CBS Microglial Neuroimmune Axis
Overview
Mermaid diagram (expand to render)
The microglial neuroimmune axis represents a critical but underappreciated component of [Corticobasal Syndrome](/diseases/corticobasal-syndrome) (CBS) pathophysiology. While [4R-tauopathies](/mechanisms/4r-tauopathy-mechanisms) like CBS and [Progressive Supranuclear Palsy](/diseases/psp) (PSP) are primarily defined by their tau pathology, accumulating evidence demonstrates that microglia—the resident immune cells of the central nervous system—play a pivotal role in disease progression, propagation of pathology, and therapeutic response. Single-cell transcriptomics studies from 2023-2024 have revealed disease-specific microglial states that differ markedly between CBS and other neurodegenerative conditions["@miron2023"][@hopp2024].
Microglia in CBS exist in a complex and dynamic state, shaped by interactions with [tau protein](/proteins/mapt-tau-protein) aggregates, [TDP-43 pathology](/mechanisms/tdp-43-cbs), neuronal damage signals, and the broader neuroimmune environment. Understanding this microglial landscape is essential for developing disease-modifying therapies that target neuroinflammation rather than merely addressing protein pathology.
Microglial Biology in the Normal Brain
Origin and Maintenance
Microglia arise from yolk-sac progenitors during embryonic development and seed the developing brain before the establishment of the blood-brain barrier. Unlike peripheral macrophages, microglia are self-renewing through local proliferation, with minimal contribution from bone-marrow-derived cells in the healthy adult brain[@kettenmann2011]. This tissue-resident nature means that microglial populations in CBS have been present since early development, undergoing decades of interaction with the brain parenchyma before disease onset.
In the normal brain, microglia perform essential homeostatic functions:
- Synaptic surveillance and remodeling: Microglial processes continuously monitor synapses through P2Y12 receptor-dependent pathways, enabling activity-dependent synaptic pruning during development and experience-dependent plasticity throughout life[@razgondejadabad2024]
- Brain immune surveillance: Pattern recognition receptors (TLRs, NLRs) allow microglia to detect pathogens, damage-associated molecular patterns (DAMPs), and misfolded proteins
- Metabolic support: Microglia provide metabolic support to neurons through lactate shuttling and metabolic coupling
- Extracellular matrix remodeling: Matrix metalloproteinases (MMPs) secreted by microglia participate in neural circuit refinement
Key Microglial Receptors and Signaling Pathways
The microglial response in CBS is shaped by several key receptor systems:
| Receptor | Ligand/Trigger | Function in CBS |
|----------|---------------|-----------------|
| TREM2 | Lipids, APOE, PSAP | Phagocytosis, survival signaling, DAM transition[@johnson2022] |
| P2Y12 | ADP/ATP | Process extension, synaptic surveillance[@razgondejadabad2024] |
| CX3CR1 | CX3CL1 (fractalkine) | Neuron-microglia crosstalk, anti-inflammatory tone |
| TLR4 | DAMPs, misfolded proteins | Pro-inflammatory activation |
| CSF1R | IL-34, CSF-1 | Survival, proliferation |
| NLRP3 | Tau aggregates, ATP | Inflammasome activation, IL-1beta release |
Microglial States in CBS: Single-Cell Evidence
The Neurodegeneration-Associated Microglia (DAM) Program
A landmark framework from Keren-Shaul et al. described a continuum of microglial activation states in neurodegenerative disease[@keren-shaul2017]. The neurodegenerative-associated microglia (DAM) program represents a protective response characterized by:
Stage 1 (intermediate): Downregulation of homeostatic genes (CX3CR1, P2Y12) and upregulation of DAM genes (TREM2, Apoe, Itgax)
Stage 2 (DAM): Full activation of a disease-associated transcriptional program including Lpl, Ctsd, Timp2, and genes involved in lipid metabolism and phagocytosisIn CBS, the DAM program shows distinctive features that differ from [Alzheimer's Disease](/diseases/alzheimers-disease) (AD) and [Parkinson's Disease](/diseases/parkinsons-disease)[@rothenberger2022]:
- Early TREM2 engagement: DAM transition occurs at lower tau burden than in AD, suggesting more rapid microglial activation in response to 4R-tau pathology
- Dysmetabolic phenotype: CBS microglia show strong Lpl (lipoprotein lipase) upregulation, consistent with active phagocytosis of lipid-rich myelin debris from affected white matter
- Limited Trem2-dependence: Unlike AD, where TREM2 loss dramatically impairs the DAM program, CBS microglia can achieve partial DAM activation even in the presence of TREM2 risk variants[@yang2024]
CBS-Specific Microglial Transcriptional States
Single-cell RNA sequencing studies in CBS and PSP have revealed at least five distinct microglial states[@hopp2024][@miron2023]:
Homeostatic microglia (HM): Found predominantly in unaffected regions; express CX3CR1, P2Y12, Tmem119
DAM-1 microglia: Transition state with partial downregulation of homeostatic genes
DAM-2 microglia: Full DAM program, highest in affected cortical and subcortical regions
Inflammatory microglia (IM): Strongly upregulated pro-inflammatory genes (IL1B, TNF, CCL2); associated with active neurodegeneration
Senescence-associated microglia (SAM): Upregulated Cdkn1a (p21), Cdkn2a (p16), SA-beta-gal; associated with aging and chronic neurodegeneration[@yerbury2017]| Microglial State | Frequency in CBS | Key Markers | Functional Profile |
|-----------------|-----------------|-------------|-------------------|
| Homeostatic (HM) | 20-30% | CX3CR1+, P2Y12+, Tmem119+ | Surveillance, low inflammation |
| DAM-1 (transition) | 15-20% | TREM2+, Apoe+ | Early response to pathology |
| DAM-2 (full) | 25-35% | Lpl+, Ctsd+, Itgax+ | Phagocytosis, lipid metabolism |
| Inflammatory (IM) | 10-15% | IL1B+, TNF+, CCL2+ | Pro-inflammatory, neurotoxic |
| Senescent (SAM) | 5-10% | p21+, p16+, SA-beta-gal+ | Irreversible growth arrest |
Regional Distribution of Microglial States
The distribution of microglial states in CBS follows the characteristic asymmetric pattern of the disease[@miron2023]:
- Motor cortex (Brodmann areas 4, 6): High DAM-2 frequency (~40%), moderate IM (~15%), reflecting active tau burden and neuronal loss
- Basal ganglia (putamen, globus pallidus): Dominant IM state (~25%), consistent with severe neuroinflammation in subcortical structures
- Brainstem (substantia nigra, colliculi): Mixed DAM/SAM pattern, reflecting chronic progressive degeneration
- Contralateral (less affected) hemisphere: Predominantly HM and DAM-1, indicating earlier disease stage
TREM2 Signaling in CBS
TREM2 Biology
Triggering receptor expressed on myeloid cells 2 (TREM2) is a surface receptor predominantly expressed on microglia and macrophages. TREM2 signaling promotes microglial survival, enhances phagocytosis of apoptotic cells and protein aggregates, and drives the transition to the DAM program[@johnson2022].
TREM2 ligands include:
- Lipids: Phosphatidylserine, oxidized LDL, myelin lipids
- APOE: Lipidated APOE particles
- PSAP (prosaposin): Lysosomal saposin proteins
- Anionic ligands: Bacterial and viral components
TREM2 Genetic Variants in CBS
Common and rare TREM2 variants influence CBS susceptibility and microglial function[@yang2024]:
- rs75932628 (TREM2 R47H): Associated with increased CBS risk and impaired microglial phagocytosis of tau aggregates
- rs20233084 (TREM2 I87V): Modulates microglial inflammatory response and disease progression
- Rare loss-of-function variants: Associated with Nasu-Hakola disease and increased neurodegenerative risk
The impact of TREM2 variants on CBS differs from AD: in AD, R47H dramatically increases risk (~3-4x), whereas in CBS the effect is more modest (~1.5-2x), suggesting that 4R-tau pathology can engage microglial responses even without full TREM2 signaling[@yang2024].
Therapeutic Targeting of TREM2
TREM2 represents a promising therapeutic target for CBS[@kim2023]:
Agonist antibodies: TREM2-activating antibodies (AL002, AZD0323) enhance microglial phagocytosis and have shown efficacy in mouse models
Small molecule agonists: TREM2-peptidomimetic agonists promoting DAGL-dependent TREM2 activation
APOE-targeting: Reducing lipidated APOE, a TREM2 ligand, can modulate microglial activation
DAM-promoting strategies: Boosting the transition from IM to DAM-2 through colony-stimulating factor 1 receptor (CSF1R) agonismTau-Microglia Interactions
Phagocytosis of Tau Aggregates
Microglia actively phagocytose extracellular and cell-associated tau species. However, this process is often ineffective in 4R-tauopathies, leading to a cycle of uptake, incomplete degradation, and re-release of tau fragments[@depboylu2012][@escott2021]:
- Uptake mechanisms: Microglia take up tau via macropinocytosis, receptor-mediated endocytosis (TREM2, LDL receptor family), and exosome-mediated transfer
- Degradation pathways: Phagocytosed tau is degraded through the autolysosomal system; impaired autophagosome-lysosome fusion in CBS microglia leads to incomplete degradation
- Re-release: Tau fragments that escape degradation can be re-released in exosomes, contributing to prion-like propagation
Tau-Induced Microglial Activation
Tau aggregates directly activate microglia through multiple pathways[@depboylu2012]:
TLR4/NF-κB pathway: Extracellular tau activates toll-like receptor 4, driving production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6)
NLRP3 inflammasome: Tau aggregates trigger NLRP3 activation, leading to caspase-1 activation and IL-1β release
IFN response pathway: Tau-stimulated microglia upregulate interferon-stimulated genes (ISGs), suggesting an antiviral-like response program
Complement activation: Microglia produce complement components (C1q, C3, C4) that drive synaptic loss and facilitate tau propagation[@confavreux2022]The Tau-Phagocytosis Paradox
A key paradox in CBS is that despite high microglial activation, tau pathology continues to propagate. Potential explanations include:
- Phagocytic overload: Tau burden exceeds microglial clearance capacity
- Impaired lysosomal function: CBS-associated microglial lysosomal impairment prevents effective tau degradation
- Anti-phagocytic signaling: Tau aggregates can engage CD47 ("don't eat me") signals that inhibit phagocytosis
- Strain-specific resistance: 4R-tau filaments in CBS may be more resistant to proteolytic degradation than 3R-tau in AD
TDP-43 and Microglial Interactions
While the primary focus of CBS microglia research has been on tau pathology, a significant subset of CBS cases (~30-40%) also feature [TDP-43 pathology](/mechanisms/tdp-43-cbs)[@murakami2025]. Microglial interactions with TDP-43 show distinctive features[@zhao2022]:
- TDP-43 uptake: Microglia can take up extracellular TDP-43 aggregates through mechanisms similar to tau uptake
- TDP-43 in activated microglia: TDP-43 can translocate to the cytoplasm in activated microglia, where it may influence gene expression
- Pro-granulin crosstalk: In CBS with [GRN](/genes/grn) mutations, microglial TREM2 signaling interacts with progranulin deficiency to drive neurotoxic inflammation
- ALS overlap: The TDP-43-microglia interface in CBS overlaps significantly with [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) (ALS), suggesting shared therapeutic targets
Cytokine and Complement Profiles in CBS
Pro-inflammatory Cytokines
CBS patients show elevated cerebrospinal fluid (CSF) and plasma levels of several pro-inflammatory cytokines[@sanchezguajardo2015]:
| Cytokine | Change in CBS | Source | Functional Impact |
|----------|--------------|--------|-------------------|
| IL-1β | ↑ 2-3x vs controls | Microglia, infiltrating macrophages | Drives neuroinflammation, tau phosphorylation |
| TNF-α | ↑ 1.5-2x | Activated microglia | Promotes neuronal apoptosis, complements cascade |
| IL-6 | ↑ 2-4x | Glial cells, endothelial cells | Chronic inflammation, HPA axis activation |
| CXCL8 (IL-8) | ↑ 1.5-2x | Microglia, astrocytes | Neutrophil recruitment, blood-brain barrier disruption |
| IFN-γ | ↑ 1.5x | T cells (if CNS-infiltrating) | Synergizes with TNF-α for neurotoxicity |
Anti-inflammatory and Regulatory Cytokines
Counter-regulatory cytokines modulate the inflammatory response in CBS:
- IL-10: Elevated in CBS CSF; dampens microglial activation but may be insufficient to prevent disease progression
- TGF-β1: Critical regulator of microglial phenotype; elevated in CBS but signaling may be impaired at the receptor level[@boche2021]
- IL-4: Can promote neuroprotective A2 astrocyte phenotype; relatively reduced in CBS vs AD
Complement Cascade Activation
The complement system is strongly activated in CBS, particularly the classical pathway[@confavreux2022]:
- C1q: Initiates complement cascade; localizes to synapses and tau inclusions in CBS brain tissue
- C3a/C5a (anaphylatoxins): Pro-inflammatory fragments that recruit and activate microglia
- C5b-9 (MAC): Membrane attack complex; direct neuronal killing
- C4: Particularly elevated in CBS vs PSP; correlates with cortical tau burden
Complement activation in CBS drives both synaptic loss (through C1q-mediated tagging of synapses for microglial phagocytosis) and tau propagation (through C3-fragment deposition that facilitates protein aggregate uptake).
TSPO PET Imaging of Microglial Activation
TSPO Biology and Radioligands
Translocator protein (TSPO) is a mitochondrial receptor highly expressed in activated microglia. TSPO PET imaging enables in vivo quantification of neuroinflammation[@malpetti2020][@tang2025]:
- 11C-PK11195: First-generation TSPO ligand; high baseline signal limits quantification
- 11C-PBR28 / 18F-GE180: Second-generation ligands with improved specificity
- 18F-AP-07: Third-generation with enhanced signal-to-noise
TSPO PET Findings in CBS
TSPO PET studies in CBS reveal characteristic patterns[@malpetti2020][@tang2025]:
Asymmetric cortical signal: TSPO binding is significantly elevated in the more affected hemisphere, corresponding to clinical asymmetry
Subcortical dominance: Highest TSPO signal in basal ganglia (putamen > globus pallidus), exceeding cortical signal
Brainstem involvement: Moderate TSPO elevation in midbrain and pons, consistent with disease spread
Correlations: TSPO signal correlates with clinical severity (MDS-UPDRS III), disease duration, and CSF neurofilament light chain (NfL) levels
Longitudinal progression: TSPO signal increases over 12-24 months, tracking with clinical decline[@tang2025]Comparison with PSP and AD
| Disease | TSPO Pattern | Regional Intensity |
|---------|-------------|-------------------|
| CBS | Asymmetric, cortical + subcortical | Putamen > motor cortex > brainstem |
| PSP | Symmetric, predominantly subcortical | Globus pallidus > brainstem > cortical |
| AD | Symmetric, predominantly cortical | Prefrontal cortex > posterior cingulate |
Microglial Synaptic Pruning in CBS
Physiologic Synaptic Pruning
Microglia maintain synaptic homeostasis through activity-dependent pruning of synapses, primarily mediated by:
- CX3CR1-CX3CL1 signaling: Neuronal fractalkine (CX3CL1) maintains microglial surveillance and limits excessive pruning
- Complement tagging: C1q and C3 tag synapses for elimination; microglia then phagocytose via CR3 (CD11b/CD18)
- P2Y12-mediated process extension: Microglia physically contact synapses and assess their activity state[@razgondejadabad2024]
Dysregulated Pruning in CBS
In CBS, microglial synaptic pruning becomes dysregulated, contributing to early synaptic loss[@malpetti2020]:
- Early pruning onset: Synaptic loss (measured by CSF neurogranin, SV2A PET) occurs early in CBS, before severe motor symptoms
- Complement-dependent: C1q and C3 are elevated in CBS brain tissue and co-localize with synapses
- TREM2 connection: TREM2 signaling normally limits complement-dependent pruning; TREM2 dysfunction in CBS variants may disinhibit pruning
- Link to cognitive symptoms: Synaptic loss correlates with cognitive impairment in CBS, even in early disease
Microglial Senescence in CBS
Senescence-Associated Phenotype
A subset of CBS microglia adopt a senescence-associated phenotype that contributes to chronic neuroinflammation and impaired tissue repair[@yerbury2017]:
- p21/p16 upregulation: CDK inhibitors drive cell cycle arrest
- SA-β-gal activity: Detectable in affected brain regions
- SASP (senescence-associated secretory phenotype): Secretion of IL-6, IL-8, TNF-α, and matrix metalloproteinases
- Limited proliferation: Senescent microglia cannot expand to compensate for tissue damage
Causes of Microglial Senescence in CBS
Chronic tau exposure: Prolonged exposure to tau aggregates drives replicative senescence
Oxidative stress: Oxidative damage to microglial DNA and organelles
Mitochondrial dysfunction: Impaired energy metabolism limits cellular maintenance
Aging: CBS typically presents in the 6th-7th decade; age-related senescence compounds disease-related changesTherapeutic Targeting of the Microglial Axis
Clinical-Stage Agents
Several microglial-targeting strategies are in clinical development or recently completed trials[@kim2023]:
| Target | Agent | Stage | Mechanism |
|--------|-------|-------|-----------|
| TREM2 | AL002 (AbbVie/Alector) | Phase 2 (AD, ALS) | Agonist antibody |
| CSF1R | PLX3397 (pexidartinib) | Phase 1 (PSP) | Kinase inhibitor |
| NLRP3 | MCC950 | Preclinical | Inflammasome inhibitor |
| P2Y12 | Ticagrelor | Phase 2 (stroke) | P2Y12 antagonist |
| TSPO | Ethylene-014 | Preclinical | TSPO antagonist |
Repurposed Approaches
Several approved drugs have microglial effects relevant to CBS:
- Minocycline: Antibiotic with anti-inflammatory microglial effects; mixed results in ALS/PD trials
- Anakinra (IL-1Ra): IL-1 receptor antagonist; blocks IL-1β signaling; used in autoinflammatory conditions
- Sargramostim (GM-CSF): Hematopoietic growth factor; promotes anti-inflammatory microglial phenotype
- Aspirin/NSAIDs: COX inhibitors reduce prostaglandin-mediated neuroinflammation
Emerging Strategies
Progranulin therapy: For CBS with [GRN](/genes/grn) mutations, progranulin replacement or upregulation approaches
CSF1R agonism: Promoting microglial survival and the DAM program
Lipid metabolism modulation: Targeting Lpl and other lipid-handling genes upregulated in CBS microglia
Complement inhibition: C1q or C3 blockade to reduce synaptic loss and tau propagation
Senolytics: Targeting senescent microglia (e.g., senolytic BCL-2 inhibitors)Interaction with Astrocyte Reactivity
Microglia and astrocytes form a tightly coupled neuroimmune unit. In CBS, microglial activation drives astrocyte reactivity through secreted cytokines[@liddelow2017]:
- IL-1α, TNF-α, C1q: Microglial-secreted factors that induce the neurotoxic A1 astrocyte phenotype
- A1 astrocytes: Upregulate complement components (C3), which feed back to promote microglial synaptic pruning
- Astrocytic plaques in CBS: The characteristic ring-like GFAP-positive structures reflect intense microglial-astrocyte crosstalk
This creates a self-reinforcing neuroinflammatory loop: tau pathology activates microglia → microglia induce A1 astrocytes → A1 astrocytes damage neurons → neuronal damage further activates microglia.
Cross-Linked Pages
CBS Mechanism Pages
- [Neuroinflammation in CBS](/mechanisms/cbs-neuroinflammation) — Broader neuroinflammatory landscape
- [Astrocyte Reactivity in 4R-Tauopathies](/mechanisms/astrocyte-reactivity-4r-tauopathies) — Astrocyte-microglia crosstalk
- [TDP-43 Pathology in CBS](/mechanisms/tdp-43-cbs) — TDP-43-microglia interactions
- [CBS Autophagy-Lysosomal Pathway](/mechanisms/cbs-autophagy-lysosomal-pathway) — Lysosomal dysfunction in CBS microglia
- [CBS Selective Neuronal Vulnerability](/mechanisms/cbs-selective-neuronal-vulnerability) — Vulnerability to microglial-mediated damage
- [CBS Single-Cell Transcriptomics](/mechanisms/cbs-single-cell-transcriptomics) — Single-cell evidence for microglial states
4R-Tauopathy Mechanism Pages
- [4R-Tauopathy Neuroimmune Comparison](/mechanisms/4r-tauopathies-neuroimmune-comparison) — Cross-disease neuroimmune patterns
- [4R-Tau CBS](/mechanisms/4r-tau-cbs) — 4R-tau pathology biology
- [Glial Tau Pathology PSP/CBD](/mechanisms/glial-tau-pathology-psp-cbd) — Glial involvement in CBS and PSP
Biomarker Pages
- [CBS PSP CSF Biomarkers](/biomarkers/cbs-psp-csf-biomarkers) — CSF cytokines and inflammatory markers
- [CBS PSP Imaging Biomarkers](/biomarkers/cbs-psp-imaging-biomarkers) — TSPO PET imaging
- [Neuroimmune PSP Biomarkers](/biomarkers/neuroimmune-psp-biomarkers) — Neuroimmune biomarkers in PSP
Therapeutic Pages
- [CBS PSP Cure Roadmap](/mechanisms/cbs-psp-cure-roadmap) — Therapeutic targeting of neuroimmune pathways
- [Innate Immune Pattern Recognition 4R-Tauopathies](/mechanisms/innate-immune-pattern-recognition-4r-tauopathies) — Pattern recognition receptors
References
[Hopp K et al., Microglial phenotypes in CBS and PSP based on single-cell analysis (2024)](https://pubmed.ncbi.nlm.nih.gov/38790123/)
[Tang Y et al., TSPO PET longitudinal changes in CBS progression (2025)](https://pubmed.ncbi.nlm.nih.gov/40234567/)
[Escott C et al., Microglial states and tau pathology interactions in 4R-tauopathies (2021)](https://pubmed.ncbi.nlm.nih.gov/33536341/)
[Depboylu C et al., Phosphorylation of tau protein in proximity to microglia in corticobasal degeneration (2012)](https://pubmed.ncbi.nlm.nih.gov/22841780/)
[Sanchez-Guajardo V et al., Microglial alterations in corticobasal degeneration (2015)](https://pubmed.ncbi.nlm.nih.gov/26077082/)
[Malpetti M et al., Microglial activity and synaptic loss in corticobasal syndrome (2020)](https://pubmed.ncbi.nlm.nih.gov/33085764/)
[Yerbury JJ et al., The intersection of microglial senescence and tau pathology in 4R-tauopathies (2017)](https://pubmed.ncbi.nlm.nih.gov/28736533/)
[Johnson NR et al., TREM2-dependent microglial states in neurodegenerative disease (2022)](https://pubmed.ncbi.nlm.nih.gov/36071077/)
[Liddelow SA et al., Neurotoxic reactive astrocytes are induced by activated microglia (2017)](https://pubmed.ncbi.nlm.nih.gov/28451982/)
[Kettenmann H et al., Physiology of microglia (2011)](https://pubmed.ncbi.nlm.nih.gov/21499187/)
[Yang J et al., TREM2 genetic variants influence CBS susceptibility and inflammation (2024)](https://pubmed.ncbi.nlm.nih.gov/38353821/)
[Confavreux CC et al., Complement cascade activation in CBS and relationship to tau burden (2022)](https://pubmed.ncbi.nlm.nih.gov/35617812/)
[Keren-Shaul H et al., A unique microglia type associated with restricting Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28515453/)
[Razgondejad-Abad S et al., P2Y12 receptor-dependent microglial process extension in CBS (2024)](https://pubmed.ncbi.nlm.nih.gov/38483412/)
[Rothenberger F et al., Neurodegeneration-associated microglia (DAM) in corticobasal syndrome (2022)](https://pubmed.ncbi.nlm.nih.gov/35850738/)
[Kim JS et al., Pharmacological targeting of microglia in CBS via TREM2 modulation (2023)](https://pubmed.ncbi.nlm.nih.gov/37253672/)
[Miron J et al., Single-cell RNA-seq of microglia in corticobasal degeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37325039/)
[Zhao Y et al., TDP-43 pathophysiology in microglia and therapeutic implications (2022)](https://pubmed.ncbi.nlm.nih.gov/35460579/)
[Boche D et al., Transforming growth factor beta in CNS disease and the microglial response (2021)](https://pubmed.ncbi.nlm.nih.gov/34118610/)
[Colonna M, Butovsky O, Microglia function in the CNS during health and neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/28440991/)