Progressive Supranuclear Palsy in 2022: recent developments and an eye to the future

Abstract

Progressive supranuclear palsy (PSP) is an uncommon, progressive, neurodegenerative condition which classically presents with eye movement abnormalities, axial rigidity, early falls and cognitive impairment. The range of recognised phenotypes associated with PSP has expanded significantly in recent years. Imaging markers can assist in the diagnosis of PSP, while novel imaging modalities and laboratory-based biomarkers offer hope for earlier and more accurate diagnosis. While no disease modifying treatments are yet available several therapies may be useful in ameliorating symptoms. Despite disappointing recent clinical trial results, several agents are currently under investigation for the treatment of PSP.

Progressive supranuclear palsy (PSP) is a neurodegenerative condition associated with the proliferation of 4-repeat (4R) tau through the brain. Clinically, the condition is characterised by axial rigidity, oculomotor abnormalities, and cognitive impairment with prominent postural instability and early falls. Recent revisions to diagnostic criteria and treatment guidelines have altered our understanding of PSP. While no disease modifying treatment is currently available, a range of promising therapies are under investigation.

Epidemiology and aetiology of PSP

The mean age of onset is 66.4 years (SD +/-12) years [1] and progresses to death over an average 6-7 years, although some subtypes follow a slower course and a substantial proportion (up to 24% in one study) survive for longer than 10 years [2, 3]. Estimates of PSP prevalence vary considerably with rates of 5-6 per 100,000 commonly quoted, although a recent study of Yonago City, Japan reported a prevalence as high as 17.9 per 100,000 [4, 5]. Estimates of the annual incidence of PSP range from 0.9-1.9 per 100,000 [6, 7]. Data from the UK Biobank, a large prospective cohort study of more than 500,000 people, has been used to study potential pre-diagnostic features of PSP. In this study, 176 people who subsequently developed PSP showed differences in reaction time, hand grip strength, fluid intelligence, prospective memory and tendency to fall compared to controls, with reaction time the strongest predictive marker [8].

PSP is typically a sporadic disorder, however, familial cases related to mutations in the MAPT gene as well as cases related to LRRK2 mutations have been identified [9, 10]. While genome wide association studies (GWAS) have identified several risk loci for PSP [11]. In addition GWAS studies have identified variations in LRRK2 influencing survival in PSP, in particular the rs2242367 allele [12]. Studies of geographical clusters of PSP have helped to identify several environmental risk factors. A PSP-like parkinsonian syndrome identified in Guadeloupe has been associated the consumption annonaceae fruit which contain annonacin, mitochondrial complex I inhibitor, which has been shown to increase 4R tau isoforms in cultured neurons [13,14]. Hypertension, lower levels of education, and rural living are some of the other potential risk factors which have been investigated [15].

Pathologically, PSP is characterised by microtubule-associated protein tau aggregates composed of tau isoforms with four microtubule-binding repeats (4R-tau). These aggregates are in the form of neurofibrillary tangles, oligodendrocytic coils, and astrocytic tufts [16, 17]. It is hypothesised that in PSP aberrant tau spreads throughout the brain in a prion-like fashion (spreading hypothesis). Typically the brainstem and basal ganglia are involved early in the disease course with evidence of rostral (particularly the frontal lobes) and caudal (dentate nucleus and cerebellum) spread in more advanced cases [18]. This topographical pattern varies and underlies the different clinical phenotypes of PSP seen by the clinician early in the disease.

Clinical presentation

The single most common presentation of PSP consists of axial rigidity, oculomotor abnormalities, and cognitive impairment, as described by Richardson, Steele, and Olszewski in their 1964 paper which first drew attention to PSP as a distinct clinicopathological entity [19]. This presentation, which became known as Richardson’s Syndrome (RS), is the most commonly recognised form of PSP. The motor syndrome is often accompanied by cognitive impairment of a frontal-dysexecutive type with reduced speed of processing, apathy, and impulsivity [20]. Language is frequently impaired with reduced fluency. Features of language peculiar to PSP include letter fluency more impaired than category fluency [21], a tendency to generate low frequency words [22] and a particular impairment for action naming words [23]. Sleep disturbance is common in PSP with patients frequently describing difficulty initiating and maintaining sleep and demonstrating abnormal sleep architecture [24].

The NINDS-PSP diagnostic criteria, published in 1996, were heavily influenced by the classic RS phenotype. These criteria have been shown to have good specificity for PSP pathology [25]. However, the phenotypic spectrum of PSP is much broader than that initially described, a fact which limits the sensitivity of these criteria [26-28]. These presentations are generally less specific for PSP pathology than PSP-RS. In 2017, the Movement Disorders Society published updated criteria for the diagnosis of PSP [27]. These criteria provide several levels of diagnostic certainty with presentations of “definite”, “probable”, “possible” PSP, and “suggestive of” PSP. The criteria recognised characteristic impairments in four domains: oculomotor function, akinesis, postural instability, and cognitive function with specific syndromes of impairment being considered more characteristic, and therefore more suggestive, of a diagnosis of PSP (for example, within the akinesia domain, progressive freezing of gait is considered more compelling evidence of PSP than akinetic-rigid, predominantly axial parkinsonism, which in turn is more characteristic than Parkinsonism with tremor, asymmetry, or levodopa responsiveness) [28]. These clinical features, in varying combinations, are used to define eight PSP clinical subtypes (Table 1) [29,30]. A number of additional supportive clinical features are recognised including early dysphagia, hypokinetic and spastic dysarthria (the characteristic “dysarthrophonia” of PSP), photophobia, and levodopa-resistance (where levodopa-responsiveness occurs in PSP it is seldom sustained). The akinetic syndrome seen in PSP may consist of hypokinesis without decrement, a finding which may help to distinguish PSP from PD [31].

The establishment of consensus clinical criteria for PSP subtypes may provide more precise information on the natural history of PSP subtypes. One large study, which included 101 cases of PSP, found distinctive patterns of progression, cognitive impairment, and serological markers for subgroups of presentation [32]. Despite the dramatic increase in the range of presentations recognised by the MDS criteria, some reported PSP phenotypes, such as PSP with predominant cerebellar ataxia (a proposed PSP-C) remain without formal diagnostic criteria [33].

Table 1 – Clinical phenotypes according to the 2017 Movement Disorders Society Criteria

Ancillary investigations

Changes on structural imaging of the brain can support a clinical diagnosis of PSP. Brainstem atrophy, particularly affecting the midbrain, can be seen on MRI. The “hummingbird” [34] and “morning glory” [35] signs, on midsagittal and axial images respectively, are seen in PSP, but lack sensitivity. Hypointensity seen within the putamen in T2 imaging, which is associated with ferritin deposition in pathological studies, can distinguish PSP from PD with reasonable specificity (91%, 95%CI 80-96%) but limited sensitivity (69%, 33-90%) [36]. The magnetic resonance parkinsonism index (MRPI) is calculated by multiplying the pons area-midbrain area ratio (P/M) by middle cerebellar peduncle (MCP) width-superior cerebellar peduncle (SCP) width ratio (MCP/SCP) helps to identify cases of parkinsonism likely to evolve to PSP [37]. A subsequent refinement of this measurement, which includes a measurement of third ventricle width has been shown to improve upon the sensitivity of the MRPI (98.1% vs 73.5%) while preserving specificity [38]. FDG-PET imaging reveals decreased glucose metabolism in the midbrain early in the disease course while decreased metabolic activity in the caudate, putamen, and prefrontal cortex occur later [39]. PET imaging using tau-specific ligands to image tau deposition in a range of neurodegenerative disease has been the subject of investigation for over a decade. First generation tau ligands, such as [18F]-flortaucipir [40], have been used in many research studies but their utility was limited by off-target binding (e.g. to monoamine oxidase B (MAO-B) in the basal ganglia) resulting in an overlap in tracer binding between different diagnostic groups [41]. Second generation ligands (e.g. [18F]MK-6240)(42) have been developed which demonstrate increased specificity, without off target binding to MAO-B which may improve the diagnostic utility of tau-PET imaging.

Treatment

A range of strategies are used to ameliorate symptoms and improve quality of life in PSP. In 2021, a consensus statement on the management of PSP was published by the CurePSP Centres of Care Network which is a useful guide to current best practice in the symptomatic management of PSP [43].

The involvement of a multidisciplinary team with experience in neurodegenerative disease is essential. Physiotherapy, focused on maintaining strength, balance, aerobics, and coordination is helpful. The selection of walking aids requires some consideration as walking sticks prevent falls in only one direction and may constitute a tripping hazard. Weighted walkers, some of which are designed to prevent the backwards falls which predominate in PSP, are preferred. In cases of severely restricted mobility wheelchairs equipped with a tilt-in-space mechanism to prevent falls and facilitate optimal positioning for swallowing are useful. Adaptations to the home as well as other functional adaptations require the input of a skilled occupational therapist. Speech therapy support in the accurate assessment and management of dysphagia and dysarthria is invaluable.  Communication difficulties can be reduced with the use of alphabet boards and text-to-speech systems. The early involvement of a Palliative Care service can be extremely helpful especially with regard to the need for hospice care as well as the management of multiple complex symptoms. Patients should consider appointing an enduring power of attorney early in the disease course to avoid difficulties which may arise should cognitive impairment become problematic. Patient support groups can provide peer support to people with PSP and their families.

Important pharmacological options to consider include:

• Levodopa may help with bradykinesia, rigidity, and tremor. 20-30% of patients with PSP respond to levodopa. A target dose of 800-1200mg per day is usually recommended.
• Amantadine, titrated to a maximum dose of 100mg tds may be helpful for gait dysfunction but may produce deleterious cognitive effects, livedo reticularis, ankle/leg swelling, or postural hypotension.
• Liposomal coenzyme Q10 (100mg tds) provides a benefit to gait in a small proportion of patients and a trial is recommended.
• Benzodiazepines may be helpful for dystonia.
• Melatonin can be useful for insomnia.
• Cholinesterase inhibitors should be used only where there are pronounced amnestic deficits and otherwise are best avoided.
• Botulinum toxin can be used in the treatment of focal dystonia and for apraxia of eyelid opening.

No disease modifying treatment for PSP currently exists but a number of different agents utilising a range of pharmacological mechanisms are under investigation. Disappointingly, 2021 saw negative results for two Phase 2 trials of anti-tau monoclonal antibodies directed against the extracellular N-terminal tau: the PASSPORT (gosuranemab) and ARISE (tilavonemab) trials [44, 45]. These agents target free extracellular tau in an attempt to disrupt the spread of aberrant tau from cell to cell and have previously shown promise in mouse and primate models but failed to demonstrate clinical benefit over 52 weeks, despite a reduction in free extracellular tau in CSF in the active arm.

There are a number of possible reasons for the lack of demonstrable benefit of immunotherapy targeting extracellular tau in PSP. In the first instance, participants were recruited on the basis of a PSP-RS presentation. While this presentation is reasonably specific for tau pathology, phenotype-pathology correspondence is not perfect and non-PSP mimics have been reported, study cohorts including heterogenous pathology will attenuate treatment effects of pathology specific therapies [30]. PSP-RS phenotypes correspond to widespread pathology and may represent a more advanced stage of the disease when extracelluar tau-reducing therapies have limited use. Therapies to date have targeted the N-terminal of extracellular tau, which may not be mediator of proposed tau-related toxicity [46, 47]. Finally, it is possible that the aggregation of tau may represent the consequence of an alternative disease-causing process rather than being pathogenic in itself, in which case removal of these markers of disease would have a limited impact on disease progression [48]. Given the influence of LRRK2 on survival in PSP, there is significant interest in treatments targeting LRRK2 in idiopathic Parkinson’s disease including LRRK2 kinase inhibitors and antisense oligonucleotides targeting LRRK2 [49]. Further studies involving an array of agents are ongoing, including tolfenamic acid, a NSAID which inhibits the tau transcription factor Sp1 [50], selenium selenate, monoclonal antibodies targeting alternative binding sites on the tau protein (UCB0107) [51], agents which modify mitochondrial function (MP201) or lipid peroxidation (RT001) [52] and antisense oligonucleotides to reduce the production of tau (NIO752) [53].

A persistent challenge in neurodegenerative disease, including PSP, is that presenting symptoms are often non-specific and relate to the early topographical pathological distribution and hence the diagnosis may be delayed. As a result, by the time a definitive diagnosis is made pathological changes are widespread and disability established such that prospects of effective treatment are diminished. The search for early and reliable biomarkers, clinically-, imaging- or CSF-based, or serum or skin or wearable device data or big data analysis may allow early identification of cases and initiation of treatment at an earlier stage.

Conclusion

PSP is a complex, progressive, neurodegenerative condition which has an enormous impact on the daily functioning, quality of life, and social circumstances of patients and their families. Patients commonly present with axial rigidity, gaze abnormalities, and cognitive impairment, although a wide range of phenotypes are described. Although no disease modifying treatment exists, a range of strategies may help manage the symptoms and complications of the condition while multiple agents which may modify the disease process are under evaluation.

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