RARE DISEASE
Progressive supranuclear palsy-corticobasal syndrome
Progressive supranuclear palsy-corticobasal syndrome
Progressive supranuclear palsy-corticobasal syndrome
Synonyms: PSP-CBS, PSP-corticobasal syndrome
Synonyms: PSP-CBS, PSP-corticobasal syndrome
Synonyms: PSP-CBS, PSP-corticobasal syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Progressive supranuclear palsy-corticobasal syndrome (PSP-CBS) is a rare late-onset neurodegenerative tauopathy characterized by asymmetric limb rigidity, apraxia, cortical sensory loss, and levodopa-unresponsive parkinsonism. It combines features of both PSP (postural instability, vertical gaze palsy) and corticobasal degeneration (alien limb phenomenon, dystonia). Neuropathology shows midfrontal/inferior parietal cortical tau pathology and brainstem neuronal loss [1][5][6][10].
Burden
Functional decline: 67-100% develop moderate-to-severe disability across motor, cognitive, and ocular domains [4][9]
Care requirements: Average 1.8 caregivers/patient, 55-78% requiring home modifications [4][8]
Survival: Median 6-7 years post-diagnosis, with frequent falls (>50%) and early dysphagia [11][19]
Therapies
Symptomatic management: Botulinum toxin for dystonia/blepharospasm, antidepressants for behavioral changes [3][8]
Rehabilitative interventions: Weighted walkers, prism lenses, speech/swallow therapy [3][9][18]
Limited pharmacological response: Transient levodopa benefit in 26% of cases, no disease-modifying therapies [12][16]
Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
117 drug discovery papers about Progressive supranuclear palsy-corticobasal syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
117 drug discovery papers about Progressive supranuclear palsy-corticobasal syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-08 | Pathology and Genetics in a Global Cohort of Parkinsonian Disorders.
Accurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of in vivo biomarkers, overlapping clinical features, and a delay in the emergence of pathognomonic features. To evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multiancestry brain bank cohort. This was a multicenter, retrospective, autopsy-confirmed cross-sectional brain bank study on donors enrolled between 1985 and 2024. Included were donors from 11 academic brain banks in the UK, US, and Australia. Among brain donors with available genetic data from participating brain banks, included were individuals with clinical diagnoses of Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies (DLB), progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls. Genetic variant carrier status and clinical diagnostic category. Outcomes included clinical diagnostic accuracy, Lewy body and Alzheimer disease pathology burden, survival, association with genetic variants, and genetically inferred ancestry. Among 5648 brain donors with available genetic data, a total of 3353 eligible donors (mean [SD] age at death, 76.8 [10.6] years; 2072 male [61.8%]) were included. Misdiagnosis rates for movement disorders ranged approximately from 10% to 20%. Clinical diagnoses of dementia with parkinsonism (ie, Parkinson disease dementia and DLB) were more strongly associated with Lewy body pathology than Parkinson disease without dementia (odds ratio [OR], 1.96; 95% CI, 1.30-3.04; P = 7.2 × 10-4). Lewy pathology was identified in 33 of 745 of neurologically normal controls (4.4%). Alzheimer disease copathology was present in 426 of 1064 cases (40.0%) with Lewy body disease. Carriers of the GBA1 variant exhibited greater Lewy body burden compared with noncarriers (OR, 1.94; 95% CI, 1.24-3.03; P = .01) or carriers of the LRRK2 variant (OR, 7.44; 95% CI, 2.16-25.64; P = .01). Pathological diagnoses differed by ancestry, with South Asian donors more likely to have progressive supranuclear palsy pathology and Ashkenazi Jewish donors more likely to have Lewy body disease (χ22 = 35.5; P < .001), independent of GBA1 and LRRK2 variant status. Findings of this cross-sectional brain bank study highlight the value of integrating genetic and pathological data to improve diagnostic accuracy. The high prevalence of Alzheimer disease copathology and ancestry-associated differences in pathology point to the need for biologically informed diagnostic tools. These results suggest supporting the integration of genetically and pathologically stratified approaches, correlating pathology with in vivo biomarkers, for future therapeutic trials.
2026-04-01 | Features and advances in diagnosis and treatment of atypical Parkinson syndromes
Parkinson syndrome (PDS) is a group of neurological syndromes characterized by bradykinesia, rigidity, resting tremor, and postural instability as core manifestations, mainly including Parkinson's disease (PD), atypical Parkinson syndromes (APSs), and secondary Parkinson syndromes. APSs are a group of neurodegenerative diseases characterized by parkinsonian motor disorders as core manifestations, but they differ significantly from typical Parkinson's disease in terms of pathological mechanisms, clinical features, imaging findings, drug responses, and prognosis. They mainly include multiple system atrophy, dementia with Lewy bodies, progressive supranuclear palsy, and corticobasal degeneration. In recent years, with the continuous updating of diagnostic criteria and the in-depth research on multimodal imaging and neuropathology, the positioning of different APS subtypes in clinical phenotypes and disease spectra has gradually become clear. In terms of treatment, APSs currently still rely primarily on symptomatic and supportive therapies. New strategies, including disease-modifying therapies targeting abnormal aggregation of α-synuclein and tau protein, as well as stem cell therapy, are being explored. This article systematically reviews the clinical and imaging features, evolution of diagnostic criteria, and treatment progress of each subtype of APSs, aiming to provide a reference for early clinical identification and standardized management.
2026-03-19 | Peripheral Treg-monocyte immune signatures relate to neurodegeneration and prognosis in patients with primary tauopathies
Background: Neuroinflammation is a common hallmark of primary tauopathies, and is associated with worse clinical outcomes over time. However, accurate prognosis in these disorders remains challenging, and current fluid biomarkers provide limited insight into the contribution of peripheral immune cells to PSP/CBS pathogenesis. Our study aims to characterise blood based immune cell profiles in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), and test their associations with neurodegeneration and clinical outcomes. Methods: Peripheral blood immune cells from fresh whole blood were characterized with high dimensional mass cytometry (29 markers) in n=60 people with PSP/CBS and n=21 age and sex matched controls. Cell type abundance was defined as the ratio of counts for each gated population divided by total live cells. Hierarchical clustering of cell types and principal component analysis were used to derive data-driven immune clusters. Correlation network analysis and diffusion based network propagation integrated cell counts with plasma inflammation markers to prioritise mediators of intercellular signalling. Associations between immunological markers, plasma concentrations of neurofilament light chain (NfL), cognition, and survival were assessed using regression and Cox proportional hazards models. Results: Patients with PSP/CBS showed a global increase in covariance among immune cell populations, indicating heightened coordination within the peripheral immune network. A monocyte driven cluster (Cluster 1) showed higher scores in PSP/CBS, reflecting impaired phenotypic transition from classical to nonclassical monocytes, which was associated with higher NfL levels, poorer cognitive performance, and worse prognosis. In contrast, a Treg driven cluster (Cluster 2) showed lower scores in PSP/CBS and was associated with better cognition and longer survival. Integrated multimodal networks identified a small set of immune regulatory molecules and cytokines mediating crosstalk between Treg/Th17-like cells and monocytic populations, supporting a dysregulated Treg and monocyte axis in PSP/CBS. Conclusions: We identified peripheral blood based immunophenotypic profiles of individuals with PSP/CBS that are associated with neurodegeneration, cognitive decline, and survival. Dysregulated monocyte maturation and reduced Treg related immune configurations are enriched in patients with worse outcomes, suggesting that specific peripheral immune cell subsets may serve as fluid biomarkers and potential immunotherapy targets in primary tauopathies.
2026-01-30 | Progressive Supranuclear Palsy in India: Insights from a Large Multicenter Clinical Cohort (Project PAIR-PSP)
Abstract Background Progressive supranuclear palsy (PSP) is a rare and devastating tauopathy with limited global data. Given India’s large population, genetic diversity, and clinical heterogeneity, large multicenter datasets are crucial to enrich global understanding of PSP. Objective To characterize the demographic, clinical, and phenotypic profiles of a large multicenter Indian PSP cohort. Methods Subjects fulfilling MDS-PSP criteria were prospectively recruited across movement disorders centers (2021–2025). Standardized demographic and clinical data were collected. Results A total of 1,035 subjects were enrolled (M:F = 709:326), with a median age of 65 years and a mean onset age of 62.2±7.9 years. Regional distribution reflected pan-Indian recruitment (South 35%, North 26%, West 21%, East 18%). PSP-Richardson’s syndrome was most common (41%), followed by PSP-Parkinsonism (18%) and PSP-CBS (11%); rarer phenotypes included PSP-PI (7%), PSP-F (7%), PSP-PGF (5%), PSP-OM (2%), PSP-SL (1%), and PSP-C (1%). Falls occurred earliest in PSP-PGF (13.7 months) and PSP-SL (16.3 months), while PSP-P showed delayed disability (falls at 31 months). Cognitive onset was prominent in PSP-F (21%) and PSP-SL (57%). Levodopa was prescribed to 893 patients; 186 (21%) reported >25% subjective benefit, and 358 (40%) reported ≤25% benefit. Amantadine was used in 351 (34%) patients, with improvement in 177. Conclusion This largest systematically profiled PSP cohort highlights both shared and distinctive features: high frequency of non-RS variants, aggressive course in PSP-RS/SL, better survival in PSP-P, and limited pharmacological benefit. These findings establish a foundation for longitudinal and genetic studies in diverse populations.
2025-12-30 | Praja1 E3 ubiquitin ligase and the role it plays in neurodegeneration
Protein aggregation and transmission are hallmarks of neurodegenerative diseases. Praja1 E3 ubiquitin ligase has been shown to suppress the aggregation of causative proteins in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Parkinson's disease, Huntington's disease, and spinocerebellar degeneration, which include transactivation response DNA-binding protein of 43 kDa, fused in sarcoma, superoxide dismutase 1, α-synuclein, huntingtin, and ataxin-3. Aoki et al. demonstrated that Praja1 ubiquitinates and degrades tau, a key molecule in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal syndrome, furthering our understanding of the role of Praja1 in neurodegenerative diseases and potential therapeutic approaches.
2026-06-08 | Pathology and Genetics in a Global Cohort of Parkinsonian Disorders.
Accurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of in vivo biomarkers, overlapping clinical features, and a delay in the emergence of pathognomonic features. To evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multiancestry brain bank cohort. This was a multicenter, retrospective, autopsy-confirmed cross-sectional brain bank study on donors enrolled between 1985 and 2024. Included were donors from 11 academic brain banks in the UK, US, and Australia. Among brain donors with available genetic data from participating brain banks, included were individuals with clinical diagnoses of Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies (DLB), progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls. Genetic variant carrier status and clinical diagnostic category. Outcomes included clinical diagnostic accuracy, Lewy body and Alzheimer disease pathology burden, survival, association with genetic variants, and genetically inferred ancestry. Among 5648 brain donors with available genetic data, a total of 3353 eligible donors (mean [SD] age at death, 76.8 [10.6] years; 2072 male [61.8%]) were included. Misdiagnosis rates for movement disorders ranged approximately from 10% to 20%. Clinical diagnoses of dementia with parkinsonism (ie, Parkinson disease dementia and DLB) were more strongly associated with Lewy body pathology than Parkinson disease without dementia (odds ratio [OR], 1.96; 95% CI, 1.30-3.04; P = 7.2 × 10-4). Lewy pathology was identified in 33 of 745 of neurologically normal controls (4.4%). Alzheimer disease copathology was present in 426 of 1064 cases (40.0%) with Lewy body disease. Carriers of the GBA1 variant exhibited greater Lewy body burden compared with noncarriers (OR, 1.94; 95% CI, 1.24-3.03; P = .01) or carriers of the LRRK2 variant (OR, 7.44; 95% CI, 2.16-25.64; P = .01). Pathological diagnoses differed by ancestry, with South Asian donors more likely to have progressive supranuclear palsy pathology and Ashkenazi Jewish donors more likely to have Lewy body disease (χ22 = 35.5; P < .001), independent of GBA1 and LRRK2 variant status. Findings of this cross-sectional brain bank study highlight the value of integrating genetic and pathological data to improve diagnostic accuracy. The high prevalence of Alzheimer disease copathology and ancestry-associated differences in pathology point to the need for biologically informed diagnostic tools. These results suggest supporting the integration of genetically and pathologically stratified approaches, correlating pathology with in vivo biomarkers, for future therapeutic trials.
2026-04-01 | Features and advances in diagnosis and treatment of atypical Parkinson syndromes
Parkinson syndrome (PDS) is a group of neurological syndromes characterized by bradykinesia, rigidity, resting tremor, and postural instability as core manifestations, mainly including Parkinson's disease (PD), atypical Parkinson syndromes (APSs), and secondary Parkinson syndromes. APSs are a group of neurodegenerative diseases characterized by parkinsonian motor disorders as core manifestations, but they differ significantly from typical Parkinson's disease in terms of pathological mechanisms, clinical features, imaging findings, drug responses, and prognosis. They mainly include multiple system atrophy, dementia with Lewy bodies, progressive supranuclear palsy, and corticobasal degeneration. In recent years, with the continuous updating of diagnostic criteria and the in-depth research on multimodal imaging and neuropathology, the positioning of different APS subtypes in clinical phenotypes and disease spectra has gradually become clear. In terms of treatment, APSs currently still rely primarily on symptomatic and supportive therapies. New strategies, including disease-modifying therapies targeting abnormal aggregation of α-synuclein and tau protein, as well as stem cell therapy, are being explored. This article systematically reviews the clinical and imaging features, evolution of diagnostic criteria, and treatment progress of each subtype of APSs, aiming to provide a reference for early clinical identification and standardized management.
2026-03-19 | Peripheral Treg-monocyte immune signatures relate to neurodegeneration and prognosis in patients with primary tauopathies
Background: Neuroinflammation is a common hallmark of primary tauopathies, and is associated with worse clinical outcomes over time. However, accurate prognosis in these disorders remains challenging, and current fluid biomarkers provide limited insight into the contribution of peripheral immune cells to PSP/CBS pathogenesis. Our study aims to characterise blood based immune cell profiles in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), and test their associations with neurodegeneration and clinical outcomes. Methods: Peripheral blood immune cells from fresh whole blood were characterized with high dimensional mass cytometry (29 markers) in n=60 people with PSP/CBS and n=21 age and sex matched controls. Cell type abundance was defined as the ratio of counts for each gated population divided by total live cells. Hierarchical clustering of cell types and principal component analysis were used to derive data-driven immune clusters. Correlation network analysis and diffusion based network propagation integrated cell counts with plasma inflammation markers to prioritise mediators of intercellular signalling. Associations between immunological markers, plasma concentrations of neurofilament light chain (NfL), cognition, and survival were assessed using regression and Cox proportional hazards models. Results: Patients with PSP/CBS showed a global increase in covariance among immune cell populations, indicating heightened coordination within the peripheral immune network. A monocyte driven cluster (Cluster 1) showed higher scores in PSP/CBS, reflecting impaired phenotypic transition from classical to nonclassical monocytes, which was associated with higher NfL levels, poorer cognitive performance, and worse prognosis. In contrast, a Treg driven cluster (Cluster 2) showed lower scores in PSP/CBS and was associated with better cognition and longer survival. Integrated multimodal networks identified a small set of immune regulatory molecules and cytokines mediating crosstalk between Treg/Th17-like cells and monocytic populations, supporting a dysregulated Treg and monocyte axis in PSP/CBS. Conclusions: We identified peripheral blood based immunophenotypic profiles of individuals with PSP/CBS that are associated with neurodegeneration, cognitive decline, and survival. Dysregulated monocyte maturation and reduced Treg related immune configurations are enriched in patients with worse outcomes, suggesting that specific peripheral immune cell subsets may serve as fluid biomarkers and potential immunotherapy targets in primary tauopathies.
2026-01-30 | Progressive Supranuclear Palsy in India: Insights from a Large Multicenter Clinical Cohort (Project PAIR-PSP)
Abstract Background Progressive supranuclear palsy (PSP) is a rare and devastating tauopathy with limited global data. Given India’s large population, genetic diversity, and clinical heterogeneity, large multicenter datasets are crucial to enrich global understanding of PSP. Objective To characterize the demographic, clinical, and phenotypic profiles of a large multicenter Indian PSP cohort. Methods Subjects fulfilling MDS-PSP criteria were prospectively recruited across movement disorders centers (2021–2025). Standardized demographic and clinical data were collected. Results A total of 1,035 subjects were enrolled (M:F = 709:326), with a median age of 65 years and a mean onset age of 62.2±7.9 years. Regional distribution reflected pan-Indian recruitment (South 35%, North 26%, West 21%, East 18%). PSP-Richardson’s syndrome was most common (41%), followed by PSP-Parkinsonism (18%) and PSP-CBS (11%); rarer phenotypes included PSP-PI (7%), PSP-F (7%), PSP-PGF (5%), PSP-OM (2%), PSP-SL (1%), and PSP-C (1%). Falls occurred earliest in PSP-PGF (13.7 months) and PSP-SL (16.3 months), while PSP-P showed delayed disability (falls at 31 months). Cognitive onset was prominent in PSP-F (21%) and PSP-SL (57%). Levodopa was prescribed to 893 patients; 186 (21%) reported >25% subjective benefit, and 358 (40%) reported ≤25% benefit. Amantadine was used in 351 (34%) patients, with improvement in 177. Conclusion This largest systematically profiled PSP cohort highlights both shared and distinctive features: high frequency of non-RS variants, aggressive course in PSP-RS/SL, better survival in PSP-P, and limited pharmacological benefit. These findings establish a foundation for longitudinal and genetic studies in diverse populations.
2025-12-30 | Praja1 E3 ubiquitin ligase and the role it plays in neurodegeneration
Protein aggregation and transmission are hallmarks of neurodegenerative diseases. Praja1 E3 ubiquitin ligase has been shown to suppress the aggregation of causative proteins in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Parkinson's disease, Huntington's disease, and spinocerebellar degeneration, which include transactivation response DNA-binding protein of 43 kDa, fused in sarcoma, superoxide dismutase 1, α-synuclein, huntingtin, and ataxin-3. Aoki et al. demonstrated that Praja1 ubiquitinates and degrades tau, a key molecule in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal syndrome, furthering our understanding of the role of Praja1 in neurodegenerative diseases and potential therapeutic approaches.
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Drug Discovery Landscape
2 orphan drug designations for Progressive supranuclear palsy-corticobasal syndrome.
2 orphan drug designations for Progressive supranuclear palsy-corticobasal syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Izaflortaucipir (proposed INN) | small molecules | FDA | 2021-04-12 | — | Lantheus Biosciences Ltd. |
2-(2-(18F)fluoropyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine | small molecules | EMA | 2020-10-19 | — | Lantheus Germany GmbH |
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