Progressive supranuclear palsy: Neuropathology, clinical presentation, diagnostic challenges, management, and emerging therapies.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the accumulation of 4R-tau protein aggregates in various brain regions. PSP leads to neuronal loss, gliosis, and tau-positive inclusions, such as neurofibrillary tangles, tufted astrocytes, and coiled bodies. These pathological changes mainly affect the brainstem and the basal ganglia, resulting in distinctive MRI features, such as the hummingbird and morning glory signs. PSP shows clinical heterogeneity and presents as different phenotypes, the most classical of which is Richardson's syndrome (PSP-RS). The region of involvement and the mode of atrophy spread can further distinguish subtypes of PSP. PSP patients can experience various signs and symptoms, such as postural instability, supranuclear ophthalmoplegia, low amplitude fast finger tapping, and irregular sleep patterns. The most common symptoms of PSP are postural instability, falls, vertical gaze palsy, bradykinesia, and cognitive impairment. These features often overlap with those of Parkinson's disease (PD) and other Parkinsonian syndromes, making the diagnosis challenging. PSP is an essential clinical topic to research because it is a devastating and incurable disease. However, there are still many gaps in knowledge about its pathophysiology, diagnosis, and treatment. Several clinical trials are underway to test noveltherapies that target tau in various ways, such as modulating its post-translational modifications, stabilizing its interaction with microtubules, or enhancing its clearance by immunotherapy. These approaches may offer new hope for slowing down the progression of PSP. In this review, we aim to provide an overview of the current knowledge on PSP, from its pathogenesis to its management. We also discuss the latest advances and future directions in PSP research.