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:
categories:
Small molecules
antibodies
2025-10-29 | 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.
2025-07-21 | A new nosology for neurodegenerative dementias: cognitive proteinopathies - Shifting from “Where” to “What”
Over the next 100 years, the neuropathology of each of these diseases was studied in greater detail. For instance, alpha-synuclein was identified in Parkinson's disease, beta-amyloid and phospho-tau in Alzheimer's disease, and tau and TDP-43 in Pick's disease. At the same time, typical and atypical forms of these pathologies began to be described. In frontotemporal disease, for instance, the classic behavioral variant and the rare aphasic variant have been described. Similarly, Alzheimer's disease has both classical (amnesic) and atypical variants including frontal, posterior cortical, aphasic and, more recently, Down's disease. Alpha-synuclein is the most important factor in Parkinson's disease, which is associated with Lewy bodies disease. However, in parkinsonian syndromes such as progressive supranuclear palsy or corticobasal degeneration, the change is a tauopathy. Therefore, these phenotypes, which only describe “where” the lesion is located cannot be maintained. For example, a patient presenting with a behavioral disturbance such as apathy and disinhibition may have tauopathy, or TDP-43-opathy, or even beta amyloidosis. Over the last 10 years, neuropathological, and genetic research, as well as the emergence of biomarkers, has enabled us to diagnose the syndrome and identify the protein change that causes it during life. This is insignificant in the context of the new diagnostic criteria, and the new treatments targeting abnormal proteins or altered pathways, such as anti-amyloid, anti-tau, anti-sortilin antibodies. In the coming years, we will therefore move from diagnosing “where” to diagnosing “what” disease produces these symptoms.
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.
2020-10-22 | Contribution of the astrocytic tau pathology to synapse loss in progressive supranuclear palsy and corticobasal degeneration
Abstract Primary 4‐repeat tauopathies with frontotemporal lobar degeneration (FTLD) like Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration (CBD) show diverse cellular pathology in various brain regions. Besides shared characteristics of neuronal and oligodendroglial cytoplasmic inclusions of accumulated hyperphosphorylated tau protein (pTau), astrocytes in PSP and CBD contain pathognomonic pTau aggregates — hence, lending the designation tufted astrocytes (TA) or astrocytic plaques (AP), respectively. pTau toxicity is most commonly assigned to neurons, whereas the implications of astrocytic pTau for maintaining neurotransmission within the tripartite synapse of human brains is not well understood. We performed immunofluorescent synapse labeling and automated puncta quantification in the medial frontal gyrus (MFG) and striatal regions from PSP and CBD postmortem samples to capture morphometric synaptic alterations. This approach indicated general synaptic losses of both, excitatory and inhibitory bipartite synapses in the frontal cortex of PSP cases, whereas in CBD lower synapse densities were only related to astrocytic plaques. In contrast to tufted astrocytes in PSP, affected astrocytes in CBD could not preserve synaptic integrity within their spatial domains, when compared to non‐affected internal astrocytes or astrocytes in healthy controls. These findings suggest a pTau pathology‐associated role of astrocytes in maintaining connections within neuronal circuits, considered as the microscopic substrate of cognitive dysfunction in CBD. By contrasting astrocytic‐synaptic associations in both diseases, we hereby highlight astrocytic pTau as an important subject of prospective research and as a potential cellular target for therapeutic approaches in the primary tauopathies PSP and CBD.
2019-11-04 | From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy
The term "propagon" is used to define proteins that may transmit misfolding in vitro, in tissues or in organisms. Among propagons, misfolded tau is thought to be involved in the pathogenic mechanisms of various "tauopathies" that include Alzheimer's disease, progressive supranuclear palsy, and argyrophilic grain disease. Here, we review the available data in the literature and point out how the prion-like tau propagation has been extended from Alzheimer's disease to tauopathies. First, in Alzheimer's disease, the progression of tau aggregation follows stereotypical anatomical stages which may be considered as spreading. The mechanisms of the propagation are now subject to intensive and controversial research. It has been shown that tau may be secreted in the interstitial fluid in an active manner as reflected by high and constant concentration of extracellular tau during Alzheimer's pathology. Animal and cell models have been devised to mimic tau seeding and propagation, and despite their limitations, they have further supported to the prion-like propagation hypothesis. Finally, such new ways of thinking have led to different therapeutic strategies in anti-tau immunotherapy among tauopathies and have stimulated new clinical trials. However, it appears that the prion-like propagation hypothesis mainly relies on data obtained in Alzheimer's disease. From this review, it appears that further studies are needed (1) to characterize extracellular tau species, (2) to find the right pathological tau species to target, (3) to follow in vivo tau pathology by brain imaging and biomarkers and (4) to interpret current clinical trial results aimed at reducing the progression of these pathologies. Such inputs will be essential to have a comprehensive view of these promising therapeutic strategies in tauopathies.
cell therapies
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.
2014-03-04 | Treatment of progressive supranuclear palsy with autologous adipose tissue-derived mesenchymal stem cells: a case report
Progressive supranuclear palsy is a relentlessly progressive neurodegenerative disorder and is clinically characterized by parkinsonism. Adipose tissue-derived mesenchymal stem cells have recently demonstrated the possibility of treating neurological disorders. Therefore, autologous adipose tissue-derived mesenchymal stem cells transplantation can be an alternative method for treating progressive supranuclear palsy.This study was approved by the Korea Food and Drug Administration through the Emergency Use Investigational New Drug Application. A 71-year-old Asian man from South Korea with progressive supranuclear palsy was treated with five intravenous infusions (each time 2×108 cells) and four intrathecal infusions (each time 5×107 cells) with autologous adipose tissue-derived mesenchymal stem cells expanded under good manufacturing practice conditions. Clinical examinations were performed immediately before treatment and throughout the six months of follow-up. The tests included: 1) Progressive Supranuclear Palsy Rating Scale; 2) Berg Balance Scale; 3) Korean Mini Mental State Examination; 4) Modified Barthel Index; 5) grip strength; 6) Box and Block Test; and 7) Nine-Hole Peg Test.The Progressive Supranuclear Palsy Rating Scale results gradually decreased, and the clinical rating scale scores of the Berg Balance Scale, Korean Mini Mental State Examination, and Modified Barthel Index gradually increased. Grip strength was maintained. Performance in the Box and Block Test and Nine-Hole Peg Test improved after adipose tissue-derived mesenchymal stem cells treatment compared to baseline throughout the six months of follow-up. Except for the intermittent mild fever and transient elevated blood pressure, the treatment of our patient with progressive supranuclear palsy with autologous adipose tissue-derived mesenchymal stem cells showed no significant adverse events, and delayed the progression of neurological deficits by achieving functional improvement in the follow-up period.These results are encouraging and hopeful for further studies in patients with progressive supranuclear palsy using autologous adipose tissue-derived mesenchymal stem cells as a safe and effective therapy. This case report is the first known study of adipose tissue-derived mesenchymal stem cells safely delaying the progression of progressive supranuclear palsy with functional improvement during the follow-up period.
small molecules
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.
2026-01-30 | 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.
2025-12-01 | Pharmacological management of tauopathies
Tauopathies, a group of neurodegenerative disorders characterized by tau protein aggregation, encompass diseases such as progressive supranuclear palsy, and corticobasal degeneration. While the development of disease-modifying therapies remains a primary research focus, current pharmacological interventions are predominantly directed towards symptomatic management. This review aims to summarize the evidence-based approaches for addressing the motor, autonomic, and systemic manifestations of tauopathies, highlighting both their therapeutic benefits and limitations. For motor dysfunction, dopaminergic agents and muscle relaxants are explored, though their benefits in PSP and CBS are often modest. Sleep disturbances and autonomic dysfunction, which are prevalent but underrecognized in tauopathies, can be managed using targeted pharmacological strategies, with emerging evidence supporting the use of melatonin and other agents. We will discuss the current significant gaps in optimizing these treatments to meet the complex needs of patients and their family. The potential for repurposing existing drugs and the role of novel symptomatic therapies is currently under investigation. By providing an updated synthesis of pharmacological management strategies, clinicians attending this session will get the evidence-based, patient-centered care skills for treatment of PSP and CBS.
2025-08-29 | Successful Treatment of Corticobasal Syndrome: Case Study
Corticobasal syndrome (CBS) is an uncommon neurodegenerative syndrome, with a prevalence of only a few thousand patients in the U.S. Symptoms include alien hand syndrome, rigidity, myoclonus, weakness (often asymmetric), dysarthria, aphasia, dementia, and dysphagia, among others. There is no known cause or effective treatment for CBS. The underlying neuropathology associated with CBS includes corticobasal degeneration (CBD), Alzheimer’s disease, progressive supranuclear palsy, Creutzfeldt-Jakob disease, vascular disease, and frontotemporal lobar degeneration. Here we report a patient with CBS who had had exposure to burn pits, was found to harbor high levels of multiple toxins, and responded to a personalized, precision medicine protocol that included detoxification, hormone optimization, brain training, hyperbaric oxygen, and diet and lifestyle enhancement. Her symptoms abated, her MoCA score increased from 21/30 to 28/30, her electrophysiological studies normalized with marked improvement in quantitative EEG, and her MRI volumetrics improved. This case study suggests the possibility that more extensive toxin evaluations in patients with CBS may be revealing, and that personalized treatment directed at identified potential drivers such as organic toxins may offer the potential for symptom improvement in a disease for which no treatment has previously shown efficacy. The results also suggest the need for a proof-of-concept clinical trial for patients with CBS.
proteins
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.
2019-05-09 | Botulinum toxin for the treatment of dystonia and pain in corticobasal syndrome
Abstract Background Dystonia is a key symptom in corticobasal syndrome (CBS), and upper limb dystonia is the most common phenotype. Dystonia‐associated pain is frequently reported and can be disabling, with poor benefit from oral treatments. Aims of the Study To investigate the role of botulinum toxin A (BoTNA) in the treatment of dystonia and associated pain in CBS. Methods Ten consecutive patients with a clinical diagnosis of probable CBS and dystonia with/without associated pain were treated with BoTNA every 3 months. Treatment efficacy was assessed during the first follow‐up visit, three months after the first injection, by means of caregiver impression (CI), evaluation of muscle tone with the Ashworth scale (AS), severity of pain measured with the visual analog scale (VAS). Results Nine subjects underwent at least three treatments, four patients discontinued for progressive reduction in efficacy or disease progression, five patients are ongoing with good response, and one completed the 10th treatment. No local or systemic side effects were reported, and levodopa equivalent daily dose remained unchanged in most cases during the observational period. Significant improvement of AS was recorded (from 2.9 ± 0.7 to 2.0 ± 0.5, p = 0.003). CI ranged from mild to moderate benefit. All patients reported efficacy on pain, with a significant reduction of VAS score (from 7.7 ± 1.7 to 1.7 ± 0.7 in the Pain group, p = 0.016). Conclusions Our study confirms safety, efficacy, and tolerability of BoTNA in the treatment of dystonia associated with CBS. Local treatment should be considered as a valid alternative to oral treatment modulation mainly in the presence of associated pain.
other
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.
antibodies
2025-10-29 | 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.
2025-07-21 | A new nosology for neurodegenerative dementias: cognitive proteinopathies - Shifting from “Where” to “What”
Over the next 100 years, the neuropathology of each of these diseases was studied in greater detail. For instance, alpha-synuclein was identified in Parkinson's disease, beta-amyloid and phospho-tau in Alzheimer's disease, and tau and TDP-43 in Pick's disease. At the same time, typical and atypical forms of these pathologies began to be described. In frontotemporal disease, for instance, the classic behavioral variant and the rare aphasic variant have been described. Similarly, Alzheimer's disease has both classical (amnesic) and atypical variants including frontal, posterior cortical, aphasic and, more recently, Down's disease. Alpha-synuclein is the most important factor in Parkinson's disease, which is associated with Lewy bodies disease. However, in parkinsonian syndromes such as progressive supranuclear palsy or corticobasal degeneration, the change is a tauopathy. Therefore, these phenotypes, which only describe “where” the lesion is located cannot be maintained. For example, a patient presenting with a behavioral disturbance such as apathy and disinhibition may have tauopathy, or TDP-43-opathy, or even beta amyloidosis. Over the last 10 years, neuropathological, and genetic research, as well as the emergence of biomarkers, has enabled us to diagnose the syndrome and identify the protein change that causes it during life. This is insignificant in the context of the new diagnostic criteria, and the new treatments targeting abnormal proteins or altered pathways, such as anti-amyloid, anti-tau, anti-sortilin antibodies. In the coming years, we will therefore move from diagnosing “where” to diagnosing “what” disease produces these symptoms.
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.
2020-10-22 | Contribution of the astrocytic tau pathology to synapse loss in progressive supranuclear palsy and corticobasal degeneration
Abstract Primary 4‐repeat tauopathies with frontotemporal lobar degeneration (FTLD) like Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration (CBD) show diverse cellular pathology in various brain regions. Besides shared characteristics of neuronal and oligodendroglial cytoplasmic inclusions of accumulated hyperphosphorylated tau protein (pTau), astrocytes in PSP and CBD contain pathognomonic pTau aggregates — hence, lending the designation tufted astrocytes (TA) or astrocytic plaques (AP), respectively. pTau toxicity is most commonly assigned to neurons, whereas the implications of astrocytic pTau for maintaining neurotransmission within the tripartite synapse of human brains is not well understood. We performed immunofluorescent synapse labeling and automated puncta quantification in the medial frontal gyrus (MFG) and striatal regions from PSP and CBD postmortem samples to capture morphometric synaptic alterations. This approach indicated general synaptic losses of both, excitatory and inhibitory bipartite synapses in the frontal cortex of PSP cases, whereas in CBD lower synapse densities were only related to astrocytic plaques. In contrast to tufted astrocytes in PSP, affected astrocytes in CBD could not preserve synaptic integrity within their spatial domains, when compared to non‐affected internal astrocytes or astrocytes in healthy controls. These findings suggest a pTau pathology‐associated role of astrocytes in maintaining connections within neuronal circuits, considered as the microscopic substrate of cognitive dysfunction in CBD. By contrasting astrocytic‐synaptic associations in both diseases, we hereby highlight astrocytic pTau as an important subject of prospective research and as a potential cellular target for therapeutic approaches in the primary tauopathies PSP and CBD.
2019-11-04 | From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy
The term "propagon" is used to define proteins that may transmit misfolding in vitro, in tissues or in organisms. Among propagons, misfolded tau is thought to be involved in the pathogenic mechanisms of various "tauopathies" that include Alzheimer's disease, progressive supranuclear palsy, and argyrophilic grain disease. Here, we review the available data in the literature and point out how the prion-like tau propagation has been extended from Alzheimer's disease to tauopathies. First, in Alzheimer's disease, the progression of tau aggregation follows stereotypical anatomical stages which may be considered as spreading. The mechanisms of the propagation are now subject to intensive and controversial research. It has been shown that tau may be secreted in the interstitial fluid in an active manner as reflected by high and constant concentration of extracellular tau during Alzheimer's pathology. Animal and cell models have been devised to mimic tau seeding and propagation, and despite their limitations, they have further supported to the prion-like propagation hypothesis. Finally, such new ways of thinking have led to different therapeutic strategies in anti-tau immunotherapy among tauopathies and have stimulated new clinical trials. However, it appears that the prion-like propagation hypothesis mainly relies on data obtained in Alzheimer's disease. From this review, it appears that further studies are needed (1) to characterize extracellular tau species, (2) to find the right pathological tau species to target, (3) to follow in vivo tau pathology by brain imaging and biomarkers and (4) to interpret current clinical trial results aimed at reducing the progression of these pathologies. Such inputs will be essential to have a comprehensive view of these promising therapeutic strategies in tauopathies.
cell therapies
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.
2014-03-04 | Treatment of progressive supranuclear palsy with autologous adipose tissue-derived mesenchymal stem cells: a case report
Progressive supranuclear palsy is a relentlessly progressive neurodegenerative disorder and is clinically characterized by parkinsonism. Adipose tissue-derived mesenchymal stem cells have recently demonstrated the possibility of treating neurological disorders. Therefore, autologous adipose tissue-derived mesenchymal stem cells transplantation can be an alternative method for treating progressive supranuclear palsy.This study was approved by the Korea Food and Drug Administration through the Emergency Use Investigational New Drug Application. A 71-year-old Asian man from South Korea with progressive supranuclear palsy was treated with five intravenous infusions (each time 2×108 cells) and four intrathecal infusions (each time 5×107 cells) with autologous adipose tissue-derived mesenchymal stem cells expanded under good manufacturing practice conditions. Clinical examinations were performed immediately before treatment and throughout the six months of follow-up. The tests included: 1) Progressive Supranuclear Palsy Rating Scale; 2) Berg Balance Scale; 3) Korean Mini Mental State Examination; 4) Modified Barthel Index; 5) grip strength; 6) Box and Block Test; and 7) Nine-Hole Peg Test.The Progressive Supranuclear Palsy Rating Scale results gradually decreased, and the clinical rating scale scores of the Berg Balance Scale, Korean Mini Mental State Examination, and Modified Barthel Index gradually increased. Grip strength was maintained. Performance in the Box and Block Test and Nine-Hole Peg Test improved after adipose tissue-derived mesenchymal stem cells treatment compared to baseline throughout the six months of follow-up. Except for the intermittent mild fever and transient elevated blood pressure, the treatment of our patient with progressive supranuclear palsy with autologous adipose tissue-derived mesenchymal stem cells showed no significant adverse events, and delayed the progression of neurological deficits by achieving functional improvement in the follow-up period.These results are encouraging and hopeful for further studies in patients with progressive supranuclear palsy using autologous adipose tissue-derived mesenchymal stem cells as a safe and effective therapy. This case report is the first known study of adipose tissue-derived mesenchymal stem cells safely delaying the progression of progressive supranuclear palsy with functional improvement during the follow-up period.
small molecules
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.
2026-01-30 | 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.
2025-12-01 | Pharmacological management of tauopathies
Tauopathies, a group of neurodegenerative disorders characterized by tau protein aggregation, encompass diseases such as progressive supranuclear palsy, and corticobasal degeneration. While the development of disease-modifying therapies remains a primary research focus, current pharmacological interventions are predominantly directed towards symptomatic management. This review aims to summarize the evidence-based approaches for addressing the motor, autonomic, and systemic manifestations of tauopathies, highlighting both their therapeutic benefits and limitations. For motor dysfunction, dopaminergic agents and muscle relaxants are explored, though their benefits in PSP and CBS are often modest. Sleep disturbances and autonomic dysfunction, which are prevalent but underrecognized in tauopathies, can be managed using targeted pharmacological strategies, with emerging evidence supporting the use of melatonin and other agents. We will discuss the current significant gaps in optimizing these treatments to meet the complex needs of patients and their family. The potential for repurposing existing drugs and the role of novel symptomatic therapies is currently under investigation. By providing an updated synthesis of pharmacological management strategies, clinicians attending this session will get the evidence-based, patient-centered care skills for treatment of PSP and CBS.
2025-08-29 | Successful Treatment of Corticobasal Syndrome: Case Study
Corticobasal syndrome (CBS) is an uncommon neurodegenerative syndrome, with a prevalence of only a few thousand patients in the U.S. Symptoms include alien hand syndrome, rigidity, myoclonus, weakness (often asymmetric), dysarthria, aphasia, dementia, and dysphagia, among others. There is no known cause or effective treatment for CBS. The underlying neuropathology associated with CBS includes corticobasal degeneration (CBD), Alzheimer’s disease, progressive supranuclear palsy, Creutzfeldt-Jakob disease, vascular disease, and frontotemporal lobar degeneration. Here we report a patient with CBS who had had exposure to burn pits, was found to harbor high levels of multiple toxins, and responded to a personalized, precision medicine protocol that included detoxification, hormone optimization, brain training, hyperbaric oxygen, and diet and lifestyle enhancement. Her symptoms abated, her MoCA score increased from 21/30 to 28/30, her electrophysiological studies normalized with marked improvement in quantitative EEG, and her MRI volumetrics improved. This case study suggests the possibility that more extensive toxin evaluations in patients with CBS may be revealing, and that personalized treatment directed at identified potential drivers such as organic toxins may offer the potential for symptom improvement in a disease for which no treatment has previously shown efficacy. The results also suggest the need for a proof-of-concept clinical trial for patients with CBS.
proteins
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.
2019-05-09 | Botulinum toxin for the treatment of dystonia and pain in corticobasal syndrome
Abstract Background Dystonia is a key symptom in corticobasal syndrome (CBS), and upper limb dystonia is the most common phenotype. Dystonia‐associated pain is frequently reported and can be disabling, with poor benefit from oral treatments. Aims of the Study To investigate the role of botulinum toxin A (BoTNA) in the treatment of dystonia and associated pain in CBS. Methods Ten consecutive patients with a clinical diagnosis of probable CBS and dystonia with/without associated pain were treated with BoTNA every 3 months. Treatment efficacy was assessed during the first follow‐up visit, three months after the first injection, by means of caregiver impression (CI), evaluation of muscle tone with the Ashworth scale (AS), severity of pain measured with the visual analog scale (VAS). Results Nine subjects underwent at least three treatments, four patients discontinued for progressive reduction in efficacy or disease progression, five patients are ongoing with good response, and one completed the 10th treatment. No local or systemic side effects were reported, and levodopa equivalent daily dose remained unchanged in most cases during the observational period. Significant improvement of AS was recorded (from 2.9 ± 0.7 to 2.0 ± 0.5, p = 0.003). CI ranged from mild to moderate benefit. All patients reported efficacy on pain, with a significant reduction of VAS score (from 7.7 ± 1.7 to 1.7 ± 0.7 in the Pain group, p = 0.016). Conclusions Our study confirms safety, efficacy, and tolerability of BoTNA in the treatment of dystonia associated with CBS. Local treatment should be considered as a valid alternative to oral treatment modulation mainly in the presence of associated pain.
other
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.
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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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