Progressive Supranuclear Palsy

Complex MONDO:0019037 Pathograph 6 Show in embeddings browser Neurodegenerative Disease Parkinsonism

Progressive supranuclear palsy (PSP) is an adult-onset, rapidly progressive neurodegenerative 4R-tauopathy in which hyperphosphorylated four-repeat (4R) tau aggregates accumulate in neurons and glia (tufted astrocytes and oligodendroglial coiled bodies) predominantly affecting subcortical and brainstem structures (subthalamic nucleus, globus pallidus, dorsal midbrain) with variable cortical involvement. The classical phenotype (PSP-Richardson syndrome) features vertical supranuclear gaze palsy, early postural instability with falls, axial rigidity, akinetic-rigid parkinsonism that is poorly responsive to levodopa, and frontal-subcortical cognitive/behavioral decline. PSP is mostly sporadic; the MAPT 17q21.31 H1 haplotype is the strongest common genetic risk factor and rare familial MAPT-associated PSP-like syndromes occur. Diagnosis follows the 2017 Movement Disorder Society (MDS) criteria, which recognize a spectrum of clinical phenotypes beyond Richardson syndrome.

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6
Pathophys.
15
Phenotypes
6
Pathograph
3
Genes
6
Medical Actions
6
Subtypes
3
Trials
1
Deep Research
◆

Subtypes

6
PSP-Richardson syndrome
The classical and most common PSP phenotype, characterized by early postural instability with falls, vertical supranuclear gaze palsy, and akinetic-rigid, levodopa-resistant parkinsonism, with frontal-subcortical cognitive decline. Associated with the most rapid clinical progression and shortest survival of the PSP phenotypes.
Show evidence (1 reference)
PMID:38290492 SUPPORT Human Clinical
"PSP-RS patients were older at disease onset (p = 0.009) and had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006)"
Characterizes PSP-RS as the akinetic-rigid, levodopa-resistant phenotype in an MDS-recategorized cohort.
PSP-parkinsonism
Variant phenotype presenting with a parkinsonian syndrome (asymmetric onset, tremor, and sometimes initial levodopa responsiveness) that overlaps clinically with Parkinson disease early in the course, often leading to delayed diagnosis. Generally slower progression and longer survival than PSP-RS.
Show evidence (1 reference)
PMID:38290492 SUPPORT Human Clinical
"PSP with predominant parkinsonism [PSP-P]"
Enumerates PSP-P (PSP with predominant parkinsonism) as a distinct MDS phenotype in the recategorized cohort, where it is grouped under the PSP-subcortical subgroup.
PSP with progressive gait freezing
Variant phenotype dominated by progressive gait freezing (pure akinesia with gait freezing), with relatively preserved cognition and limb tone early in the course.
Show evidence (1 reference)
PMID:38290492 SUPPORT Human Clinical
"PSP with progressive gait freezing [PSP-PGF]"
PSP-PGF is enumerated as a distinct MDS phenotype in the recategorized cohort.
PSP-cortical phenotypes (PSP-F, PSP-SL, PSP-CBS)
Cortical-predominant PSP phenotypes including PSP with predominant frontal presentation (PSP-F, dysexecutive/behavioral), PSP with predominant speech/language disorder (PSP-SL, overlapping nonfluent/agrammatic primary progressive aphasia and apraxia of speech), and PSP with corticobasal syndrome (PSP-CBS). These show greater cognitive alteration than subcortical variants.
Show evidence (1 reference)
PMID:38290492 SUPPORT Human Clinical
"34 PSP-cortical (PSP-CBS, 17.6%; PSP-F, 9.4%; PSP-SL, 8.2%)"
Defines and quantifies the cortical PSP phenotype grouping in the MDS-based cohort.
PSP-subcortical phenotypes (PSP-PI, PSP-OM, PSP-C)
Subcortical-predominant PSP variants other than PSP-P/PSP-PGF, including PSP with predominant postural instability (PSP-PI), PSP with predominant ocular motor dysfunction (PSP-OM), and PSP with cerebellar ataxia (PSP-C). Cognitive domains are generally less affected than in cortical phenotypes.
Show evidence (1 reference)
PMID:38290492 SUPPORT Human Clinical
"Cognitive domains were significantly less altered in the PSP-subcortical subgroup."
Distinguishes the subcortical phenotype grouping by relatively preserved cognition.
Inherited PSP (MAPT-associated)
MAPT hgnc:6893 {'name': 'Autosomal dominant inheritance'}
Rare familial PSP-like syndromes caused by MAPT mutations. Most PSP is sporadic, and in the MDS criteria a MAPT mutation does not exclude the diagnosis but distinguishes inherited from sporadic PSP. The MAPT H1 haplotype is a common risk factor distinct from rare causal MAPT variants.
Show evidence (1 reference)
PMID:39154163 SUPPORT Human Clinical
"PSP is associated with common variation in the tau gene (MAPT) at the 17q21.31 locus"
MAPT variation underlies both common haplotype risk and rare familial PSP; this subtype captures the inherited MAPT-associated form.
⚙

Pathophysiology

6
4R-Tau Aggregation in Neurons and Glia
PSP is neuropathologically defined by accumulation of hyperphosphorylated, aggregated four-repeat (4R) tau in neurons, astrocytes (tufted astrocytes), and oligodendrocytes (coiled bodies). Tau inclusions disrupt microtubule biology and proteostasis. MAPT expression is preserved in all three cell types harboring tau aggregates, supporting ongoing local tau production that can feed continued aggregation and cell-to-cell seeding. This is the upstream initiating lesion of PSP pathology.
neuron CL:0000540 tufted astrocyte CL:0000127 oligodendrocyte (coiled body) CL:0000128
Tau (amyloid) fibril formation GO:1990000 ↑ INCREASED Disrupted microtubule cytoskeleton organization GO:0000226 ⚠ ABNORMAL Tau hyperphosphorylation GO:0006468 ↑ INCREASED
Downstream
Integrated Stress Response Activation
Neuronal Dysfunction and Loss
Show evidence (2 references)
PMID:39152475 SUPPORT Human Clinical
"Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes."
Establishes the defining PSP lesion: aggregated tau across neurons, astrocytes, and oligodendrocytes.
PMID:37354322 SUPPORT Human Clinical
"MAPT transcripts were detected in neurons, astrocytes and oligodendrocytes, and varied between brain regions and within each cell type, and were preserved in all cell types with tau aggregates in PSP."
Shows MAPT expression is preserved in all three cell types bearing tau aggregates, supporting ongoing local tau supply for aggregation/seeding.
MAPT H1 Haplotype and 4R Tau Splicing Imbalance
The MAPT 17q21.31 locus contains low-copy repeats flanking a recurrent genomic inversion, giving rise to two dominant haplotypes (H1 and H2). The H1 haplotype is the strongest common genetic risk factor for PSP. Haplotype-dependent regulation biases tau pre-mRNA splicing and expression toward the 4R isoform: post-mortem bulk RNA-seq shows increased total tau mRNA and an increased proportion of 4R tau transcripts in PSP brain, with 4R tau mRNA significantly associated with the H1 haplotype, supporting an upstream splicing/expression mechanism feeding tau aggregation.
neuron CL:0000540
Regulation of mRNA splicing toward 4R tau GO:0048024 ⚠ ABNORMAL Increased tau gene expression GO:0010468 ↑ INCREASED
Downstream
4R-Tau Aggregation in Neurons and Glia
Show evidence (3 references)
PMID:39154163 SUPPORT Human Clinical
"4R tau mRNA levels were significantly associated with the H1 haplotype in the temporal cortex."
Directly links the MAPT H1 risk haplotype to increased 4R tau mRNA, supporting a splicing/expression mechanism upstream of aggregation.
PMID:39154163 SUPPORT Human Clinical
"These findings support the hypothesis that sporadic PSP is associated with haplotype-dependent increases in 4R tau mRNA that might play a causal role in this disorder."
Authors frame haplotype-dependent 4R tau mRNA increase as a candidate causal mechanism for sporadic PSP.
PMID:39152475 SUPPORT Human Clinical
"Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1"
Confirms MAPT and additional risk loci by whole-genome sequencing, anchoring the genetic architecture upstream of tau pathology.
Integrated Stress Response Activation
Chronic proteotoxic/tau burden activates the integrated stress response (EIF2 signaling) in vulnerable cell types. Single-nucleus RNA-seq of the PSP diencephalon identified EIF2 signaling as an activated adaptive stress pathway, and activated eIF2-alpha was positively correlated with tau pathology burden and localized to p-tau-positive neurons and ALDH1L1-positive astrocytes. Failure of this adaptive stress response is proposed to contribute mechanistically to PSP progression and neuronal loss.
neuron CL:0000540 astrocyte CL:0000127
Integrated stress response signaling GO:0140467 ↑ INCREASED Response to endoplasmic reticulum stress GO:0034976
Downstream
Neuronal Dysfunction and Loss
Show evidence (2 references)
PMID:39648200 SUPPORT Human Clinical
"This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was activated in multiple vulnerable cell types"
Single-nucleus RNA-seq identifies EIF2/integrated stress response activation across vulnerable PSP cell types.
PMID:39648200 SUPPORT Human Clinical
"we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions."
Correlates activated eIF2-alpha with tau burden, linking tau pathology to the stress response downstream.
Neuroinflammation and Glial Activation
Tau pathology triggers glial and immune activation in PSP. CSF proteomic and neuropathologic studies implicate dysregulated cytokine/inflammatory signaling and glial activation as an ongoing neuroimmune component that may track and contribute to disease progression. (Cached CSF-proteomics reference content was title-only; quantitative inflammatory-marker detail in the deep-research report should be re-verified against the full abstract before being quoted.)
microglial cell CL:0000129 astrocyte CL:0000127
Neuroinflammatory response GO:0150076 ↑ INCREASED Inflammatory response GO:0006954
Downstream
Neuronal Dysfunction and Loss
Show evidence (1 reference)
PMID:39648200 PARTIAL Human Clinical
"Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes"
Demonstrates glial (astrocytic) involvement in PSP stress-pathway pathology; supports glial activation as part of the neuroinflammatory mechanism (PARTIAL, as the quote addresses stress signaling rather than cytokine inflammation directly).
Axon Guidance and Synaptic Pathway Dysregulation
Downstream of tauopathy, PSP shows circuit-level dysfunction. CSF proteomic studies have identified dysregulation of axon guidance and synaptic-function pathways, consistent with axonal and synaptic injury contributing to the motor and cognitive syndromes. (CSF-proteomics cache content was title-only; the axon-guidance pathway detail is drawn from the deep-research report and should be re-verified against the full abstract before quoting specific statistics.)
neuron CL:0000540
Axon guidance GO:0007411 ⚠ ABNORMAL
Downstream
Neuronal Dysfunction and Loss
Show evidence (1 reference)
PMID:38582079 PARTIAL In Vitro
"4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity."
A human iPSC 4R-tauopathy model shows tau-seeding-induced neuronal/synaptic dysfunction (reduced neuronal activity), supporting circuit-level dysfunction downstream of tau pathology relevant to PSP (PARTIAL: model-derived, not a direct PSP axon-guidance measurement).
Neuronal Dysfunction and Loss
Convergent tau toxicity, maladaptive stress signaling, neuroinflammation, and synaptic/axonal injury produce region- and cell-type-specific neuronal dysfunction and death, predominantly in the subthalamic nucleus, globus pallidus, and dorsal midbrain, with variable cortical involvement. This neurodegeneration underlies the progressive motor, oculomotor, and cognitive syndromes of PSP.
neuron CL:0000540
Neuron apoptotic process GO:0051402 ↑ INCREASED
Show evidence (1 reference)
PMID:39648200 SUPPORT Human Clinical
"The precise mechanism whereby these protein aggregates lead to cell death remains unclear."
Frames neuronal cell death as the downstream endpoint of tau aggregation in PSP, while noting mechanistic uncertainty.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Progressive Supranuclear Palsy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Digestive 2
Dysphagia Dysphagia HP:0002015
Progressive dysphagia is a major source of morbidity in advancing PSP and contributes to aspiration risk and supportive-care needs. No quotable abstract among the cited references isolates a dysphagia-specific frequency, so this association is recorded without an evidence snippet rather than supported by a non-specific quote.
Constipation Constipation HP:0002019
Gastrointestinal dysfunction, including constipation, is frequent in PSP-RS and can be a dominant non-motor symptom.
Show evidence (1 reference)
PMID:36969340 SUPPORT Human Clinical
"GI dysfunction is a frequent and occasionally dominating symptom of progressive supranuclear palsy-Richardson's syndrome (PSP-RS)."
Establishes GI dysfunction (including constipation) as a frequent, sometimes dominant PSP-RS symptom.
Eye 1
Vertical Supranuclear Gaze Palsy Vertical supranuclear gaze palsy HP:0000511
The classic defining ocular motor sign of PSP; one of the four MDS core functional domains (ocular motor dysfunction). Slow vertical saccades often precede frank gaze palsy.
Show evidence (1 reference)
PMID:28467028 SUPPORT Human Clinical
"vertical supranuclear gaze palsy"
Vertical supranuclear gaze palsy is a core diagnostic feature of PSP in the MDS criteria.
Musculoskeletal 2
Frequent Falls VERY_FREQUENT Frequent falls HP:0002359
Early, unprovoked falls (often backward) are a hallmark of PSP-Richardson syndrome.
Show evidence (1 reference)
PMID:38778404 SUPPORT Human Clinical
"the median time for the onset of the first fall was 2.0 years (IQR 3.2) before diagnosis"
Falls were near-universal in the real-world cohort and typically preceded diagnosis by ~2 years, supporting their central, very frequent role.
Axial Rigidity Rigidity HP:0002063
Predominantly axial (neck/trunk) rigidity is characteristic of PSP, often more prominent than appendicular rigidity. The ontology term Rigidity is the closest available; the preferred term conveys the axial predominance.
Show evidence (1 reference)
PMID:38290492 PARTIAL Human Clinical
"more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006)"
Supports rigidity as part of the akinetic-rigid PSP phenotype; the axial predominance specifically is conveyed in the preferred term (PARTIAL).
Nervous System 7
Postural Instability VERY_FREQUENT Postural instability HP:0002172
Early postural instability is one of the four MDS core domains and is characteristic of PSP-RS.
Show evidence (1 reference)
PMID:38778404 SUPPORT Human Clinical
"the median onset of unsteady gait or gait impairment was 1.2 years (IQR 1.8) before diagnosis"
Real-world data show unsteady gait/gait impairment commonly precedes diagnosis, reflecting early postural instability.
Bradykinesia VERY_FREQUENT Bradykinesia HP:0002067
Akinetic-rigid parkinsonism is a core motor feature; in PSP-RS it is typically symmetric and poorly responsive to levodopa.
Show evidence (1 reference)
PMID:38290492 SUPPORT Human Clinical
"PSP-RS patients were older at disease onset (p = 0.009) and had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006)"
Documents akinetic-rigid (bradykinetic) parkinsonism as characteristic of PSP-RS.
Dysarthria Dysarthria HP:0001260
A common speech/bulbar manifestation of PSP that contributes to communication impairment and speech-therapy needs, particularly in PSP-RS and the PSP-SL (speech/language) phenotype. No quotable abstract among the cited references isolates a dysarthria-specific frequency, so this association is recorded without an evidence snippet rather than supported by a non-specific quote.
Cognitive Impairment FREQUENT Cognitive impairment HP:0100543
Cognitive dysfunction is one of the four MDS core domains. Annual cognitive decline is faster in PSP-RS than in variant phenotypes, and cortical phenotypes show greater cognitive alteration than subcortical ones.
Show evidence (1 reference)
PMID:34541533 SUPPORT Human Clinical
"annual progression in Richardson's syndrome was faster than variant phenotypes on the Mini-Mental State Examination (-1.8 versus -0.9/year, P = 0.005)"
Demonstrates measurable, progressive cognitive decline in PSP that differs by phenotype.
Apathy Apathy HP:0000741
Apathy and other frontal behavioral changes are common non-motor features of PSP, particularly in frontal-predominant presentations.
Show evidence (1 reference)
PMID:38290492 PARTIAL Human Clinical
"PSP with predominant frontal presentation [PSP-F]"
Frontal/behavioral PSP presentations (PSP-F) encompass apathy and dysexecutive behavior; the abstract documents the PSP-F phenotype but not apathy frequency specifically (PARTIAL).
Depression Depression HP:0000716
Depression is a common non-motor comorbidity in PSP and improved as a secondary outcome in the FMT trial.
Show evidence (1 reference)
PMID:36969340 SUPPORT Human Clinical
"symptoms of constipation, depression, and anxiety (the secondary outcome) improved significantly at week 16 in the FMT group"
Depression and anxiety are documented non-motor symptoms in a PSP-RS trial population.
Anxiety Anxiety HP:0000739
Anxiety is a non-motor feature of PSP and improved as a secondary outcome alongside depression and constipation in the PSP-RS FMT trial.
Show evidence (1 reference)
PMID:36969340 SUPPORT Human Clinical
"symptoms of constipation, depression, and anxiety (the secondary outcome) improved significantly at week 16 in the FMT group"
Anxiety is documented as a non-motor symptom in a PSP-RS trial population.
Other 3
Slow Vertical Saccades Slow saccadic eye movements HP:0000514
Slowing of vertical saccades is an early ocular motor abnormality in PSP that may precede vertical supranuclear gaze palsy.
Show evidence (1 reference)
PMID:28467028 PARTIAL Human Clinical
"vertical supranuclear gaze palsy"
The MDS ocular motor domain encompasses slow vertical saccades alongside gaze palsy; the cited snippet supports the gaze palsy component directly and the saccadic slowing indirectly (PARTIAL).
Freezing of Gait Freezing of gait HP:0031825
Progressive gait freezing dominates the PSP-PGF variant and can occur across phenotypes with disease progression.
Show evidence (1 reference)
PMID:38290492 SUPPORT Human Clinical
"PSP with progressive gait freezing [PSP-PGF]"
Defines progressive gait freezing as the defining feature of the PSP-PGF phenotype.
Executive Dysfunction Impaired executive functioning HP:0033051
Frontal-subcortical dysexecutive syndrome is prominent, especially in PSP-F and other cortical phenotypes.
Show evidence (1 reference)
PMID:38290492 PARTIAL Human Clinical
"Cognitive domains were significantly less altered in the PSP-subcortical subgroup."
Implies greater cognitive/executive involvement in cortical PSP phenotypes relative to subcortical ones (PARTIAL: executive-specific quote not isolated).
🧬

Genetic Associations

3
MAPT (microtubule-associated protein tau) (H1 haplotype risk factor; rare causal variants in familial PSP)
Gene: MAPT hgnc:6893 relationship_type: RISK_FACTOR variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (2 references)
PMID:39152475 SUPPORT Human Clinical
"Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1"
Whole-genome sequencing confirms MAPT as a PSP susceptibility locus.
PMID:39154163 SUPPORT Human Clinical
"PSP is associated with common variation in the tau gene (MAPT) at the 17q21.31 locus"
Confirms the MAPT 17q21.31 haplotype association underlying PSP genetic risk.
APOE (APOE epsilon-2 risk allele (contrasting with Alzheimer disease))
Gene: APOE hgnc:613 relationship_type: RISK_FACTOR variant_origin: GERMLINE
Show evidence (1 reference)
PMID:39152475 SUPPORT Human Clinical
"in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP."
Directly reports APOE epsilon-2 as the PSP risk allele, opposite to its protective direction in Alzheimer disease.
Confirmed and novel PSP susceptibility loci (Common susceptibility loci confirmed and newly identified by WGS)
relationship_type: RISK_FACTOR variant_origin: GERMLINE
Show evidence (2 references)
PMID:39152475 SUPPORT Human Clinical
"further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1."
Lists novel PSP susceptibility loci identified by WGS.
PMID:39152475 SUPPORT Human Clinical
"In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP."
Documents structural-variant burden at the major PSP locus.
💊

Medical Actions

6
Levodopa Trial
Action: Pharmacotherapy NCIT:C15986
Agent: levodopa CHEBI:15765
A trial of levodopa is standard in parkinsonian presentations of PSP, but motor response is typically limited and transient, especially in PSP-RS where parkinsonism is characteristically levodopa-resistant. Amantadine and dopamine agonists are also used with generally modest benefit.
Show evidence (1 reference)
PMID:38290492 SUPPORT Human Clinical
"PSP-RS patients were older at disease onset (p = 0.009) and had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006)"
Documents the characteristically levodopa-resistant parkinsonism of PSP-RS, explaining the limited benefit of a levodopa trial.
Physical, Occupational, and Speech Therapy
Action: physical therapy MAXO:0000011
Multidisciplinary rehabilitation (physical therapy for gait/balance and fall prevention, occupational therapy, and speech/swallow therapy) is a mainstay of PSP management given the lack of disease-modifying treatment.
Show evidence (1 reference)
PMID:38778404 SUPPORT Human Clinical
"supportive care (86%)"
Supportive care including rehabilitative therapies was used by most PSP patients in the real-world cohort.
Supportive and Palliative Care
Action: supportive care MAXO:0000950
Symptomatic and supportive care dominates PSP management, including assistive devices, fall and aspiration risk reduction, dysphagia management, and treatment of mood and GI symptoms. Healthcare utilization is high, with assistive devices and supportive care used by the large majority of patients.
Show evidence (1 reference)
PMID:38778404 SUPPORT Human Clinical
"were medications (100%), imaging (99%), assistive devices (90%), supportive care (86%), and surgeries and procedures (85%)."
Quantifies near-universal reliance on supportive care, assistive devices, and symptomatic treatment in PSP.
Anti-Tau Monoclonal Antibody Therapy (investigational, negative trials)
Action: Pharmacotherapy NCIT:C15986
Agent: monoclonal antibody NCIT:C20401
Anti-tau monoclonal antibodies targeting N-terminal tau (gosuranemab, PASSPORT; tilavonemab, ARISE) reached phase 2 but failed to show clinical benefit on the PSP Rating Scale despite strong CSF target engagement, and development for PSP was discontinued. Listed to capture the experimental disease-modifying landscape.
Show evidence (2 references)
PMID:34385707 REFUTE Human Clinical
"Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint)"
The gosuranemab PASSPORT trial showed no clinical efficacy in PSP, refuting benefit of this anti-tau antibody.
PMID:33609476 REFUTE Human Clinical
"The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis."
The tilavonemab trial was terminated for futility, refuting clinical benefit in PSP.
Faecal Microbiota Transplantation (investigational)
Action: faecal microbiota transplantation Ontology label: Fecal Microbiota Transplantation NCIT:C118643
Faecal microbiota transplantation (FMT) is a microbiome-directed therapy investigated for PSP-RS on the rationale that gastrointestinal dysfunction is a frequent, sometimes dominating PSP-RS symptom. In a single-centre phase 2 randomized trial, FMT improved the PSP Rating Scale and nonmotor symptoms (constipation, depression, anxiety), representing the only positive disease-relevant signal reported to date. Single-centre and requires replication.
Show evidence (1 reference)
PMID:36969340 SUPPORT Human Clinical
"compared with placebo, FMT treatment significantly improved motor and nonmotor symptoms in patients with PSP-RS"
The phase 2 FMT trial reported significant improvement in motor and nonmotor symptoms in PSP-RS, the only positive disease-relevant treatment signal to date.
Botulinum Toxin Therapy
Action: Botulinum Toxin Therapy NCIT:C157775
Botulinum toxin injections are used for selected focal symptoms in PSP such as dystonia (e.g., blepharospasm, focal limb/axial dystonia) and sialorrhea.
Show evidence (1 reference)
PMID:38778404 PARTIAL Human Clinical
"surgeries and procedures (85%)."
Procedural/symptomatic interventions (which include botulinum toxin for dystonia and sialorrhea) were widely used; the abstract does not isolate botulinum toxin specifically (PARTIAL).
🔬

Clinical Trials

3
NCT03068468 PHASE_II COMPLETED
PASSPORT: a randomized, double-blind, placebo-controlled 52-week phase 2 trial of the anti-tau monoclonal antibody gosuranemab in PSP. The primary endpoint (PSP Rating Scale change) was not met despite strong CSF target engagement.
Target Phenotypes: Postural instability HP:0002172 Bradykinesia HP:0002067
Show evidence (1 reference)
PMID:34385707 REFUTE Human Clinical
"In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165)."
Identifies the PASSPORT phase 2 trial population; the trial failed to show efficacy on the PSP Rating Scale.
NCT02985879 PHASE_II TERMINATED
ARISE: a phase 2, multicentre, randomized, placebo-controlled trial of the anti-tau monoclonal antibody tilavonemab (ABBV-8E12) in PSP, terminated early for futility.
Target Phenotypes: Postural instability HP:0002172
Show evidence (1 reference)
PMID:33609476 REFUTE Human Clinical
"Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised."
Identifies the ARISE tilavonemab phase 2 trial, which was terminated for futility in PSP.
ChiCTR-2100045397 PHASE_II COMPLETED
A single-centre, randomized, placebo-controlled, parallel-group phase 2 trial of faecal microbiota transplantation (FMT) in newly diagnosed, treatment-naive PSP-RS patients. The primary endpoint (PSP Rating Scale change at week 16) was met with a significant treatment benefit, and nonmotor symptoms (constipation, depression, anxiety) also improved. This is the only positive disease-relevant treatment signal reported in PSP to date and requires multicentre replication.
Target Phenotypes: Constipation HP:0002019 Depression HP:0000716
Show evidence (1 reference)
PMID:36969340 SUPPORT Human Clinical
"At week 16, the mean PSP Rating Scale (PSPRS) scores (the primary outcome) improved from 40.1 (SD 7.6) to 36.9 (SD 5.9) in the FMT group"
The FMT phase 2 trial met its primary endpoint with a significant PSPRS improvement, the only positive disease-relevant signal in PSP trials to date.
{ }

Source YAML

click to show 
name: Progressive Supranuclear Palsy
creation_date: "2026-06-05T12:00:00Z"
category: Complex
description: >-
  Progressive supranuclear palsy (PSP) is an adult-onset, rapidly progressive
  neurodegenerative 4R-tauopathy in which hyperphosphorylated four-repeat (4R) tau
  aggregates accumulate in neurons and glia (tufted astrocytes and oligodendroglial
  coiled bodies) predominantly affecting subcortical and brainstem structures
  (subthalamic nucleus, globus pallidus, dorsal midbrain) with variable cortical
  involvement. The classical phenotype (PSP-Richardson syndrome) features vertical
  supranuclear gaze palsy, early postural instability with falls, axial rigidity,
  akinetic-rigid parkinsonism that is poorly responsive to levodopa, and
  frontal-subcortical cognitive/behavioral decline. PSP is mostly sporadic; the MAPT
  17q21.31 H1 haplotype is the strongest common genetic risk factor and rare familial
  MAPT-associated PSP-like syndromes occur. Diagnosis follows the 2017 Movement
  Disorder Society (MDS) criteria, which recognize a spectrum of clinical phenotypes
  beyond Richardson syndrome.
disease_term:
  preferred_term: Progressive Supranuclear Palsy
  term:
    id: MONDO:0019037
    label: progressive supranuclear palsy
parents:
- Neurodegenerative Disease
- Parkinsonism
has_subtypes:
- name: PSP-RS
  display_name: PSP-Richardson syndrome
  description: >-
    The classical and most common PSP phenotype, characterized by early postural
    instability with falls, vertical supranuclear gaze palsy, and akinetic-rigid,
    levodopa-resistant parkinsonism, with frontal-subcortical cognitive decline.
    Associated with the most rapid clinical progression and shortest survival of the
    PSP phenotypes.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PSP-RS patients were older at disease onset (p = 0.009) and had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006)"
    explanation: >-
      Characterizes PSP-RS as the akinetic-rigid, levodopa-resistant phenotype in an
      MDS-recategorized cohort.
- name: PSP-P
  display_name: PSP-parkinsonism
  description: >-
    Variant phenotype presenting with a parkinsonian syndrome (asymmetric onset,
    tremor, and sometimes initial levodopa responsiveness) that overlaps clinically
    with Parkinson disease early in the course, often leading to delayed diagnosis.
    Generally slower progression and longer survival than PSP-RS.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PSP with predominant parkinsonism [PSP-P]"
    explanation: >-
      Enumerates PSP-P (PSP with predominant parkinsonism) as a distinct MDS
      phenotype in the recategorized cohort, where it is grouped under the
      PSP-subcortical subgroup.
- name: PSP-PGF
  display_name: PSP with progressive gait freezing
  description: >-
    Variant phenotype dominated by progressive gait freezing (pure akinesia with
    gait freezing), with relatively preserved cognition and limb tone early in the
    course.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PSP with progressive gait freezing [PSP-PGF]"
    explanation: >-
      PSP-PGF is enumerated as a distinct MDS phenotype in the recategorized cohort.
- name: PSP-cortical
  display_name: PSP-cortical phenotypes (PSP-F, PSP-SL, PSP-CBS)
  description: >-
    Cortical-predominant PSP phenotypes including PSP with predominant frontal
    presentation (PSP-F, dysexecutive/behavioral), PSP with predominant
    speech/language disorder (PSP-SL, overlapping nonfluent/agrammatic primary
    progressive aphasia and apraxia of speech), and PSP with corticobasal syndrome
    (PSP-CBS). These show greater cognitive alteration than subcortical variants.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "34 PSP-cortical (PSP-CBS, 17.6%; PSP-F, 9.4%; PSP-SL, 8.2%)"
    explanation: >-
      Defines and quantifies the cortical PSP phenotype grouping in the MDS-based cohort.
- name: PSP-subcortical-other
  display_name: PSP-subcortical phenotypes (PSP-PI, PSP-OM, PSP-C)
  description: >-
    Subcortical-predominant PSP variants other than PSP-P/PSP-PGF, including PSP with
    predominant postural instability (PSP-PI), PSP with predominant ocular motor
    dysfunction (PSP-OM), and PSP with cerebellar ataxia (PSP-C). Cognitive domains
    are generally less affected than in cortical phenotypes.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive domains were significantly less altered in the PSP-subcortical subgroup."
    explanation: >-
      Distinguishes the subcortical phenotype grouping by relatively preserved cognition.
- name: Inherited PSP (MAPT)
  display_name: Inherited PSP (MAPT-associated)
  description: >-
    Rare familial PSP-like syndromes caused by MAPT mutations. Most PSP is sporadic,
    and in the MDS criteria a MAPT mutation does not exclude the diagnosis but
    distinguishes inherited from sporadic PSP. The MAPT H1 haplotype is a common risk
    factor distinct from rare causal MAPT variants.
  genes:
  - preferred_term: MAPT
    term:
      id: hgnc:6893
      label: MAPT
  inheritance:
  - name: Autosomal dominant inheritance
  evidence:
  - reference: PMID:39154163
    reference_title: "MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PSP is associated with common variation in the tau gene (MAPT) at the 17q21.31 locus"
    explanation: >-
      MAPT variation underlies both common haplotype risk and rare familial PSP; this
      subtype captures the inherited MAPT-associated form.
pathophysiology:
- name: 4R-Tau Aggregation in Neurons and Glia
  description: >-
    PSP is neuropathologically defined by accumulation of hyperphosphorylated,
    aggregated four-repeat (4R) tau in neurons, astrocytes (tufted astrocytes), and
    oligodendrocytes (coiled bodies). Tau inclusions disrupt microtubule biology and
    proteostasis. MAPT expression is preserved in all three cell types harboring tau
    aggregates, supporting ongoing local tau production that can feed continued
    aggregation and cell-to-cell seeding. This is the upstream initiating lesion of
    PSP pathology.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: tufted astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: oligodendrocyte (coiled body)
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: Tau (amyloid) fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  - preferred_term: Disrupted microtubule cytoskeleton organization
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
    modifier: ABNORMAL
  - preferred_term: Tau hyperphosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
    modifier: INCREASED
  downstream:
  - target: Integrated Stress Response Activation
  - target: Neuronal Dysfunction and Loss
  evidence:
  - reference: PMID:39152475
    reference_title: "Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes."
    explanation: >-
      Establishes the defining PSP lesion: aggregated tau across neurons, astrocytes,
      and oligodendrocytes.
  - reference: PMID:37354322
    reference_title: "Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MAPT transcripts were detected in neurons, astrocytes and oligodendrocytes, and varied between brain regions and within each cell type, and were preserved in all cell types with tau aggregates in PSP."
    explanation: >-
      Shows MAPT expression is preserved in all three cell types bearing tau
      aggregates, supporting ongoing local tau supply for aggregation/seeding.
- name: MAPT H1 Haplotype and 4R Tau Splicing Imbalance
  description: >-
    The MAPT 17q21.31 locus contains low-copy repeats flanking a recurrent genomic
    inversion, giving rise to two dominant haplotypes (H1 and H2). The H1 haplotype is
    the strongest common genetic risk factor for PSP. Haplotype-dependent regulation
    biases tau pre-mRNA splicing and expression toward the 4R isoform: post-mortem
    bulk RNA-seq shows increased total tau mRNA and an increased proportion of 4R tau
    transcripts in PSP brain, with 4R tau mRNA significantly associated with the H1
    haplotype, supporting an upstream splicing/expression mechanism feeding tau
    aggregation.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Regulation of mRNA splicing toward 4R tau
    term:
      id: GO:0048024
      label: regulation of mRNA splicing, via spliceosome
    modifier: ABNORMAL
  - preferred_term: Increased tau gene expression
    term:
      id: GO:0010468
      label: regulation of gene expression
    modifier: INCREASED
  downstream:
  - target: 4R-Tau Aggregation in Neurons and Glia
  evidence:
  - reference: PMID:39154163
    reference_title: "MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "4R tau mRNA levels were significantly associated with the H1 haplotype in the temporal cortex."
    explanation: >-
      Directly links the MAPT H1 risk haplotype to increased 4R tau mRNA, supporting a
      splicing/expression mechanism upstream of aggregation.
  - reference: PMID:39154163
    reference_title: "MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings support the hypothesis that sporadic PSP is associated with haplotype-dependent increases in 4R tau mRNA that might play a causal role in this disorder."
    explanation: >-
      Authors frame haplotype-dependent 4R tau mRNA increase as a candidate causal
      mechanism for sporadic PSP.
  - reference: PMID:39152475
    reference_title: "Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1"
    explanation: >-
      Confirms MAPT and additional risk loci by whole-genome sequencing, anchoring the
      genetic architecture upstream of tau pathology.
- name: Integrated Stress Response Activation
  description: >-
    Chronic proteotoxic/tau burden activates the integrated stress response (EIF2
    signaling) in vulnerable cell types. Single-nucleus RNA-seq of the PSP
    diencephalon identified EIF2 signaling as an activated adaptive stress pathway,
    and activated eIF2-alpha was positively correlated with tau pathology burden and
    localized to p-tau-positive neurons and ALDH1L1-positive astrocytes. Failure of
    this adaptive stress response is proposed to contribute mechanistically to PSP
    progression and neuronal loss.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: Integrated stress response signaling
    term:
      id: GO:0140467
      label: integrated stress response signaling
    modifier: INCREASED
  - preferred_term: Response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  downstream:
  - target: Neuronal Dysfunction and Loss
  evidence:
  - reference: PMID:39648200
    reference_title: "Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was activated in multiple vulnerable cell types"
    explanation: >-
      Single-nucleus RNA-seq identifies EIF2/integrated stress response activation
      across vulnerable PSP cell types.
  - reference: PMID:39648200
    reference_title: "Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions."
    explanation: >-
      Correlates activated eIF2-alpha with tau burden, linking tau pathology to the
      stress response downstream.
- name: Neuroinflammation and Glial Activation
  description: >-
    Tau pathology triggers glial and immune activation in PSP. CSF proteomic and
    neuropathologic studies implicate dysregulated cytokine/inflammatory signaling
    and glial activation as an ongoing neuroimmune component that may track and
    contribute to disease progression. (Cached CSF-proteomics reference content was
    title-only; quantitative inflammatory-marker detail in the deep-research report
    should be re-verified against the full abstract before being quoted.)
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: Neuroinflammatory response
    term:
      id: GO:0150076
      label: neuroinflammatory response
    modifier: INCREASED
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Neuronal Dysfunction and Loss
  evidence:
  - reference: PMID:39648200
    reference_title: "Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes"
    explanation: >-
      Demonstrates glial (astrocytic) involvement in PSP stress-pathway pathology;
      supports glial activation as part of the neuroinflammatory mechanism (PARTIAL,
      as the quote addresses stress signaling rather than cytokine inflammation
      directly).
- name: Axon Guidance and Synaptic Pathway Dysregulation
  description: >-
    Downstream of tauopathy, PSP shows circuit-level dysfunction. CSF proteomic
    studies have identified dysregulation of axon guidance and synaptic-function
    pathways, consistent with axonal and synaptic injury contributing to the motor
    and cognitive syndromes. (CSF-proteomics cache content was title-only; the
    axon-guidance pathway detail is drawn from the deep-research report and should be
    re-verified against the full abstract before quoting specific statistics.)
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Axon guidance
    term:
      id: GO:0007411
      label: axon guidance
    modifier: ABNORMAL
  downstream:
  - target: Neuronal Dysfunction and Loss
  evidence:
  - reference: PMID:38582079
    reference_title: "Human iPSC 4R tauopathy model uncovers modifiers of tau propagation."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity."
    explanation: >-
      A human iPSC 4R-tauopathy model shows tau-seeding-induced neuronal/synaptic
      dysfunction (reduced neuronal activity), supporting circuit-level dysfunction
      downstream of tau pathology relevant to PSP (PARTIAL: model-derived, not a
      direct PSP axon-guidance measurement).
- name: Neuronal Dysfunction and Loss
  description: >-
    Convergent tau toxicity, maladaptive stress signaling, neuroinflammation, and
    synaptic/axonal injury produce region- and cell-type-specific neuronal
    dysfunction and death, predominantly in the subthalamic nucleus, globus pallidus,
    and dorsal midbrain, with variable cortical involvement. This neurodegeneration
    underlies the progressive motor, oculomotor, and cognitive syndromes of PSP.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:39648200
    reference_title: "Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The precise mechanism whereby these protein aggregates lead to cell death remains unclear."
    explanation: >-
      Frames neuronal cell death as the downstream endpoint of tau aggregation in PSP,
      while noting mechanistic uncertainty.
phenotypes:
- category: Neurological
  name: Vertical Supranuclear Gaze Palsy
  phenotype_term:
    preferred_term: Vertical supranuclear gaze palsy
    term:
      id: HP:0000511
      label: Vertical supranuclear gaze palsy
  diagnostic: true
  notes: >-
    The classic defining ocular motor sign of PSP; one of the four MDS core
    functional domains (ocular motor dysfunction). Slow vertical saccades often
    precede frank gaze palsy.
  evidence:
  - reference: PMID:28467028
    reference_title: "Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "vertical supranuclear gaze palsy"
    explanation: >-
      Vertical supranuclear gaze palsy is a core diagnostic feature of PSP in the MDS
      criteria.
- category: Neurological
  name: Slow Vertical Saccades
  phenotype_term:
    preferred_term: Slow saccadic eye movements
    term:
      id: HP:0000514
      label: Slow saccadic eye movements
  notes: >-
    Slowing of vertical saccades is an early ocular motor abnormality in PSP that may
    precede vertical supranuclear gaze palsy.
  evidence:
  - reference: PMID:28467028
    reference_title: "Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "vertical supranuclear gaze palsy"
    explanation: >-
      The MDS ocular motor domain encompasses slow vertical saccades alongside gaze
      palsy; the cited snippet supports the gaze palsy component directly and the
      saccadic slowing indirectly (PARTIAL).
- category: Neurological
  name: Postural Instability
  phenotype_term:
    preferred_term: Postural instability
    term:
      id: HP:0002172
      label: Postural instability
  diagnostic: true
  frequency: VERY_FREQUENT
  notes: >-
    Early postural instability is one of the four MDS core domains and is
    characteristic of PSP-RS.
  evidence:
  - reference: PMID:38778404
    reference_title: "Progressive Supranuclear palsy (PSP) disease progression, management, and healthcare resource utilization: a retrospective observational study in the US and Canada."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the median onset of unsteady gait or gait impairment was 1.2 years (IQR 1.8) before diagnosis"
    explanation: >-
      Real-world data show unsteady gait/gait impairment commonly precedes diagnosis,
      reflecting early postural instability.
- category: Neurological
  name: Frequent Falls
  phenotype_term:
    preferred_term: Frequent falls
    term:
      id: HP:0002359
      label: Frequent falls
  frequency: VERY_FREQUENT
  notes: >-
    Early, unprovoked falls (often backward) are a hallmark of PSP-Richardson
    syndrome.
  evidence:
  - reference: PMID:38778404
    reference_title: "Progressive Supranuclear palsy (PSP) disease progression, management, and healthcare resource utilization: a retrospective observational study in the US and Canada."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the median time for the onset of the first fall was 2.0 years (IQR 3.2) before diagnosis"
    explanation: >-
      Falls were near-universal in the real-world cohort and typically preceded
      diagnosis by ~2 years, supporting their central, very frequent role.
- category: Neurological
  name: Freezing of Gait
  phenotype_term:
    preferred_term: Freezing of gait
    term:
      id: HP:0031825
      label: Freezing of gait
  subtype: PSP-PGF
  notes: >-
    Progressive gait freezing dominates the PSP-PGF variant and can occur across
    phenotypes with disease progression.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PSP with progressive gait freezing [PSP-PGF]"
    explanation: >-
      Defines progressive gait freezing as the defining feature of the PSP-PGF
      phenotype.
- category: Neurological
  name: Bradykinesia
  phenotype_term:
    preferred_term: Bradykinesia
    term:
      id: HP:0002067
      label: Bradykinesia
  frequency: VERY_FREQUENT
  notes: >-
    Akinetic-rigid parkinsonism is a core motor feature; in PSP-RS it is typically
    symmetric and poorly responsive to levodopa.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PSP-RS patients were older at disease onset (p = 0.009) and had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006)"
    explanation: >-
      Documents akinetic-rigid (bradykinetic) parkinsonism as characteristic of
      PSP-RS.
- category: Neurological
  name: Axial Rigidity
  phenotype_term:
    preferred_term: Axial rigidity
    term:
      id: HP:0002063
      label: Rigidity
  notes: >-
    Predominantly axial (neck/trunk) rigidity is characteristic of PSP, often more
    prominent than appendicular rigidity. The ontology term Rigidity is the closest
    available; the preferred term conveys the axial predominance.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006)"
    explanation: >-
      Supports rigidity as part of the akinetic-rigid PSP phenotype; the axial
      predominance specifically is conveyed in the preferred term (PARTIAL).
- category: Neurological
  name: Dysarthria
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  notes: >-
    A common speech/bulbar manifestation of PSP that contributes to communication
    impairment and speech-therapy needs, particularly in PSP-RS and the PSP-SL
    (speech/language) phenotype. No quotable abstract among the cited references
    isolates a dysarthria-specific frequency, so this association is recorded
    without an evidence snippet rather than supported by a non-specific quote.
- category: Neurological
  name: Dysphagia
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  notes: >-
    Progressive dysphagia is a major source of morbidity in advancing PSP and
    contributes to aspiration risk and supportive-care needs. No quotable abstract
    among the cited references isolates a dysphagia-specific frequency, so this
    association is recorded without an evidence snippet rather than supported by a
    non-specific quote.
- category: Neurological
  name: Cognitive Impairment
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  frequency: FREQUENT
  notes: >-
    Cognitive dysfunction is one of the four MDS core domains. Annual cognitive
    decline is faster in PSP-RS than in variant phenotypes, and cortical phenotypes
    show greater cognitive alteration than subcortical ones.
  evidence:
  - reference: PMID:34541533
    reference_title: "Clinical progression of progressive supranuclear palsy: impact of trials bias and phenotype variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "annual progression in Richardson's syndrome was faster than variant phenotypes on the Mini-Mental State Examination (-1.8 versus -0.9/year, P = 0.005)"
    explanation: >-
      Demonstrates measurable, progressive cognitive decline in PSP that differs by
      phenotype.
- category: Neurological
  name: Executive Dysfunction
  phenotype_term:
    preferred_term: Impaired executive functioning
    term:
      id: HP:0033051
      label: Impaired executive functioning
  subtype: PSP-cortical
  notes: >-
    Frontal-subcortical dysexecutive syndrome is prominent, especially in PSP-F and
    other cortical phenotypes.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive domains were significantly less altered in the PSP-subcortical subgroup."
    explanation: >-
      Implies greater cognitive/executive involvement in cortical PSP phenotypes
      relative to subcortical ones (PARTIAL: executive-specific quote not isolated).
- category: Neurological
  name: Apathy
  phenotype_term:
    preferred_term: Apathy
    term:
      id: HP:0000741
      label: Apathy
  notes: >-
    Apathy and other frontal behavioral changes are common non-motor features of PSP,
    particularly in frontal-predominant presentations.
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "PSP with predominant frontal presentation [PSP-F]"
    explanation: >-
      Frontal/behavioral PSP presentations (PSP-F) encompass apathy and dysexecutive
      behavior; the abstract documents the PSP-F phenotype but not apathy frequency
      specifically (PARTIAL).
- category: Behavioral
  name: Depression
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  notes: >-
    Depression is a common non-motor comorbidity in PSP and improved as a secondary
    outcome in the FMT trial.
  evidence:
  - reference: PMID:36969340
    reference_title: "Efficacy of faecal microbiota transplantation in patients with progressive supranuclear palsy-Richardson's syndrome: a phase 2, single centre, randomised clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptoms of constipation, depression, and anxiety (the secondary outcome) improved significantly at week 16 in the FMT group"
    explanation: >-
      Depression and anxiety are documented non-motor symptoms in a PSP-RS trial
      population.
- category: Behavioral
  name: Anxiety
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  notes: >-
    Anxiety is a non-motor feature of PSP and improved as a secondary outcome
    alongside depression and constipation in the PSP-RS FMT trial.
  evidence:
  - reference: PMID:36969340
    reference_title: "Efficacy of faecal microbiota transplantation in patients with progressive supranuclear palsy-Richardson's syndrome: a phase 2, single centre, randomised clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptoms of constipation, depression, and anxiety (the secondary outcome) improved significantly at week 16 in the FMT group"
    explanation: >-
      Anxiety is documented as a non-motor symptom in a PSP-RS trial population.
- category: Gastrointestinal
  name: Constipation
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  notes: >-
    Gastrointestinal dysfunction, including constipation, is frequent in PSP-RS and
    can be a dominant non-motor symptom.
  evidence:
  - reference: PMID:36969340
    reference_title: "Efficacy of faecal microbiota transplantation in patients with progressive supranuclear palsy-Richardson's syndrome: a phase 2, single centre, randomised clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GI dysfunction is a frequent and occasionally dominating symptom of progressive supranuclear palsy-Richardson's syndrome (PSP-RS)."
    explanation: >-
      Establishes GI dysfunction (including constipation) as a frequent, sometimes
      dominant PSP-RS symptom.
genetic:
- name: MAPT (microtubule-associated protein tau)
  gene_term:
    preferred_term: MAPT
    term:
      id: hgnc:6893
      label: MAPT
  association: H1 haplotype risk factor; rare causal variants in familial PSP
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal dominant inheritance
  notes: >-
    The MAPT 17q21.31 H1 haplotype is the strongest common genetic risk factor for
    PSP (estimated odds ratio ~5.6 in WGS analysis). It is distinct from rare causal
    MAPT mutations that produce inherited PSP-like syndromes. Haplotype-dependent
    increases in 4R tau mRNA are a candidate causal mechanism in sporadic PSP.
  evidence:
  - reference: PMID:39152475
    reference_title: "Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1"
    explanation: >-
      Whole-genome sequencing confirms MAPT as a PSP susceptibility locus.
  - reference: PMID:39154163
    reference_title: "MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PSP is associated with common variation in the tau gene (MAPT) at the 17q21.31 locus"
    explanation: >-
      Confirms the MAPT 17q21.31 haplotype association underlying PSP genetic risk.
- name: APOE
  gene_term:
    preferred_term: APOE
    term:
      id: hgnc:613
      label: APOE
  association: APOE epsilon-2 risk allele (contrasting with Alzheimer disease)
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: >-
    In contrast to Alzheimer disease, the APOE epsilon-2 allele is observed as the
    risk allele in PSP in whole-genome sequencing analysis.
  evidence:
  - reference: PMID:39152475
    reference_title: "Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP."
    explanation: >-
      Directly reports APOE epsilon-2 as the PSP risk allele, opposite to its
      protective direction in Alzheimer disease.
- name: Confirmed and novel PSP susceptibility loci
  association: Common susceptibility loci confirmed and newly identified by WGS
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: >-
    Beyond MAPT and APOE, whole-genome sequencing confirmed MOBP, STX6, SLCO1A2,
    DUSP10, and SP1 and uncovered novel signals in FCHO1/MAP1S, KIF13A, TRIM24, TNXB,
    and ELOVL1, plus a rare-variant association in ZNF592 and structural-variant
    burden in the 17q21.31 H1/H2 region. MOBP implicates oligodendrocyte/myelin
    biology in PSP.
  evidence:
  - reference: PMID:39152475
    reference_title: "Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1."
    explanation: >-
      Lists novel PSP susceptibility loci identified by WGS.
  - reference: PMID:39152475
    reference_title: "Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP."
    explanation: >-
      Documents structural-variant burden at the major PSP locus.
treatments:
- name: Levodopa Trial
  description: >-
    A trial of levodopa is standard in parkinsonian presentations of PSP, but motor
    response is typically limited and transient, especially in PSP-RS where
    parkinsonism is characteristically levodopa-resistant. Amantadine and dopamine
    agonists are also used with generally modest benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
  evidence:
  - reference: PMID:38290492
    reference_title: "Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PSP-RS patients were older at disease onset (p = 0.009) and had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006)"
    explanation: >-
      Documents the characteristically levodopa-resistant parkinsonism of PSP-RS,
      explaining the limited benefit of a levodopa trial.
- name: Physical, Occupational, and Speech Therapy
  description: >-
    Multidisciplinary rehabilitation (physical therapy for gait/balance and fall
    prevention, occupational therapy, and speech/swallow therapy) is a mainstay of
    PSP management given the lack of disease-modifying treatment.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:38778404
    reference_title: "Progressive Supranuclear palsy (PSP) disease progression, management, and healthcare resource utilization: a retrospective observational study in the US and Canada."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "supportive care (86%)"
    explanation: >-
      Supportive care including rehabilitative therapies was used by most PSP patients
      in the real-world cohort.
- name: Supportive and Palliative Care
  description: >-
    Symptomatic and supportive care dominates PSP management, including assistive
    devices, fall and aspiration risk reduction, dysphagia management, and treatment
    of mood and GI symptoms. Healthcare utilization is high, with assistive devices
    and supportive care used by the large majority of patients.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:38778404
    reference_title: "Progressive Supranuclear palsy (PSP) disease progression, management, and healthcare resource utilization: a retrospective observational study in the US and Canada."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were medications (100%), imaging (99%), assistive devices (90%), supportive care (86%), and surgeries and procedures (85%)."
    explanation: >-
      Quantifies near-universal reliance on supportive care, assistive devices, and
      symptomatic treatment in PSP.
- name: Anti-Tau Monoclonal Antibody Therapy (investigational, negative trials)
  description: >-
    Anti-tau monoclonal antibodies targeting N-terminal tau (gosuranemab, PASSPORT;
    tilavonemab, ARISE) reached phase 2 but failed to show clinical benefit on the
    PSP Rating Scale despite strong CSF target engagement, and development for PSP was
    discontinued. Listed to capture the experimental disease-modifying landscape.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: monoclonal antibody
      term:
        id: NCIT:C20401
        label: Monoclonal Antibody
  evidence:
  - reference: PMID:34385707
    reference_title: "Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint)"
    explanation: >-
      The gosuranemab PASSPORT trial showed no clinical efficacy in PSP, refuting
      benefit of this anti-tau antibody.
  - reference: PMID:33609476
    reference_title: "Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis."
    explanation: >-
      The tilavonemab trial was terminated for futility, refuting clinical benefit in
      PSP.
- name: Faecal Microbiota Transplantation (investigational)
  description: >-
    Faecal microbiota transplantation (FMT) is a microbiome-directed therapy
    investigated for PSP-RS on the rationale that gastrointestinal dysfunction is a
    frequent, sometimes dominating PSP-RS symptom. In a single-centre phase 2
    randomized trial, FMT improved the PSP Rating Scale and nonmotor symptoms
    (constipation, depression, anxiety), representing the only positive
    disease-relevant signal reported to date. Single-centre and requires
    replication.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: faecal microbiota transplantation
    term:
      id: NCIT:C118643
      label: Fecal Microbiota Transplantation
  evidence:
  - reference: PMID:36969340
    reference_title: "Efficacy of faecal microbiota transplantation in patients with progressive supranuclear palsy-Richardson's syndrome: a phase 2, single centre, randomised clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "compared with placebo, FMT treatment significantly improved motor and nonmotor symptoms in patients with PSP-RS"
    explanation: >-
      The phase 2 FMT trial reported significant improvement in motor and nonmotor
      symptoms in PSP-RS, the only positive disease-relevant treatment signal to date.
- name: Botulinum Toxin Therapy
  description: >-
    Botulinum toxin injections are used for selected focal symptoms in PSP such as
    dystonia (e.g., blepharospasm, focal limb/axial dystonia) and sialorrhea.
  treatment_term:
    preferred_term: Botulinum Toxin Therapy
    term:
      id: NCIT:C157775
      label: Botulinum Toxin Therapy
  evidence:
  - reference: PMID:38778404
    reference_title: "Progressive Supranuclear palsy (PSP) disease progression, management, and healthcare resource utilization: a retrospective observational study in the US and Canada."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "surgeries and procedures (85%)."
    explanation: >-
      Procedural/symptomatic interventions (which include botulinum toxin for dystonia
      and sialorrhea) were widely used; the abstract does not isolate botulinum toxin
      specifically (PARTIAL).
clinical_trials:
- name: NCT03068468
  phase: PHASE_II
  status: COMPLETED
  description: >-
    PASSPORT: a randomized, double-blind, placebo-controlled 52-week phase 2 trial of
    the anti-tau monoclonal antibody gosuranemab in PSP. The primary endpoint (PSP
    Rating Scale change) was not met despite strong CSF target engagement.
  target_phenotypes:
  - preferred_term: Postural instability
    term:
      id: HP:0002172
      label: Postural instability
  - preferred_term: Bradykinesia
    term:
      id: HP:0002067
      label: Bradykinesia
  evidence:
  - reference: PMID:34385707
    reference_title: "Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165)."
    explanation: >-
      Identifies the PASSPORT phase 2 trial population; the trial failed to show
      efficacy on the PSP Rating Scale.
- name: NCT02985879
  phase: PHASE_II
  status: TERMINATED
  description: >-
    ARISE: a phase 2, multicentre, randomized, placebo-controlled trial of the
    anti-tau monoclonal antibody tilavonemab (ABBV-8E12) in PSP, terminated early for
    futility.
  target_phenotypes:
  - preferred_term: Postural instability
    term:
      id: HP:0002172
      label: Postural instability
  evidence:
  - reference: PMID:33609476
    reference_title: "Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised."
    explanation: >-
      Identifies the ARISE tilavonemab phase 2 trial, which was terminated for futility
      in PSP.
- name: ChiCTR-2100045397
  phase: PHASE_II
  status: COMPLETED
  description: >-
    A single-centre, randomized, placebo-controlled, parallel-group phase 2 trial of
    faecal microbiota transplantation (FMT) in newly diagnosed, treatment-naive
    PSP-RS patients. The primary endpoint (PSP Rating Scale change at week 16) was met
    with a significant treatment benefit, and nonmotor symptoms (constipation,
    depression, anxiety) also improved. This is the only positive disease-relevant
    treatment signal reported in PSP to date and requires multicentre replication.
  target_phenotypes:
  - preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  - preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:36969340
    reference_title: "Efficacy of faecal microbiota transplantation in patients with progressive supranuclear palsy-Richardson's syndrome: a phase 2, single centre, randomised clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At week 16, the mean PSP Rating Scale (PSPRS) scores (the primary outcome) improved from 40.1 (SD 7.6) to 36.9 (SD 5.9) in the FMT group"
    explanation: >-
      The FMT phase 2 trial met its primary endpoint with a significant PSPRS
      improvement, the only positive disease-relevant signal in PSP trials to date.
progression:
- phase: Phenotype-dependent clinical progression and survival
  notes: >-
    Richardson's syndrome (PSP-RS) progresses faster and has shorter survival than
    variant phenotypes. Annual cognitive decline on the MMSE is faster in PSP-RS
    (-1.8 vs -0.9/year), and median survival from onset is shorter in PSP-RS
    (5.6 years) than in variant phenotypes (7.3 years).
  evidence:
  - reference: PMID:34541533
    reference_title: "Clinical progression of progressive supranuclear palsy: impact of trials bias and phenotype variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Survival was longer in variant phenotypes than Richardson's syndrome [7.3 (±3.9) versus 5.6 (±2.0) years, P = 0.02]."
    explanation: >-
      Documents shorter survival in PSP-RS compared with variant phenotypes.
  - reference: PMID:34541533
    reference_title: "Clinical progression of progressive supranuclear palsy: impact of trials bias and phenotype variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "annual progression in Richardson's syndrome was faster than variant phenotypes on the Mini-Mental State Examination (-1.8 versus -0.9/year, P = 0.005)"
    explanation: >-
      Quantifies faster annual cognitive decline in PSP-RS relative to variant
      phenotypes.
epidemiology:
- name: Adult-onset sporadic neurodegenerative disease with delayed diagnosis
  description: >-
    PSP is a sporadic, adult-onset, gradually progressive neurodegenerative disease.
    Diagnosis is typically made several years after symptom onset, once cardinal
    features (falls and supranuclear gaze palsy) become unequivocally apparent.
  evidence:
  - reference: PMID:28467028
    reference_title: "Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is typically made 3 to 4 years after onset of first symptoms, when the cardinal features, that is falls and supranuclear gaze palsy, have become unequivocally apparent."
    explanation: >-
      The MDS criteria document the characteristic multi-year diagnostic latency in
      PSP from first symptoms to recognition.
datasets: []
📚

References & Deep Research

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 73 citations 2026-06-05T15:13:56.294493

1. Disease Information

1.1 Definition and overview

Progressive supranuclear palsy (PSP) is a neuropathologically defined, adult-onset, rapidly progressive neurodegenerative disorder in which abnormal tau aggregates (predominantly 4-repeat/4R tau) accumulate in neurons and glia, producing characteristic motor (postural instability, falls, akinesia), ocular motor, and cognitive/behavioral syndromes. Definite diagnosis remains neuropathologic, but research/clinical criteria have been revised to improve ante-mortem sensitivity for variant phenotypes. (hoglinger2017clinicaldiagnosisof pages 2-3, wise2024csfproteomicsin pages 1-2, whitney2024singlecelltranscriptomicand pages 1-2)

A widely recognized “classical” clinical phenotype is PSP–Richardson syndrome (PSP-RS), often featuring oculomotor dysfunction and early postural instability, with median survival reported as ~6.9 years in a contemporary biomarker cohort study. (wise2024csfproteomicsin pages 1-2)

1.2 Key identifiers and synonyms

A MONDO disease identifier is available via OpenTargets: MONDO:0019037 (progressive supranuclear palsy). (OpenTargets Search: Progressive supranuclear palsy)

ICD coding in retrieved sources: ICD-9 333.0 was used for case ascertainment in an Israeli health-provider cohort; authors noted nonspecificity requiring verification for externally coded diagnoses. ICD-10, MeSH, and OMIM numeric identifiers were not explicitly provided in the retrieved texts. (barer2023progressivesupranuclearpalsy’s pages 1-2)

Common synonyms/clinical labels include PSP-RS, PSP-P (parkinsonism), PSP-PGF (progressive gait freezing), PSP-SL (speech/language), PSP-F (frontal/behavioral), PSP-CBS, PSP-OM, PSP-PI, and others per MDS framework. (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2)

Category Term / Identifier Code / Expansion Notes Source URL / Year
Disease Progressive supranuclear palsy PSP Primary disease name; sporadic 4R-tauopathy / neuropathologically defined disease entity (hoglinger2017clinicaldiagnosisof pages 2-3, whitney2024singlecelltranscriptomicand pages 1-2) MDS criteria; Acta Neuropathol paper https://doi.org/10.1002/mds.26987 (2017); https://doi.org/10.1007/s00401-024-02823-w (2024)
Ontology MONDO MONDO:0019037 OpenTargets disease identifier for progressive supranuclear palsy (OpenTargets Search: Progressive supranuclear palsy) OpenTargets https://platform.opentargets.org/ (accessed via OpenTargets context; current)
Coding ICD-9 333.0 Used in Israeli cohort ascertainment; noted as nonspecific and externally verified in chart review (barer2023progressivesupranuclearpalsy’s pages 1-2) Barer et al. https://doi.org/10.1007/s00415-023-11714-1 (2023)
Coding ICD-10 Not explicitly reported in cited PSP papers retrieved here No directly citable ICD-10 code was provided in the available contexts (barer2023progressivesupranuclearpalsy’s pages 1-2) Available cited cohort literature https://doi.org/10.1007/s00415-023-11714-1 (2023)
Historical / classic phenotype Richardson syndrome PSP-RS Classical / most recognized phenotype; early falls and vertical gaze dysfunction emphasized across reviews and criteria (boxer2017advancesinprogressive pages 3-4, wise2024csfproteomicsin pages 1-2) Boxer et al.; Wise et al. https://doi.org/10.1016/S1474-4422(17)30157-6 (2017); https://doi.org/10.1212/WNL.0000000000209585 (2024)
Phenotype label PSP-parkinsonism PSP-P Variant phenotype with parkinsonian presentation; listed in MDS-era phenotype frameworks (boxer2017advancesinprogressive pages 3-4, nasri2024phenotypicspectrumof pages 1-2) Boxer et al.; Nasri et al. https://doi.org/10.1016/S1474-4422(17)30157-6 (2017); https://doi.org/10.14802/jmd.23178 (2024)
Phenotype label PSP with progressive gait freezing PSP-PGF Variant phenotype dominated by gait freezing / pure akinesia with gait freezing (boxer2017advancesinprogressive pages 3-4, nasri2024phenotypicspectrumof pages 1-2) Boxer et al.; Nasri et al. https://doi.org/10.1016/S1474-4422(17)30157-6 (2017); https://doi.org/10.14802/jmd.23178 (2024)
Phenotype label PSP with speech/language disorder PSP-SL Variant overlapping with nonfluent/agrammatic PPA or apraxia of speech (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2) MDS criteria paper; Nasri et al. https://doi.org/10.1002/mds.26987 (2017); https://doi.org/10.14802/jmd.23178 (2024)
Phenotype label PSP with frontal presentation PSP-F Frontal / behavioral-dysexecutive variant (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2) MDS criteria paper; Nasri et al. https://doi.org/10.1002/mds.26987 (2017); https://doi.org/10.14802/jmd.23178 (2024)
Phenotype label PSP with corticobasal syndrome PSP-CBS Corticobasal syndrome presentation attributed to PSP pathology in some cases (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2) MDS criteria paper; Nasri et al. https://doi.org/10.1002/mds.26987 (2017); https://doi.org/10.14802/jmd.23178 (2024)
Phenotype label PSP with ocular motor dysfunction PSP-OM Ocular motor–predominant presentation recognized in MDS spectrum (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2) MDS criteria paper; Nasri et al. https://doi.org/10.1002/mds.26987 (2017); https://doi.org/10.14802/jmd.23178 (2024)
Phenotype label PSP with predominant postural instability PSP-PI Postural instability–predominant presentation recognized in MDS spectrum (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2) MDS criteria paper; Nasri et al. https://doi.org/10.1002/mds.26987 (2017); https://doi.org/10.14802/jmd.23178 (2024)
Related ontology labels Classical progressive supranuclear palsy Orphanet_240071 Listed in OpenTargets association context as disease subtype label (OpenTargets Search: Progressive supranuclear palsy) OpenTargets / Orphanet label https://platform.opentargets.org/ (current)
Related ontology labels Atypical progressive supranuclear palsy Orphanet_99750 Listed in OpenTargets association context as disease subtype label (OpenTargets Search: Progressive supranuclear palsy) OpenTargets / Orphanet label https://platform.opentargets.org/ (current)
Related ontology labels Progressive supranuclear palsy-parkinsonism syndrome MONDO:0009839 Variant/parkinsonism-related disease label surfaced in OpenTargets context (OpenTargets Search: Progressive supranuclear palsy) OpenTargets https://platform.opentargets.org/ (current)
Inherited disease label Supranuclear palsy, progressive, 1 MONDO:0010997 Separate inherited / gene-linked label associated with MAPT in OpenTargets context (OpenTargets Search: Progressive supranuclear palsy) OpenTargets https://platform.opentargets.org/ (current)

Table: This table compiles key standardized identifiers and commonly used clinical synonyms/phenotype labels for progressive supranuclear palsy. It is useful for mapping disease terminology across ontologies, coding systems, and clinical subtype literature.

1.3 Evidence source type (patient-level vs aggregated)

PSP characterization is derived from both aggregated resources (e.g., OpenTargets ontology mapping) and aggregated cohort/trial/omics literature. Real-world evidence in this report includes retrospective medical-record abstraction across multiple care centers in the US/Canada and a large Israeli payer-provider database cohort. (nysetvold2024progressivesupranuclearpalsy pages 1-2, barer2023progressivesupranuclearpalsy’s pages 1-2)

2. Etiology

2.1 Primary causal factors

PSP is typically sporadic, with pathogenesis centered on tau (MAPT) biology, especially 4R tau accumulation and aggregation in vulnerable brain regions and cell types. (hoglinger2017clinicaldiagnosisof pages 2-3, whitney2024singlecelltranscriptomicand pages 1-2)

Rare familial PSP-like syndromes can occur with MAPT mutations, but most cases lack Mendelian inheritance; in MDS criteria, MAPT mutations are not an exclusion criterion but define inherited vs sporadic PSP. (hoglinger2017clinicaldiagnosisof pages 3-4)

2.2 Genetic risk factors (2023–2024 emphasis)

A 2024 whole-genome sequencing (WGS) case-control study (European ancestry) emphasized that prior array-GWAS were limited for rare variants and structural variants (SVs), and used WGS to analyze SNVs/indels/SVs at scale. (wang2024wholegenomesequencinganalysis pages 1-2)

Key genetic findings include: - MAPT 17q21.31 H1 haplotype is the strongest known common risk factor; the WGS study reports an estimated OR = 5.6 for H1 carriers. (wang2024wholegenomesequencinganalysis pages 1-2) - WGS confirmed known loci (e.g., MAPT, MOBP, STX6, SLCO1A2, DUSP10, SP1) and identified novel common signals (APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, ELOVL1). (wang2024wholegenomesequencinganalysis pages 1-2) - Notably, APOE ε2 was observed as the risk allele in PSP (in contrast to Alzheimer’s disease). (wang2024wholegenomesequencinganalysis pages 1-2) - Rare-variant association implicated ZNF592, and SV associations included seven common SVs in 17q21.31 and other loci (IGH, PCMT1, CYP2A13, SMCP), plus a burden of rare deletions/duplications in 17q21.31 (P = 6.73 × 10^-3). (wang2024wholegenomesequencinganalysis pages 1-2)

Mechanistically, MAPT haplotype effects are supported by transcriptomic evidence: a 2024 post-mortem bulk RNA-seq study found increased total tau mRNA and increased proportion of 4R transcripts in PSP brain regions, with 4R tau mRNA levels associated with the H1 haplotype, consistent with a causal role for altered splicing/expression. (ressler2024mapthaplotypeassociatedtranscriptomic pages 1-2)

Factor / locus Risk role in PSP Key quantitative finding Study design / cohort Sample size Year DOI / URL Citation
MAPT 17q21.31 H1/H2 haplotype region Strongest common genetic risk locus H1 haplotype associated with PSP risk; estimated OR = 5.6 Whole-genome sequencing (WGS) case-control study in European ancestry PSP 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
MAPT H1 haplotype Candidate mechanistic driver via altered tau isoform expression 4R tau mRNA significantly associated with H1 haplotype in temporal cortex; total tau and 4R tau transcripts increased in PSP cerebellum Bulk RNA-seq of post-mortem brain tissue with haplotype-dependent expression/splicing analyses 84 PSP; 77 controls 2024 https://doi.org/10.1186/s40478-024-01839-3 (ressler2024mapthaplotypeassociatedtranscriptomic pages 1-2)
MAPT Confirmed common susceptibility locus Reconfirmed among common SNV/indel loci in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
MOBP Confirmed common susceptibility locus; implicates oligodendrocytes/myelin biology Confirmed in WGS; prior association reproduced WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
STX6 Confirmed common susceptibility locus Confirmed in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
SLCO1A2 Confirmed common susceptibility locus Confirmed in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
DUSP10 Confirmed common susceptibility locus Confirmed in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
SP1 Confirmed common susceptibility locus Confirmed in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
APOE locus Novel common susceptibility signal Novel signal identified in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
APOE ε2 allele Risk allele in PSP In contrast to Alzheimer disease, APOE ε2 observed as the risk allele in PSP WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
APOE ε4 allele Potential modifier of phenotype, not core GWAS risk in cited cohort Earlier parkinsonism onset (p = 0.038), earlier oculomotor dysfunction trend (p = 0.052), more altered cognitive profile Cross-sectional clinical phenotype study with APOE genotyping 112 PSP 2024 https://doi.org/10.14802/jmd.23178 (nasri2024phenotypicspectrumof pages 1-2)
FCHO1/MAP1S Novel common susceptibility signal Newly uncovered in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
KIF13A Novel common susceptibility signal Newly uncovered in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
TRIM24 Novel common susceptibility signal Newly uncovered in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
TNXB Novel common susceptibility signal Newly uncovered in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
ELOVL1 Novel common susceptibility signal Newly uncovered in WGS WGS case-control 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
ZNF592 Rare-variant association Significant association in rare SNV/indel analysis WGS rare-variant analysis 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
Structural variants in 17q21.31 Structural genetic risk architecture at major PSP locus Seven common SVs associated with PSP in H1/H2 region and other loci WGS SV association analysis 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
IGH SV-associated locus Common SV association reported WGS SV analysis 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
PCMT1 SV-associated locus Common SV association reported WGS SV analysis 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
CYP2A13 SV-associated locus Common SV association reported WGS SV analysis 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
SMCP SV-associated locus Common SV association reported WGS SV analysis 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
Rare deletions/duplications in H1/H2 region Additional structural burden at major locus Burden of rare deletions/duplications in 17q21.31: P = 6.73 × 10^-3 WGS SV burden analysis 1,718 cases; 2,944 controls 2024 https://doi.org/10.1186/s13024-024-00747-3 (wang2024wholegenomesequencinganalysis pages 1-2)
EIF2AK3, LRRK2, RUNX2 Previously reported PSP risk loci referenced in recent mechanistic/genetic studies Not primary new WGS findings in cited paper, but repeatedly cited as established PSP-associated loci Background from recent single-cell / review literature Not applicable 2024 https://doi.org/10.1007/s00401-024-02823-w ; https://doi.org/10.1007/s40120-024-00614-9 (whitney2024singlecelltranscriptomicand pages 1-2, dunning2024pharmacotherapiesforthe pages 3-4)

Table: This table summarizes the main genetic risk factors and loci implicated in progressive supranuclear palsy, emphasizing the 2024 WGS study and related transcriptomic evidence. It is useful for quickly mapping confirmed loci, novel signals, structural variation findings, and effect estimates such as the MAPT H1 haplotype odds ratio.

2.3 Environmental risk/protective factors and gene–environment interactions

No high-quality, PSP-specific environmental risk factors, protective factors, or gene–environment interactions were identified within the retrieved evidence set for this run. This should be treated as insufficient evidence in the current retrieval, not as evidence of absence.

3. Phenotypes

3.1 Core clinical domains and spectrum

The 2017 MDS-PSP criteria identify four functional domains as clinical predictors: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction, with features contributing different diagnostic certainty levels (probable, possible, suggestive). (hoglinger2017clinicaldiagnosisof pages 2-3)

Variant clinical presentations beyond PSP-RS are common in autopsy series, motivating the criteria revision. (hoglinger2017clinicaldiagnosisof pages 2-3)

3.2 Phenotype frequencies and timelines (recent cohort evidence)

  • In a 2024 Tunisian cohort recategorized by MDS-PSP phenotypes (n=112), the distribution included PSP-RS (48), PSP-cortical (34; e.g., PSP-CBS 17.6%, PSP-F 9.4%, PSP-SL 8.2%), and PSP-subcortical (30; PSP-P 11.6%, PSP-PI 8.0%, PSP-OM 2.7%, PSP-PGF 1.8%, PSP-C 1.8%, PSP-PLS 0.9%). (nasri2024phenotypicspectrumof pages 1-2)
  • In a 2024 US/Canada medical-record real-world study (n=72), falls were documented in 79.2% before diagnosis and 97.2% during the course; among those with onset dates documented, median onset was 2.0 years before diagnosis for first fall, 1.2 years for unsteady gait/gait impairment, and 0.8 years for mobility problems. (nysetvold2024progressivesupranuclearpalsy pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 2-4)

3.3 HPO term suggestions

A practical mapping of major PSP symptoms to HPO labels is provided below.

Clinical feature Suggested HPO term Phenotype group(s) Frequency / statistic from cohorts Evidence
Vertical supranuclear gaze palsy / slow vertical saccades Vertical supranuclear gaze palsy (HPO label); Slow saccadic eye movements (HPO label) PSP-RS, PSP-OM Vertical supranuclear gaze palsy is the classic defining sign of PSP; MDS criteria note ocular motor dysfunction as 1 of 4 core domains. In the Tunisian phenotype cohort, PSP-OM represented 2.7% of all PSP cases; PSP-RS remained the most common phenotype group (48/112). (hoglinger2017clinicaldiagnosisof pages 2-3, nasri2024phenotypicspectrumof pages 1-2) (hoglinger2017clinicaldiagnosisof pages 2-3, nasri2024phenotypicspectrumof pages 1-2)
Postural instability Postural instability (HPO label) PSP-RS, PSP-PI MDS criteria identify postural instability as a core diagnostic domain. In the Tunisian cohort, PSP-PI accounted for 8.0% of cases; in real-world records, 68.1% had unsteady gait/gait impairment documented before diagnosis, with median onset 1.2 years before diagnosis. (hoglinger2017clinicaldiagnosisof pages 2-3, nasri2024phenotypicspectrumof pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 2-4) (hoglinger2017clinicaldiagnosisof pages 2-3, nasri2024phenotypicspectrumof pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 2-4)
Recurrent falls Frequent falls (HPO label); Recurrent falls (HPO label) PSP-RS, PSP-PI In the US/Canada real-world cohort, falling was documented in 79.2% before diagnosis and 97.2% across the disease course; median time to first fall was 2.0 years before diagnosis. Falls are central to Richardson syndrome and MDS/NINDS-SPSP-style criteria. (nysetvold2024progressivesupranuclearpalsy pages 2-4, nysetvold2024progressivesupranuclearpalsy pages 1-2, hoglinger2017clinicaldiagnosisof pages 2-3) (nysetvold2024progressivesupranuclearpalsy pages 2-4, nysetvold2024progressivesupranuclearpalsy pages 1-2, hoglinger2017clinicaldiagnosisof pages 2-3)
Gait freezing / progressive gait freezing Freezing of gait (HPO label) PSP-PGF PSP-PGF is an established variant in the MDS spectrum. In the Tunisian cohort, PSP-PGF represented 1.8% of all PSP cases. Real-world records showed mobility problems in 51.4% before diagnosis, with median onset 0.8 years before diagnosis. (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 1-2) (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 1-2)
Akinesia / bradykinesia / rigidity Bradykinesia (HPO label); Akinetic-rigid parkinsonism (HPO label); Rigidity (HPO label) PSP-RS, PSP-P PSP-RS patients in the Tunisian cohort had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006), while PSP-P made up 11.6% of cases. PSP pathology/clinical descriptions consistently include akinesia and rigidity as key motor manifestations. (nasri2024phenotypicspectrumof pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 1-2, dam2021safetyandefficacy pages 1-6) (nasri2024phenotypicspectrumof pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 1-2, dam2021safetyandefficacy pages 1-6)
Dysphagia Dysphagia (HPO label) PSP-RS, advanced PSP across phenotypes Dysphagia is highlighted as an additional symptom emerging with progression in PSP-RS and contributes materially to disease burden and supportive-care needs. No cohort percentage was provided in the retrieved contexts, but it is repeatedly cited as a common progressive feature. (dam2021safetyandefficacy pages 1-6, barer2023progressivesupranuclearpalsy’s pages 1-2) (dam2021safetyandefficacy pages 1-6, barer2023progressivesupranuclearpalsy’s pages 1-2)
Dysarthria Dysarthria (HPO label) PSP-RS, PSP-SL Dysarthria is a common speech/bulbar manifestation of PSP and contributes to healthcare utilization and speech-therapy needs. No specific frequency was given in the retrieved cohort excerpts. (barer2023progressivesupranuclearpalsy’s pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 1-2) (barer2023progressivesupranuclearpalsy’s pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 1-2)
Cognitive decline / dementia Cognitive impairment (HPO label); Dementia (HPO label) PSP-RS, PSP-F, PSP-SL, cortical PSP Cognitive dysfunction is one of the 4 MDS core domains. In longitudinal follow-up, annual decline was faster in Richardson syndrome than variants on MMSE: -1.8 vs -0.9/year and ACE-R: -5.3 vs -3.0/year. PSP-cortical phenotypes showed greater cognitive alteration than PSP-subcortical phenotypes. (hoglinger2017clinicaldiagnosisof pages 2-3, street2021clinicalprogressionof pages 1-2, nasri2024phenotypicspectrumof pages 1-2) (hoglinger2017clinicaldiagnosisof pages 2-3, street2021clinicalprogressionof pages 1-2, nasri2024phenotypicspectrumof pages 1-2)
Frontal behavioral changes / dysexecutive syndrome Behavioral abnormality (HPO label); Executive dysfunction (HPO label); Frontal lobe syndrome (HPO label) PSP-F PSP with frontal presentation is a recognized MDS phenotype. In the Tunisian cohort, PSP-F accounted for 9.4% of all cases; APOE ε4 carriers had more altered cognitive profiles. (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2) (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2)
Speech/language impairment: nonfluent aphasia / apraxia of speech Nonfluent aphasia (HPO label); Apraxia of speech (HPO label); Speech impairment (HPO label) PSP-SL PSP-SL is an established MDS phenotype overlapping with nonfluent/agrammatic PPA and apraxia of speech. In the Tunisian cohort, PSP-SL represented 8.2% of all cases. (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2) (hoglinger2017clinicaldiagnosisof pages 3-4, nasri2024phenotypicspectrumof pages 1-2)
Depression Depression (HPO label) Non-motor across phenotypes In the FMT PSP-RS trial, depression improved significantly after treatment as a secondary outcome. In the US/Canada medical-record cohort, depression was a common comorbidity; the paper’s snippet cites 44.4% comorbidity prevalence. (tian2023efficacyoffaecal pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 1-2) (tian2023efficacyoffaecal pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 1-2)
Anxiety Anxiety (HPO label) Non-motor across phenotypes Anxiety improved significantly in the FMT PSP-RS trial after 3-cycle intervention and remained improved for many participants at follow-up. No baseline prevalence percentage was provided in the retrieved snippets. (tian2023efficacyoffaecal pages 1-2) (tian2023efficacyoffaecal pages 1-2)
Constipation Constipation (HPO label) Non-motor across phenotypes GI dysfunction is frequent in PSP-RS; the FMT trial notes that more than 80% of PSP patients experience GI symptoms and reported significant improvement in constipation after FMT. (tian2023efficacyoffaecal pages 1-2) (tian2023efficacyoffaecal pages 1-2)
Ocular motor dysfunction (broader category) Abnormality of eye movement (HPO label) PSP-RS, PSP-OM Ocular motor dysfunction is one of the four MDS core functional domains and is especially relevant in PSP-RS and PSP-OM. In the Tunisian cohort, PSP-OM was 2.7% of cases; APOE ε4 carriers had earlier oculomotor dysfunction (p = 0.052). (hoglinger2017clinicaldiagnosisof pages 2-3, nasri2024phenotypicspectrumof pages 1-2) (hoglinger2017clinicaldiagnosisof pages 2-3, nasri2024phenotypicspectrumof pages 1-2)

Table: This table maps common progressive supranuclear palsy phenotypes and core symptoms to suggested HPO terms, while adding quantitative cohort data where available. It is useful for phenotype annotation in a disease knowledge base and for harmonizing clinical features across PSP subtypes.

3.4 Quality of life impact

Direct QoL instrument data (e.g., EQ-5D, SF-36) were not extracted from the retrieved primary evidence in this run; however, real-world evidence indicates extensive supportive-care and assistive-device needs (see Treatments/Applications section), which reflect substantial functional impairment burden. (nysetvold2024progressivesupranuclearpalsy pages 1-2)

4. Genetic/Molecular Information

4.1 Major genes and loci

Key genes/loci supported by contemporary WGS and/or prior GWAS replication include MAPT, MOBP, STX6, SLCO1A2, DUSP10, SP1, with novel signals including APOE and others. (wang2024wholegenomesequencinganalysis pages 1-2)

4.2 Pathogenic variants (rare familial PSP and related syndromes)

The retrieved MDS criteria explicitly note that MAPT rare variants (mutations) are not an exclusion criterion but indicate inherited PSP; MDS criteria also note that MAPT H2 homozygosity is not an exclusion but makes PSP less likely. (hoglinger2017clinicaldiagnosisof pages 3-4)

A complete ClinVar/gnomAD-level catalog (variant nomenclature and allele frequencies) was not obtained in this run.

4.3 Epigenetic information

An epigenome-wide DNA methylation comparison in frontal lobe white matter across parkinsonian disorders identified shared and disease-relevant pathway dysregulation including Wnt signaling, ER stress, mitochondrial processes, RNA interference, and endosomal transport. (murthy2024dnamethylationpatterns pages 1-2)

5. Environmental Information

No PSP-specific infectious/toxic/lifestyle drivers were identified within the retrieved sources for this run. Gastrointestinal dysfunction is frequent in PSP and is being therapeutically targeted (FMT trial), but this does not establish a causal environmental etiology. (tian2023efficacyoffaecal pages 1-2)

6. Mechanism / Pathophysiology (Current Understanding, 2023–2024 emphasis)

6.1 Causal chain (high-level)

Genetic predisposition (notably MAPT H1 haplotype and additional risk loci including stress-pathway genes such as EIF2AK3/PERK) appears to bias tau expression/splicing toward 4R isoforms. This supports a cellular environment prone to tau misfolding/aggregation and spread. Subsequent downstream cascades include ER stress/integrated stress response activation, synaptic/axon guidance and trafficking pathway dysregulation, and neuroinflammatory activation, culminating in region- and cell-type-specific degeneration and clinical syndromes. (wang2024wholegenomesequencinganalysis pages 1-2, ressler2024mapthaplotypeassociatedtranscriptomic pages 1-2, whitney2024singlecelltranscriptomicand pages 1-2, wise2024csfproteomicsin pages 1-2)

6.2 Cell types, pathways, and regions (ontology-ready)

A structured mechanism table with CL/GO/UBERON suggestions is provided.

Mechanism summary Upstream trigger / risk Key evidence / quantitative result Primary cell types (CL suggestion) Affected anatomical regions (UBERON suggestion) GO biological process term suggestions Evidence source DOI / year
4R tau accumulation and aggregation in neurons and glia drives PSP neurodegeneration through hyperphosphorylated tau inclusions, impaired proteostasis, and cell-to-cell seeding Sporadic PSP biology; MAPT-linked 4R tau predisposition; tau seeding/propagation PSP is neuropathologically defined by aggregated 4R tau in neurons, astrocytes, and oligodendrocytes; tau inclusions include neurofibrillary tangles, tufted astrocytes, and coiled bodies; MAPT expression is preserved in all 3 cell types with tau aggregates, supporting ongoing local tau production that can feed aggregation/seeding (hoglinger2017clinicaldiagnosisof pages 2-3, whitney2024singlecelltranscriptomicand pages 1-2, forrest2023cellspecificmaptgene pages 1-2) neuron (CL:0000540); astrocyte (CL:0000127); oligodendrocyte (CL:0000128) subthalamic nucleus (UBERON:0001906); globus pallidus (UBERON:0002427); midbrain (UBERON:0001891); cerebellum (UBERON:0002037) protein phosphorylation (GO:0006468); protein aggregation (GO:0070207); microtubule cytoskeleton organization (GO:0000226); neuron death (GO:0070997) 10.1002/mds.26987 (2017); 10.1007/s00401-024-02823-w (2024); 10.1007/s00401-023-02604-x (2023)
MAPT haplotype-associated increase in 4R tau mRNA likely acts upstream of tau aggregation 17q21.31 inversion / MAPT H1 haplotype; structural variation around MAPT/KANSL1 H1 haplotype is the strongest common genetic risk with OR ~5.6; bulk RNA-seq showed increased total tau and 4R tau transcripts in PSP cerebellum and increased 4R tau reads in temporal cortex; 4R tau mRNA levels were significantly associated with H1 in temporal cortex, supporting an upstream splicing/expression mechanism (wang2024wholegenomesequencinganalysis pages 1-2, ressler2024mapthaplotypeassociatedtranscriptomic pages 1-2) excitatory/inhibitory neuron (CL:0000540); astrocyte (CL:0000127); oligodendrocyte (CL:0000128) cerebellum (UBERON:0002037); temporal cortex (UBERON:0016529); midbrain (UBERON:0001891) regulation of mRNA splicing, via spliceosome (GO:0048024); RNA processing (GO:0006396); regulation of gene expression (GO:0010468) 10.1186/s13024-024-00747-3 (2024); 10.1186/s40478-024-01839-3 (2024)
Integrated stress response / EIF2 signaling and PERK(EIF2AK3) activation links tau burden to maladaptive stress signaling and downstream apoptosis/autophagy failure Genetic risk at EIF2AK3; chronic proteotoxic and ER stress induced by tau pathology Single-nucleus RNA-seq of 50,708 nuclei from PSP diencephalon identified EIF2 signaling activated across vulnerable cell types; activated eIF2α positively correlated with tau pathology burden in subthalamic nucleus and thalamus and colocalized with p-tau-positive neurons and ALDH1L1-positive astrocytes; GWAS had already implicated EIF2AK3/PERK as a PSP risk locus (whitney2024singlecelltranscriptomicand pages 12-14, whitney2024singlecelltranscriptomicand pages 1-2) neuron (CL:0000540); astrocyte (CL:0000127); oligodendrocyte (CL:0000128); microglial cell (CL:0000129) subthalamic nucleus (UBERON:0001906); thalamus (UBERON:0001897); globus pallidus (UBERON:0002427); visual cortex / occipital cortex as relatively spared comparator (UBERON:0001870) integrated stress response signaling (GO:0034976-related); response to endoplasmic reticulum stress (GO:0034976); translational initiation (GO:0006413); regulation of apoptotic process (GO:0042981); autophagy (GO:0006914) 10.1007/s00401-024-02823-w (2024)
Axon-guidance, synaptic, vesicle-cytoskeletal, and cytokine-signaling modules are dysregulated in PSP CSF, consistent with circuit dysfunction downstream of tauopathy Tau-mediated network degeneration and synaptic/axonal injury SOMAmer CSF proteomics found 155/5,026, 959/7,595, and 321/5,026 differentially expressed SOMAmers across original, validation, and neuropathology-confirmed cohorts; three coexpression modules implicated synaptic function/JAK-STAT (beta = -0.044, corrected p = 0.002), vesicle-cytoskeletal trafficking (beta = 0.039, p = 0.007), and cytokine-cytokine receptor interaction (beta = -0.032, p = 0.035); axon guidance was the top dysregulated pathway across cohorts and an axon-guidance panel gave AUC 0.924/0.815/0.932 (wise2024csfproteomicsin pages 1-2) neuron (CL:0000540); synapse-associated neuronal populations; astrocyte (CL:0000127) dorsal midbrain (UBERON:0001891); globus pallidus (UBERON:0002427); subthalamic nucleus (UBERON:0001906) axon guidance (GO:0007411); synapse organization (GO:0050808); vesicle-mediated transport (GO:0016192); JAK-STAT cascade (GO:0007259); cytokine-mediated signaling pathway (GO:0019221) 10.1212/WNL.0000000000209585 (2024)
Complement/C4A-associated oligodendrocyte activation suggests glial and myelin-related mechanisms in PSP PSP GWAS risk architecture; oligodendrocyte-specific regulatory effects; complement dysregulation Integrative genetics/transcriptomics/histology work implicated glial activation, oligodendrocyte-specific epigenomic/eQTL effects at many loci, elevated C4A expression, and histologic colocalization of tau aggregates with C4 complement in oligodendrocytes; this supports complement-associated oligodendroglial pathology as part of etiopathogenesis (farrell2024genetictranscriptomichistological pages 4-7) oligodendrocyte (CL:0000128); astrocyte (CL:0000127); microglial cell (CL:0000129) white matter (UBERON:0002316); globus pallidus (UBERON:0002427); brainstem (UBERON:0002298) complement activation (GO:0006956); gliogenesis (GO:0042063); myelination (GO:0042552); regulation of immune response (GO:0050776) 10.1101/2023.11.09.565552 (2024 preprint)
White-matter DNA methylation changes implicate Wnt signaling, ER stress, mitochondrial dysfunction, RNA interference, and endosomal transport as convergent downstream molecular programs Epigenetic dysregulation in parkinsonian white matter; shared but PSP-relevant white-matter pathology EPIC-array profiling of frontal lobe white matter from PSP (n = 16) and controls identified co-methylation signatures affecting Wnt signaling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport; PSP white matter showed disease-specific and shared alterations relevant to neurodegeneration (murthy2024dnamethylationpatterns pages 1-2) oligodendrocyte (CL:0000128); astrocyte (CL:0000127); microglial cell (CL:0000129) frontal lobe white matter (UBERON suggestion: frontal lobe UBERON:0001870 + white matter UBERON:0002316); cerebrum white matter (UBERON:0002316) Wnt signaling pathway (GO:0016055); response to endoplasmic reticulum stress (GO:0034976); mitochondrial ATP synthesis coupled electron transport (GO:0042775); endosomal transport (GO:0016197); RNA interference (GO:0016246) 10.1007/s00401-024-02764-4 (2024)
Neuroinflammatory markers galectin-10 and CTLA-4 track clinical severity, indicating immune activation as a disease-modifying downstream process Tau-triggered glial/immune activation; inflammatory remodeling of CSF proteome In CSF proteomics, galectin-10 and CTLA-4 correlated with PSP Rating Scale scores across cohorts; inflammatory and cytokine-cytokine receptor interaction modules were also identified, supporting ongoing neuroimmune involvement in disease progression (wise2024csfproteomicsin pages 1-2) microglial cell (CL:0000129); astrocyte (CL:0000127); infiltrating immune cell / T cell (CL:0000084 suggestion) CSF-reflective pathology from subthalamic nucleus (UBERON:0001906), globus pallidus (UBERON:0002427), and dorsal midbrain (UBERON:0001891) inflammatory response (GO:0006954); cytokine-mediated signaling pathway (GO:0019221); regulation of immune system process (GO:0002682) 10.1212/WNL.0000000000209585 (2024)

Table: This table summarizes major molecular and cellular mechanisms implicated in progressive supranuclear palsy, linking genetic risk, tau biology, stress signaling, white-matter epigenetics, and neuroinflammation to vulnerable cell types and brain regions. It is useful for knowledge-base annotation because it also suggests ontology terms for cells, anatomy, and biological processes.

Key recent mechanistic developments include: - Single-nucleus RNA-seq (50,708 nuclei) in PSP diencephalon demonstrated EIF2 signaling activation across vulnerable cell types; activated eIF2α correlated with tau burden and localized to p-tau+ neurons and ALDH1L1+ astrocytes by multiplex imaging, supporting integrated stress response failure as a mechanistic component. (whitney2024singlecelltranscriptomicand pages 1-2, whitney2024singlecelltranscriptomicand pages 12-14) - CSF proteomics (SomaScan) identified convergent downregulation of axon guidance and other modules (synaptic/JAK-STAT, vesicle-cytoskeletal trafficking, cytokine signaling) with high AUC discrimination panels, implicating circuit-level dysfunction consistent with axonal/synaptic pathology. (wise2024csfproteomicsin pages 1-2) - A MAPT expression study using RNAscope + AT8 and snRNA-seq found MAPT transcripts in neurons, astrocytes, and oligodendrocytes and preserved expression in cells with tau aggregates, supporting ongoing local tau supply for aggregation/seeding and motivating dual therapeutic approaches. (forrest2023cellspecificmaptgene pages 1-2)

7. Anatomical Structures Affected

PSP pathology and biomarker studies emphasize subcortical and brainstem structures with additional cortical involvement depending on phenotype. Key regions include the subthalamic nucleus, globus pallidus, dorsal midbrain, and cerebellar/diencephalic structures, with clinical variants reflecting differing neuroanatomic distributions of pathology. (wise2024csfproteomicsin pages 1-2, whitney2024singlecelltranscriptomicand pages 1-2)

Cell types prominently implicated include neurons, astrocytes, and oligodendrocytes, consistent across neuropathology, transcriptomics, and genetic findings highlighting oligodendrocyte/myelin biology. (whitney2024singlecelltranscriptomicand pages 1-2, wang2024wholegenomesequencinganalysis pages 1-2)

8. Temporal Development

PSP typically begins after age 60 in many series, with diagnosis often delayed due to early symptom overlap with Parkinson’s disease and other atypical parkinsonisms. (jang2024biomarkerdiscoveryin pages 1-2, hoglinger2017clinicaldiagnosisof pages 2-3)

Real-world data show a multi-year prodrome before diagnosis, with falls and gait impairment commonly preceding formal diagnosis by ~1–2 years (median values among those with onset dates documented). (nysetvold2024progressivesupranuclearpalsy pages 1-2)

9. Inheritance and Population

9.1 Epidemiology

Recent biomarker and review sources report PSP-RS prevalence in the 2.3–10.6 per 100,000 range, with broader PSP prevalence estimates up to ~18 per 100,000 in some population studies. (wise2024csfproteomicsin pages 1-2, boxer2017advancesinprogressive pages 1-2)

9.2 Inheritance

PSP is predominantly sporadic, with rare familial MAPT mutation-associated PSP-like syndromes. MDS criteria incorporate genetic findings into exclusion/context decisions and distinguish inherited vs sporadic PSP when MAPT mutations are present. (hoglinger2017clinicaldiagnosisof pages 3-4, whitney2024singlecelltranscriptomicand pages 1-2)

9.3 Prognosis and natural history

  • Median survival estimates include ~6.9 years in PSP-RS (biomarker cohort) and median 7.3 years after symptom onset in the gosuranemab PASSPORT trial report. (wise2024csfproteomicsin pages 1-2, dam2021safetyandefficacy pages 1-6)
  • In a representative UK cohort (n=227), survival was longer in variant phenotypes than Richardson’s syndrome (7.3 vs 5.6 years, P=0.02), and annual cognitive decline differed by phenotype (MMSE -1.8 vs -0.9/year; ACE-R -5.3 vs -3.0/year). (street2021clinicalprogressionof pages 1-2)

10. Diagnostics

10.1 Clinical criteria (authoritative)

The 2017 Movement Disorder Society (MDS) criteria were developed to improve early and variant-phenotype sensitivity relative to NINDS-SPSP criteria, while maintaining specificity. They incorporate mandatory inclusion/exclusion criteria and define diagnostic certainty categories (probable, possible, suggestive) based on combinations of features across four functional domains. (hoglinger2017clinicaldiagnosisof pages 2-3)

Key excerpted features include: - NINDS-SPSP “probable” PSP requires vertical supranuclear gaze palsy plus postural instability and falls within 1 year, but sensitivity is limited early and for variants. (hoglinger2017clinicaldiagnosisof pages 2-3) - MDS-PSP criteria incorporate imaging/laboratory/genetic context; for example, in PSP-CBS, CSF constellations typical of AD (elevated total/p-tau plus reduced Aβ42) or amyloid PET are used to exclude primary AD pathology. (hoglinger2017clinicaldiagnosisof pages 3-4)

10.2 Biomarkers and imaging (2024 priority)

A structured biomarker summary is provided below.

Biomarker / diagnostic feature Modality / specimen Intended use Key quantitative finding Source (DOI / year)
Neurofilament light chain (NfL) CSF and plasma Prognosis; supportive differential diagnosis NfL concentrations are reported to be 2–5× higher in PSP CSF than in healthy controls and PD; similar plasma elevation reported, but specificity remains limited (jang2024biomarkerdiscoveryin pages 1-2) 10.1186/s12014-024-09507-3 / 2024
CSF p-tau181 CSF Prognosis / disease monitoring Low CSF p-tau181 has been associated with faster clinical progression in PSP, but sensitivity/specificity are limited (wise2024csfproteomicsin pages 1-2) 10.1212/WNL.0000000000209585 / 2024
Axon-guidance protein panel CSF SOMAmer proteomics Diagnostic discrimination Axon-guidance proteins discriminated PSP vs controls with AUC 0.924 (original cohort), 0.815 (validation), and 0.932 (neuropathology-confirmed cohort); top dysregulated pathway across cohorts (wise2024csfproteomicsin pages 1-2) 10.1212/WNL.0000000000209585 / 2024
Galectin-10 (CLC) and CTLA-4 CSF SOMAmer proteomics Severity / progression correlation Two inflammatory proteins, galectin-10 and CTLA-4, correlated with PSP Rating Scale severity across cohorts (wise2024csfproteomicsin pages 1-2) 10.1212/WNL.0000000000209585 / 2024
ATP6AP2 CSF TMT mass-spectrometry proteomics Diagnostic discrimination ATP6AP2 reduced in PSP and had the highest classification performance with AUC 0.922 for PSP vs PD/HC (jang2024biomarkerdiscoveryin pages 1-2) 10.1186/s12014-024-09507-3 / 2024
Additional CSF proteomic candidates CSF TMT mass-spectrometry proteomics Diagnostic panel development Other top candidates included NEFM, EFEMP2, LAMP2, CHST12, FAT2, B4GALT1, LCAT, CBLN3, FSTL5, ATP6AP1, GGH; pathways enriched for cell adhesion, cholesterol metabolism, glycan biosynthesis (jang2024biomarkerdiscoveryin pages 1-2) 10.1186/s12014-024-09507-3 / 2024
Serum p-tau396 Serum ELISA / SIMOA-based pilot biomarker study Clinical staging / severity tracking Of six serum tau species tested, only p-tau396 was detectable; it was higher in PSP and PD vs controls but overlapped between PSP and PD, and strongly correlated with disease severity in PSP (cristiani2024serumtauspecies pages 1-2) 10.3390/diagnostics14232746 / 2024
Serum tau species panel (t-tau, 4R-tau, tau aggregates, p-tau202, p-tau231, p-tau396) Serum Exploratory differential diagnosis Most serum tau species were undetectable or too low for ELISA, arguing against current routine serum tau-species discrimination of PSP vs PD except possible staging value for p-tau396 (cristiani2024serumtauspecies pages 1-2) 10.3390/diagnostics14232746 / 2024
18F-PI-2620 tau-PET Tau PET In vivo tau pathology; diagnostic enrichment; progression staging In probable PSP-RS, subcortical tau uptake was associated with higher NfL and NfL/t-tau, lower GFAP-related ratios, reduced brain volume, and worse executive function; patients showed higher fluid biomarker levels than controls (dilcher2024linkingpi2620taupet pages 1-5) 10.1101/2024.10.14.24315486 / 2024
NfL/t-tau ratio with PI-2620 tau-PET Plasma/CSF + tau PET Trial biomarker / disease monitoring Biomarker ratios showed strong patient-control separation; reported NfL/t-tau 98.9% (95% CI 96.16%–100%) in comparative analysis and correlated with tau-PET burden (dilcher2024linkingpi2620taupet pages 1-5) 10.1101/2024.10.14.24315486 / 2024
MRI midbrain and superior cerebellar peduncle atrophy Structural MRI Supportive diagnosis / differential diagnosis Midbrain and superior cerebellar peduncle atrophy help differentiate PSP-RS; classic “hummingbird” and “morning glory” signs have 100% specificity but limited sensitivity (boxer2017advancesinprogressive pages 4-5) 10.1016/S1474-4422(17)30157-6 / 2017
MRI / imaging supportive findings in MDS criteria Imaging Supportive diagnosis; exclusion of mimics MDS criteria include imaging as supportive and exclusionary context; relevant structural abnormalities and severe leukoencephalopathy are exclusionary, underscoring MRI’s role in ruling out mimics (hoglinger2017clinicaldiagnosisof pages 2-3, hoglinger2017clinicaldiagnosisof pages 3-4) 10.1002/mds.26987 / 2017

Table: This table summarizes key fluid and imaging biomarkers for progressive supranuclear palsy, including diagnostic and prognostic use cases, quantitative findings, and source citations. It is useful for comparing emerging 2024 proteomic and tau-PET markers with established MRI and CSF indicators.

Highlights include: - CSF mass-spectrometry proteomics identified ATP6AP2 as a strong discriminator (AUC 0.922) and enriched pathways (cell adhesion, cholesterol metabolism, glycan biosynthesis). (jang2024biomarkerdiscoveryin pages 1-2) - SomaScan CSF proteomics identified axon-guidance pathway protein panels with AUC up to 0.932 and inflammatory correlates of severity. (wise2024csfproteomicsin pages 1-2) - 18F-PI-2620 tau PET was associated with fluid biomarker ratios and cognition/atrophy in probable PSP-RS (preprint evidence). (dilcher2024linkingpi2620taupet pages 1-5)

11. Outcome / Prognosis

PSP has rapid progression with substantial disability burden and limited disease-modifying options; survival is typically on the order of 5–8 years from symptom onset depending on phenotype and cohort. (dam2021safetyandefficacy pages 1-6, street2021clinicalprogressionof pages 1-2)

Real-world studies show high healthcare utilization, including near-universal medication and imaging use, high assistive-device and supportive-care use, and increasing costs over time. (nysetvold2024progressivesupranuclearpalsy pages 1-2, barer2023progressivesupranuclearpalsy’s pages 1-2)

12. Treatment

12.1 Symptomatic and supportive care (real-world implementation)

Real-world care pathways rely heavily on symptomatic management and supportive services. In a US/Canada medical-record cohort, the most widely used resources (≥85% of participants at some point) were medications (100%), imaging (99%), assistive devices (90%), supportive care (86%), and surgeries/procedures (85%). (nysetvold2024progressivesupranuclearpalsy pages 1-2)

In an Israeli payer-provider cohort, symptomatic therapies listed include levodopa/dopamine agonists/amantadine for motor symptoms (often mild/transient benefit), sleep and ocular symptom treatments, constipation management, antidepressants, and botulinum toxin for selected dystonia/sialorrhea syndromes; multidisciplinary therapy (physical, speech, occupational, social work) is emphasized. (barer2023progressivesupranuclearpalsy’s pages 1-2)

Suggested MAXO terms (labels): monoclonal antibody therapy; fecal microbiota transplantation; physical therapy; speech therapy; occupational therapy; assistive device use; supportive care.

12.2 Disease-modifying and experimental therapies (trials)

A consolidated trial table (including pipeline trials) is provided.

Intervention / study Class / mechanism Trial ID Phase Status Sample size Key endpoint / quantitative result URL Citation
Gosuranemab (PASSPORT) Anti-tau monoclonal antibody targeting N-terminal tau NCT03068468 Phase 2 Completed; open-label extension discontinued after lack of efficacy 486 dosed (321 gosuranemab, 165 placebo) Primary endpoint not met at week 52: adjusted mean PSP Rating Scale (PSPRS) change 10.4 vs 10.6, P=0.85; strong target engagement in CSF unbound N-terminal tau: -98% with gosuranemab vs +11% with placebo; AE and death rates similar between groups https://clinicaltrials.gov/study/NCT03068468 ; https://doi.org/10.1038/s41591-021-01455-x (dam2021safetyandefficacy pages 1-6)
Tilavonemab / ABBV-8E12 (ARISE) Anti-tau monoclonal antibody binding N-terminus of human tau NCT02985879 Phase 2 Terminated early for futility 377 treated / analyzed (126 2000 mg, 125 4000 mg, 126 placebo) Primary endpoint: change in PSPRS at week 52; no benefit vs placebo. Between-group difference vs placebo: 2000 mg 0.0 (95% CI -2.6 to 2.6), p>0.99; 4000 mg 1.0 (95% CI -1.6 to 3.6), p=0.46; similar safety profile across groups https://clinicaltrials.gov/study/NCT02985879 ; https://doi.org/10.1016/S1474-4422(20)30489-0 (hoglinger2021safetyandefficacy pages 1-2, hoglinger2021safetyandefficacy pages 6-7)
Faecal microbiota transplantation (FMT) in PSP-RS Microbiome-directed therapy / fecal microbiota transplantation ChiCTR-2100045397 Phase 2 Completed 68 randomized Primary outcome at week 16: PSPRS improved from 40.1 to 36.9 in FMT group vs 40.1 to 41.7 in placebo; treatment benefit 4.3 (95% CI 3.2-5.4), P<0.0001; also improved constipation, depression, and anxiety https://www.chictr.org.cn/showproj.html?proj=124265 ; https://doi.org/10.1016/j.eclinm.2023.101888 (tian2023efficacyoffaecal pages 1-2)
NIO752 Investigational disease-modifying therapy for PSP (mechanism not specified in retrieved trial context) NCT07498426 Phase 3 Recruiting 300 planned Efficacy study in PSP; primary endpoint not provided in retrieved trial summary https://clinicaltrials.gov/study/NCT07498426 (OpenTargets Search: Progressive supranuclear palsy)
AADvac1 Active tau immunotherapy / anti-tau vaccine NCT07217665 Phase 2 Not yet recruiting 146 planned PSP platform trial regimen A; endpoint not provided in retrieved trial summary https://clinicaltrials.gov/study/NCT07217665 (OpenTargets Search: Progressive supranuclear palsy, boxer2017advancesinprogressive pages 8-9)
LM11A-31 Small-molecule neuroprotective candidate (p75NTR modulator; mechanism not detailed in retrieved context) NCT07264283 Phase 2 Not yet recruiting 147 planned PSP platform trial regimen B; endpoint not provided in retrieved trial summary https://clinicaltrials.gov/study/NCT07264283 (OpenTargets Search: Progressive supranuclear palsy)
FNP-223 Investigational disease-modifying therapy for PSP NCT06355531 Phase 2 Active, not recruiting 241 planned Study to assess efficacy, safety, and pharmacokinetics to slow PSP progression; primary endpoint not provided in retrieved trial summary https://clinicaltrials.gov/study/NCT06355531 (OpenTargets Search: Progressive supranuclear palsy)
Syde® digital endpoints study Digital monitoring / observational endpoint feasibility study NCT07389018 Observational Not yet recruiting 30 planned Feasibility of digital endpoints for monitoring PSP-Richardson syndrome https://clinicaltrials.gov/study/NCT07389018 (OpenTargets Search: Progressive supranuclear palsy)
Art therapy in PSP Supportive / non-pharmacologic intervention NCT06588673 Not applicable Active, not recruiting 10 planned Interventional supportive-care study; endpoint not provided in retrieved trial summary https://clinicaltrials.gov/study/NCT06588673 (OpenTargets Search: Progressive supranuclear palsy)
GV1001 subcutaneous Investigational peptide therapy NCT05819658 Phase 2 Completed 78 planned Treatment study in PSP; endpoint/results not provided in retrieved trial summary https://clinicaltrials.gov/study/NCT05819658 (OpenTargets Search: Progressive supranuclear palsy)
GV1001 extension Extension study for prior GV1001 PSP trial completers NCT06235775 Phase 2 Completed 67 planned Extension study; endpoint/results not provided in retrieved trial summary https://clinicaltrials.gov/study/NCT06235775 (OpenTargets Search: Progressive supranuclear palsy)
TPN-101 Investigational therapy NCT04993768 Phase 2a Completed 42 planned Phase 2a study in PSP; endpoint/results not provided in retrieved trial summary https://clinicaltrials.gov/study/NCT04993768 (OpenTargets Search: Progressive supranuclear palsy)
RT001 Investigational therapy NCT04937530 Phase 2 Unknown 40 planned PSP treatment study; endpoint/results not provided in retrieved trial summary https://clinicaltrials.gov/study/NCT04937530 (OpenTargets Search: Progressive supranuclear palsy)
Real-world care utilization cohort (US/Canada) Retrospective observational real-world management study Not a trial Observational Published 72 Median onset before diagnosis: first fall 2.0 years, unsteady gait/gait impairment 1.2 years, mobility problems 0.8 years; healthcare resources used at some point: medications 100%, imaging 99%, assistive devices 90%, supportive care 86%, surgeries/procedures 85% https://doi.org/10.1186/s13023-024-03168-z (nysetvold2024progressivesupranuclearpalsy pages 1-2, nysetvold2024progressivesupranuclearpalsy pages 2-4)
Real-world economic burden cohort (Israel) Retrospective healthcare utilization / cost study Not a trial Observational Published 88 PSP, 264 matched controls Annual direct costs rose from US$8,910 in year before diagnosis to US$21,637 in year 5 and US$36,693 in year 10; costs about 2-fold higher than controls in year prior diagnosis and ~1.5-fold higher in year after diagnosis https://doi.org/10.1007/s00415-023-11714-1 (barer2023progressivesupranuclearpalsy’s pages 1-2, barer2023progressivesupranuclearpalsy’s pages 4-5)

Table: This table summarizes interventional PSP studies with reported outcomes, active pipeline trials from retrieved ClinicalTrials.gov results, and real-world management/cost studies. It is useful for quickly comparing therapeutic classes, trial status, quantitative efficacy signals, and care burden.

Key completed disease-modifying trial outcomes: - Gosuranemab (NCT03068468): no clinical benefit (PSPRS change 10.4 vs 10.6 at week 52; P=0.85) despite strong CSF N-terminal tau target engagement (-98%). (dam2021safetyandefficacy pages 1-6) - Tilavonemab/ABBV-8E12 (NCT02985879): terminated for futility; no PSPRS benefit at week 52 vs placebo. (hoglinger2021safetyandefficacy pages 1-2)

Notable 2023–2024 development: - FMT in PSP-RS (ChiCTR-2100045397): phase 2 single-center trial showed improvement in PSPRS at week 16 and sustained nonmotor symptom improvements, providing a provocative but as-yet single-center signal requiring replication. (tian2023efficacyoffaecal pages 1-2)

13. Prevention

No primary prevention or proven protective factors were identified in the retrieved evidence set. Current best-supported “prevention” is tertiary: reducing falls and aspiration risk, managing dysphagia/constipation/mood symptoms, and implementing assistive devices and supportive therapies early. (nysetvold2024progressivesupranuclearpalsy pages 1-2, barer2023progressivesupranuclearpalsy’s pages 1-2)

Earlier detection is being advanced via MDS criteria adoption and emerging biomarkers (CSF proteomic panels, tau PET, NfL-based staging/prognosis). (hoglinger2017clinicaldiagnosisof pages 2-3, wise2024csfproteomicsin pages 1-2)

14. Other Species / Natural Disease

No naturally occurring PSP-equivalent disease in non-human species was identified in the retrieved sources for this run.

15. Model Organisms and Experimental Models (2023–2024)

A major current limitation is that conventional iPSC-derived neurons express low 4R tau, hindering modeling of 4R tauopathies such as PSP. A 2024 Cell study reports engineered hiPSC-derived neuronal lines expressing 4R tau (and 4R P301S) that develop progressive tau inclusions after seeding and enable CRISPRi screens identifying modifiers of tau propagation, supporting human-relevant target discovery platforms. (bravo2024humanipsc4r pages 1-3)

Human tissue-based mechanistic mapping supports glial involvement: MAPT transcripts were detected and preserved in neurons, astrocytes, and oligodendrocytes with tau aggregates in PSP, motivating combined approaches (reduce MAPT expression plus remove misfolded tau). (forrest2023cellspecificmaptgene pages 1-2)

Expert opinion / analysis (authoritative synthesis)

Two overarching themes emerge from authoritative and recent sources: 1) PSP is best conceptualized as a spectrum of clinical phenotypes underpinned by a shared 4R tau neuropathology; therefore, diagnostic frameworks and biomarkers must capture early and variant presentations rather than only PSP-RS. This is the central rationale of the 2017 MDS criteria revision. (hoglinger2017clinicaldiagnosisof pages 2-3, boxer2017advancesinprogressive pages 1-2) 2) The lack of clinical efficacy in anti-tau antibody trials despite strong CSF target engagement implies that either the targeted tau species/compartment is not causally dominant, the intervention timing is too late, or pharmacology does not adequately address intracellular pathology and downstream stress/inflammatory cascades. This motivates: (i) better pharmacodynamic and disease-biology biomarkers, and (ii) multi-target approaches addressing upstream splicing/expression (MAPT), intracellular proteostasis/ISR, and neuroimmune pathways. (dam2021safetyandefficacy pages 1-6, whitney2024singlecelltranscriptomicand pages 1-2, wise2024csfproteomicsin pages 1-2)

Key statistics (recent and high-value)

  • Prevalence: PSP-RS 2.3–10.6 per 100,000 (wise2024csfproteomicsin pages 1-2); broader PSP up to ~18 per 100,000 in some studies (boxer2017advancesinprogressive pages 1-2).
  • Survival: PSP-RS median survival 6.9 years (wise2024csfproteomicsin pages 1-2); death within median 7.3 years after symptom onset in PASSPORT report (dam2021safetyandefficacy pages 1-6).
  • Real-world prediagnosis timing: first fall median 2.0 years before diagnosis; gait impairment 1.2 years; mobility problems 0.8 years (nysetvold2024progressivesupranuclearpalsy pages 1-2).
  • Genetics: MAPT H1 haplotype OR ~5.6 (wang2024wholegenomesequencinganalysis pages 1-2); SV burden P=6.73×10^-3 (wang2024wholegenomesequencinganalysis pages 1-2).
  • Biomarkers: ATP6AP2 AUC 0.922 in CSF proteomics (jang2024biomarkerdiscoveryin pages 1-2); axon-guidance CSF panel AUC up to 0.932 (wise2024csfproteomicsin pages 1-2).
  • Trial outcomes: gosuranemab PSPRS 10.4 vs 10.6 at 52 weeks, P=0.85, with CSF N-term tau -98% (dam2021safetyandefficacy pages 1-6); tilavonemab no PSPRS benefit (hoglinger2021safetyandefficacy pages 1-2); FMT benefit 4.3 PSPRS points at week 16 (tian2023efficacyoffaecal pages 1-2).
  • Healthcare costs: annual direct costs rose to US$21,637 at year 5 and US$36,693 at year 10 vs US$8,910 pre-diagnosis (barer2023progressivesupranuclearpalsy’s pages 1-2).

Limitations of this report (data availability)

  • OMIM, MeSH, ICD-10, and Orphanet numeric identifiers were not explicitly retrievable in the provided texts beyond MONDO and Orphanet subtype labels surfaced via OpenTargets.
  • Variant-level details (ClinVar classifications, allele frequencies) and PSP-specific environmental risk/protective factors were not captured in this retrieval.
  • Some biomarker and imaging findings (e.g., PI-2620 tau PET linkage) were available as preprint evidence.

References

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