CoChat
Sign Up
Cited by 459Neuroinflammation and Neurodegeneration MechanismsPharmacological Receptor Mechanisms and EffectsNeurological Disease Mechanisms and Treatments

The DOI matches its Crossref record; 75 of the 75 references it cites were found in a registry or an index; 14 of the 47 sources its claims cite were checked for support.

Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

Open access
Cosenza‐Nashat, M., Zhao, M.‐L., Suh, H.‐S., Morgan, J., Natividad, R., Morgello, S., Lee, S. C.·2009·Neuropathology and Applied Neurobiology
DOI 10.1111/j.1365-2990.2008.01006.xPMC PMC2693902
Open this paper in CoChat — free accountOpen PDF

Abstract

AIMS: Microglia are involved in neurodegeneration, are prime targets for anti-inflammatory therapy and are potential biomarkers of disease progression. For example, positron emission tomography imaging employing radioligands for the mitochondrial translocator protein of 18 kDa (TSPO, formerly known as the peripheral benzodiazepine receptor) is being scrutinized to detect neuroinflammation in various diseases. TSPO is presumably present in activated microglia, but may be present in other neural cells. METHODS: We sought to elucidate the protein expression in normal human central nervous system, several neurological diseases (HIV encephalitis, Alzheimer's disease, multiple sclerosis and stroke) and simian immunodeficiency virus encephalitis by performing immunohistochemistry with two anti-TSPO antibodies. RESULTS: Although the overall parenchymal staining was minimal in normal brain, endothelial and smooth muscle cells, subpial glia, intravascular monocytes and ependymal cells were TSPO-positive. In disease states, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes, but the distribution of TSPO varied depending on the disease, disease stage and proximity to the lesion or relation to infection. Staining with the two antibodies correlated well in white matter, but one antibody also stained cortical neurones. Quantitative analysis demonstrated a significant increase in TSPO in the white matter of HIV encephalitis compared with brains without encephalitis. TSPO expression was also increased in simian immunodeficiency virus encephalitis. CONCLUSIONS: This report provides the first comprehensive immunohistochemical analysis of the expression of TSPO. The results are useful for informing the usage of positron emission tomography as an imaging modality and have an impact on the potential use of TSPO as an anti-inflammatory pharmacological target.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This study used two anti-TSPO antibodies to map TSPO immunohistochemically in normal and diseased human and macaque CNS. It found that TSPO is minimally expressed in normal brain parenchyma but is upregulated chiefly in microglia and macrophages, and in some hypertrophic astrocytes, in HIV encephalitis, SIV encephalitis, Alzheimer’s disease, multiple sclerosis and stroke.

Key findings

  • In normal brain, overall parenchymal staining was minimal, but TSPO was positive in endothelial and smooth muscle cells, subpial glia, intravascular monocytes and ependymal cells.
  • In disease, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes; distribution varied by disease, disease stage, proximity to lesion and relation to infection.
  • Quantitative white matter analysis showed significantly increased TSPO in HIV encephalitis versus HIV− and HIV+ groups for both antibodies (Kruskal-Wallis p < 0.001; Dunn pairwise p < 0.001). HIVE average percent area stained ranged from 0.27–1.24% for mAb and 0.01–0.5% for pAb, with the highest observed image at 4.7%; HIV− ranged from 0.02–0.12% (mAb) and 0.03–0.11% (pAb), and HIV+ from 0.01–0.10% (mAb) and 0.01–0.08% (pAb). HIV− and HIV+ did not differ significantly.
  • TSPO expression was also increased in SIV encephalitis; TSPO+ oligodendrocytes were present in the optic tract in one SIVE and the SIV− brain, and TSPO+ hypertrophic astrocytes were noticeably lacking in SIVE.

Methods

  • Immunohistochemistry with two anti-TSPO antibodies—a rabbit polyclonal and a mouse monoclonal—was performed on formalin-fixed, paraffin-embedded brain tissue from HIV− (n=4), HIV+ without encephalitis (n=5) and HIVE (n=10) cases, plus Alzheimer’s disease (n=9), multiple sclerosis and ischemic infarct cases, and macaque brains (SIV− n=1, SIV+ n=1, SIVE n=2).
  • Single- and double-label colorimetric and fluorescent IHC were used with cell markers including CD68, CD45, GFAP, Iba1, HIV-1 p24 and amyloid-β; antibody absorption was performed for the polyclonal antibody.
  • Quantitative image analysis used NIH ImageJ on 20 random 400X white matter fields per case, expressed as percent area stained; groups were compared by Kruskal-Wallis with Dunn’s multiple comparison tests, and antibody agreement was assessed by Spearman correlation.

Limitations

  • The paper states that the antibody absorption experiment was not repeated because peptide cost was prohibitive, and that neuronal staining with the polyclonal antibody remains a conundrum that may be non-specific, though possible TSPO isoforms or related molecules could not be dismissed.
  • The paper notes that cases of conditions other than HIV were not quantitatively analyzed because corresponding normal controls were not available from each site, and that only two SIVE cases were studied, limiting conclusions about the lack of astrocytic staining in SIVE.
  • Evident from the text: group sizes are small, especially HIV− (n=4), HIV+ (n=5) and macaque groups (n=1 each), and much cell-type assessment was semi-quantitative by morphology; the reported Spearman correlation between antibodies was statistically significant but weak (r = 0.08).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/j.1365-2990.2008.01006.x

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

14 of 47 cited sources checked · 4 supported · 1 flagged · accuracy not yet measured

  • Findingcitation

    In HIVE cases with diffuse infection, ramified glial cells had enhanced TSPO positivity, most of which were clearly identifiable as activated microglia.

    “In cases where the infection was diffuse [23], ramified glial cells had enhanced TSPO positivity, most of which were clearly identifiable as activated microglia.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Cosenza MA Zhao ML Si Q Lee SC Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis Brain Pathol 2002 12 442 455 12408230 PMC8095974 source

      The Abstract reports HIV-1 infection of parenchymal microglia in HIV encephalitis, but the available passages do not establish that the infection was diffuse. The citation is attached to the diffuse-infection condition; the subsequent TSPO observation appears to be the citing authors’ own finding. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • Premisecitation

    PET studies show generally increased retention of [11C]-PK11195 in various neurodegenerative conditions including HIVE, SIVE, AD, Huntington's disease, MS, PD, stroke, ALS, and CNS neoplasms.

    “PET studies show that there is generally an increased retention of [11C]-PK11195 in various neurodegenerative conditions including HIV encephalitis (HIVE), and its simian model SIV encephalitis (SIVE), Alzheimer’s disease (AD), Huntington’s disease, multiple sclerosis (MS), Parkinson’s disease (PD), stroke, amyotrophic lateral sclerosis, and CNS neoplasms (see [14;15] for review).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [14] Venneti S Lopresti BJ Wiley CA The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging Prog Neurobiol 2006 80 308 322 17156911 PMC1849976 source

      Table 1 (in the indexed section labeled “Abstract > 1.0 MICROGLIA IN HEALTH AND DISEASE”; page unavailable) reports increased [11C]-PK11195 retention for SIVE, AD, Huntington’s disease, MS, PD, stroke and ALS, and higher binding in glioblastoma. It does not establish the same finding specifically for human HIV encephalitis (HIVE): its human studies are labeled HIV infection, and one reports no increase in the group studied. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [15] Cagnin A Kassiou M Meikle SR Banati RB Positron emission tomography imaging of neuroinflammation Neurotherapeutics 2007 4 443 452 17599710 PMC7479716 source

      The Dementia, Movement disorders, Multiple sclerosis, and Stroke sections report increased [11C](R)-PK11195 binding or PET signal in AD, Huntington’s disease, PD, MS, and stroke. The passages found do not report PET findings for HIVE, SIVE, ALS, or CNS neoplasms, so the full list is not supported by this source. Page numbers were not supplied in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingcitation

    Infiltrating T lymphocytes in HIVE brains appear negative for TSPO.

    “Infiltrating T lymphocytes present in many of these brains [32], appear negative for TSPO.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Cosenza-Nashat MA Kim MO Zhao ML Suh HS Lee SC CD45 isoform expression in microglia and inflammatory cells in HIV-1 encephalitis Brain Pathol 2006 16 256 265 17107594 PMC1804203 source
  • Findingown data

    One TSPO antibody also stained cortical neurons.

    “Staining with the two antibodies correlated well in white matter, but one antibody also stained cortical neurons.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In disease states, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes.

    “In disease states, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes, but the distribution of TSPO varied depending on the disease, disease stage and proximity to the lesion or relation to infection.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 23
  • It may state two separate claims as one. 28

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    It is generally accepted that microglia and macrophages are the primary cell types exhibiting an increased number of TSPO binding sites in human pathologies, and that astrocytes are not significant contributors to increased TSPO binding sites.

    “It is generally accepted that microglia and macrophages are the primary cell types exhibiting an increased number of TSPO binding sites in human pathologies, and that astrocytes are not significant contributors to increased TSPO binding sites [44;45].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [44] Venneti S Lopresti BJ Wang G Hamilton RL Mathis CA Klunk WE Apte UM Wiley CA PK11195 labels activated microglia in Alzheimer’s disease and in vivo in a mouse model using PET Neurobiol Aging 2008 PMC2745919 18178291 source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [45] Banati RB Goerres GW Myers R Gunn RN Turkheimer FE Kreutzberg GW Brooks DJ Jones T Duncan JS [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis Neurology 1999 53 2199 2203 10599809 source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Premisecitation

    Immunohistochemical determination of TSPO expression in the human CNS would be an adjunctive means of studying TSPO.

    “Immunohistochemical determination of TSPO expression in the human CNS would be an adjunctive means of studying TSPO [14].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Venneti S Lopresti BJ Wiley CA The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging Prog Neurobiol 2006 80 308 322 17156911 PMC1849976 source

      In the section on PBR in CNS disease (page not provided), the review describes combining autoradiography with immunohistochemistry for astrocytes and microglia. It also calls for comparing human histopathologic data with ligand-binding studies. This supports histology as an adjunct, but the cited passages do not establish immunohistochemical determination of TSPO expression itself in the human CNS. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Traditional autoradiography studies of postmortem tissues confirm that TSPO binding sites are increased in many neurodegenerative diseases and that these binding sites are primarily in microglia.

    “Traditional autoradiography studies of postmortem tissues confirm that TSPO binding sites are increased in many of these diseases and that these binding sites are primarily in microglia.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [14] Venneti S Lopresti BJ Wiley CA The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging Prog Neurobiol 2006 80 308 322 17156911 PMC1849976 source
    • cites [15] Cagnin A Kassiou M Meikle SR Banati RB Positron emission tomography imaging of neuroinflammation Neurotherapeutics 2007 4 443 452 17599710 PMC7479716 source

      The Cellular source and function section (page unavailable) reports that microautoradiography finds increased PK11195 binding predominantly on activated microglia, though it also identifies binding on infiltrating blood-borne cells. The Dementia and Movement disorders sections describe increased binding in several neurodegenerative diseases, but chiefly from in vivo PET studies; the paper does not establish that postmortem autoradiography confirmed those increases across many such diseases. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    TSPO-binding radioligands used to assess neuroinflammation via PET imaging may have value as a biosensor of ongoing disease and may also be a target to reduce inflammation-mediated damage in diseases such as HIV-associated neurological disorders and dementia.

    “Use of TSPO-binding radioligands to assess neuroinflammation via PET imaging indicates that they may have value as a biosensor of ongoing disease and may also be a target to reduce inflammation-mediated damage in diseases such as HIV-associated neurological disorders and dementia ([17] and see [15;18] for review).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [17] Herholz K Carter SF Jones M Positron emission tomography imaging in dementia Br J Radiol 2007 80 Spec No 2 S160 S167 18445746 source
    • cites [15] Cagnin A Kassiou M Meikle SR Banati RB Positron emission tomography imaging of neuroinflammation Neurotherapeutics 2007 4 443 452 17599710 PMC7479716 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [18] Chen MK Guilarte TR Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair Pharmacol Ther 2008 118 1 17 18374421 PMC2453598 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Both pAb and mAb labeled some endothelial cells and smooth muscle cells.

    “The pAb (but not mAb) labeled neuronal cell bodies with punctuate spots (B), and both pAb and mAb labeled some endothelial cells (F) and smooth muscle cells, in agreement with other studies [27;31].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [27] Morgan J Oseroff AR Cheney RT Expression of the peripheral benzodiazepine receptor is decreased in skin cancers in comparison with normal skin Br J Dermatol 2004 151 846 856 15491426 source
    • cites [31] Tomasi G Edison P Bertoldo A Roncaroli F Singh P Gerhard A Cobelli C Brooks DJ Turkheimer FE Novel reference region model reveals increased microglial and reduced vascular binding of 11C-(R)-PK11195 in patients with Alzheimer’s disease J Nucl Med 2008 49 1249 1256 18632810 source

      The Pathologic Examination reports PBBS staining in endothelial and smooth muscle cells, supporting the cell types named in the claim. The Immunohistochemical Data section specifies a monoclonal antibody for this staining; our copy does not establish that a polyclonal antibody (pAb) also labeled those cells. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Papadopoulos and colleagues have shown that the Sp1/Sp3 and members of the Ets family of transcription factors control basal expression of the TSPO.

    “Papadopoulos and colleagues have shown that the Sp1/Sp3 and members of the Ets family of transcription factors control basal expression of the TSPO [61].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [61] Giatzakis C Batarseh A Dettin L Papadopoulos V The role of Ets transcription factors in the basal transcription of the translocator protein (18 kDa) Biochemistry 2007 46 4763 4774 17402746 PMC2529463 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In the human CNS, microglia and endothelial cells have been shown to express TSPO readily.

    “In the human CNS, microglia and endothelial cells have been shown to express TSPO readily ([31] and see [14] for review).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [31] Tomasi G Edison P Bertoldo A Roncaroli F Singh P Gerhard A Cobelli C Brooks DJ Turkheimer FE Novel reference region model reveals increased microglial and reduced vascular binding of 11C-(R)-PK11195 in patients with Alzheimer’s disease J Nucl Med 2008 49 1249 1256 18632810 source
    • cites [14] Venneti S Lopresti BJ Wiley CA The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging Prog Neurobiol 2006 80 308 322 17156911 PMC1849976 source

      Section 2.1.2 says PBR (TSPO) was detected in microglia, and section 2.1.3 discusses microglial PBR-ligand binding in brain tissue, including multiple sclerosis. The passages do not establish TSPO expression in endothelial cells of the human CNS, so that part of the claim is unsupported. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    TSPO+ astrocytes have been rarely observed in humans and are particularly noted in hepatic encephalopathy.

    “but TSPO+ astrocytes have been rarely observed in humans and are particularly noted in hepatic encephalopathy [48].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Lavoie J Layrargues GP Butterworth RF Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy Hepatology 1990 11 874 878 2161396 source

      The Discussion (page not specified in our copy) reports increased peripheral-type benzodiazepine receptor binding in brain samples from patients with hepatic encephalopathy and says this most likely reflects astrocytic changes. It does not establish that receptor-positive astrocytes were directly observed, or that they are rarely observed in humans. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Rarely, TSPO+ cells resembling oligodendrocytes were observed.

    “Rarely, TSPO+ cells resembling oligodendrocytes were also observed (not shown, but see Figure 2 for macaque brains).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The pAb, but not the mAb, labeled neuronal cell bodies with punctate spots.

    “The pAb (but not mAb) labeled neuronal cell bodies with punctuate spots (B), and both pAb and mAb labeled some endothelial cells (F) and smooth muscle cells, in agreement with other studies [27;31].”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingnone given

    The mAb was better than the pAb in staining vessel-associated TSPO.

    “In general, the mAb was better than the pAb in staining vessel-associated TSPO.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The quality of TSPO staining was punctate.

    “The quality of the staining was punctate which is consistent with the reported mitochondrial localization of TSPO protein.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingnone given

    Qualitatively, the staining intensity in some HIVE cases appears to be higher.

    “Qualitatively, however, the staining intensity in some HIVE cases appears to be higher (not shown).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    CD45 demonstrated double-positive perivascular macrophages as well as MGCs.

    “The leukocyte marker CD45 also demonstrated double-positive perivascular macrophages as well as MGCs (Figure 4E, F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    A CNS lymphoma in HIVE demonstrated tumour cells to be TSPO+, as well as infiltrating macrophages and phagocytic microglia.

    “Of note, a CNS lymphoma in HIVE demonstrated tumour cells to be TSPO+, as well as the infiltrating macrophages and phagocytic microglia (not shown).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In our study, TSPO+ astrocytes were present in all human disease states, but much less frequently than TSPO+ microglia.

    “In our study, TSPO+ astrocytes were present in all human disease states, but much less frequently than TSPO+ microglia, suggesting that astrocytic expression may be shorter-lived and/or it occurs only in a subset of astrocytes.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Double labeling with GFAP showed that astrocytes can express TSPO, but astrocyte expression was not as widespread as microglial expression.

    “Double labeling with the astrocyte marker GFAP showed that astrocytes can express TSPO (arrowheads, Figure 5A, D), but that astrocyte expression was not as widespread as microglial expression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    TSPO+ oligodendrocytes were present in the optic tract (and vicinity) in one SIVE and the SIV− brain.

    “An additional point of interest was that TSPO+ oligodendrocytes were present in the optic tract (and vicinity) in one SIVE and the SIV− brain (Figure 2E).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The highest observed TSPO expression in the captured images was 4.7% area stained.

    “Some nodules had very high TSPO labeling; the highest observed TSPO expression in the captured images was 4.7% area stained (which contributed to the large range shown for the HIVE cases).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The two anti-TSPO antibodies used in this study had good agreement in their level of staining, although there were some differences.

    “We find that these antibodies were both useful and generally had good agreement in their level of staining (see Figure 1 and Table 3), although there were some differences.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    TSPO+ vessels appeared in approximately one out of three 400X fields on average, with no differences observed between the groups.

    “The results show that TSPO+ vessels appeared in approximately one out of three 400X fields on average, with no differences observed between the groups (Figure 3C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In HIVE, TSPO levels ranged greatly such that some areas appeared to have low, normal-appearing TSPO expression while microglial nodules had very high levels of TSPO.

    “In HIVE, TSPO levels ranged greatly such that some areas appeared to have low, normal-appearing TSPO expression while microglial nodules had very high levels of TSPO.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    TSPO+ vasculature was present in brains regardless of whether they were HIV−, HIV+ or HIVE, and there does not seem to be a significant increase in HIVE brains.

    “We observed that TSPO+ vasculature was present in brains regardless of whether they were HIV−, HIV+ or HIVE and there does not seem to be a significant increase in HIVE brains, suggesting that unlike glial cell TSPO, endothelial TSPO might be constitutive.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Most MGCs were CD68+ and TSPO+.

    “Most MGCs were CD68+ and TSPO+ (Figure 4B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In ischaemic brains, TSPO expression was limited to the lesion and areas juxtaposed to the lesion, while areas away from the lesion exhibited reduced, normal levels of TSPO.

    “The sections from brains with ischaemia were large and TSPO expression was limited to the lesion and areas juxtaposed to the lesion, but areas away from the lesion exhibited reduced, normal levels of TSPO (not shown).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Brain areas adjacent to an infarct showed many positive hypertrophic TSPO+ astrocytes, as well as amoeboid microglia with punctate TSPO+ stain.

    “In addition, the brain areas adjacent to the infarct showed many positive hypertrophic TSPO+ astrocytes, as well as amoeboid microglia with punctate TSPO+ stain (Figure 6F & G).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    TSPO+ hypertrophic astrocytes were noticeably lacking in SIVE, whereas they were present in most HIVE cases.

    “What were noticeably lacking in SIVE were the TSPO+ hypertrophic astrocytes that were present in most HIVE cases.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The percent area stained between HIV− and HIV+ groups was not significantly different for either antibody.

    “The percent area stained between HIV− and HIV+ groups was not significantly different for either antibody.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Adjacent brain in acute MS showed neuronal staining as well as focal microglial staining.

    “Adjacent brain showed neuronal staining as well as focal microglial staining.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The percent area stained in the HIV+ group ranged from 0.01 to 0.10% for the mAb and 0.01 to 0.08% for the pAb.

    “The percent area stained in the HIV+ group ranged from 0.01 to 0.10% for the mAb and 0.01 to 0.08% for the pAb.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Our own preliminary data indicates that interleukin-1β can increase TSPO in primary human astrocytes.

    “Our own preliminary data indicates that interleukin-1β can increase TSPO in primary human astrocytes (not shown).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductcitation

    Tissue microarray ensured that different brain tissues were subjected to identical staining conditions, eliminating variables.

    “TMA ensured that the different brain tissues were subjected to identical staining conditions thus eliminating variables (S. Morgello et al., manuscript in preparation).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites S. Morgello et al., manuscript in preparation

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.

    Interpretationnone given

    The results are useful for informing the usage of PET as an imaging modality and have an impact on the potential use of TSPO as an anti-inflammatory pharmacological target.

    “The results are useful for informing the usage of PET as an imaging modality and have an impact on the potential use of TSPO as an anti-inflammatory pharmacological target.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationown data

    The punctate quality of TSPO staining is consistent with the reported mitochondrial localization of TSPO protein.

    “The quality of the staining was punctate which is consistent with the reported mitochondrial localization of TSPO protein.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    TSPO staining in single-stained slides was analyzed semi-quantitatively by two independent observers with good agreement.

    “The TSPO staining in single-stained slides was first analyzed semi-quantitatively by two independent observers using a grading system from no staining (−) to high levels of intense staining across the slide (++++) in various cell types, with good agreement between the two observers.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    HIVE cases with concurrent infections were not used for image analysis.

    “The HIVE cases with concurrent infections (one had neurosyphillis and had CNS lymphoma) were not used for image analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    Cases of conditions other than HIV were not analyzed because corresponding normal controls were not available from each site.

    “Cases of conditions other than HIV were not analyzed because corresponding normal controls were not available from each site.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Administration of TSPO ligands in vivo or in vitro suppresses microglial activation, including inhibition of cytokine expression.

    “In the CNS, TSPO is thought to be expressed by activated microglia and, in addition, administration of the TSPO ligands in vivo or in vitro results in suppression of microglialactivation including inhibition of cytokine expression [12;13].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Choi HB Khoo C Ryu JK van BE Kim SU McLarnon JG Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumor necrosis factor-alpha and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195 J Neurochem 2002 83 546 555 12390516 source
    • cites [13] Veiga S Carrero P Pernia O Azcoitia I Garcia-Segura LM Translocator protein 18 kDa is involved in the regulation of reactive gliosis Glia 2007 55 1426 1436 17674368 source

  • It may state two separate claims as one.

    Premisecitation

    TSPO ligands have anti-inflammatory properties, suggesting a role for TSPO in neuroinflammation.

    “Additionally, since TSPO ligands have anti-inflammatory properties, suggesting a role for TSPO in neuroinflammation [12;13;22], an understanding of its cell type expression in various disease states may be a key resource in how to target the TSPO in these diseases.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Choi HB Khoo C Ryu JK van BE Kim SU McLarnon JG Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumor necrosis factor-alpha and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195 J Neurochem 2002 83 546 555 12390516 source
    • cites [13] Veiga S Carrero P Pernia O Azcoitia I Garcia-Segura LM Translocator protein 18 kDa is involved in the regulation of reactive gliosis Glia 2007 55 1426 1436 17674368 source
    • cites [22] Ryu JK Choi HB McLarnon JG Peripheral benzodiazepine receptor ligand PK11195 reduces microglial activation and neuronal death in quinolinic acid-injected rat striatum Neurobiol Dis 2005 20 550 561 15916899 source

  • Probably not a substantial claim.

    Premisecitation

    In the CNS, TSPO is thought to be expressed by activated microglia.

    “In the CNS, TSPO is thought to be expressed by activated microglia and, in addition, administration of the TSPO ligands in vivo or in vitro results in suppression of microglialactivation including inhibition of cytokine expression [12;13].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Choi HB Khoo C Ryu JK van BE Kim SU McLarnon JG Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumor necrosis factor-alpha and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195 J Neurochem 2002 83 546 555 12390516 source
    • cites [13] Veiga S Carrero P Pernia O Azcoitia I Garcia-Segura LM Translocator protein 18 kDa is involved in the regulation of reactive gliosis Glia 2007 55 1426 1436 17674368 source

  • It may state two separate claims as one.

    Interpretationown data

    The pattern of TSPO expression differs between normal and diseased CNS, as well as among different diseases and cell types.

    “The results demonstrate that a variety of CNS cells are capable of expressing TSPO but that the pattern of expression differs between normal and diseased CNS, as well as among different diseases and cell types.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductcitation

    The specificity of both antibodies has been confirmed by immunoblotting and subcellular localization has been verified by electron microscopy.

    “The specificity of both antibodies has been confirmed by immunoblotting and subcellular localization has been verified by electron microscopy [27;28;54].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Morgan J Oseroff AR Cheney RT Expression of the peripheral benzodiazepine receptor is decreased in skin cancers in comparison with normal skin Br J Dermatol 2004 151 846 856 15491426 source
    • cites [28] Bribes E Carriere D Goubet C Galiegue S Casellas P Simony-Lafontaine J Immunohistochemical assessment of the peripheral benzodiazepine receptor in human tissues J Histochem Cytochem 2004 52 19 28 14688214 source
    • cites [54] Dussossoy D Carayon P Feraut D Belugou S Combes T Canat X Vidal H Casellas P Development of a monoclonal antibody to immuno-cytochemical analysis of the cellular localization of the peripheral benzodiazepine receptor Cytometry 1996 24 39 48 8723901 source

  • It may state two separate claims as one.

    Interpretationown data

    Astrocytic TSPO expression may be shorter-lived and/or occur only in a subset of astrocytes.

    “In our study, TSPO+ astrocytes were present in all human disease states, but much less frequently than TSPO+ microglia, suggesting that astrocytic expression may be shorter-lived and/or it occurs only in a subset of astrocytes.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    When the TSPO protein was incubated with the primary antibody, glial cell staining was reduced to approximately half (52% by ImageJ) but neuronal staining was not reduced.

    “When the TSPO protein was incubated with the primary antibody, the glial cell staining was reduced to approximately half (52% by ImageJ) but the neuronal staining was not reduced (not shown).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    The antibody absorption experiment was not repeated because the cost of the peptide was prohibitive.

    “The experiment was not repeated because the cost of the peptide was prohibitive”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Neuronal expression of TSPO has been observed in rodents but not in humans.

    “Neuronal expression of TSPO has been observed in rodents [35;36;55] but not in humans”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [35] Weissman BA Bolger GT Isaac L Paul SM Skolnick P Characterization of the binding of [3H]Ro 5–4864, a convulsant benzodiazepine, to guinea pig brain J Neurochem 1984 42 969 975 6321666 source
    • cites [36] Karchewski LA Bloechlinger S Woolf CJ Axonal injury-dependent induction of the peripheral benzodiazepine receptor in small-diameter adult rat primary sensory neurons Eur J Neurosci 2004 20 671 683 15255978 source
    • cites [55] Mills C Makwana M Wallace A Benn S Schmidt H Tegeder I Costigan M Brown RH Jr Raivich G Woolf CJ Ro5–4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats Eur J Neurosci 2008 27 937 946 18333964 source
46 of 46

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • TSPO expression was found in microglia in active and chronic active lesions.

    “Similar to previous studies, TSPO expression was found in microglia in active and chronic active lesions (Cosenza-Nashat et al., 2009; Martin et al., 2010; Lavisse et al., 2012a; Loth et al., 2016; Kaunzner et al., 2019).”

    From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Cosenza-Nashat et al., 2009

    The Results section, “Expression of TSPO in MS” (page not provided), says macrophages and microglia represent the bulk of TSPO-positive cells in acute MS lesions. It does not report TSPO-positive microglia in chronic active lesions; the chronic lesion it describes is a chronic silent plaque with TSPO-positive astrocytes. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The abundance of TSPO expression in astrocytes in the centres of chronic active lesions may suggest a more important role for TSPO in the pathophysiology of multiple sclerosis than previous data suggested.

    “The abundance of TSPO expression in astrocytes in the centres of chronic active lesions may suggest a more important role for TSPO in the pathophysiology of multiple sclerosis than previous data suggested (Cosenza-Nashat et al., 2009).”

    From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Cosenza-Nashat et al., 2009

    The Results section, “Expression of TSPO in MS” (page unavailable), reports TSPO staining in scattered astrocytes in a chronic silent MS plaque, supporting astrocytic expression in chronic lesions. It does not describe abundant expression in the centres of chronic active lesions. The Discussion (page unavailable) says TSPO-positive astrocytes were much less frequent than TSPO-positive microglia and does not establish the suggested greater role in MS pathophysiology. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In models of Alzheimer's-like neurodegeneration, TSPO positive microglia, astrocytes and endothelium are all increased.

    “Similarly, others have found that TSPO positive microglia, astrocytes and endothelium are all increased in models of Alzheimer’s-like neurodegeneration [48–51] and in postmortem human Alzheimer’s disease brains [27].”

    From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [51]

    The Results section, “Expression of TSPO in AD” (page unavailable), reports widespread TSPO-positive glia in human AD brains, predominantly microglia, with some astrocytes. It also notes TSPO-positive vessels, but does not show that endothelial TSPO increased. The Discussion (page unavailable) describes endothelial TSPO as potentially constitutive and reports a decrease in vascular staining with AD. This citation attaches to the human postmortem AD portion of the sentence, not the animal-model portion. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Neuroimaging of TSPO using PET is a good marker of neuroinflammation.

    “Thus, it has been proposed that neuroimaging of TSPO using PET is a good marker of neuroinflammation (Cosenza-Nashat et al., 2009; Pasqualetti et al., 2015).”

    From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Cosenza-Nashat et al., 2009

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reported antibody correlation is incompatible with its sample size

    Major

    With eight paired cases, a Spearman correlation of 0.08 cannot have p < 0.05. The reported significance therefore does not support the conclusion that staining by the two antibodies is correlated.

1 of 1

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Lee SC, 2006, Cytokines and the CNS, 1

Cited by

Sorted by citations

Related

Metadata

Authors
Cosenza‐Nashat, M., Zhao, M. ‐., Suh, H. ‐., Morgan, J., Natividad, R., Morgello, S., & Lee, S. C.
Affiliations
  • Albert Einstein College of Medicine (US)
  • Roswell Park Comprehensive Cancer Center (US)
  • Borough of Manhattan Community College (US)
  • Mount Sinai Hospital (US)
ORCID
Venue
Neuropathology and Applied Neurobiology
Publisher
Wiley
Published
2009-04-29
Volume
35
Issue
3
Pages
306-328
ISSN
  • 0305-1846 (ISSN-L)
  • 1365-2990
DOI
10.1111/j.1365-2990.2008.01006.x
PMC
PMC2693902
OpenAlex
W1990912256
Semantic Scholar
38e98dba9bfc7ea94aa338bd608e9ad903c7c1ec
Cited by
459
References
73
Citations by year
2026: 8 · 2025: 26 · 2024: 29 · 2023: 25 · 2022: 30 · 2021: 60 · 2020: 47 · 2019: 40 · 2018: 41 · 2017: 34 · 2016: 24 · 2015: 25 · 2014: 24 · 2013: 14 · 2012: 12
FWCI
3.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropathology and Applied Neurobiology (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Sanofi
  • City University of New York
  • National Institutes of Health (RO1 MH55477, AI 51519)
  • Center for AIDS Research, University of Washington
  • National Institute of Mental Health (U01MH083545, R01 MH 55477, U24 MH100931, R24MH059724, R01 MH055477, R25 MH080663)
  • National Institute of Allergy and Infectious Diseases (P30-AI-51519, P30AI051519)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
TSPO, translocator protein (TSPO), microglia, macrophages, astrocytes, neuroinflammation, HIV encephalitis, Alzheimer's disease, multiple sclerosis, stroke, white matter, positron emission tomography
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Brain, Brain Diseases, Endothelium, Female, Humans, Macaca mulatta, Macaca nemestrina, Macrophages, Middle Aged, Multiple Sclerosis, Muscle, Smooth, Neurons, Simian Immunodeficiency Virus, HIV Infections, Microglia, Receptors, GABA, Encephalitis, Viral, Stroke

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-18, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-18 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review