How can we manage progressive supranuclear palsy syndrome with pharmacotherapy?

ABSTRACT

Introduction

Tauopathies are a spectrum of clinicopathological neurodegenerative disorders with increased aggregates included in glia and/or neurons of hyperphosphorylated insoluble tau protein, a microtubule-associated protein. Progressive supranuclear palsy (PSP) is an atypical dopaminergic-resistant parkinsonian syndrome, considered as a primary tauopathy with possible alteration of tau isoform ratio, and tau accumulations characterized by 4 R tau species as the main neuropathological lesions.

Areas covered

In the present review article, we analyzed and discussed viable disease-modifying and some symptomatic pharmacological therapeutics for PSP syndrome (PSPS).

Expert opinion

Pharmacological therapy for PSPS may interfere with the aggregation process or promote the clearance of abnormal tau aggregates. A variety of past and ongoing disease-modifying therapies targeting tau in PSPS included genetic, microtubule-stabilizing compounds, anti-phosphorylation, and acetylation agents, antiaggregant, protein removal, antioxidant neuronal and synaptic growth promotion therapies. New pharmacological gene-based approaches may open alternative prevention pathways for the deposition of abnormal tau in PSPS such as antisense oligonucleotide (ASO)-based drugs. Moreover, kinases and ubiquitin-proteasome systems could also be viable targets.

KEYWORDS:

• Dementia
• frontotemporal lobar degeneration
• primary tauopathies
• progressive supranuclear palsy
• tau protein
• oligonucleotide therapy
• kinase
• gene-based therapy

Article highlights

• Primary tauopathies have a primary underlying neurodegenerative process characterized by increased of abnormal tau aggregates.

• Among frontotemporal lobar degeneration phenotypes, Progressive Supranulcear Palsy Syndrome (PSPS) is characterized by a wide range of clinical presentations, principally with motor disorders.

• Several clinical variants are included in this tauopathy such as PSP-parkinsonism, PSP-corticobasal syndrome, PSP-behavioral variant of frontotemporal dementia, PSP-pure akinesia and gait freezing, PSP-primary lateral sclerosis, PSP-cerebellar and PSP-speech apraxia.

• Actual treatment for PSPS are only available to help ease symptoms of the disorder; the clinical heterogeneity adds to the difficulties for developement of a disease-modifyng treatment.

• Principal disease-modifying approaches for PSPS included in ongoing Research Clinical Trials (RCTs) are: activation of tau clearance (passive and active immunotherapeutics); modulation of tau phosphorylation and acetylation; microtubule stabilization; modulation of MAPT (microtubule-associated protein tau) expression; target of mitochondrial dysunction and oxidative stress, including nutrient combinations.

• Beyond gene-based approach, also kinases and ubiquitin-proteasome systems are pursued as new therapeutic targets.

• Unfortunately several RCTs were halted for futility because of the difficulty in diagnostic process in preclinical stages of PSPS.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by the Project “Development of an ensemble learning-based, multi-dimensional sensory impairment score to predict cognitive impairment in an elderly cohort of Southern Italy” funded by the European Union – Next Generation EU – NRRP M6C2 – Investment 2.1 Enhancement and Strengthening of NHS biomedical research [Grant Agreement PNRR-MAD-2022-12376656].