplasmic neuronal inclusions, and tangles and threads in all
previously mentioned areas, particularly in the substantia nigra, in the
cerebellar dentate nucleus, in the pons, and in the motor and premotor
cortex. Tau-positive inclusions of different types were present in differ-
ent degrees in the basal ganglia, in the midbrain, and in the cerebellum.
The most significant antibody reaction against the isoform of tau pro-
tein DR4 was present only in the midbrain, while in the temporal lobe
in some areas the DR3 isoform predominated. The intensity of these
changes in both cases was very similar, with a slightly higher accentua-
tion in the midbrain area in case 2. Both cases reached a score of 6 to 7
according to the Williams scoring system . A positive antibody
reaction against ß-amyloid peptide demonstrated various numbers of
different types of amyloid plaques in case 1, where amyloid plaques of
different types were seen in the basal ganglia as well (Fig. 3A). Neuro-
pathologicalchanges in bothcases were consistentwiththe neocortical
stage ofAlzheimer'sdisease, asdefined bythenewly published consen-
sual NIA criteria for diagnosis of Alzheimer's disease; they reached the
“high” level in ABC scoring system .
The overall pathological picture corresponded to a rare combina-
tion of two neurodegenerative entities: 4R tauopathy (meeting the
diagnostic criteria for typical progressive supranuclear palsy) and a
neocortical stage of Alzheimer's disease.
In their clinico-pathological study, Williams and Lees stated that
“Neurologists could not correctly diagnose PSP early in most patients
and instead recorded a diagnosis of PD” . In contrast, the mistaken
diagnosis of PSP in a case of pathologically confirmed Parkinson's dis-
ease was the least frequent in their retrospective study. Their study
Fig. 2. Case 2: Sagittal T1-weighted MRI, showing near-normal shape of the brain stem
with slight atrophy of the cerebellum. Courtesy of J. Keller, Department of Radiology,
Na Homolce Hospital, Prague, Czech Republic.
Fig. 3. Different morphologies of amyloid plaques and cerebral amyloid angiopathy in positive immunohistochemical reaction with monoclonal antibody against amyloid-ß-peptide
in case 1 (A), and neurofibrillary degenerative structures stained with monoclonal antibody against hyperphosphorylated tau protein in case 2 (B) showing Alzheimer's
disease-related neuropathology. Numerous deposits of hyperphosphorylated tau protein (C) positive with monoclonal antibody against DR4 subtype of tau protein (D) in
substantia nigra proved PSP. Original magnification: 200×.
K. Menšíková et al. / Journal of the Neurological Sciences 329 (2013) 34–37
Author's personal copy Download full-text
involved the primary referral pattern of PD patients who were diag-
nosed post-mortem with atypical parkinsonism. In our situation, the
initial diagnoses of synucleinopathy in two patients (MSA and DLB
changed until their deaths, and the pathological diagnosis of tauopathy
was a surprise.
The variability of initial symptoms of neurodegenerative parkin-
sonism is a well-known feature , and a precise initial diagnosis
may be a challenge despite the use of instrumental assessments
[15,16]. The fact that corticobasal degeneration can mimic practically
any other atypical parkinsonian syndromes is also seen as a useful
paradigm [7,17]. A recent retrospective study showed that PD might
mimic PSP in some cases, including eye movement abnormalities
and subcortical cognitive dysfunction; the authors concluded that
this is an advantage for the correct diagnosis of PSP, and in particular
in the identification of cases of PSP-P. They also stated that the pa-
tients with the clinical syndromes of DLB and underlying Lewy body
pathology are unlikely to be confused with PSP-P because of the
early cognitive decline and visual hallucinations that are major com-
ponents in the clinical diagnostic criteria of DLB . We had a differ-
ent experience. We had to manage patients in whom the diagnoses of
typical synucleinopathies (probable MSA-P and probable DLB) were
made on the basis of current and validated clinical diagnostic criteria.
Despite the relatively long course of disease in both patients (7 and
6 years), there were never any reasons to change the diagnosis that
was made in the first year after disease onset. MR imaging in either
case did not bring any important diagnostic information. In case 1,
one should expect on MR images atrophy of putamen, peduncles or
cerebellum. However, the absence of these signs is not an exclusion
criterion for the diagnosis of MSA. This fact has been confirmed in
the recent clinico-pathological study, in which the atrophy of puta-
men was present in 50% cases, cerebellar atrophy in 38% of cases,
and the peduncular or pontine atrophy in only 33% of cases . On
the other hand, the presence on non-specific white matter lesions
has been frequently reported in MSA cases in the recent years, and
has been confirmed in a more recent double-blind MRI study .
All these facts make, in our opinion, another argument in support of
the discussion of the usefulness of any rigid clinical diagnostic criteria
for atypical parkinsonian syndromes, as it appears periodically in the
literature [2,7]. We are aware of the necessity to have consensual diag-
nostic criteria for any given nosological entity for the purpose of trans-
lational and pharmacological research. However, these criteria should
be seen as a secondary tool in the differential diagnosis of parkinsonian
syndromes, since they only reflect the state of knowledge at the time.
Gilman's (et al.) MSA criteria can serve as a shining example, since
they were changed over the course of 8 years [11,21].
The interesting feature in both our cases was the presence of dual
pathology: diffuse tauopathy and Alzheimer's pathology in the limbic
stage. There is a report of a PSP patient mimicking synucleinopathy of
MSA-P type, but without any signs of cognitive decline and without
the presence of Alzheimer's pathology . Dual pathology was de-
scribed in a patient with the PSP-P phenotype of atypical parkinson-
ism; the tauopathy and alpha-synucleinopathy co-occurred in this
case . From this point of view, our two unique cases should
serve as an evidence that CBS and PSP might mimic practically any-
thing from the family of atypical parkinsonian syndromes, particular-
ly when another concomitant neurodegenerative disease is present.
Conflict of interest
The authors report no conflict of interest.
Supported by the grants IGA LF UP 2012-013, IGA MZ CR NT-12221,
NT-12094-5/2011, and the Institutional Support from the Ministry of
Health, Czech Republic.
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