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Progressive supranuclear palsy (PSP): Clinical features and diagnosis

Progressive supranuclear palsy (PSP): Clinical features and diagnosis
Authors:
Stewart A Factor, DO
Christine Doss Esper, MD
Section Editor:
Howard I Hurtig, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Jan 04, 2022.

INTRODUCTION — Symptoms and signs of Parkinsonism (ie, tremor, bradykinesia, rigidity, and postural instability) can be prominent in neurodegenerative disorders other than idiopathic Parkinson disease, particularly in atypical parkinsonian disorders, which include corticobasal degeneration, multiple system atrophy, and progressive supranuclear palsy (PSP).

PSP, also known as Steele-Richardson-Olszewski syndrome, is an uncommon but not rare parkinsonian syndrome. Characteristic features of PSP and its variants include vertical supranuclear gaze palsy, postural instability with unexplained falls, akinesia, and cognitive dysfunction. This topic will review specifically the clinical features and diagnosis of PSP. Management and prognosis are reviewed elsewhere. (See "Progressive supranuclear palsy (PSP): Management and prognosis".)

Other neurodegenerative parkinsonian syndromes are discussed separately. (See "Clinical manifestations of Parkinson disease" and "Corticobasal degeneration" and "Multiple system atrophy: Clinical features and diagnosis" and "Diagnosis and differential diagnosis of Parkinson disease", section on 'Differential diagnosis'.)

HISTORICAL BACKGROUND — In 1964, Steele, Richardson, and Olszewski were the first to describe PSP when their seminal report of nine cases with neuropathology was published [1]. As a result of their pioneering work, some have referred to the disease as the Steele-Richardson-Olszewski syndrome. Since that time, hundreds of additional cases have been recorded, and the disease is now a well-recognized atypical parkinsonian syndrome (or Parkinson-plus disorder). As originally described, PSP was characterized by progressive supranuclear ophthalmoplegia, gait disorder and postural instability, dysarthria, dysphagia, rigidity, and frontal cognitive disturbance [1]. The consistent pathologic features of PSP consist of neuronal loss, globose neurofibrillary tangles, tau-positive inclusions found in tufted astrocytes, and gliosis mainly in the basal ganglia, cerebellum, brainstem, and, to a lesser extent, cerebral cortex [2]. In addition, astrocytic plaques and tufts of abnormal fibers are highly characteristic of typical PSP [3]. A set of diagnostic criteria for PSP was initially proposed in 1996 [4] and revised in 2017 [5]. (See 'Diagnostic criteria' below.)

PSP is now recognized to encompass several phenotypic variants. The classical phenotype is now referred to as Richardson syndrome (PSP-RS), and other common variants include PSP with progressive gait freezing (PSP-PGF), PSP with predominant parkinsonism (PSP-P), and PSP with predominant frontal presentation (PSP-F).

EPIDEMIOLOGY — PSP is the most common of the degenerative forms of atypical parkinsonism, with an estimated prevalence of 3 to 7 per 100,000 adults [6-12]. In a report of 998 unselected serial autopsy cases from Japan, PSP diagnosed according to pathologic criteria was present with a higher prevalence (approximately 3 percent) than expected [13].

Early studies found that the annual incidence rates of PSP ranged from 0.3 to 0.4 per 100,000 person-years [14-16]. However, a study published in 1999 reported an annual incidence rate of 1.1 per 100,000 person-years [6,17]. The greater incidence found in later studies may be a result of better case ascertainment due in part to increased recognition of the disorder [6]. The annual incidence increases with age from 1.7 cases per 100,000 person-years at ages 50 to 59 years to 14.7 per 100,000 person-years at 80 to 89 years [18]. The true incidence may be higher still with the subsequent discovery of additional phenotypes. (See 'Variant phenotypes' below.)

The mean age of onset for PSP is approximately 65 years [8,9,19], which is older than in idiopathic Parkinson disease. Virtually no cases of autopsy-confirmed PSP have been reported in patients younger than age 40 years [5]. The original clinical report noted a strong male predominance of approximately eight to one [1]. However, later reports have found no definitive sex predominance in PSP [20-28].

In a series of 121 patients with probable PSP, there were no significant male-female differences for a variety of disease measures including age at onset, clinical characteristics, and disease duration [29].

Risk factors — There are no proven risk factors for the development of PSP except age. Some studies have reported that education level or environmental exposures may be associated with increased risk, but the findings have been inconclusive [30-36].

Genetic susceptibility — Although PSP is considered to be a sporadic disorder, some observations suggest that genetic susceptibility has a role. A few reports have found a positive family history of PSP and other types of parkinsonism [37-39]. However, these are distinctly rare.

Other studies have suggested that rare mutations of the microtubule-associated protein tau (MAPT) gene may lead to inherited phenocopies of sporadic PSP [5,40]. A genome-wide association study reported an increased risk of PSP for two independent variants of MAPT [41]. In addition, the study found an increased risk associated with several additional genes (syntaxin 6 [STX6], eukaryotic translation initiation factor 2 alpha kinase 3 [EIF2AK3], and myelin-associated oligodendrocyte basic protein [MOBP]), the significance of which is unclear. Furthermore, several reports have demonstrated an increased risk of PSP associated with the MAPT H1 haplotype, driven by several subhaplotypes (H1d, H1g, and H1o) [42-45]. This has implied biologic plausibility since the tau protein is abundant in the brains of subjects with PSP. However, the H1 haplotype is also more common in patients with Parkinson disease compared with controls, even though tau accumulation and aggregation is not a part of the pathological picture of Parkinson disease [46]. Hence, the meaning of this finding still needs to be clarified.

CLINICAL CHARACTERISTICS — With the most common "classic" phenotype of PSP, known as Richardson syndrome (PSP-RS), the most frequent initial feature is a disturbance of gait resulting in falls. Supranuclear ophthalmoparesis or ophthalmoplegia is the hallmark of PSP (hence the name of the disease). Dysarthria, dysphagia, pseudobulbar palsy, rigidity, bradykinesia, frontal cognitive abnormalities, and sleep disturbances are additional common clinical features. However, the clinical presentation is quite varied and a large proportion of patients present with variant phenotypes [8,19]. (See 'Variant phenotypes' below.)

Postural instability and falls — Patients with classic PSP-RS have a stiff and broad-based gait, with a tendency to have their knees and trunk extended (as opposed to the flexed posture of idiopathic Parkinson disease) and arms slightly abducted. They demonstrate impulsivity, probably from the frontal lobe involvement, and hence tend to lurch and stagger. Step length is varied, as is base width. Instead of turning en bloc as seen in Parkinson disease, they tend to pivot quickly, further compromising their balance and indicating an inability to take protective measures. This is sometimes referred to as the "drunken sailor gait." When they fall, it is usually backwards. Over the course of the illness, such falls can result in a spectrum of injuries that include bruises, lacerations, bone/skull fractures, subdural hematomas, and sometimes death [47]. When postural instability and falls are the only features of the disease, an abnormal response to the postural reflex testing (pulling patients gently but firmly by the shoulders from behind to see if they stagger backward uncontrollably) may be the only abnormality in a patient's examination [48].

Oculomotor findings — Supranuclear ophthalmoparesis or ophthalmoplegia is the hallmark of PSP, but it may take as long as 10 years to develop. The average is three to four years [49]. This distinctive ocular finding is first noted as slowing of vertical saccades (an important feature allowing earlier diagnosis), followed by a limitation of saccadic range. Concomitant limitation of lateral gaze is often present but is less prominent. Pursuit movements of the eyes are slow, jerky, and hypometric with unstable fixation [50]. The ophthalmoparesis is initially overcome by the oculocephalic (doll's eyes) maneuver, but with disease progression and brainstem involvement, vestibuloocular reflexes may be lost.

Other oculomotor findings in PSP include saccadic intrusions into fixation ("square wave jerks" ), loss of optokinetic nystagmus (particularly in the vertical direction), loss of convergence, blepharospasm, and eyelid-opening apraxia [51,52].

The combination of rare blinking, facial dystonia with eyelid retraction, and gaze abnormalities leads to the development of a classic facial expression of perpetual surprise or astonishment [48]. Vertical gaze impairment commonly leads to problems with reading, spilling food while eating, and tripping while walking [47].

Motor involvement — Bradykinesia with marked micrographia is a primary feature of parkinsonism in PSP, all types. Unlike the classic bradykinesia of Parkinson disease with slowing and decrement of amplitude on a finger-tapping task, patients with PSP may show nondecrementing, very low-amplitude, fast tapping. Rigidity in patients with PSP is usually more apparent in axial muscles, especially the neck and upper trunk, than in limb muscles. It can be demonstrated on examination by resistance to passive movement of the neck.

Retrocollis was emphasized as an important physical finding in the original description of the disorder [1] but is now estimated to occur in less than 25 percent of cases [53]. In addition to the retrocollis, other types of dystonia include blepharospasm and, more rarely, limb or hemidystonia [54,55]. Apraxia of eyelid opening can be mistaken for typical blepharospasm but is distinguished by the absence of forced closure of the eyes. In many patients this is not a true apraxia but may be a form of blepharospasm due to isolated contraction of the pretarsal orbicularis oculi.

The face is stiff, immobile, and deeply furrowed (the look of surprise) due to dystonia [20]. Approximately one-third of patients with PSP develop pyramidal signs, including hyperreflexia and Babinski signs. Facial and jaw jerks are exaggerated. The tongue is tightly contracted and movements are slow. Spastic dysarthria, dysphonia, and dysphagia are profound in the middle to later stages of disease. Other clinical features of PSP include stuttering and palilalia (the involuntary repetition of words or phrases).

A proportion of patients with PSP show a moderate response to dopaminergic agents in the early stages of disease (generally the PSP with predominant parkinsonism [PSP-P] variant), but most do not [48]. In some, the gait and balance problems actually worsen with levodopa.

Cognitive and behavioral abnormalities — The neuropsychological profile of PSP primarily involves frontal lobe dysfunction. The patients manifest impaired abstract thought, decreased verbal fluency, motor perseveration, and frontal behavioral disturbances [48].

The presence of early and severe frontal cognitive (executive) deficits is a common finding in PSP [56-58]. Executive dysfunction may be the presenting symptom of PSP in some patients but is more characteristic of the middle to later stages of the disease.

In a cohort of 311 patients with PSP, global cognition was impaired in approximately 57 percent [59], while impairment for a single or multiple domains was observed in 40 percent each and frontal impairment was observed in 62 percent. Cognitive impairment was seen in the early stages in 50 percent. Ideomotor apraxia is seen in a proportion of patients with PSP, typically those manifesting features of corticobasal syndrome (referred to as PSP with predominant corticobasal syndrome or PSP-CBS). In a Queen Square Brain Bank series, CBS was linked to a number of diverse pathologies including corticobasal degeneration, PSP-CBS, and Alzheimer disease [60].

Behavioral abnormalities are also common in patients with PSP. In a case series of 22 patients with PSP, the most common behavioral symptoms were apathy (91 percent), disinhibition (36 percent), dysphoria (18 percent), and anxiety (18 percent) [61]. One study of 188 patients with PSP demonstrated depression in 50 percent and anxiety in 37 percent [62], while another study of 74 patients with PSP reported obsessive-compulsive symptoms in 24 percent [63].

Pseudobulbar palsy is another characteristic feature of PSP. Emotional incontinence is much less common than in other forms of pseudobulbar palsy [20], but patients with PSP commonly manifest the characteristic hoarse groaning voice along with moaning. Speech perseveration and anomia, but not true aphasia, are usually observed [48]. Some patients with PSP present with a variant of nonfluent aphasia (PSP with predominant speech/language disorder, or PSP-SL). (See 'Variant phenotypes' below.)

Sleep disturbances — Early or late insomnia and difficulties in maintaining sleep have all been reported in patients with PSP. Polysomnographic evaluation of 10 patients with moderate to severe PSP revealed marked sleep abnormalities, all with significant periods (two to six hours) of insomnia [64]. Marked rigidity may result in the inability to remain comfortable in bed, further contributing to the sleep complaints. A prospective case-control study found that circadian activity rhythms are disrupted in individuals with PSP [65].

By contrast, rapid eye movement sleep behavior disorder (RBD) is infrequently associated with PSP [66]. This negative finding, similar to the case of preserved olfaction (see 'Potential disease markers' below), can be helpful in differentiating PSP, a tau disorder, from Parkinson disease and multiple system atrophy, both of which are synucleinopathies and commonly demonstrate symptoms of RBD.

Variant phenotypes — Evidence from pathologic studies suggests that there is a wide spectrum of clinical variability in PSP. In a 2017 systematic review of 261 patients with pathologically diagnosed PSP and 231 pathologically diagnosed disease controls, there was a high prevalence of PSP phenotypes other than Richardson syndrome [8]. Similarly, an earlier multicenter report of 100 pathologically confirmed cases of PSP found that the Richardson syndrome accounted for only 24 percent of cases, while various other presentations accounted for the remainder [19]. Many of the variants appear to have a slower progressive course than those with the Richardson syndrome.

Many variants of PSP, with tau pathology at autopsy in a pattern that is typical of PSP, have considerable clinical overlap with other neurodegenerative disorders [8]. The recognized phenotypes of PSP included the following [5]:

PSP with Richardson syndrome (PSP-RS) – PSP-RS, the classic form of PSP, is characterized by early onset of postural instability and falls, slowing of vertical saccades followed by a supranuclear vertical gaze palsy, and cognitive dysfunction [67]. Axial rigidity is more prominent than appendicular rigidity and retrocollis is often present. It makes up approximately 24 percent of PSP cases.

The other phenotypes described are based on what features are early and predominant, but this distinction fades with the progression and development of other features. This scheme was developed to try to improve early diagnosis.

PSP with predominant parkinsonism (PSP-P) – PSP-P is characterized by asymmetric onset of limb symptoms, including tremor, and a moderate initial therapeutic response to levodopa [67-69]. These cases are frequently confused with idiopathic Parkinson disease. PSP-P has a slower rate of disease progression than PSP-RS [11]. Falls and cognitive impairment occur later in PSP-P than in PSP-RS.

PSP with predominant oculomotor dysfunction (PSP-OM) – PSP-OM is characterized by presentation with oculomotor features of PSP (eg, vertical supranuclear gaze palsy, slow velocity of vertical saccades) and minimal or no evidence of postural instability, akinesia, or cognitive dysfunction [8,19,49].

PSP with predominant postural instability (PSP-PI) – PSP-PI is characterized by presentation with postural instability and delayed development of oculomotor dysfunction [19,70].

PSP with progressive gait freezing (PSP-PGF) – PSP-PGF is characterized by early (initial feature or frequently present in the first year) gait freezing, bradykinesia, rigidity, and unresponsiveness to dopaminergic medications [8,71-74]. However, this syndrome can be the result of several underlying diseases [75], as shown in a prospective study of nine patients with progressive gait freezing who were followed for 6 to 16 years [74]. Three were ultimately diagnosed clinically with PSP, one was diagnosed on clinical grounds with corticobasal syndrome (which could have been a variant phenotype of PSP), and one patient each was diagnosed pathologically with dementia with Lewy bodies and pallidonigroluysian degeneration.

PSP with predominant frontal presentation (PSP-F) – PSP-F is characterized by cognitive impairment or behavioral change attributed to frontal lobe dysfunction, including behavioral variant frontotemporal dementia [49,76-78]. The most common PSP-F syndrome encompasses features such as apathy, bradyphrenia, executive dysfunction, decreased verbal fluency, disinhibition, impulsivity, and perseveration [8].

PSP with predominant speech/language disorder (PSP-SL) – PSP-SL presents with the nonfluent/agrammatic variant of primary progressive aphasia or with progressive apraxia of speech [79-83].

PSP with predominant corticobasal syndrome (PSP-CBS) – PSP-CBS is characterized by progressive asymmetric apraxia, dystonia, cortical sensory loss, alien limb syndrome, and levodopa unresponsiveness [60,84-88]. PSP-CBS is a rare presentation of PSP pathology and was only present in 6 of 179 pathologically diagnosed PSP cases in the Queen Square Brain Bank series [60]. Nevertheless, among the causes of CBS, PSP is second only to corticobasal degeneration. (See "Corticobasal degeneration".)

PSP with predominant cerebellar ataxia (PSP-C) – PSP-C is characterized by cerebellar ataxia as the initial and principal symptom before developing the cardinal features of PSP-RS [89-93].

PSP with predominant primary lateral sclerosis (PSP-PLS) – PSP-PLS is characterized by upper motor neuron disease and degeneration of the corticospinal tracts [94,95].

Neuroimaging — In patients with PSP-RS, neuroimaging studies using computed tomography (CT) and magnetic resonance imaging (MRI) of the brain demonstrate generalized and brainstem atrophy, particularly involving the midbrain. The radiologic "hummingbird sign" (image 1), also called the "penguin silhouette" sign, results from the prominent midbrain atrophy with a relatively preserved pons, resembling a hummingbird or penguin in silhouette on midsagittal MRI of the brain [96-98]. Superior cerebellar peduncle atrophy is common in PSP and correlates with disease duration [99]. On axial T2-weighted MRI, profound midbrain atrophy with concavity of the lateral margin of the midbrain tegmentum is termed the "morning glory" flower sign [100].

Aside from midbrain atrophy, degeneration of the pons, thalamus, and striatum, as well as atrophy of frontal, prefrontal, insular, premotor, and supplementary motor areas, has been demonstrated by voxel-based morphometry [101]. The application of volumetric measures to assess the specificity of brainstem/midbrain atrophy observed in PSP is discussed below. (See 'Potential disease markers' below.)

PATHOLOGY AND PATHOPHYSIOLOGY

Gross pathology – Gross examination of the brain in patients with PSP reveals midbrain and, to a lesser extent, cerebral cortical atrophy, hypopigmentation of the substantia nigra and locus ceruleus, and enlargement of the third ventricle and Sylvian aqueduct [20,102]. Microscopic findings in PSP are distinctive and prominent. The most consistent sites of pathology are in the basal ganglia, particularly in the substantia nigra, subthalamic nucleus, and internal globus pallidus, in addition to the cerebellum, oculomotor complex, periaqueductal gray matter, superior colliculi, basis pontis, dentate nucleus, and prefrontal cortex [102]. Involvement of the cerebral cortex is also increasingly recognized [27]. PSP pathology has also been reported in the spinal cord, explaining the possible urinary disturbances [103].

Histopathology – The histologic characteristics of PSP include neuronal loss, gliosis, and the presence of tau-positive filamentous inclusions in specific anatomic areas involving astrocytes, oligodendrocytes, and neurons (picture 1). Tau cytoplasmic inclusions in surviving neurons, known as globose neurofibrillary tangles, are classically described in PSP, but are not specific to PSP. Neurofibrillary tangles are found also in Alzheimer disease, postencephalitic parkinsonism, chronic traumatic encephalopathy, and the parkinsonism-dementia complex of Guam. Tau-positive inclusions commonly seen in oligodendrocytes are called "coiled bodies." When seen in astrocytes, the tau-positive inclusions are called "tufted astrocytes," and these are considered a hallmark of PSP [104,105].

Microstructural changes – The major structural element of the neurofibrillary tangles in PSP is an abnormally phosphorylated tau protein. Tau is a protein that is involved in axonal transport and stabilization of neuronal microtubules. It is thought that abnormal phosphorylation of tau interferes with microtubule function, impairs axonal transport, and leads to tau aggregation into neurofibrillary tangles.

Ultrastructurally, the neurofibrillary tangles of PSP are composed of single straight tau filaments, in contrast to the paired helical filaments that predominate in Alzheimer disease [106]. The tangles in PSP are predominantly of the globose (globular) type; in other neurodegenerative diseases with tau pathology, the tangles are flame shaped. When resolved under cryo-electron microscopy, the tau filaments in most cases of PSP have a three-layer folded conformation [107]. In addition to the neuronal and glial tau inclusions characteristic of PSP, other abnormal aggregated proteins (eg, amyloid-beta, alpha synuclein, and TDP-4), termed copathologies, are commonly present at autopsy in patients with a pathologic diagnosis of PSP [108].

Genetics – Normal brain tau contains six isoforms that are generated by the alternative splicing of a single tau gene (MAPT) on chromosome 17. Dominantly inherited mutations in the MAPT gene cause frontotemporal dementia with and without parkinsonism as well as PSP. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'MAPT mutations'.)

PSP also shares a degree of genotypic overlap with corticobasal degeneration, as both disorders are more frequently associated with homozygosity for the H1 tau haplotype, which is an inversion of 900 kb on chromosome 17 that includes the MAPT gene (an association also seen in Parkinson disease, but with different subhaplotype) [109,110]. Furthermore, a genome-wide association study (see 'Genetic susceptibility' above) confirmed that the risk of PSP is associated with two independent variants of the MAPT gene, one of which influences MAPT brain expression [41]. In addition, isoforms common to both PSP and corticobasal degeneration tauopathies are aggregates of the four-repeat (4R) microtubule-binding domains that occur because of splicing of exon 10, in contrast to other tau disorders, where the three-repeat (3R) form dominates in the aggregates [111]. The normal ratio of 3R and 4R tau is approximately equal.

Neurochemical changes – The degenerative process in PSP involves dopaminergic neurons that innervate the striatum, as well as cholinergic interneurons and gamma-aminobutyric acid (GABA) efferent neurons in the striatum and other basal ganglionic and brainstem nuclei [112,113]. Postmortem studies of patients with PSP have demonstrated a marked reduction in striatal D2 receptors, whereas the striatal D1 receptors are relatively spared [114,115].

In the brainstem, degeneration of cholinergic neurons is observed in the Edinger-Westphal nucleus, rostral interstitial nucleus of Cajal, medial longitudinal fasciculus, superior colliculus, and pedunculopontine nucleus [116,117]. A reduction in the acetylcholine vesicular transporter potentially may differentiate PSP from other types of neurodegenerative disorders [118]. Glutamate is increased in the striatum, pallidum, nucleus accumbens, and occipital and temporal cortex [119]. One postmortem study demonstrated a 50 to 60 percent reduction of the GABAergic basal ganglia output neurons, which may, in part, explain the poor response to dopaminergic therapy in most patients who have this disorder [120].

DIAGNOSIS — The diagnosis of PSP during life is based upon the clinical features. Suspicion for PSP is raised when new-onset neurologic, cognitive, or behavioral deficits progress in absence of other identifiable causes in a patient ≥40 years of age. The core clinical features include early postural instability with falls; oculomotor deficits, especially slowing of vertical saccades followed by a vertical gaze palsy; akinesia/parkinsonism; frontal lobe impairments, including speech and language problems and behavioral change; and lack of response to levodopa. However, early diagnosis is difficult, as the disease varies quite a lot clinically.

No laboratory or imaging studies are diagnostic. Imaging can be supportive if there is predominant midbrain atrophy on magnetic resonance imaging (MRI), but the absence of this feature does not rule out the diagnosis of PSP, especially in patients at the earliest stages or presenting with a non-Richardson syndrome phenotype.

A levodopa trial in patients with parkinsonism and suspected PSP can assist with the diagnosis; a poor or unsustained response to levodopa therapy is generally observed in patients with PSP and can help to distinguish PSP from idiopathic Parkinson disease. (See 'Supportive features' below and "Progressive supranuclear palsy (PSP): Management and prognosis", section on 'Pharmacologic treatments'.)

Neuropathologic examination remains the gold standard for its definitive diagnosis. The pathologic diagnosis of PSP is based upon the identification of neurofibrillary tangles in a distribution considered typical for PSP [121]. The diagnosis requires a high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brainstem [102]. As mentioned earlier, astrocytic plaques and tau-positive tufts of abnormal fibers are highly characteristic of typical PSP [3].

Diagnostic criteria — In 2017, the Movement Disorder Society (MDS) proposed new diagnostic criteria for PSP [5]. The MDS-PSP criteria include the following components:

Basic features (inclusion and exclusion criteria) necessary for the diagnosis (see 'Inclusion and exclusion criteria' below)

Four core functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as characteristic manifestations of PSP (see 'Core features' below)

Supportive clinical features that increase diagnostic confidence (see 'Supportive features' below)

Operationalized definitions for the core features and supportive features (see 'Operationalized definitions' below)

Four levels of diagnostic certainty (see 'Certainty levels' below)

Inclusion and exclusion criteria — Basic features for the diagnosis of PSP of any phenotype and at any stage include mandatory inclusion criteria, mandatory exclusion criteria, and context-dependent exclusion criteria [5].

Mandatory inclusion criteria:

Sporadic occurrence

Age 40 years or older at onset of first PSP-related symptom

Consider any new-onset neurologic, cognitive, or behavioral deficit that subsequently progresses during the clinical course in absence of other identifiable cause as a PSP-related symptom. Note that rare variants (mutations) of the MAPT gene may lead to inherited phenocopies of sporadic PSP.

Mandatory clinical exclusion criteria:

Predominant, otherwise unexplained impairment of episodic memory, suggestive of Alzheimer disease

Predominant, otherwise unexplained autonomic failure (eg, orthostatic hypotension suggestive of multiple system atrophy or Lewy body disease)

Predominant, otherwise unexplained visual hallucinations or fluctuations in alertness, suggestive of dementia with Lewy bodies

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)

Sudden onset or stepwise or rapid progression of symptoms, in conjunction with corresponding imaging or laboratory findings, suggestive of vascular etiology, autoimmune encephalitis, metabolic encephalopathies, or prion disease

History of encephalitis

Prominent appendicular ataxia

Identifiable cause of postural instability (eg, primary sensory deficit, vestibular dysfunction, severe spasticity, or lower motor neuron syndrome)

Mandatory imaging exclusion criteria:

Severe cerebral leukoencephalopathy

Relevant structural abnormality (eg, normal pressure or obstructive hydrocephalus; basal ganglia, diencephalic, mesencephalic, pontine, or medullary infarctions, hemorrhages, hypoxic-ischemic lesions, tumors, or malformations)

Context-dependent imaging exclusion criteria:

In syndromes with sudden onset or stepwise 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

In cases with very rapid progression, exclude cortical and subcortical hyperintensities on DWI-MRI suggestive of prion disease

Context-dependent laboratory exclusion criteria:

In patients with PSP-CBS, exclude primary Alzheimer disease pathology (typical cerebrospinal fluid [CSF] constellation [ie, both elevated total tau and phospho-tau protein and reduced beta-amyloid 42] or pathological beta-amyloid positron emission tomography [PET] imaging)

In patients <45 years of age, exclude:

-Wilson disease

-Niemann-Pick disease, type C

-Hypoparathyroidism

-Neuroacanthocytosis

-Neurosyphilis

In rapidly progressive patients, exclude:

-Prion disease

-Paraneoplastic encephalitis

-In patients with suggestive features (ie, gastrointestinal symptoms, arthralgias, fever, younger age, and atypical neurologic features such as myorhythmia), exclude Whipple disease

Context-dependent genetic exclusion criteria:

MAPT rare variants (mutations) are not an exclusion criterion, but their presence defines inherited, as opposed to sporadic, PSP

MAPT H2 haplotype homozygosity is not an exclusion criterion but renders the diagnosis unlikely

Leucine-rich repeat kinase 2 (LRRK2) and Parkin rare variants have been observed in patients with autopsy-confirmed PSP, but their causal relationship is unclear so far

Known rare variants in other genes are exclusion criteria because they may mimic aspects of PSP clinically but differ neuropathologically; these include:

-Non-MAPT-associated frontotemporal dementia (eg, C9orf72, GRN, FUS, TARDBP, VCP, CHMP2B)

-Parkinson disease (eg, SYNJ1, GBA)

-Alzheimer disease (APP, PSEN1, PSEN2)

-Niemann-Pick disease, type C (NPC1, NPC2)

-Kufor-Rakeb syndrome (ATP13A2)

-Perry syndrome (DCTN1)

-Mitochondrial diseases (POLG, mitochondrial rare variants)

-Dentatorubral pallidoluysian atrophy (ATN1)

-Prion-related diseases (PRNP)

-Huntington disease (HTT)

-Spinocerebellar ataxia (ATXN1, 2, 3, 7, 17)

Core features — Four core functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) are the characteristic manifestations of PSP [5]. Within each domain, there are three characteristic clinical features (table 1), which are stratified by presumed level of certainty as 1 (highest), 2 (middle), and 3 (lowest).

Ocular motor dysfunction:

(O1) Vertical supranuclear gaze palsy

(O2) Slow velocity of vertical saccades

(O3) Frequent macro square wave jerks or "eyelid-opening apraxia"

Postural instability:

(P1) Repeated unprovoked falls within three years

(P2) Tendency to fall on the pull test within three years

(P3) More than two steps backward on the pull test within three years

Akinesia:

(A1) Progressive gait freezing within three years

(A2) Parkinsonism, akinetic-rigid, predominantly axial, and levodopa resistant

(A3) Parkinsonism, with tremor and/or asymmetric and/or levodopa responsive

Cognitive dysfunction:

(C1) Speech/language disorder (ie, nonfluent/agrammatic variant of primary progressive aphasia or progressive apraxia of speech)

(C2) Frontal cognitive/behavioral presentation

(C3) Corticobasal syndrome

Levels with lower numbers are considered to contribute higher certainty to a diagnosis of PSP than levels with higher numbers [5].

Supportive features — Supportive features can increase diagnostic confidence but do not qualify as diagnostic features [5]. They are divided into clinical clues and imaging findings.

Clinical clues:

(CC1) Levodopa resistance

(CC2) Hypokinetic, spastic dysarthria

(CC3) Dysphagia

(CC4) Photophobia

Imaging findings:

(IF1) Predominant midbrain atrophy or hypometabolism

(IF2) Postsynaptic striatal dopaminergic degeneration

Operationalized definitions — The MDS-PSP criteria provide detailed descriptions (table 1) for each of the core features and supportive features to standardize the application of the diagnostic criteria [5].

Certainty levels — The MDS-PSP criteria specify four levels of diagnostic certainty (table 2), which are derived by combinations of core clinical features and clinical clues [5].

Definite PSP, the gold standard, can be diagnosed only postmortem by neuropathological examination.

Probable PSP is diagnosed when clinical features with a high specificity are present.

Possible PSP is diagnosed in the presence of clinical features considered to substantially increase the sensitivity for PSP.

Clinical syndromes suggestive of PSP encompass syndromes with features that may constitute early or subtle evidence for PSP.

Predominance types — The MDS-PSP criteria determine clinical predominance types (table 2) based upon the combination of clinical features [5]. Recognized predominance types correspond to the variant phenotypes discussed previously (see 'Variant phenotypes' above):

PSP with Richardson syndrome (PSP-RS)

PSP with predominant parkinsonism (PSP-P)

PSP with predominant oculomotor dysfunction (PSP-OM)

PSP with predominant postural instability (PSP-PI)

PSP with progressive gait freezing (PSP-PGF)

PSP with predominant frontal presentation (PSP-F)

PSP with predominant speech/language disorder (PSP-SL)

PSP with predominant corticobasal syndrome (PSP-CBS)

The MDS-PSP diagnostic criteria omitted two other recognized but rare variant phenotypes (PSP with predominant cerebellar ataxia [PSP-C] and PSP with predominant primary lateral sclerosis [PSP-PLS]) because the sparse clinicopathologic evidence about them was inadequate for devising clinical diagnostic criteria with sufficient specificity [5].

Potential disease markers — There are no established laboratory or imaging markers for the diagnosis of PSP. However, imaging findings of predominant midbrain atrophy, midbrain hypometabolism, and postsynaptic striatal dopaminergic degeneration are supportive features (see 'Supportive features' above) that increase diagnostic confidence [5]. Routine analysis of blood and urine are normal. Routine investigations of CSF in PSP are also normal.

Potential markers of PSP include levels of neurotransmitters and brain metabolites in the CSF, but these are not validated for routine use.

As noted earlier (see 'Neuroimaging' above), neuroimaging of patients with PSP using computed tomography (CT) and MRI of the brain demonstrates generalized atrophy and brainstem atrophy, most pronounced in the midbrain. A number of small studies have used volumetric measures in an attempt to assess the specificity of this pattern of atrophy, and the following observations have been made [122-128]:

The anterior-posterior diameter of the suprapontine midbrain was significantly lower in patients with PSP than in patients with idiopathic Parkinson disease [122].

The average midbrain area of patients with PSP (56 mm2) was significantly lower than in patients with Parkinson disease (103 mm2) or multiple system atrophy-parkinsonism (97 mm2) [123]. The ratio of midbrain to pontine area was found to reliably differentiate the three disorders.

Compared with matched controls, the ratio of the midsagittal pons area to midbrain area was significantly higher in the PSP group [124].

The midbrain-to-pons ratio, measured from the anterior-posterior distance on midsagittal MRI, was significantly reduced for patients with pathologically confirmed PSP compared with controls and patients with pathologically confirmed multiple system atrophy or Parkinson disease [128].

Other studies have suggested that the magnetic resonance parkinsonism index (MRPI) can distinguish patients with PSP from those with Parkinson disease and other atypical parkinsonian syndromes such as multiple system atrophy [125-127]. The MRPI requires measurement of the area of the pons (P) and midbrain (M) and width of the middle cerebellar peduncle (MCP) on sagittal T1-weighted MRI and the width of the superior cerebellar peduncle (SCP) on coronal MRI. The index is calculated from the formula MRPI = (P/M) × (MCP/SCP) [129]. A modified version that incorporates the width of the third ventricles has improved sensitivity and specificity [101].

PET scanning reveals decreased glucose metabolism in the midbrain as the earliest sign of PSP [130], followed by decreased metabolic activity in the caudate, putamen, and prefrontal cortex as the disease progresses [131-134]. PET measures of striatal dopamine D2 receptor density using 11C-raclopride showed a 24 percent reduction in D2 density in the caudate and 9 percent reduction in the putamen of patients with PSP, but this finding has been observed with other atypical parkinsonian syndromes as well [135]. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'DaTscan'.)

Another study supports the use of both iodine-123-labeled FP-CIT single-photon emission computed tomography (SPECT) as well as MRI [129]. The SPECT portion was found to have high sensitivity while the MRI had high specificity for the diagnosis of PSP, thereby reaching a more confident clinical diagnosis of PSP when used together [129].

Resting-state functional MRI (fMRI) may be a promising imaging biomarker for PSP. A small prospective case-control study showed significant connectivity disruptions in the brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions as opposed to healthy controls [136].

Longitudinal electro-oculographic recordings may help to distinguish PSP from other parkinsonian syndromes at early stages [137]. Patients with PSP have normal latency but decreased saccade amplitude and velocity, whereas the opposite is observed in patients with corticobasal syndrome. Many of these electrophysiologic tests have been used for research purposes and are not generally available.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PSP by common clinical symptoms and signs is listed in the table (table 3). The disorders that are the most difficult to differentiate from PSP are the other neurodegenerative parkinsonian disorders such as idiopathic Parkinson disease, corticobasal degeneration, multiple system atrophy, and dementia with Lewy bodies, as well as vascular parkinsonism.

Unsteady gait and freezing of gait appear early in the course of PSP with Richardson syndrome (PSP-RS) and PSP with progressive gait freezing (PSP-PGF) compared with Parkinson disease. The parkinsonism of PSP-RS differs from that of idiopathic Parkinson disease in ways other than the early falling. Resting tremor is rare in PSP and rigidity tends to be much more pronounced in the neck than the limbs. In contrast to the symptomatic benefit of levodopa in Parkinson disease, an absent, poor, or rapidly waning response to levodopa is a characteristic feature of PSP. In addition, the relative preservation of olfaction in PSP can help distinguish it from Parkinson disease, which is characterized by hyposmia early in the course. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Olfactory testing'.)

The initial clinical presentation of PSP with predominant parkinsonism (PSP-P) may resemble idiopathic Parkinson disease, and the two disorders can be difficult to distinguish early on. However, with disease progression, symptoms such as levodopa-induced dyskinesia, autonomic dysfunction, and visual hallucinations are much less common in PSP-P, which can help distinguish it from Parkinson disease [11]. Furthermore, patients with early PSP-P often lose their levodopa response and develop other clinical features suggestive of PSP (eg, oculomotor abnormalities).

PSP with predominant corticobasal syndrome (PSP-CBS) refers to the clinical CBS phenotype of neuropathologically defined PSP, characterized by a variable combination of progressive asymmetric limb rigidity, apraxia, cortical sensory loss, alien limb, and bradykinesia that is unresponsive to levodopa. PSP-CBS is a rare presentation of PSP pathology and was present in only 6 of 179 pathologically diagnosed PSP cases in the Queen Square Brain Bank series [11,60]. Patients with CBS frequently present with asymmetric signs, whereas in PSP-RS they are usually but not always symmetric. The development of cortical sensory features, ideomotor apraxia, myoclonus, severe dystonia, and increased latency of saccades should suggest a diagnosis of corticobasal degeneration. However, since PSP-CBS is the second most common cause of CBS after corticobasal degeneration, distinguishing these disorders is extraordinarily difficult in life. Multiple system atrophy is considered in younger patients and in the presence of severe autonomic signs or cerebellar disturbances. Nevertheless, these disorders overlap enough (including the presence of gaze-evoked nystagmus in PSP) that clinical differentiation may be difficult, especially in the early course of illness.

PSP and multiple system atrophy are the most likely causes of unexplained postural instability and falls occurring within the first year of symptom onset [48]. Instability and falls in multiple system atrophy may be attributable to orthostatic hypotension and autonomic disturbances, although this may not be the case in multiple system atrophy with predominant parkinsonism, in which autonomic signs occur later [138]. By contrast, a later study suggests that orthostatic hypotension is uncommon in PSP [139]. Instability or falls, even freezing of gait, may develop in patients with corticobasal degeneration in the first year, particularly when the first symptom affects a leg [1,4]. However, falls may occur early in dementia with Lewy bodies, usually in association with significant cognitive disturbances [48]. In a case series of 58 patients diagnosed with PSP, evidence of a multi-infarct state by computed tomography (CT), magnetic resonance imaging (MRI), or autopsy was found in 19 patients (33 percent) [140]. Other incorrect diagnoses that are often assigned to older adult patients who fall include vestibulopathy, myelopathy, basilar artery ischemia, cardiac syncope, and epilepsy [141].

Although supranuclear gaze palsy is a key feature in diagnosing all subtypes of PSP, it may occasionally be present in other disorders, such as dementia with Lewy bodies, Alzheimer disease, idiopathic Parkinson disease, vascular parkinsonism, multiple system atrophy, prion disease (eg, Creutzfeldt-Jakob disease), Whipple disease, or corticobasal degeneration [48,138,142]. In PSP, the vertical supranuclear palsy precedes the development of the horizontal gaze palsy, but in corticobasal degeneration, ocular motor apraxia usually precedes the supranuclear gaze palsy, which usually affects both the horizontal and vertical gaze [48]. The saccades in corticobasal degeneration have increased latency but normal speed and are similarly affected in the vertical and horizontal plane, whereas in multiple system atrophy, the saccades have normal speed and latency. Blink rate, diminished in idiopathic Parkinson disease and multiple system atrophy, is usually less impaired in PSP. In addition, the upward gaze palsy, which may be the first indication of an ocular motor abnormality, should be differentiated from the limitation of upward gaze observed in healthy older adult patients, in whom saccades have normal speed [48].

A midbrain or third ventricular tumor could cause vertical gaze palsy, extensor truncal rigidity, and pyramidal symptoms and/or incoordination [1,143]. A tumor of the pineal gland can produce the so-called Parinaud syndrome characterized by limited upgaze, sluggishly reactive and large pupils, and retraction nystagmus.

Because patients with PSP usually exhibit early frontal lobe cognitive disturbances, and sometimes frank dementia, they can be confused with cortical dementias such as frontotemporal dementia or Alzheimer disease. Pseudobulbar palsy, especially early in the disease course, can be confused with depression and other psychiatric illnesses. In cases of PSP with rapidly progressive moderate to severe dementia, Creutzfeldt-Jakob disease might be suspected.

Anti-IgLON5 disease is a rare antibody-mediated neurodegenerative disorder that can mimic PSP [144,145]. Clinical features are reviewed separately. (See "Paraneoplastic and autoimmune encephalitis", section on 'Anti-IgLON5 disease'.)

On rare occasions, patients who manifest classic features of PSP, including eye movement abnormalities, early falls, and parkinsonism, will be found to have the pathology of other disorders including multiple system atrophy, corticobasal degeneration, Alzheimer disease, and idiopathic Parkinson disease [146].

MANAGEMENT AND PROGNOSIS — The management and prognosis of PSP is discussed in detail separately. (See "Progressive supranuclear palsy (PSP): Management and prognosis".)

SUMMARY AND RECOMMENDATIONS

As originally described, progressive supranuclear palsy (PSP) is characterized by progressive supranuclear ophthalmoplegia, gait disorder and postural instability, dysarthria, dysphagia, rigidity, and frontal cognitive disturbance. PSP is now recognized to encompass a number of phenotypic variants. The two most common are Richardson syndrome (PSP-RS; the classic form of PSP) and PSP with predominant parkinsonism (PSP-P). (See 'Historical background' above.)

PSP is the most common degenerative form of atypical parkinsonism. The mean age of onset for PSP is approximately 65 years. No cases of PSP have been reported in patients younger than age 40 years. (See 'Epidemiology' above.)

With the most common "classic" phenotype of PSP, known as PSP-RS, the most frequent initial feature is a disturbance of gait resulting in falls. Supranuclear ophthalmoparesis or plegia is the hallmark of PSP but may come on later. An important earlier manifestation is slowing of vertical saccades. Dysarthria, dysphagia, rigidity, frontal cognitive abnormalities, and sleep disturbances are additional common clinical features. PSP-P is characterized by asymmetric onset of limb symptoms, tremor, and a moderate initial therapeutic response to levodopa. It may be confused with idiopathic Parkinson disease. (See 'Clinical characteristics' above and 'Variant phenotypes' above.)

Additional variant phenotypes of PSP are classified as early predominance types, based upon their presentation and early clinical manifestations. These include (see 'Variant phenotypes' above and 'Predominance types' above):

PSP with predominant oculomotor dysfunction (PSP-OM)

PSP with predominant postural instability (PSP-PI)

PSP with progressive gait freezing (PSP-PGF)

PSP with predominant frontal presentation (PSP-F)

PSP with predominant speech/language disorder (PSP-SL)

PSP with predominant corticobasal syndrome (PSP-CBS)

The radiologic hummingbird sign (also called the penguin silhouette sign) results from the prominent midbrain atrophy in PSP with a relatively preserved pons, resembling a hummingbird or penguin in silhouette on midsagittal magnetic resonance imaging (MRI) of the brain (image 1). (See 'Neuroimaging' above.)

The most consistent sites of microscopic findings in PSP are in the basal ganglia, particularly in the substantia nigra, subthalamic nucleus, and internal globus pallidus, in addition to the oculomotor complex, periaqueductal gray matter, superior colliculi, basis pontis, and dentate nucleus. Involvement of the cerebral cortex is also increasingly recognized. The histologic characteristics of PSP include neuronal loss, gliosis, and the presence of tau-positive filamentous inclusions in specific anatomic areas involving astrocytes (most notably the hallmark finding of tufted astrocytes), oligodendrocytes, and neurons (picture 1). Tau cytoplasmic inclusions in surviving neurons, known as globose neurofibrillary tangles, are classically described in PSP, but are not specific to PSP. (See 'Pathology and pathophysiology' above.)

The diagnosis of PSP during life is based upon the clinical features. Suspicion for PSP is raised when new-onset neurologic, cognitive, or behavioral deficits progress in absence of other identifiable cause in a patient ≥40 years of age. The core clinical features include postural instability; oculomotor deficits, especially vertical gaze palsy; akinesia/parkinsonism; and frontal lobe impairments, including speech and language problems and behavioral change. No laboratory or imaging studies are diagnostic. Neuropathologic examination remains the gold standard for its definitive diagnosis. (See 'Diagnosis' above and 'Diagnostic criteria' above.)

The differential diagnosis of PSP by common clinical symptoms and signs is listed in the table (table 3). The disorders that are the most difficult to differentiate from PSP are the other neurodegenerative parkinsonian disorders such as idiopathic Parkinson disease, corticobasal degeneration, multiple system atrophy, and dementia with Lewy bodies, as well as vascular parkinsonism. (See 'Differential diagnosis' above.)

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Topic 14136 Version 23.0

References

1 : PROGRESSIVE SUPRANUCLEAR PALSY. A HETEROGENEOUS DEGENERATION INVOLVING THE BRAIN STEM, BASAL GANGLIA AND CEREBELLUM WITH VERTICAL GAZE AND PSEUDOBULBAR PALSY, NUCHAL DYSTONIA AND DEMENTIA.

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8 : Which ante mortem clinical features predict progressive supranuclear palsy pathology?

9 : Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes.

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30 : Follow-up study of risk factors in progressive supranuclear palsy.

31 : A geographical cluster of progressive supranuclear palsy in northern France.

32 : PSP risk factors.

33 : Four cases of progressive supranuclear palsy in patients exposed to organic solvents.

34 : Environmental and occupational risk factors for progressive supranuclear palsy: Case-control study.

35 : The Role of Stress as a Risk Factor for Progressive Supranuclear Palsy.

36 : Clinical Features Observed in General Practice Associated With the Subsequent Diagnosis of Progressive Supranuclear Palsy.

37 : Familial progressive supranuclear palsy. Description of a pedigree and review of the literature.

38 : Clinical genetics of familial progressive supranuclear palsy.

39 : Familial aggregation of parkinsonism in progressive supranuclear palsy.

40 : Genetics of Progressive Supranuclear Palsy.

41 : Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.

42 : The structure of the tau haplotype in controls and in progressive supranuclear palsy.

43 : High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.

44 : Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.

45 : Association of MAPT Subhaplotypes With Risk of Progressive Supranuclear Palsy and Severity of Tau Pathology.

46 : Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease.

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48 : Update on progressive supranuclear palsy.

49 : Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a clinicopathological study.

50 : The ocular motor defects in progressive supranuclear palsy.

51 : Eye movement abnormalities in movement disorders.

52 : Clinical analysis of blepharospasm and apraxia of eyelid opening in patients with parkinsonism.

53 : Clinical analysis of blepharospasm and apraxia of eyelid opening in patients with parkinsonism.

54 : Dystonia in progressive supranuclear palsy.

55 : Limb dystonia in progressive supranuclear palsy.

56 : Slowing of cognitive processing in progressive supranuclear palsy. A comparison with Parkinson's disease.

57 : Heterogeneity of cognitive impairment in progressive supranuclear palsy, Parkinson's disease, and Alzheimer's disease.

58 : An 81-year-old man with imbalance and memory impairment.

59 : Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy.

60 : Does corticobasal degeneration exist? A clinicopathological re-evaluation.

61 : Neuropsychiatric aspects of progressive supranuclear palsy.

62 : A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy.

63 : Obsessive-compulsive behavior as a symptom of dementia in progressive supranuclear palsy.

64 : Sleep abnormalities in progressive supranuclear palsy.

65 : Rest-activity rhythm disruption in progressive supranuclear palsy.

66 : Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism.

67 : Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism.

68 : Progressive supranuclear palsy diagnosis and confounding features: report on 16 autopsied cases.

69 : What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsy-parkinsonism (PSP-P)?

70 : An autopsy-confirmed case of progressive supranuclear palsy with predominant postural instability.

71 : Pure akinesia with gait freezing: a third clinical phenotype of progressive supranuclear palsy.

72 : Pure akinesia as initial presentation of PSP: a clinicopathological study.

73 : Long lasting pure freezing of gait preceding progressive supranuclear palsy: a clinicopathological study.

74 : Primary progressive freezing gait: a syndrome with many causes.

75 : The natural history of the syndrome of primary progressive freezing gait.

76 : Frontal presentation in progressive supranuclear palsy.

77 : Behavioral changes as the earliest clinical manifestation of progressive supranuclear palsy.

78 : Autopsy-proven progressive supranuclear palsy presenting as behavioral variant frontotemporal dementia.

79 : Progressive nonfluent aphasia and subsequent aphasic dementia associated with atypical progressive supranuclear palsy pathology.

80 : Apraxia of speech and nonfluent aphasia: a new clinical marker for corticobasal degeneration and progressive supranuclear palsy.

81 : Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration.

82 : Progressive supranuclear palsy presenting with primary progressive aphasia--clinicopathological report of an autopsy case.

83 : Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech.

84 : Corticobasal syndrome with tau pathology.

85 : Pathologic heterogeneity in clinically diagnosed corticobasal degeneration.

86 : Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome.

87 : Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP.

88 : Characteristics of progressive supranuclear palsy presenting with corticobasal syndrome: a cortical variant.

89 : Cerebellar involvement in progressive supranuclear palsy: A clinicopathological study.

90 : An autopsied case of progressive supranuclear palsy presenting with cerebellar ataxia and severe cerebellar involvement.

91 : Early clinical features of patients with progressive supranuclear palsy with predominant cerebellar ataxia.

92 : Cerebellar ataxia in progressive supranuclear palsy: An autopsy study of PSP-C.

93 : Clinical and imaging findings of progressive supranuclear palsy with predominant cerebellar ataxia.

94 : Atypical progressive supranuclear palsy with corticospinal tract degeneration.

95 : Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking parkinsonism, gaze palsy, aphasia, or dementia.

96 : Teaching NeuroImages: "Penguin" or "hummingbird" sign and midbrain atrophy in progressive supranuclear palsy.

97 : Study of the rostral midbrain atrophy in progressive supranuclear palsy.

98 : 'Hummingbird' sign in progressive supranuclear palsy.

99 : Atrophy of superior cerebellar peduncle in progressive supranuclear palsy.

100 : Morning glory sign: a particular MR finding in progressive supranuclear palsy.

101 : Neuroimaging Advances in Parkinson's Disease and Atypical Parkinsonian Syndromes.

102 : Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy).

103 : Neuronal loss in Onuf's nucleus in three patients with progressive supranuclear palsy.

104 : Morphological and biochemical correlations of abnormal tau filaments in progressive supranuclear palsy.

105 : Astrocytic inclusions in progressive supranuclear palsy and corticobasal degeneration.

106 : Neurodegenerative disorders with extensive tau pathology: a comparative study and review.

107 : Structure-based classification of tauopathies.

108 : Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.

109 : Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.

110 : An extended 5'-tau susceptibility haplotype in progressive supranuclear palsy.

111 : Progressive supranuclear palsy and corticobasal degeneration: lumping versus splitting.

112 : Cholinergic neuronal loss in the basal forebrain and mesopontine tegmentum of progressive supranuclear palsy and corticobasal degeneration.

113 : The basal ganglia cholinergic neurochemistry of progressive supranuclear palsy and other neurodegenerative diseases.

114 : Dopamine D1 and D2 receptors in progressive supranuclear palsy: an autoradiographic study.

115 : D1 and D2-type dopamine receptors in patients with Parkinson's disease and progressive supranuclear palsy.

116 : Mesencephalic cholinergic nuclei in progressive supranuclear palsy.

117 : Loss of pedunculopontine neurons in progressive supranuclear palsy.

118 : Cholinergic vesicular transporters in progressive supranuclear palsy.

119 : [3H]MK-801 binding to NMDA glutamatergic receptors in Parkinson's disease and progressive supranuclear palsy.

120 : Alterations of GABAergic neurons in the basal ganglia of patients with progressive supranuclear palsy: an in situ hybridization study of GAD67 messenger RNA.

121 : Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges.

122 : Measurement of the midbrain diameter on routine magnetic resonance imaging: a simple and accurate method of differentiating between Parkinson disease and progressive supranuclear palsy.

123 : New and reliable MRI diagnosis for progressive supranuclear palsy.

124 : Morphometric analysis of subcortical structures in progressive supranuclear palsy: In vivo evidence of neostriatal and mesencephalic atrophy.

125 : MR imaging index for differentiation of progressive supranuclear palsy from Parkinson disease and the Parkinson variant of multiple system atrophy.

126 : Accuracy of magnetic resonance parkinsonism index for differentiation of progressive supranuclear palsy from probable or possible Parkinson disease.

127 : MRI measurements predict PSP in unclassifiable parkinsonisms: a cohort study.

128 : The midbrain to pons ratio: a simple and specific MRI sign of progressive supranuclear palsy.

129 : Diagnostic Performance of 123I-FPCIT SPECT Specific Binding Ratio in Progressive Supranuclear Palsy: Use of Core Clinical Features and MRI for Comparison.

130 : Midbrain hypometabolism as early diagnostic sign for progressive supranuclear palsy.

131 : Positron emission tomography study in progressive supranuclear palsy. Brain hypometabolic pattern and clinicometabolic correlations.

132 : Cerebral hypometabolism in progressive supranuclear palsy studied with positron emission tomography.

133 : Positron tomography demonstrates frontal lobe hypometabolism in progressive supranuclear palsy.

134 : Clinical, MRI and 18F-FDG-PET/CT analysis of progressive supranuclear palsy.

135 : Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography.

136 : Intrinsic connectivity network disruption in progressive supranuclear palsy.

137 : Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy.

138 : Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases.

139 : Progressive supranuclear palsy is not associated with neurogenic orthostatic hypotension.

140 : Progressive supranuclear palsy and a multi-infarct state.

141 : A differential diagnosis of Parkinsonism.

142 : Precipitous Deterioration of Motor Function, Cognition, and Behavior.

143 : Further observations in progressive supranuclear palsy.

144 : Recognition of Movement Disorders as Cardinal Features of Anti-Iglon5 Disease: Expanding The Clinical Spectrum.

145 : Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease.

146 : Progressive supranuclear palsy: neuropathologic and clinical heterogeneity.