Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches

Abstract

Progressive supranuclear palsy (PSP), previously believed to be a common cause of atypical parkinsonism, is now recognised as a range of motor and behavioural syndromes that are associated with a characteristic 4-repeat tau neuropathology. New research criteria that recognise early presentations of PSP and operationalise diagnosis of the full spectrum of clinical phenotypes have been reported. The Movement Disorders Society PSP diagnostic criteria include syndromes with few or mild symptoms that are suggestive of underlying PSP pathology and could provide an opportunity for earlier therapeutic interventions in the future. These criteria also include definitions for variant PSP syndromes with different patterns of movement, language, or behavioural features than have been conclusively associated with PSP pathology. Data from new diagnostic biomarkers can be combined with the clinical features of disease to increase the specificity of the new criteria for underlying PSP pathology. Because PSP is associated with tau protein abnormalities, there is growing interest in clinical trials of new tau-directed therapies. These therapies are hypothesised to have disease-modifying effects by reducing the concentration of toxic forms of tau in the brain or by compensating for loss of tau function. Since tau pathology is also central to Alzheimer's disease and chronic traumatic encephalopathy, a successful tau therapeutic for PSP might inform treatment of other neurodegenerative diseases.

Figure 1. Model of the clinical trajectory of progressive supranuclear palsy (PSP)

Hypothetical model for the pathological-clinical continuum of PSP. PSP is defined as a continuum of disease from a presymptomatic phase (presymptomatic PSP) through a suggestive phase (soPSP) to a fully symptomatic stage that in many cases would meet the full research criteria for PSP-Richardson’s syndrome (PSP-RS) or another clinical variant of PSP (vPSP). Not all presymptomatic or soPSP will progress to a fully developed PSP phenotype.

Figure 2. Clinical syndromes of progressive supranuclear palsy (PSP)

PSP, progressive supranuclear palsy; PSP-F, PSP with predominant frontal presentation; PSP-C, PSP with predominant cerebellar ataxia; PSP-CBS, PSP-corticobasal syndrome; nfvPPA, non-fluent variant Primary Progressive Aphasia; bvFTD, behavioral variant Frontotemporal Dementia; PSP-P, PSP with predominant parkinsonism; PSP-SL, PSP with predominant speech/language disorder; PSP-PGF, PSP with progressive gait freezing. Relative proportions of each syndrome are speculative. Nomenclature reflect MDS PSP diagnostic criteria.

Figure 3. The MAPT gene locus, mutations and human brain tau protein isoforms

The MAPT gene locus located on chr. 17q21 exists as two major haplotypes, termed H1 and H2. Most people are H1/H1 haplotype. Mutations producing PSP-like phenotypes are indicated. Alternative splicing of exons 2, 3 and 10 of the MAPT gene gives rise to six isoforms of the encoded tau protein expressed in the human brain. Increased 4 microtubule binding domain repeat (4R) tau containing exon 10 are associated with PSP and CBD. Equal ratio of 3R and 4R tau in AD. Binding sites for monoclonal antibodies (tau 12, HT7, BT2, and tau5/AT120) from CSF tau assays. 3R, three repeat; 4R, Alzheimer’s disease, AD; Argyrophilic grain disease, AGD; corticobasal degeneration, CBD; chronic traumatic encephalopathy, CTE; MAPT, microtubule-associated protein tau; Niemann–Pick disease type C, NPD type C.

Figure 4. Potential mechanism based therapies for PSP

Three general categories of intervention are under development. (1) Modulation of MAPT gene expression, via antisense oligonucleotides and splicing modulators. (2) Modulation of tau protein post-translational modifications, including phosphorylation, acetylation and O-GlcNAc modification; degradation by both the ubiquitin proteasome system (UPS) and autophagy; modulation of the unfolded protein response (UPR). (3) Inhibition of tau propagation via trans-synaptic pathways or mediated by microglia. Modulating inflammation may alter tau pathology. 26S/UPS, ubiquitin proteasome system; GSK, glycogen synthetase kinase; p300, acetyltransferase