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Cited by 11Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchMultiple Sclerosis Research Studies

Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy

Open access
Bougnères, Pierre, Le Stunff, Catherine·2025·Genes
DOI 10.3390/genes16050590PMC PMC12111468
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Abstract

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults. The accumulation of undegraded VLCFA in glial cell membranes and myelin has long been thought to be the central mechanism of X-ALD. Methods: This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis. Results: In the Abcd1 knockout (KO) mouse that mimics the spinal cord disease, the late manifestations of axonopathy are rapidly reversed by ABCD1 gene transfer into spinal cord oligodendrocytes (OLs). In a peroxin-5 KO mouse model, the selective impairment of peroxisomal biogenesis in OLs achieves an almost perfect phenocopy of cerebral ALD. A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells. Other mouse models showed the critical role of OLs in providing energy substrates to axons. In addition, studies on microglial changing substates have improved our understanding of neuroinflammation. Conclusions: Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms. Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons.

AI snapshot

Written from the paper’s full text.

TL;DR

This review revisits X-linked adrenoleukodystrophy pathogenesis, arguing that oligodendrocyte dysfunction and axonal pathology are primary while microglial neuroinflammation is secondary, based largely on mouse, Drosophila, and human postmortem/imaging evidence. It concludes that ABCD1 mutations are necessary but not sufficient for cerebral ALD, with unidentified genetic, epigenetic, environmental, and stochastic factors determining phenotype.

Key findings

  • In 40 Abcd1−/− mice followed to 24 months, motor and coordination deficits appeared in ~25% at 18 months, ~70% had severe motor manifestations at 24 months, and 33% still showed no clinical pathology; no brain lesions, significant demyelination, or neuroinflammation were detected.
  • OL-targeted ABCD1 gene transfer reversed late AMN-like axonopathy: after intracisternal AAV9-MAG-hABCD1 at 18 months, treated mice had restored near-normal motor performances within 1–3 months, with hABCD1 expression at 24 months in 22% of cervical spinal cord white matter OLs and 22% of astrocytes.
  • A CNP-Pex5 KO mouse with OL-selective peroxisome impairment produced an almost perfect phenocopy of cerebral ALD, including VLCFA accumulation, axonal loss, lower plasmalogens, early microglial increase, demyelination, and inflammation; Drosophila showed VLCFA accumulation in glial myelinating cells generates toxic S1P that poisons axons and activates inflammatory cells.
  • Clinical/epidemiological data cited include annual incidence ~1/10,000 by neonatal screening, silent adrenal insufficiency in 80% of boys/adolescents with cALD and 70% of AMN patients, slowly progressive AMN symptoms in ~65% of heterozygous women by age 60, and 172 “likely pathogenic” plus 825 “pathogenic” ABCD1 variants in the registry.

Methods

  • Narrative review; the abstract states it discusses studies in mouse and Drosophila models that have modified views of X-ALD pathogenesis.
  • Evidence synthesized includes human postmortem CNS specimens, MRI/DTI/MRS/PET imaging, Abcd1 KO and other mouse models, Drosophila, zebrafish, C. elegans, patient fibroblasts, iPSCs, multi-omics, and gene therapy studies.
  • No new primary data or systematic search/meta-analysis is described; the main analysis is an interpretive synthesis of published findings.

Limitations

  • Paper-stated: the review “will raise more hypotheses than certainties”; primary and secondary mechanisms are intermingled, and the spatiotemporal trajectory leading to cALD versus AMN is currently impossible to discern.
  • Paper-stated: animal models cannot faithfully replicate human mechanisms and disease course, notably neuroinflammatory responses; postmortem human CNS studies are limited to advanced cALD/AMN stages and have rarely been performed since the late 1970s; iPSC models often resemble a fetal state, reprogramming alters epigenetic marks, and X-ALD iPSC studies rely on only one or two patient lines.
  • Evident from the text: as a narrative review, it does not systematically appraise all evidence or quantify certainty; many mechanistic claims rest on small animal or human samples and cross-species extrapolation.

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

Integrity signals

Registry

Crossref · 10.3390/genes16050590

Cites

514 of 515 references verified1 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

221 of 528 cited sources checked · 101 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    When microglia fail to degrade VLCFA-enriched myelin fragments and undergo apoptosis, their contents may be released into surrounding tissue and trigger an inflammatory reaction.

    “When microglia fail to degrade VLCFA-enriched myelin fragments and undergo apoptosis, their contents may be released into surrounding tissue and trigger an inflammatory reaction [178].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [178] Gong, 2017, Microglial dysfunction as a key pathological change in adrenomyeloneuropathy, Ann. Neurol. source

      The Results (page unavailable) report increased microglial phagocytosis and neuronal injury in AMN, explicitly in the absence of overt inflammation. The Discussion (page unavailable) describes microglial apoptosis only in connection with excess free VLCFA, not failure to degrade VLCFA-enriched myelin fragments. The paper does not describe apoptotic microglia releasing contents that trigger inflammation; its reported mechanism points in the opposite direction. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Interpretationcitation

    cALD is likely less frequent than the previously reported 30-50% of X-ALD patients.

    “However, in light of the recent estimation of overall X-ALD incidence [2], it is likely that cALD is less frequent.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Moser, A.B., Jones, R.O., Hubbard, W.C., Tortorelli, S., Orsini, J.J., Caggana, M., Vogel, B.H., and Raymond, G.V. (2016). Newborn screening for X-linked adrenoleukodystrophy. Int. J. Neonatal Screen., 2. source
  • Premisecitation

    Allogeneic transplantation of hematopoietic stem cells derived from bone marrow can induce remission of childhood cALD.

    “In 1990, a single patient showed that allogeneic transplantation of hematopoietic stem cells (HSCs) derived from bone marrow could induce remission of childhood cALD [24], opening the way for dozens of patients to receive the only treatment available for this disease [25] and”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Aubourg, 1990, Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation, N. Engl. J. Med. source
  • Premisecitation

    Electron microscopy reveals characteristic cytoplasmic inclusions (spicules) in oligodendrocytes, perivascular macrophages, and/or microglia but not in astrocytes.

    “Electron microscopy reveals characteristic cytoplasmic inclusions (“spicules”) in OLs, perivascular macrophages, and/or microglia but not in astrocytes.”
    Quote in the paperNot a substantial claim1 of 10 sources checked
    • cites [17] Schaumburg, 1975, Adrenoleukodystrophy: A clinical and pathological study of 17 cases, Arch. Neurol. source
    • cites [20] Budka, 1976, Spastic paraplegia associated with Addison’s disease: Adult variant of adreno-leukodystrophy, J. Neurol. source
    • cites [22] Igarashi, 1976, Fatty acid abnormality in adrenoleukodystrophy, J. Neurochem. source
    • cites [74] Schaumburg, 1974, Adreno-leukodystrophy (sex-linked Schilder disease). Ultrastructural demonstration of specific cytoplasmic inclusions in the central nervous system, Arch. Neurol. source
    • cites [75] Johnson, 1976, Histochemical characteristics of the striated inclusions of adrenoleukodystrophy, J. Histochem. Cytochem. source
    • cites [76] Powers, 1973, The adrenal cortex in adreno leukodystrophy, Arch. Pathol. Lab. Med.
    • cites [77] Powers, 2005, Adreno-leukodystrophy: A personal historical note, Acta Neuropathol. source
    • cites [78] Menkes, 1977, Adrenoleukodystrophy: Accumulation of cholesterol esters with very long chain fatty acids, Neurology source
    • cites [79] Gong, 2024, Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans, Ann. Neurol. source
    • cites [80] Espinosa, 2012, Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy, Hum. Mol. Genet. source

      The Introduction discusses inflammatory pathology in cerebral ALD, and Materials and Methods (Human brain samples) describes staining brain sections, but neither reports electron microscopy or cytoplasmic spicules. Searches for “spicules” and for electron-microscopy inclusions in the named cell types found no passage addressing the claim; page numbers were unavailable in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    In some X-ALD patients, pyramidal tract signals may become as intense as in cALD.

    “In some patients, the pyramidal tract signals may become as intense as in cALD [31].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. source

      The Adrenomyeloneuropathy (AMN) section says pyramidal-tract MRI signals can become more intense, and that this is considered a manifestation of cerebral ALD when the abnormality also extends beyond the internal capsules. It does not make a direct intensity comparison with cerebral ALD, and the claim omits the extension criterion. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 69
  • May combine two claims. 129
  • The quote only partly states this claim. 3

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Based on neonatal screening in the USA since 2013, the annual incidence of X-ALD is approximately 1/10,000, much higher than previously thought.

    “Based on neonatal screening in the USA since 2013, the annual incidence was found to be ~1/10,000 [2,7], much higher than previously thought [15].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [2] Moser, A.B., Jones, R.O., Hubbard, W.C., Tortorelli, S., Orsini, J.J., Caggana, M., Vogel, B.H., and Raymond, G.V. (2016). Newborn screening for X-linked adrenoleukodystrophy. Int. J. Neonatal Screen., 2. source

      The New York screening section says screening began on 30 December 2013, but the Discussion reports a birth incidence of one in 14,700—not approximately one in 10,000. It also describes that rate as close to the earlier estimate of one in 17,000. In the citing sentence, the separate claim that incidence was 'much higher than previously thought' is attached to [15], not to this source. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [7] Priestley, J.R.C., Adang, L.A., Drewes Williams, S., Lichter-Konecki, U., Menello, C., Engelhardt, N.M., DiPerna, J.C., DiBoscio, B., Ahrens-Nicklas, R.C., and Edmondson, A.C. (2022). Newborn Screening for X-Linked Adrenoleukodystrophy: Review of Data and Outcomes in Pennsylvania. Int. J. Neonatal Screen., 8. source
    • cites [15] Wiesinger, 2015, The genetic landscape of X-linked adrenoleukodystrophy: Inheritance, mutations, modifier genes, and diagnosis, Appl. Clin. Genet.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMN is characterized by loss of sensation in the legs followed by a spastic gait with positive Babinski reflex, progressing inexorably, associated with ataxia, leg pain, impotence, and voiding abnormalities.

    “Loss of sensation in the legs is followed by a spastic gait with positive Babinski reflex, which progresses inexorably, associated with ataxia, leg pain, impotence, and voiding abnormalities [49,50,51,52].”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [49] Powers, 2000, Adrenomyeloneuropathy: A neuropathologic review featuring its noninflammatory myelopathy, J. Neuropathol. Exp. Neurol. source
    • cites [50] Corre, 2021, Beyond gait and balance: Urinary and bowel dysfunction in X-linked adrenoleukodystrophy, Orphanet J. Rare Dis. source

      The Background and Discussion (page not provided) describe AMN as involving sensory impairment, a slowly progressive spastic gait disorder, sensory ataxia, and bladder dysfunction. They do not establish that leg sensory loss precedes gait changes or report a positive Babinski reflex, leg pain, or impotence. The Results (Cross-sectional symptom prevalence and age of onset; page not provided) instead report that urinary or bowel symptoms preceded other myelopathy symptoms in 57.8% of symptomatic patients. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [51] Hofereiter, 2015, Bladder and bowel dysfunction is common in both men and women with mutation of the ABCD1 gene for X-linked adrenoleukodystrophy, JIMD Rep. source
    • cites [52] Silveri, 2004, Voiding dysfunction in X-linked adrenoleukodystrophy: Symptom score and urodynamic findings, J. Urol. source

  • May combine two claims.

    Premisecitation

    The same ABCD1 mutation can cause either childhood cerebral inflammatory demyelination or, more often, adult-onset progressive spinal cord axonopathy.

    “Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [30] Powers, 1985, Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex), Clin. Neuropathol.

      Not checked in the free run.

    • cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. source

      The ‘Evolution over time’ section says identical ABCD1 mutations can produce markedly different neurological phenotypes. The ‘Cerebral ALD’ and ‘Adrenomyeloneuropathy (AMN)’ sections describe childhood inflammatory brain demyelination and a usually slowly progressive spinal-cord axonopathy, respectively. However, the paper says AMN usually develops in the third or fourth decade, not specifically in middle age; it also notes that AMN and cerebral demyelination can occur in the same person rather than being strictly either-or outcomes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Anecdotal cases of head trauma precipitating cALD with inflammatory demyelination beginning at the contusion site have been reported.

    “Anecdotical cases of head trauma precipitating cALD have been reported with inflammatory demyelination beginning at the site of the contusion [43,44,45,46].”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [43] Bouquet, 2015, Dramatic worsening of adult-onset X-linked adrenoleukodystrophy after head trauma, Neurology source
    • cites [44] Weller, 1992, Very-late-onset adrenoleukodystrophy: Possible precipitation of demyelination by cerebral contusion, Neurology source
    • cites [45] Raymond, 2010, Head trauma can initiate the onset of adreno-leukodystrophy, J. Neurol. Sci. source
    • cites [46] Budhram, 2017, Activation of cerebral X-linked adrenoleukodystrophy after head trauma, Can. J. Neurol. Sci. source

      The case description reports cerebral X-ALD developing after head trauma, with new frontal-predominant white matter abnormalities in the region of traumatic microbleeds. The discussion says abnormalities may be most prominent at the site of injury, but does not establish that inflammatory demyelination began at a contusion site; it describes inflammation as a possible mechanism. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Slowly progressive AMN symptoms occur in approximately 65% of heterozygous women by age 60 due to inactivation of the non-mutated X chromosome and mosaic expression of X-linked genes in neural cells.

    “Although ALD is an X-linked disease, slowly progressive AMN symptoms occur in ~65% of heterozygous women by the age of 60 years [31,47,59,60] due to the inactivation of the non-mutated X chromosome and the mosaic expression of X-linked genes in neural cells [60,61,62,63].”
    Quote in the paperNot a substantial claim3 of 7 sources checked
    • cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. source

      The “Women with X-ALD” section (page unavailable) estimates that AMN in heterozygous women is likely to approach 65% by age 60. It describes skewed X-inactivation in neuronal cells as a possible contributor, not an established cause, and says a recent study did not confirm its association with symptoms. It does not state that mosaic expression of X-linked genes in neural cells causes the symptoms. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [47] Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D. (2001). X-linked adrenoleukodystrophy. The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill.

      Not checked in the free run.

    • cites [59] Moser, 1984, Adrenoleukodystrophy: Clinical and biochemical manifestations in carriers, Neurology source
    • cites [60] Huffnagel, 2019, Disease progression in women with X-linked adrenoleukodystrophy is slow, Orphanet J. Rare Dis. source

      The Background (page not provided) says that more than 80% of women with ALD eventually develop progressive spinal cord disease, and the Results > Progression rates section describes progression as very slow. The paper does not give the claimed ~65% prevalence by age 60 or attribute symptoms to inactivation of the non-mutated X chromosome and mosaic expression in neural cells. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [61] Naidu, S., Washington, C., Thirumalai, S., Smith, K., Moser, H., and Watkins, P. (1997). X-Chromosome Inactivation in Symptomatic Heterozygotes of X-Linked Adrenoleukodystrophy, Lippincott-Raven Publ.

      Not checked in the free run.

    • cites [62] Maier, 2002, Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation, Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc. source
    • cites [63] Salsano, 2012, Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms, Orphanet J. Rare Dis. source

      The Background (page unavailable) describes progressive AMN-like symptoms in female X-ALD carriers and explains that X-inactivation makes females mosaic for X-linked gene expression. But it estimates symptoms in about 20% of carriers, not 65% by age 60. The Discussion (page unavailable) reports no significant association between symptoms and X-inactivation patterns in blood; it says X-inactivation in carriers’ brains was not investigated, so it does not establish the claimed cause in neural cells. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Spicules are straight and curved striated structures made of degenerated myelin, also observed in 15% of Schwann cells surrounding myelinated axons in the adrenals.

    “Spicules are straight and curved striated structures made of degenerated myelin [17,20,22,74,75,76,77,78,79,80], which are also observed in 15% of Schwann cells surrounding myelinated axons in the adrenals [19,81].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [19] Powell, 1975, Adrenoleukodystrophy: Electron microscopic findings, Arch. Neurol. source
    • cites [81] Budka, 2023, A historical look using virtual microscopy: The first case report of adrenomyeloneuropathy (AMN), Free Neuropathol. source

      The citation appears attached to the claim about 15% of Schwann cells surrounding myelinated axons in the adrenals. The Fig. 4 Adrenal section describes occasional cytoplasmic striations in cortical cells, but our copy does not mention Schwann cells or the 15% figure; searches for those terms found no supporting passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    MRI can detect early demyelinating lesions in X-ALD generally localized in the splenium of the corpus callosum, which progress to involve adjacent parieto-occipital white matter.

    “During the follow-up of a patient’s brother with elevated VLCFAs or a child found positive at neonatal screening, MRI is able to detect early demyelinating lesions generally localized in the splenium of the corpus callosum (a region with a very high density of OLs), which progress to involve the adjacent parieto-occipital white matter [14,31,90,91,92].”
    Quote in the paperNot a substantial claim4 of 5 sources checked
    • cites [14] Bonaventura, E., Alberti, L., Lucchi, S., Cappelletti, L., Fazzone, S., Cattaneo, E., Bellini, M., Izzo, G., Parazzini, C., and Bosetti, A. (2023). Newborn screening for X-linked adrenoleukodystrophy in Italy: Diagnostic algorithm and disease monitoring. Front. Neurol., 13. source

      The Neuroradiological assessment section says MRI can detect early cALD lesions, most often in the genu or splenium of the corpus callosum. It does not describe progression into adjacent parieto-occipital white matter, and it notes that some early lesions may arrest rather than progress. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. source
    • cites [90] Mallack, 2021, MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines, J. Inherit. Metab. Dis. source

      The Introduction says lesions most often begin in the splenium of the corpus callosum and spread into adjacent white matter, and the Results describe early lesions detectable on MRI. Our copy does not specify that the adjacent white matter is parieto-occipital or support the parenthetical claim about oligodendrocyte density. No page numbers were provided for these passages. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [91] Liberato, 2019, MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy, Neurology source
    • cites [92] Kemp, 2001, ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations, Hum. Mutat. source

      The Diagnosis section (page unavailable) says MRI shows parieto-occipital demyelination in approximately 80% of patients with the childhood cerebral phenotype. It does not describe lesions beginning in the splenium and progressing into adjacent white matter, or establish that pattern for X-ALD generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    As of 15 May 2025, the ABCD1 registry contains 172 variants annotated as likely pathogenic and 825 as pathogenic.

    “While writing this review, we updated the previous counts [100] and found a total of 172 variants annotated as “likely pathogenic” and 825 as “pathogenic” in the ABCD1 registry (https://adrenoleukodystrophy.info, accessed on 15 May 2025).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [100] Mallack, E.J., Gao, K., Engelen, M., and Kemp, S. (2022). Structure and function of the ABCD1 variant database: 20 years, 940 pathogenic variants, and 3400 cases of adrenoleukodystrophy. Cells, 11. source

  • May combine two claims.

    Premisecitation

    At more advanced stages, typical confluent and symmetrical areas of T2 hyperintensity reflect demyelination in the splenium of the corpus callosum, parieto-occipital or frontal white matter, or pyramidal tracts within the internal capsules, pons, and brainstem.

    “At more advanced stages, typical confluent and symmetrical areas of T2 hyperintensity reflect demyelination in the splenium of the corpus callosum, parieto-occipital or frontal white matter, or pyramidal tracts within the internal capsules, pons, and brainstem.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. source
    • cites [93] Pasco, 1991, Contribution of MRI to the diagnosis of cerebral lesions of adrenoleukodystrophy, Pediatr. Radiol. source
    • cites [94] Loes, 2003, Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy, Neurology source

  • May combine two claims.

    Premisecitation

    Gadolinium extravasation, a hallmark of neuroinflammation and blood-brain barrier breach, can occur early when demyelinating lesions are still restricted to the corpus callosum or pyramidal tracts but is often seen later, once lesions have extended.

    “Gadolinium extravasation, a hallmark of neuroinflammation and blood–brain barrier (BBB) breach, can occur early when demyelinating lesions are still restricted to the corpus callosum or pyramidal tracts but is often seen later, once the demyelinating lesions have extended [31,93,94].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. source
    • cites [93] Pasco, 1991, Contribution of MRI to the diagnosis of cerebral lesions of adrenoleukodystrophy, Pediatr. Radiol. source
    • cites [94] Loes, 2003, Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy, Neurology source

  • May combine two claims.

    Premisecitation

    Residual peroxisomal β-oxidation of VLCFA is approximately 20% of normal in X-ALD fibroblasts and can be restored by ABCD2 or ABCD3 overexpression.

    “Consistently, the residual peroxisomal β-oxidation of VLCFA is ~20% of normal in X-ALD fibroblasts [150,151] and can be restored by ABCD2 or ABCD3 overexpression [152,153].”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [150] McGuinness, 2001, Evaluation of pharmacological induction of fatty acid β-oxidation in X-linked Adrenoleukodystrophy, Mol. Genet. Metab. source
    • cites [151] Kemp, 2004, Method for measurement of peroxisomal very-long-chain fatty acid β-oxidation in human skin fibroblasts using stable-isotope-labeled tetracosanoic acid, Clin. Chem. source
    • cites [152] Netik, 1999, Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): Implications for therapy, Hum. Mol. Genet. source
    • cites [153] Kemp, 1998, Gene redundancy and pharmacological gene therapy: Implications for X-linked adrenoleukodystrophy, Nat. Med. source

  • May combine two claims.

    Premisecitation

    Abcd1−/− mice, despite being congenic littermates living in the same cage, show variable motor deficits at different ages, supporting the importance of stochasticity for determining phenotypes.

    “Abcd1−/− mice, despite being congenic littermates living in the same cage, show variable motor deficits at different ages, thereby supporting the importance of stochasticity for determining phenotypes [136].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [136] Singh, 2010, Pathomechanisms underlying X-adrenoleukodystrophy: A three-hit hypothesis, Brain Pathol. source

      The Introduction (page unavailable) reports motor and locomotor deficits in ABCD1-null mice at around 20 months of age. It also suggests stochastic factors may affect outcomes in people with X-ALD, but does not report variable ages of motor deficits among congenic, same-cage mouse littermates or draw that inference from mice. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    ALDP transport involves cooperative binding of two VLCFAcyl-CoAs, ATP binding, and ALDP homodimerization, followed by outward-facing conformational change allowing release of VLCFAcylCoA into the peroxisome matrix, where VLCFAcyl-CoA undergoes peroxisomal β-oxidation.

    “Transport involves cooperative binding of two VLCFAcyl-CoAs, ATP binding, and ALDP homodimerization [147], followed by outward-facing ALDP conformational change allowing for the release of VLCFAcylCoA into the peroxisome matrix [148], where VLCFAcyl-CoA undergoes peroxisomal β-oxidation [149].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [147] Kemp, 2011, Mammalian peroxisomal ABC transporters: From endogenous substrates to pathology and clinical significance, Br. J. Pharmacol. source
    • cites [148] Chen, 2022, Structural basis of substrate recognition and translocation by human very long-chain fatty acid transporter ABCD1, Nat. Commun. source
    • cites [149] Wanders, 2023, The physiological functions of human peroxisomes, Physiol. Rev. source

  • May combine two claims.

    Interpretationcitation

    Modifier-gene variants likely exist but may only be identified if agnostic whole-genome analysis studies recruit and compare thousands of well-defined cALD and pure AMN patients.

    “Unless they are relatively common and have a major phenotypic effect, modifier-gene variants (likely to exist) may only be identified if agnostic whole-genome analysis studies are able to recruit and compare thousands of well-defined patients with cALD with thousands of patients with “pure” AMN [117,118].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [117] Semmler, 2009, Genetic variants of methionine metabolism and X-ALD phenotype generation: Results of a new study sample, J. Neurol. source
    • cites [118] Barbier, M., Sabbagh, A., Kasper, E., Asheuer, M., Ahouansou, O., Pribill, I., Forss-Petter, S., Vidaud, M., Berger, J., and Aubourg, P. (2012). CD1 gene polymorphisms and phenotypic variability in X-linked adrenoleukodystrophy. PLoS ONE, 7. source

      The Discussion (page unavailable) says genetic variants may contribute to X-ALD phenotypic differences and that the candidate-gene strategy has major limitations. The Methods describe comparing well-defined childhood cerebral ALD and “pure” AMN groups. The paper does not say that identifying modifier variants requires agnostic whole-genome analysis or thousands of patients in each group. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Influenza infection may enter the brain through several routes or send deleterious signals to the brain via sensory neurons and trigger neuroinflammation or associated chronic alterations in the CNS.

    “Influenza infection may enter the brain through several routes [122,123] or send deleterious signals to the brain via sensory neurons [124] and trigger neuroinflammation or associated chronic alterations in the CNS [125].”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [122] Kitamura, 2024, Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy, Acta Neuropathol. source
    • cites [123] Constant, O., Maarifi, G., Blanchet, F.P., Van de Perre, P., Simonin, Y., and Salinas, S. (2022). Role of Dendritic Cells in Viral Brain Infections. Front. Immunol., 13. source

      The Discussion (page unavailable) says viral brain infection can lead to neuroinflammation and that infection-related inflammation can have chronic CNS consequences. It does not establish these outcomes specifically for influenza; the only influenza mention found is in a reference title. The routes and sensory-neuron clauses are assigned to other citations, not this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [124] Bin, 2023, An airway-to-brain sensory pathway mediates influenza-induced sickness, Nature source
    • cites [125] Hosseini, 2018, Long-term neuroinflammation induced by influenza A virus infection and the impact on hippocampal neuron morphology and function, J. Neurosci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    COVID-19 is very rarely neuroinvasive, but its impact on the brain might be immune-mediated and cause glial neuroinflammation.

    “Indeed, while COVID-19 is very rarely neuroinvasive [127], its impact on the brain might be immune-mediated [126] and cause glial neuroinflammation [128,129,130].”
    Quote in the paperNot a substantial claim4 of 5 sources checked
    • cites [127] Meinhardt, 2024, The neurobiology of SARS-CoV-2 infection, Nat. Rev. Neurosci. source
    • cites [126] Wood, 2025, Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction, Nat. Med. source
    • cites [128] Dunai, C., Collie, C., and Michael, B.D. (2022). Immune-mediated mechanisms of COVID-19 neuropathology. Front. Neurol., 13. source
    • cites [129] Needham, 2022, Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses, Brain source
    • cites [130] Zhang, 2024, Brain-wide alterations revealed by spatial transcriptomics and proteomics in COVID-19 infection, Nat. Aging source

  • May combine two claims.

    Premisecitation

    All of these metabolites must be transferred into mitochondria for full β-oxidation into CO2 and H2O because peroxisomes lack a Krebs' cycle.

    “All of these metabolites must be transferred into mitochondria for full β-oxidation into CO2 and H2O because peroxisomes lack a Krebs’ cycle [162].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [162] Wanders, R.J., Waterham, H.R., and Ferdinandusse, S. (2016). Metabolic interplay between peroxisomes and other subcellular organelles including mitochondria and the endoplasmic reticulum. Front. Cell Dev. Biol., 3. source

  • May combine two claims.

    Premisecitation

    By binding to ATP, ALDP transports VLCFAcyl-CoA into the peroxisomal matrix, where they are β-oxidized into medium-chain fatty acids (MCFAs) and MCFAcyl-carnitines, propionyl-CoA, and acetyl-CoA.

    “By binding to ATP, ALDP transports VLCFAcyl-CoA into the peroxisomal matrix [143,159,160], where they are β-oxidized into medium-chain fatty acids (MCFAs) and MCFAcyl-carnitines [161], propionyl-CoA, and acetyl-CoA.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [143] Visser, 2008, The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl–CoA esters, FASEB J. source
    • cites [159] Postis, 2013, Intrinsic acyl-CoA thioesterase activity of a peroxisomal ATP binding cassette transporter is required for transport and metabolism of fatty acids, Proc. Natl. Acad. Sci. USA source

      The Introduction (p. 2) identifies ALDP as a peroxisomal ABC transporter involved in very-long-chain fatty-acid metabolism, and Fig. 4 (p. 4) describes ATP-powered transport for the related plant transporter CTS. But the paper's model says acyl-CoA is cleaved and free fatty acid enters the peroxisome; it does not establish that ALDP transports intact VLCFA-acyl-CoA into the matrix. The listed β-oxidation products are outside the clause citing this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [160] Theodoulou, 2016, How to move an amphipathic molecule across a lipid bilayer: Different mechanisms for different ABC transporters?, Biochem. Soc. Trans. source

      The 'Fatty acid import into peroxisomes' section identifies ALDP as an ATP-binding cassette transporter that preferentially imports very-long-chain fatty acids. But the 'Transport substrates and mechanism' section describes fatty acyl-CoA as a substrate accepted at the membrane, with CoA cleaved during or after transport and the fatty acid re-activated inside the peroxisome; it does not establish transport of intact VLCFA-acyl-CoA into the matrix. The later list of β-oxidation products is not attached to this citation. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [161] Wanders, 2001, Peroxisomal fatty acid α-and β-oxidation in humans: Enzymology, peroxisomal metabolite transporters and peroxisomal diseases, Biochem. Soc. Trans. source

  • May combine two claims.

    Premisecitation

    Drosophila abcd1 mutant flies had fewer peroxisomes, demonstrating an ABCD1 role in peroxisomal biogenesis.

    “These mutant flies had fewer peroxisomes, demonstrating an ABCD1 role in peroxisomal biogenesis [194].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [194] Manor, J., Jangam, S.V., Chung, H.-l., Bhagwat, P., Andrews, J., Chester, H., Kondo, S., Srivastav, S., Botas, J., and Moser, A.B. (2024). Genetic analysis of the X-linked Adrenoleukodystrophy ABCD1 gene in Drosophila uncovers a role in Peroxisomal dynamics. bioRxiv. source

      The Results (page not provided) report fewer peroxisomes per cell area after Abcd1 RNAi knockdown, supporting the reduced-number finding. They do not report that the Abcd1Δ4 mutant flies had fewer peroxisomes. The paper links inhibited biogenesis to overexpression of human ABCD1 and presents that mechanism as an interpretation, not as demonstrated by the mutant flies. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Loss of the pmp-4 gene, the Caenorhabditis elegans ortholog of ABCD1, induces VLCFA accumulation, axonal degeneration, and locomotor dysfunction.

    “Loss of the pmp-4 gene, the Caenorhabditis elegans ortholog of ABCD1, induces VLCFA accumulation, axonal degeneration, and locomotor dysfunction [195].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [195] Coppa, 2020, The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance: A worm model for adrenoleukodystrophy, Free Radic. Biol. Med. source

  • May combine two claims.

    Premisecitation

    OL peroxisomes are largely responsible for VLCFA synthesis and degradation in the adult brain.

    “OL peroxisomes are largely responsible for VLCFA synthesis [204] and degradation [166] in the adult brain.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [204] van de Beek, M.C., Dijkstra, I.M., van Lenthe, H., Ofman, R., Goldhaber-Pasillas, D., Schauer, N., Schackmann, M., Engelen-Lee, J.Y., Vaz, F.M., and Kulik, W. (2016). C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man. PLoS ONE, 11. source

      In Results and Discussion, under “Targeting ELOVL1 Expression to Oligodendrocytes” (page not specified), the paper concludes that oligodendrocytes are largely responsible for brain VLCFA synthesis and degradation. But this source is cited for the synthesis portion of the sentence, and it does not attribute that synthesis specifically to oligodendrocyte peroxisomes; its ELOVL1 results place the synthesis enzyme at the endoplasmic reticulum. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [166] Kassmann, 2007, Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes, Nat. Genet. source

  • May combine two claims.

    Premisecitation

    Abcd1:Abcd2 double KO mice had an earlier onset of symptoms with more severe motor deficits, axonal degeneration, and myelin alterations, but no cerebral pathology.

    “Abcd1: Abcd2 double KO mice had an earlier onset of symptoms with more severe motor deficits (at 20 months of age, 6 out of 11 mice were not able to perform motor tests), axonal degeneration, and myelin alterations, but no cerebral pathology.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [190] Pujol, 2004, Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: A therapeutic target for X-adrenoleukodystrophy, Hum. Mol. Genet. source

      The Neurological phenotype passage reports earlier, more severe motor impairment in double mutants, and Spinal cord histopathology reports more severe axonal and myelin pathology (page numbers unavailable). The copy does not establish an absence of cerebral pathology or report that 6 of 11 mice could not perform motor tests at 20 months; the n=11 figure in Table 2 concerns nerve-conduction studies. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [196] Ferrer, 2005, Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage, Hum. Mol. Genet. source

  • May combine two claims.

    Premisecitation

    Electron microscopy in Abcd2 KO mice showed the first signs of spinal cord axonal pathology at 12 months, yet no histological abnormalities.

    “Electron microscopy in Abcd2 KO mice showed the first signs of spinal cord axonal pathology at 12 months, yet no histological abnormalities.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [190] Pujol, 2004, Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: A therapeutic target for X-adrenoleukodystrophy, Hum. Mol. Genet. source

      The Spinal cord histopathology section (page unavailable) reports the first marker of pathology at 12 months in Abcd2-knockout mice: synaptophysin-positive deposits in swollen axons. It identifies this finding through immunostaining, not electron microscopy, and the deposits are histopathological abnormalities; the claim’s assertion of no histological abnormalities is therefore unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [196] Ferrer, 2005, Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage, Hum. Mol. Genet. source

      The Biochemical function of ALDRP section (page not supplied) says histological abnormalities in the spinal cord were not demonstrable at 12 months, while the first signs of pathology at that age were APP and synaptophysin accumulations in axonal swellings. It attributes those early findings to immunohistochemical analysis, not electron microscopy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    At 12 months of age, Abcd2 KO mice already displayed a marked impairment in motor performance, which aggravated up to 20 months.

    “At 12 months of age, Abcd2 KO mice already displayed a marked impairment in their motor performance, which aggravated up to 20 months.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [190] Pujol, 2004, Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: A therapeutic target for X-adrenoleukodystrophy, Hum. Mol. Genet. source

      The Neurological phenotype passage (page unavailable) reports impaired rotarod performance in ABCD1/ABCD2 double mutants by 15 months and in ABCD1-deficient mice at 20 months. It does not report marked motor-performance impairment in Abcd2-only knockout mice at 12 months or worsening through 20 months. The Electrophysiology of the PNS section (page unavailable) instead reports no detectable abnormality in Abcd2-only mutants at 12 months, though that is a different measure. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [196] Ferrer, 2005, Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage, Hum. Mol. Genet. source

  • May combine two claims.

    Premisecitation

    Histological abnormalities in spinal cord dorsal and ventral columns of Abcd2 KO mice became evident at 20 months, while atrophy or death of Purkinje cells was detected in the cerebellum.

    “Histological abnormalities in spinal cord dorsal and ventral columns became evident at 20 months, while atrophy or death of Purkinje cells was detected in the cerebellum.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [190] Pujol, 2004, Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: A therapeutic target for X-adrenoleukodystrophy, Hum. Mol. Genet. source

      The Spinal cord histopathology section reports abnormalities in ALDR−/− (Abcd2 knockout) mice, but it identifies an axonal marker at 12 months and describes further pathology at 22 months—not its first appearance at 20 months. The examined sections were of the dorsal spinal cord; our copy does not report ventral-column abnormalities or Purkinje-cell atrophy or death in the cerebellum. Page numbers were not available in the indexed passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [196] Ferrer, 2005, Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage, Hum. Mol. Genet. source

  • May combine two claims.

    Premisecitation

    In Drosophila, increased S1P-not VLCFA accumulation per se-triggers direct axonal loss, stimulation of immune cells, and neuroinflammation.

    “In the fly brain, increased S1P—not VLCFA accumulation per se—triggers direct axonal loss, stimulation of immune cells, and neuroinflammation [273], meaning that VLCFA accumulation in OLs is noxious to the CNS, as they can transport S1P to axons [273].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [273] Chung, 2023, Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation, Cell Metab. source

      The Introduction and the Discussion’s “Immune activation and neuroinflammation” section report that elevated glial S1P is toxic to neurons and drives immune activation, macrophage recruitment, and neuroinflammation in flies, rather than VLCFA accumulation alone. The copy does not establish direct axonal loss in flies: its reference to axonal damage concerns inflammatory responses during MS. It shows S1P transfer from fly glia to neurons, not specifically from oligodendrocytes to axons. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    OL energy demand is enormous, reaching a maximum during early myelination and remaining at a high level throughout life.

    “To perform all of their tasks, OL energy demand is enormous, reaching a maximum during early myelination and remaining at a high level throughout life [284].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [284] Harris, 2012, The energetics of CNS white matter, J. Neurosci. source

      The Materials and Methods section, “The energetic costs and benefits of myelination” (page unavailable), describes an initial ATP cost for making myelin and an ongoing cost of maintaining the myelinating oligodendrocyte’s resting potential. The Discussion, “The energetic cost and benefit of myelin” (page unavailable), likewise reports substantial resting-potential expenditure. These passages support energy demands during myelination and afterward, but do not establish that oligodendrocyte demand peaks during early myelination or remains high throughout life. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    OLs provide axons with glucose and FAs for mitochondrial oxidation, with FAs being their major energy source.

    “Because axons are not self-sufficient for their energy demand, OLs provide them with glucose and FAs for mitochondrial oxidation, with FAs being their major energy source [278].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [278] Asadollahi, 2024, Oligodendroglial fatty acid metabolism as a central nervous system energy reserve, Nat. Neurosci. source

      The Main section says oligodendrocytes supply axons with lactate or pyruvate for ATP generation. The Results section says oligodendrocytes oxidize fatty acids when glucose is limited, allowing them to share more glucose-derived pyruvate or lactate with axons. It does not establish that oligodendrocytes supply axons with fatty acids for mitochondrial oxidation or that fatty acids are axons’ major energy source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    When glucose availability is scarce, myelin synthesis declines and FA-derived acetyl-CoA supports mitochondrial respiration and OL survival.

    “When glucose availability is scarce, myelin synthesis declines and FA-derived acetyl-CoA supports mitochondrial respiration and OL survival [278].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [278] Asadollahi, 2024, Oligodendroglial fatty acid metabolism as a central nervous system energy reserve, Nat. Neurosci. source

  • May combine two claims.

    Interpretationcitation

    VLCFA accumulation in OLs is noxious to the CNS, as OLs can transport S1P to axons.

    “In the fly brain, increased S1P—not VLCFA accumulation per se—triggers direct axonal loss, stimulation of immune cells, and neuroinflammation [273], meaning that VLCFA accumulation in OLs is noxious to the CNS, as they can transport S1P to axons [273].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [273] Chung, 2023, Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation, Cell Metab. source

      The Results section, “S1P is transported from glia to neuron” (page not provided), reports that S1P produced in fly glia reaches neurons. The Discussion, “VLCFA toxicity in glia” (page not provided), notes that oligodendrocytes express genes in the S1P pathway. The paper does not establish that oligodendrocytes specifically transport S1P to axons, so that part of the citing sentence is an extrapolation. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    VLCFAs increase membrane stiffness, thereby decreasing fluidity, and are likely critical for proper myelin function, myelination, myelin maintenance, and neuron polarity during CNS development.

    “VLCFAs increase membrane stiffness, thereby decreasing fluidity, and they are likely critical for proper myelin function [191,213,214,217], myelination [218], myelin maintenance [207,213,215], and neuron polarity during CNS development [219].”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [191] Strachan, 2017, A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination, Hum. Mol. Genet. source
    • cites [213] Sassa, T., and Kihara, A. (2014). Metabolism of very long-chain fatty acids: Genes and pathophysiology. Biomol. Ther., 22. source
    • cites [214] Sassa, 2012, A shift in sphingolipid composition from C24 to C16 increases susceptibility to apoptosis in HeLa cells, Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids source

      The Discussion (page unavailable) reports that membrane vesicles from mice deficient in C24 sphingolipids had increased fluidity, supporting the membrane-fluidity point. It also links VLCFA accumulation in X-linked adrenoleukodystrophy to progressive demyelination, but does not establish that VLCFAs are critical for proper myelin function. The separate claims about myelination, maintenance, and neuron polarity have other citations in the citing sentence. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [217] Simons, 1997, Functional rafts in cell membranes, Nature source

  • May combine two claims.

    Premisecitation

    Acox1-KO mice accumulate VLCFAs in their brains but have neither axonal loss nor any neurodegenerative phenotype.

    “Acox1-KO mice accumulate VLCFAs in their brains but have neither axonal loss [267] nor any neurodegenerative phenotype [268].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [267] Fan, 1996, Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene, J. Biol. Chem. source

      The Discussion reports no appreciable neurological manifestations in ACOX-null mice by six months of age. It does not establish that the mice lack any neurodegenerative phenotype at all ages; the authors explicitly leave open whether neurological dysfunction develops later. The separate axonal-loss clause is attached to citation [267], not this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [268] Giles, 2018, Peroxisomal β-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease, JCI Insight source

      Citation [268] is attached to the claim that the mice have no neurodegenerative phenotype. The Introduction (page unavailable) calls Acox1-deficiency–associated disease in humans neurodegenerative, but the passages found for “neurodegenerative,” brain VLCFAs, and axonal loss do not assess whether the mice have a neurodegenerative phenotype. The paper’s reported mouse findings concern chiefly liver disease and inflammation. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia comprise 0.5-16.6% of the total cell population in the adult brain and spinal cord, depending on anatomical region, sex, and stage of development.

    “Microglia comprise 0.5–16.6% of the total cell population in the adult brain and spinal cord, depending on the anatomical region, sex, and stage of development, among other variables [307,308].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [307] Mittelbronn, 2001, Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude, Acta Neuropathol. source
    • cites [308] Tan, 2020, Microglial regional heterogeneity and its role in the brain, Mol. Psychiatry source

      The section “Heterogeneity in microglial density across CNS regions” reports regional differences in microglial abundance, including lower abundance in the cerebellum and spinal cord than in cortical regions, and describes heterogeneity in embryonic and adult brains. It does not give the claimed 0.5–16.6% share of total cells or establish sex as a determinant of that share. Its 0.5–2.5% figure refers instead to a proliferation rate. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Microglia live 0.5-3.4 years in the mouse brain and up to 20 years in the human brain.

    “Microglia live 0.5–3.4 years in the mouse brain [313] and up to 20 years in the human brain [314].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [313] Hefendehl, 2017, Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging, Nat. Neurosci. source
    • cites [314] Khosravi, 2017, The lifespan and turnover of microglia in the human brain, Cell Rep. source

  • May combine two claims.

    Premisecitation

    Peroxisomes are few in neuron perikarya or dendrites, rare within axons, and absent in synaptic terminals in the spinal cord except during early development.

    “While mitochondria fill dendrites and axons, peroxisomes are few in neuron perikarya or dendrites, rare within axons [251,253,254,255,292,293], and absent in synaptic terminals in the spinal cord [255] except during early development [255].”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [251] Ahlemeyer, 2007, Differential expression of peroxisomal matrix and membrane proteins during postnatal development of mouse brain, J. Comp. Neurol. source
    • cites [253] Kassmann, 2014, Myelin peroxisomes–Essential organelles for the maintenance of white matter in the nervous system, Biochimie source
    • cites [254] Kassmann, 2011, A role for myelin-associated peroxisomes in maintaining paranodal loops and axonal integrity, FEBS Lett. source
    • cites [255] Holtzman, 1973, Notes on synaptic vesicles and related structures, endoplasmic reticulum, lysosomes and peroxisomes in nervous tissue and the adrenal medulla, J. Histochem. Cytochem. source
    • cites [292] Toncheva, 2021, Regulation of peroxisomal trafficking and distribution, Cell. Mol. Life Sci. source

      In “Factors that modulate peroxisomal transport and distribution” (page unavailable), the paper says neuronal peroxisomes are largely absent from axons and that their localisation likely changes during development. It instead describes them as predominantly located in somata and proximal dendrites; it does not establish that they are few there or absent from spinal-cord synaptic terminals except during early development. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [293] Wang, Y., Metz, J., Costello, J.L., Passmore, J., Schrader, M., Schultz, C., and Islinger, M. (2018). Intracellular redistribution of neuronal peroxisomes in response to ACBD5 expression. PLoS ONE, 13. source

      The Introduction says peroxisomes are virtually absent from axons in mature projection neurons and accumulate in axon terminals during early postnatal development. It does not establish that they are few in perikarya or dendrites. The spinal-cord-specific statement is attached to a different citation in the citing sentence and is not assessed against this paper. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Activated microglia migrate to the site of damage via chemotaxis and release chemokines, pro- and anti-inflammatory cytokines, and other inflammatory mediators.

    “Activated microglia migrate to the site of damage via a process called chemotaxis and release chemokines (e.g., CCL2 and CXCL1), pro- and anti-inflammatory cytokines (e.g., IL-12, IL-10, TNF, TGF-β), and a variety of other inflammatory mediators [341].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [341] Rodríguez-Gómez, J.A., Kavanagh, E., Engskog-Vlachos, P., Engskog, M.K., Herrera, A.J., Espinosa-Oliva, A.M., Joseph, B., Hajji, N., Venero, J.L., and Burguillos, M.A. (2020). Microglia: Agents of the CNS pro-inflammatory response. Cells, 9. source

      Section 2.1 (page unavailable) describes microglial inflammatory signaling involving cytokines, including IL-12 and TNF, and chemokines, including CXCL1. Section 2 also lists other inflammatory factors, while section 5.3 discusses IL-10 expression in microglia. The passages found do not establish that activated microglia migrate to damage by chemotaxis or that they release TGF-β. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    During aging or disease states, axonal degeneration boosts microglial phagocytosis.

    “If this occurs during aging or disease states, axonal degeneration boosts microglial phagocytosis [328].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [328] Sierra, 2010, Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis, Cell Stem Cell source

      The Results section on aging reports that microglial phagocytic efficiency in the hippocampal neurogenic niche remains constant across the ages studied; the Discussion also describes that efficiency as preserved during acute inflammation. Neither passage addresses whether axonal degeneration boosts phagocytosis during aging or disease (searched: axonal degeneration, degenerating axons). No page numbers were available in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Age decreases microglia-mediated clearance of myelin fragments, but white matter-restricted microglia are an age-dependent state able to clear age-associated damaged myelin.

    “Age decreases microglia-mediated clearance of myelin fragments [329], but white matter-restricted microglia (WAM) are an age-dependent state able to clear age-associated damaged myelin [330].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [329] Safaiyan, 2016, Age-related myelin degradation burdens the clearance function of microglia during aging, Nat. Neurosci. source

      The paper reports that microglia clear myelin fragments in aging mice and that age-related myelin accumulation contributes to microglial senescence (Abstract; no page given). It does not directly show that aging decreases microglia-mediated clearance of myelin fragments: the reported decline in uptake concerns other materials or a disease model. The WAM clause carries a different citation and is not assessed here. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [330] Safaiyan, 2021, White matter aging drives microglial diversity, Neuron source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The turnover half-time of resident macrophages averages 150 days.

    “The turnover half-time of resident macrophages averages 150 days [317].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [317] Diebold, 2024, Advances in understanding the immunity of the brain and its borders: Focus on brain macrophages, Clin. Transl. Med. source

      The keypoints passage reports a 150-day turnover half-time for perivascular macrophages specifically, not an average for resident macrophages generally. It gives different half-times for macrophages in other brain compartments, ranging from 62 to 265 days; no page number is provided in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia constantly eliminate cell debris and dead cells through highly efficient phagocytosis.

    “Microglia constantly eliminate cell debris and dead cells through highly efficient phagocytosis using specific recognition, engulfment, and degradation processes to maintain brain homeostasis in health and disease [310,325,326,327].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [310] Sierra, A., Miron, V.E., Paolicelli, R.C., and Ransohoff, R.M. (2024). Microglia in Health and Diseases: Integrative Hubs of the Central Nervous System (CNS). Cold Spring Harb. Perspect. Biol., 16. source
    • cites [325] Sierra, A., Abiega, O., Shahraz, A., and Neumann, H. (2013). Janus-faced microglia: Beneficial and detrimental consequences of microglial phagocytosis. Front. Cell. Neurosci., 7. source
    • cites [326] Hammond, 2018, Microglia and the brain: Complementary partners in development and disease, Annu. Rev. Cell Dev. Biol. source
    • cites [327] Bohlen, 2019, Microglia in brain development, homeostasis, and neurodegeneration, Annu. Rev. Genet. source

      The “Microglial Clearance of Apoptotic Cells” section says microglia remove dead cells through phagocytosis and describes receptors involved in that process. The cited passages do not establish that they do so constantly or with the claimed high efficiency, and the passage mentioning cellular debris concerns complement-mediated clearance in the periphery. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Aged microglia become more responsive to pro-inflammatory stimuli, a phenomenon called microglial priming.

    “Aged microglia also become more responsive to pro-inflammatory stimuli (“microglial priming”) (reviewed in [331]).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [331] Wolf, 2017, Microglia in physiology and disease, Annu. Rev. Physiol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia support myelin formation and myelin integrity during CNS development and throughout life.

    “Microglia also support myelin formation and myelin integrity during CNS development and throughout life [319].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [319] McNamara, 2023, Microglia regulate central nervous system myelin growth and integrity, Nature source

      The Abstract and Discussion say microglia preserve myelin integrity and regulate myelin growth in adulthood. But the section “Microglia are dispensable for myelination” reports that developmental myelin ensheathment proceeded without microglia. The claim’s extension to supporting myelin formation during development and throughout life is therefore not supported. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Yolk sac-derived precursors of resident macrophages are only in the perivascular compartment and maintain their cellular origin in adulthood.

    “The yolk sac-derived precursors of resident macrophages are only in the perivascular compartment [360,361], where they maintain their cellular origin in adulthood [362,363,364].”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [360] Schulz, 2013, Development and homeostasis of “resident” myeloid cells: The case of the microglia, Glia source
    • cites [361] Faraco, 2017, Brain perivascular macrophages: Characterization and functional roles in health and disease, J. Mol. Med. source

      The section “Where do brain perivascular macrophages come from?” reports that embryonically labeled perivascular macrophages retained their label in six-week-old mice, supporting persistence of their developmental lineage into adulthood. But it also identifies embryonically labeled meningeal and choroid plexus macrophages, so the claim that such cells are only in the perivascular compartment is not supported. The paper describes a yolk-sac origin for perivascular macrophages as likely, not established. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [362] Masuda, 2022, Specification of CNS macrophage subsets occurs postnatally in defined niches, Nature source
    • cites [363] Goldmann, 2016, Origin, fate and dynamics of macrophages at central nervous system interfaces, Nat. Immunol. source

      The Results section (‘Prenatal yolk sac origin of CNS macrophages’) reports that perivascular and meningeal macrophages retained yolk sac lineage labels in adult mice, supporting persistence into adulthood. It also identifies yolk sac-derived macrophages in the meninges and choroid plexus, so they are not only in the perivascular compartment; choroid plexus macrophages, unlike the other two populations, lost their labels over time. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [364] Martens, 2019, A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment, Nat. Neurosci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The microglia population is highly heterogeneous, comprised of cells in discrete transcriptional dynamic substates that appear in defined contexts and brain regions.

    “Indeed, the microglia population is highly heterogeneous, comprised of cells in discrete transcriptional dynamic “substates” that appear in defined contexts and brain regions [333,334,335,336].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [333] Masuda, 2020, Microglia heterogeneity in the single-cell era, Cell Rep. source
    • cites [334] Amor, 2022, White matter microglia heterogeneity in the CNS, Acta Neuropathol. source
    • cites [335] Hammond, 2019, Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes, Immunity source
    • cites [336] Li, 2019, Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing, Neuron source

      The Introduction (page unavailable) reports greater heterogeneity in early postnatal microglia and identifies a transient population in specific developing brain regions, supporting context- and region-associated transcriptional states. But the Results section, “Limited transcriptomic heterogeneity of adult homeostatic microglia” (page unavailable), finds little variation across adult brain regions. The unqualified claim that the microglia population is highly heterogeneous overstates this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Under pathological conditions, microglia can acquire a detrimental pro-inflammatory phenotype that actively contributes to neuroinflammation, express genes involved with phagocytosis and lipid metabolism, and phagocytose unwanted material and synapses.

    “Indeed, under pathological conditions, microglia can acquire a detrimental pro-inflammatory phenotype that actively contributes to neuroinflammation, express genes involved with phagocytosis and lipid metabolism [343], and phagocytose unwanted material and synapses [344].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [343] Rangaraju, 2018, Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease, Mol. Neurodegener. source
    • cites [344] Colonna, 2017, Microglia function in the central nervous system during health and neurodegeneration, Annu. Rev. Immunol. source

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

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Monocytes have been implicated as Trojan horses during viral infections, carrying infectious virus particles to immune-privileged sites and/or to sites protected by the blood-brain barrier.

    “It is also interesting that monocytes have been implicated as “Trojan horses” during viral infections, carrying infectious virus particles to immune-privileged sites and/or to sites protected by the blood–brain barrier (reviewed in [123]).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [123] Constant, O., Maarifi, G., Blanchet, F.P., Van de Perre, P., Simonin, Y., and Salinas, S. (2022). Role of Dendritic Cells in Viral Brain Infections. Front. Immunol., 13. source

  • May combine two claims.

    Premisecitation

    Skull bone marrow cells continuously sample CSF to monitor brain status and can respond to CNS perturbations.

    “Skull bone marrow cells continuously sample CSF to monitor brain status by accessing CSF-derived cues and thus can respond to CNS perturbations [388].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [388] Herisson, 2018, Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration, Nat. Neurosci. source

      The Results report that skull-marrow neutrophils migrate toward the dura more frequently after stroke or induced brain inflammation. The Discussion proposes that signals from the inflamed brain may reach skull marrow, but the paper does not show that marrow cells continuously sample CSF or access CSF-derived cues to monitor brain status. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    ABCD1 mutations might play a pivotal role in viral infection and host defenses, prompting consideration of viral triggers in cALD.

    “ABCD1 mutations might thus play a pivotal role of in viral infection and host defenses, prompting consideration of viral triggers in cALD and suggesting new candidate disease mechanisms [391].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [391] Weinhofer, I., Buda, A., Kunze, M., Palfi, Z., Traunfellner, M., Hesse, S., Villoria-Gonzalez, A., Hofmann, J., Hametner, S., and Regelsberger, G. (2022). Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response. Commun. Biol., 5. source

  • May combine two claims.

    Premisecitation

    Single-cell profiling suggested that CAMs share functions with microglia and astrocytes in maintaining CNS homeostasis and regulating barrier functions.

    “Single-cell profiling suggested functions shared with microglia and astrocytes in maintaining CNS homeostasis [372] and regulating barrier functions [367,378,379,380].”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [372] Sankowski, 2019, Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation, Science source
    • cites [367] Kierdorf, 2019, Macrophages at CNS interfaces: Ontogeny and function in health and disease, Nat. Rev. Neurosci. source
    • cites [378] Amann, 2023, Mechanisms of myeloid cell entry to the healthy and diseased central nervous system, Nat. Immunol. source
    • cites [379] Prinz, 2021, Microglia and central nervous system–associated macrophages—From origin to disease modulation, Annu. Rev. Immunol. source

      The ‘CNS Macrophages as Tissue-Resident Immune Cells’ section says resident immune cells help maintain tissue homeostasis, and the ‘Functions of Microglia and CAMs During Development and Homeostasis’ section describes CAMs as possible regulators of immune responses at CNS borders. But our copy does not say that single-cell profiling identified functions CAMs share with both microglia and astrocytes, or that CAMs regulate barrier functions; it says CAM functions remain poorly understood. Page numbers were not available in the indexed passages. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [380] Weller, 2018, The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS, Acta Neuropathol. source

      The cited reference is attached to the sentence’s barrier-functions clause. In “Leptomeninges as barriers and facilitators in the CNS” (page unavailable), the review describes barrier functions of leptomeningeal cells, but it does not attribute those functions to CAMs or establish shared functions through single-cell profiling. The homeostasis clause carries a different citation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Perivascular macrophages function at the interface between blood and brain parenchyma as first responders in diverse neuroimmune interactions.

    “Thus, perivascular macrophages function at the interface between blood and brain parenchyma as first responders in diverse neuroimmune interactions [366].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [366] Rustenhoven, 2022, Brain borders at the central stage of neuroimmunology, Nature source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Perivascular macrophages belong to CNS border-associated macrophages (CAMs).

    “They belong to CNS border-associated macrophages (CAMs) [367,368].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [367] Kierdorf, 2019, Macrophages at CNS interfaces: Ontogeny and function in health and disease, Nat. Rev. Neurosci. source
    • cites [368] Mrdjen, 2018, High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease, Immunity source

  • May combine two claims.

    Premisecitation

    Monocytes normally strongly express ALDP and are most severely affected metabolically by defective beta-oxidation and VLCFA accumulation.

    “Monocytes normally strongly express ALDP and are most severely affected metabolically by defective β-oxidation and VLCFA accumulation [158].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [158] Weber, 2014, X-linked adrenoleukodystrophy: Very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes, Hum. Mol. Genet. source

  • May combine two claims.

    Premisecitation

    A comparative analysis with acute multiple sclerosis showed a similar extent of pro-inflammatory activation but strikingly less anti-inflammatory CD206 and CD163 receptors expressed on cALD macrophages.

    “A comparative analysis with acute multiple sclerosis showed a similar extent of pro-inflammatory activation but strikingly less anti-inflammatory CD206 and CD163 receptors expressed on cALD macrophages.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [355] Weinhofer, 2018, Impaired plasticity of macrophages in X-linked adrenoleukodystrophy, Brain source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CAMs control cerebral spinal fluid dynamics and homeostasis.

    “In addition, they control cerebral spinal fluid (CSF) dynamics and homeostasis [381].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [381] Drieu, 2022, Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid, Nature source

      The Abstract (page unavailable) says that parenchymal border macrophages regulate CSF flow dynamics under homeostatic conditions, and the section on extracellular matrix remodeling describes how they do so. The paper studies this macrophage subset, not CAMs generally, and does not establish that they control CSF homeostasis as a separate outcome. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Whole-transcriptome analysis showed AMN monocytes' normal macrophage differentiation and phagocytosis but a pro-inflammatory profile.

    “Those authors’ whole-transcriptome analysis showed AMN monocytes’ normal macrophage differentiation and phagocytosis but a pro-inflammatory profile.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [355] Weinhofer, 2018, Impaired plasticity of macrophages in X-linked adrenoleukodystrophy, Brain source

      The Results section reports that whole-transcriptome analysis found a pro-inflammatory expression pattern in AMN monocytes. It also reports unimpaired macrophage differentiation and no significant change in monocyte phagocytic ability, but those findings came from separate functional assays, not the whole-transcriptome analysis. Page numbers are unavailable in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CAMs clear harmful substances through phagocytosis, antigen presentation, and cytokine production.

    “As immune surveillants, CAMs clear harmful substances through phagocytosis, antigen presentation, and cytokine production [364,368,371,372,373,374,375,376]”
    Quote in the paperNot a substantial claim6 of 8 sources checked
    • cites [364] Martens, 2019, A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment, Nat. Neurosci. source
    • cites [368] Mrdjen, 2018, High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease, Immunity source

      The BAM-subsets section (p. 384–385) identifies CNS border-associated macrophages with MHCII expression, a marker relevant to antigen presentation. But the paper does not show BAMs clearing harmful substances by antigen presentation, phagocytosis, or cytokine production; its Discussion describes their functions as subjects for future study. The phagocytosis passage in the Discussion (p. 391) concerns infiltrating monocyte-derived cells, not BAMs. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [371] Ajami, 2018, Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models, Nat. Neurosci. source

      The Results (pages not provided) include meningeal and perivascular macrophages among the CNS-resident myeloid cells studied, report cytokine production in those cell populations, and suggest antigen presentation may be a role for one population. The paper does not establish these functions specifically for CAMs, or show that CAMs clear harmful substances through phagocytosis. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [372] Sankowski, 2019, Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation, Science source
    • cites [373] Kearns, 2023, Dissecting the human leptomeninges at single-cell resolution, Nat. Commun. source

      The Discussion (page not available) says border-associated macrophages (BAMs) contribute to border immunity and that mouse studies suggest a role in vascular amyloid-β clearance. It does not establish that CAMs clear harmful substances through phagocytosis, antigen presentation, and cytokine production; its mentions of antigen-presenting cells and cytokine-related genes do not demonstrate those clearance mechanisms. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [374] Sankowski, 2024, Multiomic spatial landscape of innate immune cells at human central nervous system borders, Nat. Med. source

      The Results section, “Multiomics reveal diversity of steady-state human CAMs” (page unavailable), reports MHC-II-associated and chemokine/cytokine-activity gene signatures in CAMs, consistent with antigen-presentation and cytokine-related roles. The copy does not show CAMs clearing harmful substances by phagocytosis, nor does it demonstrate that antigen presentation or cytokine production performs that clearance. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [375] Schonhoff, 2023, Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease, Nat. Commun. source

      The Introduction identifies CAMs as border-associated macrophages (BAMs) and describes BAMs as highly phagocytic. The Results report phagocytosis-related genes and the Discussion supports BAM antigen presentation, but neither establishes that these activities clear harmful substances. The Discussion links BAM-mediated T-cell restimulation to local cytokine production; it does not establish cytokine production by CAMs as a clearance mechanism. Page numbers were not provided in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [376] Yang, 2022, A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk, Nature source

      The ‘Cells of the human brain vasculature’ section identifies brain border macrophages but does not describe these functions. The Discussion discusses debris clearance and neuroimmune surveillance, chiefly in relation to microglia and vascular cells; searches for phagocytosis, antigen presentation, and cytokine production found no passage attributing the claimed mechanisms to CAMs. Page numbers were not provided in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Compared to multiple sclerosis, only a few macrophages in cALD brain lesions express anti-inflammatory markers, whereas macrophages with pro-inflammatory markers are present in both diseases.

    “Compared to multiple sclerosis, only a few macrophages in cALD brain lesions express anti-inflammatory markers, whereas macrophages with pro-inflammatory markers are present in both diseases [355].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [355] Weinhofer, 2018, Impaired plasticity of macrophages in X-linked adrenoleukodystrophy, Brain source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CAMs contribute to the maintenance of CNS homeostasis.

    “and they contribute to the maintenance of CNS homeostasis (reviewed in [377]).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [377] Glavan, 2024, The niche matters: Origin, function and fate of CNS-associated macrophages during health and disease, Acta Neuropathol. source

  • May combine two claims.

    Premisecitation

    Skull bone marrow cells can mount a tailored immune response and supply immune cells to the brain borders and parenchyma post-inflammation.

    “They can mount a tailored immune response [387,389]. They supply immune cells to the brain borders and parenchyma post-inflammation [388,389].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [387] Mazzitelli, 2023, Skull bone marrow channels as immune gateways to the central nervous system, Nat. Neurosci. source
    • cites [389] Cugurra, 2021, Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma, Science source

      The Results section reports that myeloid cells from CNS-adjacent bone marrow infiltrate the CNS after injury or neuroinflammation, and the Discussion describes skull bone marrow supplying cells to the meninges. The paper finds differing transcriptional profiles but treats distinct immune roles as a possibility; it does not establish that these cells mount a tailored immune response. The findings are in mice; page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [388] Herisson, 2018, Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration, Nat. Neurosci. source

      The Introduction and Results report preferential recruitment of skull-marrow neutrophils to the inflamed brain, including cells found in the parenchyma; the Discussion reports leukocytes at the brain surface and in the dura after stroke. The paper does not establish that these cells mount a tailored immune response: its Discussion presents local conditioning of leukocytes as a possibility, not a demonstrated finding. The reported evidence comes from mouse models of acute brain inflammation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CAMs can respond to inflammatory and chemical cues, including signals from microbiota and mechanical cues.

    “Being directly exposed to peripheral stimuli, they can respond to inflammatory and chemical cues, including signals from microbiota [369] and mechanical cues [370].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [369] Sankowski, 2021, Commensal microbiota divergently affect myeloid subsets in the mammalian central nervous system during homeostasis and disease, EMBO J. source
    • cites [370] Faraco, 2016, Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension, J. Clin. Investig. source

      Citation [370] is attached to “mechanical cues,” not the microbiota signals attributed to [369]. The paper’s Discussion describes perivascular macrophage activation by angiotensin II, a chemical signal, but the passages searched for mechanical stimuli, pressure sensing, and shear stress do not establish that these cells respond to mechanical cues. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Infiltrating monocytes expand locally and give rise to macrophages and inflammatory dendritic cells, but are unable to generate resident microglia.

    “These infiltrating monocytes expand locally and give rise to macrophages and inflammatory dendritic cells [390], but they are unable to generate resident microglia.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [390] Geissmann, 2010, Development of monocytes, macrophages, and dendritic cells, Science source

      The section ‘Are monocytes effector cells or circulating precursors?’ (page not provided) says inflammatory monocytes give rise to macrophages and dendritic cells, including inflammatory dendritic cells. The cited paper does not say that infiltrating monocytes expand locally. The microglia clause follows the citation and is not attributed to this source by the citing sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the short term, HSC transplantation reverses neuroinflammation and halts demyelination progression, as indicated by brain MRI.

    “In the short term, HSC transplantation reverses neuroinflammation and halts demyelination progression, as indicated by brain MRI [24,392,393].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [24] Aubourg, 1990, Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation, N. Engl. J. Med. source

      The Neurodiagnostic Studies (pp. 3, 5) report that MRI lesions resolved over 6–18 months in one patient, and the Discussion (p. 6) concludes that early transplantation can reverse the demyelinating process. The paper does not establish reversal of neuroinflammation by MRI; it also reports that some lesions initially enlarged after transplantation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [392] Lund, 2020, Volume of gadolinium enhancement and successful repair of the blood-brain barrier in cerebral adrenoleukodystrophy, Biol. Blood Marrow Transplant. source
    • cites [393] Lauer, 2023, Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy, Nat. Commun. source

      In Results and discussion, MRI contrast enhancement, a marker of inflammatory activity, disappeared 60–100 days after allo-HSCT in most patients. The lesion analysis reports that allo-HSCT decelerated lesion growth, while gene therapy halted progression in a large proportion of patients. The claim overstates these findings by saying HSC transplantation reverses neuroinflammation and halts demyelination progression without those qualifications. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    HSC transplantation normalizes white matter permeability and microvascular flow.

    “HSC transplantation normalizes white matter permeability and microvascular flow [393].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [393] Lauer, 2023, Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy, Nat. Commun. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Each astrocyte is in contact with up to four capillaries and enwraps about four neuronal cell bodies and 105 synapses.

    “Interposed between neurons and the vasculature, each astrocyte is in contact with up to four capillaries and enwraps about four neuronal cell bodies and 105 synapses [395,396,397].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [395] Bushong, 2002, Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains, J. Neurosci. source

      In “Astrocyte heterogeneity and anatomical domains” (page unavailable), the paper estimates that an astrocyte in adult rat CA1 would oversee approximately 140,000 synapses, broadly consistent with about 10^5, but it does not establish that each synapse is enwrapped. In “Spatial relationships between neighboring protoplasmic astrocytes” (page unavailable), it says nearly every astrocyte forms end-feet with at least one blood vessel; it does not give an upper limit of four capillaries or say that an astrocyte enwraps about four neuronal cell bodies. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [396] Oberheim, 2008, Loss of astrocytic domain organization in the epileptic brain, J. Neurosci. source

      The Introduction (page unavailable) estimates that one astrocytic domain encompasses about 140,000 synapses in rodents, broadly supporting the claim’s 10^5-synapse figure; it gives a different estimate of 2,000,000 for humans. The passages found do not support the specific counts of up to four capillaries or about four neuronal cell bodies per astrocyte. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [397] Halassa, 2007, Synaptic islands defined by the territory of a single astrocyte, J. Neurosci. source

      The section ‘Single astrocytes enwrap multiple neuronal cell bodies’ reports an average of four neuronal somata per cortical astrocyte. The Introduction reports that a hippocampal astrocyte can contact more than 100,000 synapses, citing earlier work; it does not establish that number for each astrocyte. No passage found supports contact with up to four capillaries. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Astrocytes recycle neurotransmitters, clear extracellular fluid potassium, contribute to synaptic plasticity and transmission, maintain the blood-brain barrier, release lactate to fuel neurons and axons, buffer free radicals, and regulate blood flow.

    “Indeed, they recycle neurotransmitters, e.g., removing excessive glutamate through their glutamate transporters. Astrocytes clear extracellular fluid potassium, contribute to synaptic plasticity and transmission, maintain the BBB, release lactate to fuel neurons and axons, buffer free radicals, and regulate blood flow (reviewed in [398,399]).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [398] Weber, B., and Barros, L.F. (2015). The astrocyte: Powerhouse and recycling center. Cold Spring Harb. Perspect. Biol., 7. source

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

      Experimental — accuracy not yet measured
    • cites [399] Liddelow, S.A., Olsen, M.L., and Sofroniew, M.V. (2024). Reactive astrocytes and emerging roles in central nervous system (CNS) disorders. Cold Spring Harb. Perspect. Biol., 16. source

      The “Functions and Effects of Astrocyte Reactivity” section (page unavailable) identifies neurotransmitter reuptake and recycling and synapse stabilization as physiological functions. The “Reactive Astrocytes in Traumatic Injury and Stroke” section also says reactive astrocytes can influence synaptic plasticity. Our copy does not substantiate the remaining specific functions attributed here: extracellular potassium clearance, BBB maintenance, lactate fueling neurons and axons, free-radical buffering, or blood-flow regulation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Conduction velocity in isolated sciatic nerves of CNP-Pex5 KO mice is diminished and compound action potentials are lower, despite unchanged axon numbers and sizes.

    “However, the conduction velocity in isolated sciatic nerves of these mice is diminished and compound action potentials are lower, despite unchanged axon numbers and sizes [252].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [252] Kleinecke, 2017, Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy, Elife source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cortisol synthesis could be impaired by a relative lack of cholesterol necessary for its production.

    “Alternatively, cortisol synthesis could be impaired by a relative lack of cholesterol necessary for its production [30,426].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [30] Powers, 1985, Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex), Clin. Neuropathol.

      Not checked in the free run.

    • cites [426] Buda, A., Forss-Petter, S., Hua, R., Jaspers, Y., Lassnig, M., Waidhofer-Söllner, P., Kemp, S., Kim, P., Weinhofer, I., and Berger, J. (2023). ABCD1 transporter deficiency results in altered cholesterol homeostasis. Biomolecules, 13. source

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). The quote only partly states this claim.

    Interpretationreasoning

    Lipid droplet-peroxisome communication is abnormal in X-ALD adrenals.

    “Since the tethering of LDs to peroxisomes involves ABCD1 [431], it is tempting to postulate that LD–peroxisome communication is abnormal in X-ALD adrenals.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [431] Chang, 2019, Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III, J. Cell Biol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The membrane of adrenal cells is disrupted by altered microviscosity when exposed to C26:0, which supposedly leads to impaired response to adrenocorticotropic hormone.

    “The membrane of adrenal cells is disrupted by altered microviscosity when exposed to C26:0, which supposedly leads to impaired response to adrenocorticotropic hormone (ACTH) [425].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [425] Whitcomb, 1988, Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro, J. Clin. Investig. source

  • May combine two claims.

    Premisecitation

    Initial neurological deficits associated with non-inflammatory demyelinating lesions are minor, but once inflammation sets in, demyelination accelerates dramatically due to the ruptured blood-brain barrier and infiltration of mononuclear, T-helper, and cytotoxic T cells and B cells.

    “Initial neurological deficits associated with non-inflammatory demyelinating lesions [288] are minor, but once the inflammation sets in, demyelination accelerates dramatically due to the ruptured BBB and infiltration of mononuclear, T-helper, and cytotoxic T cells and B cells.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [288] Berger, 2014, Pathophysiology of X-linked adrenoleukodystrophy, Biochimie 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

  • May combine two claims.

    Premisecitation

    Astrocyte and microglia iPSC models partially recapitulate the transcriptomes of their in vivo counterparts and may capture authentic neurodegenerative disease phenotypes.

    “Astrocyte and microglia iPSC models partially recapitulate the transcriptomes of their in vivo counterparts and may capture authentic neurodegenerative disease phenotypes [345,406,480,481,482,483,484].”
    Quote in the paperNot a substantial claim6 of 7 sources checked
    • cites [345] Garland, E.F., Hartnell, I.J., and Boche, D. (2022). Microglia and Astrocyte Function and Communication: What Do We Know in Humans?. Front. Neurosci., 16. source

      The Microglial and Astrocytic Cell Culture Models sections report that iPSC-derived cells express characteristic markers and show Alzheimer’s-related changes, supporting the possibility that these models capture disease phenotypes. The copy does not establish that both models partially recapitulate the transcriptomes of their in vivo counterparts; the Introduction’s Table 1 instead cautions that iPSC-derived cells may differ from glia in vivo. Page numbers were not provided for these passages. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [406] Patani, 2023, Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration, Nat. Rev. Neurol. source
    • cites [480] Franklin, H., Clarke, B.E., and Patani, R. (2021). Astrocytes and microglia in neurodegenerative diseases: Lessons from human in vitro models. Prog. Neurobiol., 200. source
    • cites [481] Summers, 2024, Novel human iPSC models of neuroinflammation in neurodegenerative disease and regenerative medicine, Trends Immunol. source
    • cites [482] Lanciotti, A., Brignone, M.S., Macioce, P., Visentin, S., and Ambrosini, E. (2021). Human iPSC-derived astrocytes: A powerful tool to study primary astrocyte dysfunction in the pathogenesis of rare leukodystrophies. Int. J. Mol. Sci., 23. source

      Section 5 reports that iPSC-derived astrocytes acquire adult astrocyte genes and that a 3D model closely recapitulates aspects of in vivo astrocyte development. Section 3.2 reports disease-related defects in patient-derived iPSC astrocytes. The paper does not establish transcriptome-level similarity for both cell types or describe an iPSC microglia model capturing disease phenotypes; its disease examples concern rare leukodystrophies. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [483] Sharma, 2020, Multi-lineage human iPSC-derived platforms for disease modeling and drug discovery, Cell Stem Cell source

      The Introduction’s section on hiPSC-derived assembloids (page unavailable) says multi-lineage models have been used to study neural–glial interplay in Alzheimer’s disease, supporting the possibility of modeling neurodegenerative disease. But neither that section nor the transcriptomics discussion establishes that iPSC-derived astrocytes and microglia partially recapitulate the transcriptomes of their in vivo counterparts; the Conclusions also caution that hiPSC-derived tissues have not been shown to be transcriptionally identical to adult tissue. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [484] Haenseler, 2017, A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response, Stem Cell Rep. source

      The Results report transcriptomic similarity between iPSC-derived co-culture microglia and primary microglia; the Discussion says their profile resembles fetal microglia and identifies disease-relevant genes. The paper presents the model as useful for studying neurodegenerative disease genes, but it does not establish that it captures disease phenotypes or assess iPSC-derived astrocyte models. Page numbers were not supplied in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Head trauma is amenable to experimental research in mice.

    “and is amenable to experimental research in mice [502,503].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [502] Gihring, A., Gärtner, F., Schirmer, M., Wabitsch, M., and Knippschild, U. (2022). Recent Developments in Mouse Trauma Research Models: A Mini-Review. Front. Physiol., 13. source
    • cites [503] Kahriman, 2021, Mouse closed head traumatic brain injury replicates the histological tau pathology pattern of human disease: Characterization of a novel model and systematic review of the literature, Acta Neuropathol. Commun. source

  • May combine two claims.

    Premisecitation

    AMN patient-specific iPSC-derived OLs showed elevated VLCFA levels compared to healthy controls, but lower levels than those derived from cALD patients in two studies.

    “AMN patient-specific iPSC-derived OLs showed elevated VLCFA levels/, compared to healthy controls, but lower levels than those derived from cALD patients in two studies [477,478]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [477] Baarine, M., Khan, M., Singh, A., and Singh, I. (2015). Functional characterization of IPSC-derived brain cells as a model for X-linked adrenoleukodystrophy. PLoS ONE, 10. source
    • cites [478] Wang, 2012, The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis, Stem Cell Res. Ther. source

      The Results section on comparative lipid profiling (page unavailable) measures CCALD fibroblasts and undifferentiated iPSCs, not AMN patient-derived oligodendrocytes. The Discussion mentions oligodendrocytes only as a cell type for future investigation. Searches for AMN oligodendrocytes and their VLCFA levels found no comparison with healthy controls or CCALD-derived oligodendrocytes in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • The quote only partly states this claim.

    Premisecitation

    iPSC-derived astrocytes from two AMN and two cALD patients accumulated VLCFAs.

    “Those iPSC-derived astrocytes accumulated VLCFAs”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [485] Kaur, N., and Singh, J. (2025). Generation and Characterization of Human iPSC-Derived Astrocytes with Potential for Modeling X-Linked Adrenoleukodystrophy Phenotypes. Int. J. Mol. Sci., 26. source

  • May combine two claims.

    Premisecitation

    Moving towards higher levels of iPSC model complexity is thought to improve the 'brain-like' authenticity of disease mechanisms, but little available evidence currently supports this idea.

    “While moving towards higher levels of iPSC model complexity is thought to improve the ‘brain-like’ authenticity of disease mechanisms, little available evidence currently supports this idea [403].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [403] Maguire, 2023, Human iPSC-derived glia models for the study of neuroinflammation, J. Neuroinflammation source

      The Conclusion says increasing iPSC model complexity is assumed to improve the ‘brain-like’ authenticity of inflammatory responses, but that little evidence supports the assumption because cross-model comparisons are scarce. The citing sentence broadens this specific point about inflammatory responses to disease mechanisms generally. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Traumatic brain injury may be a significant environmental risk factor for several progressive neurodegenerative disorders.

    “Traumatic brain injury may be a significant environmental risk factor for several progressive neurodegenerative disorders [496].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [496] Gardner, 2015, Epidemiology of mild traumatic brain injury and neurodegenerative disease, Mol. Cell Neurosci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Head trauma is known to cause microglial activation and neuroinflammation.

    “Head trauma is known to cause microglial activation and neuroinflammation [498,499,500,501]”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [498] Shao, F., Wang, X., Wu, H., Wu, Q., and Zhang, J. (2022). Microglia and Neuroinflammation: Crucial Pathological Mechanisms in Traumatic Brain Injury-Induced Neurodegeneration. Front. Aging Neurosci., 14. source
    • cites [499] Velayudhan, 2021, Temporal patterns of microglial activation in white matter following experimental mild traumatic brain injury: A systematic literature review, Acta Neuropathol. Commun. source
    • cites [500] Pybus, 2024, Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries, J. Neuroinflammation source
    • cites [501] Lenzlinger, 1997, Production of cytokines following brain injury: Beneficial and deleterious for the damaged tissue, Mol. Psychiatry source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A study using diffusion-weighted MRI built a microstructural model of diffusion based on the ramified morphology of glial cells.

    “Interestingly, a study using diffusion-weighted MRI built a microstructural model of diffusion based on the ramified morphology of glial cells [509].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [509] Drakesmith, 2022, Mapping microglia and astrocyte activation in vivo using diffusion MRI, Sci. Adv. source

  • May combine two claims.

    Premisecitation

    The diffusion model was tested on rats under several conditions and was validated for glial cell detection via immuno-labeling of the rat brain for microglia and astrocytes (GFAP).

    “The model was tested on rats under several conditions and was validated for glial cells detection via immuno-labeling of the rat brain for microglia and astrocytes (GFAP).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [509] Drakesmith, 2022, Mapping microglia and astrocyte activation in vivo using diffusion MRI, Sci. Adv. source

  • May combine two claims.

    Premisecitation

    The diffusion model appears not only to be able to distinguish between microglia and astrocytes but also to assess the presence of neurodegeneration.

    “Interestingly, the model appears not only to be able to distinguish between microglia and astrocytes but also to assess the presence of neurodegeneration [510].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [510] Li, 2024, In vivo imaging of astrocytes in the whole brain with engineered AAVs and diffusion-weighted magnetic resonance imaging, Mol. Psychiatry source

      The Perspective (page unavailable) says the diffusion-weighted MRI method images astrocytes and may identify regions with abnormal astrocytes under pathological conditions. The Assessment of astrocyte-specific rAAV-AQP1 section (page unavailable) mentions microglia only as a marker used to check cytotoxicity; it does not show that the imaging method distinguishes microglia from astrocytes. The paper also does not show that the method assesses the presence of neurodegeneration. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    At 24 months, about 70% of Abcd1−/− mice had severe motor manifestations but 33% still showed no clinical pathology.

    “At 24 months, ~70% of mice had severe motor manifestations but 33% still showed no clinical pathology (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No significant demyelination or neuroinflammation was detected in Abcd1−/− mice.

    “No brain or spinal cord lesions were visible macroscopically or using light microscopy, and no significant demyelination or neuroinflammation was detected.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    At 24 months of age, hABCD1 expression was present in 22% of white matter cervical spinal cord OLs and 22% of astrocytes.

    “At 24 months of age, hABCD1 expression was present in 22% in the white matter cervical spinal cord OLs and 22% of astrocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [176] 2025, Intracisternal AAV9-MAG-hABCD1 Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice, Hum. Gene Ther. source

  • May combine two claims.

    Findingcitation

    No ABCD1 expression was detected in motor cortex or DRG neurons, parental somata of the corticospinal and spinocerebellar tracts, or in the spinal cord or brain microglia.

    “No ABCD1 expression was detected in motor cortex or DRG neurons, parental somata of the corticospinal and spinocerebellar tracts, or in the spinal cord or brain microglia [176].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [176] 2025, Intracisternal AAV9-MAG-hABCD1 Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice, Hum. Gene Ther. source

  • May combine two claims.

    Findingcitation

    As early as 1-3 months post-injection, treated mice had restored and near-normal motor performances, whereas untreated mice experienced neurological deterioration.

    “As early as 1–3 months post-injection, the treated mice had restored and near-normal motor performances, whereas untreated mice experienced neurological deterioration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [176] 2025, Intracisternal AAV9-MAG-hABCD1 Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice, Hum. Gene Ther. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Around 20% of AMN patients develop brain demyelination (cAMN).

    “Around 20% of AMN patients develop brain demyelination (cerebral AMN/cAMN) [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Bezman, 2001, Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy, Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Around 5% of cALD cases occur in adolescents or adults, with slower evolution.

    “Around 5% of cALD cases occur in adolescents or adults, with symptoms resembling those listed above but whose evolution is slower.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Virtually all patients with ABCD1 mutations who reach adulthood develop AMN, usually in their 3rd or 4th decade.

    “Virtually all patients with ABCD1 mutations who reach adulthood develop AMN, usually in their 3rd or 4th decade.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For unknown reasons, 10% of children, adolescents, or men with cALD escape demyelination and neuroinflammation worsening; after 10-15 years of stability, they suffer sudden neurological deterioration due to recurring neuroinflammation.

    “Intriguingly, for still unknown reasons, 10% of children, adolescents, or men with cALD escape demyelination and neuroinflammation worsening. Nevertheless, after 10–15 years of stability, these patients suffer neurological deterioration of a sudden onset in due to recurring neuroinflammation [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D. (2001). X-linked adrenoleukodystrophy. The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cognitive decline and psychiatric manifestations in cALD are often misdiagnosed.

    “The cognitive decline [39] and psychiatric manifestations are often misdiagnosed [40,41,42].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [39] Edwin, 1990, Cognitive impairment in adult-onset adrenoleukodystrophy, Mol. Chem. Neuropathol. source
    • cites [40] Rosebush, 1999, The neuropsychiatry of adult-onset adrenoleukodystrophy, J. Neuropsychiatry Clin. Neurosci. source
    • cites [41] Mehta, 2021, Adult-onset adrenoleukodystrophy presenting with status epilepticus and psychosis, BMJ Case Rep. source
    • cites [42] Levinson, 1999, Late-onset adrenoleukodystrophy associated with long-standing psychiatric symptoms, J. Clin. Psychiatry source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Subacute demyelination attacks the brain of a subset of X-ALD patients, most often during childhood (cALD).

    “While developmental myelination seems to proceed normally until 3 years of age, subacute demyelination attacks the brain of a subset of X-ALD patients, most often during childhood (cerebral ALD, cALD).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In a Drosophila knockout model, VLCFA accumulation in glial myelinating cells causes production of a toxic lipid able to poison axons and activate inflammatory cells.

    “A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Most often, insidious signs of cALD appear in children older than 3 years, first as inattention, regression of verbal comprehension and reasoning, or decline in school or behavioral symptoms.

    “Most often, insidious signs appear in children older than 3 years, first as inattention, regression of verbal comprehension and reasoning, or decline in school or behavioral symptoms [35,36].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Kitchin, 1987, Adrenoleukodystrophy: Frequency of presentation as a psychiatric disorder, Biol. Psychiatry source
    • cites [36] Fis, 2011, X-Linked adrenoleukodystrophy in a 7-year-old boy presenting with psychiatric symptoms, Eur. Child. Adolesc. Psychiatry source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Primary causes and secondary mechanisms of X-ALD are intermingled over long years in different CNS regions, and it is currently impossible to discern which spatiotemporal trajectory leads to cALD or AMN.

    “The primary causes and secondary mechanisms of the disease are intermingled over long years in different regions of the central nervous system (CNS), and it is currently impossible to discern which spatiotemporal trajectory of events leads to cALD or AMN.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    In almost all cALD cases, deficits become major within a few weeks, leading 90% of children or adolescents to become bedridden, blind, confused, and unable to communicate verbally before entering a vegetative state that leads to death within 3-4 years.

    “Deficits become major within a few weeks, leading 90% of children or adolescents to become bedridden, blind, confused, and unable to communicate verbally before entering a vegetative state that leads to death within 3–4 years.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Plasma VLCFA measurement enables X-ALD diagnosis.

    “Plasma VLCFA measurement enables X-ALD diagnosis [37,38].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Moser, 1998, Adrenoleukodystrophy: Increased plasma content of saturated very long chain fatty acids, Neurology source
    • cites [38] Aubourg, 1985, Capillary gas-liquid chromatographic-mass spectrometric measurement of very long chain (C22 to C26) fatty acids in microliter samples of plasma, J. Lipid Res. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ABCD1 was identified as the causal gene for X-ALD in 1993.

    “However, despite the identification of the ATP binding cassette subfamily B member-1 gene (ABCD1) as the causal gene in 1993 [23] and the discovery that impaired VLCFA peroxisomal transport is the primary biochemical defect, the mechanisms of X-ALD pathology remained largely obscure.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Mosser, 1993, Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters, Nature source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The rapid progression of cALD symptoms reflects mounting demyelination and inflammation.

    “The rapid progression of symptoms soon reflects mounting demyelination and inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Within 10-15 years of AMN, motor disability of the legs becomes severe, whereas arm and hand deficits remain mild.

    “Within 10–15 years, motor disability of the legs becomes severe, whereas arm and hand deficits remain mild [53,54].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Kararizou, 2006, Polyneuropathies in teenagers: A clinicopathological study of 45 cases, Neuromuscul. Disord. source
    • cites [54] Engelen, 2011, X-linked adrenomyeloneuropathy due to a novel missense mutation in the ABCD1 start codon presenting as demyelinating neuropathy, J. Peripher. Nerv. Syst. source

  • May combine two claims.

    Premisecitation

    An Abcd1 knockout mouse model created in 1997 closely mimics AMN but not cALD.

    “A mouse KO model of the Abcd1 gene, created in 1997, closely mimics AMN but not cALD [26,27,28,29].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [26] Werner, 1997, Targeted inactivation of the X-linked adrenoleukodystrophy gene in mice, J. Neurosci. Res. source
    • cites [27] Lu, 1997, A mouse model for X-linked adrenoleukodystrophy, Proc. Natl. Acad. Sci. USA source
    • cites [28] Kobayashi, 1997, Adrenoleukodystrophy protein-deficient mice represent abnormality of very long chain fatty acid metabolism, Biochem. Biophys. Res. Commun. source
    • cites [29] Pujol, 2002, Late onset neurological phenotype of the X-ALD gene inactivation in mice: A mouse model for adrenomyeloneuropathy, Hum. Mol. Genet. source

  • May combine two claims.

    Interpretationreasoning

    Animal models support a primary role of oligodendrocytes and axonal pathology and a secondary role of microglia in X-ALD.

    “Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from mouse and Drosophila models of X-ALD are informative about human X-ALD pathogenesis.

  • May combine two claims.

    Interpretationreasoning

    Beyond ABCD1 mutations, X-ALD pathogenesis depends on unidentified contributors, including genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types.

    “Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    X-ALD is a white matter disease caused by mutations in ABCD1, which encodes a transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes.

    “X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Mosser, 1993, Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters, Nature source

  • The quote only partly states this claim.

    Premisecitation

    cALD brain histopathology shows marked regional disparity with contiguous white matter areas ranging from intact myelinated axons to chronic gliotic lesions.

    “Histopathology of five brains showed marked disparity across regions [72] with contiguous white matter areas [73]: (i) intact zones showing densely packed myelinated axons and normal-looking oligodendrocytes (OLs); (ii) zones of limited demyelination showing occasional astrocytes and lipid-containing macrophages; (iii) zones of active demyelination with loss of axons and myelin, variable loss of O”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Powers, 1992, The inflammatory myelinopathy of adreno-leukodystrophy: Cells, effector molecules, and pathogenetic implications, J. Neuropathol. Exp. Neurol. source
    • cites [73] Reinecke, 1985, The correlation between biochemical and histopathological findings in adrenoleukodystrophy, J. Neurol. Sci. source

  • May combine two claims.

    Premisecitation

    In AMN patients, the fasciculus gracilis shows a prominent loss of myelinated fibers and oligodendrocytes, associated with axonal atrophy and very thin or disintegrating myelin sheaths.

    “In AMN patients, the fasciculus gracilis shows a prominent loss of myelinated fibers and OLs [18], associated with axonal atrophy and very thin or disintegrating myelin sheaths [49,82].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Schaumburg, 1976, The myeloneuropathy variant of adrenoleukodystrophy, J. Neuropathol. Exp. Neurol. source
    • cites [49] Powers, 2000, Adrenomyeloneuropathy: A neuropathologic review featuring its noninflammatory myelopathy, J. Neuropathol. Exp. Neurol. source
    • cites [82] Probst, 1980, Adrenomyeloneuropathy. A protracted, pseudosystematic variant of adrenoleukodystrophy, Acta Neuropathol. source

  • May combine two claims.

    Premisecitation

    Peripheral neuropathy is electrophysiologically detectable in a majority of AMN patients, but its clinical contribution is hidden by prominent myelopathy symptoms.

    “Peripheral neuropathy is electrophysiologically detectable in a majority of patients [57], but its clinical contribution is hidden by the prominent myelopathy symptoms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Koelman, 1996, Peripheral nerve abnormalities in adrenomyeloneuropathy: A clinical and electrodiagnostic study, Neurology source

  • May combine two claims.

    Premisecitation

    Heterozygous women with X-ALD rarely experience cerebral involvement and adrenal insufficiency.

    “These women rarely experience cerebral involvement and adrenal insufficiency [47,64].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D. (2001). X-linked adrenoleukodystrophy. The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill.

      Not checked in the free run.

    • cites [64] Naidu, 1997, Assessment of adrenal function in women heterozygous for adrenoleukodystrophy, J. Clin. Endocrinol. Metab.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Microglia are present in AMN lesions, but there are no infiltrates of circulating inflammatory cells, indicating that myelopathy is a non-inflammatory process.

    “Microglia are present in lesions, but there are no infiltrates of circulating inflammatory cells, indicating that myelopathy is a non-inflammatory process.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Terminal-stage postmortem CNS lesions in X-ALD patients reflect the disease mechanisms that lead to cALD or AMN.

  • May combine two claims.

    Interpretationreasoning

    AMN is considered a dying-back axonopathy, with the longest vulnerable axons in the spinal cord suffering the greatest damage, because the cell bodies of parental neurons are intact and in normal numbers.

    “Because the cell bodies of these parental neurons are intact and in normal numbers, AMN is considered a “dying back” axonopathy, with the longest vulnerable axons in the spinal cord suffering the greatest damage.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Terminal-stage postmortem CNS lesions in X-ALD patients reflect the disease mechanisms that lead to cALD or AMN.

  • May combine two claims.

    Premisecitation

    AMN patients show a variety of mild brain lesions, including microscopic dysmyelinated foci, activated microglia and macrophages, and relative total sparing of axons and oligodendrocytes.

    “AMN patients show a variety of mild brain lesions. A few of them had no white matter lesions [49], but almost all showed microscopic dysmyelinated foci, activated microglia and macrophages, and relative to total sparing of axons and OLs [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Powers, 2000, Adrenomyeloneuropathy: A neuropathologic review featuring its noninflammatory myelopathy, J. Neuropathol. Exp. Neurol. source

  • May combine two claims.

    Premisecitation

    At diagnosis, 80% of boys or adolescents with cALD and 70% of AMN patients have hormonal evidence of clinically silent adrenal insufficiency.

    “At diagnosis, 80% of boys or adolescents with cALD and 70% of AMN patients have hormonal evidence of clinically silent adrenal insufficiency [65,66,67,68,69].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [65] Dubey, 2005, Diffusion tensor–based imaging reveals occult abnormalities in adrenomyeloneuropathy, Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc. source
    • cites [66] Moser, 1991, Clinical aspects of adrenoleukodystrophy and adrenomyeloneuropathy, Dev. Neurosci. source
    • cites [67] Kemp, 2016, Adrenoleukodystrophy–neuroendocrine pathogenesis and redefinition of natural history, Nat. Rev. Endocrinol. source
    • cites [68] Laureti, 1996, X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison’s disease in young adult male patients, J. Clin. Endocrinol. Metab. source
    • cites [69] Hsieh, 2011, Presentation of primary adrenal insufficiency in childhood, J. Clin. Endocrinol. Metab. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    No obvious macroscopic lesions were described in the spinal cord of young patients who died from cALD.

    “No obvious macroscopic lesions were described in the spinal cord of young patients who died from cALD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sural nerves in AMN suffer more specific involvement of large myelinated fibers, causing deficits in position and vibratory sensations.

    “Sural nerves suffer more specific involvement of large myelinated fibers [87], causing deficits in position and vibratory sensations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Tanaka, 1985, Adrenomyeloneuropathy: Report of a family and electron microscopical findings in peripheral nerve, J. Neurol. source

  • May combine two claims.

    Premisenone given

    Sural and peroneal nerves in AMN show loss of large and small diameter myelinated fibers, endoneurial fibrosis, and thin myelin sheaths.

    “Sural and peroneal nerves show loss of large and small diameter myelinated fibers, endoneurial fibrosis, and thin myelin sheaths.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The de novo mutation rate in X-ALD ranges from 4 to 19%.

    “The de novo mutation rate ranged from 4 to 19% [32,101].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Bezman, 2001, Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening, Ann. Neurol. source
    • cites [101] Wang, 2011, X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism, Mol. Genet. Metab. source

  • May combine two claims.

    Premisenone given

    Late spinal cord MR images in AMN may show some atrophy, but no demyelination or gadolinium enhancement.

    “Late spinal cord MR images may show some atrophy, but no demyelination or gadolinium enhancement.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In arrested cALD, MRI is stabilized and gadolinium enhancement disappears for a decade or more.

    “In the few cases of “arrested cALD”, MRI is stabilized and gadolinium enhancement disappears for a decade or more [95,96].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [95] Springer (2005). Magnetic Resonance of Myelination and Myelin Disorders, Springer Science & Business Media. [3rd ed.].

      Not checked in the free run.

    • cites [96] Korenke, 1996, Arrested cerebral adrenoleukodystrophy: A clinical and proton magnetic resonance spectroscopy study in three patients, Pediatr. Neurol. source

  • May combine two claims.

    Interpretationreasoning

    An ABCD1 mutation is sufficient to cause pure AMN, while being necessary but not sufficient to cause cALD or cAMN.

    “In summary, an ABCD1 mutation is sufficient to cause “pure” AMN, while being necessary but not sufficient to cause cALD or cAMN.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A large segregation analysis suggested the presence of a single major autosomal modifier locus in X-ALD.

    “Although a large segregation analysis suggested the presence of a single “major” autosomal modifier locus [111], attempts to identify a modifier variant among 16 candidate genes, including some involved in inflammatory processes, had no success [15,112,113,114,115,116], as reviewed in [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Moser, 1992, Adrenoleukodystrophy: Phenotypic variability and implications for therapy, J. Iherited Metab. Dis. source

  • May combine two claims.

    Premisecitation

    ALDP is synthesized on free cytosolic ribosomes then targeted to peroxisomes via a Pex19p-dependent pathway, then inserted post-translationally into the peroxisomal membrane.

    “ALDP is synthesized on free cytosolic ribosomes then targeted to peroxisomes via a peroxisomal biogenesis factor-19 (Pex19p)-dependent pathway, then inserted post-translationally into the peroxisomal membrane [141].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Gloeckner, 2000, Human adrenoleukodystrophy protein and related peroxisomal ABC transporters interact with the peroxisomal assembly protein PEX19p, Biochem. Biophys. Res. Commun. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Unraveling putative environmental factors or variable epigenetic blueprints would require very large cohorts, currently out of reach.

    “Unraveling putative environmental factors or variable epigenetic blueprints would also require very large cohorts, currently out of reach.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Modifier genes are implicated in X-ALD phenotypic variability.

    “Therefore, the implication of “modifier genes” was suspected, as in all monogenic diseases with variable penetrance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    VLCFAs cannot enter mitochondria; therefore, mitochondria cannot β-oxidize them.

    “VLCFAs cannot enter mitochondria; therefore, mitochondria cannot β-oxidize them.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the CNP-Pex5 mouse brain, VLCFA accumulation is prominent in oligodendrocytes, notable in astrocytes, and non-existent in neurons.

    “In the 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP)-Pex5 mouse brain, VLCFA accumulation is prominent in OLs, notable in astrocytes, and non-existent in neurons [166].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Kassmann, 2007, Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes, Nat. Genet. source

  • May combine two claims.

    Premisecitation

    White matter areas appearing histologically intact in cALD also show VLCFA accumulation in PC and more limited VLCFA increases in CEs.

    “White matter areas appearing histologically intact also showed VLCFA accumulation in PC and more limited VLCFA increases in CEs.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [163] Theda, 1992, Phospholipids in X-linked adrenoleukodystrophy white matter: Fatty acid abnormalities before the onset of demyelination, J. Neurol. Sci. source
    • cites [164] Wilson, 1993, Lipid and fatty acid composition of brain tissue from adrenoleukodystrophy patients, J. Neurochem. source

  • May combine two claims.

    Premisecitation

    ALDP expression varies in other oligodendrocyte subpopulations, is weak in subcortical white matter, cerebellum, brainstem, and pons, and is absent in cerebral cortex or cerebellar neurons.

    “ALDP expression varied in other OL subpopulations, weak in subcortical white matter, cerebellum, brainstem, and pons, and absent in cerebral cortex or cerebellar neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Fouquet, 1997, Expression of the adrenoleukodystrophy protein in the human and mouse central nervous system, Neurobiol. Dis. source

  • May combine two claims.

    Premisecitation

    Drosophila abcd1 mutants have brain VLCFA accumulation, locomotor impairment, and other abnormalities.

    “Drosophila abcd1 mutants were found to have brain VLCFA accumulation, locomotor impairment, and other abnormalities [192].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Parsons, 2020, The Drosophila melanogaster as Genetic Model System to Dissect the Mechanisms of Disease that Lead to Neurodegeneration in Adrenoleukodystrophy, Peroxisome Biol. Exp. Models Peroxisomal Disord. Neurol. Dis. source

  • May combine two claims.

    Premisecitation

    The abcd1 mutation in zebrafish demonstrated a major and likely primary role of OLs, with VLCFA accumulation, altered myelination, increased apoptosis, abnormal OL patterning, cell death, early motor impairment, and shortened survival.

    “The abcd1 mutation in zebrafish demonstrated a major and likely primary role of OLs, with VLCFA accumulation, altered myelination, increased apoptosis, and abnormal OL patterning, cell death, early motor impairment, and shortened survival [191].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Strachan, 2017, A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination, Hum. Mol. Genet. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Myelin is composed of 35% cholesterol, 25% phospholipids, and 40% sphingolipids.

    “Myelin is composed of 35% cholesterol, 25% phospholipids, and 40% sphingolipids [210,211,212].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [210] Williams, 1993, The structure and function of central nervous system myelin, Crit. Rev. Clin. Lab. Sci. source
    • cites [211] Sampson, 1965, Fatty acid and fatty aldehyde composition of the major brain lipids in normal human gray matter, white matter, and myelin, J. Lipid Res. source
    • cites [212] Norton, 1973, Myelination in rat brain: Method of myelin isolation 1, J. Neurochem. source

  • May combine two claims.

    Interpretationreasoning

    Various impairments in peroxisomal VLCFA β-oxidation induce brain pathology in humans, and animal-model results must be interpreted with caution.

    “These findings indicate that various impairments in peroxisomal VLCFA β-oxidation induce brain pathology in humans, and that animal-model results must be interpreted with caution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Children with ACOX1 deficiency suffer devastating neonatal CNS disease, with VLCFA accumulation and early death.

    “In contrast, children with ACOX1 deficiency suffer devastating neonatal CNS disease, with VLCFA accumulation and early death [269], and dACOX1 mutant Drosophila have glial and axonal loss [270].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [269] Ferdinandusse, 2007, Clinical, biochemical, and mutational spectrum of peroxisomal acyl–coenzyme A oxidase deficiency, Hum. Mutat. source

  • May combine two claims.

    Premisecitation

    The brains of CNP-Pex5 mutant mice showed strong VLCFA accumulation in myelin, severe axonal loss, severely lower plasmalogen levels, and early microglial increase in white matter, followed by demyelination with characteristic regional variability and inflammation with infiltrating perivascular macrophages and B and T cells.

    “The brains of these mice showed strong VLCFA accumulation in myelin, severe axonal loss, severely lower plasmalogen levels, and early microglial increase in white matter, followed by demyelination with characteristic regional variability and inflammation with infiltrating perivascular macrophages and B and T cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Kassmann, 2007, Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes, Nat. Genet. source

  • May combine two claims.

    Premisecitation

    Hsd17b4-ablated mice displayed severe coordination problems and massive neuroinflammation, which was less severe but still present in mice lacking hsd17b4 specifically in neural cells (Nestin-Hsd17b4 mice).

    “These mice displayed severe coordination problems and massive neuroinflammation, which was less severe but still present in mice lacking hsd17b4 specifically in neural cells (Nestin-Hsd17b4 mice) [272].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [272] Verheijden, 2013, Peroxisomal multifunctional protein-2 deficiency causes neuroinflammation and degeneration of Purkinje cells independent of very long chain fatty acid accumulation, Neurobiol. Dis. source

  • May combine two claims.

    Study design and conductcitation

    Interpretation of neuron-targeting gene therapy results is hampered by the short-term design of these studies and by the fact that motor test performances were unexpectedly found comparable in 20-month-old untreated Abcd1−/− and wild type mice.

    “The interpretation of these results is also hampered by the short-term design of these studies, and by the fact that motor test performances were unexpectedly found comparable in 20-month-old untreated Abcd1−/− and wild type mice [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Gong, 2024, Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans, Ann. Neurol. source

  • May combine two claims.

    Interpretationreasoning

    This does not rule out, but questions, a contribution of these neurons to Abcd1−/− mouse pathology.

    “This does not rule out, but nevertheless questions, a contribution of these neurons to Abcd1−/− mouse pathology.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The principal mechanisms of axon degeneration are metabolic stress, disturbed axonal transport, and mitochondrial dysfunction.

    “The principal mechanisms of axon degeneration are metabolic stress, disturbed axonal transport, and mitochondrial dysfunction [301].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [301] Coleman, 2005, Axon degeneration mechanisms: Commonality amid diversity, Nat. Rev. Neurosci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia can change their lipid metabolism in response to the lipid flux that occurs when neurons and OL die in neurodegenerative contexts.

    “Microglia can change their lipid metabolism in response to the lipid flux that occurs when neurons and OL die in neurodegenerative contexts [339].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [339] Nugent, 2020, TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge, Neuron source

  • May combine two claims.

    Premisecitation

    Microglia have abundant peroxisome content and express abundant ALDP in normal microglia in human and mouse brains.

    “Their peroxisome content is abundant [166,253,315], and they express abundant ALDP in normal microglia in human and mouse brains [156].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [166] Kassmann, 2007, Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes, Nat. Genet. source
    • cites [253] Kassmann, 2014, Myelin peroxisomes–Essential organelles for the maintenance of white matter in the nervous system, Biochimie source
    • cites [315] Boda, 2021, Myelin and oligodendrocyte lineage cell dysfunctions: New players in the etiology and treatment of depression and stress-related disorders, Eur. J. Neurosci. source
    • cites [156] Fouquet, 1997, Expression of the adrenoleukodystrophy protein in the human and mouse central nervous system, Neurobiol. Dis. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia are different in the brain and spinal cord.

    “Microglia are different in the brain and spinal cord [334].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [334] Amor, 2022, White matter microglia heterogeneity in the CNS, Acta Neuropathol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Perivascular macrophages are located outside the parenchyma in the perivascular compartment surrounding arteries and veins as they penetrate into the brain parenchyma.

    “They are located outside the parenchyma in the perivascular compartment surrounding arteries and veins, as they penetrate into the brain parenchyma (reviewed in [365].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [365] Hiraga, 2024, Common principles of macrophage biology in blood–tissue barriers, Clin. Exp. Neuroimmunol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The normal protective role of microglia is disrupted in response to CNS damage, inducing microglia to proliferate as reactive microgliosis.

    “That normal protective role is disrupted in response to CNS damage, inducing microglia to proliferate as reactive “microgliosis” [309].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [309] Prinz, 2019, Microglia biology: One century of evolving concepts, Cell source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Normal microglia can suppress neuroinflammation and protect brain tissue by releasing anti-inflammatory mediators such as IL-10 and TGFβ.

    “Normal microglia can suppress neuroinflammation and protect brain tissue by releasing anti-inflammatory mediators, such as IL-10 and TGFβ (reviewed in [309]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [309] Prinz, 2019, Microglia biology: One century of evolving concepts, Cell source

  • May combine two claims.

    Interpretationreasoning

    Tissue regeneration and remyelination do not occur in cALD.

    “Those two processes do not occur in cALD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lipid-laden macrophages are a pathognomonic feature of peroxisomal disorders, likely due to the inability of these cells to fully degrade VLCFAs.

    “Lipid-laden macrophages are a pathognomonic feature of peroxisomal disorders [385,386], likely due to the inability of these cells to fully degrade VLCFAs.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [385] Depreter, 2003, Human peroxisomal disorders, Microsc. Res. Tech. source
    • cites [386] Gilchrist, 1976, Studies of malformation syndromes of man XIB: The cerebro-hepato-renal syndrome of Zellweger: Comparative pathology, Eur. J. Pediatr. source

  • May combine two claims.

    Premisecitation

    Myelin uptake directly affects macrophage function by inducing an anti-inflammatory polarization state, which promotes tissue regeneration and remyelination.

    “Myelin uptake directly affects macrophage function by inducing an anti-inflammatory polarization state, which promotes tissue regeneration and remyelination [324].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [324] Prinz, 2014, Microglia and brain macrophages in the molecular age: From origin to neuropsychiatric disease, Nat. Rev. Neurosci. source

  • May combine two claims.

    Interpretationreasoning

    ABCD1 deficiency leads to impaired macrophage plasticity and incomplete establishment of anti-inflammatory responses.

    “Thus, ABCD1 deficiency leads to impaired macrophage plasticity and incomplete establishment of anti-inflammatory responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Once on-site, monocytes differentiate into macrophages and, together with CNS-resident microglia, reinforce defense mechanisms to clear the damaged site by producing neurotoxic cytokines and reactive oxygen species, and by phagocytosing myelin debris.

    “Once on-site, monocytes differentiate into macrophages and, together with CNS-resident microglia, reinforce defense mechanisms to clear the damaged site by producing neurotoxic cytokines and reactive oxygen species, and by phagocytosing myelin debris.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Astrocytes are essential to neuron survival and function and are responsible for functions relevant to CNS homeostasis.

    “Astrocytes are essential to neuron survival and function, and they are responsible for a number of functions relevant to CNS homeostasis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Autopsy brain tissue from cALD patients suggested that the blood-brain barrier is compromised and can contribute to the invasion of circulating monocytes and lymphocytes into brain parenchyma.

    “The results of studying autopsy brain tissue from cALD patients suggested that the BBB is compromised [417] and can contribute to the invasion of circulating monocytes and lymphocytes into brain parenchyma.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [417] Musolino, 2015, Brain endothelial dysfunction in cerebral adrenoleukodystrophy, Brain source

  • May combine two claims.

    Interpretationreasoning

    The imported macrophage population slowly declines and may no longer ensure efficient phagocytosis.

    “It is probable that the imported macrophage population, which has a limited lifespan, slowly declines and may no longer ensure efficient phagocytosis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The imported macrophage population has a limited lifespan.

  • May combine two claims.

    Interpretationreasoning

    HSCs either could not engraft in the spinal cord white matter or, more likely, microglia pathology and HSC replacement are not involved in AMN pathogenesis.

    “indicates that HSCs either could not engraft in the spinal cord white matter or, more likely, that microglia pathology and HSC replacement are not involved in AMN pathogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    HSCs provided vascular elements to the cerebral microvasculature and restored microvascular function in brain white matter.

    “Those observations suggested that HSCs provided vascular elements to the cerebral microvasculature and restored the microvascular function in brain white matter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Oligodendrocytes, by far the main VLCFA producers, accumulate most VLCFAs because they are unable to degrade them and use them to synthesize toxic lipids, such as S1P.

    “OLs, by far the main VLCFA producers, accumulate most of them, because they are unable to degrade them and use them to synthesize toxic lipids, such as S1P.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Over time, chronic accumulation is thought to trigger apoptosis and adrenal cortex shrinkage, leading to markedly decreased cortisol production.

    “Over time, this chronic accumulation is thought to trigger apoptosis and adrenal cortex shrinkage, leading to markedly decreased cortisol production [423].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [423] Powers, 1980, A correlative study of the adrenal cortex in adreno-leukodystrophy--evidence for a fatal intoxication with very long chain saturated fatty acids, Investig. Cell Pathol.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Axon dysfunction slowly worsens in the CNS, reaching its maximum in the long axons of the spinal cord tracts, which leads to progressive manifestations in patients' legs.

    “Axon dysfunction slowly worsens in the CNS, reaching its maximum in the long axons of the spinal cord tracts, which leads to progressive manifestations in patients’ legs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    HSC transplantation to cALD patients does not restore adrenal steroidogenesis; thus, grafted patients with pre-existing adrenal insufficiency must continue cortisol supplementation post-transplantation.

    “HSC transplantation to cALD patients does not restore adrenal steroidogenesis; thus, grafted patients with pre-existing adrenal insufficiency must continue cortisol supplementation post-transplantation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cultured fibroblasts from X-ALD patients are not representative of neurons or glial cells and therefore could only provide limited biochemical insights into pathogenesis.

    “Although useful for the study of biochemical defects, these cells are not representative of neurons or glial cells and therefore could only provide limited biochemical insights into pathogenesis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    cALD occurrence and subacute course are seen as an accident of yet unknown causality in the otherwise progressive evolution of X-ALD towards AMN.

    “We see its occurrence and subacute course as an “accident” of yet unknown causality in the otherwise progressive evolution of X-ALD towards AMN.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: cALD occurs in a still unpredictable subset of ABCD1-mutated patients, most often children, and rarely adolescents or young adults.

  • May combine two claims.

    Interpretationreasoning

    Abnormal myelin composition may progressively impair signal propagation in axons and decrease the supply of fuels, thereby impairing axonal oxidative metabolism and transport.

    “The abnormal myelin composition may progressively impair signal propagation in axons and decrease the supply of fuels, thereby impairing axonal oxidative metabolism and transport.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Soon, microglia, resident macrophages, and astrocytes become the actors of a stochastic perfect storm.

    “Soon, microglia, resident macrophages, and astrocytes become the actors of a stochastic “perfect storm”.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cholesterol, along with saturated VLCFAs, accumulates in the fasciculata and reticularis zonae, which are responsible for the production of cortisol and androgens, respectively.

    “Cholesterol, along with saturated VLCFAs, accumulates in the fasciculata and reticularis zonae, which are responsible for the production of cortisol and androgens, respectively [423].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [423] Powers, 1980, A correlative study of the adrenal cortex in adreno-leukodystrophy--evidence for a fatal intoxication with very long chain saturated fatty acids, Investig. Cell Pathol.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At the highest dose, leriglitazone reduced axonal degeneration and microglia activation in the white matter of the spinal cord and improved motor performance of Abcd1:Abcd2 double KO mice.

    “At the highest dose, leriglitazone reduced axonal degeneration and microglia activation in the white matter of the spinal cord. Moreover, leriglitazone was able to improve the motor performance of the mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [456] Vilalta, 2021, The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy, Sci. Transl. Med. source

  • May combine two claims.

    Premisecitation

    In core gliotic areas, microglia seem to return to their normal distribution and re-express the homeostatic markers that were previously lost.

    “In core gliotic areas, microglia seem to mysteriously return to their normal distribution and re-express the homeostatic markers that were previously lost [353].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [353] Eichler, 2008, Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?, Ann. Neurol. source

  • May combine two claims.

    Interpretationreasoning

    Several factors can explain the absence of critical neuroinflammation in the CNS in AMN: limited axon degeneration, no severe peroxisomal dysfunction in oligodendrocytes and other glial cells, only mildly perturbed redox state, and preserved homeostatic neuroprotective functions of microglia, resident macrophages, and astrocytes that may be resilient to inflammatory signals.

    “Several factors can explain the absence of critical neuroinflammation in the CNS: limited axon degeneration, no severe peroxisomal dysfunction in OLs and other glial cells, only mildly perturbed redox state, and preserved homeostatic neuroprotective functions of microglia, resident macrophages, and astrocytes that may be resilient to inflammatory signals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In the Abcd1-/- mouse, a short-lived species, spinal cord axons have a shorter length than humans and are exposed to deleterious mechanisms during less than 3 years; thus, 1.5 to 2 year-old mice are expected to show only limited motor deficits.

    “In the Abcd1−/− mouse, a short-lived species, spinal cord axons have a shorter length than humans and are exposed to deleterious mechanisms during less than 3 years. It is thus expected that 1.5 to 2 year-old-mice only show limited motor deficits.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Brain axon degeneration may induce clinical manifestations before MRI can be used to visualize demyelination.

    “Brain axon degeneration may induce clinical manifestations before MRI can be used to visualize demyelination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    X-ALD pathogenesis seems to be governed by two major mechanisms acting primarily in oligodendrocytes: VLCFA accumulation, which causes AMN and is cALD permissive, and a secondary peroxisomal pathology, suggested to be a necessary added mechanism of cALD.

    “X-ALD pathogenesis seems to be governed by two major mechanisms acting primarily in OLs: VLCFA accumulation, which causes AMN and is cALD permissive, and a secondary peroxisomal pathology, suggested to be a necessary added mechanism of cALD [166].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Kassmann, 2007, Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes, Nat. Genet. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Decreased plasmalogens may contribute to cALD neuroinflammation.

    “Decreased plasmalogens may contribute.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Intrinsic accumulation of VLCFAs may weaken the proper neuroprotective capacities of microglia and astrocytes, generating pro-inflammatory signals.

    “Possibly, the intrinsic accumulation of VLCFAs may weaken the proper neuroprotective capacities of microglia and astrocytes, generating pro-inflammatory signals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    AMN is the unavoidable adult phenotype of X-ALD, characterized by a spinal cord pathology progressing from childhood to adulthood and only interrupted by death in cALD patients.

    “We see it as the unavoidable adult phenotype of X-ALD, characterized by a spinal cord pathology progressing from childhood to adulthood and only interrupted by death in cALD patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    PET ligands bind to receptors whose expression is related to the activation of microglia (TSPO ligands) and astrocytes (MAO-B, upregulated in activated astrocytes, and TSPO ligands).

    “Indeed, these ligands bind to receptors whose expression is related to the activation of microglia (TSPO ligands) and astrocytes (PET tracers targeting monoamine oxidase B (MAO-B), which is upregulated in activated astrocytes and TSPO ligands).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Type-2 imidazoline receptors (I2Rs) are common targets developed for the detection of astrocytosis using PET.

    “Other common targets developed for the detection of astrocytosis using PET are the type-2 imidazoline receptors (I2Rs).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Removal of primary microglia and astrocytes from the brain and further in vitro culture may skew these cells towards a more pro-inflammatory state that could affect subsequent experimental procedures.

    “However, since microglia and astrocytes are highly responsive to their environment, removal of primary cells from the brain and further in vitro culture may skew these cells towards a more pro-inflammatory state that could affect subsequent experimental procedures.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Microglia and astrocytes are highly responsive to their environment.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    If one studies CNS postmortem specimens, he can only analyze advanced stages of the two disease forms, be it cALD brain or AMN spinal cord.

    “If he studies CNS postmortem specimens, he can only analyze advanced stages of the two disease forms, be it cALD brain or AMN spinal cord.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    If one derives iPSCs from patients' fibroblasts, he could obtain information on gene expression in an artificially differentiated cell type outside of its spatiotemporal context.

    “If one derives iPSCs from patients’ fibroblasts, he could obtain information on gene expression in an artificially differentiated cell type outside of its spatiotemporal context.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Better cellular specificity might be achieved by measuring the diffusion of cell-specific endogenous metabolites with magnetic resonance spectroscopy.

    “However, better cellular specificity might be achieved by measuring the diffusion of cell-specific endogenous metabolites with magnetic resonance spectroscopy [511,512,513].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [511] Ligneul, 2019, Diffusion-weighted magnetic resonance spectroscopy enables cell-specific monitoring of astrocyte reactivity in vivo, NeuroImage source
    • cites [512] Genovese, G., Palombo, M., Santin, M.D., Valette, J., Ligneul, C., Aigrot, M.S., Abdoulkader, N., Langui, D., Millecamps, A., and Baron-Van Evercooren, A. (2021). Inflammation-driven glial alterations in the cuprizone mouse model probed with diffusion-weighted magnetic resonance spectroscopy at 11.7 T. NMR Biomed., 34. source
    • cites [513] Ronen, 2022, Diffusion-weighted MR spectroscopy (DW-MRS) is sensitive to LPS-induced changes in human glial morphometry: A preliminary study, Brain Behav. Immun. source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The limited incidence of X-ALD precludes hope of applying new cellular and molecular technologies to several dozen patients, as for Parkinson's or Alzheimer's disease, unless international repositories of iPSCs and postmortem samples are established and span many years.

    “The limited incidence of X-ALD precludes hope of applying new cellular and molecular technologies to several dozen patients, as for Parkinson’s or Alzheimer’s disease, unless international repositories of iPSCs and postmortem samples are established and span many years.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Accidental environmental factors, such as head trauma or viral infections, may be key pathogenic mechanisms and should not be neglected by cALD researchers.

    “Accidental environmental factors, such as head trauma or viral infections, may be key pathogenic mechanisms and should not be neglected by cALD researchers.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    MRI has been less utilized than PET to assess gliosis due to its lack of cell specificity.

    “MRI has been less utilized than PET to assess gliosis due to its lack of cell specificity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Specialized MRI techniques can measure the diffusion of water within tissue and highlight areas of gliosis, where water diffusion is affected by alterations in cell morphology during neuroinflammation.

    “Specialized MRI techniques can measure the diffusion of water within tissue and highlight areas of gliosis, where water diffusion is affected by alterations in cell morphology during neuroinflammation.”
    Quote in the paperNot a substantial claim
180 of 180

  • The paper relies on this without support.

    Findings from mouse and Drosophila models of X-ALD are informative about human X-ALD pathogenesis.

    “This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis.”

  • The paper relies on this without support.

    Terminal-stage postmortem CNS lesions in X-ALD patients reflect the disease mechanisms that lead to cALD or AMN.

    “The only data we have come from ten adult male patients who were autopsied ten to twenty years after diagnosis at terminal stages of AMN disease [16,18,20,21,30,49,82,83], who showed spinal cord atrophy.”

  • The paper relies on this without support.

    VLCFAs make up only 5% of the total body fatty acids.

    “Because VLCFAs are rare fatty acids (FAs) that make up only 5% of the total body FAs, their rich content of normal myelin is remarkable.”

  • The paper relies on this without support.

    The individual variation in motor phenotype among Abcd1−/− mice cannot be explained by genetic or environmental factors in congenic littermates living in the same cage.

    “This individual variation cannot be explained by genetic or environmental factors in congenic littermates living in the same cage.”

  • The paper relies on this without support.

    The positive results of HSC transplantation were due to donor monocyte-derived macrophages that could migrate to the brain and limit inflammation when resident microglia are overwhelmed.

    “In fact, it is now known that the positive results of HSC transplantation were due to donor monocyte-derived macrophages that could migrate to the brain and limit inflammation when resident microglia are overwhelmed.”

  • The paper relies on this without support.

    The imported macrophage population has a limited lifespan.

    “It is probable that the imported macrophage population, which has a limited lifespan, slowly declines and may no longer ensure efficient phagocytosis.”

  • The paper relies on this without support.

    Oligodendrocytes do not remyelinate the demyelinated brain areas.

    “OLs do not remyelinate the demyelinated brain areas.”

  • The paper relies on this without support.

    cALD occurs in a still unpredictable subset of ABCD1-mutated patients, most often children, and rarely adolescents or young adults.

    “cALD occurs in a still unpredictable subset of ABCD1-mutated patients, most often children; rarely adolescents or young adults.”

  • The paper relies on this without support.

    Neurons do not oxidize VLCFAs.

    “neurons do not oxidize VLCFAs”

  • The paper relies on this without support.

    Microglia and astrocytes are highly responsive to their environment.

    “since microglia and astrocytes are highly responsive to their environment”

  • The paper relies on this without support.

    iPSC models often resemble a fetal state rather than an adult state.

    “primarily, these iPSC models often resemble a fetal state rather than an adult state, which is a key difference from the intended application of these models.”

  • The paper relies on this without support.

    Systematic research of modifier gene variants using blind whole-genome research requires thousands of patients.

    “Systematic research of modifier gene variants using blind whole-genome research requires thousands of patients.”

  • The paper relies on this without support.

    Blind environmental studies that would prospectively investigate the first years of life of patients screened at birth will also require thousands of patients.

    “Blind environmental studies that would prospectively investigate the first years of life of patients screened at birth will also require thousands of patients.”
13 of 13

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.

  • Leriglitazone described as tested only in cALD despite a cited AMN trial

    Minor

    The text says leriglitazone has only been tested in patients with cALD, yet it cites a randomized trial whose title explicitly identifies participants as men with adrenomyeloneuropathy.

  • Conflicting locations for the typical onset of cALD demyelination

    Minor

    The imaging section says early demyelinating lesions are generally localized in the splenium of the corpus callosum, but the cALD pathophysiology section says demyelination typically starts in the genu.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D. (2001). X-linked adrenoleukodystrophy. The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill.
  2. Bezman, 2001, Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy, Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc., 49, 186
  3. Springer (2005). Magnetic Resonance of Myelination and Myelin Disorders, Springer Science & Business Media. [3rd ed.].
  4. Powers, 1974, A pathogenetic hypothesis based on ultrastructural lesions in adrenal cortex, peripheral nerve and testis, Am. J. Pathol., 76, 481

Cited by

Sorted by citations

Related

Authors
Bougnères, P., & Le Stunff, C.
Affiliations
MIRCen Institute, Commissariat à l’Energie Atomique, Laboratoire des Maladies Neurodégénératives, 92260 Fontenay-aux-Roses, France
Venue
Genes
Publisher
MDPI AG
Published
2025-05-17
Volume
16
Issue
5
Pages
590
ISSN
2073-4425 (ISSN-L)
DOI
10.3390/genes16050590
PMC
PMC12111468
OpenAlex
W4410524994
Cited by
11
References
515
Citations by year
2026: 8 · 2025: 3
FWCI
5.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Genes (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
Funders
GETDOC (Groupe d’Etude et de Thérapeutique pour le Diabète, l’Obésité, la Croissance) Association (24/25-01)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
X-linked adrenoleukodystrophy, ABCD1 gene, very long chain fatty acids, peroxisome biogenesis, oligodendrocytes, axonopathy, demyelination, microglial neuroinflammation, Drosophila model, lipotoxicity
MeSH terms
ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Animals, Disease Models, Animal, Drosophila, Fatty Acids, Humans, Mutation, Oligodendroglia, Mice, Knockout, Peroxisomes, Mice

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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

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