RARE DISEASE
Progressive supranuclear palsy-predominant parkinsonism syndrome
Progressive supranuclear palsy-predominant parkinsonism syndrome
Progressive supranuclear palsy-predominant parkinsonism syndrome
Synonyms: PSP-p, PSP-parkinsonism
Synonyms: PSP-p, PSP-parkinsonism
Synonyms: PSP-p, PSP-parkinsonism
Drug discovery
0
drugs
With orphan designations
Overview
Progressive supranuclear palsy-parkinsonism predominant (PSP-P) is an atypical tauopathy variant characterized by asymmetric limb rigidity, tremor, and transient levodopa responsiveness initially resembling Parkinson's disease. It evolves into classic PSP features (vertical gaze palsy, postural instability) over 5-7 years, with neuropathology showing subthalamic nucleus and substantia nigra degeneration [6][10][17].
Burden
Survival averages 11.2 years (vs 6.8 years in PSP-RS), with aspiration pneumonia causing 50% of deaths [10][17].
Rapid functional decline: 80% require wheelchairs within 5 years; 90% develop dysphagia requiring PEG tubes [6][12].
Higher caregiver burden than Parkinson's due to earlier cognitive/behavioral changes and frequent falls [7][20].
Therapies
Limited levodopa efficacy (20-30% transient response at 500-1,200 mg/day) [7][15], combined with physical therapy for gait/balance [2][19].
Multidisciplinary care: speech therapy for dysarthria/dysphagia, prism glasses for visual deficits, antidepressants (SSRIs) for pseudobulbar affect [2][7][12].
Botulinum toxin for blepharospasm/nuchal dystonia; weighted walkers to prevent falls [2][11].
Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
86 drug discovery papers about Progressive supranuclear palsy-predominant parkinsonism syndrome. Recent publications:
86 drug discovery papers about Progressive supranuclear palsy-predominant parkinsonism syndrome. Recent publications:
categories:
Small molecules
proteins
2026-07-03 | Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women
Progressive supranuclear palsy (PSP) is a fatal tauopathy presenting an unmet medical need. Davunetide, targeting tauopathy, has been previously tested in PSP, which, when separated by sex, implied efficacy in women. Here, efficacy was evaluated using longitudinal data (52 weeks) and applying for the first time, the US Food and Drug Administration (FDA) -recommended 10-item PSP Rating Scale (PSPRS-10) compared to the 28-item PSPRS (primary endpoint). Time-, sex-, and treatment-related effects were analyzed using linear mixed-effects models including the FDA-recommended Mixed Models for Repeated Measures (MMRM). Cognitive evaluations used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Clinical analyses at the individual level accentuated the impact of the 10 PSPRS chosen items and revealed a significant treatment effect favoring women when accounting for time, sex, and treatment interactions (P = 0.0005). Motor measurements were highlighted. RBANS analyses demonstrated women's significant improvements in total raw score, letter-number sequencing, and language scores. Correlating cerebrospinal fluid (CSF) phosphorylated Tau/Tau with functional outcomes revealed significance with p-Tau/Tau ratio and grasping/imitative/utilizing behavior (assessing involuntary actions in PSPRS-28). This correlation was opposite in direction between females (r = 0.77; P = 0.006) and males (r = -0.62; P = 0.075), with sex difference showing a P = 0.0002 value. Similar results were obtained for language. Predicting the final PSPRS score (week 52), addressing all clinical measures, a clear woman-treatment-specific pattern in outcome importance was discovered, highlighting significance for the primary endpoint Schwab and England Activity of Daily Living (SEADL) scale, and stressing the necessity for sex-specific medicine with davunetide as a lead compound.
2026-03-08 | GV1001 reduces pathological 4R tau and functional deficits in models relevant to progressive supranuclear palsy
GV1001, a peptide drug derived from human telomerase reverse transcriptase, has showed the therapeutic effect in the animal model of Alzheimer’s disease (AD), a representative chronic neurodegenerative disease having impaired learning and memory. In our previous studies, GV1001 has showed the multi-functions including anti-apoptosis, anti-oxidative stress, and anti-neuroinflammation in AD-related in vitro and in vivo systems. Here, in addition to these previously reported functions, GV1001 was discovered to reduce the protein level of 4R tau isoform in the pathological condition. There is no studies providing the potential of GV1001 as a therapeutic drug for neurodegenerative movement disorders. Progressive supranuclear palsy (PSP) is a rare atypical Parkinsonism in the midbrain region, leading to more severe motor symptoms and very rapid pathological progression. Increased 4R tau isoform in an affected brain region of the primary 4R tauopathy is a distinct pathological character in PSP patients. In this study, GV1001 down-regulated the protein level of 4R tau specifically in an annonacin-induced PSP in vitro neuronal model as well as in vivo study using 4R TauP301L-BiFC mouse model. These findings suggest a novel role of GV1001 in 4R tauopathy and support its disease-modifying potential within the context of 4R tau–driven neurodegenerative models, including PSP.
2024-12-01 | Exploring the Therapeutic Role of Rab8a in 4R‐Tauopathy
Abstract Background Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are characterized by abnormal aggregation and deposition of tau proteins in neurons and supporting brain cells. The underlying pathophysiology of these 4R‐tauopathy disorders remains unclear. In Alzheimer’s disease (AD), a related tauopathy, vesicle trafficking deficits, and impaired protein clearance are observed early in disease progression. Rab GTPase proteins play an important role in vesicular trafficking, endocytosis, and endosomal‐lysosomal pathways and have been implicated in Parkinson’s disease (PD) and AD pathology. In AD, the normal function of specific Rab proteins is disrupted early and may contribute to abnormal tau accumulation and neurofibrillary tangle formation. Among various Rabs GTPases, Rab8a’s role in AD pathology is explored and shown to accelerate endocytosed Aβ trafficking to the lysosomes and has expression found to decrease in PS1 mutant expressing cells. In contrast, Rab proteins, including Rab8a, and their contribution to 4R tauopathies such as PSP and CBD are little known. Method In the postmortem tissues from AD, PSP, and CBD, Rab8a protein expression was determined using western blot analysis. Further, human neuroglioma H4 cells were co‐transfected with wild‐type or mutant Rab8a and 4R0N or self‐aggregating mutant tau[P301L/S320F]. Result In H4 cells, overexpression of Rab8a resulted in a marked reduction of total and phospho‐tau. The reduction in total and p‐tau was not observed with mutant (non‐functional) Rab8a overexpression. The Rab8a protein expression was found to be decreased in postmortem brain tissues (frontal cortex) from PSP and CBD compared to control tissue. Conclusion The study demonstrates the Rab GTPase, Rab8a, expression in neuropathological tissues from 4R‐tauopathy disorders (PSP and CBD) and AD. In addition, the study provides evidence that Rab8a may regulate tau and associated pathology.
2024-02-02 | The significance of glial cell line-derived neurotrophic factor analysis in Progressive Supranuclear Palsy
Abstract Progressive Supranuclear Palsy (PSP) is an atypical parkinsonism. Major subtypes of the disease: PSP-Richardson’s Syndrome (PSP-RS) and PSP Parkinsonism Predominant (PSP-P) vary in clinical features, the pathomechanism remains unexplored. The aim of this work is to analyze the relevance of glial cell line-derived neurotrophic factor (GDNF) evaluation in the serum and cerebrospinal fluid (CSF) in PSP subtypes and to verify its significance as a possible factor in the in vivo examination. Authors assessed the concentration of GDNF in the serum and CSF of 12 patients with PSP-RS, 12 with PSP-P and 12 controls. Additionally authors evaluated patients using Unified Parkinson’s Disease Rating Scale—III part (UPDRS-III), Frontal Assessment Battery (FAB) and Magnetic Resonance Imaging (MRI). The evaluation revealed significantly increased concentrations of GDNF in the CSF among PSP-RS patients and substantially increased concentrations of GDNF in the serum in PSP-P. Though the GDNF concentrations differentiated PSP subtypes, no correlations between with clinical factors were observed however certain correlations with atrophic changes in MRI were detected. GDNF is a factor which may impact the pathogenesis of PSP. Possible implementation of GDNF as a therapeutic factor could be a perspective in the search for therapy in this currently incurable disease.
2023-10-16 | Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women
Abstract Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in a 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences in brain ventricular volumes, a secondary endpoint. Dramatic baseline ventricular volume-dependent/volume increase correlations were observed in 52-week-placebo-treated females ( r = 0.74, P = 2.36 –9 ), whereas davunetide-treated females (like males) revealed no such effects. Assessment of primary endpoints, by the PSP Rating Scale (PSPRS) and markedly more so by the Schwab and England Activities of Daily Living (SEADL) scale, showed significantly faster deterioration in females, starting at trial week 13 ( P = 0.01, and correlating with most other endpoints by week 52). Twice daily davunetide treatments slowed female disease progression and revealed significant protection according to the SEADL scale as early as at 39 weeks ( P = 0.008), as well as protection of the bulbar and limb motor domains considered by the PSPRS, including speaking and swallowing difficulties caused by brain damage, and deterioration of fine motor skills, respectably ( P = 0.01), at 52 weeks. Furthermore, at 52 weeks of trial, the exploratory Geriatric Depression Scale (GDS) significantly correlated with the SEADL scale deterioration in the female placebo group and demonstrated davunetide-mediated protection of females. Female-specific davunetide-mediated protection of ventricular volume corresponded to clinical efficacy. Together with the significantly slower disease progression seen in men, the results reveal sex-based drug efficacy differences, demonstrating the neuroprotective and disease-modifying impact of davunetide treatment for female PSP patients.
small molecules
2026-04-15 | Biomarkers of Leucine‐Rich Repeat Kinase 2 ( LRRK2) and Lysosomal Dysfunction in Progressive Supranuclear Palsy
Abstract Background Common and rare genetic variants in leucine‐rich repeat kinase 2 (LRRK2) have been linked with sporadic and familial Parkinson's disease (PD). Recently, we discovered that common genetic variation near the LRRK2 locus determined survival in progressive supranuclear palsy (PSP). Our study aimed to explore biomarkers of LRRK2 and lysosomal dysfunction in PSP. Methods Immunoblotting was used to measure total LRRK2 and LRRK2‐dependent Rab10 phosphorylation at the threonine 73 residue (pRab10 Thr73 ) in neutrophil and monocyte samples from PSP and control participants. Urine samples were applied to a multiplexed assay to quantitate bis(monoacylglycerol)phosphate (BMP) species as markers of lysosomal dysfunction. Cerebrospinal fluid (CSF) samples from a wider cohort of PSP and control participants were applied to a stable isotope standards and capture by anti‐peptide antibodies assay to measure total LRRK2 and pRab10 Thr73 levels. LRRK2 genotypes (rs76904798 and rs2242367) and 1‐year change in Progressive Supranuclear Palsy Rating Scale (PSPRS) scores were obtained. Results A total of 61 PSP and 34 control participants were included. Total urine 22:6‐BMP levels were higher in PSP versus control samples ( P = 0.04) and correlated with CSF total LRRK2 levels ( r = 0.49, P = 0.04). There were no group‐level differences in monocyte and CSF levels of total LRRK2 and pRab10 Thr73 . In PSP, carriers of the alternate allele (CT and TT genotypes) at the LRRK2 PD risk variant, rs76904798, had higher levels of CSF total LRRK2 versus CC genotype ( P = 0.02). Baseline monocyte total LRRK2 levels predicted 1‐year change in the PSPRS score ( P = 0.008). Conclusions Biochemically defined lysosomal dysfunction is evident in PSP. Genetic and biochemical stratification may identify PSP patients that would benefit from LRRK2‐targeting therapies. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2026-01-22 | Subtracting First Principal Component May Improve 4R Tau Detectability on [ 18 F]Flortaucipir Tau PET
[18F]flortaucipir PET imaging has shown relatively low sensitivity for detecting four-repeat (4R) tau, which limits its utility in 4R tauopathies such as progressive supranuclear palsy (PSP). Previous studies have suggested that the first component of principal-component analysis includes non-disease-related uptake in non-Alzheimer tauopathies. In this study, we tested the hypothesis that subtracting this component could increase sensitivity to 4R tau using a large PSP cohort. Methods: Prospectively recruited patients with PSP (n = 141; 80 Richardson syndrome, 44 PSP-subcortical, and 17 PSP-cortical variants) and controls (n = 102) underwent [18F]flortaucipir PET. The first principal component (PC1) was extracted from the SUV ratio (SUVR) images of 62 controls and then subtracted from the remaining controls (n = 40) and all PSP patients. We compared the diagnostic performance before and after PC1 subtraction by evaluating SUVR differences between PSP and controls, as well as across PSP clinical variants, and by calculating correlation coefficients between SUVR and the severity of tau pathology. Results: Area under the receiver operating characteristic curves differentiating PSP and controls were improved by PC1 subtraction in the frontal white matter (0.54 to 0.67; P = 0.002) and subcortical (0.69 to 0.87; P < 0.001) regions. In the frontal regions, no differences were observed across PSP clinical variants before PC1 subtraction, whereas the PSP-cortical variant showed an SUVR higher than that of the PSP Richardson syndrome and PSP-subcortical variants after PC1 subtraction (adjusted P < 0.05). A correlation with the severity of tau pathology was observed only in the red nucleus before PC1 subtraction, whereas correlations were observed in the precentral, superior frontal gyrus, and red nucleus after PC1 subtraction (adjusted P < 0.05). Conclusion: Our approach enhanced the diagnostic performance of [18F]flortaucipir PET in PSP and increased sensitivity to 4R tau, suggesting that subtracting the first principal component improves the detectability of subtle 4R tau uptake and the potential utility of [18F]flortaucipir PET imaging for non-Alzheimer tauopathies.
2025-12-22 | 18F-FDG, 18F-FP-CIT, and 18F-Florzolotau PET Imaging in Progressive Supranuclear Palsy
PURPOSE: Imaging protocols for progressive supranuclear palsy (PSP) are increasingly incorporating different PET modalities-including 18 F-fluorodeoxyglucose ( 18 F-FDG; cerebral glucose metabolism), 18 F-FP-CIT (dopamine transporter [DAT] activity), and 18 F-Florzolotau (tau pathology) PET-to improve diagnostic accuracy. In this cross-sectional study, we characterized tracer-specific imaging patterns and evaluated their interrelationships in patients with PSP to clarify the underlying pathophysiological mechanisms. MATERIALS AND METHODS: Twenty-eight patients with clinically diagnosed PSP underwent 18 F-FDG, 18 F-FP-CIT, and 18 F-Florzolotau PET imaging. Quantitative voxel-based and region-of-interest analyses were conducted. Standardized uptake value ratios (SUVRs) were calculated and compared with sex-matched controls (n=20 per PET modality). RESULTS: In patients with PSP compared with controls, 18 F-FDG PET revealed significant glucose hypometabolism in frontal, parietal, cerebellar, and subcortical regions. 18 F-FP-CIT PET demonstrated reduced DAT availability in the striatum and midbrain. Finally, 18 F-Florzolotau PET showed elevated tau deposition in the thalamus, midbrain, pons, and precentral gyrus. An inverse correlation linked midbrain tau burden with local glucose metabolism ( r =-0.39, P =0.04). Frontal hypometabolism correlated strongly with subcortical metabolic deficits ( r =0.61, P <0.001). Only the left putamen showed a moderate negative association between DAT loss and tau accumulation ( r =-0.42, P =0.03). CONCLUSIONS: Patients with PSP exhibit metabolic deficits in cortical-subcortical networks, dopaminergic denervation in striatal-midbrain regions, and tau pathology localized to brainstem and thalamic areas. Tracer-specific SUVRs correlations revealed specific interplay among glucose hypometabolism, DAT deficiency, and tau accumulation.
2025-12-17 | Inflammatory and Neurotrophic Factors and Their Connection to Quality of Life in Progressive Supranuclear Palsy—Single-Center Study
Progressive supranuclear palsy (PSP) is a condition classified as atypical parkinsonism. Pathologically, it is a four-repeat tauopathy; clinically, it is a disease comprising oculomotor dysfunction, postural instability, akinesia, and cognitive/language disorders. Its pathogenesis is not fully recognized; however, neuroinflammation is considered to likely be a significant aspect, though it is not known whether inflammation is a cause or consequence of neurodegeneration. In this study, the authors analyzed the association between inflammatory/neurotrophic factors and parameters linked to quality of life, based on examinations of 10 controls and 11 patients with PSP. They found a negative correlation between mPSPRS (Modified Progressive Supranuclear Palsy Rating Scale) and the glial cell-line-derived neurotrophic factor levels (GDNF) (r = −0.772727, p = 0.003) in the serum, a less pronounced negative correlation between progressive supranuclear palsy–quality of life parameter (PSP-QoL) and GDNF (r = −0.68390, p = 0.011) in the serum, and no correlations were observed in the analyses of inflammatory factors. The obtained results show the association between lower levels of GDNF and more pronounced clinical deterioration. Further analysis in the field based on larger groups of patients is required.
2025-12-01 | Biomarkers of LRRK2 and lysosomal dysfunction in Progressive Supranuclear Palsy
Abstract Background Common and rare genetic variants in LRRK2 have been linked with sporadic and familial Parkinson’s disease (PD). Recently, we discovered that common genetic variation near the LRRK2 locus determined survival in progressive supranuclear palsy (PSP). Our study aimed to explore biomarkers of LRRK2 and lysosomal dysfunction in PSP. Methods Immunoblotting was used to measure total LRRK2 and LRRK2-dependent Rab10 phosphorylation at Threonine73 (pRab10 Thr73 ) in neutrophil and monocyte samples from PSP and control participants. Urine samples were applied to a multiplexed assay to quantitate bis(monoacylglycerol)phosphate (BMP) species as markers of lysosomal dysfunction. CSF samples from a wider cohort of PSP and control participants were applied to a stable isotope standards and capture by anti-peptide antibodies assay to measure total LRRK2 and pRab10 Thr73 levels. LRRK2 genotypes (rs76904798 and rs2242367) and 1-year change in PSP rating scale scores were obtained. Results 61 PSP and 34 control participants were included. Total urine 22:6-BMP levels were higher in PSP vs. control samples (p=0.04) and correlated with CSF total LRRK2 levels (r=0.49, p=0.04). In PSP, carriers of the alternate allele (CT and TT genotypes) at the LRRK2 PD risk variant, rs76904798, had higher levels of CSF total LRRK2 vs. CC genotype (p=0.02). A similar but non-significant trend was observed for the LRRK2 PSP survival variant, rs2242367 (p=0.08). Baseline monocyte total LRRK2 levels predicted 1-year change in the PSP rating scale score (p=0.008). Conclusions Biochemically defined lysosomal dysfunction is evident in PSP. Genetic and biochemical stratification may identify PSP patients that would benefit from LRRK2-targetting therapies.
cell therapies
2026-03-17 | Natural Killer Subset Changes and Vascular Endothelial Growth Factor‐A Plasma Profile in Progressive Supranuclear Palsy: The NKscape Study
These findings identify a potentially disease-specific transcriptional signature with repercussions on the cyto-chemokine plasma profile. Further investigation of the NK cell-mediated immune response in PSP may provide new insights into disease mechanisms and open avenues for immunomodulatory therapeutic strategies. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2025-07-21 | Neuroinflammation distinguishes HLA haplotypes in progressive supranuclear palsy
Objectives: Progressive supranuclear palsy (PSP) is a neurodegenerative 4R tauopathy clinically presenting with atypical parkinsonism or cognitive behavioral changes and a relatively uniform neuropathology. We recently identified rare HLA haplotypes in PSP and now examine whether HLA haplotypes are associated with different cytopathological and clinical phenotypes. Methods: Retrospective collection of clinical data and mapping of T and B cells, microglia, and phosphorylated-tau (p-Tau) cytopathologies in 32 PSP cases. Machine learning was used to analyze whether pathological variables and their ratios, or the sequence of clinical symptoms cluster or predict HLA haplotypes. Results: Four groups were defined based on HLA haplotypes: i) 12 cases with the haplotype associated with narcolepsy (DRB1*15:01-DQB1*06:02); ii) 11 cases with other DQ5-DQ6 haplotypes; iii) 8 cases with various haplotypes frequent in the general population; and iv) one case with the haplotype frequent in IgLON5-disease (DRB1*10:01-DQB1*05:01). Neuropathology revealed regional differences in the severity of microglia load, density of cytotoxic T cells, and p-Tau cytopathologies between groups. HLA haplotypes were most distinguishable using machine learned features of inflammatory markers and ratios of neuropathological variables (clustering accuracy: 86.96% and 91.30%, respectively). The sequence of clinical symptoms and the ratios of neuropathological variables were the strongest predictors of HLA haplotypes (prediction accuracy=80.00% and 71.43%, respectively). Interpretation: PSP pathology might be associated with various etiological-pathogenic events including targetable autoimmune mechanisms. The HLA-haplotype dependent diversity of neuroinflammatory markers should be evaluated in clinical and biomarker studies in, and beyond, PSP to understand its relevance for patient stratification in disease modifying therapy trials.
2021-10-12 | Safety and Effectiveness of Cell Therapy in Neurodegenerative Diseases: Take-Home Messages From a Pilot Feasibility Phase I Study of Progressive Supranuclear Palsy
Mesenchymal stromal cells (MSCs) are multipotent cells with anti-inflammatory properties. Here we tested the safety of MSCs in patients with progressive supranuclear palsy (PSP; ClinicalTrials.gov: NCT01824121; Eudract No. 2011-004051-39). Seven patients were treated. To improve the safety, protocol adjustments were made during the performance of the study. The objectives of our work were: (1) to assess the safety of MSCs and (2) to identify critical issues in cell therapies for neurodegenerative diseases. Autologous MSCs from the bone marrow of PSP patients were administered through the internal carotid arteries. 1-year survival and number of severe adverse events were considered as safety endpoints. Clinical rating scales, neuropsychological assessments, gait and posture analysis, single-photon emission computed tomography, positron emission tomography, and brain magnetic resonance (BMR) were performed at different follow-up times. Peripheral blood levels of inflammatory cytokines were measured before and after cell infusion. Six of the seven treated patients were living 1 year after cell infusion. Asymptomatic spotty lesions were observed at BMR after 24 h in six of the seven treated patients. The last patient in the preliminary cohort (Case 5) exhibited transiently symptomatic BMR ischemic alterations. No severe adverse events were recorded in the last two treated patients. Interleukin-8 serum concentrations decreased in three patients (Case 2, 3, and 4). An adaptive study design, appropriate and up-to-date efficacy measures, adequate sample size estimation, and, possibly, the use of a cellular and/or allogeneic cell sources may help in performing phase II trials in the field.
antibodies
2025-10-01 | Neuronal-specific antibody in patients with multiple system atrophy and progressive supranuclear palsy
Anti-neuronal antibodies can manifest with diverse movement disorders, including parkinsonism and ataxia, and may mimic neurodegeneration. The prevalence of neuronal-specific antibodies in atypical parkinsonism remains unclear. We examined 166 patients, including 136 patients with clinically diagnosed progressive supranuclear palsy (PSP) and 30 patients with multiple system atrophy (MSA) from the Taiwan PSP/CBS Consortium using an integrated set of tissue-based immunofluorescence assays and a subsequent fixed cell-based assay as well as confirmatory tests to detect neuronal-specific antibodies. We observed one PSP-Richardson syndrome patient (0.74 %) was CASPR2-IgG positive, and one MSA-cerebellar subtype patient (3.33 %) showed GAD65 positivity with a hot-cross bun sign on MRI. The latter showed clinical improvement after immunotherapy. Neither patient had sleep-related symptoms. These findings indicate that neuronal-specific antibodies may mimic MSA or PSP and warrant antibody testing in atypical parkinsonism to identify reversible autoimmune causes.
2025-07-01 | C3 and C3a as indicators of complement dysregulation in tauopathies and FTLD-associated disorders
Dementia encompasses a range of neurodegenerative diseases (NDDs) presenting with progressive decline in memory, cognition, language and ability to complete daily tasks. Whilst Alzheimer’s disease (AD) is the most common form of dementia, less prevalent subtypes include frontotemporal lobar degenerative associated disorders (FTLD) frontotemporal dementia (FTD), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). FTLD are NDDs characterised by progressive atrophy and neuronal loss in brain frontal and temporal lobes, predominately affecting behaviour, language and cognition. Of these, FTLD, CBS and PSP are primary tauopathies, pathologically classified by predominant accumulation of aggregates of tau, a microtubule-associated protein responsible for mediating intracellular transport and structure. Some FTD subtypes, such as Pick’s disease, are also defined by tau pathology. Although complement dysregulation is broadly accepted as a feature of AD, this has not been convincingly shown in tauopathies and FTLD. Here we measured a panel of complement biomarkers in serum from FTLD and tauopathy cases and compared these with non-demented matched controls (HC). In-house ELISAs were used to quantify twelve complement analytes, comprising activation products (C3a, iC3b, TCC), regulators (Factor H (FH), Properdin, Clusterin) and components (C1q, C3, FB, C5, C7, C9) in serum samples. Samples were matched for age and sex from FTLDs: CBS (n = 16), FTD (n = 57), PSP (n = 42), healthy controls (HC; n = 41). Compared to HC, C3, C3a and properdin were elevated in FTLD (p = 0.0002, p = 0.0187, p = 0.0451 respectively). Other complement analytes were not significantly different between FTLD and HC samples. Subgroup analysis demonstrated significantly higher C3 and C3a compared to HC in FTD (p < 0.00001 and p = 0.0455 respectively) and PSP (p = 0.0051 and p = 0.0179 respectively) but not CBS, while properdin was significantly increased only in FTD cases (p = 0.0097). The data demonstrates a degree of complement dysregulation in tauopathies and FTLD across the different disease subtypes with C3, C3a and properdin levels significantly different to matched controls. These findings suggest dysregulation in the alternative pathway and lead us to suggest that complement dysregulation represents a potential therapeutic target for FTLD and tauopathies.
2025-05-13 | The Role of Tau in Neuronal Function and Neurodegeneration
Tau protein plays a pivotal role in maintaining neuronal structure and function through its regulation of microtubule stability and neuronal polarity. Encoded by the MAPT gene, Tau exists in multiple isoforms due to alternative mRNA splicing, with differential expression in the central and peripheral nervous systems. In healthy neurons, tau mRNA is selectively localized and translated in axons, a process tightly regulated by untranslated regions (UTRs) and RNA-binding proteins such as HuD and FMRP. Pathologically, Tau undergoes hyperphosphorylation, misfolding, and aggregation, which contribute to neurodegeneration in a range of disorders collectively known as tauopathies. Alzheimer's disease (AD) is the most prevalent tauopathy, where abnormal Tau accumulation in the temporal and frontal lobes correlates with cognitive decline and behavioral symptoms. Other tauopathies, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Frontotemporal Dementia with Parkinsonism (FTDP-17), and Pick's disease, are distinguished by the predominance of specific Tau isoforms (3R or 4R), cellular distribution, and affected brain regions. Notably, astroglial tauopathies highlight the pathological role of Tau accumulation in glial cells, expanding the understanding of neurodegeneration beyond neurons. Despite advances in imaging biomarkers (e.g., Tau-PET) and molecular diagnostics, effective disease-modifying therapies for tauopathies remain elusive. Ongoing research targets Tau through immunotherapies, splicing modulators, kinase inhibitors, and antisense oligonucleotides, aiming to mitigate Tau pathology and its deleterious effects. Understanding the multifaceted roles of Tau in neuronal and glial contexts is critical for developing future therapeutic strategies against tauopathies.
2025-01-19 | Investigation of the HLA locus in autopsy-confirmed progressive supranuclear palsy
ABSTRACT Objectives Progressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen ( HLA ) locus on chromosome 6 is a polymorphic region with complex linkage patterns that has been implicated in several autoimmune and neurological disorders. The HLA locus has not been systematically examined in PSP. It is unclear whether tau and HLA can interact to induce an autoimmune disease mechanism. Methods We evaluated an autopsy confirmed PSP cohort (n=44) and compared allele/haplotype frequencies to those of the reference group of a local deceased Canadian donor pool. We performed HLA/Tau peptide binding prediction and modelling of HLA Class II and Tau Peptide interactions. Findings Odds ratio was 2.94 (95% CI 1.01 to 8.55; p=0.047) for DQB1 *06:01 allele, and 2.59 (95% CI 1.39 to 4.83; p=0.0025) for the narcolepsy associated haplotype ( DRB1 *15:01 DQB1 *06:02). One patient with 4 repeat tau PSP type pathology was a carrier of the IgLON5-associated haplotype ( DRB1 *10:01 DQB1 *05:01). HLA/Tau peptide binding prediction and modelling of HLA Class II/Tau Peptide interactions revealed strong binding tau peptides but not the PSP protofilament fold for alleles DQA1* 01:02DQB1* 06:02 and DQA1* 01:03DQB1* 06:01. Conclusion Our study suggests that epitopes within the tau peptide may bind to HLA alleles that are found in a subset of PSP patients supporting the notion of an autoimmune pathophysiological component. These findings have implications for subtyping and stratifying patients for therapies, including those targeting immune modulation.
2024-08-29 | Long-standing preservation of levodopa response in progressive supranuclear palsy
The clinical and neuropathological characteristics of progressive supranuclear palsy (PSP) with preservation of levodopa (L-dopa) response are described in this report. We present the case of a 73-year-old Japanese man with a 13-year history of dopa-responsive Parkinsonism and abnormalities observed in metaiodobenzylguanidine (MIBG) myocardial scintigraphy, suggesting Parkinson's disease. However, autopsy results revealed PSP pathology, including tuft-shaped astrocytes and globose-type neurofibrillary tangles, without Lewy body pathology. The degeneration was moderately to severely distributed in the globus pallidus, subthalamic nucleus, and substantia nigra, whereas striatal degeneration was mild. These findings suggest an intact response to L-dopa therapy throughout the patient's lifetime. Pathological examination of cardiac sympathetic nerves revealed intact nerves, suggesting functional involvement in the MIBG abnormality. This study provides further evidence of the clinical and pathological heterogeneity of PSP. Homozygosity for both the rs564309-C allele at TRIM11 and the rs2242367-G allele at SLC2A13 might have played a protective role. This case indicates a protracted course-PSP, which may hold promise for future treatments.
proteins
2026-07-03 | Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women
Progressive supranuclear palsy (PSP) is a fatal tauopathy presenting an unmet medical need. Davunetide, targeting tauopathy, has been previously tested in PSP, which, when separated by sex, implied efficacy in women. Here, efficacy was evaluated using longitudinal data (52 weeks) and applying for the first time, the US Food and Drug Administration (FDA) -recommended 10-item PSP Rating Scale (PSPRS-10) compared to the 28-item PSPRS (primary endpoint). Time-, sex-, and treatment-related effects were analyzed using linear mixed-effects models including the FDA-recommended Mixed Models for Repeated Measures (MMRM). Cognitive evaluations used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Clinical analyses at the individual level accentuated the impact of the 10 PSPRS chosen items and revealed a significant treatment effect favoring women when accounting for time, sex, and treatment interactions (P = 0.0005). Motor measurements were highlighted. RBANS analyses demonstrated women's significant improvements in total raw score, letter-number sequencing, and language scores. Correlating cerebrospinal fluid (CSF) phosphorylated Tau/Tau with functional outcomes revealed significance with p-Tau/Tau ratio and grasping/imitative/utilizing behavior (assessing involuntary actions in PSPRS-28). This correlation was opposite in direction between females (r = 0.77; P = 0.006) and males (r = -0.62; P = 0.075), with sex difference showing a P = 0.0002 value. Similar results were obtained for language. Predicting the final PSPRS score (week 52), addressing all clinical measures, a clear woman-treatment-specific pattern in outcome importance was discovered, highlighting significance for the primary endpoint Schwab and England Activity of Daily Living (SEADL) scale, and stressing the necessity for sex-specific medicine with davunetide as a lead compound.
2026-03-08 | GV1001 reduces pathological 4R tau and functional deficits in models relevant to progressive supranuclear palsy
GV1001, a peptide drug derived from human telomerase reverse transcriptase, has showed the therapeutic effect in the animal model of Alzheimer’s disease (AD), a representative chronic neurodegenerative disease having impaired learning and memory. In our previous studies, GV1001 has showed the multi-functions including anti-apoptosis, anti-oxidative stress, and anti-neuroinflammation in AD-related in vitro and in vivo systems. Here, in addition to these previously reported functions, GV1001 was discovered to reduce the protein level of 4R tau isoform in the pathological condition. There is no studies providing the potential of GV1001 as a therapeutic drug for neurodegenerative movement disorders. Progressive supranuclear palsy (PSP) is a rare atypical Parkinsonism in the midbrain region, leading to more severe motor symptoms and very rapid pathological progression. Increased 4R tau isoform in an affected brain region of the primary 4R tauopathy is a distinct pathological character in PSP patients. In this study, GV1001 down-regulated the protein level of 4R tau specifically in an annonacin-induced PSP in vitro neuronal model as well as in vivo study using 4R TauP301L-BiFC mouse model. These findings suggest a novel role of GV1001 in 4R tauopathy and support its disease-modifying potential within the context of 4R tau–driven neurodegenerative models, including PSP.
2024-12-01 | Exploring the Therapeutic Role of Rab8a in 4R‐Tauopathy
Abstract Background Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are characterized by abnormal aggregation and deposition of tau proteins in neurons and supporting brain cells. The underlying pathophysiology of these 4R‐tauopathy disorders remains unclear. In Alzheimer’s disease (AD), a related tauopathy, vesicle trafficking deficits, and impaired protein clearance are observed early in disease progression. Rab GTPase proteins play an important role in vesicular trafficking, endocytosis, and endosomal‐lysosomal pathways and have been implicated in Parkinson’s disease (PD) and AD pathology. In AD, the normal function of specific Rab proteins is disrupted early and may contribute to abnormal tau accumulation and neurofibrillary tangle formation. Among various Rabs GTPases, Rab8a’s role in AD pathology is explored and shown to accelerate endocytosed Aβ trafficking to the lysosomes and has expression found to decrease in PS1 mutant expressing cells. In contrast, Rab proteins, including Rab8a, and their contribution to 4R tauopathies such as PSP and CBD are little known. Method In the postmortem tissues from AD, PSP, and CBD, Rab8a protein expression was determined using western blot analysis. Further, human neuroglioma H4 cells were co‐transfected with wild‐type or mutant Rab8a and 4R0N or self‐aggregating mutant tau[P301L/S320F]. Result In H4 cells, overexpression of Rab8a resulted in a marked reduction of total and phospho‐tau. The reduction in total and p‐tau was not observed with mutant (non‐functional) Rab8a overexpression. The Rab8a protein expression was found to be decreased in postmortem brain tissues (frontal cortex) from PSP and CBD compared to control tissue. Conclusion The study demonstrates the Rab GTPase, Rab8a, expression in neuropathological tissues from 4R‐tauopathy disorders (PSP and CBD) and AD. In addition, the study provides evidence that Rab8a may regulate tau and associated pathology.
2024-02-02 | The significance of glial cell line-derived neurotrophic factor analysis in Progressive Supranuclear Palsy
Abstract Progressive Supranuclear Palsy (PSP) is an atypical parkinsonism. Major subtypes of the disease: PSP-Richardson’s Syndrome (PSP-RS) and PSP Parkinsonism Predominant (PSP-P) vary in clinical features, the pathomechanism remains unexplored. The aim of this work is to analyze the relevance of glial cell line-derived neurotrophic factor (GDNF) evaluation in the serum and cerebrospinal fluid (CSF) in PSP subtypes and to verify its significance as a possible factor in the in vivo examination. Authors assessed the concentration of GDNF in the serum and CSF of 12 patients with PSP-RS, 12 with PSP-P and 12 controls. Additionally authors evaluated patients using Unified Parkinson’s Disease Rating Scale—III part (UPDRS-III), Frontal Assessment Battery (FAB) and Magnetic Resonance Imaging (MRI). The evaluation revealed significantly increased concentrations of GDNF in the CSF among PSP-RS patients and substantially increased concentrations of GDNF in the serum in PSP-P. Though the GDNF concentrations differentiated PSP subtypes, no correlations between with clinical factors were observed however certain correlations with atrophic changes in MRI were detected. GDNF is a factor which may impact the pathogenesis of PSP. Possible implementation of GDNF as a therapeutic factor could be a perspective in the search for therapy in this currently incurable disease.
2023-10-16 | Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women
Abstract Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in a 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences in brain ventricular volumes, a secondary endpoint. Dramatic baseline ventricular volume-dependent/volume increase correlations were observed in 52-week-placebo-treated females ( r = 0.74, P = 2.36 –9 ), whereas davunetide-treated females (like males) revealed no such effects. Assessment of primary endpoints, by the PSP Rating Scale (PSPRS) and markedly more so by the Schwab and England Activities of Daily Living (SEADL) scale, showed significantly faster deterioration in females, starting at trial week 13 ( P = 0.01, and correlating with most other endpoints by week 52). Twice daily davunetide treatments slowed female disease progression and revealed significant protection according to the SEADL scale as early as at 39 weeks ( P = 0.008), as well as protection of the bulbar and limb motor domains considered by the PSPRS, including speaking and swallowing difficulties caused by brain damage, and deterioration of fine motor skills, respectably ( P = 0.01), at 52 weeks. Furthermore, at 52 weeks of trial, the exploratory Geriatric Depression Scale (GDS) significantly correlated with the SEADL scale deterioration in the female placebo group and demonstrated davunetide-mediated protection of females. Female-specific davunetide-mediated protection of ventricular volume corresponded to clinical efficacy. Together with the significantly slower disease progression seen in men, the results reveal sex-based drug efficacy differences, demonstrating the neuroprotective and disease-modifying impact of davunetide treatment for female PSP patients.
small molecules
2026-04-15 | Biomarkers of Leucine‐Rich Repeat Kinase 2 ( LRRK2) and Lysosomal Dysfunction in Progressive Supranuclear Palsy
Abstract Background Common and rare genetic variants in leucine‐rich repeat kinase 2 (LRRK2) have been linked with sporadic and familial Parkinson's disease (PD). Recently, we discovered that common genetic variation near the LRRK2 locus determined survival in progressive supranuclear palsy (PSP). Our study aimed to explore biomarkers of LRRK2 and lysosomal dysfunction in PSP. Methods Immunoblotting was used to measure total LRRK2 and LRRK2‐dependent Rab10 phosphorylation at the threonine 73 residue (pRab10 Thr73 ) in neutrophil and monocyte samples from PSP and control participants. Urine samples were applied to a multiplexed assay to quantitate bis(monoacylglycerol)phosphate (BMP) species as markers of lysosomal dysfunction. Cerebrospinal fluid (CSF) samples from a wider cohort of PSP and control participants were applied to a stable isotope standards and capture by anti‐peptide antibodies assay to measure total LRRK2 and pRab10 Thr73 levels. LRRK2 genotypes (rs76904798 and rs2242367) and 1‐year change in Progressive Supranuclear Palsy Rating Scale (PSPRS) scores were obtained. Results A total of 61 PSP and 34 control participants were included. Total urine 22:6‐BMP levels were higher in PSP versus control samples ( P = 0.04) and correlated with CSF total LRRK2 levels ( r = 0.49, P = 0.04). There were no group‐level differences in monocyte and CSF levels of total LRRK2 and pRab10 Thr73 . In PSP, carriers of the alternate allele (CT and TT genotypes) at the LRRK2 PD risk variant, rs76904798, had higher levels of CSF total LRRK2 versus CC genotype ( P = 0.02). Baseline monocyte total LRRK2 levels predicted 1‐year change in the PSPRS score ( P = 0.008). Conclusions Biochemically defined lysosomal dysfunction is evident in PSP. Genetic and biochemical stratification may identify PSP patients that would benefit from LRRK2‐targeting therapies. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2026-01-22 | Subtracting First Principal Component May Improve 4R Tau Detectability on [ 18 F]Flortaucipir Tau PET
[18F]flortaucipir PET imaging has shown relatively low sensitivity for detecting four-repeat (4R) tau, which limits its utility in 4R tauopathies such as progressive supranuclear palsy (PSP). Previous studies have suggested that the first component of principal-component analysis includes non-disease-related uptake in non-Alzheimer tauopathies. In this study, we tested the hypothesis that subtracting this component could increase sensitivity to 4R tau using a large PSP cohort. Methods: Prospectively recruited patients with PSP (n = 141; 80 Richardson syndrome, 44 PSP-subcortical, and 17 PSP-cortical variants) and controls (n = 102) underwent [18F]flortaucipir PET. The first principal component (PC1) was extracted from the SUV ratio (SUVR) images of 62 controls and then subtracted from the remaining controls (n = 40) and all PSP patients. We compared the diagnostic performance before and after PC1 subtraction by evaluating SUVR differences between PSP and controls, as well as across PSP clinical variants, and by calculating correlation coefficients between SUVR and the severity of tau pathology. Results: Area under the receiver operating characteristic curves differentiating PSP and controls were improved by PC1 subtraction in the frontal white matter (0.54 to 0.67; P = 0.002) and subcortical (0.69 to 0.87; P < 0.001) regions. In the frontal regions, no differences were observed across PSP clinical variants before PC1 subtraction, whereas the PSP-cortical variant showed an SUVR higher than that of the PSP Richardson syndrome and PSP-subcortical variants after PC1 subtraction (adjusted P < 0.05). A correlation with the severity of tau pathology was observed only in the red nucleus before PC1 subtraction, whereas correlations were observed in the precentral, superior frontal gyrus, and red nucleus after PC1 subtraction (adjusted P < 0.05). Conclusion: Our approach enhanced the diagnostic performance of [18F]flortaucipir PET in PSP and increased sensitivity to 4R tau, suggesting that subtracting the first principal component improves the detectability of subtle 4R tau uptake and the potential utility of [18F]flortaucipir PET imaging for non-Alzheimer tauopathies.
2025-12-22 | 18F-FDG, 18F-FP-CIT, and 18F-Florzolotau PET Imaging in Progressive Supranuclear Palsy
PURPOSE: Imaging protocols for progressive supranuclear palsy (PSP) are increasingly incorporating different PET modalities-including 18 F-fluorodeoxyglucose ( 18 F-FDG; cerebral glucose metabolism), 18 F-FP-CIT (dopamine transporter [DAT] activity), and 18 F-Florzolotau (tau pathology) PET-to improve diagnostic accuracy. In this cross-sectional study, we characterized tracer-specific imaging patterns and evaluated their interrelationships in patients with PSP to clarify the underlying pathophysiological mechanisms. MATERIALS AND METHODS: Twenty-eight patients with clinically diagnosed PSP underwent 18 F-FDG, 18 F-FP-CIT, and 18 F-Florzolotau PET imaging. Quantitative voxel-based and region-of-interest analyses were conducted. Standardized uptake value ratios (SUVRs) were calculated and compared with sex-matched controls (n=20 per PET modality). RESULTS: In patients with PSP compared with controls, 18 F-FDG PET revealed significant glucose hypometabolism in frontal, parietal, cerebellar, and subcortical regions. 18 F-FP-CIT PET demonstrated reduced DAT availability in the striatum and midbrain. Finally, 18 F-Florzolotau PET showed elevated tau deposition in the thalamus, midbrain, pons, and precentral gyrus. An inverse correlation linked midbrain tau burden with local glucose metabolism ( r =-0.39, P =0.04). Frontal hypometabolism correlated strongly with subcortical metabolic deficits ( r =0.61, P <0.001). Only the left putamen showed a moderate negative association between DAT loss and tau accumulation ( r =-0.42, P =0.03). CONCLUSIONS: Patients with PSP exhibit metabolic deficits in cortical-subcortical networks, dopaminergic denervation in striatal-midbrain regions, and tau pathology localized to brainstem and thalamic areas. Tracer-specific SUVRs correlations revealed specific interplay among glucose hypometabolism, DAT deficiency, and tau accumulation.
2025-12-17 | Inflammatory and Neurotrophic Factors and Their Connection to Quality of Life in Progressive Supranuclear Palsy—Single-Center Study
Progressive supranuclear palsy (PSP) is a condition classified as atypical parkinsonism. Pathologically, it is a four-repeat tauopathy; clinically, it is a disease comprising oculomotor dysfunction, postural instability, akinesia, and cognitive/language disorders. Its pathogenesis is not fully recognized; however, neuroinflammation is considered to likely be a significant aspect, though it is not known whether inflammation is a cause or consequence of neurodegeneration. In this study, the authors analyzed the association between inflammatory/neurotrophic factors and parameters linked to quality of life, based on examinations of 10 controls and 11 patients with PSP. They found a negative correlation between mPSPRS (Modified Progressive Supranuclear Palsy Rating Scale) and the glial cell-line-derived neurotrophic factor levels (GDNF) (r = −0.772727, p = 0.003) in the serum, a less pronounced negative correlation between progressive supranuclear palsy–quality of life parameter (PSP-QoL) and GDNF (r = −0.68390, p = 0.011) in the serum, and no correlations were observed in the analyses of inflammatory factors. The obtained results show the association between lower levels of GDNF and more pronounced clinical deterioration. Further analysis in the field based on larger groups of patients is required.
2025-12-01 | Biomarkers of LRRK2 and lysosomal dysfunction in Progressive Supranuclear Palsy
Abstract Background Common and rare genetic variants in LRRK2 have been linked with sporadic and familial Parkinson’s disease (PD). Recently, we discovered that common genetic variation near the LRRK2 locus determined survival in progressive supranuclear palsy (PSP). Our study aimed to explore biomarkers of LRRK2 and lysosomal dysfunction in PSP. Methods Immunoblotting was used to measure total LRRK2 and LRRK2-dependent Rab10 phosphorylation at Threonine73 (pRab10 Thr73 ) in neutrophil and monocyte samples from PSP and control participants. Urine samples were applied to a multiplexed assay to quantitate bis(monoacylglycerol)phosphate (BMP) species as markers of lysosomal dysfunction. CSF samples from a wider cohort of PSP and control participants were applied to a stable isotope standards and capture by anti-peptide antibodies assay to measure total LRRK2 and pRab10 Thr73 levels. LRRK2 genotypes (rs76904798 and rs2242367) and 1-year change in PSP rating scale scores were obtained. Results 61 PSP and 34 control participants were included. Total urine 22:6-BMP levels were higher in PSP vs. control samples (p=0.04) and correlated with CSF total LRRK2 levels (r=0.49, p=0.04). In PSP, carriers of the alternate allele (CT and TT genotypes) at the LRRK2 PD risk variant, rs76904798, had higher levels of CSF total LRRK2 vs. CC genotype (p=0.02). A similar but non-significant trend was observed for the LRRK2 PSP survival variant, rs2242367 (p=0.08). Baseline monocyte total LRRK2 levels predicted 1-year change in the PSP rating scale score (p=0.008). Conclusions Biochemically defined lysosomal dysfunction is evident in PSP. Genetic and biochemical stratification may identify PSP patients that would benefit from LRRK2-targetting therapies.
cell therapies
2026-03-17 | Natural Killer Subset Changes and Vascular Endothelial Growth Factor‐A Plasma Profile in Progressive Supranuclear Palsy: The NKscape Study
These findings identify a potentially disease-specific transcriptional signature with repercussions on the cyto-chemokine plasma profile. Further investigation of the NK cell-mediated immune response in PSP may provide new insights into disease mechanisms and open avenues for immunomodulatory therapeutic strategies. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2025-07-21 | Neuroinflammation distinguishes HLA haplotypes in progressive supranuclear palsy
Objectives: Progressive supranuclear palsy (PSP) is a neurodegenerative 4R tauopathy clinically presenting with atypical parkinsonism or cognitive behavioral changes and a relatively uniform neuropathology. We recently identified rare HLA haplotypes in PSP and now examine whether HLA haplotypes are associated with different cytopathological and clinical phenotypes. Methods: Retrospective collection of clinical data and mapping of T and B cells, microglia, and phosphorylated-tau (p-Tau) cytopathologies in 32 PSP cases. Machine learning was used to analyze whether pathological variables and their ratios, or the sequence of clinical symptoms cluster or predict HLA haplotypes. Results: Four groups were defined based on HLA haplotypes: i) 12 cases with the haplotype associated with narcolepsy (DRB1*15:01-DQB1*06:02); ii) 11 cases with other DQ5-DQ6 haplotypes; iii) 8 cases with various haplotypes frequent in the general population; and iv) one case with the haplotype frequent in IgLON5-disease (DRB1*10:01-DQB1*05:01). Neuropathology revealed regional differences in the severity of microglia load, density of cytotoxic T cells, and p-Tau cytopathologies between groups. HLA haplotypes were most distinguishable using machine learned features of inflammatory markers and ratios of neuropathological variables (clustering accuracy: 86.96% and 91.30%, respectively). The sequence of clinical symptoms and the ratios of neuropathological variables were the strongest predictors of HLA haplotypes (prediction accuracy=80.00% and 71.43%, respectively). Interpretation: PSP pathology might be associated with various etiological-pathogenic events including targetable autoimmune mechanisms. The HLA-haplotype dependent diversity of neuroinflammatory markers should be evaluated in clinical and biomarker studies in, and beyond, PSP to understand its relevance for patient stratification in disease modifying therapy trials.
2021-10-12 | Safety and Effectiveness of Cell Therapy in Neurodegenerative Diseases: Take-Home Messages From a Pilot Feasibility Phase I Study of Progressive Supranuclear Palsy
Mesenchymal stromal cells (MSCs) are multipotent cells with anti-inflammatory properties. Here we tested the safety of MSCs in patients with progressive supranuclear palsy (PSP; ClinicalTrials.gov: NCT01824121; Eudract No. 2011-004051-39). Seven patients were treated. To improve the safety, protocol adjustments were made during the performance of the study. The objectives of our work were: (1) to assess the safety of MSCs and (2) to identify critical issues in cell therapies for neurodegenerative diseases. Autologous MSCs from the bone marrow of PSP patients were administered through the internal carotid arteries. 1-year survival and number of severe adverse events were considered as safety endpoints. Clinical rating scales, neuropsychological assessments, gait and posture analysis, single-photon emission computed tomography, positron emission tomography, and brain magnetic resonance (BMR) were performed at different follow-up times. Peripheral blood levels of inflammatory cytokines were measured before and after cell infusion. Six of the seven treated patients were living 1 year after cell infusion. Asymptomatic spotty lesions were observed at BMR after 24 h in six of the seven treated patients. The last patient in the preliminary cohort (Case 5) exhibited transiently symptomatic BMR ischemic alterations. No severe adverse events were recorded in the last two treated patients. Interleukin-8 serum concentrations decreased in three patients (Case 2, 3, and 4). An adaptive study design, appropriate and up-to-date efficacy measures, adequate sample size estimation, and, possibly, the use of a cellular and/or allogeneic cell sources may help in performing phase II trials in the field.
antibodies
2025-10-01 | Neuronal-specific antibody in patients with multiple system atrophy and progressive supranuclear palsy
Anti-neuronal antibodies can manifest with diverse movement disorders, including parkinsonism and ataxia, and may mimic neurodegeneration. The prevalence of neuronal-specific antibodies in atypical parkinsonism remains unclear. We examined 166 patients, including 136 patients with clinically diagnosed progressive supranuclear palsy (PSP) and 30 patients with multiple system atrophy (MSA) from the Taiwan PSP/CBS Consortium using an integrated set of tissue-based immunofluorescence assays and a subsequent fixed cell-based assay as well as confirmatory tests to detect neuronal-specific antibodies. We observed one PSP-Richardson syndrome patient (0.74 %) was CASPR2-IgG positive, and one MSA-cerebellar subtype patient (3.33 %) showed GAD65 positivity with a hot-cross bun sign on MRI. The latter showed clinical improvement after immunotherapy. Neither patient had sleep-related symptoms. These findings indicate that neuronal-specific antibodies may mimic MSA or PSP and warrant antibody testing in atypical parkinsonism to identify reversible autoimmune causes.
2025-07-01 | C3 and C3a as indicators of complement dysregulation in tauopathies and FTLD-associated disorders
Dementia encompasses a range of neurodegenerative diseases (NDDs) presenting with progressive decline in memory, cognition, language and ability to complete daily tasks. Whilst Alzheimer’s disease (AD) is the most common form of dementia, less prevalent subtypes include frontotemporal lobar degenerative associated disorders (FTLD) frontotemporal dementia (FTD), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). FTLD are NDDs characterised by progressive atrophy and neuronal loss in brain frontal and temporal lobes, predominately affecting behaviour, language and cognition. Of these, FTLD, CBS and PSP are primary tauopathies, pathologically classified by predominant accumulation of aggregates of tau, a microtubule-associated protein responsible for mediating intracellular transport and structure. Some FTD subtypes, such as Pick’s disease, are also defined by tau pathology. Although complement dysregulation is broadly accepted as a feature of AD, this has not been convincingly shown in tauopathies and FTLD. Here we measured a panel of complement biomarkers in serum from FTLD and tauopathy cases and compared these with non-demented matched controls (HC). In-house ELISAs were used to quantify twelve complement analytes, comprising activation products (C3a, iC3b, TCC), regulators (Factor H (FH), Properdin, Clusterin) and components (C1q, C3, FB, C5, C7, C9) in serum samples. Samples were matched for age and sex from FTLDs: CBS (n = 16), FTD (n = 57), PSP (n = 42), healthy controls (HC; n = 41). Compared to HC, C3, C3a and properdin were elevated in FTLD (p = 0.0002, p = 0.0187, p = 0.0451 respectively). Other complement analytes were not significantly different between FTLD and HC samples. Subgroup analysis demonstrated significantly higher C3 and C3a compared to HC in FTD (p < 0.00001 and p = 0.0455 respectively) and PSP (p = 0.0051 and p = 0.0179 respectively) but not CBS, while properdin was significantly increased only in FTD cases (p = 0.0097). The data demonstrates a degree of complement dysregulation in tauopathies and FTLD across the different disease subtypes with C3, C3a and properdin levels significantly different to matched controls. These findings suggest dysregulation in the alternative pathway and lead us to suggest that complement dysregulation represents a potential therapeutic target for FTLD and tauopathies.
2025-05-13 | The Role of Tau in Neuronal Function and Neurodegeneration
Tau protein plays a pivotal role in maintaining neuronal structure and function through its regulation of microtubule stability and neuronal polarity. Encoded by the MAPT gene, Tau exists in multiple isoforms due to alternative mRNA splicing, with differential expression in the central and peripheral nervous systems. In healthy neurons, tau mRNA is selectively localized and translated in axons, a process tightly regulated by untranslated regions (UTRs) and RNA-binding proteins such as HuD and FMRP. Pathologically, Tau undergoes hyperphosphorylation, misfolding, and aggregation, which contribute to neurodegeneration in a range of disorders collectively known as tauopathies. Alzheimer's disease (AD) is the most prevalent tauopathy, where abnormal Tau accumulation in the temporal and frontal lobes correlates with cognitive decline and behavioral symptoms. Other tauopathies, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Frontotemporal Dementia with Parkinsonism (FTDP-17), and Pick's disease, are distinguished by the predominance of specific Tau isoforms (3R or 4R), cellular distribution, and affected brain regions. Notably, astroglial tauopathies highlight the pathological role of Tau accumulation in glial cells, expanding the understanding of neurodegeneration beyond neurons. Despite advances in imaging biomarkers (e.g., Tau-PET) and molecular diagnostics, effective disease-modifying therapies for tauopathies remain elusive. Ongoing research targets Tau through immunotherapies, splicing modulators, kinase inhibitors, and antisense oligonucleotides, aiming to mitigate Tau pathology and its deleterious effects. Understanding the multifaceted roles of Tau in neuronal and glial contexts is critical for developing future therapeutic strategies against tauopathies.
2025-01-19 | Investigation of the HLA locus in autopsy-confirmed progressive supranuclear palsy
ABSTRACT Objectives Progressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen ( HLA ) locus on chromosome 6 is a polymorphic region with complex linkage patterns that has been implicated in several autoimmune and neurological disorders. The HLA locus has not been systematically examined in PSP. It is unclear whether tau and HLA can interact to induce an autoimmune disease mechanism. Methods We evaluated an autopsy confirmed PSP cohort (n=44) and compared allele/haplotype frequencies to those of the reference group of a local deceased Canadian donor pool. We performed HLA/Tau peptide binding prediction and modelling of HLA Class II and Tau Peptide interactions. Findings Odds ratio was 2.94 (95% CI 1.01 to 8.55; p=0.047) for DQB1 *06:01 allele, and 2.59 (95% CI 1.39 to 4.83; p=0.0025) for the narcolepsy associated haplotype ( DRB1 *15:01 DQB1 *06:02). One patient with 4 repeat tau PSP type pathology was a carrier of the IgLON5-associated haplotype ( DRB1 *10:01 DQB1 *05:01). HLA/Tau peptide binding prediction and modelling of HLA Class II/Tau Peptide interactions revealed strong binding tau peptides but not the PSP protofilament fold for alleles DQA1* 01:02DQB1* 06:02 and DQA1* 01:03DQB1* 06:01. Conclusion Our study suggests that epitopes within the tau peptide may bind to HLA alleles that are found in a subset of PSP patients supporting the notion of an autoimmune pathophysiological component. These findings have implications for subtyping and stratifying patients for therapies, including those targeting immune modulation.
2024-08-29 | Long-standing preservation of levodopa response in progressive supranuclear palsy
The clinical and neuropathological characteristics of progressive supranuclear palsy (PSP) with preservation of levodopa (L-dopa) response are described in this report. We present the case of a 73-year-old Japanese man with a 13-year history of dopa-responsive Parkinsonism and abnormalities observed in metaiodobenzylguanidine (MIBG) myocardial scintigraphy, suggesting Parkinson's disease. However, autopsy results revealed PSP pathology, including tuft-shaped astrocytes and globose-type neurofibrillary tangles, without Lewy body pathology. The degeneration was moderately to severely distributed in the globus pallidus, subthalamic nucleus, and substantia nigra, whereas striatal degeneration was mild. These findings suggest an intact response to L-dopa therapy throughout the patient's lifetime. Pathological examination of cardiac sympathetic nerves revealed intact nerves, suggesting functional involvement in the MIBG abnormality. This study provides further evidence of the clinical and pathological heterogeneity of PSP. Homozygosity for both the rs564309-C allele at TRIM11 and the rs2242367-G allele at SLC2A13 might have played a protective role. This case indicates a protracted course-PSP, which may hold promise for future treatments.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.