PSP is a neurodegenerative tauopathy in which abnormal accumulation of hyperphosphorylated four-repeat tau protein forms neurofibrillary tangles and other pathological inclusions within neurons and glial cells. The MAPT gene, located on chromosome 17, encodes the tau protein and has been implicated in the pathogenesis of PSP and related conditions. Specific MAPT haplotypes, particularly the H1 haplotype, are recognized as genetic risk factors for sporadic PSP. In cases associated with MAPT pathogenic variants, inheritance of frontotemporal dementia and parkinsonian features including PSP-like manifestations can occur, representing MAPT-related frontotemporal dementia as part of a broader disease spectrum. The precise molecular mechanisms by which tau accumulation leads to selective neurodegeneration in PSP remain an area of active investigation. Environmental factors and additional genetic modifiers are thought to contribute to disease susceptibility, though the majority of PSP cases occur sporadically without a clear familial pattern. The relationship between tau isoform imbalance, tau aggregation, and subsequent neuronal dysfunction and death forms the central pathophysiological framework for understanding this condition.

The diagnosis of PSP is based on clinical criteria incorporating the characteristic combination of supranuclear gaze palsy, postural instability with falls, progressive rigidity, and cognitive decline. Published diagnostic criteria for PSP exist and are used to categorize patients into probable and possible diagnostic tiers based on the presence and certainty of core clinical features. No consensus clinical diagnostic criteria specific to MAPT-related forms have been formally published. Neuroimaging, particularly magnetic resonance imaging, may reveal characteristic findings including midbrain atrophy producing the so-called hummingbird sign on sagittal imaging, reflecting selective volume loss in the midbrain tegmentum relative to the pons. Nuclear medicine imaging with tau-specific positron emission tomography tracers, including compounds such as izaflortaucipir, which holds orphan designation, is being investigated as a diagnostic and research tool to visualize in vivo tau pathology. Genetic testing for MAPT pathogenic variants may be considered in individuals with a family history consistent with autosomal dominant inheritance or atypical features. Cerebrospinal fluid biomarkers and blood-based tau assays represent evolving diagnostic tools. The differential diagnosis includes Parkinson disease, corticobasal degeneration, multiple system atrophy, and other atypical parkinsonian syndromes, making thorough clinical and paraclinical evaluation essential for accurate classification.

No disease-modifying therapy has been established for PSP, and no cure currently exists. Management is directed toward supportive care aimed at improving quality of life, maximizing functional capacity, and reducing complications arising from motor, swallowing, and cognitive impairment. Multidisciplinary care involving neurology, physical therapy, occupational therapy, speech-language pathology, nutritional support, and neuropsychology or psychiatry addresses the diverse manifestations of the disease. Dopaminergic agents used in Parkinson disease generally provide limited and inconsistent benefit in PSP. Prism glasses may be employed to address functional vision difficulties related to gaze palsy. Management of dysphagia is critical to reducing aspiration risk, with dietary modifications and in advanced stages consideration of enteral feeding. Behavioral and cognitive symptoms may be addressed pharmacologically on an individual basis. Several agents carry orphan designations for PSP, including fasudil, tertomotide, and a fully human IgG1 kappa anti-PD-L1 monoclonal antibody, reflecting ongoing therapeutic development efforts, though designation does not imply regulatory approval.

PSP follows a relentlessly progressive course without remission. The rate of decline varies among individuals, but motor and cognitive functions deteriorate steadily over years. Falls resulting from postural instability represent a major source of morbidity, with associated injury risk increasing as the disease advances. Dysphagia progressing to a severity requiring nutritional support is common in later stages. Aspiration pneumonia arising from swallowing dysfunction is a leading cause of morbidity and mortality. The median survival from symptom onset has been reported in the range of approximately five to ten years in various clinical series, though individual trajectories differ. The combination of motor disability, cognitive decline, and swallowing difficulty ultimately leads to significant dependence in activities of daily living. The broader spectrum of MAPT-related disease suggests that clinical heterogeneity influences disease course and functional outcomes across affected individuals.

Research in PSP is advancing across multiple domains, with particular focus on tau biology, biomarker development, and therapeutic intervention. Eight active clinical trials are ongoing, reflecting substantial investigational interest. Tau-targeted therapies represent a major research direction, including approaches aimed at reducing tau aggregation, promoting tau clearance, or modifying tau phosphorylation. Immunotherapy strategies, reflected by the orphan designation of an anti-PD-L1 monoclonal antibody, are being explored for their potential neuroimmunological effects in tauopathies. Tertomotide, an immunomodulatory peptide, also carries orphan designation and is under investigation. Tau positron emission tomography imaging using agents such as izaflortaucipir, also bearing orphan designation, is being developed as both a diagnostic instrument and a pharmacodynamic biomarker to assess treatment effects on tau burden in vivo. The identification of reliable fluid biomarkers for early diagnosis and disease monitoring remains an active area. Genetic studies of MAPT haplotypes and their relationship to PSP susceptibility continue to inform understanding of disease mechanisms. Preclinical models of four-repeat tauopathy are supporting therapeutic target identification and validation.