Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy
Open accessAbstract
Microglia are resident macrophages of the central nervous system, and their unique molecular signature is dependent upon CSF-1 signaling. Previous studies have demonstrated the importance of CSF-1R in survival and development of microglia in animal models, but the findings are of uncertain relevance to understanding the influence of CSF-1R on microglia in humans. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) [also known as adult onset leukoencephalopathy with spheroids and pigmented glia (ALSP)] is a neurodegenerative disorder primarily affecting cerebral white matter, most often caused by mutations of CSF1R. Therefore, we hypothesized that the molecular profile of microglia may be affected in HDLS. Semi-quantitative immunohistochemistry and quantitative transcriptomic profiling revealed reduced expression of IBA-1 and P2RY12 in both white and gray matter microglia of HDLS. In contrast, there was increased expression of CD68 and CD163 in microglia in affected white matter. In addition, expression of selective and specific microglial markers, including P2RY12, CX3CR1 and CSF-1R, were reduced in affected white matter. These results suggest that microglia in white matter in HDLS lose their homeostatic phenotype. Supported by gene ontology analysis, it is likely that an inflammatory phenotype is a key pathogenic feature of microglia in vulnerable brain regions of HDLS. Our findings suggest a potential mechanism of disease pathogenesis by linking aberrant CSF-1 signaling to altered microglial phenotype. They also support the idea that HDLS may be a primary microgliopathy. We observed increased expression of CSF-2 in gray matter compared to affected white matter, which may contribute to selective vulnerability of white matter in HDLS. Our findings suggest that methods that restore the homeostatic phenotype of microglia might be considered treatment approaches in HDLS.
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TL;DR
In postmortem HDLS brains with CSF1R mutations, affected frontal white matter microglia lose homeostatic markers (IBA-1, P2RY12, CX3CR1, CSF-1R) and show increased inflammatory/amoeboid markers (CD68, CD163), with transcriptomic changes enriched for CSF-1 and immune pathways. The findings suggest HDLS may be a primary microgliopathy and that restoring homeostatic microglia might be a treatment approach.
Key findings
- In affected HDLS white matter, IBA-1 and P2RY12 immunoreactivity was reduced, while CD68-positive macrophages and parenchymal CD163-positive cells were increased; CD163 cells were minimal in controls.
- Transcriptomic profiling showed the greatest changes in frontal white matter: 16 genes decreased and 87 increased, versus 2 decreased/44 increased in frontal gray matter and 9 decreased/14 increased in cerebellar white matter.
- In frontal white matter, P2RY12 (p = 0.0033) and CX3CR1 (p = 0.0086) were significantly decreased; CSF-1 was significantly increased in both frontal white and gray matter, while CSF-1R was significantly decreased only in white matter.
- Age at death was younger in women than men (average 48 vs 59 years, p = 0.032), and affected frontal white matter showed increased transcripts associated with an MGnD phenotype (e.g., APOE, GPNMB, LGALS3) and decreased M0 markers (e.g., TMEM119, GPR34, TGFA).
Methods
- Immunohistochemistry and immunofluorescence were performed on formalin-fixed, paraffin-embedded medial frontal lobe and cerebellar sections from HDLS cases with CSF1R mutations (n = 11) and controls without significant neuropathologic changes (n = 11), using IBA-1, CD68, CD163, and P2RY12; images were quantified with Aperio software.
- A customized NanoString nCounter MG447 human microglia chip (376 microglial transcripts, 40 inflammation-related transcripts, 6 positive reference genes, 8 negative controls) was used on frontal white matter, frontal neocortex, and cerebellar white matter from HDLS (n = 6) and normal controls (n = 6, one excluded as an outlier, leaving n = 5), with randomized, double-blinded analysis.
- Statistical analyses included Kruskal-Wallis ANOVA with Dunn’s post-hoc, one-way ANOVA with Holm-Sidak post-hoc, Mann-Whitney U tests, PCA/heat maps, ANOVA for differentially expressed transcripts, and MetaCore enrichment analysis.
Limitations
- Stated: the study used autopsy tissue, where variable postmortem delay and agonal changes may have contributed to findings; controls were susceptible to the same shortcomings.
- Stated/evident: sample sizes were small (e.g., n = 11 HDLS and n = 11 controls for morphologic studies; n = 6 HDLS and n = 5 controls for expression after exclusion), limiting statistical power.
- Evident: the markers used cannot definitively distinguish a changed phenotype of resident microglia from infiltration of peripheral monocyte-derived macrophages; the authors explicitly note this alternative interpretation.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
32 of 59 cited sources checked · 14 supported · 1 flagged · accuracy not yet measured
- Premisecitation
The unique molecular signature of microglia is dependent upon CSF-1 signaling.
“Moreover, this unique molecular signature is dependent upon CSF-1 [7].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143 source
The Abstract and Discussion identify the unique microglial signature as dependent on TGF-β signaling, not CSF-1 signaling. The Results section, “TGF-β is required for development of microglia in vitro,” reports that adding TGF-β1 to MCSF increased expression of signature genes compared with MCSF alone. MCSF was used in the culture conditions, but the paper does not attribute the signature’s dependence to it. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation
Autosomal dominant mutations in CSF1R are the major genetic cause of HDLS.
“It has been discovered that autosomal dominant mutations in CSF1R, resulting in partial loss of function in CSF-1R signaling, are the major genetic cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS) [22, 40, 44].”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [22] Konno T, Kasanuki K, Ikeuchi T, Dickson DW, Wszolek ZK (2018) CSF1R-related leukoencephalopathy: a major player in primary microgliopathies. Neurology 91:1092–1104 source
- cites [40] Pridans C, Sauter KA, Baer K, Kissel H, Hume DA (2013) CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function. Sci Rep 3:3013 source
The Abstract (page not provided) describes HDLS as autosomal dominant, reports CSF1R mutations in multiple affected families, and identifies loss of function in the mutations tested. It does not establish that CSF1R mutations are the major genetic cause of HDLS; no comparison with other genetic causes is reported. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [44] Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Ea S, Aasly J, MacKenzie J, Roeber S, Ha K, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Ja VG, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Oa R, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK (2012) Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 44:200–205 source
- Premisecitation
The inflammatory phenotype observed in HDLS has been reported in other studies investigating consequences of loss of CSF-1 signaling.
“In addition, the inflammatory phenotype we observe in HDLS has been reported in other studies investigating consequences of loss of CSF-1 signaling [16, 43].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [16] Hamilton JA (1997) CSF-1 signal transduction. J Leukoc Biol 62:145–155 source
- cites [43] Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–1272 source
The Results section on macrophage polarization reports that CSF-1R inhibition reduced M2-associated markers in treated gliomas, with IL-1β as an exception among M1-associated genes. It does not report an HDLS-like inflammatory phenotype; the same passage says other M1 genes were not correspondingly upregulated. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
HDLS is related to a loss of function of CSF-1R.
“Several lines of evidence support our observation that HDLS is related to a loss of function of CSF-1R [40].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [40] Pridans C, Sauter KA, Baer K, Kissel H, Hume DA (2013) CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function. Sci Rep 3:3013 source
- Premisecitation
P2RY12 expression is decreased and lost in macrophages that exhibit an inflammatory phenotype.
“Moreover, P2RY12 expression is decreased and lost in macrophages that exhibit an inflammatory phenotype [19, 31].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [19] Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan W-B, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9:1512–1519 source
- cites [31] Moore CS, Ase AR, Kinsara A, Rao VTS, Michell-Robinson M, Leong SY, Butovsky O, Ludwin SK, Seguela P, Bar-Or A, Antel JP (2015) P2Y12 expression and function in alternatively activated human microglia. Neurology 2:e80–e80 source
The Discussion reports that inflammatory conditions decrease P2Y12 expression in microglia and that P2Y12 was absent from microglia/macrophages in active multiple sclerosis lesions (page not supplied). However, the Results report no detectable P2Y12 in resting monocyte-derived macrophages, so the paper does not establish that macrophages lose expression when they acquire an inflammatory phenotype. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
CSF-2 promotes migration of blood-borne monocytes across the blood-brain barrier, which then differentiate into macrophages in the presence of CSF-1 and CSF-2.
“CSF-2 promotes migration of blood-borne monocytes across the blood-brain barrier, which then differentiate into macrophages in the presence of CSF-1 and CSF-2 [16, 17, 26, 52].”
Quote in the paperSubstantial claim1 of 4 sources checked- cites [16] Hamilton JA (1997) CSF-1 signal transduction. J Leukoc Biol 62:145–155 source
- cites [17] Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8:533–544 source
- cites [26] Lee SC, Liu W, Brosnan CF, Dickson DW (1994) GM-CSF promotes proliferation of human fetal and adult microglia in primary cultures. Glia 12:309–318 source
- cites [52] Vogel DYS, Kooij G, Heijnen PDAM, Breur M, Peferoen LAN, van der Valk P, de Vries HE, Amor S, Dijkstra CD (2015) GM-CSF promotes migration of human monocytes across the blood brain barrier. Eur J Immunol 45:1808–1819 source
The Discussion reports that GM-CSF (CSF-2) increased human monocyte migration across a blood-brain-barrier endothelial layer in vitro, and says monocytes mature into macrophages after entering the CNS. The Introduction and Human macrophages methods describe GM-CSF-associated maturation and macrophage culture, but do not establish that the migrated monocytes subsequently differentiate in the presence of both CSF-1 and CSF-2. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Inhibition of CSF-1R leads to a phenotypic shift in microglia from anti-inflammatory/homeostatic to primed/activated.
“Inhibition of CSF-1R has been shown to lead to a phenotypic shift in microglia from anti-inflammatory/homeostatic to primed/activated [43].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [43] Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–1272 source
The Results section, “CSF-1R inhibition reduces M2 macrophage polarization in treated gliomas” (page not specified), reports reduced M2-associated gene expression in glioma-associated macrophages and similar results in microglia cell lines. It does not establish a shift of microglia from a homeostatic state to a primed or activated state; the same section says M1 activation genes were generally not upregulated. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Interpretationcitation
The phenotype of microglia observed in HDLS is similar to that found in an SOD1 ALS mouse model and in multiple sclerosis patients, in which the molecules associated with the homeostatic microglial phenotype (e.g., P2RY12, CSF-1R) are down-regulated and inflammatory markers are up-regulated.
“Interestingly, the phenotype of microglia we observed in HDLS is similar to that found in an SOD1 ALS mouse model and in multiple sclerosis patients, in which the molecules associated with the homeostatic microglial phenotype (e.g., P2RY12, CSF-1R) are down-regulated and inflammatory markers are up-regulated [24, 57].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [24] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47(566–581):e569 source
The Results section, “Reciprocal induction of APOE and suppression of TGFβ signaling in disease-associated microglia” (page unavailable), reports reduced P2ry12 and Csf1r and increased inflammatory molecules in the SOD1 ALS mouse model and EAE, a mouse model of MS. It does not establish those changes in multiple sclerosis patients. The HDLS observation is the citing authors’ own comparison, not a finding attributed to this source. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [57] Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H (2017) Loss of 'homeostatic' microglia and patterns of their activation in active multiple sclerosis. Brain 140:1900–1913 source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
- Findingown data
There were clear differences between HDLS and controls in frontal white matter transcriptome.
“Similar to heat map observations (Fig. 4a), there were clear differences between HDLS and controls in FW (Fig. 4c).”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
The transcriptome of frontal gray matter was clearly different from frontal white matter and cerebellar white matter.
“Not unexpectedly, the transcriptome of FG was clearly different from FW and CW (Fig. 4b).”
Quote in the paperNot a substantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
The presence of CD68-positive, IBA-1-negative macrophages in the white matter of HDLS was confirmed.
“The presence of CD68-positive, IBA-1-negative macrophages in the white matter of HDLS was confirmed (Fig. 3a and b).”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Findingown data
In contrast to frontal white matter, there was no clear distinction between control and HDLS in frontal gray matter or cerebellar white matter.
“In contrast to FW, there was no clear distinction between control and HDLS in FG or CW, suggesting that the basal microglial transcriptomic signatures were not significantly different between control and HDLS in these areas (Fig. 4a).”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
Semiquantitative analysis revealed significantly decreased IBA-1 immunoreactivity in both subcortical and deep white matter and in both superficial and deep cortical layers of HDLS compared with normal controls.
“Semiquantitative analysis of IBA-1 expression in these brain regions revealed significantly decreased IBA-1 immunoreactivity in both subcortical and deep white matter and in both superficial and deep cortical layers of HDLS compared with normal controls (Fig. 2a).”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
- Findingown data
More marked white matter pathology, including axonal loss, tissue vacuolation and gliosis, was observed in deep white matter compared with white matter near the gray-white junction in HDLS.
“We observed more marked white matter pathology, including axonal loss, tissue vacuolation and gliosis, in deep white matter compared with the white matter near the gray-white junction (i.e. arcuate fibers).”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Findingown data
Many immune response-related pathways were significantly enriched in frontal white matter, but not in frontal gray matter.
“In addition, many immune response-related pathways were significantly enriched in FW, but not in FG (Fig. 5c, highlighted in yellow color and Figure S1a).”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
There were no obvious differences in transcriptome patterns in cerebellar white matter of HDLS and controls.
“There were also no obvious differences in transcriptome patterns in CW of HDLS and controls (Fig. 4e).”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
Many amoeboid CD68-positive macrophages are observed in HDLS lesional white matter.
“Many amoeboid CD68 (e & f) macrophages are observed in HDLS lesional white matter.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
- Findingown data
Pathways involved in CSF-1 signaling are enriched only in affected frontal white matter.
“Interestingly, pathways involved in CSF-1 signaling are enriched only in affected FW (Fig. 5c, highlighted in orange color).”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
CD68 immunoreactivity was most marked in superficial cerebral white matter and less in deep white matter and cerebellar white matter of HDLS.
“In contrast, CD68 immunoreactivity was most marked in superficial cerebral white matter and less in deep white matter and in cerebellar white matter of HDLS (Fig. 2b).”
Quote in the paperNot a substantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
- Findingown data
S-100 and CD68 double immunofluorescence revealed S-100-positive and CD68-positive cells in HDLS white matter.
“S-100 and CD68 double immunofluorescence revealed S-100-positive and CD68-positive cells (Fig. 3c and d).”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Findingown data
Three of the six HDLS cases had a distinctive gray matter expression pattern.
“Interestingly, three of the six HDLS cases had a distinctive gray matter expression pattern (Fig. 4d).”
Quote in the paperNot a substantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
Despite loss of IBA-1 and P2RY12 immunoreactive microglia, there were many CD68-positive macrophages in affected white matter of HDLS.
“Despite the loss of IBA-1 and P2RY12 immunoreactive microglia, there were many CD68-positive macrophages in affected white matter (Fig. 1e and f).”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
- Findingown data
The study found CD68 and CD163 immunoreactive macrophages in HDLS white matter.
“Here, we found CD68 and CD163 immunoreactive macrophages in HDLS white matter (Figs. 1 and 2).”
Quote in the paperSubstantial claim - Findingown data
The vulnerable cerebral white matter also had macrophages with an inflammatory phenotype.
“The vulnerable cerebral white matter also had macrophages with an inflammatory phenotype.”
Quote in the paperSubstantial claim - Findingown data
GO processes related to synaptic organization, synaptic transmission and nervous system development were enriched in frontal gray matter.
“The GO processes related to synaptic organization, synaptic transmission and nervous system development were enriched in FG (Figure S1b, highlighted in blue color).”
Quote in the paperNot a substantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
Concurrent with decreased microglia-specific markers such as P2RY12, the study found increased CD68 immunoreactivity in microglia of affected white matter.
“Concurrent with decreased microglia-specific markers, such as P2RY12, we found increased CD68 immunoreactivity in microglia of affected white matter (Figs. 1, 2, 3).”
Quote in the paperSubstantial claim - Findingown data
A subset of cells in HDLS was positive for markers CD163 and S100.
“A subset of cells was positive for markers CD163 and S100, consistent with infiltration of peripheral myeloid cells and their subsequent differentiation into cells of a dendritic lineage.”
Quote in the paperSubstantial claim - Findingown data
The level of CSF-1 was significantly increased in both frontal white matter and frontal gray matter of HDLS.
“The level of CSF-1 was significantly increased in both FW and FG (Fig. 6).”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
The observed clusters of microglia did not appear to be associated with any obvious pathology, such as ballooned neurons, blood-brain barrier damage, tissue vacuolation, hypertrophic astrocytes or reactive astrocytosis.
“The observed clusters of microglia did not appear to be associated with any obvious pathology, such as ballooned neurons, blood-brain barrier damage, tissue vacuolation, hypertrophic astrocytes or reactive astrocytosis.”
Quote in the paperSubstantial claim - Findingown data
A majority of white matter-specific transcriptional changes were related to immune response.
“A majority of white matter-specific transcriptional changes were related to immune response (Fig. 5c, highlighted in yellow).”
Quote in the paperSubstantial claim - Findingown data
These changes in immune function were not found in unaffected cerebral gray matter.
“These changes in immune function were not found in unaffected cerebral gray matter.”
Quote in the paperSubstantial claim - Findingown data
CSF-2 expression is increased in gray matter compared to affected white matter in HDLS.
“We observed increased expression of CSF-2 in gray matter compared to affected white matter”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingnone given
There is no evidence of a specific blood-brain barrier abnormality in HDLS.
“There is no evidence of a specific blood-brain barrier abnormality in HDLS.”
Quote in the paperNot a substantial claim - Findingown data
Several distinctive GO processes enriched in affected frontal white matter include those related to axonal function, cell differentiation and cell migration processes.
“Several distinctive GO processes enriched in affected FW include those related to axonal function, cell differentiation and cell migration processes (Fig. 5d, highlighted in blue, purple, and pink, respectively).”
Quote in the paperNot a substantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Findingown data
Analysis of the HDLS cases revealed that age at death was younger in women than men (p = 0.032).
“Analysis of our HDLS cases revealed that age at death was younger in women than men (p = 0.032).”
Quote in the paperNot a substantial claim - Interpretationown data
There might be region-specific changes in microglial phenotype in HDLS.
“Our immunohistochemical studies suggested that there might be region-specific changes in microglial phenotype in HDLS.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Interpretationown data
This reflects differences in molecular profiles between microglia in white matter and gray matter.
“This reflects the differences in molecular profiles between microglia in white matter and gray matter.”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Interpretationown data
Basal microglial transcriptomic signatures were not significantly different between control and HDLS in frontal gray matter or cerebellar white matter.
“In contrast to FW, there was no clear distinction between control and HDLS in FG or CW, suggesting that the basal microglial transcriptomic signatures were not significantly different between control and HDLS in these areas (Fig. 4a).”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Interpretationown data
The decrease in IBA-1 and CD68 in superficial and deep gray matter is suggestive of a decrease in gray matter microglial cells.
“Taken together, the decrease in IBA-1 and CD68 in superficial and deep gray matter is suggestive of a decrease in gray matter microglial cells, as well as the previously described non-uniform distribution.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Interpretationown data
At least a subpopulation of macrophages in HDLS white matter may be peripheral monocyte-derived cells.
“This suggests that at least a subpopulation of macrophages in HDLS white matter may be peripheral monocyte-derived cells.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Interpretationown data
A sub-population of the infiltrating myeloid-derived cells are aberrantly differentiating into cells of a dendritic lineage that are not normally present in the brain parenchyma.
“These results suggest a sub-population of the infiltrating myeloid-derived cells are aberrantly differentiating into cells of a dendritic lineage that are not normally present in the brain parenchyma.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Premisecitation
CSF-1R signaling is critical for microglial development.
“CSF-1R-mediated signaling is critical for microglial development.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8:533–544 source
- Premisecitation
IBA-1 is a pan-macrophage marker.
“We used IBA-1 as a pan-macrophage marker [1].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Ahmed Z, Shaw G, Sharma VP, Yang C, McGowan E, Dickson DW (2007) Actin-binding proteins coronin-1a and IBA-1 are effective microglial markers for immunohistochemistry. J Histochem Cytochem 55:687–700 source
- Interpretationown data
An inflammatory phenotype is likely a key pathogenic feature of microglia in vulnerable brain regions of HDLS.
“Supported by gene ontology analysis, it is likely that an inflammatory phenotype is a key pathogenic feature of microglia in vulnerable brain regions of HDLS.”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Interpretationreasoning
The reliance of HDLS patients on CSF-2 signaling due to genetically driven deficiencies in CSF-1 signaling may account for the observed cellular profiles.
“Thus, the reliance of HDLS patients on CSF-2 signaling due to genetically driven deficiencies in CSF-1 signaling may account for the observed cellular profiles.”
Quote in the paperSubstantial claim - Premisecitation
The study's results are in agreement with previous data in a small Japanese cohort of HDLS cases that illustrated similar pathologic hallmarks.
“These results are in agreement with previous data in a small Japanese cohort of HDLS cases that illustrated similar pathologic hallmarks [50].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Tada M, Konno T, Tada M, Tezuka T, Miura T, Mezaki N, Okazaki K, Arakawa M, Itoh K, Yamamoto T, Yokoo H, Yoshikura N, Ishihara K, Horie M, Takebayashi H, Toyoshima Y, Naito M, Onodera O, Nishizawa M, Takahashi H, Ikeuchi T, Kakita A (2016) Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids. Ann Neurol 80:554–565 source
- Interpretationown data
Abnormalities of CSF-1 signaling may explain pathologic events in cerebral white matter based on gene enrichment analysis.
“Abnormalities of CSF-1 signaling may explain pathologic events in cerebral white matter based on gene enrichment analysis (Fig. 5).”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Interpretationown data
The CD163 and S100 positivity is consistent with infiltration of peripheral myeloid cells and their subsequent differentiation into cells of a dendritic lineage.
“A subset of cells was positive for markers CD163 and S100, consistent with infiltration of peripheral myeloid cells and their subsequent differentiation into cells of a dendritic lineage.”
Quote in the paperSubstantial claim - Interpretationreasoning
The observed region-specific changes in expression of genes related to immune functions may be downstream of haploinsufficiency of CSF-1R.
“The observed region-specific changes in expression of genes related to immune functions may be downstream of haploinsufficiency of CSF-1R (Fig. 6).”
Quote in the paperSubstantial claim - Interpretationown data
Both immunohistochemistry and gene array results highlight a possible role of infiltrating monocyte-derived cells in HDLS.
“Both immunohistochemistry and gene array results highlight a possible role of infiltrating monocyte-derived cells in HDLS.”
Quote in the paperSubstantial claim - Study design and conductown data
The data from the enrichment analysis support the possibility of alteration in macrophage population or distribution.
“The data from our enrichment analysis support the possibility of alteration in macrophage population or distribution (Fig. 5d, highlighted in purple and pink).”
Quote in the paperSubstantial claim - Premisecitation
CSF-2 in isolation also promotes differentiation of monocytes into a dendritic cell lineage, which maintains a phagocytic phenotype (CD68 immunopositive).
“CSF-2 in isolation also promotes their differentiation into a dendritic cell lineage, which maintains a phagocytic phenotype (CD68 immunopositive) [17, 30].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17] Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8:533–544 source
- cites [30] Menetrier-Caux C, Montmain G, Dieu MC, Bain C, Favrot MC, Caux C, Blay JY (1998) Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 92:4778–4791 source
- Interpretationown data
The microglial molecular signature in affected white matter clearly differs from unaffected frontal gray matter.
“Our results suggest that the microglial molecular signature in affected white matter clearly differs from unaffected frontal gray matter.”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Interpretationown data
HDLS may be a primary microgliopathy.
“They also support the idea that HDLS may be a primary microgliopathy.”
Quote in the paperSubstantial claim - Interpretationown data
The GO process findings may correlate with pathologic changes observed in frontal white matter of HDLS, including axonal damage, altered microglial phenotype and infiltration of peripheral macrophages.
“The GO process findings may correlate with pathologic changes observed in FW of HDLS, including the axonal damage, altered microglial phenotype and infiltration of peripheral macrophages (Figs. 1 and 2).”
Quote in the paperNot a substantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
- Interpretationreasoning
Based on the level of CSF-1R, the loss of homeostatic microglia in cerebral white matter may be due to significant loss of CSF-1 signaling.
“Based on the level of CSF-1R, the loss of homeostatic microglia in cerebral white matter may be due to significant loss of CSF-1 signaling.”
Quote in the paperSubstantial claim - Interpretationown data
We demonstrated an altered phenotype of macrophages in frontal white matter of HDLS.
“We demonstrated an altered phenotype of macrophages in FW of HDLS.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Interpretationreasoning
In the white matter, the abnormal microglial distribution is in part a response to the myelin and axonal damage as microglia undergo chemotactic migration towards areas of insult.
“In the white matter, this abnormality is in part a response to the myelin and axonal damage as microglia undergo chemotactic migration towards areas of insult.”
Quote in the paperSubstantial claim - Interpretationreasoning
The presence of leukoencephalopathy without apparent microglia reinforces the vital importance of microglia on white matter integrity.
“The presence of leukoencephalopathy without apparent microglia reinforces the vital importance of microglia on white matter integrity.”
Quote in the paperSubstantial claim - Interpretationreasoning
The study suggests that compensatory microglial signaling (e.g., CSF-2) may be deficient in frontal white matter.
“While the nature of the selective vulnerability of frontal white matter is still unknown, our study suggests that compensatory microglial signaling (e.g., CSF-2) may be deficient in frontal white matter.”
Quote in the paperSubstantial claim
- May combine two claims. 49
- Classified as probably not a substantial claim. 28
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationCD163 is expressed exclusively on perivascular macrophages in the brain under normal conditions, as well as peripheral cells of monocyte lineage.
“CD163 is a hemoglobin-haptoglobulin scavenger receptor that is considered to be expressed exclusively on perivascular macrophages in the brain under normal conditions, as well as peripheral cells of monocyte lineage [38, 56].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [38] Pey P, Pearce RK, Kalaitzakis ME, Griffin WST, Gentleman SM (2014) Phenotypic profile of alternative activation marker CD163 is different in Alzheimer's and Parkinson's disease. Acta Neuropathol Commun 2:21 source
The Discussion describes CD163 as generally considered a perivascular-macrophage marker and reports that expression in neurologically normal controls was restricted to those macrophages. The Results qualify the exclusivity claim: in 12 of 16 control cases, staining also appeared in meningeal and choroid-plexus macrophages. The Results also describe CD163 as a marker specific for monocytes, supporting the lineage part of the claim. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [56] Zhang Z, Zhang ZY, Wu Y, Schluesener HJ (2012) Lesional accumulation of CD163+ macrophages/microglia in rat traumatic brain injury. Brain Res 1461:102–110 source
Classified as probably not a substantial claim.
PremisecitationP2RY12 is a specific microglia marker.
“P2RY12, a purinergic receptor increasingly considered to be a specific microglia marker [7].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCSF-1 and CSF-2 signaling represent opposing influences on the phenotype of macrophages, with CSF-1 being protective against inflammation.
“It has been also suggested that CSF-1 and CSF-2 signaling represent opposing influences on the phenotype of macrophages, with CSF-1 being protective against inflammation [12].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [12] Fleetwood AJ, Lawrence T, Hamilton JA, Cook AD (2007) Granulocyte-macrophage Colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol 178:5245–5252 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBrain parenchymal CD163 positive macrophages correlate with blood-brain barrier damage in other white matter disorders.
“Brain parenchymal CD163 positive macrophages correlate with blood-brain barrier damage in other white matter disorders [5, 45, 56].”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [5] Borda JT, Alvarez X, Mohan M, Hasegawa A, Bernardino A, Jean S, Aye P, Lackner AA (2008) CD163, a marker of perivascular macrophages, is up-regulated by microglia in simian immunodeficiency virus encephalitis after haptoglobin-hemoglobin complex stimulation and is suggestive of breakdown of the blood-brain barrier. Am J Pathol 172:725–737 source
The Histopathology section reports that simian immunodeficiency virus encephalitis lesions occurred predominantly in white matter. The In Terminal AIDS with SIVE section finds CD163-positive parenchymal microglia near those lesions, and the Discussion suggests their activation resulted from vascular compromise. The paper does not establish this association across other white matter disorders, and its blood–brain barrier interpretation is suggestive rather than a measured correlation. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [45] Roberts ES, Masliah E, Fox HS (2004) CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE). J Neuropathol Exp Neurol 63:1255–1264 source
The Results and Discussion (page unavailable) report CD163-positive cells in the brain parenchyma, including white matter, in HIV/SIV encephalitis. They do not report a correlation with blood–brain barrier damage or establish that relationship in other white matter disorders. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [56] Zhang Z, Zhang ZY, Wu Y, Schluesener HJ (2012) Lesional accumulation of CD163+ macrophages/microglia in rat traumatic brain injury. Brain Res 1461:102–110 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCSF1R regulates microglial density and distribution in zebrafish.
“It has recently been reported that CSF1R regulates microglial density and distribution in zebrafish [37], supporting our finding of altered microglial distribution in CSF1R-related leukoencephalopathy.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] Oosterhof N, Kuil LE, van der Linde HC, Burm SM, Berdowski W, van Ijcken WFJ, van Swieten JC, Hol EM, Verheijen MHG, van Ham TJ (2018) Colony-stimulating factor 1 receptor (CSF1R) regulates microglia density and distribution, but not microglia differentiation in vivo. Cell Rep 24(1203–1217):e1206 source
May combine two claims.
InterpretationreasoningThe two disorders may lie on a disease spectrum, possibly converging via the TREM2-APOE pathway previously reported to be associated with MGnD.
“The two disorders may lie on a disease spectrum, possibly converging via the TREM2-APOE pathway previously reported to be associated with MGnD [24].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [24] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47(566–581):e569 source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationLoss of the M0-homeostatic microglial signature in animal models of amyotrophic lateral sclerosis (ALS) is associated with up-regulation of inflammatory genes, which correlates with disease severity.
“Loss of the M0-homeostatic microglial signature in animal models of amyotrophic lateral sclerosis (ALS) is associated with up-regulation of inflammatory genes, which correlates with disease severity [6].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, Greco DJ, Wu PM, Doykan CE, Kiner O, Lawson RJ, Frosch MP, Pochet N, Fatimy RE, Krichevsky AM, Gygi SP, Lassmann H, Berry J, Cudkowicz ME, Weiner HL (2015) Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol 77:75–99 source
The Results section on the microglial signature reports loss of M0-associated genes alongside up-regulation of inflammatory genes in SOD1 mice. A separate Results section links stronger inflammatory-gene activation to greater disease severity in male than female SOD1 mice. The claim omits that the severity comparison is sex-specific and presents findings from one SOD1 model as applying to animal models more broadly; page numbers are unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUnder these conditions, there is suppression of 19 genes, many associated with a pro-inflammatory response.
“Under these conditions, there is suppression of 19 genes, many associated with a pro-inflammatory response [7].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [7] Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143 source
May combine two claims.
PremisecitationMGnD represents an induced inflammatory signature mediated by the TREM2-APOE pathway, which suppresses the M0 signature.
“MGnD represents an induced inflammatory signature mediated by the triggering receptor expressed on myeloid cells 2 (TREM2)-apolipoprotein E (APOE) pathway, which suppresses the M0 signature.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47(566–581):e569 source
Classified as probably not a substantial claim.
PremisecitationA neurodegenerative disease-associated microglial signature has been described, termed MGnD.
“A neurodegenerative disease-associated microglial signature has also been described, termed MGnD [24].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47(566–581):e569 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRecent work in a mouse Csf1r+/− model illustrated a potential role in neuronal development and hypermyelination in early disease.
“Recent work in a mouse Csf1r+/− model illustrated a potential role in neuronal development and hypermyelination in early disease [9].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Chitu V, Gokhan S, Gulinello M, Ca B, Patil M, Basu R, Stoddart C, Mehler MF, Stanley ER (2015) Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP). Neurobiol Dis 74:219–228 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTargeting CSF-1R has recently been reported to ameliorate AD pathology in APP/PS1 mice, where inhibition of CSF-1R reduced microglial proliferation and decreased the inflammatory phenotype of microglia around amyloid plaques.
“Targeting CSF-1R has recently been reported to ameliorate AD pathology in APP/PS1 mice, where inhibition of CSF-1R reduced microglial proliferation and decreased the inflammatory phenotype of microglia around amyloid plaques [35].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [35] Olmos-Alonso A, Schetters ST, Sri S, Askew K, Mancuso R, Vargas-Caballero M, Holscher C, Perry VH, Gomez-Nicola D (2016) Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain 139:891-907 source
The Results (Figure 4; page unavailable in our copy) report that CSF1R inhibition reduced microglial proliferation and inflammatory mediator expression in APP/PS1 mice. The Discussion says treatment prevented cognitive decline, but the inflammatory measurements were from cortical samples, not specifically microglia around amyloid plaques; that location-specific part is not established. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSome individuals with similar clinical and pathologic features to HDLS have mutations in AARS2.
“In addition to mutations in CSF1R, some individuals with similar clinical and pathologic features have mutations in AARS2 [29].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [29] Lynch DS, Jia Zhang W, Lakshmanan R, Kinsella JA, Altıokka Uzun G, Karbay M, Tüfekçioğlu Z, Hanağası H, Burke G, Foulds N, Hammans SR, Bhattacharjee A, Wilson H, Adams M, Walker M, R Nicoll JA, Chataway J, Fox N, Davagnanam I, Phadke R, Houlden H (2016) Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia, pp 1–2 source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationPeripheral administration of anti-miR155 in SOD1 mice reversed this abnormal phenotype of microglia and ameliorated the disease.
“It has been reported that peripheral administration of anti-miR155 in SOD1 mice reversed this abnormal phenotype of microglia and ameliorated the disease [6].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, Greco DJ, Wu PM, Doykan CE, Kiner O, Lawson RJ, Frosch MP, Pochet N, Fatimy RE, Krichevsky AM, Gygi SP, Lassmann H, Berry J, Cudkowicz ME, Weiner HL (2015) Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol 77:75–99 source
The Results report that peripheral anti-miR-155 improved performance and prolonged survival in SOD1 mice. But the same section explicitly says peripheral treatment had no effect on the pro-inflammatory microglial profile; it reversed the inflammatory profile of peripheral monocytes instead. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA sex-difference in susceptibility has been reported in a Japanese cohort of HDLS associated with CSF1R mutations.
“A sex-difference in susceptibility has been reported in a Japanese cohort of HDLS associated with CSF1R mutations [23].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] Konno T, Yoshida K, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda SI, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T (2017) Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation. Eur J Neurol 24:37–45 source
The Results (Clinical data; page unavailable) report a significant sex difference in age-dependent disease penetrance among CSF1R mutation carriers, supporting the susceptibility claim. The Methods (Study subjects and extracting data; page unavailable) identify 26 Japanese cases, but the reported sex-difference analysis used a larger set of cases that also included cases from the literature, so describing the finding as arising from a Japanese cohort alone is too narrow. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIL-34 is a newly identified ligand for CSF-1R, and it is reported to support maintenance of microglia.
“In addition, IL-34 is newly identified ligand for CSF-1R, and it is reported to support maintenance of microglia [14].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThere is a well-established sex-related link between severity and vulnerability to chronic (but not acute) inflammatory disorders in disorders such as cystic fibrosis and multiple sclerosis.
“There is a well-established sex-related link between severity and vulnerability to chronic (but not acute) inflammatory disorders in disorders such as cystic fibrosis and multiple sclerosis [8, 18].”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [8] Casimir GJA, Duchateau J (2011) Gender differences in inflammatory processes could explain poorer prognosis for males. J Clin Microbiol 49:478 source
The main discussion (page unavailable) reports poorer prognosis for females with chronic inflammatory diseases including cystic fibrosis, supporting a sex-related difference in severity. It does not name multiple sclerosis, and it also describes sex-related differences in acute conditions, including greater male vulnerability to shock and acute mumps infection. The claim’s exclusion of acute disorders is therefore not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [18] Harbo HF, Gold R, Tintoré M (2013) Sex and gender issues in multiple sclerosis. Ther Adv Neurol Disord 6:237–248 source
The Introduction (page unavailable) describes multiple sclerosis as a chronic inflammatory disease, reports that it is more prevalent in women, and notes evidence of sex differences in disability progression. It does not address cystic fibrosis or establish the claimed contrast with acute inflammatory disorders. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationPatients with homozygous CSF1R mutations can have a severe leukoencephalopathy with apparent congenital absence of microglia as well as skeletal dysplasia in some patients.
“Recent studies have described patients with homozygous CSF1R mutations causing a severe leukoencephalopathy with apparent congenital absence of microglia as well as skeletal dysplasia in some patients [15, 36].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [15] Guo L, Bertola DR, Takanohashi A, Saito A, Segawa Y, Yokota T, Ishibashi S, Nishida Y, Yamamoto GL, Franco J, Honjo RS, Kim CA, Musso CM, Timmons M, Pizzino A, Taft RJ, Lajoie B, Knight MA, Fischbeck KH, Singleton AB, Ferreira CR, Wang Z, Yan L, Garbern JY, Simsek-Kiper PO, Ohashi H, Robey PG, Boyde A, Matsumoto N, Miyake N, Spranger J, Schiffmann R, Vanderver A, Nishimura G, Passos-Bueno M, Simons C, Ishikawa K, Ikegawa S (2019) Bi-allelic CSF1R mutations cause skeletal dysplasia of Dysosteosclerosis-Pyle disease Spectrum and degenerative encephalopathy with brain malformation. Am J Hum Genet source
- cites [36] Oosterhof N, Chang IJ, Karimiani EG, Kuil LE, Jensen DM, Daza R, Young E, Astle L, van der Linde HC, Shivaram GM, Demmers J, Latimer CS, Keene CD, Loter E, Maroofian R, van Ham TJ, Hevner RF, Bennett JT (2019) Homozygous mutations in CSF1R cause a pediatric-onset Leukoencephalopathy and can result in congenital absence of microglia. Am J Hum Genet 104:936–947 source
Classified as probably not a substantial claim.
PremisecitationA unique signature of microglia leads to a more quiescent, anti-inflammatory phenotype when microglia are cultured with CSF-1.
“There is evidence to suggest that a unique signature of microglia leads to a more quiescent, anti-inflammatory phenotype when microglia are cultured with CSF-1.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143 source
In Results (‘TGF-β is required for development of microglia in vitro’; page not available), the paper reports that MCSF (CSF-1) culture suppressed several pro-inflammatory genes. But the adult-like microglial signature required MCSF plus TGF-β1; the paper does not show that the signature itself causes a quiescent, anti-inflammatory phenotype with CSF-1 alone. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataThe distribution of IBA-1 positive cells in white and gray matter of HDLS was variable, with areas in deeper white matter with no IBA-1 positive cells and other areas closer to the gray-white junction with seemingly increased density of IBA-1 positive cells.
“More interestingly, the distribution of IBA-1 positive cells in white and gray matter was variable, including areas in deeper white matter with no IBA-1 positive cells and other areas, closer to the gray-white junction, with seemingly increased density of IBA-1 positive cells.”
Quote in the paperNot a substantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
May combine two claims.
Findingown dataIn HDLS, parenchymal CD163-positive cells were present in affected white matter and almost absent in normal parenchyma.
“Presence of parenchymal CD163 (g & h) positive cells are confined to the lesional white matter of HDLS, with almost no cells detected seen in normal parenchyma.”
- Also stated in: § Alterations in microglial and macrophage phenotypes in HDLS · plain
“Interestingly, there were many parenchymal CD163-positive cells in affected white matter of HDLS (Fig. 1g and h).”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
- Also stated in: § Alterations in microglial and macrophage phenotypes in HDLS · plain
May combine two claims.
Findingown dataFrontal gray matter showed fewer differences between HDLS and controls, as well as greater sample-to-sample heterogeneity.
“In contrast, FG showed fewer differences between HDLS and controls, as well as greater sample-to-sample heterogeneity.”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
May combine two claims.
FindingcitationWhite matter near the cortical gray-white junction had many axonal spheroids, frequent lipid-laden macrophages, relatively intact oligodendroglia, and less myelin loss.
“We also noted that white matter near the cortical gray-white junction had many axonal spheroids, frequent lipid-laden macrophages, relatively intact oligodendroglia, and less myelin loss [3].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Baba Y, Ghetti B, Baker MC, Uitti RJ, Hutton ML, Yamaguchi K, Bird T, Lin W, DeLucia MW, Dickson DW, Wszolek ZK (2006) Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred. Acta Neuropathol 111:300–311 source
- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
May combine two claims.
Findingown dataP2RY12 staining pattern was similar to IBA-1, with loss of staining in affected white matter and relative sparing in adjacent neocortical gray matter.
“The staining pattern of P2RY12 was similar to that of IBA-1, with loss of staining in affected white matter and relative sparing in the adjacent neocortical gray matter (Fig. 1c and d).”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
May combine two claims.
Findingown dataIn HDLS, frontal white matter had 16 down- and 87 up-regulated genes; frontal gray matter had 2 down- and 44 up-regulated; cerebellar white matter had 9 down- and 14 up-regulated.
“Among the three brain regions, FW showed the greatest differences in HDLS, with decreased expression of 16 and increased expression of 87 genes. In FG two genes were decreased and 44 genes were increased. In CW, nine genes were decreased and 14 genes were increased.”
Quote in the paperNot a substantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
May combine two claims.
Findingown dataIn affected white matter of HDLS, IBA-1 immunoreactivity was almost undetectable, but relatively spared in adjacent cortex.
“In affected white matter of HDLS, IBA-1 immunoreactivity was almost undetectable, but relatively spared in adjacent cortex (Fig. 1a and b).”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
May combine two claims.
Findingown dataThere was a significant increase in CD163 immunoreactive cells in both superficial and deep white matter of HDLS, but minimal CD163 cells in any region of controls.
“We also observed significant increase in CD163 immunoreactive cells in both superficial and deep white matter of HDLS (Fig. 2c), but minimal CD163 cells in any region of controls.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
May combine two claims.
Findingown dataHierarchical clustering based on gene expression patterns in frontal white matter was clearly different between control and HDLS, and they formed distinct clusters.
“Hierarchical clustering based on gene expression patterns in FW was clearly different between control and HDLS, and they formed distinct clusters (Fig. 4a and b).”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
May combine two claims.
Findingown dataThere were significant decreases in P2RY12 and CX3CR1 levels in frontal white matter, yet little change in frontal gray matter.
“On the other hand, there were significant decreases in P2RY12 and CX3CR1 levels in FW, yet little change in FG.”
Quote in the paperSubstantial claim- Rests on an assumption: P2RY12 and CX3CR1 are uniquely or highly expressed in microglia, whereas IBA-1 can be detected both in microglia and monocyte-derived macrophages.
- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
May combine two claims.
Findingown dataThe results highlight an aberrant and skewed inflammatory phenotype in affected frontal white matter that differed from unaffected cerebral gray matter and unaffected cerebellar white matter.
“These results highlight an aberrant and skewed inflammatory phenotype in affected frontal white matter that differed from unaffected cerebral gray matter and unaffected cerebellar white matter.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe study demonstrated loss of IBA-1 and P2RY12 in vulnerable white matter, but not in relatively unaffected cortical gray matter or in unaffected cerebellar white matter.
“We demonstrate loss of IBA-1 and P2RY12 in vulnerable white matter, but not in relatively unaffected cortical gray matter or in unaffected cerebellar white matter.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe level of CSF-1R was significantly decreased in frontal white matter, but not in frontal gray matter of HDLS.
“On the other hand, the level of CSF-1R was significantly decreased in FW, but not in FG.”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
May combine two claims.
Findingown dataExpression of IBA-1 trended to decrease in frontal white matter, but not in frontal gray matter.
“Expression of IBA-1 trended to decrease in FW, but not in FG (Fig. 6).”
Quote in the paperNot a substantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
May combine two claims.
FindingcitationIn the HDLS cohort, the study observed an abnormal distribution of microglia, corroborating data from a previous study in a Japanese cohort.
“In our HDLS cohort, we observed an abnormal distribution of microglia, corroborating data from a previous study in a Japanese cohort [50].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Tada M, Konno T, Tada M, Tezuka T, Miura T, Mezaki N, Okazaki K, Arakawa M, Itoh K, Yamamoto T, Yokoo H, Yoshikura N, Ishihara K, Horie M, Takebayashi H, Toyoshima Y, Naito M, Onodera O, Nishizawa M, Takahashi H, Ikeuchi T, Kakita A (2016) Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids. Ann Neurol 80:554–565 source
- Rests on an assumption: In normal brains, microglia are relatively evenly distributed throughout gray and white matter.
May combine two claims.
Findingown dataDespite little overt neocortical pathology in HDLS, with the exception of ballooned or chromatolytic neurons, the study also observed heterogeneous distribution of microglia in neocortex.
“Despite little overt neocortical pathology in HDLS, with the exception of ballooned or chromatolytic neurons [3], we also observed heterogeneous distribution of microglia in neocortex.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Baba Y, Ghetti B, Baker MC, Uitti RJ, Hutton ML, Yamaguchi K, Bird T, Lin W, DeLucia MW, Dickson DW, Wszolek ZK (2006) Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred. Acta Neuropathol 111:300–311 source
May combine two claims.
Findingown dataThe study's gene expression data from affected frontal white matter showed a significant increase in several transcripts associated with the MGnD phenotype (e.g., APOE, GPNMB and LGALS3) and decrease in M0 signature markers (e.g. TMEM119, GPR34 and TGFA).
“Interestingly, our gene expression data from affected frontal white matter showed a significant increase in several transcripts associated with the MGnD phenotype (e.g., APOE, GPNMB and LGALS3) and decrease in M0 signature markers (e.g. TMEM119, GPR34 and TGFA) and (Table S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe study defined distinct microglial populations in affected frontal white matter in HDLS with immunohistochemistry and transcriptome profiling, which differed from microglia in unaffected frontal gray matter and cerebellar white matter.
“In conclusion, we defined distinct microglial populations in affected frontal white matter in HDLS with immunohistochemistry and transcriptome profiling, which differed from microglia in unaffected frontal gray matter and cerebellar white matter.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe average age at death of women was 48 years, while that of men was 59 years.
“The average age at death of women was 48 years, while that of men was 59 years.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataSemi-quantitative analyses suggest either an altered phenotype of resident microglia or influx of peripheral monocytes into both superficial and deep white matter of HDLS.
“These semi-quantitative analyses suggest either an altered phenotype of resident microglia or influx of peripheral monocytes into both superficial and deep white matter of HDLS.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCSF-1R is the main receptor for CSF-1.
“CSF-1R is the main receptor for CSF-1 (also known as M-CSF), which is one of two major macrophage trophic factors, with CSF-2 (also known as GM-CSF) being the other [26].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Lee SC, Liu W, Brosnan CF, Dickson DW (1994) GM-CSF promotes proliferation of human fetal and adult microglia in primary cultures. Glia 12:309–318 source
Classified as probably not a substantial claim.
PremisecitationS-100 is expressed in both mature and immature dendritic cells.
“it is also expressed in both mature and immature dendritic cells, such as Langerhans cells of the skin [47, 51].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [47] Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Capello E, Mancardi GL, Aloisi F (2006) Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells. J Neuropathol Exp Neurol 65:124–141 source
- cites [51] Takahashi K, Isobe T, Ohtsuki Y, Sonobe H, Takeda I, Akagi T (1984) Immunohistochemical localization and distribution of S-100 proteins in the human lymphoreticular system. Am J Pathol 116:497–503
May combine two claims.
Interpretationown dataAlterations in macrophage markers indicate the possibility of an altered phenotype of resident microglia and/or migration of peripheral monocytes into affected white matter of HDLS.
“Taken together, alterations in macrophage markers seem to indicate the possibility of an altered phenotype of resident microglia and/or migration of peripheral monocytes into affected white matter of HDLS.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
Classified as probably not a substantial claim.
PremisecitationCD68 detects a lysosomal antigen in inflammatory or amoeboid macrophages and microglia.
“CD68 detects a lysosomal antigen in inflammatory or amoeboid macrophages and microglia [4].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Barros MHM, Hauck F, Dreyer JH, Kempkes B, Niedobitek G (2013) Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One 8:1–11 source
May combine two claims.
Interpretationown dataTranscriptional changes in cerebral white matter differ from those of gray matter, and cerebellar white matter is preserved in HDLS, suggesting that white matter changes in transcriptome patterns are both disease- and region-specific.
“These heat map and PCA map findings indicate that transcriptional changes in cerebral white matter differ from those of gray matter. Moreover, cerebellar white matter is preserved in HDLS, suggesting that white matter changes in transcriptome patterns are both disease- and region-specific.”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHDLS is a progressive neurodegenerative disorder characterized by cerebral white matter degeneration with axonal spheroids, ballooned cortical neurons, reactive astrocytosis, and lipid- and pigment-laden macrophages.
“HDLS, also known as adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) [23], is a progressive neurodegenerative disorder characterized by cerebral white matter degeneration with axonal spheroids, ballooned cortical neurons, reactive astrocytosis, and lipid- and pigment-laden macrophages [2, 3, 28].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [2] Axelsson R, Röyttä M, Sourander P, Akesson HO, Andersen O (1984) Hereditary diffuse leucoencephalopathy with spheroids. Acta Psychiatr Scand Suppl 314:1–65
- cites [3] Baba Y, Ghetti B, Baker MC, Uitti RJ, Hutton ML, Yamaguchi K, Bird T, Lin W, DeLucia MW, Dickson DW, Wszolek ZK (2006) Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred. Acta Neuropathol 111:300–311 source
- cites [28] Lin WL, Wszolek ZK, Dickson DW (2010) Hereditary diffuse leukoencephalopathy with spheroids: ultrastructural and immunoelectron microscopic studies. Int J Clin Exp Pathol 3:665–674
May combine two claims.
InterpretationcitationTaken together, the partial loss of CSF-1R signaling was associated with loss of microglial characteristics and presence of an inflammatory phenotype, which likely contributes to white matter damage in HDLS.
“Taken together, the partial loss of CSF-1R signaling was associated with loss of microglial characteristics and presence of an inflammatory phenotype, which likely contributes to white matter damage in HDLS [25].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Lassmann H (2014) Mechanisms of white matter damage in multiple sclerosis. Glia 62:1816–1830 source
May combine two claims.
Interpretationown dataEnriched 'regulation of cell differentiation' and 'cell migration' GO processes indicate that the loss of CSF-1R may induce differentiation to alternative cell populations other than microglia or cause monocyte infiltration.
“Enriched “regulation of cell differentiation” and “cell migration” GO processes indicate that the loss of CSF-1R may induce differentiation to alternative cell populations other than microglia or cause monocyte infiltration.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Interpretationown dataIncreased CSF-2 in gray matter may contribute to selective vulnerability of white matter in HDLS.
“which may contribute to selective vulnerability of white matter in HDLS.”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
May combine two claims.
Interpretationown dataResults from gene array analysis are consistent with findings from immunohistochemistry and suggest cerebral white matter microglia have an altered phenotype in HDLS and lose their homeostatic phenotype.
“Results from gene array analysis are consistent with findings from immunohistochemistry and suggest cerebral white matter microglia have an altered phenotype in HDLS and lose their homeostatic phenotype.”
Quote in the paperSubstantial claim- Rests on an assumption: Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe CSF-1 signaling pathway is required for microglial motility.
“Other studies have shown that the CSF-1 signaling pathway is required for microglial motility [39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Pixley FJ, Stanley ER (2004) CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol 14:628–638 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMicroglia usually become heterogeneously distributed when they respond to an insult or stimulus.
“Microglia usually become heterogeneously distributed when they respond to an insult or stimulus [39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Pixley FJ, Stanley ER (2004) CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol 14:628–638 source
May combine two claims.
Study design and conductown dataThe changes in macrophage phenotype and the selective vulnerability of cerebral white matter were confirmed by expression array data.
“These changes in macrophage phenotype and the selective vulnerability of cerebral white matter were confirmed by expression array data (Figs. 4 and 5).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIn spite of loss of normal CSF-1 signaling due to mutations in CSF1R, macrophages remain abundant in HDLS, but either they have loss of the unique and homeostatic microglia phenotype or there is infiltration of peripheral macrophages.
“This suggests that in spite of loss of normal CSF-1 signaling due to mutations in CSF1R, macrophages remain abundant in HDLS, but either they have loss of the unique and homeostatic microglia phenotype or there is infiltration of peripheral macrophages.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDecreased levels of CX3CR1 and P2RY12 in HDLS suggest that the disease process is associated with altered phenotype of microglia in cerebral white matter, but not in unaffected white matter such as cerebellar white matter.
“Thus, decreased levels of CX3CR1 and P2RY12 in HDLS suggest that the disease process is associated with altered phenotype of microglia in cerebral white matter microglia, but not in unaffected white matter, such as CW.”
Quote in the paperSubstantial claim- Rests on an assumption: P2RY12 and CX3CR1 are uniquely or highly expressed in microglia, whereas IBA-1 can be detected both in microglia and monocyte-derived macrophages.
- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
Classified as probably not a substantial claim. May combine two claims.
InterpretationreasoningParenchymal CD68- and CD163-positive cells in HDLS may be related to an altered phenotype of brain microglia or alternatively, migration of peripheral monocytes into brain parenchyma.
“Parenchymal CD68- and CD163-positive cells in HDLS may be related to an altered phenotype of brain microglia or alternatively, migration of peripheral monocytes into brain parenchyma.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataSignificant reduction of CSF-1R expression is coupled with decreased expression of microglial markers in frontal white matter.
“These results suggest that significant reduction of CSF-1R expression is coupled with decreased expression of microglial markers in FW.”
Quote in the paperSubstantial claim- Rests on an assumption: Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
May combine two claims.
InterpretationreasoningCerebral gray matter was relatively spared, perhaps because CSF-1 signaling is less critical in gray matter where microglia retained their homeostatic signature.
“In contrast, cerebral gray matter was relatively spared, perhaps because CSF-1 signaling is less critical in gray matter where microglia retained their homeostatic signature (Fig. 6).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThis additional link between HDLS and autoimmune disorders implicated inflammation as a potential pathogenic mechanism and suggests that HDLS may be considered a primary microgliopathy.
“This additional link between HDLS and autoimmune disorders implicated inflammation as a potential pathogenic mechanism and suggests that HDLS may be considered a primary microgliopathy.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThis homeostatic signature, termed M0, suggests that peripheral blood-borne macrophages have a more proinflammatory phenotype under baseline conditions.
“This homeostatic signature, termed M0, suggests that peripheral blood-borne macrophages have a more proinflammatory phenotype under baseline conditions.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningThis change in brain-resident macrophage phenotype may be attributed to a change in microglial phenotype, or a loss of parenchymal microglia and a compensatory infiltration of peripheral monocytes.
“This change in brain-resident macrophage phenotype may be attributed to a change in microglial phenotype, or a loss of parenchymal microglia and a compensatory infiltration of peripheral monocytes.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningMicroglia are similar in these disorders and other inflammatory disorders may also exhibit an MGnD phenotype when microglia lose their homeostatic signature.
“This suggests that microglia are similar in these disorders and suggests other inflammatory disorders may also exhibit an MGnD phenotype when microglia lose their homeostatic signature.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe more severe phenotype, which was associated with bone malformation, bears similarity to TREM2-associated Nasu-Hakola disease and suggests CSF-1 and TREM2 act on convergent pathways.
“The more severe phenotype, which was associated with bone malformation, bears similarity to TREM2-associated Nasu-Hakola disease and suggests CSF-1 and TREM2 act on convergent pathways.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningGiven the probable need for long-term treatment, adverse response to CSF-1R inhibition may be white matter damage mediated by microglial dysfunction.
“While these short-term preclinical models might suggest that antagonism of CSF-1R may be a promising treatment in AD, given the probable need for long-term treatment and adverse response to CSF-1R inhibition may be white matter damage mediated by microglial dysfunction.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationThe unique vulnerability of frontal white matter in HDLS may be accounted for by differences in abundance of the two main microglial trophic factors between brain regions, with CSF-2 being significantly up-regulated in gray matter compared to white matter and vice versa for CSF-1.
“The unique vulnerability of frontal white matter in HDLS may also be accounted for by differences in abundance of the two main microglial trophic factors between brain regions, with CSF-2 being significantly up-regulated in gray matter compared to white matter and vice versa for CSF-1 [26].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Lee SC, Liu W, Brosnan CF, Dickson DW (1994) GM-CSF promotes proliferation of human fetal and adult microglia in primary cultures. Glia 12:309–318 source
May combine two claims.
Interpretationown dataThe molecular characteristics of microglia in HDLS changes with CSF-1R haploinsufficiency and microglia in affected frontal white matter develop a MGnD phenotype.
“This result suggests that the molecular characteristics of microglia in HDLS changes with CSF-1R haploinsufficiency and that microglia in affected frontal white matter develop a MGnD phenotype.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe study links aberrant CSF-1 signaling to region-specific loss of a homeostatic phenotype (M0) and acquisition of a phenotype (MGnD) characteristic of degenerative and demyelinating disorders.
“Specifically, our study links aberrant CSF-1 signaling to region-specific loss of a homeostatic phenotype (M0) and acquisition of a phenotype (MGnD) characteristic of degenerative and demyelinating disorders.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningControls were susceptible to the same shortcomings.
“On the other hand, controls were susceptible to the same shortcomings.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenA limitation of this study is that it was based on autopsy tissue where variable postmortem delay and agonal changes may have contributed to findings.
“A limitation of this study is that it was based on autopsy tissue where variable postmortem delay and agonal changes may have contributed to findings.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThis may contribute to likely compensatory influx of peripheral macrophages and other myeloid-derived cells that explain both the observations of parenchymal cells of a dendritic lineage and a skewed inflammatory phenotype of the parenchymal macrophages.
“This may contribute to likely compensatory influx of peripheral macrophages and other myeloid-derived cells that explain both our observations of parenchymal cells of a dendritic lineage and a skewed inflammatory phenotype of the parenchymal macrophages.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Postmortem brain tissue reflects the antemortem microglial phenotype and disease process in HDLS.
“we investigated molecular and pathological effects of loss of CSF-1 signaling due to mutations in CSF1R in postmortem brain tissues of 11 patients with HDLS.”
The paper relies on this without support.
Control cases without significant neuropathologic changes are appropriate to represent normal microglial phenotype.
“controls without significant neuropathologic changes (n = 11)”
The paper relies on this without support.
P2RY12 and CX3CR1 are uniquely or highly expressed in microglia, whereas IBA-1 can be detected both in microglia and monocyte-derived macrophages.
“Of note, P2RY12 and CX3CR1 are uniquely or highly expressed in microglia, whereas IBA-1 can be detected both in microglia and monocyte-derived macrophages.”
The paper relies on this without support.
Gene expression changes measured in bulk brain tissue reflect changes in microglia specifically.
“We measured expression levels of 460 macrophage-associated genes in frontal white matter (FW), frontal gray matter (FG) and cerebellar white matter (CW).”
The paper relies on this without support.
In normal brains, microglia are relatively evenly distributed throughout gray and white matter.
“In normal brains, microglia are relatively evenly distributed throughout gray and white matter.”
The paper relies on this without support.
CSF1R mutations affect cells that are dependent upon CSF-1 signaling in both gray and white matter of all brain regions.
“The selectivity of certain regions of cerebral white matter in HDLS (e.g., frontal white matter) is difficult to explain given that CSF1R mutations should affect cells that are dependent upon CSF-1 signaling in both gray and white matter of all brain regions.”
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.
Discussion denies cortical IBA-1 loss reported in results
MajorThe discussion says IBA-1 loss was absent from relatively unaffected cortical gray matter, while the results report a significant decrease in both superficial and deep cortical layers.
“We demonstrate loss of IBA-1 and P2RY12 in vulnerable white matter, but not in relatively unaffected cortical gray matter or in unaffected cerebellar white matter.”
“Semiquantitative analysis of IBA-1 expression in these brain regions revealed significantly decreased IBA-1 immunoreactivity in both subcortical and deep white matter and in both superficial and deep cortical layers of HDLS compared with normal controls (Fig. 2a).”
Figure 4 PCA component percentages exceed 100%
MinorThe stated PC1 and PC2 percentages sum to 103.9%, exceeding both 100% and the accompanying reported PCA percentage of 65.7%.
Reported 65.7 · recomputed 103.9
“PCA 65.7%, PC1 81.5%, PC2 22.4%”
Op/op mutation is assigned to receptor rather than ligand
MinorThe discussion describes op/op mice as having a deletion of csf1r, but the paper's cited reference identifies the op/op mutation as being in the macrophage colony-stimulating factor gene, not its receptor.
“A spontaneous mutant mouse (op/op [55]) with deletion of csf1r has bone disease due to inefficient bone remodeling by osteoclasts [55].”
“The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene”
Figure 2 sample sizes exceed the stated morphologic cohorts
MinorThe figure reports 12 HDLS cases and 12 controls for every stain and region, whereas the methods specify 11 cases in each morphologic cohort.
“HDLS (n = 12 for all stains and regions) and Normals (n = 12 for all stains and regions)”
“Inclusion criteria for morphologic studies were presence of formalin-fixed, paraffin-embedded tissue of HDLS (n = 11) and controls without significant neuropathologic changes (n = 11) (Table 1).”
Illustrated HDLS case is listed as a normal control
MinorFigure 1 identifies case #7 as an HDLS case, but Table 1 lists case #7 in the Normal group.
“a representative HDLS case (case #7) and a representative normal control (case #8)”
“| Normal | 7 | F | 61 | | – | + |”
Cites
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · cited 2× · see citing works
“While the cell bodies remain relatively stationary, the processes of microglia are extremely motile [34, 53].”
BackgroundAstrocytes: Biology and pathology
Sofroniew, M. V., & Vinters, H. V. (2010) · Acta Neuropathologica · doi:10.1007/s00401-009-0619-8 · Cited by 5,196 · cited 1× · see citing works
“While S-100 is often used as an astrocytic marker [48, 49], it is also expressed in both mature and immature Fig.”
BackgroundFate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., et al. (2010) · Science · doi:10.1126/science.1194637 · Cited by 5,175 · cited 1× · see citing works
“In addition, IL-34 is newly identified ligand for CSF-1R, and it is reported to support maintenance of microglia [14].”
BackgroundKrasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979 · cited 9× · see citing works
“A neurodegenerative disease-associated microglial signature has also been described, termed MGnD [24].”
BackgroundInfluentialSelf-citationIdentification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543 · cited 5× · see citing works
“Under these conditions, there is suppression of 19 genes, many associated with a pro-inflammatory response [7].”
BackgroundInfluentialSelf-citationCSF-1R inhibition alters macrophage polarization and blocks glioma progression
Pyonteck, S. M., Akkari, L., Schuhmacher, A. J., Bowman, R. L., Sevenich, L., Quail, D. F., Olson, O. C., Quick, M. L., Huse, J. T., Teijeiro, V., et al. (2013) · Nature Medicine · doi:10.1038/nm.3337 · Cited by 2,463 · cited 1× · see citing works
“In addition, the inflammatory phenotype we observe in HDLS has been reported in other studies investigating consequences of loss of CSF-1 signaling [16, 43].”
BackgroundElmore, M. R. P., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E., Rice, R. A., Kitazawa, M., Matusow, B., Nguyen, H., West, B. L., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.040 · Cited by 1,968 · cited 1× · see citing works
“A number of animal studies have demonstrated a role for CSF-1R in survival and development of macrophages [10, 54, 55].”
BackgroundYoshida, H., Hayashi, S.-I., Kunisada, T., Ogawa, M., Nishikawa, S., Okamura, H., Sudo, T., Shultz, L. D., & Nishikawa, S.-I. (1990) · Nature · doi:10.1038/345442a0 · Cited by 1,789 · cited 2× · see citing works
“A number of animal studies have demonstrated a role for CSF-1R in survival and development of macrophages [10, 54, 55].”
BackgroundThe P2Y12 receptor regulates microglial activation by extracellular nucleotides
Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W.-B., & Julius, D. (2006) · Nature Neuroscience · doi:10.1038/nn1805 · Cited by 1,542 · see citing works
The microglial sensome revealed by direct RNA sequencing
Hickman, S. E., Kingery, N. D., Ohsumi, T. K., Borowsky, M. L., Wang, L.-C., Means, T. K., & El Khoury, J. (2013) · Nature Neuroscience · doi:10.1038/nn.3554 · Cited by 1,511 · cited 1× · see citing works
“Recent studies have identified a specific molecular and functional signature of microglia, separating them from macrophages as well as other brain cell types [6, 7, 20, 27].”
BackgroundMicroglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease
Prinz, M., & Priller, J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3722 · Cited by 1,329 · cited 1× · see citing works
“Microglia are a unique population of macrophages of the central nervous system populated in early gestation from yolk sac-derived precursor cells, with replenishment by local proliferation rather than influx of blood borne cells [41, 42].”
BackgroundColony-stimulating factors in inflammation and autoimmunity
Hamilton, J. A. (2008) · Nature reviews. Immunology · doi:10.1038/nri2356 · Cited by 1,305 · cited 15× · see citing works
“Thus, it might be interesting to further investigate whether alteration in CSF-2 or IL-34 mediated pathways account for, or compensate, the phenotypic changes in brain regions less vulnerable to pathology in HDLS.”
BackgroundInfluentialAstrocyte barriers to neurotoxic inflammation
Sofroniew, M. V. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3898 · Cited by 1,202 · cited 1× · see citing works
“While S-100 is often used as an astrocytic marker [48, 49], it is also expressed in both mature and immature Fig.”
BackgroundMicroglia: new roles for the synaptic stripper
Kettenmann, H., Kirchhoff, F., & Verkhratsky, A. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.023 · Cited by 1,173 · cited 2× · see citing works
“In addition to their immune functions, microglia play important roles in synaptic development and myelin maintenance [21, 46].”
BackgroundLi, Q., Cheng, Z., Zhou, L., Darmanis, S., Neff, N. F., Okamoto, J., Gulati, G., Bennett, M. L., Sun, L. O., Clarke, L. E., et al. (2019) · Neuron · doi:10.1016/j.neuron.2018.12.006 · Cited by 1,129 · see citing works
CSF-1 regulation of the wandering macrophage: complexity in action
Pixley, F. J., & Stanley, E. R. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.09.016 · Cited by 807 · cited 2× · see citing works
“Other studies have shown that the CSF-1 signaling pathway is required for microglial motility [39].”
BackgroundLoss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis
Zrzavy, T., Hametner, S., Wimmer, I., Butovsky, O., Weiner, H. L., & Lassmann, H. (2017) · Brain · doi:10.1093/brain/awx113 · Cited by 684 · cited 1× · see citing works
“, P2RY12, CSF-1R) are down-regulated and inflammatory markers are up-regulated [24, 57].”
BackgroundSelf-citationErblich, B., Zhu, L., Etgen, A. M., Dobrenis, K., & Pollard, J. W. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026317 · Cited by 649 · cited 1× · see citing works
“Some studies report white matter pathology and others report no overt white matter pathology in op/op mice [11, 54].”
BackgroundFleetwood, A. J., Lawrence, T., Hamilton, J. A., & Cook, A. D. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.8.5245 · Cited by 607 · see citing works
Age-related myelin degradation burdens the clearance function of microglia during aging
Safaiyan, S., Kannaiyan, N., Snaidero, N., Brioschi, S., Biber, K., Yona, S., Edinger, A. L., Jung, S., Rossner, M. J., & Simons, M. (2016) · Nature Neuroscience · doi:10.1038/nn.4325 · Cited by 604 · see citing works
Menetrier-Caux, C., Montmain, G., Dieu, M. C., Bain, C., Favrot, M. C., Caux, C., & Blay, J. Y. (1998) · Blood · doi:10.1182/blood.v92.12.4778 · Cited by 590 · cited 1× · see citing works
“phagocytic phenotype (CD68 immunopositive) [17, 30].”
Rademakers, R., Baker, M., Nicholson, A. M., Rutherford, N. J., Finch, N., Soto-Ortolaza, A., Lash, J., Wider, C., Wojtas, A., DeJesus-Hernandez, M., et al. (2012) · Nature Genetics · doi:10.1038/ng.1027 · Cited by 571 · cited 3× · see citing works
“ously reported or included in genetic studies of HDLS [3, 33, 44].”
BackgroundSelf-citationMacrophage Polarisation: an Immunohistochemical Approach for Identifying M1 and M2 Macrophages
Barros, M. H., Hauck, F., Dreyer, J., Kempkes, B., & Niedobitek, G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080908 · Cited by 556 · cited 1× · see citing works
“CD68 detects a lysosomal antigen in inflammatory or amoeboid macrophages and microglia [4].”
BackgroundOlmos-Alonso, A., Schetters, S. T. T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., Holscher, C., Perry, V. H., & Gomez-Nicola, D. (2016) · Brain · doi:10.1093/brain/awv379 · Cited by 532 · cited 1× · see citing works
“Targeting CSF-1R has recently been reported to ameliorate AD pathology in APP/PS1 mice, where inhibition of CSF-1R reduced microglial proliferation and decreased the inflammatory phenotype of microglia around amyloid plaques [35].”
BackgroundSex and gender issues in multiple sclerosis
Harbo, H. F., Gold, R., & Tintoré, M. (2013) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756285613488434 · Cited by 529 · cited 1× · see citing works
“chronic (but not acute) inflammatory disorders in disorders such as cystic fibrosis and multiple sclerosis [8, 18].”
BackgroundMicroglia: actively surveying and shaping neuronal circuit structure and function
Wake, H., Moorhouse, A. J., Miyamoto, A., & Nabekura, J. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.11.007 · Cited by 448 · cited 1× · see citing works
“While the cell bodies remain relatively stationary, the processes of microglia are extremely motile [34, 53].”
BackgroundOntogeny and homeostasis of CNS myeloid cells
Prinz, M., Erny, D., & Hagemeyer, N. (2017) · Nature Immunology · doi:10.1038/ni.3703 · Cited by 391 · cited 1× · see citing works
“Microglia are a unique population of macrophages of the central nervous system populated in early gestation from yolk sac-derived precursor cells, with replenishment by local proliferation rather than influx of blood borne cells [41, 42].”
BackgroundButovsky, O., Jedrychowski, M. P., Cialic, R., Krasemann, S., Murugaiyan, G., Fanek, Z., Greco, D. J., Wu, P. M., Doykan, C. E., Kiner, O., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24304 · Cited by 358 · cited 3× · see citing works
“It has been reported that peripheral administration of anti-miR155 in SOD1 mice reversed this abnormal phenotype of microglia and ameliorated the disease [6].”
BackgroundSelf-citationMelchiorre, M. G., Chiatti, C., Lamura, G., Torres-Gonzales, F., Stankūnas, M., Lindert, J., Ioannidi‐Kapolou, E., Barros, H., Macassa, G., & Soares, J. F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054856 · Cited by 274 · see citing works
Ahmed, Z., Shaw, G., Sharma, V. P., Yang, C., McGowan, E., & Dickson, D. W. (2007) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.6a7156.2007 · Cited by 258 · cited 1× · see citing works
“We used IBA-1 as a pan-macrophage marker [1].”
MethodSelf-citationOosterhof, N., Chang, I. J., Karimiani, E. G., Kuil, L. E., Jensen, D. M., Daza, R., Young, E., Astle, L., van der Linde, H. C., Shivaram, G. M., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.03.010 · Cited by 247 · cited 1× · see citing works
“Recent studies have described patients with homozygous CSF1R mutations causing a severe leukoencephalopathy with apparent congenital absence of microglia as well as skeletal dysplasia in some patients [15, 36].”
BackgroundRelationship of Apolipoprotein E and Age at Onset to Parkinson Disease Neuropathology
Ghebremedhin, E., Tredici, K. D., Vukšić, M., Rüb, U., Thal, D. R., Burbach, G. J., Rosenberger, A., Bickeböller, H., Deller, T., de Vos, R. A. I., et al. (2006) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000199572.96472.1c · Cited by 237 · cited 2× · see citing works
“dendritic cells, such as Langerhans cells of the skin [47, 51].”
BackgroundP2Y12 expression and function in alternatively activated human microglia
Moore, C. S., Ase, A. R., Kinsara, A., Rao, V. T. S., Michell-Robinson, M., Leong, S. Y., Butovsky, O., Ludwin, S. K., Séguéla, P., Bar-Or, A., et al. (2015) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000080 · Cited by 212 · see citing works
Self-citationMacrophages: sentinels and regulators of the immune system
Franken, L., Schiwon, M., & Kurts, C. (2016) · Cellular Microbiology · doi:10.1111/cmi.12580 · Cited by 211 · cited 1× · see citing works
“They play vital roles in defense against pathogens as well as clearance of tissue debris and repair of damaged tissue [13].”
BackgroundGM‐CSF promotes proliferation of human fetal and adult microglia in primary cultures
Lee, S. C., Liu, W., Brosnan, C. F., & Dickson, D. W. (1994) · Glia · doi:10.1002/glia.440120407 · Cited by 209 · cited 6× · see citing works
“It should be noted that although human microglia depend on CSF-1 (M-CSF) signaling, they also respond to CSF-2 (GM-CSF), especially in response to injury-associated astrocytic signaling [26].”
BackgroundInfluentialSelf-citation<i>CSF1R</i> -related leukoencephalopathy: A major player in primary microgliopathies
Konno, T., Kasanuki, K., Ikeuchi, T., Dickson, D. W., & Wszolek, Z. K. (2018) · Neurology · doi:10.1212/wnl.0000000000006642 · Cited by 208 · see citing works
Self-citationHamilton, J. A. (1997) · Journal of Leukocyte Biology · doi:10.1002/jlb.62.2.145 · Cited by 206 · cited 14× · see citing works
“Thus, it might be interesting to further investigate whether alteration in CSF-2 or IL-34 mediated pathways account for, or compensate, the phenotypic changes in brain regions less vulnerable to pathology in HDLS.”
BackgroundInfluentialMechanisms of white matter damage in multiple sclerosis
Lassmann, H. (2014) · Glia · doi:10.1002/glia.22597 · Cited by 191 · cited 1× · see citing works
“likely contributes to white matter damage in HDLS [25].”
BackgroundKonno, T., Yoshida, K., Mizuno, T., Kawarai, T., Tada, M., Nozaki, H., Ikeda, S. ‐., Nishizawa, M., Onodera, O., Wszolek, Z. K., et al. (2017) · European Journal of Neurology · doi:10.1111/ene.13125 · Cited by 179 · cited 9× · see citing works
“That recessive mutations in AARS2 [29] could produce a similar, but not identical phenotype (ALSP), suggests that more than one pathogenic process can produce cerebral white matter pathology with axonal spheroids and pigment-laden macrophages.”
BackgroundInfluentialSelf-citationOosterhof, N., Kuil, L. E., van der Linde, H. C., Burm, S. M., Berdowski, W., van Ijcken, W. F. J., van Swieten, J. C., Hol, E. M., Verheijen, M. H. G., & van Ham, T. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.113 · Cited by 178 · cited 1× · see citing works
“It has recently been reported that CSF1R regulates microglial density and distribution in zebrafish [37], supporting our finding of altered microglial distribution in CSF1R-related leukoencephalopathy.”
BackgroundSerafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E., Capello, E., Mancardi, G. L., & Aloisi, F. (2006) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/65.2.124 · Cited by 176 · see citing works
CSF1R mutations link POLD and HDLS as a single disease entity
Nicholson, A. M., Baker, M. C., Finch, N. A., Rutherford, N. J., Wider, C. W., Graff‐Radford, N. R., Nelson, P. T., Clark, H. B., Wszołek, Z. K., Dickson, D. W., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e31828726a7 · Cited by 162 · cited 1× · see citing works
“ously reported or included in genetic studies of HDLS [3, 33, 44].”
BackgroundSelf-citation(1984) · PubMed · Cited by 150 · see citing works
(1984) · PubMed Central · Cited by 145 · see citing works
Guo, L., Bertola, D. R., Takanohashi, A., Saito, A., Segawa, Y., Yokota, T., Ishibashi, S., Nishida, Y., Yamamoto, G. L., Franco, J. F. D. S., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.03.004 · Cited by 133 · cited 1× · see citing works
“Recent studies have described patients with homozygous CSF1R mutations causing a severe leukoencephalopathy with apparent congenital absence of microglia as well as skeletal dysplasia in some patients [15, 36].”
BackgroundPey, P., Pearce, R. K., Kalaitzakis, M. E., Griffin, W. S. T., & Gentleman, S. M. (2014) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-2-21 · Cited by 128 · cited 1× · see citing works
“CD163 is a hemoglobin-haptoglobulin scavenger receptor that is considered to be expressed exclusively on perivascular macrophages in the brain under normal conditions, as well as peripheral cells of monocyte lineage [38, 56].”
BackgroundWęgiel, J., Wı́sniewski, H. M., Dziewiątkowski, J., Tarnawski, M. J., Kozielski, R., Trenkner, E., & Wiktor-Jędrzejczak, W. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00618-0 · Cited by 120 · cited 2× · see citing works
“A number of animal studies have demonstrated a role for CSF-1R in survival and development of macrophages [10, 54, 55].”
BackgroundChitu, V., Gokhan, S., Gulinello, M., Branch, C. A., Patil, M., Basu, R., Stoddart, C., Mehler, M. F., & Stanley, E. R. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.12.001 · Cited by 119 · cited 2× · see citing works
“Recent work in a mouse Csf1r model illustrated a potential role in neuronal development and hypermyelination in early disease [9].”
BackgroundBorda, J. T., Alvarez, X., Mohan, M., Hasegawa, A., Bernardino, A., Jean, S., Aye, P., & Lackner, A. A. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.070848 · Cited by 115 · cited 1× · see citing works
“Brain parenchymal CD163 positive macrophages correlate with blood-brain barrier damage in other white matter disorders [5, 45, 56].”
BackgroundBaba, Y., Ghetti, B., Baker, M. C., Uitti, R. J., Hutton, M. L., Yamaguchi, K., Bird, T., Lin, W., DeLucia, M. W., Dickson, D. W., et al. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0046-z · Cited by 106 · cited 4× · see citing works
“cephalopathy with spheroids and pigmented glia (ALSP) [23], is a progressive neurodegenerative disorder characterized by cerebral white matter degeneration with axonal spheroids, ballooned cortical neurons, reactive astrocytosis, and lipid- and pigment-laden macrophages [2, 3, 28].”
BackgroundInfluentialSelf-citationCD163 Identifies a Unique Population of Ramified Microglia in HIV Encephalitis (HIVE)
Roberts, E. S., Masliah, E., & Fox, H. S. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.12.1255 · Cited by 100 · cited 1× · see citing works
“Brain parenchymal CD163 positive macrophages correlate with blood-brain barrier damage in other white matter disorders [5, 45, 56].”
BackgroundMurray, M. E., Vemuri, P., Preboske, G. M., Murphy, M. C., Schweitzer, K. J., Parisi, J. E., Jack, C. R., & Dickson, D. W. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318277387e · Cited by 100 · cited 1× · see citing works
“Frontal white matter is also susceptible to ageassociated white matter rarefaction that appears to be closely linked to small vessel pathology [32].”
BackgroundSelf-citationGM‐CSF promotes migration of human monocytes across the blood brain barrier
Vogel, D. Y. S., Kooij, G., Heijnen, P. D. A. M., Breur, M., Peferoen, L. A. N., van der Valk, P., de Vries, H. E., Amor, S., & Dijkstra, C. D. (2015) · European Journal of Immunology · doi:10.1002/eji.201444960 · Cited by 94 · cited 13× · see citing works
“Thus, it might be interesting to further investigate whether alteration in CSF-2 or IL-34 mediated pathways account for, or compensate, the phenotypic changes in brain regions less vulnerable to pathology in HDLS.”
BackgroundInfluentialLynch, D. S., Zhang, W. J., Lakshmanan, R., Kinsella, J. A., Uzun, G. A., Karbay, M., Tüfekçioglu, Z., Hanagasi, H., Burke, G., Foulds, N., et al. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.2229 · Cited by 90 · see citing works
Lesional Accumulation of CD163+ Macrophages/microglia in Rat Traumatic Brain Injury
Zhang, Z., Zhang, Z.-Y., Wu, Y., & Schluesener, H. J. (2012) · Brain Research · doi:10.1016/j.brainres.2012.04.038 · Cited by 83 · cited 2× · see citing works
“Brain parenchymal CD163 positive macrophages correlate with blood-brain barrier damage in other white matter disorders [5, 45, 56].”
BackgroundCSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function
Pridans, C., Sauter, K. A., Baer, K., Kissel, H., & Hume, D. A. (2013) · Scientific Reports · doi:10.1038/srep03013 · Cited by 74 · cited 2× · see citing works
“Several lines of evidence support our observation that HDLS is related to a loss of function of CSF-1R [40].”
Tada, M., Konno, T., Tada, M., Tezuka, T., Miura, T., Mezaki, N., Okazaki, K., Arakawa, M., Itoh, K., Yamamoto, T., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24754 · Cited by 70 · see citing works
Gender Differences in Inflammatory Processes Could Explain Poorer Prognosis for Males
Casimir, G. J. A., & Duchateau, J. (2011) · Journal of Clinical Microbiology · doi:10.1128/jcm.02096-10 · Cited by 64 · cited 1× · see citing works
“chronic (but not acute) inflammatory disorders in disorders such as cystic fibrosis and multiple sclerosis [8, 18].”
Background(2010) · PubMed Central · Cited by 27 · see citing works
Self-citationBarros, S. P., Suruki, R., Loewy, Z. G., Beck, J. D., & Offenbacher, S. (2013) · PLoS ONE · doi:10.1371/annotation/066cd415-327b-41cb-adce-3db7e5cb527d · Cited by 19 · see citing works
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Microglia regulate central nervous system myelin growth and integrity
McNamara, N. B., Munro, D. A. D., Bestard-Cuche, N., Uyeda, A., Bogie, J. F. J., Hoffmann, A., Holloway, R. K., Molina-Gonzalez, I., Askew, K. E., Mitchell, S., et al. (2023) · Nature · doi:10.1038/s41586-022-05534-y · Cited by 507 · see citing works
Activated microglia drive demyelination via <scp>CSF1R</scp> signaling
Marzan, D. E., Brügger‐Verdon, V., West, B. L., Liddelow, S., Samanta, J., & Salzer, J. L. (2021) · Glia · doi:10.1002/glia.23980 · Cited by 147 · see citing works
Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders
Hu, B., Duan, S., Wang, Z., Li, X., Zhou, Y., Zhang, X., Zhang, Y., Xu, H., & Zheng, H. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.789834 · Cited by 105 · see citing works
Arreola, M. A., Soni, N., Crapser, J. D., Hohsfield, L. A., Elmore, M. R. P., Matheos, D. P., Wood, M. A., Swarup, V., Mortazavi, A., & Green, K. N. (2021) · Science Advances · doi:10.1126/sciadv.abg1601 · Cited by 89 · see citing works
White matter microglia heterogeneity in the CNS
Amor, S., McNamara, N. B., Gerrits, E., Marzin, M. C., Kooistra, S. M., Miron, V. E., & Nutma, E. (2022) · Acta Neuropathologica · doi:10.1007/s00401-021-02389-x · Cited by 89 · see citing works
Chadarevian, J. P., Hasselmann, J., Lahian, A., Capocchi, J. K., Escobar, A., Lim, T. E., Le, L., Tu, C., Nguyen, J., Kiani Shabestari, S., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.05.023 · Cited by 83 · see citing works
Self-citationPapapetropoulos, S., Pontius, A., Finger, E. C., Karrenbauer, V. D., Lynch, D. S., Brennan, M. J., Zappia, S., Koehler, W., Schöls, L. J., Hayer, S. N., et al. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2021.788168 · Cited by 80 · see citing works
“ALSP is presumably caused by haploinsufficiency of CSF1R due to inactivating mutations, usually in the kinase domain, which results in dysfunctional microglia leading to neurodegenerative pathology, such as neuroinflammation, dementia, and white matter loss (29).”
BackgroundAttenuated CSF‐1R signalling drives cerebrovascular pathology
Delaney, C. P., Farrell, M., Doherty, C. P., Brennan, K., O’Keeffe, E., Greene, C., Byrne, K., Kelly, E., Birmingham, N., Hickey, P. P., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012889 · Cited by 68 · see citing works
“Furthermore, MIF expression has been demonstrated to enhance tight junction breakdown and blood – brain barrier permeability in stroke (Liu et al , 2018), and MIF-mediated processes are reported to be significantly altered in ALSP frontal cortex white matter (Kempthorne et al , 2020).”
Han, J., Sarlus, H., Wszolek, Z. K., Karrenbauer, V. D., & Harris, R. A. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01093-3 · Cited by 65 · see citing works
Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence
Anderson, S. R., Roberts, J. M., Ghena, N., Irvin, E., Schwakopf, J., Cooperstein, I. B., Bosco, A., & Vetter, M. L. (2022) · eLife · doi:10.7554/elife.76564 · Cited by 57 · see citing works
Colony stimulating factors in the nervous system
Chiţu, V., Biundo, F., & Stanley, E. R. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101511 · Cited by 55 · see citing works
Microglia and Microglia-Like Cells: Similar but Different
Cuadros, M. Á., Sepúlveda, M. R., Martín‐Oliva, D., Marín‐Teva, J. L., & Neubrand, V. E. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.816439 · Cited by 55 · see citing works
“…use myeloid transplants to treat CNS diseases with defective microglia, as neuropathologies developing in aged people when microglia is dysfunctional (Ng et al., 2021), or some forms of leukoencephalopathies in which CSFR-1 is deficient and microglial phenotype is altered (Kempthorne et al., 2020).”
BackgroundBerdowski, W. M., van der Linde, H. C., Breur, M., Oosterhof, N., Beerepoot, S., Sanderson, L. E., Wijnands, L. I., de Jong, P., Tsai-Meu-Chong, E., de Valk, W. G., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02440-5 · Cited by 49 · see citing works
Treatment of CSF1R ‐Related Leukoencephalopathy: Breaking New Ground
Tipton, P. W., Kenney‐Jung, D. L., Rush, B. K., Middlebrooks, E. H., Nascene, D. R., Singh, B., Holtan, S. G., Ayala, E., Broderick, D. F., Lund, T. C., et al. (2021) · Movement Disorders · doi:10.1002/mds.28734 · Cited by 50 · see citing works
“HSCT is considered to supply a population of microglia with normal CSF-1/CSF-2 receptor homeostasis, which is required for proper microglial function and appropriate inflammatory suppression.(2,20,22) Cerebrospinal fluid analysis of patient 4 showed 100% donor chimerism.”
BackgroundModeling CSF‐1 receptor deficiency diseases – how close are we?
Chiţu, V., Gökhan, Ş., & Stanley, E. R. (2021) · FEBS Journal · doi:10.1111/febs.16085 · Cited by 50 · see citing works
Investigating Microglia in Health and Disease: Challenges and Opportunities
Miron, V. E., & Priller, J. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.07.002 · Cited by 41 · see citing works
Li, Y., Zhang, H., Yang, J., Zhan, M., Hu, X., Liu, Y., Yu, L., Yan, X., Liang, S., Zhang, R., et al. (2021) · Chinese Medicine · doi:10.1186/s13020-021-00553-9 · Cited by 36 · see citing works
Stables, J., Green, E. K., Sehgal, A., Patkar, O. L., Keshvari, S., Taylor, I., Ashcroft, M. E., Grabert, K., Wollscheid-Lengeling, E., Szymkowiak, S., et al. (2022) · Development · doi:10.1242/dev.200237 · Cited by 37 · see citing works
Ardura-Fabregat, A., Bosch, L. F. P., Wogram, E., Mossad, O., Sankowski, R., Aktories, P., Kieger, L., Cook, J., Hasavci, D., Ulupinar, H., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02006-0 · Cited by 42 · see citing works
“Furthermore, genetic mutations reducing CSF1R signaling capacity are associated with development of hereditary diffuse leukoencephalopathy with spheroids 47–49 .”
Differential regulation of microglial states by colony stimulating factors
Stanley, E. R., Biundo, F., Gökhan, Ş., & Chiţu, V. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1275935 · Cited by 30 · see citing works
“Studies to date indicate that reduced CSF-1R signaling causes a dyshomeostatic microglial phenotype (Chitu et al., 2020; Kempthorne et al., 2020; Arreola et al., 2021; Biundo et al., 2021, 2023b) that is in part mediated by increased expression of GM-CSF and G-CSF.”
BackgroundZhou, L., Wang, Y., Xu, Y., Zhang, Y., & Zhu, C. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03232-2 · Cited by 26 · see citing works
“In individuals with HDLS caused by CSF-1R mutations, the normal functioning of microglia is disrupted, resulting in chronic inflammation, impaired clearance of cellular debris, and damage to white matter in the brain [5, 9].”
BackgroundIs Pre‐Symptomatic Immunosuppression Protective in CSF1R ‐ Related Leukoencephalopathy?
Tipton, P. W., Stanley, E. R., Chiţu, V., & Wszołek, Z. K. (2021) · Movement Disorders · doi:10.1002/mds.28515 · Cited by 25 · see citing works
“and CD163 in affected white matter and reduced expression of P2RY12, CX3CR1 and CSF1R in affected white matter.(31) Furthermore, the elevation of CSF-2 and expression of several markers of oxidative stress, altered cholesterol metabolism and demyelination observed in the mouse model also occur in ALSP patients.”
BackgroundLi, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02774-1 · Cited by 25 · see citing works
“Intriguingly, several studies have reported finding microglial dyshomeostasis in human ALSP patients [37, 39].”
BackgroundResultInfluentialTaddei, R. N., Sanchez-Mico, M. V., Bonnar, O., Connors, T. R., Gaona, A., Denbow, D., Frosch, M. P., & Gómez‐Isla, T. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01370-3 · Cited by 23 · see citing works
“Loss of the homeostatic phenotype of microglia is in fact a hallmark of proinflammatory states in general and a key element across various neurological conditions [47, 100].”
BackgroundDorion, M., Casas, D., Shlaifer, I., Yaqubi, M., Fleming, P., Karpilovsky, N. C., Chen, C. X. ‐., Nicouleau, M., Piscopo, V. E. C., MacDougall, E. J., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00723-x · Cited by 20 · see citing works
“In contrast, increased number of dysmorphic CD68 + cells have been observed [59, 61].”
BackgroundInfluentialThe Role of Microglia in Inherited White-Matter Disorders and Connections to Frontotemporal Dementia
Sirkis, D. W., Bonham, L. W., & Yokoyama, J. S. (2021) · The Application of Clinical Genetics · doi:10.2147/tacg.s245029 · Cited by 18 · see citing works
Pan, J., Forés-Martos, J., Nouh, C. D., Jensen, T. D., Vallejo, K., Cayrol, R., Ahmadian, S. S., Ashley, E. A., Greicius, M. D., & Cobos, I. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01853-5 · Cited by 15 · see citing works
“Both haploinsufficiency and dominant negative models have been proposed for CSF1R deficiency in CSF1R-RD [24, 32, 35, 62].”
InfluentialChen, J., Luo, S., Li, N., Li, H., Han, J., & Li, L. (2020) · International Journal of General Medicine · doi:10.2147/ijgm.s286421 · Cited by 14 · see citing works
The multicellular interplay of microglia in health and disease: lessons from leukodystrophy
Berdowski, W. M., Sanderson, L. E., & van Ham, T. J. (2021) · Disease Models & Mechanisms · doi:10.1242/dmm.048925 · Cited by 14 · see citing works
“GLD patients who received HSCT showed an improvement in axonal integrity andmyelin thickness, as well as a reduction of phagocytic CD68+ microglia, fewer D is ea se M o d el s & M ec h an is m s multinucleated phagocyte clumps (also termed globoid cells) and reduced substrate accumulation in macrophages (Weinstock et…”
BackgroundInfluentialChiţu, V., Biundo, F., Oppong‐Asare, J., Gökhan, Ş., Aguilan, J. T., Dulski, J., Wszolek, Z. K., Sidoli, S., & Stanley, E. R. (2023) · Glia · doi:10.1002/glia.24446 · Cited by 13 · see citing works
“However, studies in both CRL (Kempthorne et al., 2020) and in the Csf1r mouse model of the disease (Chitu et al.”
BackgroundSelf-citationLarson, K. C., Gergits, F. W., Renoux, A. J., Weisman, E. J., Dejanovic, B., Huang, L., Pandya, B. A., McLaren, D. G., Lynch, B. A., Fisher, R., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03346-1 · Cited by 14 · see citing works
“These surviving microglia demonstrate an abnormal tissue distribution, altered morphology, and increased inflammatory phenotype, which likely contributes to the loss of white matter and changes in ventricular volume observed in CSF1R-ALSP [12–14].”
Żur‐Wyrozumska, K., Kaczmarska, P., & Mensah‐Glanowska, P. (2021) · Neurologia i Neurochirurgia Polska · doi:10.5603/pjnns.a2021.0012 · Cited by 13 · see citing works
“This finding suggests a potential mechanism of disease pathogenesis by linking aberrant CSF-1 signalling to altered microglial phenotype [3].”
BackgroundMizobuchi, H., Yamamoto, K., Yamashita, M., Nakata, Y., Inagawa, H., Kohchi, C., & Soma, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.650176 · Cited by 13 · see citing works
<scp>CNS</scp> macrophage contributions to myelin health
Hoffmann, A., & Miron, V. E. (2024) · Immunological Reviews · doi:10.1111/imr.13416 · Cited by 13 · see citing works
“74,78,79 With regards to the latter, the remaining microglia have an amoe-boid morphology, downregulation of homeostatic genes, and an elevated stress response.”
First Polish case of CSF1R-related leukoencephalopathy
Wszołek, Z. K. (2021) · Neurologia i Neurochirurgia Polska · doi:10.5603/pjnns.a2021.0022 · Cited by 12 · see citing works
“However, a better understanding of the pathophysiology and molecular biology of this illness makes development of a halting progression therapy a possibility [4].”
BackgroundPhase 1, First‐In‐Human, Single‐/Multiple‐Ascending Dose Study of Iluzanebart in Healthy Volunteers
Meier, A., Papapetropoulos, S., Marsh, A., Neelon, K., Stiles, D. A., O'Mara, R., Thackaberry, E. A., Colonna, M., & Rajagovindan, R. (2025) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.70033 · Cited by 13 · see citing works
Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease
Ferreira, S. A., Li, C., Klæstrup, I. H., Vitic, Z., Rasmussen, R. K., Kirkegaard, A., Toft, G. U., Betzer, C., Svendsen, P., Jensen, P. H., et al. (2023) · npj Parkinson s Disease · doi:10.1038/s41531-023-00606-w · Cited by 12 · see citing works
“According to scRNA-seq studies, CD163 is absent in homeostatic microglia 21 – 23 , thus its expression in the DAM indicates an ectopic expression due to a loss of the microglia identity during disease 78,79 , or, alternatively a de-differentiation of in fi ltrated CD163-macrophages.”
Koga, S., Tipton, P. W., Wierenga, K. J., et al. (2022) · Movement Disorders · doi:10.1002/mds.28919 · Cited by 11 · see citing works
“This finding is consistent with observations of the microglial phenotype in previous studies of CSF1R-related leukoencephalopathy.(5) There were a few pigmented macrophages with autofluorescent granular material in affected white matter, which is a common finding in CSF1R-related leukoencephalopathy.”
ResultSelf-citationBasic Microglial Functions and How They Go Awry in Neurodegenerative Disease
McKinney, J. E., Bennett, M. L., & Bennett, F. C. (2026) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-042624-114332 · Cited by 12 · see citing works
Stables, J., Pal, R., Bradford, B. M., Carter‐Cusack, D., Taylor, I., Pridans, C., Khan, N., Woodruff, T. M., Irvine, K. M., SUMMERS, K. M., et al. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106743 · Cited by 9 · see citing works
Biundo, F., Chiţu, V., Tindi, J. O., Burghardt, N. S., Shlager, G. G. L., Ketchum, H. C., Deture, M. A., Dickson, D. W., Wszolek, Z. K., Khodakhah, K., et al. (2022) · Glia · doi:10.1002/glia.24310 · Cited by 9 · see citing works
Self-citationDulski, J., Koga, S., Dickson, D. W., & Wszołek, Z. K. (2022) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.13650 · Cited by 8 · see citing works
“Previous studies demonstrated that CSF1R is essential for the proliferation, development, activation, and maintenance of microglia.(3,4,10) Most likely, the CSF1R mutations result in haploinsufficiency and disturb the regulation of microglia.”
BackgroundSelf-citationTrem2 Enhances Demyelination in the Csf1r+/− Mouse Model of Leukoencephalopathy
Biundo, F., Chiţu, V., Gökhan, Ş., Chen, E., Oppong‐Asare, J., & Stanley, E. R. (2023) · Biomedicines · doi:10.3390/biomedicines11082094 · Cited by 8 · see citing works
“Furthermore, transcriptomic profiling has provided evidence of loss of microglial homeostatic phenotype [16].”
BackgroundHe, W., Zhang, L., Zheng, D., Tang, L., Zhang, Y., Peng, M., Wang, Z., Xu, C., Chen, Z., Liu, Y., et al. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.04.026 · Cited by 7 · see citing works
Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy
Jiang, J., Li, W., Wang, X., Du, Z., Chen, J., Liu, Y., Li, W., Lu, Z., Wang, Y., & Xu, J. L. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.902067 · Cited by 6 · see citing works
“Semi-quantitative immunohistochemistry and quantitative transcriptomic profiling in patients with HDLS has revealed that CSF1R mutations can result in the loss of microglial homeostatic phenotype (M0) in the white matter (Kempthorne et al., 2020).”
BackgroundBergner, C. G., Schäfer, L., Vučinić, V., Schetschorke, B., Lier, J., Scherlach, C., Rullmann, M., Sabri, O., Claßen, J., Platzbecker, U., et al. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1163107 · Cited by 7 · see citing works
“Heterozygous variants in the CSF1R gene are assumed to alter microglia polarization and survival and thus CSF1Rassociated leukoencephalopathy is a paradigmatic genetic microgliopathy (12, 13).”
BackgroundLiu, M., Li, S., Ma, C., Wang, X., Yu, S., Lin, H., Guan, Z., & Yang, L. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11781 · Cited by 5 · see citing works
Li, X., Hu, B., Wu, C., Wang, Z., Fan, H., Xiaoyan, G., Xie, S., Chen, D., Huang, X., Sun, H., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.102641 · Cited by 5 · see citing works
Wong, W. J., Zhu, Y., Wang, H. T., et al. (2024) · eLife · doi:10.7554/elife.96693.2.sa0 · Cited by 3 · see citing works
Wong, W. J., Zhu, Y., Wang, H. T., Qian, J. W., Li, Z., Li, S., Liu, Z. Y., Guo, W., Zhang, S. Y., Su, B., et al. (2025) · eLife · doi:10.7554/elife.96693.3 · Cited by 3 · see citing works
Microglial phagoptosis in development, health, and disease
Li, Y., Chen, S., & Liu, Y. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107211 · Cited by 3 · see citing works
Sharma, A., & Singh, T. G. (2026) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2026.104097 · Cited by 5 · see citing works
Hao, Z., Guo, X., Li, L., Lei, X., Tang, Z., Zhai, M., & Yuan, J. (2024) · Food and Chemical Toxicology · doi:10.1016/j.fct.2024.115098 · Cited by 3 · see citing works
Correction to: Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy
Kempthorne, L., Yoon, H., Madore, C., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00970-1 · Cited by 3 · see citing works
Self-citationWong, W. J., Zhu, Y., Wang, H. T., Qian, J. W., Li, Z., Li, S., Liu, Z. Y., Guo, W., Zhang, S. Y., Su, B., et al. (2024) · eLife · doi:10.7554/elife.96693 · Cited by 4 · see citing works
“…with HDLS have few, small, microglia that are distributed abnormally within the neocortex and that express low levels of the homeostatic marker P2RY12 and high levels of the inflammatory marker CD68, compared to healthy controls ( Kempthorne et al., 2020 ; Konno et al., 2018 ; Tada et al., 2016 ).”
Loss of homeostatic microglia in rare neurological disorders: implications for cell transplantation
Ikeuchi, T., Fitrah, Y. A., & Shu, B. (2021) · Folia Pharmacologica Japonica · doi:10.1254/fpj.21017 · Cited by 2 · see citing works
Sakaguchi, H., Hasegawa, I., Minatani, S., Miyazawa, N., Okamoto, K., Mino, T., Takeda, A., Hatsuta, H., Yoshizaki, T., Abe, T., et al. (2021) · Neurology and Clinical Neuroscience · doi:10.1111/ncn3.12525 · Cited by 1 · see citing works
Soluble CSF1R alleviates microgliopathy in a CSF1R-related leukoencephalopathy (CRL) mouse model
Zhou, Y., Hu, B., Luo, J., Wang, X., Huang, X., Li, Y., Zhang, X., Bu, G., Zhang, H., Zhang, Y., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03648-4 · Cited by 1 · see citing works
“Previous studies indicated that CRL was a primary microgliopathy [10–12].”
Stables, J., Green, E. K., Sehgal, A., Patkar, O. L., Keshvari, S., Taylor, I., Ashcroft, M. E., Grabert, K., Wollscheid-Lengeling, E., Szymkowiak, S., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.29.462493 · Cited by 1 · see citing works
Microglia are not required for normal postnatal brain development and cognitive function in the ratPreprint
Green, E. K., Li, X., Guo, Y., Carter‐Cusack, D., Rojo, R., Lyall, M., Bell, A., Zheng, H., Teenan, O., Till, S. M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.22.694658 · Cited by 1 · see citing works
Biundo, F., Chiţu, V., Tindi, J. O., Burghardt, N. S., Shlager, G. G. L., Ketchum, H. C., Deture, M. A., Dickson, D. W., Wszolek, Z. K., Khodakhah, K., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.02.21.481325
Self-citationDorion, M., Casas, D., Yaqubi, M., Fleming, P., Chen, C. X. ‐., Piscopo, V. E. C., Nicouleau, M., Goldsmith, T., Shlaifer, I., MacDonald, A., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.08.556933
“Interestingly, increased GM-CSF expression has been previously detected in the grey matter of ALSP patients (44, 53).”
BackgroundInfluentialWong, W. J., Zhu, Y., Wang, H. T., Qian, J. W., Li, Z., Li, S., Liu, Z. Y., Guo, W., Zhang, S. Y., Su, B., et al. (2024) · eLife · doi:10.7554/elife.96693.1
Wong, W. J., Zhu, Y. W., Wang, H. T., Qian, J. W., Li, Z., Li, S., Liu, Z. Y., Guo, W., Zhang, S. Y., Su, B., et al. (2024) · eLife · doi:10.7554/elife.96693.2.sa3
Wong, W. J., Zhu, Y., Wang, H. T., et al. (2024) · eLife · doi:10.7554/elife.96693.2.sa1
Wong, W. J., Zhu, Y. W., Wang, H. T., Qian, J. W., Li, Z., Li, S., Liu, Z. Y., Guo, W., Zhang, S. Y., Su, B., et al. (2024) · eLife · doi:10.7554/elife.96693.2
Neuropathology of white matter disorders
Jaunmuktane, Z. (2024) · Handbook of clinical neurology · doi:10.1016/b978-0-323-99209-1.00011-9 · Cited by 1 · see citing works
Adult leukoencephalopathy with axonal spheroids and pigmented glia
Rushkevich, Y. N., Павловская, Т. С., Левшук, О. Н., Антоненко, Д. А., Sa, L., & Мальгина, Е. В. (2025) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro2025125021130
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593178
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593163
Dorion, M.-F., Casas, D., Shlaifer, I., Yaqubi, M., Fleming, P., Karpilovsky, N. C., Chen, C. X. ‐., Nicouleau, M., Piscopo, V. E. C., MacDougall, E. J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26702383
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593166
Dorion, M.-F., Casas, D., Shlaifer, I., Yaqubi, M., Fleming, P., Karpilovsky, N. C., Chen, C. X. ‐., Nicouleau, M., Piscopo, V. E. C., MacDougall, E. J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25546980
Pan, J., Forés-Martos, J., Nouh, C. D., Jensen, T. D., Vallejo, K., Cayrol, R., Ahmadian, S. S., Ashley, E. A., Greicius, M. D., & Cobos, I. (2024) · Figshare · doi:10.6084/m9.figshare.26944581
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593160
Dorion, M.-F., Casas, D., Shlaifer, I., Yaqubi, M., Fleming, P., Karpilovsky, N. C., Chen, C. X. ‐., Nicouleau, M., Piscopo, V. E. C., MacDougall, E. J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26702377
Dorion, M.-F., Casas, D., Shlaifer, I., Yaqubi, M., Fleming, P., Karpilovsky, N. C., Chen, C. X. ‐., Nicouleau, M., Piscopo, V. E. C., MacDougall, E. J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25547144
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593169
Dorion, M.-F., Casas, D., Shlaifer, I., Yaqubi, M., Fleming, P., Karpilovsky, N. C., Chen, C. X. ‐., Nicouleau, M., Piscopo, V. E. C., MacDougall, E. J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26702380
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593175
Pan, J., Forés-Martos, J., Nouh, C. D., Jensen, T. D., Vallejo, K., Cayrol, R., Ahmadian, S. S., Ashley, E. A., Greicius, M. D., & Cobos, I. (2024) · Figshare · doi:10.6084/m9.figshare.26944587
Pan, J., Forés-Martos, J., Nouh, C. D., Jensen, T. D., Vallejo, K., Cayrol, R., Ahmadian, S. S., Ashley, E. A., Greicius, M. D., & Cobos, I. (2024) · Figshare · doi:10.6084/m9.figshare.26944590
Pan, J., Forés-Martos, J., Nouh, C. D., Jensen, T. D., Vallejo, K., Cayrol, R., Ahmadian, S. S., Ashley, E. A., Greicius, M. D., & Cobos, I. (2024) · Figshare · doi:10.6084/m9.figshare.26944593
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593172
Pan, J., Forés-Martos, J., Nouh, C. D., Jensen, T. D., Vallejo, K., Cayrol, R., Ahmadian, S. S., Ashley, E. A., Greicius, M. D., & Cobos, I. (2024) · Figshare · doi:10.6084/m9.figshare.26944584
Ayurvedic Supplements for Healthy Brain and Longevity
Yadav, H., Thapliyal, A., Maurya, S. K., & Mishra, R. (2026) · Healthy ageing and longevity · doi:10.1007/978-3-032-11608-6_10
Ddx20, DEAD-box helicase 20 is essential for maintaining microglial homeostasis
Kawai, Y., Bizen, N., Nishiyama, K., & Takebayashi, H. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.115743
CSF1R-related leukoencephalopathy: experimental models and potential for treatment
Hume, D. A., & Irvine, K. M. (2026) · Disease Models & Mechanisms · doi:10.1242/dmm.052957
“Immunolocalisation assessment of microglia in the brains of patients with dominant CSF1R mutations indicates reduced numbers, redistribution of remaining microglia to foci of apparent injury and the relative loss of homeostatic markers (Berdowski et al., 2022; Kempthorne et al., 2020).”
- Authors
- Kempthorne, L., Yoon, H., Madore, C., Smith, S., Wszolek, Z. K., Rademakers, R., Kim, J., Butovsky, O., & Dickson, D. W.
- Affiliations
- Mayo Clinic (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Dickson, Dennis W.
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2020-05-19
- Volume
- 8
- Issue
- 1
- Pages
- 72-72
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC7236286
- OpenAlex
- W3027370519
- Semantic Scholar
- 6faa68150ee7aec3492f0da393a0babe74b62a07
- Cited by
- 77
- References
- 60
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 20 · 2023: 7 · 2022: 12 · 2021: 17 · 2020: 6
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-06-24)
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (Le Centre pour la Communication Scientifique Directe) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (P30 AG062677)
- National Institute of Neurological Disorders and Stroke (R01 NS088137)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- CSF1R, microglial phenotype, Iba1, P2Y12 receptor, CD68, CD163, CX3CR1, neuroinflammation, pathogenesis
- MeSH terms
- Aged, Brain, Calcium-Binding Proteins, Female, Homeostasis, Humans, Male, Microfilament Proteins, Middle Aged, Phenotype, Signal Transduction, Receptor, Macrophage Colony-Stimulating Factor, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Microglia, Leukoencephalopathies, Receptors, Purinergic P2Y12, Transcriptome, White Matter, Gray Matter
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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.
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