RESEARCH ARTICLE

Clinical Diagnosis of Progressive Supranuclear Palsy:

The Movement Disorder Society Criteria
Gunter U. Hoglinger, MD ,1,2* Gesine Respondek, MD,1,2 Maria Stamelou, MD ,3 Carolin Kurz, MD,4
Keith A. Josephs, MD, MST, MSc,5 Anthony E. Lang, MD,6 Brit Mollenhauer, MD,7 Ulrich Mu ller, MD,8 Christer Nilsson, MD,9
Jennifer L. Whitwell, PhD,10 Thomas Arzberger, MD,2,4,11 Elisabet Englund, MD,12 Ellen Gelpi, MD,13 Armin Giese, MD,11
David J. Irwin, MD,14 Wassilios G. Meissner, MD, PhD ,15,16,17 Alexander Pantelyat, MD,18 Alex Rajput, MD,19
John C. van Swieten, MD,20 Claire Troakes, PhD, MSc,21 Angelo Antonini, MD,22 Kailash P. Bhatia, MD ,23
Yvette Bordelon, MD, PhD,24 Yaroslau Compta, MD, PhD,25 Jean-Christophe Corvol, MD, PhD,26 Carlo Colosimo, MD, FEAN,27
Dennis W. Dickson, MD,28 Richard Dodel, MD,29 Leslie Ferguson, MD,19 Murray Grossman, MD,14 Jan Kassubek, MD,30
Florian Krismer, MD, PhD,31 Johannes Levin, MD,2,32 Stefan Lorenzl, MD,33,34,35 Huw R. Morris, MD,36 Peter Nestor, MD,37
Wolfgang H. Oertel, MD,38 Werner Poewe, MD,31 Gil Rabinovici, MD,39 James B. Rowe, MD,40 Gerard D. Schellenberg, PhD,41
Klaus Seppi, MD,31 Thilo van Eimeren, MD,42 Gregor K. Wenning, MD, PhD,31 Adam L. Boxer, MD, PhD,39
Lawrence I. Golbe, MD,43 and Irene Litvan, MD44 ; for the Movement Disorder Societyendorsed PSP Study Group.

1
Department of Neurology, Technische Universita t Mu nchen, Munich, Germany
2
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
3
Second Department of Neurology, Attikon University Hospital, University of Athens, Athens, Greece
4
Department of Psychiatry, Ludwig-Maximilians-Universita t, Munich, Germany
5
Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
6
Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinsons Disease,
Toronto Western Hospital, Toronto, Canada
7
Paracelsus-Elena Klinik, Kassel, Germany, and University Medical Center Go ttingen, Institute of Neuropathology, Go
ttingen, Germany
8
Institute of Human Genetics, Giessen, Germany
9
Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden
10
Department of Radiology, Mayo Clinic, Rochester, Minnesoya, USA
11
Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universita t, Munich, Germany
12
Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden
13
Neurological Tissue Bank of the Biobank - Hospital Clnic de Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain
14
Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
15
Universite de Bordeaux, Institut des Maladies Neurode ge ne
ratives, UMR 5293, Bordeaux, France
16
CNRS, Institut des Maladies Neurode ge
neratives, UMR 5293, Bordeaux, France
17
Service de Neurologie, Ho ^pital Pellegrin, CHU de Bordeaux, Bordeaux, France
18
Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
19
Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada
20
Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands
21
London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London,
United Kingdom
22
Parkinson and Movement Disorders Unit, IRCCS Hospital San Camillo, Venice, and Department of Neurosciences,
Padova University, Padova, Italy
23
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London,
United Kingdom
24
Department of Neurology, University of California, Los Angeles, California, USA
25
Parkinsons Disease & Movement Disorders Unit, Neurology Service, Hospital Clinic/IDIBAPS/University of Barcelona, Barcelona, Catalonia,
Spain
26
Sorbonne Universite s, UPMC Univ Paris 06; and INSERM UMRS_1127, CIC_1422; and CNRS UMR_7225; and AP-HP; and ICM,
Ho^pital Pitie-Salpe
^triere, Departement des maladies du systeme nerveux, Paris, France
27
Department of Neurology, Santa Maria University Hospital of Terni, Terni, Italy

------------------------------------------------------------------------------------------------------------------------------
*Correspondence to: Prof. Dr. Gu glinger, Department of
nter U. Ho Relevant conflicts of interest/financial disclosures: Nothing to report.
Translational Neurodegeneration, German Center for Neurodegenerative Full financial disclosures and author roles may be found in the online ver-
Diseases (DZNE), Feodor-Lynen Strae 17, D-81677 Munich, Germany; sion of this article.
E-mail: [email protected]
Received: 9 January 2017; Revised: 9 February 2017; Accepted: 16
glinger, Respondek, Stamelou, Golbe, Boxer, and Litvan made
Drs. Ho February 2017
an equal contribution.
Published online 3 May 2017 in Wiley Online Library
Funding agencies: The project was supported by the Bischof Dr. Karl
(wileyonlinelibrary.com). DOI: 10.1002/mds.26987
Golser Stiftung, CurePSP, Deutsche Forschungsgemeinschaft (DFG, HO
2402/11-1), German Center for Neurodegenerative Diseases e.V. (DZNE),
German PSP Gesellschaft, Tau Consortium, UK PSP Association, and
the International Parkinson and Movement Disorder Society.

Movement Disorders, Vol. 32, No. 6, 2017 853

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H O E T A L

28
Mayo Clinic, Jacksonville, Florida, USA
29
Department of Geriatric Medicine, University Hospital Essen, Essen, Germany
30
Department of Neurology, University of Ulm, Ulm, Germany
31
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
32
Department of Neurology, Ludwig-Maximilians-Universita t, Munich, Germany
33
Institute of Nursing Science and Practice, Paracelsus Medical University, Salzburg, Austria
34
Department of Neurology, Hospital Agatharied, Agatharied, Germany
35
Department of Palliative Medicine, Munich University Hospital, LMU Munich, Munich, Germany
36
Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom
37
German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
38
Department of Neurology, Philipps Universita t, Marburg, Germany
39
Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
40
Department of Clinical Neurosciences, Cambridge University, Cambridge, United Kingdom
41
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
42
Departments of Nuclear Medicine and Neurology, University of Cologne, Cologne, Germany
43
Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
44
Department of Neurology, University of California, San Diego, California, USA

A B S T R A C T : Background: PSP is a neuropathologi- Results: Defined clinical, imaging, laboratory, and

cally defined disease entity. Clinical diagnostic criteria, genetic findings serve as mandatory basic features,
published in 1996 by the National Institute of Neurologi- mandatory exclusion criteria, or context-dependent
cal Disorders and Stroke/Society for PSP, have excel- exclusion criteria. We identified four functional domains
lent specificity, but their sensitivity is limited for variant (ocular motor dysfunction, postural instability, akinesia,
PSP syndromes with presentations other than Richard- and cognitive dysfunction) as clinical predictors of PSP.
sons syndrome. Within each of these domains, we propose three clinical
Objective: We aimed to provide an evidence- and features that contribute different levels of diagnostic
consensus-based revision of the clinical diagnostic cri- certainty. Specific combinations of these features define
teria for PSP. the diagnostic criteria, stratified by three degrees of
Methods: We searched the PubMed, Cochrane, Med- diagnostic certainty (probable PSP, possible PSP, and
line, and PSYCInfo databases for articles published in suggestive of PSP). Clinical clues and imaging findings
English since 1996, using postmortem diagnosis or represent supportive features.
highly specific clinical criteria as the diagnostic stan- Conclusions: Here, we present new criteria aimed to
dard. Second, we generated retrospective standardized optimize early, sensitive, and specific clinical diagnosis
clinical data from patients with autopsy-confirmed PSP of PSP on the basis of currently available evidence.
C 2017 International Parkinson and Movement Disorder
V
and control diseases. On this basis, diagnostic criteria
were drafted, optimized in two modified Delphi evalua- Society
tions, submitted to structured discussions with consen-
sus procedures during a 2-day meeting, and refined in K e y W o r d s : progressive supranuclear palsy; evi-
three further Delphi rounds. dence-based; consensus-based; clinical diagnostic criteria

PSP was first described in 1964 on the basis of a The clinical criteria proposed by the National Insti-
small case series as an adult-onset, rapidly progressive tute of Neurological Disorders and Stroke and Society
neurodegenerative disease with the leading feature of for PSP (NINDS-SPSP) are currently the most widely
vertical supranuclear gaze palsy and nerve cell degen- used criteria for the ante mortem diagnosis of PSP.5
eration mainly in the brain stem.1 They rely on the demonstration of a vertical supranu-
Since then, major advances have led PSP to be clear gaze palsy plus postural instability and falls
defined by intracerebral aggregation of the within the first year of symptom onset to diagnose
microtubule-associated protein tau, predominantly probable PSP. Possible PSP is diagnosed in the
involving isoforms with four microtubule-binding presence of either supranuclear gaze palsy or a combi-
repeats (4R-tau), in neurofibrillary tangles, oligoden- nation of slow vertical saccades and postural instabil-
drocytic coils, and, specifically, astrocytic tufts.2-4 ity with falls within the first year.
Thus, a definite diagnosis of PSP currently requires The NINDS-SPSP criteria, as validated by autopsy,
neuropathological examination.2,5 have excellent specificity, around 95% to 100% for

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 M D S C L I N I C A L D I A G N O S T I C C R I T E R I A F O R P S P

probable PSP and around 80% to 93% for possible Methodology of Criteria Generation
PSP.6-8 The combination of early onset postural insta-
bility and falls with vertical ocular motor dysfunction The MDS-PSP criteria were generated by the MDS-
is now usually referred to as Richardsons syndrome PSP study group in a three-step approach.
(PSP-RS)9 and is well captured by the NINDS-SPSP First, we performed a systematic literature review
criteria.10 However, the criterias sensitivity for PSP covering the time since publication of the NINDS-
overall is limited (median, 24%; range, 14%83%) at SPSP criteria. In brief, the steering committee (G.U.H.,
the first clinical visit.5,7,8,11-13 Diagnosis is typically M.S., A.L.B., L.I.G., and I.L.) assembled expert work-
made 3 to 4 years after onset of first symptoms, when ing groups for specific questions relevant to the diag-
the cardinal features, that is falls and supranuclear nosis of PSP. We searched the PubMed, Cochrane,
gaze palsy, have become unequivocally apparent.13 Medline, and PSYCInfo databases for articles, system-
Whereas inadequate ocular motor examinations may atic reviews, and meta-analyses published in English
partly explain the low sensitivity early in the disease from 1996 to 2015, applying either postmortem diag-
course, the NINDS-SPSP criteria also have low sensi- nosis or the NINDS-SPSP criteria. Study group mem-
tivity for PSP patients presenting with variant PSP syn- bers were encouraged to add relevant articles to be
dromes syndromes other than PSP-RS.10 considered throughout the project period (end of
Patients with autopsy-confirmed PSP have been 2016), particularly those published after 2015. The lit-
reported with variant PSP clinical presentations, includ- erature was analyzed following the Scottish Intercolle-
ing initial predominance of ocular motor dysfunction giate Guidelines Network recommendations.37 From
(PSP-OM),10,14 postural instability (PSP-PI),10,15 Par- N 5 5,903 identified articles, N 5 462 met the inclu-
kinsonism resembling idiopathic Parkinsons disease sion standards. The literature-based evidence was then
(PSP-P),9,11,16 frontal lobe cognitive or behavioral pre- summarized by the working groups for imaging and
sentations (PSP-F), including behavioral variant fronto- clinical aspects and is published in detail in accompa-
temporal dementia (bvFTD),14,17-19 progressive gait nying papers in this issue of Movement Disorders.38,39
freezing (PSP-PGF),20-22 corticobasal syndrome (PSP- Second, we collected the largest autopsy-confirmed
CBS),23-26 primary lateral sclerosis (PSP-PLS),27,28 cere- case series reported so far for PSP and disease controls
bellar ataxia (PSP-C),29-32 and speech/language disor- (CBD, MSA-P, PD, and FTLD-bvFTD) from nine
ders (PSP-SL), including nonfluent/agrammatic primary brain banks with a proven track record of a close col-
progressive aphasia (nfaPPA) and progressive apraxia laboration with tertiary clinical referral centers, both
of speech (AOS).33-36 Patients with presentations other with excellent experience in neurodegenerative dis-
than PSP-RS occurred in 76% of autopsy-confirmed eases (Amsterdam, Netherlands; Baltimore, MD; Bar-
PSP cases in a recent series and met the NINDS-SPSP celona, Spain; Bordeaux, France; London, UK; Lund,
criteria at significantly lower frequencies and longer Sweden; Munich, Germany; Philadelphia, PA; and Sas-
latencies from symptom onset.10 katchewan, Canada). High-quality original natural his-
Thus, early and reliable diagnosis of PSP remains a tory data were available from patients with autopsy-
major clinical challenge, but is justifiably demanded by confirmed PSP (N 5 206), CBD (N 5 54), MSA-P
patients and their carers and is highly important for esti- (N 5 51), PD (N 5 53), and FTLD-bvFTD (N 5 73).
mation of prognosis, appropriate allocation to therapeu- We extracted demographic data and predefined clini-
tic trials, and development of new diagnostic tools. cal features (absence/presence/onset) in a standardized
Therefore, the International Parkinson and Movement manner locally from the clinical records and collected
Disorder Society (MDS)-endorsed PSP Study Group set them centrally. These data were used to estimate and
out to provide an evidence- and consensus-based revision stratify the diagnostic value of the clinical items
of the NINDS-SPSP criteria. We aimed at improving the selected from a comprehensive literature review and
clinical detection of underlying PSP pathology by main- are reported in detail in an accompanying paper.38
taining high diagnostic sensitivity for PSP-RS, improving Third, on the basis of the evidence obtained in the
sensitivity for early and variant PSP presentations, and first two steps, the steering committee drafted an ini-
achieving high specificity versus alternative diagnoses tial proposal of the criteria, which was distributed to
such as Parkinsons disease (PD), MSA with predomi- the MDS-PSP study group members. They provided
nant parkinsonism (MSA-P), corticobasal syndrome written feedback to the process coordinator (G.U.H.),
(CBS) attributed to corticobasal degeneration (CBD) or who incorporated the comments into optimized crite-
alternative proteinopathies, and frontotemporal lobar ria in two modified Delphi rounds. In March 2016,
degeneration (from any underlying non-PSP/CBD pro- the group convened for a 2-day consensus meeting in
teinopathy) presenting as bvFTD (FTLD-bvFTD). Munich to present and discuss all aspects of the crite-
Here, we propose official MDS clinical diagnostic ria (structure, basic features, exclusion criteria,
criteria for PSP (MDS-PSP criteria) for use in research core functional domains, operationalized clinical fea-
and clinical practice. tures, supportive findings, imaging, biomarkers, and

Movement Disorders, Vol. 32, No. 6, 2017 855

 TABLE 1. Basic features

B1: Mandatory 1. Sporadic occurrence*

inclusion criteria 2. Age 40 or older at onset** of first PSP-related symptom***
3. Gradual progression of PSP-related symptoms***
B2: Mandatory Clinical findings
exclusion criteriaa 1. Predominant, otherwise unexplained impairment of episodic memory, suggestive of AD
2. Predominant, otherwise unexplained autonomic failure, e.g., orthostatic hypotension (orthostatic reduction in blood
pressure after 3 minutes standing  30 mm Hg systolic or  15 mm Hg diastolic), suggestive of multiple system
atrophy or Lewy body disease
3. Predominant, otherwise unexplained visual hallucinations or fluctuations in alertness,
suggestive of dementia with Lewy bodies
4. Predominant, otherwise unexplained multisegmental upper and lower motor neuron signs,
suggestive of motor neuron disease (pure upper motor neuron signs are not an exclusion criterion)
5. Sudden onset or step-wise or rapid progression of symptoms, in conjunction with corresponding imaging or laboratory
findings, suggestive of vascular etiology, autoimmune encephalitis, metabolic encephalopathies, or prion disease
6. History of encephalitis
7. Prominent appendicular ataxia
8. Identifiable cause of postural instability, e.g., primary sensory deficit, vestibular dysfunction,
severe spasticity, or lower motor neuron syndrome
Imaging findings
1. Severe leukoencephalopathy, evidenced by cerebral imaging
2. Relevant structural abnormality, e.g., normal pressure or obstructive hydrocephalus; basal ganglia, diencephalic,
mesencephalic, pontine or medullary infarctions, hemorrhages, hypoxic-ischemic lesions, tumors, or malformations
B3: Context dependent Imaging findings
exclusion criteriaa,b 1. In syndromes with sudden onset or step-wise progression, exclude stroke, cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or severe cerebral amyloid angiopathy,
evidenced by diffusion-weighted imaging (DWI), fluid attenuated inversion recovery, or T2*-MRI
2. In cases with very rapid progression, exclude cortical and subcortical hyperintensities on DWI-MRI suggestive
of prion disease
Laboratory findings
1. In patients with PSP-CBS, exclude primary AD pathology (typical CSF constellation [i.e., both elevated total
tau/phospho-tau protein and reduced b-amyloid 42] or pathological b-amyloid PET imaging)
2. In patients aged < 45 years, exclude
a. Wilsons disease (e.g., reduced serum ceruloplasmin, reduced total serum copper, increased copper
in 24 hour urine, and Kayser-Fleischer corneal ring)
b. Niemann-Pick disease, type C (e.g., plasma cholestan-3,5a,6-triol level, filipin test on skin fibroblasts)
c. Hypoparathyroidism
d. Neuroacanthocytosis (e.g., Bassen-Kornzweig, Levine Critchley, McLeod disease)
e. Neurosyphilis
3. In rapidly progressive patients, exclude
a. Prion disease (e.g., elevated 14-3-3, neuron-specific enolase, very high total tau protein [>1,200 pg/mL],
or positive real-time quaking-induced conversion in CSF)
b. Paraneoplastic encephalitis (e.g., anti-Ma1, Ma2 antibodies)
4. In patients with suggestive features (i.e., gastrointestinal symptoms, arthralgias, fever, younger age, and atypical
neurological features such as myorhythmia), exclude Whipples disease (e.g., T. Whipplei DNA polymerase chain
reaction in CSF)
Genetic findingsc
1. MAPT rare variants (mutations) are no exclusion criterion, but their presence defines inherited, as
opposed to sporadic PSP.
2. MAPT H2 haplotype homozygosity is not an exclusion criterion, but renders the diagnosis unlikely.
3. LRRK2 and Parkin rare variants have been observed in patients with autopsy confirmed PSP, but their
causal relationship is unclear so far.
4. Known rare variants in other genes are exclusion criteria, because they may mimic aspects of PSP
clinically, but differ neuropathologically; these include
a. Non-MAPT associated frontotemporal dementia (e.g., C9orf72, GRN, FUS, TARDBP, VCP, CHMP2B)
b. PD (e.g., SYNJ1, GBA)
c. AD (APP, PSEN1, PSEN2)
d. Niemann-Pick disease, type C (NPC1, NPC2)
e. Kufor-Rakeb syndrome (ATP13A2)
f. Perry syndrome (DCTN1)
g. Mitochondrial diseases (POLG, mitochondrial rare variants)
h. Dentatorubral pallidoluysian atrophy (ATN1)
i. Prion-related diseases (PRNP)
j. Huntingtons disease (HTT)
k. Spinocerebellar ataxia (ATXN1, 2, 3, 7, 17)

*MAPT rare variants (mutations) may lead to inherited phenocopies of the sporadic disease with a Mendelian trait pattern.
**MAPT rare variants carriers may have earlier disease onset.
***Consider any new onset neurological, cognitive, or behavioral deficit that subsequently progresses during the clinical course in absence of other identifiable
cause as a PSP-related symptom.
a
Suggestive of other conditions, which may mimic aspects of PSP clinically.
b
Need to be verified only if suggestive clinical findings are present.
c
Perform genetic counseling and testing, if at least one first- or second-degree relative has a PSP-like syndrome with a Mendelian inheritance trait or known
rare variants; high-risk families may be identified as described elsewhere49; the list of genes proposed reflects current knowledge and will evolve with time.
 M D S C L I N I C A L D I A G N O S T I C C R I T E R I A F O R P S P

TABLE 2. Core clinical features

Functional Domain

Levels of Ocular Motor

Certainty Dysfunction Postural Instability Akinesia Cognitive Dysfunction

Level 1 O1: P1: A1: C1:

Vertical supranuclear Repeated unprovoked falls Progressive gait freezing Speech/language disorder, i.e.,
gaze palsy within 3 years within 3 years nonfluent/agrammatic
variant of primary progressive
aphasia or progressive apraxia
of speech
Level 2 O2: P2: A2: C2:
Slow velocity of Tendency to fall on the Parkinsonism, akinetic-rigid, Frontal cognitive/behavioral
vertical saccades pull-test within 3 years predominantly axial, and presentation
levodopa resistant
Level 3 O3: P3: A3: C3:
Frequent macro square More than two steps Parkinsonism, with tremor Corticobasal syndrome
wave jerks or backward on the pull-test and/or asymmetric and/or
eyelid opening apraxia within 3 years levodopa responsive

Levels with lower numbers are considered to contribute higher certainty to a diagnosis of PSP than levels with higher numbers. Operationalized definitions of
the core clinical features are provided in Table 4.

genetics). For each of these items, the data obtained in domain, we propose three characteristic core clinical
the first two steps were presented by the subgroup features, stratified by presumed levels of certainty
coordinators. Thereafter, the written draft of the crite- (1 [highest], 2 [mid], and 3 [lowest]) that they contrib-
ria was discussed stepwise. Modifications were inte- ute to the diagnosis of PSP (Table 2).
grated until the entire group unanimously agreed to
the items under discussion. After the meeting, the
written document was circulated again and optimized Supportive Features
in three further Delphi rounds, in particular, dealing Supportive features (Table 3) are those having posi-
with precise wording, operationalized definition of tive predictive values insufficient to qualify them as
clinical examination guidelines, and newly evolving diagnostic features, but sufficient to provide helpful
aspects, such as tau PET imaging. After final approval, ancillary evidence to increase informal diagnostic con-
the current manuscript was written (G.U.H.) and cir- fidence. These are classified as clinical clues (CC1
culated to incorporate final modifications. CC4) and imaging findings (IF1, IF2).
Here, we present the MDS clinical diagnostic crite-
ria for PSP.
Operationalized Definitions
Basic Features The core clinical features, supportive clinical clues,
Basic features need to be present in a patient in and supportive imaging findings were operationalized
order to be considered for the diagnosis of PSP of any in an attempt to standardize the application of the
phenotype and at any stage (Table 1). Mandatory MDS-PSP criteria (Table 4).
inclusion criteria (Table 1, B1) indicate the presence
of a sporadic, adult-onset, gradually progressive neu- TABLE 3. Supportive features
rodegenerative disease. Mandatory exclusion criteria Clinical Clues Imaging Findings
(Table 1, B2) rule out PSP and need to be applied in
any patient. Context-dependent exclusion criteria CC1: IF1:
(Table 1, B3) also rule out PSP, but should be applied Levodopa-resistance Predominant midbrain atrophy or
hypometabolism
only in patients presenting with suggestive, unusual
clinical features justifying further investigation. CC2: IF2:
Hypokinetic, spastic dysarthria Postsynaptic striatal dopaminergic
degeneration
Core Features
CC3:
We propose four core functional domains as charac- Dysphagia
teristic clinical manifestations of PSP (ocular motor
dysfunction [O], postural instability [P], akinesia [A], CC4:
Photophobia
and cognitive dysfunction [C]; Table 2). In each

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TABLE 4. Operationalized definitions of core clinical features, supportive clinical clues, and supportive imaging findings
Domain Feature Definition

Ocular motor dysfunction

O1 Vertical supranuclear gaze palsy A clear limitation of the range of voluntary gaze in the vertical more than in the horizontal plane,
affecting both up- and downgaze, more than expected for age, which is overcome by activation
with the vestibulo-ocular reflex; at later stages, the vestibulo-ocular reflex may be lost, or the
maneuver prevented by nuchal rigidity.
O2 Slow velocity of vertical saccades Decreased velocity (and amplitude) of vertical greater than horizontal saccadic eye movements;
this may be established by quantitative measurements of saccades, such as infrared
oculography, or by bedside testing; gaze should be assessed by command
(Look at the flicking finger) rather than by pursuit (Follow my finger), with the
target >20 degrees from the position of primary gaze; to be diagnostic, saccadic
movements are slow enough for the examiner to see their movement (eye rotation),
rather than just initial and final eye positions in normal subjects; a delay in saccade
initiation is not considered slowing; findings are supported by slowed or absent fast
components of vertical optokinetic nystagmus (i.e., only the slow following
component may be retained).
O3 Frequent macro square wave jerks Macro square wave jerks are rapid involuntary saccadic intrusions during fixation,
or eyelid opening apraxia displacing the eye horizontally from the primary position, and returning it to the
target after 200 to 300 milliseconds; most square wave jerks are <1 degree in
amplitude and rare in healthy controls, but up to 3 to 4 degrees and more frequent
(>10/min) in PSP.50 Eyelid opening apraxia is an inability to voluntarily initiate
eyelid opening after a period of lid closure in the absence of involuntary forced
eyelid closure (i.e., blepharospasm); the term is written in quotation marks because
the inability to initiate eyelid opening is often attributed to activation of the pretarsal
component of the orbicularis oculi (i.e., pretarsal blepharospasm) rather than failure
to activate the levator palpebrae.
Postural instability
P1 Repeated unprovoked falls within Spontaneous loss of balance while standing, or history of more than one unprovoked fall,
3 years within 3 years after onset of PSP-related features.
P2 Tendency to fall on the pull-test Tendency to fall on the pull-test if not caught by examiner, within 3 years after onset of
within 3 years PSP-related features. The test examines the response to a quick, forceful pull on the
shoulders with the examiner standing behind the patient and the patient standing
erect with eyes open and feet comfortably apart and parallel, as described in
the MDS-UPDRS item 3.12.
P3 More than two steps backward on More than two steps backward, but unaided recovery, on the pull-test, within
the pull-test within 3 years 3 years after onset of PSP-related features.
Akinesia
A1 Progressive gait freezing within Sudden and transient motor blocks or start hesitation are predominant within
3 years 3 years after onset of PSP-related symptoms, progressive and not responsive
to levodopa; in the early disease course, akinesia may be present, but limb
rigidity, tremor, and dementia are absent or mild.
A2 Parkinsonism, akinetic-rigid, Bradykinesia and rigidity with axial predominance, and levodopa resistance
predominantly axial and (see Clinical Clue CC1 for operationalized definition).
levodopa resistant
A3 Parkinsonism, with tremor and/or Bradykinesia with rigidity and/or tremor, and/or asymmetric predominance of
asymmetric and/or levodopa limbs, and/or levodopa responsiveness (see Clinical Clue CC1 for
responsive operationalized definition).
Cognitive dysfunction
C1 Speech/language disorder Defined as at least one of the following features, which has to be persistent
(rather than transient):
1. Nonfluent/agrammatic variant of primaryLoss of grammar and/or telegraphic speech or writing
progressive aphasia (nfaPPA) or
2. Progressive apraxia of speech (AOS) Effortful, halting speech with inconsistent speech
sound errors and distortions or slow syllabically
segmented prosodic speech patterns
with spared single-word comprehension, object knowledge, and word retrieval during sentence
repetition.
C2 Frontal cognitive/behavioral Defined as at least three of the following features, which have to be persistent (rather than transient):
presentation 1. Apathy Reduced level of interest, initiative, and spontaneous
activity; clearly apparent to informant or patient.
2. Bradyphrenia Slowed thinking; clearly apparent to informant or patient.
(Continued)

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TABLE 4. Continued

Domain Feature Definition

3. Dysexecutive syndrome E.g., reverse digit span, Trails B or Stroop test,

Luria sequence (at least 1.5 standard
deviations below mean of age- and
education-adjusted norms).
4. Reduced phonemic verbal fluency E.g., D, F, A, or S words per minute
(at least 1.5 standard deviations below mean of
age- and education-adjusted norms).
5. Impulsivity, disinhibition, or E.g., socially inappropriate behaviors, overstuffing
perseveration the mouth when eating, motor recklessness,
applause sign, palilalia, echolalia.
C3 CBS Defined as at least one sign each from the following two groups (may be asymmetric or symmetric):
1. Cortical signs a. Orobuccal or limb apraxia.
b. Cortical sensory deficit.
c. Alien limb phenomena.
(more than simple levitation).
2. Movement disorder signs a. Limb rigidity.
b. Limb akinesia.
c. Limb myoclonus.
Clinical clues
CC1 Levodopa resistance Levodopa resistance is defined as improvement of the
MDS-UPDRS motor scale by 30%; to fulfill this criterion
patients should be assessed having been given
at least 1,000 mg (if tolerated) at least 1 month OR once
patients have received this treatment they could be formally
assessed following a challenge dose of at least 200 mg.
CC2 Hypokinetic, spastic dysarthria Slow, low volume and pitch, harsh voice.
CC3 Dysphagia Otherwise unexplained difficulty in swallowing, severe
enough to request dietary adaptations.
CC4 Photophobia Intolerance to visual perception of light attributed to
adaptative dysfunction.
Imaging findings
IF1 Predominant midbrain atrophy or hypometabolism Atrophy or hypometabolism predominant in midbrain
relative to pons, as demonstrated, e.g., by MRI or [18F]DG-PET.
IF2 Postsynaptic striatal dopaminergic degeneration Postsynaptic striatal dopaminergic degeneration,
as demonstrated, e.g., by [123I]IBZM-SPECT or [18F]-DMFP-PET.

Certainty Levels Patients with possible PSP-SL or PSP-CBS also qualify

Four levels of diagnostic certainty are proposed for the diagnosis of a probable 4R-tauopathy.
(Table 5). Definite PSP is the neuropathological gold
standard defining the disease entity, regardless of its Discussion
clinical presentation. Probable PSP is diagnosed in the
presence of a combination of clinical features with Here, we propose new MDS-PSP criteria, which are
high specificity. Possible PSP is diagnosed in the pres- aimed to optimize early, sensitive, and specific clinical
ence of clinical features considered to substantially diagnosis of PSP on the basis of currently available
evidence. They are intended for use in both clinical
increase the sensitivity for PSP. Clinical syndromes
practice and research, including the diagnosis of early
suggestive of PSP have features that alone or in combi-
and variant PSP for clinical trials.
nation may constitute early, subtle evidence for PSP
The new diagnostic criteria accept the neuropatho-
with modest, but still useful, positive predictive value.
logical examination as the gold standard to define
Additional presence of imaging findings (IF1 or IF2)
PSP as a disease entity.2-4,40 The appropriateness of this
qualifies for the label imaging supported diagnosis.
definition is demonstrated by the unique morphological
(e.g., tufted astrocytes, globose tangles),3,4 biochemical
Predominance Types (e.g., straight filaments, 4R-tauopathy),3,4 and genetic
Clinical predominance types are determined based features (e.g., the statistically robust findings obtained
on the combination of clinical features (Table 5). in a genome-wide association study)41 obtained in
These include PSP-RS, PSP-OM, PSP-PI, PSP-P, PSP-F, patients on the basis of this disease definition.
PSP-PGF, PSP-CBS, and PSP-SL, per our literature The development of the MDS-PSP clinical criteria
analysis reported in an accompanying article.38 was based on the NINDS-SPSP criteria, which are

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TABLE 5. Degrees of diagnostic certainty, obtained by combinations of clinical features and clinical clues

Diagnostic Certainty Definition Combinations Predominance Type Abbreviation

Definite PSP Gold standard defining the Neuropathological Any clinical presentation def. PSP
disease entity diagnosis
Probable PSP Highly specific, but not very (O1 or O2) 1 (P1 or P2) PSP with Richardsons prob. PSP-RS
sensitive for PSP syndrome
Suitable for therapeutic and (O1 or O2) 1 A1 PSP with progressive gait prob. PSP-PGF
biological studies freezing
(O1 or O2) 1 (A2 or A3) PSP with predominant prob. PSP-P
parkinsonism
(O1 or O2) 1 C2 PSP with predominant frontal prob. PSP-F
presentation
Possible PSP Substantially more sensitive, O1 PSP with predominant ocular poss. PSP-OM
but less specific for PSP motor dysfunction
Suitable for descriptive O2 1 P3 PSP with Richardsons poss. PSP-RS
epidemiological studies and syndrome
clinical care A1 PSP with progressive gait poss. PSP-PGF
freezing
(O1 or O2) 1 C1 PSP with predominant speech/ poss. PSP-SL
language disordera
(O1 or O2) 1 C3 PSP with predominant CBSa poss. PSP-CBS
Suggestive of PSP Suggestive of PSP, but not O2 or O3 PSP with predominant ocular s.o. PSP-OM
passing the threshold for motor dysfunction
possible or probable PSP P1 or P2 PSP with predominant postural s.o. PSP-PI
Suitable for early identification instability
O3 1 (P2 or P3) PSP with Richardsons s.o. PSP-RS
syndrome
(A2 or A3) 1 (O3, P1, P2, C1, PSP with predominant s.o. PSP-P
C2, CC1, CC2, CC3, or CC4) parkinsonism
C1 PSP with predominant speech/ s.o. PSP-SL
language disorder
C2 1 (O3 or P3) PSP with predominant frontal s.o. PSP-F
presentation
C3 PSP with predominant CBS s.o. PSP-CBS

The basic features B11B21B3 (see Table 1) apply for all probable, possible, and suggestive criteria. Core clinical features are defined by their functional
domain (ocular motor dysfunction [O], postural instability [P], akinesia [A], and cognitive dysfunction [C]), and stratified by presumed levels of certainty (1
[highest], 2 [mid], 3 [lowest]) they contribute to the diagnosis of PSP (see Table 2). Supportive clinical clues (CC) are presented in Table 3. Operationalized
definitions of clinical features and clinical clues are given in Table 4.
a
Probable 4R-tauopathy (i.e., either PSP or CBD).

known to be very specific for the clinical prediction of of PSP-related symptoms as including neurological, cog-
pathologically defined PSP.7,8,13 For this reason, nitive, or behavioral deficits to reflect current knowl-
NINDS-SPSP possible and probable cases are edge of the broad clinical spectrum over which PSP
now jointly classified as probable PSP-RS, as proposed may range. Inclusion and exclusion criteria have been
previously,42 thus allowing comparability with the carefully adapted to the current state of knowledge, as
past published literature. presented in accompanying papers.38,39
The mandatory inclusion criteria of the NINDS-SPSP Whereas the NINDS-SPSP criteria focused on two
criteria were largely maintained. We still consider PSP core functional domains (ocular motor dysfunction,
as a sporadic, not as a monogenic disease, because clin- postural instability), the MDS-PSP criteria added two
ical or pathological phenocopies resulting from rare further domains (akinesia, cognitive dysfunction). This
genetic variants (mutations) in MAPT do not share an accounts for the results obtained by hypothesis-free
identical etiology to sporadic PSP. Because sporadic cluster analyses in two independent large clinicopatho-
occurrence does not ultimately rule out underlying logical series of definite PSP patients, identifying these
monogenic inheritance, particularly in small families, four domains as most representative of characteristic
MAPT sequencing may be considered, where higher disease manifestations.9,10 Within each domain, we
certainty is warranted. We continue to set the mini- specified three characteristic clinical features, stratified
mum age at onset as 40, given that no autopsy- by levels of certainty for the diagnosis of PSP. These
confirmed case has been demonstrated to manifest ear- were identified through the systematic literature review,
lier, whereas some PSP look-alikes (e.g., Niemann-Pick validated quantitatively in the clinicopathological
disease, type C) may do so. We also specified the onset cohort, and specified where required by expert

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consensus. Of note, these levels may coincide with a diagnose PSP-OM,10,14 PSP-PI,10,15 PSP-P,9,11,16 PSP-
typical temporal evolution of symptoms in some (e.g., F,14,17-19 PSP-CBS,23-26 PSP-PGF,20-22 and PSP-SL.33-36
ocular motor dysfunction, postural instability), but not We did not attempt to provide criteria for PSP-
in other domains (e.g., akinesia, cognitive dysfunction). PLS27,28 and PSP-C,29-32 although we do acknowledge
Using this 12-unit grid, we were able to allocate most the existence of these manifestations. This decision
symptoms considered as characteristic for the spectrum reflects the very rare occurrence of PSP-PLS and PSP-C
displayed by autopsy-confirmed PSP patients. and the sparse published clinicopathological evidence,
These 12 clinical features help to diagnose PSP with which was not perceived to delineate features specific
differing sensitivity and specificity38: enough to allow ante mortem diagnosis. The study
group declined to risk including patients with predom-
 high sensitivity and high specificity, for example, inant PLS or cerebellar ataxia, because this would
vertical supranuclear palsy, frequently observed in have weakened the distinction of PSP from motor neu-
PSP with high diagnostic relevance; ron disease and MSA-C and other adult-onset sporadic
 high sensitivity, but reduced specificity, for exam- cerebellar ataxias, respectively.
ple, parkinsonism, with tremor and/or asymmetry The MDS-PSP clinical diagnostic criteria are strati-
and/or levodopa responsiveness, representing con- fied by diagnostic certainty and may therefore be used
ditions that help to identify PSP patients, but for different purposes. The concept underlying this
depend on presence of other PSP-specific features stratification has been described in detail elsewhere.43
to qualify for the diagnosis; The following diagnostic categories are proposed:
 low sensitivity, but high specificity, for example,
 Definite PSP can only be diagnosed by neuropath-
progressive gait freezing within 3 years of symp-
ological examination at present. Currently, no other
tom onset, representing a very rare condition,
biomarker, imaging, or genetic finding with close to
however with a very high positive predictive value
100% sensitivity and specificity is available.
for the diagnosis of PSP; and
 Probable PSP is diagnosed in the presence of a
 low sensitivity and low specificity, for example, CBS,
combination of clinical features that may not be
which is observed regularly in specialized centers and
very sensitive for PSP, but are considered to be
needs to be considered as a possible manifestation of
highly specific, thus being ideally suited for thera-
PSP as one of several possible underlying pathologies.
peutic and biological studies, where it is impor-
We also propose a list of supportive clinical clues to tant to exclude non-PSP from the subject group.
increase diagnostic confidence. We are aware of sev-  Possible PSP is diagnosed in the presence of clin-
eral other clinical signs that have been proposed to ical features that substantially increase sensitivity,
indicate the diagnosis of PSP, for example, retropul- but at the possible cost of decreased specificity.
sion with spontaneous backward falls, falling back This category is therefore suitable for descriptive
into a chair when precipitously attempting to rise epidemiologic studies and clinical care, where it is
from it without attributed caution (rocket sign), important not to exclude any cases of true PSP.
clumsily and unsteadily walk (drunken sailor gait), With the addition of biomarkers to increase diag-
nuchal dystonia with retrocollis, raised eyebrows nostic specificity, these individuals might also be
attributed to frontalis muscle overactivity (astonished reasonably included in a therapeutic study.
facies), vertical wrinkles in the glabella region attrib-  Conditions suggestive of PSP represent subtle
uted to procerus muscle overactivity (procerus sign), early signs of PSP, but do not meet the threshold
low frequency of blinking (Mona Lisa gaze), and for possible or probable PSP, and are suitable for
messy-tie sign attribute to an inability to look down early identification of individuals in whom the
when eating. Whereas these signs may indeed be help- diagnosis may be confirmed as the disease
ful to raise suspicion about PSP, we found no clear evolves, thereby justifying close clinical follow-up
evidence suggesting that they would indeed contribute examinations, especially in longitudinal observa-
reliable information to substantiate the diagnosis of tional studies to further characterize the natural
PSP. history of PSP with the overall goal of improving
Until now, there have been no uniformly accepted diagnosis of patients in early-stage disease. This
clinical diagnostic criteria available for the variant PSP diagnostic category has been newly introduced in
manifestations of neuropathologically defined PSP the MDS-PSP criteria in analogy to other progres-
other than PSP-RS. Therefore, most of these cases sive neurological diseases, in which defined condi-
were not identified early (or at all) for the purposes of tions have been identified with predictable risk of
routine clinical care, standardized acquisition of natu- converting to the established disease of interest
ral history data, or inclusion in therapeutic trials. Our (e.g., rapid eye movement sleep behavior disorder
proposed criteria overcome these limitations by pro- for PD, mild cognitive impairment for Alzheimers
viding evidence- and consensus-based guidelines to disease [AD], or clinically isolated syndrome for

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multiple sclerosis). From a scientific perspective,  Brain imaging is relevant to rule out alternative
this new category appears highly relevant for the diagnoses. Demonstration of predominant mid-
prospective development of new clinical diagnos- brain atrophy or hypometabolism and/or postsyn-
tic tools and biomarkers permitting a diagnosis of aptic striatal dopaminergic degeneration increases
PSP at an earlier stage. This diagnostic category the diagnostic confidence in patients diagnosed on
would also be highly relevant for the development the basis of clinical features and qualifies for the
of disease-modifying therapies that would ideally label of imaging supported diagnosis. However,
be initiated in the very early course, before exten- only limited data are currently available, which
sive neurodegeneration has occurred. would suggest that current imaging techniques
may eventually help to anticipate or strongly con-
For the first time, we also introduce a new category
solidate the diagnosis as compared to diagnoses
for probable 4R-tauopathies, comprising patients
based on clinical features alone, given that most
with possible PSP-SL or PSP-CBS. By introducing this
imaging studies have not been performed at a
category, we acknowledge that these clinically defined
time point preceding the clinical diagnosis and
conditions have a high likelihood of underlying PSP or have not been evaluated against the neuropatho-
CBD pathology, provided that the corresponding logical gold standard. Tau-PET may evolve as an
context-dependent exclusion criteria to rule out AD in vivo modality supportive of the pathological
and genetic forms of FTLD-TDP are applied. PSP and PSP diagnosis at the individual patient level.47,48
CBD are two primary tauopathies with predominant However, the currently available evidence with
aggregation of four-repeat tau isoforms, which are regard to its sensitivity and specificity, as assessed
very difficult to differentially diagnose without neuro- against the neuropathological gold standard, is
pathological examination. Their joint ante mortem too limited to draw firm diagnostic conclusions.
recognition as probable 4R-tauopathies, however, may
offer opportunities for neurobiological investigations In summary, we propose the MDS clinical diagnostic
of shared pathological mechanisms (e.g., previous criteria for PSP, incorporating the advances in knowl-
works41,44 or rational disease-modifying interventions. edge about PSP and its differential diagnoses from the
Obviously, all probable PSP categories are also past 20 years. The MDS-PSP study group aims to
probable 4R-tauopathies, however, with high proba- develop a web-based tool to facilitate the broad imple-
bility of underlying PSP, but not CBD pathology. mentation of the new criteria in clinical practice and a
We carefully evaluated the added diagnostic value video-based tutorial to facilitate standardized applica-
obtained by supportive investigations, the results of tion. The study group is engaged in international activi-
which are presented in accompanying papers.38,39 In ties to validate these criteria prospectively in
short, we adapted the following conclusions for the clinicopathological studies. We acknowledge that the
MDS-PSP criteria: MDS-PSP criteria will require continuous, adaptive
modification as our understanding of PSP advances.
 Genetic analyses do not help to support the clinical
diagnosis of PSP, but known rare genetic variants Acknowledgments: We thank all brain donors and their families for
their generous donation allowing to advance our knowledge about PSP,
(mutations) in some genes are exclusion criteria, clinicians for providing reliable clinical data, Ina B. Kopp for guidance
because they may mimic aspects of PSP clinically, in the methods of evidence-based medicine, and Judith Dams for con-
ducting the database inquiry. G.U.H. was supported by the Deutsche
but differ neuropathologically. Furthermore, MAPT Forschungsgemeinschaft (DFG; HO2402/6-2). W.H.O. is senior research
H2 haplotype homozygosity renders the diagnosis professor of the charitable Hertie Foundation, Frankfurt/Main, Ger-
many. J.L.W. and K.A.J. were supported by NIH grants R01-NS89757
unlikely, but is not an exclusion criterion. and R01-DC12519. Y.C. is supported by CERCA Programme/Generali-
 Established fluid biomarkers do not help to sup- tat de Catalunya, Catalonia, Spain. Autopsy patient data from the Uni-
versity of Pennsylvania was obtained through NIH-funded program
port the clinical diagnosis of PSP, but can rule projects P01-AG017586, P50-NS053488, and P30-AG010124. The Lon-
out alternative non-neurodegenerative diagnoses don Neurodegenerative Diseases Brain Bank, Kings College London was
supported by the MRC and Brains for Dementia Researchjointly
in patients with similar clinical presentations funded by the Alzheimers Society and Alzheimers Research UK.
(Table 1, B3). Cerebrospinal fluid (CSF) bio- H.R.M. is supported by the PSP Association and CBD-Solutions. J.B.R.
is supported by the Wellcome Trust (103838) The project was supported
markers for AD may be useful in research investi- by the Bischof Dr. Karl Golser Stiftung, CurePSP, Deutsche Forschungs-
gations and help exclude patients with underlying gemeinschaft (DFG; HO 2402/11-1), German Center for Neurodegenera-
tive Diseases e.V. (DZNE), German PSP Gesellschaft, Tau Consortium,
AD neuropathology in CBS, which has a high fre- UK PSP Association, and the International Parkinson and Movement
quency of patients with primary AD neuropathol- Disorder Society.
ogy (20%) that can mimic PSP-CBS25,45;
however, caution should be used in interpretation Appendix
of these results in other forms of clinical PSP syn-
dromes, given that secondary age-associated AD The MDS Endorsed PSP Study Group
neuropathology can influence levels of CSF tau Adam L. Boxer, Alex Rajput, Alexander Pantelyat,
and b-amyloid in patients with PSP pathology.46 Angelo Antonini, Anthony E. Lang, Armin Giese, Brit

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Mollenhauer, Carlo Colosimo, Caroline Kurz, Christer supranuclear palsy with predominant postural instability. Acta
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