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Fifty years of progressive supranuclear palsy
  1. Carlo Colosimo1,
  2. Thomas H Bak2,
  3. Matteo Bologna3,
  4. Alfredo Berardelli1,3
  1. 1Department of Neurology and Psychiatry, “Sapienza” University, Rome, Italy
  2. 2School of Philosophy, Psychology and Language Sciences (PPLS) & Centre for Clinical Brain Sciences (CCBS), University of Edinburgh, Edinburgh, UK
  3. 3Neuromed Institute IRCCS, Pozzilli (IS), Italy
  1. Correspondence to Dr Carlo Colosimo, Dipartimento di Neurologia e Psichiatria, Sapienza Università di Roma, Viale dell'Università 30, Roma 00185, Italy; carlo.colosimo{at}uniroma1.it

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Introduction

Fifty years ago, in 1963, at the American Neurological Association annual meeting in Atlantic City, John Clifford Richardson, John Steele and Jerzy Olszewski presented eight patients seen in Toronto who had gaze paresis, nuchal rigidity, gait difficulties, dysphagia, dysarthria and dementia (figure 1). The description of these cases was published in the Transactions of the American Neurological Association,1 ,2 and led in the following year to what is considered the first comprehensive description of progressive supranuclear palsy (PSP) published.3 Here, Richardson and coworkers described the clinical features in nine patients and detailed the neuropathological changes in seven of them. In this report, the authors fended off arguments that the condition in the patients they described reflected a genetic mutation or environmental toxin geographically confined to the Toronto area.

Figure 1

First page of the original description of progressive supranuclear palsy by Richardson, Steele and Oszewski.1

Some speculate that earlier descriptions might exist,4 given that Richardson et al explicitly mention a case described by Chavany et al5 Much earlier, in 1889, Dutil cited by Goetz6 also reported a case of abnormal posture in a parkinsonian patient (‘attitude anormale dans la paralysie agitante’). What is most intriguing, however, is that the first description possibly came not from a physician but from a novelist. In ‘The Lazy Tour of Two Idle Apprentices’ Charles Dickens describes a memorable appearance of a man

A chilled, slow, earthy, fixed man. A cadaverous man of measured speech. A man who seemed as unable to wink, as if his eyelids had been nailed to his forehead. A man whose eyes—two spots of fire—had no more motion than if they had been connected with the back of his skull by screws driven through them, and riveted and bolted outside among his gray hair. He had come in and shut the door, and he now sat down. He did not bend himself to sit as other people do, but seemed to sink bolt upright, as if in water, until the chair stopped him.7

The pathological underpinnings of PSP became clearer in 1986, when Pollock et al reported that the filamentous aggregates found in brain autopsies from patients with PSP shared antigenic determinants with microtubule-associated protein tau8; histopathological studies then confirmed that PSP is characterised by abnormal hyperphosphorylated tau protein deposition forming fibrillary aggregates in neurons and glia from numerous areas in the central nervous system.9 These findings suggest that PSP should be classified as a tauopathy along with corticobasal degeneration (CBD), frontotemporal dementia (FTD) and Alzheimer's disease (AD).10

Epidemiology and clinical features

The prevalence of PSP varies in the published studies from 1.3 to 4.911 ,12 and the annual incidence ranges from 0.3 to 1.1 cases per 100 000 persons, increasing up to 5.3/100 000 in people over the age of 50 years.13 A single retrospective study conducted in Switzerland showed an increased risk of PSP associated with arterial hypertension,14 a finding which other groups failed to confirm.15 Smoking habits are similar to those in healthy controls.16

The most frequently reported symptoms at onset are impaired balance, movement slowness, subtle personality changes (apathy, disinhibition), bulbar symptoms and impaired eye motion.17 In the early stage in patients manifesting the classic PSP phenotype, the motor symptoms respond poorly to dopaminergic drugs.

In the more advanced stages, patients manifesting classic PSP generally have bradykinesia, rigidity and imbalance with severe gait unsteadiness. The prominent axial rigidity influences the standing posture, which may be characteristically erect like the cases reported by Richardson and collaborators (who depicted it as ‘nuchal dystonia’), or more closely resemble the stooped posture seen in Parkinson's disease (PD). The imbalance causes repeated and frequent falls (usually backward). Some patients may have postural tremor and less commonly tremor at rest, whereas fewer than 20% manifest the classic pill-rolling resting tremor seen in PD.18 Patients with PSP often experience dysphagia and a characteristic growling high-pitched severe dysarthria, with mixed spastic and parkinsonian features.3 ,17 The diagnostic feature that best distinguishes PSP is a vertical gaze limitation with preserved oculocephalic reflexes. Vertical gaze problems may be absent in up to 50% of the cases, however, and are rarely the presenting symptom of PSP.9 Because upgaze limitations can be present also in healthy persons (owing to anatomical changes within the orbit during aging), downgaze limitations are a far more specific finding suggesting PSP. Patients with PSP manifest widely varying oculomotor disorders (see online supplementary table S1). Oculomotor alterations mainly account for the characteristic facial expression, often described as ‘worried’ or ‘astonished’, together with facial muscle dystonia (frontalis, procerus and corrugator muscles) and facial hypomimia.19 ,20 An important point in the differential diagnosis is that several medical conditions other than PSP can manifest with apparently similar oculomotor dysfunction and vertical ophthalmoplegia (see online supplementary table S2).21–23

Already Steele and Richardson noted that the disease they described extended beyond the motor system to include ‘mental symptoms’, ‘personality changes’, and ‘dementia’.1–3 Indeed, cognitive and behavioural symptoms can occur early, be the only presenting features and reach the severity of dementia.24–26 The prominent bradykinesia characterising PSP is paralleled by cognitive slowing, difficulty in generating words, and severe apathy.27 By contrast, other cognitive functions, such as language comprehension, recognition memory and visuospatial functions remain relatively well preserved.27 ,28

Research over the past decade clarified that several clinical syndromes other than classic PSP may have PSP-tau pathology (box 1). The previous literature already referred to occasional patients with pathologically definite PSP, whose initial clinical features differed from those so well described by Richardson and colleagues.29 Only in 2005 did a large clinicopathological series of patients with PSP collected at the Queen Square Brain Bank by Williams et al,30 underline that a clinical picture closely resembling that in PD (rest tremor, asymmetrical bradykinesia, and a good response to levodopa) is far more common than previously recognised. These researchers renamed the classic PSP form as Richardson's syndrome (RS), and proposed the term PSP-parkinsonism (PSP-P) for the clinical phenotype similar to PD, which accounted for up to one-third of all PSP cases in their series.30 Clinical PSP variants other than RS and PSP-P include corticobasal syndrome (CBS),31 and pure akinesia with gait freezing (PAGF).32 CBS usually manifests with unilateral, levodopa unresponsive parkinsonism with apraxia, dystonia and myoclonus. Data from the Queen Square London group show that 29% of the patients manifesting CBS in life had underlying PSP pathology at postmortem,33 making PSP the most common CBS substrate (even higher than CBD pathology). Overlap between PSP and CBD is also emphasised by the observation that CBD pathology may, in turn, manifest with a classical PSP syndrome, as recognised by the new criteria for the diagnosis of CBD published in 2013.34 Differences between cognitive profiles of PSP and CBD (eg, the higher rate of language and visuospatial impairment in CBD) might be in fact more helpful in differentiating the two diseases than the motor symptoms.27 ,28 ,35

Box 1

Progressive supranuclear palsy (PSP): clinical presentations

  • Richardson's syndrome (classic phenothype)

  • PSP-parkinsonism

  • Corticobasal syndrome

  • Pure akinesia with gait freezing

  • Progressive non-fluent aphasia

  • Dementia (frontotemporal-like or Alzheimer-like)

  • Cerebellar ataxia

  • Motor neuron disease

Patients who present with a progressive, levodopa unresponsive gait disturbance, and hypophonia, and in whom severe freezing subsequently develops unaccompanied by cognitive dysfunction, tremor, rigidity and eye movement abnormalities in the early disease stages are classified as PAGF, a variant which seems the least common among those we have described. from rare cases of pathologically proven PSP presenting as a progressive upper motor neuron syndrome36 and cerebellar ataxia have been reported from Japan.37 Unusual cases with tau-positive globular oligodendroglial inclusions presenting with clinical features of motor neuron disease and/or FTD have also been reported. Although these cases have overlapping pathological features with PSP, the globular nature of glial inclusions and the non-fibrillar properties of tau in astrocytes distinguish these cases from PSP. The term globular glial tauopathy has been therefore proposed to classify these distinct disease entities.38

The various clinical PSP forms depend on the different distribution of tau pathology, but they share histopathologic, biochemical and genetic features with classic PSP. The major difference relates to the regional distribution of pathology and the resulting clinical phenomenology, with greater tau burden in RS than in other clinical variants.39 Since the original description of PSP, an abnormally high prevalence of atypical Parkinsonism, often resembling clinically and pathologically PSP, has been reported in geographic isolates, including Guam, New Guinea, the Kii peninsula, and New Caledonia in the Asia–Pacific region and Guadeloupe in the Caribbean.40–42 In some instances, the phenotype of these clusters had overlap with dementia and amyotrophic lateral sclerosis, although most of the cases were often unclassifiable according to the current diagnostic criteria. Since Annonaceae tropical fruits and herbal teas are largely consumed in most of these geographical locations, an environmental cause has been proposed for these cases. Annonaceae contain several neurotoxins, particularly acetogenins which, by acting as selective complex I inhibitors in the mitochondria may induce neuron loss in several regions of the basal ganglia.40–42

New PSP classifications based on the data from the Queen Square brain bank, a PD referral centre, should nevertheless take into account possible biases in patient recruitment as well as the scarce cognitive data provided in many retrospective studies. Centres with a more cognitive focus are likely to see a higher percentage of patients with an early and pronounced cognitive presentation, classifiable as a cognitive behavioural subform.24 An open question is whether the clinical heterogeneity is best accounted for by distinct phenotypes or by different clusters of symptoms within the same disease spectrum.

Natural history of the disease

The clinical symptoms commonly begin in the seventh decade, but they can also start as early as the fifth decade. The median onset age is of 63 years, and the disease affects both sexes despite a slight male predominance.17

PSP is a disease characterised by a progressive worsening of neurological symptoms and increasing disability. In a comparative clinicopathological study, latencies to onset of falls were shorter in patients with PSP than in other forms of parkinsonism.43 Frequent falls in the early stage (first year) of the disease onset predicted PSP in 68% of the patients.44 Cognitive and behavioural symptoms also progress, but tend to remain selective until the late stages of the disease.27 The behavioural picture remains dominated by the pronounced apathy. Despite the presence of frontodysexecutive syndrome and deficits in social cognition24 patients rarely experience a full-blown FTD with disinhibited and challenging behaviour.28

PSP carries a poor prognosis, and the disease leads to death within a few years after symptom onset. Mean survival ranges from 5.9 to 9.7 years according to the different series. These data come from series including mainly patients with the RS phenotype: other clinical variants differ in disease progression rates and disease duration, often having a longer disease course than RS.30 ,33 No markers have been described for disease progression.

Diagnostic criteria and rating scales

After Lees originally proposed formal clinical diagnostic criteria in 1987, it became easier to identify patients with PSP clinically.17 Others then proposed various sets of diagnostic criteria, mainly based on personal experience.45–47 The most recent criteria were developed in 1996 under the auspices of the National Institute for Neurological Disorders and Stroke and the Society for PSP (NINDS-SPSP).48 The Consensus participants defined three diagnostic categories of increasing certainty: possible, probable and definite. The diagnosis of possible and probable PSP is based on clinical grounds alone, whereas a definite diagnosis requires a typical PSP neuropathological lesion pattern with tau-positive inclusions. A controversial issue is that according to the NINDS-SPSP criteria PSP cannot be diagnosed without eye movement abnormalities, whereas observations in patients with pathologically confirmed PSP have shown that gaze palsy can manifest late or even never.9 In their retrospective study evaluating the NINDS-SPSP criteria and the other existing sets of clinical diagnostic criteria for PSP in a large series of pathologically proven cases from the Queen Square Brain Bank for Neurological Disorders, Osaki et al49 concluded that none of the diagnostic criteria could significantly improve the accuracy of the final clinical diagnosis. This conclusion underlines the pressing need to seek new and more sensitive criteria, including laboratory, neuroimaging or neurophysiological-supported diagnostic categories.

In an attempt to standardise severity assessment in specialised clinics and research programmes worldwide, Golbe and Ohman–Strickland in 2007 developed a clinical rating scale for PSP (PSPRS).50 The PSPRS is a prospectively validated clinical tool that measures overall disability and disease progression. Since its publication, the PSPRS has been widely used in multicenter clinical trials as a measure of disease progression. For cognitive assessment, patients with PSP usually achieve scores within the normal range on the Mini Mental State Examination, a test insensitive to frontal dysfunction.51 Better suited to measure frontal executive functions are the Frontal Assessment Battery or multidimensional screening batteries including frontal tasks, such as the Dementia Rating Scale and Addenbrooke's Cognitive Examination.26 These two tools can also provide information about specific cognitive impairment patterns and help to distinguish PSP from other disorders.

Genetics

The importance of tau aggregates in causing PSP has received further support from genetic studies. PSP is associated with a specific haplotype in the tau gene (H1). Investigations in different populations have shown that patients with PSP (like those with CBD) consistently have a higher prevalence of the H1 haplotype and the H1/H1 genotype than controls.52 Fine-mapping for this region showed a variation in a single intron regulating tau expression on the H1 background.53 A genome-wide association study subsequently disclosed a second major susceptibility locus on chromosome 11 with several possible candidate genes.54 Mutations in the leucine-rich repeat kinase gene (LRRK2) have been also reported to cause neuropathological alterations including PSP-like tau pathology. However, the screening for mutations in exon 31 in a cohort of patients with PSP did not confirm that mutations of LRRK2 gene is a major risk factor for PSP. These results, however, did not exclude that other genetic variations in LRRK2 may be associated with PSP.55

PSP is considered a sporadic condition, with only 7% of patients reporting a positive family history.56 Reports in the last two decades have described several families with inherited PSP. Most of these families have an autosomal dominant transmission with reduced penetrance. Screening large cohorts with sporadic PSP has so far failed to identify tau gene mutations, and even in patients with familial PSP, tau mutations are rare and often associated with an atypical disease presentation.57 ,58 In their report, Pastor and colleagues described an interesting family in which two brothers had atypical PSP.57 A homozygous deletion at codon IN296 of the tau gene on chromosome 17 was identified in one of the affected siblings, whereas two members with probable PD were identified among the heterozygous carriers. Another large Spanish pedigree with autosomal-dominant PSP has been described and linked to a locus on another chromosome (1q31), but the gene responsible for the disease in this family has yet to be identified.59

In an international genome-wide association study conducted in 2011 to identify common genetic variations contributing to the risk for PSP, and comparing 1114 individuals with PSP versus Controls, the investigators found an association with PSP risk at three loci encoding proteins for vesicle-membrane fusion at the Golgi–endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin component.60

Neuropathological features

The postmortem examination conducted by the neuropathologist Jerzy Olszewski in the original cases seen by Richardson and Steele showed nerve cell loss and gliosis in the pallidum, red nucleus and subthalamic nuclei, and in the reticular formation.3 Similar changes were noted in substantia nigra, locus coeruleus, superior colliculi, vestibular and dentate nuclei. The same areas also contained neurofibrillary tangles (NFTs) and granuovacuolar changes. No cortical pathology was described in the original cases. Further studies in the following three decades, helped to clarify the pathology of this disease.61

The typical pathological changes in PSP can already be recognised at macroscopic examination as atrophy in the midbrain and pontine tegmentum, together with depigmentation in the substantia nigra, red nucleus and locus coeruleus. In PSP, the major pathological damage involves the ventromedial substantia nigra, whereas in PD, the most severe neuronal loss affects the ventrolateral area. The cortex is relatively preserved (apart from mild frontal lobe atrophy) and globus pallidus atrophy not always visible.9 The lateral ventricles, the third ventricle and the aqueduct of Sylvius are usually enlarged.

At microscopic examination, PSP is characterised by neuronal loss, gliosis and tau accumulation in neurons and glial cells in the frontal cortex, substantia nigra, striatum, medial globus pallidus, subthalamic nucleus and several brainstem nuclei. In the brainstem, the nuclei affected by the pathological process include the rostral interstitial nucleus of the medial longitudinal fasciculus, the interstitial nucleus of Cajal, the nucleus of Darkschewitsch, the nucleus of Edinger–Westphal, the superior colliculus, the peduncolopontine nucleus, the raphe nuclei and the locus coeruleus. NFTs are already present at haematoxyline and eosin-stained sections, whereas tau protein, which accumulates inside the cells as NFTs and neuropil threads, is detectable with silver impregnation staining, such as the Gallyas technique, or tau immunohistochemistry. Morphologically, the cortical NFTs seen in patients with PSP resemble those seen in AD, whereas those observed in the brainstem differ. Ultrastructural examination shows that PSP NFTs predominantly contain bundles of straight filaments, whereas, AD NFTs contain paired helical filaments.62–64

The major pathological change in PSP is abnormal hyperphosphorylated tau protein aggregates. Tau is an abundant protein in the central and peripheral nervous systems. It is mainly found in neuronal cells where it tends to concentrate in the axons. The physiological role of tau is to promote tubulin polymerisation, reducing microtubule instability and maintaining axonal transport and cell integrity.56 In the human brain, alternative splicing involving exons 2, 3, and 10 in the tau gene generates six tau isoforms. Including or excluding exon 10 produces isoforms with four (4R) or three (3R) microtubule binding sites. Healthy controls have comparable amounts of 4R and 3R, whereas in PSP this ratio shifts in favour of 4R tau. The revised neuropathologic criteria for PSP proposed in 1994, require high NFT and neuropil threads densities in at least three of the following brain areas: striatum, oculomotor complex, medulla, or dentate nucleus.63 A grading system was developed in 2007 by Williams et al,39 in order to provide an easy-to-use and sensitive tool for the morphological assessment of PSP-tau pathology in different PSP variants.

The pathological changes in PSP involve the primary motor area in the frontal lobe, and degeneration in this area (together with the selective changes involving the ventrolateral posterior thalamus) is a possible cause for early falls.64 Including dementia in the original description of the disease was controversial given the predominantly subcortical pathology (JC Steele, personal communication, 2010). But 10 years later, Albert et al65 used PSP as a model for their concept of ‘subcortical dementia’, whereas, subsequent pathological studies demonstrated substantial cortical involvement.66 Subcortical (basal ganglia and basal forebrain) and frontal lobe pathology may both contribute to cognitive decline. Additionally, recent studies suggest that the disease also involves cortical areas outside the frontal lobe, such as the supramarginal gyrus.67 PSP and CBD share several pathological features, suggesting that the two diseases might belong to the same disease spectrum. The tau aggregates in PSP and in CBD mainly contain 4R isoforms and accumulate in neuronal and glial cells. However, tau-positive ‘tufted astrocytes’ are a characteristic feature in PSP and differentiate it from CBD. Astrocytic alterations probably reflect primary neurodegeneration rather than secondary changes due to gliosis.

Transgenic mice expressing mutant human tau in nerve cells have been developed to study mechanisms of degenerations and possible therapeutic interventions in tauopathies. These animal models show most of the essential pathological features of tauopathies, including neurodegeneration and abundant filaments of hyperphosphorylated tau.68

Neuroimaging

In patients with PSP, routine and volumetric MRI techniques disclose midbrain atrophy, a finding not present in patients with PD or other atypical parkinsonian disorders. By measuring midbrain diameter other investigators found that a diameter of <17 mm on axial MRI scans differentiates patients with PSP from controls.69 Other studies showed that mid-sagittal images can demonstrate midbrain atrophy better than axial images, and the midbrain atrophy seen on sagittal MRI slices resembles a ‘penguin’ or ‘humming-bird’ silhouette.70 In a study designed to quantify the midbrain area, others found a significant reduction in patients with PSP but not in those with PD and healthy controls.71 The relationship between the midbrain area/pons area was also significantly lower in patients with PSP than in patients with PD and controls. Overall, although these measurements differentiate patients with PSP from those with multiple system atrophy (MSA), and PD as groups, because the imaging changes overlapped among diseases, they were therefore unhelpful for a diagnosis on an individual basis.

In an MRI study using volumetric T1-weighted sequences to investigate morphometric MRI changes, others show that the atrophy related to PSP involves the midbrain and superior cerebellar peduncle, whereas the atrophy related to MSA involves the pons and the middle cerebellar peduncle. Patients with PD and control subjects had normal brainstem size. The authors proposed a new index (area pons/area midbrain×middle cerebellar peduncle diameter/superior cerebellar peduncle diameter) obtained by combining the single measurements found in the various cerebral structures. This index was significantly higher in PSP than in the other conditions, and differentiated individual patients with PSP from those with MSA and PD.72

A study using diffusion-weighted imaging shows that patients with PSP and MSA have higher apparent diffusion coefficients values in the putamen and globus pallidus than patients with PD.73 The increased putaminal apparent diffusion coefficients in PSP probably reflect ongoing striatal degeneration.

In a study using MRI-based volumetry, patients with PSP and MSA had significantly lower mean striatal and brainstem volumes than patients with PD. Patients with MSA also showed reduced cerebellar volumes.74 A study using voxel-based morphometry comparing patients with probable PSP and controls showed that patients with PSP had a decreased volume in several cortical areas in the frontal, temporal and insular lobes.75 The decreased brain atrophy probably accounts for the cognitive and behavioural deficits associated with PSP.

Using positron-emission tomography others showed reduced putaminal uptake of the presynaptic dopaminergic marker 18F-fluorodopa in PSP. Caudate uptake was markedly reduced in PSP but only moderately reduced in PD.76 Positron emission tomography with raclopride showed similar dopamine D2 receptor density loss in patients with PSP, advanced PD and MSA.77 A study with single photon emission tomography evaluating dopamine transporter using [123I]β-CIT showed reduced uptake in patients with PSP. This technique is therefore unable to distinguish PSP from PD,78 although patients with PSP more frequently have a symmetric loss of dopamine transporter (consistent with the more symmetric clinical manifestations) than patients with typically asymmetric PD.

Scintigraphic visualisation of postganglionic sympathetic cardiac neurons with [123I]metaiodobenzylguanidine yields normal findings in PSP and is usually reduced neuronal changes in PD, but the results cannot discriminate PSP from MSA.79

Neurophysiological investigations and pathophysiology

Over the next decades neurophysiological advances allowed researchers to investigate central nervous system dysfunction at multiple levels in PSP.

Transcranial magnetic stimulation highlighted a prolonged central motor conduction time, suggesting pyramidal tract involvement,80 enhanced corticospinal excitability and reduced intracortical inhibition,81 probably related to cortical GABA-ergic interneuron degeneration. More advanced transcranial magnetic stimulation techniques have also highlighted abnormally enhanced cortical synaptic plasticity in PSP, possibly due to a mechanism involving cortical GABA-ergic interneurons in primary motor cortex.82 By contrast, short-latency afferent inhibition, a neurophysiological marker that reflects the excitability in intracortical cholinergic circuits is normal.83 Postural instability and cognitive impairment may therefore reflect dysfunction in striatal cholinergic interneurons and degeneration involving major cholinergic nuclei, such as the pedunculopontine nucleus and Meynert's nucleus basalis. Cortical abnormalities in PSP are also reflected in an enlarged somatosensory-evoked potential, suggesting a disease-specific dysfunction in cortical interneuron sensory processing.84 Patients with PSP also exhibit voluntary, spontaneous and reflex blinking abnormalities,85 ,86 due to widespread degeneration in cortical, subcortical and brainstem areas.8 ,77 Brainstem degeneration in PSP also leads to abnormal eye motility, absent or reduced startle responses to acoustic and somesthesic stimulation,87 ,88 and absent trigemino-cervical reflexes.89 Finally, neurophysiological and kinematic analysis of finger movements demonstrated that bradykinesia in PSP differs from bradykinesia in PD.90

The relationships between these neurophysiological abnormalities and the major PSP symptoms is still unclear. Future studies should investigate patients in the early stages of disease, and follow-up abnormalities over the disease course. Given that most of the neurophysiological abnormalities present in PSP are also shared by patients with other atypical parkinsonian disorders, further effort is needed to define the specific neurophysiological changes in PSP.

Cerebrospinal fluid examination

Studies on cerebrospinal fluid (CSF) showed that the neurofilament protein content, a measure mainly reflecting axonal neuronal degeneration is significantly increased in PSP, whereas total tau protein levels match those in controls.91 ,92 A more recent study found that proteolytic tau fragment patterns in CSF from patients with PSP differ from those in patients with other neurodegenerative conditions or healthy controls,93 suggesting that tau fragments are a promising biomarker for the early diagnosis of PSP. Equally promising is a novel sensitive immuno-PCR assay developed for measuring the trace amounts of tau isoforms in CSF in patients with PSP and other tauopathies. Using this method, a decreased amount of immunoreactive tau isoforms with four microtubule-binding repeat domains has been found in patients with PSP.94 These findings are likely due to several mechanisms, including the increased sequestration of these 4R-tau isoforms in brain tau aggregates of PSP. Similar findings, were found in patients with AD but not in CBD. In conclusion, further studies are needed before PSP biomarkers in CSF can be applied in routine clinical practice.

Treatment

A number of trials using putative disease-modifying agents for PSP have been launched in the last decade (see online supplementary table S3). Trials with Coenzyme Q1095 and riluzole96 gave disappointing results; more recently, davunetide, a peptide thought to impact neuronal integrity and cell survival by stabilising microtubules,97 and tideglusib, a glycogen synthase kinase 3 (GSK-3) inhibitor, which could reduce hyperphosphorylation of tau protein, did not show any modification in disease progression (G Höglinger, personal communication, 2013).

Given the lack of controlled studies, the symptomatic management of PSP is largely based on empirical evidence (see online supplementary table S4). Dopaminergic treatment produces only a modest improvement in parkinsonian features in PSP and open-label and retrospective studies reported a benefit (usually short lasting) in only 30% of patients with PSP.17 ,30 Amantadine can occasionally benefit some patients, but an open study in PSP reported no significant improvement in motor function.98 Although brain biochemical changes in PSP involve not only the dopaminergic but also the cholinergic systems,99 the cholinesterase inhibitor donepezil failed to improve cognitive deficits in patients with PSP.100 Serotonin reuptake inhibitors are often used for apathy and flattened affect, but clear evidence is lacking. Blepharospasm, apraxia of eyelid opening, sialorrhea, as well as limb and nuchal dystonia, may respond well to botulinum neurotoxin injected locally into affected muscles.101

Dysphagia may require food thickeners, feeding via a nasogastric tube and later a percutaneous endoscopic gastrostomy. Constipation is relieved by increasing intraluminal fluid by giving a macrogol–water solution. Physiotherapy helps in maintaining mobility and preventing contractures, and speech therapy can improve speech and swallowing. Patients should be encouraged to use a wheelchair before postural instability causes repeated falls. Psychological support is crucial for patients and for their caregivers.

Conclusions

Despite intense research for decades and far-reaching discoveries in PSP, the classic description, remarkably accurate, insightful and complete, still underlies our understanding of the disease. The recent scientific advances in PSP engendered consensus that the main pathogenetic event in this disorder is abnormal 4R tau deposition in brainstem, basal ganglia and neocortical areas. The clinical spectrum and disease classification has been expanded to incorporate several clinical syndromes each having distinctive features deriving from the original classic description by Richardson and coworkers. Although neuroimaging and neurophysiological advances have helped us to understand the pathophysiology of the disease, several concerns deserve further investigations. At the same time, although the symptomatic pharmacological treatment of PSP is still unsatisfactory, the first disease-modifying trials have been launched, possibly heralding a new therapeutic era for this devastating disorder.

References

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Footnotes

  • Contributors CC, THB and AB: conception and drafting of the article, AB: drafting of the article, revision of the intellectual content, final approval.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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