UC San Diego
UC San Diego Previously Published Works
Title
Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and
therapeutic approaches.
Permalink
https://escholarship.org/uc/item/47w3f88w
Journal
The Lancet. Neurology, 16(7)
ISSN
1474-4422
Authors
Boxer, Adam L
Yu, Jin-Tai
Golbe, Lawrence I
et al.
Publication Date
2017-07-01
DOI
10.1016/s1474-4422(17)30157-6
Peer reviewed
eScholarship.org Powered by the California Digital Library
University of California
552
www.thelancet.com/neurology Vol 16 July 2017
Review
Lancet Neurol 2017; 16: 552–63
Department of Neurology,
Memory and Aging Center,
University of California,
San Francisco, CA, USA
(Prof A L Boxer MD);
Department of Neurology,
Qingdao Municipal Hospital,
Qingdao University, Qingdao,
China (Prof J-T Yu MD);
Department of Neurology,
Rutgers Robert Wood Johnson
Medical School,
New Brunswick, NJ, USA
(Prof L I Golbe MD); Department
of Neurology, University of
California, San Diego, CA, USA
(Prof I Litvan MD); Department
of Neurology, University of
Toronto, Toronto, ON, Canada
(Prof A E Lang MD);
Department of Neurology,
Technical University of Munich,
Munich, Germany
(Prof G U Höglinger MD);
Department of Translational
Neurodegeneration, German
Center for Neurodegenerative
Diseases (DZNE), Munich,
Germany (Prof G U Höglinger);
and Munich Cluster for Systems
Neurology SyNergy, Munich,
Germany (Prof G U Höglinger)
Correspondence to:
Prof Adam L Boxer, Memory and
Aging Center, Department of
Neurology, University of
California, Sandler Neurosciences
Center, San Francisco,
CA 94158, USA
adam.boxer@ucsf.edu
Advances in progressive supranuclear palsy: new diagnostic
criteria, biomarkers, and therapeutic approaches
Adam L Boxer, Jin-Tai Yu, Lawrence I Golbe, Irene Litvan, Anthony E Lang, Günter U Höglinger
Progressive supranuclear palsy (PSP), previously believed to be a common cause of atypical parkinsonism, is now
recognised as a range of motor and behavioural syndromes that are associated with a characteristic 4-repeat tau
neuropathology. New research criteria that recognise early presentations of PSP and operationalise diagnosis of
the full spectrum of clinical phenotypes have been reported. The Movement Disorders Society PSP diagnostic
criteria include syndromes with few or mild symptoms that are suggestive of underlying PSP pathology and could
provide an opportunity for earlier therapeutic interventions in the future. These criteria also include definitions
for variant PSP syndromes with dierent patterns of movement, language, or behavioural features than have been
conclusively associated with PSP pathology. Data from new diagnostic biomarkers can be combined with the
clinical features of disease to increase the specificity of the new criteria for underlying PSP pathology. Because
PSP is associated with tau protein abnormalities, there is growing interest in clinical trials of new tau-directed
therapies. These therapies are hypothesised to have disease-modifying eects by reducing the concentration of
toxic forms of tau in the brain or by compensating for loss of tau function. Since tau pathology is also central to
Alzheimer’s disease and chronic traumatic encephalopathy, a successful tau therapeutic for PSP might inform
treatment of other neurodegenerative diseases.
Introduction
Progressive supranuclear palsy (PSP) was initially
believed to be a cause of atypical parkinsonism; however,
during the past decade, PSP was found to encompass a
range of clinical phenotypes involving behavioural,
language, and movement abnormalities.
1
The classic
movement disorder clinical phenotype, now referred to
as Richardson’s syndrome (PSP-RS), was first described
in 1964 by Steele, Richardson, and Olszewski.
2
Since
then, no eective treatments for this uniformly fatal
disorder have been identified.
3
However, because PSP
is strongly linked to tau-protein abnormalities, both
neuropathologically and genetically,
4
there is an
increased interest in clinical trials of new tau-directed
therapies. PSP-RS is considered to be a rare disease,
with a prevalence of about 5–7 cases per 100 000 people.
5
A study in the UK
5
showed a peak prevalence between
the ages of 70 and 74 years of about 18 cases per
100 000 people. However, a study in Japan
6
that included
other PSP phenotypes in addition to PSP-RS found a
total prevalence of 18 cases per 100 000 across all ages.
This higher prevalence is consistent with estimates from
autopsy series,
7
and suggests that the prevalence of the
full spectrum of PSP syndromes is substantially higher
than prevalence estimates based on PSP-RS cases only.
Findings from a cluster of PSP cases in an industrial city
in France
8
and a multicentre case-control study
9
suggest
that environmental risk factors aect PSP incidence.
In this Review, we describe advances in clinical
diagnosis, neuropathology, genetics, biomarkers, and
therapeutics of PSP. An important advance has been the
development of the new International Parkinson’s and
Movement Disorder Society (MDS) Criteria for the
Diagnosis of PSP,
10
which recognise early, suggestive
forms of PSP, and operationalise diagnosis of
non-Richardson’s PSP phenotypes.
10
The spectrum of progressive supranuclear palsy
The MDS PSP Diagnostic Criteria
10
were based on a
comprehensive literature review by the MDS PSP
Working Group, followed by a consensus conference in
March, 2016, in collaboration with patient advocacy
groups. In this Review, we outline the essential
components and guidleines of these new criteria; the
detailed criteria have been published elsewhere.
10
Most neurodegenerative diseases begin with a pre-
symptomatic phase in which neuropathological changes
accumulate, but have not yet crossed the threshold
necessary to produce clinical symptoms. A wealth of
evidence supports this sequence of pathological events
in Alzheimer’s disease and Parkinson’s disease,
11,12
and
the description of mild asymptomatic PSP pathology in
some clinically healthy elderly people suggests that a
similar sequence of events might occur in PSP.
7,13,14
Therefore, it is likely that PSP starts with a
presymptomatic phase, in which neuropathological
abnormalities begin to accumulate but clinical features
are absent, continues with a suggestive-of-PSP (soPSP)
phase, in which individuals develop mild or isolated
symptoms but do not meet the full MDS research
criteria for a possible or probable PSP syndrome, and
culminates with a fully symptomatic stage that, in many
cases, would meet the research criteria for PSP-RS or
another clinical variant of PSP (vPSP; figure 1). As PSP
progresses, many patients with vPSP syndromes
eventually develop features of PSP-RS.
1,15
Patients
who only display a vPSP phenotype are dicult to
conclusively diagnose before death.
16
Most patients with PSP syndromes eventually develop
some or all of the clinical features of PSP-RS; however,
in approximately two-thirds of the patients with neuro-
pathologically defined PSP, as determined in brain bank
studies, the initial presentation in the first 2 years is not
www.thelancet.com/neurology Vol 16 July 2017
553
Review
PSP-RS.
1,15
Other vPSP syndromes, named according to
their predominant clinical features, might account for
about one-third to two-thirds of initial presentations, and
include PSP with predominant parkinsonism (PSP-P),
17
pure akinesia with gait freezing (formerly PAGF, and
now PSP with progressive gait freezing [PSP-PGF]),
18
corticobasal syndrome (PSP-CBS),
15,19
primary progressive
apraxia of speech or non-fluent variant primary
progressive aphasia (nfvPPA; when caused by PSP, this
disease is named PSP with predominant speech or
language disorder [PSP-SL]),
20–22
behavioural variant
frontotemporal dementia (bvFTD; when caused by PSP,
this disease is named PSP with predominant frontal
presentation [PSP-F]),
15,23
and PSP with predominant
cerebellar ataxia (PSP-C; figure 2).
25
Presymptomatic PSP phase
Presymptomatic PSP occurs in individuals who are
asymptomatic but at high risk of developing symptoms of
PSP. Currently, the presymptomatic phase can only be
identified post mortem from evidence of PSP-associated
neuropathological changes in individuals who are
considered to be otherwise healthy.
7,13,14
Because the new
MDS PSP criteria focus on clinical diagnosis, they do not
include the presymptomatic PSP phase, but the criteria
are consistent with this notion. In one community-based
autopsy series,
26
PSP neuropathology was present in
five (2·1%) of 233 individuals. Another two studies with
similar methodology found PSP pathology in five (4·2%)
of 119 elderly individuals in a clinically healthy cohort
13
and in 29 (4·6%) of 626 individuals older than 60 years in
a large forensic autopsy series in Japan.
7
These numbers
are in striking contrast to the low estimated prevalence of
PSP-RS in epidemiological studies,
5
which suggests that,
if these findings are correct, most individuals with
presymptomatic PSP do not develop overt disease.
Suggestive-of-PSP phase
soPSP refers to the early symptomatic phase of PSP that
occurs before development of a fully symptomatic PSP
syndrome, during which a few clinical symptoms or
signs are clearly present, but do not warrant a diagnosis
of PSP. Inherent in the definition of soPSP is some
uncertainty as to whether the individual will progress to
PSP-RS, to vPSP, or to a non-PSP diagnosis. In the
future, diagnostic bio markers for PSP might help to
mitigate this uncertainty. The soPSP category also
includes individuals who have developed one or more
major features of PSP-RS or of a vPSP syndrome, but do
not fulfil diagnostic criteria for these syndromes
(figure 1), such as individuals with isolated saccadic
slowing or unexplained postural instability.
15
A diagnosis
of soPSP can be made only when individuals are
suspected to have PSP pathology but do not fully meet
the criteria for PSP diagnosis, and when other causes
have been excluded. Recognition of individuals in the
soPSP phase of disease might allow neuroprotective
treatment to be initiated early enough to stabilise these
patients before the onset of substantial disability.
Symptomatic PSP phenotypes
The clinical features of the dierent PSP phenotypes have
been described in detail in several reviews.
1,27
Importantly,
the language and behavioural presentations of PSP can
also frequently meet criteria for fronto temporal lobar
Figure 1: Hypothetical model of the clinical trajectories of progressive
supranuclear palsy
Progressive supranuclear palsy is considered as a pathological continuum from a
presymptomatic phase, through a suggestive phase, to a fully symptomatic phase
that, in many cases, would meet research criteria for possible or probable
PSP-Richardson’s syndrome by the Movement Disorder Society criteria,
10
or a
variant PSP syndrome. Not all cases of presymptomatic or suggestive PSP will
progress to a PSP phenotype. PSP=progressive supranuclear palsy.
Figure 2: Clinical syndromes in progressive supranuclear palsy
PSP=progressive supranuclear palsy. RS=Richardson’s syndrome. PSP-P=PSP with predominant parkinsonism.
PSP-PGF=PSP with progressive gait freezing. PSP-CBS=PSP-corticobasal syndrome. nfvPPA=non-fluent variant
primary progressive aphasia. PSP-SL=PSP with predominant speech or language disorder. bvFTD=behavioural
variant frontotemporal dementia. PSP-F=PSP with predominant frontal presentation. PSP-C=PSP with
predominant cerebellar ataxia. Relative proportions of each syndrome (illustrated by bar length) are speculative.
PSP pathology means meeting neuropathological criteria for PSP.
1,24
Mixed pathology means meeting
neuropathological criteria for PSP plus another disorder such as Alzheimer’s or Parkinson’s disease. Other
pathology means meeting neuropathological criteria for another disorder such as Parkinson’s disease, but not
meeting criteria for PSP. Nomenclature reflect Movement Disorder Society PSP diagnostic criteria.
10
Death
Richardson’s syndrome
Variant PSP syndromes
Suggestive of PSP
Asymptomatic
Disease severity
Time
Presymptomatic PSP No clinical progression
Clinical syndrome
Richardson’s syndrome
Parkinsonism
Gait freezing
Corticobasal syndrome
nfvPPA
bvFTD
Cerebellar ataxia
PSP pathology
Other pathology
PSP with mixed pathology
RS not due to PSP
PSP-RS
PSP-P
PSP-PGF
PSP-CBS
PSP-SL
PSP-F
PSP-C
554
www.thelancet.com/neurology Vol 16 July 2017
Review
degeneration. We briefly describe each syndrome, as
classified by the new MDS PSP criteria, in the following
section, with particular attention to new evidence from the
past 7 years. We also highlight the changes in nomenclature
introduced by the new MDS PSP Criteria.
10
Richardson’s syndrome
PSP-RS refers to the classically described phenotype of
PSP that was originally codified in the 1996 National
Institute for Neurological Disorders and Society for
PSP research criteria.
28
The most frequently reported
symptoms at onset are unexplained falls, unsteady gait,
bradykinesia, subtle personality changes (apathy,
disinhibition), cognitive slowing (bradyphenia), executive
dysfunction (diculty planning or multitasking), slow,
ataxic, spastic, and hypophonic speech, dysphagia, and
impaired ocular movement (ie, slowing of vertical
saccades, diculty reading, or apraxia of eyelid opening).
1
Vertical supranuclear gaze palsy is the definitive
diagnostic feature, but its onset is variable, and might not
present until 3–4 years after disease onset. Decreased
velocity (slowing) and gain (amplitude) of vertical greater
than horizontal saccadic eye movements and decreased
or absent optokinetic nystagmus are early signs of
PSP-RS that are detected at neurological examination.
29
PSP-parkinsonism
PSP-P was first defined as a clinical phenotype of PSP on
the basis of an autopsy series,
1
in which a subset of
patients had early features of Parkinson’s disease and a
more benign disease course than patients with PSP would
usually have. Patients with PSP-P often present with
an asymmetric onset of tremor, bradykinesia, rigidity,
a moderate initial response to levodopa therapy, and
a slower rate of disease progression than patients with
PSP-RS. The clinical presentation of PSP-P resembles
idiopathic Parkinson’s disease suciently that the
two disorders are dicult to distinguish early on.
17
Later in
the disease course, most patients develop features of
PSP-RS and they are retrospectively diagnosed with
PSP-P. It is impossible to conclusively diagnose patients
with PSP-P premortem if they do not develop symptoms
of PSP-RS. However, later in the disease course, levodopa-
induced dyskinesias, autonomic dysfunction, and visual
hallucinations are much less common in patients with
PSP-P than in those with Parkinson’s disease, which can
help to distinguish these diseases.
27
PSP with progressive gait freezing
Pure akinesia with gait freezing, now referred to as
PSP-PGF, is a clinical phenotype of PSP that initially
presents with an isolated gait disorder years before
development of other PSP-RS features.
18
PSP-PGF is
characterised by progressive gait disturbance with start
hesitation and subsequent freezing of gait, sometimes
also involving diculties with initiating or completing
speech or writing, without tremor, rigidity, dementia, or
eye movement abnormalities during the first 5 years of
the disease. PSP-PGF has been reported to be highly
predictive of PSP pathology.
1
PSP-corticobasal syndrome
CBS is the best recognised presentation of corticobasal
degeneration, a 4-repeat tauopathy closely related to
PSP. Clinically and genetically, there is substantial
overlap between corticobasal degeneration and PSP
neuropathology. The diagnostic research criteria for
corticobasal degeneration
30
acknowledge a syndrome
caused by corticobasal degen eration pathology that
resembles PSP-RS, which under scores this frequent
overlap; both corticobasal degeneration and PSP feature
4-repeat tauopathy, but morphology, anatomical
distribution, and biochemical features dier between
these diseases. In contrast, PSP-CBS refers to the clinical
CBS phenotype of neuropathologically defined PSP,
characterised by a variable combination of progressive
limb rigidity, apraxia, cortical sensory loss, alien limb,
and bradykinesia, and that is unresponsive to levodopa.
PSP-CBS is a rare presentation of PSP pathology and
was present in only six of the 179 pathologically
diagnosed PSP cases in the Queen Square Brain Bank
series.
19
Distinction of PSP-CBS from corticobasal
degeneration-CBS based on clinical features is
impossible ante-mortem
19
and, for this reason, the new
MDS PSP Criteria designate PSP-CBS as possible PSP,
but probable 4-repeat tauopathy (either corticobasal
degeneration or PSP pathology).
10
PSP-speech language
nfvPPA is a progressive syndrome characterised by either
agrammatism in language production or eortful, halting
speech with inconsistent speech sound errors and
distortions (apraxia of speech).
31
The MDS PSP criteria
10
recognise a clinical phenotype of PSP that initially
presents with predominant speech or language disorder
features of nfvPPA, before developing motor features of
PSP-RS.
20,21
A longitudinal study
20
of 13 patients with
primary progressive apraxia of speech, which has similar
initial symptoms to nfvPPA, found that five of these
patients developed a syndrome similar to PSP-RS about
5 years after onset, and 22 of 25 patients with nfvPPA in a
larger series
22
were found to have tau pathology post
mortem, most commonly 4-repeat tauopathy. Similar to
PSP-CBS, the new PSP criteria designate PSP-SL as
possible PSP, but probable 4-repeat tauopathy, because
determination of which PSP-SL cases have PSP pathology
based on clinical findings is impossible ante-mortem.
10
PSP with frontal presentation
PSP-F refers to cases that present with clinical features of
behavioural variant frontotemporal dementia years
before the presentation of motor features of PSP-RS.
bvFTD is a clinical syndrome characterised by an early
and progressive deterioration of personality, social
www.thelancet.com/neurology Vol 16 July 2017
555
Review
comportment, behaviour (such as apathy, rigidity,
disinhibition, and hyperorality), and cognition.
32
PSP-F is
uncommon. Only three (4·5%) of 66 autopsy-proven PSP
cases in the Mayo Clinic series
23
presented with the
behavioural and personality changes of bvFTD. However,
a European series
15
of autopsy-proven PSP suggested a
higher prevalence of FTD-like symptoms at onset of 12 of
100 autopsy-confirmed PSP cases.
PSP with predominant cerebellar ataxia
PSP-C is a rare clinical phenotype. Patients present with
cerebellar ataxia as the initial and principal symptom
before developing cardinal features of PSP-RS, such as
saccade impairments and falls, during the disease course.
In contrast to the proportion of three cases of 22 patients
reported in an earlier Japanese study,
33
a Mayo Clinic
autopsy study
25
identified only five patients with PSP-C
among 1085 pathologically confirmed PSP cases, four of
whom were clinically misdiagnosed with multiple system
atrophy type C. In these four patients, clinical features of
PSP-C were similar to those of multiple system atrophy
type C, but they did not have the dysautonomia required to
meet criteria for a diagnosis of multiple system atrophy.
25
Because PSP-C is dicult to diagnose ante-mortem, and
ataxia is more frequently suggestive of neurodegenerative
diseases other than PSP, this variant is not included in the
new MDS PSP criteria.
PSP with mixed pathology
Although strong associations exist between the hallmark
neuropathological features of PSP and clinical features,
there is an increased recognition that a subset of patients
might have also other neuropathologies that aect
their clinical phenotype. Various co-pathologies have
been described in association with PSP including,
most frequently, Alzheimer’s disease pathology, but
also Parkinson’s disease pathology, TDP-43 deposition,
argyrophilic grain disease, or cerebrovascular disease. In a
study
34
evaluating 64 cases of pathologically proven PSP,
36% of patients had concomitant Alzheimer’s disease,
20% had Parkinson’s disease, 1% had dementia with Lewy
bodies, 44% had argyrophilic grain disease, 52% had
cerebral white matter rarefaction, and 25% had cerebral
amyloid angiopathy.
Neuropathology
The National Institute of Neurological Disorders and
Stroke neuropathological criteria for PSP were validated
in 1996,
24
and require the presence of neurofibrillary
tangles or neuropil threads (composed of tau protein), or
both, in the basal ganglia and the brainstem. Microscopic
features include neuronal loss, gliosis, neurofibrillary
tangles, neuropil threads, tufted astrocytes, and oligo-
dendroglial coiled bodies.
35
The regional distribution of tau pathology and neuronal
loss is a source of pathological and, consequentially,
clinical heterogeneity in PSP.
35
More severe and
widespread cortical tau pathology has been documented
in PSP syndromes with more severe cortical symptoms
ante-mortem, such as PSP-CBS,
36
PSP-SL,
22
and PSP-F,
than in movement-predominant PSP syndromes, such
as PSP-P and PSP-PGF. Brainstem-predominant PSP
syndromes, such as PSP-P and PSP-PGF, have less
severe cortical tau pathology and more severe
degeneration in the globus pallidus, subthalamic
nucleus, and substantia nigra compared with PSP-RS.
1
Studies
37,38
using brain tissue from patients with PSP
have shown that inoculation of tau transgenic mice with
human tissue can recapitulate PSP-associated tau
inclusions in mouse brains and enable identification of
specific strains of transmissible tau in cell culture
models. It is hypothesised that the dierent PSP disease
phenotypes might emerge from the preferential spread
of tau through dierent brain networks that are
functionally and neuroanatomically connected.
39
Genetics
MAPT polymorphisms and haplotypes
The locus most strongly linked with risk of PSP is the
gene for the microtubule-associated protein tau (MAPT).
4
Genetic studies,
4
including genome-wide association
studies, have identified both an inversion polymorphism
and haplotype-specific MAPT polymorphisms that aect
the risk of PSP (figure 3). The odds ratio (OR) for PSP in
carriers of the MAPT H1/H1 haplotype is 5·5, which is
higher than the OR for the APOE ε3/ε4 genotype (~3·0)
as a risk factor for Alzheimer’s disease.
4,40
The underlying
molecular mechanisms for PSP risk conferred by the
H1 haplotype is unclear. A rare coding MAPT variant
(152A→T) alters microtubule assembly and is a strong
risk factor for both PSP and frontotemporal dementia.
41
MAPT mutations
PSP is a sporadic disease, but very rare familial forms of
PSP have been described,
42,43
and 12 (7%) of 172 patients
with PSP-RS in one series
42
fulfilled criteria for an
autosomal dominant mode of inheritance; however, this
finding was not replicated in a subsequent study.
9
Although a causative mutation has not been identified for
most familial cases, mutations in the MAPT gene have
been identified as pathological mutations in several
families with autosomal dominant pattern of disease
inheritance, including some families with pathologically
confirmed PSP.
43
Notably, most of these variants are
located in exon 10 and its splicing regulatory region
(figure 3). Insoluble 4-repeat tau protein deposits are
characteristic of PSP pathology, therefore mutations that
enhance splicing in MAPT exon 10 might promote disease
by enhancing production of 4-repeat tau isoforms.
44
Emerging loci from genome-wide association studies
The first large genome-wide association study
4
in patients
with PSP identified three new genetic risk factors: STX6,
EIF2AK3, and MOBP. The mechanisms by which these
