Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy

In the paper

“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].”

What the sources say

• Disputed

  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.

  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. sourceExperimental — accuracy not yet measured
• Supported

  The Results (§3.4) estimate U.S. X-ALD incidence at about 1 in 10,500 live births from newborn-screening data across seven states. The Discussion says screening has taken place since 2013 and that the aggregate estimate is higher than the previous estimate of 1 in 17,000 births. The claim’s ~1 in 10,000 is a reasonable approximation. (LLM, conf=0.93)

  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
• Not checked yetcites [15] Wiesinger, 2015, The genetic landscape of X-linked adrenoleukodystrophy: Inheritance, mutations, modifier genes, and diagnosis, Appl. Clin. Genet.

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [49] Powers, 2000, Adrenomyeloneuropathy: A neuropathologic review featuring its noninflammatory myelopathy, J. Neuropathol. Exp. Neurol. source
• Partly supported

  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)

  cites [50] Corre, 2021, Beyond gait and balance: Urinary and bowel dysfunction in X-linked adrenoleukodystrophy, Orphanet J. Rare Dis. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction describes AMN as slowly progressive spastic paraparesis with sensory disturbances, and the Discussion reports that lower urinary tract symptoms are common. Neither section establishes that loss of sensation precedes a spastic gait or documents a positive Babinski reflex, ataxia, leg pain, or impotence. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [52] Silveri, 2004, Voiding dysfunction in X-linked adrenoleukodystrophy: Symptom score and urodynamic findings, J. Urol. source

In the paper

“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.”

What the sources say

• Not checked yetcites [30] Powers, 1985, Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex), Clin. Neuropathol.
• Partly supported

  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)

  cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. sourceExperimental — accuracy not yet measured

In the paper

“Anecdotical cases of head trauma precipitating cALD have been reported with inflammatory demyelination beginning at the site of the contusion [43,44,45,46].”

What the sources say

• ?Not checked — no full text of the sourcecites [43] Bouquet, 2015, Dramatic worsening of adult-onset X-linked adrenoleukodystrophy after head trauma, Neurology source
• ?Not checked — no full text of the sourcecites [44] Weller, 1992, Very-late-onset adrenoleukodystrophy: Possible precipitation of demyelination by cerebral contusion, Neurology source
• ?Not checked — no full text of the sourcecites [45] Raymond, 2010, Head trauma can initiate the onset of adreno-leukodystrophy, J. Neurol. Sci. source
• Partly supported

  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)

  cites [46] Budhram, 2017, Activation of cerebral X-linked adrenoleukodystrophy after head trauma, Can. J. Neurol. Sci. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. sourceExperimental — accuracy not yet measured
• Not checked yetcites [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 — no full text of the sourcecites [59] Moser, 1984, Adrenoleukodystrophy: Clinical and biochemical manifestations in carriers, Neurology source
• Partly supported

  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)

  cites [60] Huffnagel, 2019, Disease progression in women with X-linked adrenoleukodystrophy is slow, Orphanet J. Rare Dis. sourceExperimental — accuracy not yet measured
• Not checked yetcites [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 — no full text of the sourcecites [62] Maier, 2002, Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation, Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc. source
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [19] Powell, 1975, Adrenoleukodystrophy: Electron microscopic findings, Arch. Neurol. source
• ?Could not verify

  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)

  cites [81] Budka, 2023, A historical look using virtual microscopy: The first case report of adrenomyeloneuropathy (AMN), Free Neuropathol. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Supported

  The “Cerebral ALD” section states that in 80% of patients the initial lesion is in the splenium of the corpus callosum and progresses into adjacent parieto-occipital white matter. The “Clinical management” section recommends MRI screening to detect early abnormalities, including limited changes in the splenium. Page numbers are not provided in our copy. (LLM, conf=0.94)

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

  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)

  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. sourceExperimental — accuracy not yet measured
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [91] Liberato, 2019, MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy, Neurology source
• Partly supported

  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)

  cites [92] Kemp, 2001, ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations, Hum. Mutat. sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  Section 2.4 reports the ABCD1 database’s previous count: 948 unique (likely) pathogenic variants as of December 2021. In the citing sentence, [100] is attached to “the previous counts”; the authors say they themselves updated those counts and found the May 2025 figures. The 172 and 825 figures are therefore not attributed to this source. (LLM, conf=0.88)

  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

In the paper

“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.”

What the sources say

• Supported

  The Cerebral ALD section describes demyelinating lesions that progress from the corpus callosum into parieto-occipital or frontal white matter, as well as lesions involving the pyramidal tracts. It reports increased T2 signal in the listed regions. The Differential diagnosis section also describes confluent white-matter changes with increased T2 signal. (LLM, conf=0.90)

  cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. source
• ?Not checked — no full text of the sourcecites [93] Pasco, 1991, Contribution of MRI to the diagnosis of cerebral lesions of adrenoleukodystrophy, Pediatr. Radiol. source
• ?Not checked — no full text of the sourcecites [94] Loes, 2003, Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy, Neurology source

In the paper

“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].”

What the sources say

• Supported

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

  cites [31] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J. Rare Dis. source
• ?Not checked — no full text of the sourcecites [93] Pasco, 1991, Contribution of MRI to the diagnosis of cerebral lesions of adrenoleukodystrophy, Pediatr. Radiol. source
• ?Not checked — no full text of the sourcecites [94] Loes, 2003, Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy, Neurology source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [150] McGuinness, 2001, Evaluation of pharmacological induction of fatty acid β-oxidation in X-linked Adrenoleukodystrophy, Mol. Genet. Metab. source
• Supported

  This source is cited for the residual β-oxidation figure, not for the separate overexpression claim, which has its own citations. Table 1 reports that X-ALD fibroblasts formed D₃-C16:0 at 15% of the control amount; the paper identifies this measure as an indicator of peroxisomal β-oxidation activity. That supports the citing sentence’s approximate figure of 20%. (LLM, conf=0.88)

  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
• ?Not checked — no full text of the sourcecites [152] Netik, 1999, Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): Implications for therapy, Hum. Mol. Genet. source
• ?Not checked — no full text of the sourcecites [153] Kemp, 1998, Gene redundancy and pharmacological gene therapy: Implications for X-linked adrenoleukodystrophy, Nat. Med. source

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [136] Singh, 2010, Pathomechanisms underlying X-adrenoleukodystrophy: A three-hit hypothesis, Brain Pathol. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [147] Kemp, 2011, Mammalian peroxisomal ABC transporters: From endogenous substrates to pathology and clinical significance, Br. J. Pharmacol. source
• Supported

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

  cites [148] Chen, 2022, Structural basis of substrate recognition and translocation by human very long-chain fatty acid transporter ABCD1, Nat. Commun. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [149] Wanders, 2023, The physiological functions of human peroxisomes, Physiol. Rev. source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [117] Semmler, 2009, Genetic variants of methionine metabolism and X-ALD phenotype generation: Results of a new study sample, J. Neurol. source
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The citation is attached to the claim that influenza may enter the brain through several routes, not to the later claims about sensory neurons or chronic CNS changes. The Discussion (page unavailable) says that routes of CNS invasion have long been debated, discusses hematogenous spread, and reports viral antigen in the brains of both intravenously and intranasally inoculated mice. (LLM, conf=0.86)

  cites [122] Kitamura, 2024, Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy, Acta Neuropathol. source
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Supported

  Citation [124] is attached to the claim that influenza sends signals to the brain via sensory neurons, not to the separate claims about viral entry or chronic CNS changes. The Abstract and Discussion describe influenza-induced prostaglandin signals detected by peripheral sensory neurons and conveyed to the brain, where they mediate sickness responses. (LLM, conf=0.90)

  cites [124] Bin, 2023, An airway-to-brain sensory pathway mediates influenza-induced sickness, Nature source
• Supported

  Citation [125] is attached to the claim that influenza infection may trigger neuroinflammation and chronic CNS alterations, not to the preceding claims about routes of entry or sensory neurons. The Discussion reports that neuroinflammation following influenza infection produced long-lasting changes in hippocampal neurons, synapses, and cognitive function in adult animals. (LLM, conf=0.91)

  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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [127] Meinhardt, 2024, The neurobiology of SARS-CoV-2 infection, Nat. Rev. Neurosci. source
• Supported

  The citation to this paper is attached to the immune-mediated explanation, not to the separate claims about neuroinvasion or glial neuroinflammation. The Main section explicitly hypothesizes that COVID-19’s impact on the brain may occur through immune-mediated para- and postinfectious phenomena. (LLM, conf=0.94)

  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
• Supported

  The Introduction says indirect effects of SARS-CoV-2, including a dysregulated immune response, are hypothesised to cause neurological complications. The Discussion likewise says many complications involve neuroinflammation driven by inflammatory responses rather than direct infection. This citation [126] supports the immune-mediated part of the sentence; the neuroinvasion and glial claims have separate citations. (LLM, conf=0.93)

  cites [128] Dunai, C., Collie, C., and Michael, B.D. (2022). Immune-mediated mechanisms of COVID-19 neuropathology. Front. Neurol., 13. source
• Supported

  The citation is attached to the claim that COVID-19’s impact on the brain might be immune-mediated, not to the separate claims about neuroinvasion or glial neuroinflammation. The Discussion says brain injury during acute COVID-19 may result from dysregulated host responses and describes inflammatory mechanisms that may drive neurological injury. (LLM, conf=0.93)

  cites [129] Needham, 2022, Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses, Brain source
• Supported

  The citation to this paper [126] supports the immune-mediated part of the sentence, not the separate claims about rare neuroinvasion or glial neuroinflammation. In the Discussion (page not provided), the authors say brain changes are not solely attributable to direct infection and likely reflect a response to peripheral infection involving immune activity. (LLM, conf=0.92)

  cites [130] Zhang, 2024, Brain-wide alterations revealed by spatial transcriptomics and proteomics in COVID-19 infection, Nat. Aging source

In the paper

“All of these metabolites must be transferred into mitochondria for full β-oxidation into CO2 and H2O because peroxisomes lack a Krebs’ cycle [162].”

What the sources say

• Supported

  The Introduction states that chain-shortened acyl-CoAs produced in peroxisomes can be fully oxidized to CO2 and H2O only in mitochondria, which contain the Krebs cycle. The fatty acid beta-oxidation section also says that peroxisomal products must be transferred to mitochondria for full oxidation. (LLM, conf=0.93)

  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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [143] Visser, 2008, The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl–CoA esters, FASEB J. source
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [160] Theodoulou, 2016, How to move an amphipathic molecule across a lipid bilayer: Different mechanisms for different ABC transporters?, Biochem. Soc. Trans. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [161] Wanders, 2001, Peroxisomal fatty acid α-and β-oxidation in humans: Enzymology, peroxisomal metabolite transporters and peroxisomal diseases, Biochem. Soc. Trans. source

In the paper

“These mutant flies had fewer peroxisomes, demonstrating an ABCD1 role in peroxisomal biogenesis [194].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“Loss of the pmp-4 gene, the Caenorhabditis elegans ortholog of ABCD1, induces VLCFA accumulation, axonal degeneration, and locomotor dysfunction [195].”

What the sources say

• Supported

  The Results section identifies pmp-4 as the C. elegans orthologue of ABCD1 and reports elevated VLCFAs, reduced motility, and significant axonal damage in pmp-4(ok396) loss-of-function mutants. The Discussion explicitly summarizes VLCFA accumulation, axonal degeneration, and associated locomotor dysfunction in pmp-4-deficient worms. (LLM, conf=0.95)

  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

In the paper

“OL peroxisomes are largely responsible for VLCFA synthesis [204] and degradation [166] in the adult brain.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [166] Kassmann, 2007, Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes, Nat. Genet. source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [190] Pujol, 2004, Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: A therapeutic target for X-adrenoleukodystrophy, Hum. Mol. Genet. sourceExperimental — accuracy not yet measured
• Supported

  The Behavioral deficits section reports more severe motor impairment in double mutants, including six of 11 unable to complete the balance-bar test at 20 months. The Biochemical function section says double mutants had earlier, more severe pathological signs; its account of axonal and myelin changes, together with the Discussion’s report of no detectable cerebral-cortex abnormalities, supports the remaining claims. The paper does report cerebellar pathology, which is distinct from cerebral-cortex pathology. (LLM, conf=0.87)

  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

In the paper

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

What the sources say

• Partly supported

  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)

  cites [190] Pujol, 2004, Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: A therapeutic target for X-adrenoleukodystrophy, Hum. Mol. Genet. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly supported

  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)

  cites [190] Pujol, 2004, Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: A therapeutic target for X-adrenoleukodystrophy, Hum. Mol. Genet. sourceExperimental — accuracy not yet measured
• Supported

  The “Behavioral deficits in ALDRP-deficient mice” section reports marked impairment on the rotarod in Abcd2-null mice at 12 months compared with wild-type littermates. It also states that their performance was even more impaired when tested again around 20 months. (LLM, conf=0.95)

  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

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [190] Pujol, 2004, Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: A therapeutic target for X-adrenoleukodystrophy, Hum. Mol. Genet. sourceExperimental — accuracy not yet measured
• Supported

  The 'Biochemical function of ALDRP' passages report that histological abnormalities in the dorsal and ventral spinal cord columns of Abcd2-deficient mice were not demonstrable at 12 months but became evident at 20 months. The same section reports that cerebellar staining confirmed atrophy or death of Purkinje cells at 20 months. (LLM, conf=0.94)

  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

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [273] Chung, 2023, Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation, Cell Metab. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [284] Harris, 2012, The energetics of CNS white matter, J. Neurosci. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [278] Asadollahi, 2024, Oligodendroglial fatty acid metabolism as a central nervous system energy reserve, Nat. Neurosci. sourceExperimental — accuracy not yet measured

In the paper

“When glucose availability is scarce, myelin synthesis declines and FA-derived acetyl-CoA supports mitochondrial respiration and OL survival [278].”

What the sources say

• Supported

  The Results section (‘Oligodendrocyte lipid metabolism supports axonal function in starved optic nerves’) states that, when glucose availability is reduced in the GLUT1 icKO mouse model, myelin synthesis drops and FA-derived acetyl-CoA supports mitochondrial respiration and oligodendroglial survival. This directly supports the paraphrase within the paper’s modeled condition. (LLM, conf=0.94)

  cites [278] Asadollahi, 2024, Oligodendroglial fatty acid metabolism as a central nervous system energy reserve, Nat. Neurosci. source

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [273] Chung, 2023, Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation, Cell Metab. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  In the C24 VLCFAs in Sphingolipids section, the paper reports defects in myelin-sheath stability when C22–C24 myelin lipids are nearly absent. The 2-Hydroxylated VLCFAs in the Myelin section also identifies these lipids as important for myelin maintenance. These passages support the myelin-function and maintenance points for which this source is cited; the other points in the sentence have different citations. (LLM, conf=0.90)

  cites [213] Sassa, T., and Kihara, A. (2014). Metabolism of very long-chain fatty acids: Genes and pathophysiology. Biomol. Ther., 22. source
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [217] Simons, 1997, Functional rafts in cell membranes, Nature source

In the paper

“Acox1-KO mice accumulate VLCFAs in their brains but have neither axonal loss [267] nor any neurodegenerative phenotype [268].”

What the sources say

• Partly supported

  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)

  cites [267] Fan, 1996, Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Could not verify

  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)

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  cites [308] Tan, 2020, Microglial regional heterogeneity and its role in the brain, Mol. Psychiatry sourceExperimental — accuracy not yet measured

In the paper

“Microglia live 0.5–3.4 years in the mouse brain [313] and up to 20 years in the human brain [314].”

What the sources say

• ?Not checked — no full text of the sourcecites [313] Hefendehl, 2017, Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging, Nat. Neurosci. source
• Supported

  Citation [314] is attached only to the human-brain lifespan claim, not the mouse figure. The Results report that some human microglia can be more than 20 years old, supporting the claim that they can live 20 years; the paper does not present 20 years as a strict maximum. (LLM, conf=0.91)

  cites [314] Khosravi, 2017, The lifespan and turnover of microglia in the human brain, Cell Rep. source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [251] Ahlemeyer, 2007, Differential expression of peroxisomal matrix and membrane proteins during postnatal development of mouse brain, J. Comp. Neurol. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [253] Kassmann, 2014, Myelin peroxisomes–Essential organelles for the maintenance of white matter in the nervous system, Biochimie source
• ?Not checked — no full text of the sourcecites [254] Kassmann, 2011, A role for myelin-associated peroxisomes in maintaining paranodal loops and axonal integrity, FEBS Lett. source
• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  cites [292] Toncheva, 2021, Regulation of peroxisomal trafficking and distribution, Cell. Mol. Life Sci. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“Microglia can change their lipid metabolism in response to the lipid flux that occurs when neurons and OL die in neurodegenerative contexts [339].”

What the sources say

• Partly supported

  The Summary and Discussion report that microglia alter cholesterol transport and metabolism during chronic exposure to myelin debris, supporting a response to lipid material from oligodendrocyte-associated myelin. The paper does not establish that lipid flux from dying neurons drives this response; the Summary instead describes neuronal damage as an outcome. (LLM, conf=0.85)

  cites [339] Nugent, 2020, TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge, Neuron sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“Their peroxisome content is abundant [166,253,315], and they express abundant ALDP in normal microglia in human and mouse brains [156].”

What the sources say

• ?Not checked — no full text of the sourcecites [166] Kassmann, 2007, Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes, Nat. Genet. source
• ?Could not verify

  The citation to this paper is attached to the claim that normal human and mouse microglia express abundant ALDP. Section 2.1 reports peroxisomes in microglial processes, and Section 3 discusses a role for microglial peroxisomes, but neither reports ALDP expression in normal microglia. Searches for ALDP and microglial expression found no passage addressing that claim. (LLM, conf=0.72)

  cites [253] Kassmann, 2014, Myelin peroxisomes–Essential organelles for the maintenance of white matter in the nervous system, Biochimie sourceExperimental — accuracy not yet measured
• ?Could not verify

  The citation to this paper is attached to the claim about abundant ALDP expression in normal human and mouse microglia; the preceding peroxisome-content claim has different citations. The ‘Myelin and oligodendroglia alterations’ section discusses activated microglia and oxidative stress, but searches for ALDP, peroxisomes, and normal human and mouse microglia found no passage addressing that expression claim. No page number was available for the indexed passages. (LLM, conf=0.75)

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [156] Fouquet, 1997, Expression of the adrenoleukodystrophy protein in the human and mouse central nervous system, Neurobiol. Dis. source

In the paper

“If this occurs during aging or disease states, axonal degeneration boosts microglial phagocytosis [328].”

What the sources say

• ?Could not verify

  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)

  cites [328] Sierra, 2010, Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis, Cell Stem Cell sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [329] Safaiyan, 2016, Age-related myelin degradation burdens the clearance function of microglia during aging, Nat. Neurosci. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [330] Safaiyan, 2021, White matter aging drives microglial diversity, Neuron source

In the paper

“The turnover half-time of resident macrophages averages 150 days [317].”

What the sources say

• Partly supported

  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)

  cites [317] Diebold, 2024, Advances in understanding the immunity of the brain and its borders: Focus on brain macrophages, Clin. Transl. Med. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  In “Microglia as Integrative Hubs for External and Local Signals” (page not provided), the paper says microglia engulf apoptotic cells and that their phagocytosis is very efficient under physiological conditions. It does not support constant, highly efficient clearance in disease: the same section says epileptic seizures can hinder detection and removal of apoptotic cells. (LLM, conf=0.87)

  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. sourceExperimental — accuracy not yet measured
• Supported

  The Definition of phagocytosis section reports rapid clearance of dead cells by microglia and describes their prompt elimination of cell debris. The section on apoptotic cells during development and in neurogenic niches reports high phagocytic efficiency, while Digest-me describes phagocytosis as essential to brain tissue homeostasis. (LLM, conf=0.91)

  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
• ?Not checked — no full text of the sourcecites [326] Hammond, 2018, Microglia and the brain: Complementary partners in development and disease, Annu. Rev. Cell Dev. Biol. source
• Partly supported

  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)

  cites [327] Bohlen, 2019, Microglia in brain development, homeostasis, and neurodegeneration, Annu. Rev. Genet. sourceExperimental — accuracy not yet measured

In the paper

“Aged microglia also become more responsive to pro-inflammatory stimuli (“microglial priming”) (reviewed in [331]).”

What the sources say

• Supported

  Section 7, “Microglia Priming,” directly states that aged microglia become more responsive to proinflammatory stimuli and calls this process microglia priming. (LLM, conf=0.95)

  cites [331] Wolf, 2017, Microglia in physiology and disease, Annu. Rev. Physiol. source

In the paper

“Microglia also support myelin formation and myelin integrity during CNS development and throughout life [319].”

What the sources say

• Partly supported

  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)

  cites [319] McNamara, 2023, Microglia regulate central nervous system myelin growth and integrity, Nature sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [360] Schulz, 2013, Development and homeostasis of “resident” myeloid cells: The case of the microglia, Glia source
• Partly supported

  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)

  cites [361] Faraco, 2017, Brain perivascular macrophages: Characterization and functional roles in health and disease, J. Mol. Med. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [362] Masuda, 2022, Specification of CNS macrophage subsets occurs postnatally in defined niches, Nature source
• Partly supported

  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)

  cites [363] Goldmann, 2016, Origin, fate and dynamics of macrophages at central nervous system interfaces, Nat. Immunol. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [364] Martens, 2019, A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment, Nat. Neurosci. source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [333] Masuda, 2020, Microglia heterogeneity in the single-cell era, Cell Rep. source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [334] Amor, 2022, White matter microglia heterogeneity in the CNS, Acta Neuropathol. source
• Supported

  The Results section identifies nine transcriptionally distinct microglial states whose prevalence changes with development, aging, and injury. The Discussion describes their distinct spatial signatures, supporting the claim that substates occur in defined contexts and brain regions. No page numbers are available in our copy. (LLM, conf=0.92)

  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
• Partly supported

  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)

  cites [336] Li, 2019, Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing, Neuron sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

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

  cites [343] Rangaraju, 2018, Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease, Mol. Neurodegener. source
• Partly supported

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

  cites [344] Colonna, 2017, Microglia function in the central nervous system during health and neurodegeneration, Annu. Rev. Immunol. sourceExperimental — accuracy not yet measured

In the paper

“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]).”

What the sources say

• Supported

  The section “The Trojan Horse Mechanism” describes infected immune cells transporting viruses into the CNS and specifically reports HIV-infected monocytes crossing the blood–brain barrier. This supports the citing sentence’s characterization of monocytes as viral Trojan horses. (LLM, conf=0.92)

  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

In the paper

“Skull bone marrow cells continuously sample CSF to monitor brain status by accessing CSF-derived cues and thus can respond to CNS perturbations [388].”

What the sources say

• Partly supported

  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)

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

In the paper

“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].”

What the sources say

• Supported

  The Abstract identifies a pivotal role for ABCD1 in viral infection and host defence and describes X-ALD as inherited ABCD1 deficiency. The Discussion calls for considering other viruses as possible contributors to cerebral ALD onset, while explicitly finding no support for EBV as a trigger in the children studied. (LLM, conf=0.89)

  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

In the paper

“Single-cell profiling suggested functions shared with microglia and astrocytes in maintaining CNS homeostasis [372] and regulating barrier functions [367,378,379,380].”

What the sources say

• ?Not checked — no full text of the sourcecites [372] Sankowski, 2019, Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation, Science source
• ?Not checked — no full text of the sourcecites [367] Kierdorf, 2019, Macrophages at CNS interfaces: Ontogeny and function in health and disease, Nat. Rev. Neurosci. source
• ?Not checked — no full text of the sourcecites [378] Amann, 2023, Mechanisms of myeloid cell entry to the healthy and diseased central nervous system, Nat. Immunol. source
• Partly supported

  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)

  cites [379] Prinz, 2021, Microglia and central nervous system–associated macrophages—From origin to disease modulation, Annu. Rev. Immunol. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“Thus, perivascular macrophages function at the interface between blood and brain parenchyma as first responders in diverse neuroimmune interactions [366].”

What the sources say

• Supported

  The section “Brain border macrophages promote leukocyte recruitment and control CSF dynamics” directly describes meningeal and perivascular macrophages as situated between brain parenchyma and peripheral blood and functioning as first responders in diverse neuroimmune interactions. The claim accurately paraphrases that statement as it applies to perivascular macrophages. (LLM, conf=0.95)

  cites [366] Rustenhoven, 2022, Brain borders at the central stage of neuroimmunology, Nature source

In the paper

“They belong to CNS border-associated macrophages (CAMs) [367,368].”

What the sources say

• ?Not checked — no full text of the sourcecites [367] Kierdorf, 2019, Macrophages at CNS interfaces: Ontogeny and function in health and disease, Nat. Rev. Neurosci. source
• Supported

  The Introduction describes CNS border-associated macrophages (BAMs) as lining the perivascular spaces. The section ‘Specific BAM Subsets Are Enriched in Distinct CNS Compartments’ also reports locating BAMs in the perivascular space. Page numbers were not provided in our copy. (LLM, conf=0.94)

  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

In the paper

“Monocytes normally strongly express ALDP and are most severely affected metabolically by defective β-oxidation and VLCFA accumulation [158].”

What the sources say

• Supported

  The Discussion reports high ABCD1 expression in healthy monocytes and says that, in X-ALD, monocytes have among the highest VLCFA accumulation and markedly reduced peroxisomal β-oxidation. The Results report a 69.7% reduction in C26:0 β-oxidation activity in monocytes compared with healthy controls. ABCD1 expression was measured as mRNA. (LLM, conf=0.90)

  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

In the paper

“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.”

What the sources say

• Supported

  The Results section comparing active CALD and multiple sclerosis lesions reports no significant difference in the density of cells positive for the pro-inflammatory marker CD86. It also reports significantly fewer macrophages expressing the anti-inflammatory markers CD206 and CD163 in CALD lesions. (LLM, conf=0.93)

  cites [355] Weinhofer, 2018, Impaired plasticity of macrophages in X-linked adrenoleukodystrophy, Brain source

In the paper

“In addition, they control cerebral spinal fluid (CSF) dynamics and homeostasis [381].”

What the sources say

• Partly supported

  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)

  cites [381] Drieu, 2022, Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid, Nature sourceExperimental — accuracy not yet measured

In the paper

“Those authors’ whole-transcriptome analysis showed AMN monocytes’ normal macrophage differentiation and phagocytosis but a pro-inflammatory profile.”

What the sources say

• Partly supported

  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)

  cites [355] Weinhofer, 2018, Impaired plasticity of macrophages in X-linked adrenoleukodystrophy, Brain sourceExperimental — accuracy not yet measured

In the paper

“As immune surveillants, CAMs clear harmful substances through phagocytosis, antigen presentation, and cytokine production [364,368,371,372,373,374,375,376]”

What the sources say

• ?Not checked — no full text of the sourcecites [364] Martens, 2019, A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment, Nat. Neurosci. source
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [371] Ajami, 2018, Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models, Nat. Neurosci. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [372] Sankowski, 2019, Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation, Science source
• Partly supported

  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)

  cites [373] Kearns, 2023, Dissecting the human leptomeninges at single-cell resolution, Nat. Commun. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

  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)

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

  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)

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

In the paper

“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].”

What the sources say

• Supported

  The Results section comparing active CALD and multiple sclerosis CNS lesions reports significantly fewer macrophages expressing the anti-inflammatory markers CD206 and CD163 in CALD lesions. It also reports CD86-positive cells in both diseases, with no significant difference in their density. The claim accurately paraphrases those findings for the lesions studied. (LLM, conf=0.93)

  cites [355] Weinhofer, 2018, Impaired plasticity of macrophages in X-linked adrenoleukodystrophy, Brain source

In the paper

“and they contribute to the maintenance of CNS homeostasis (reviewed in [377]).”

What the sources say

• Supported

  The “CAMs in homeostasis” section explicitly says CAMs clear potentially harmful substances and contribute to the maintenance of CNS homeostasis. It also describes their role in maintaining CNS barrier integrity. (LLM, conf=0.95)

  cites [377] Glavan, 2024, The niche matters: Origin, function and fate of CNS-associated macrophages during health and disease, Acta Neuropathol. source

In the paper

“They can mount a tailored immune response [387,389]. They supply immune cells to the brain borders and parenchyma post-inflammation [388,389].”

What the sources say

• Supported

  The Introduction describes skull marrow as rapidly responsive to CNS perturbations and as a source of immune cells for the meninges. In “Stroke and CNS injury” (page unavailable), the paper reports skull marrow-derived neutrophils and monocytes reaching ischemic brain tissue after injury; it also describes their mobilization to the meninges after CNS infection. These examples support the paraphrase that skull marrow can respond to CNS conditions and supply immune cells to brain borders and tissue after inflammation or injury. (LLM, conf=0.87)

  cites [387] Mazzitelli, 2023, Skull bone marrow channels as immune gateways to the central nervous system, Nat. Neurosci. source
• Partly supported

  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)

  cites [389] Cugurra, 2021, Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma, Science sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

In the paper

“Being directly exposed to peripheral stimuli, they can respond to inflammatory and chemical cues, including signals from microbiota [369] and mechanical cues [370].”

What the sources say

• Supported

  The Introduction reports that microbiota affect CAMs and determine their response to acute viral infection. The Discussion likewise reports that CAM innate immune responses were attenuated in mice lacking intestinal microbes. The separate claim about mechanical cues is attributed to citation [370], not this paper. (LLM, conf=0.90)

  cites [369] Sankowski, 2021, Commensal microbiota divergently affect myeloid subsets in the mammalian central nervous system during homeostasis and disease, EMBO J. source
• ?Could not verify

  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)

  cites [370] Faraco, 2016, Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension, J. Clin. Investig. sourceExperimental — accuracy not yet measured

In the paper

“These infiltrating monocytes expand locally and give rise to macrophages and inflammatory dendritic cells [390], but they are unable to generate resident microglia.”

What the sources say

• Partly supported

  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)

  cites [390] Geissmann, 2010, Development of monocytes, macrophages, and dendritic cells, Science sourceExperimental — accuracy not yet measured

In the paper

“In the short term, HSC transplantation reverses neuroinflammation and halts demyelination progression, as indicated by brain MRI [24,392,393].”

What the sources say

• Partly supported

  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)

  cites [24] Aubourg, 1990, Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation, N. Engl. J. Med. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [392] Lund, 2020, Volume of gadolinium enhancement and successful repair of the blood-brain barrier in cerebral adrenoleukodystrophy, Biol. Blood Marrow Transplant. source
• Partly supported

  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)

  cites [393] Lauer, 2023, Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy, Nat. Commun. sourceExperimental — accuracy not yet measured

In the paper

“HSC transplantation normalizes white matter permeability and microvascular flow [393].”

What the sources say

• Supported

  The Results and discussion section states that correction of HSCs can normalize BBB permeability and capillary flow dynamics beyond CALD lesions. It also reports normalization of perilesional microvascular flow disturbances after both gene therapy and allogeneic HSC transplantation. The finding is in cerebral adrenoleukodystrophy. (LLM, conf=0.90)

  cites [393] Lauer, 2023, Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy, Nat. Commun. source

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [395] Bushong, 2002, Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains, J. Neurosci. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

  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)

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

In the paper

“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]).”

What the sources say

• Partly supported

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

  cites [398] Weber, B., and Barros, L.F. (2015). The astrocyte: Powerhouse and recycling center. Cold Spring Harb. Perspect. Biol., 7. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Results identify the mutants as Cnp-Cre::Pex5flox/flox mice and report diminished nerve conduction velocity and compound action potentials in isolated sciatic nerves at 2 months. A subsequent Results passage reports normal axonal numbers and calibers despite the reduced compound action potentials. (LLM, conf=0.94)

  cites [252] Kleinecke, 2017, Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy, Elife source

In the paper

“Alternatively, cortisol synthesis could be impaired by a relative lack of cholesterol necessary for its production [30,426].”

What the sources say

• Not checked yetcites [30] Powers, 1985, Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex), Clin. Neuropathol.
• Supported

  In Results §3.6, the authors hypothesize that altered cholesterol homeostasis could lock cholesterol in cholesteryl esters, reducing free cholesterol available for cortisol production. This supports the citing sentence’s tentative explanation; the paper does not claim that reduced cortisol production was observed in the tested fibroblasts. (LLM, conf=0.90)

  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

In the paper

“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.”

What the sources say

• Supported

  The citation supports the sentence’s premise that ABCD1 participates in tethering lipid droplets to peroxisomes, not the citing authors’ subsequent hypothesis about X-ALD adrenals. In the Results section (“ABCD1 forms a tethering complex with M1 Spastin via the PXI region”; page not provided), ABCD1 knockdown significantly reduced LD–peroxisome contacts. The source does not test LD–peroxisome communication in X-ALD adrenals. (LLM, conf=0.92)

  cites [431] Chang, 2019, Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III, J. Cell Biol. source

In the paper

“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].”

What the sources say

• Supported

  The Abstract reports that human adrenocortical cells exposed to C26:0 had increased membrane microviscosity and reduced ACTH-stimulated cortisol release. It presents the proposed link between those changes as a hypothesis, consistent with the citing sentence’s 'supposedly.' (LLM, conf=0.93)

  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

In the paper

“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.”

What the sources say

• Partly supported

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

  cites [288] Berger, 2014, Pathophysiology of X-linked adrenoleukodystrophy, Biochimie sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Partly supported

  The 'Translating transcriptomics to function' section reports that hiPSC-derived astrocyte cultures can recapitulate an in vivo inflammatory transcriptomic signature. The 'Reactive versus disease states' section also describes neurodegenerative disease phenotypes in patient-derived astrocytes. These passages do not establish comparable transcriptomic recapitulation or disease phenotypes for iPSC-derived microglia, or a general match between either model and its in vivo counterpart. Page numbers were not provided in our copy. (LLM, conf=0.86)

  cites [406] Patani, 2023, Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration, Nat. Rev. Neurol. sourceExperimental — accuracy not yet measured
• Supported

  The Conclusions state that human in vitro astrocyte and microglia models partially recapitulate their in vivo counterparts’ transcriptomes and capture authentic disease phenotypes. The section on using these models in neurodegeneration identifies iPSC-derived models in this context; the citing sentence’s “may” is more cautious than the source. (LLM, conf=0.95)

  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
• Supported

  The section on 2D glial cultures says hiPSC-derived astrocytes have transcriptomes characteristic of astrocytes in vivo and that hiPSC-derived microglia can recapitulate their in-vivo counterparts’ transcriptomes. The Concluding Remarks say these models have the potential to reproduce neurodegenerative phenotypes observed in human diseased brains, matching the claim’s cautious wording. The supplied passages do not include page numbers. (LLM, conf=0.91)

  cites [481] Summers, 2024, Novel human iPSC models of neuroinflammation in neurodegenerative disease and regenerative medicine, Trends Immunol. source
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“and is amenable to experimental research in mice [502,503].”

What the sources say

• Supported

  The Introduction’s Table 1 lists experimental mouse models of repetitive traumatic brain injury. The Abstract also says investigators use mice to study trauma, including head trauma. Together, these passages support the claim that head trauma can be studied experimentally in mice. (LLM, conf=0.93)

  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
• Supported

  The Methods sections describe an experiment in which mice received closed-head traumatic brain injury or sham treatment, followed by histological analysis. The Introduction also explains the value of mouse models for studying TBI-associated pathology. These passages support the broad claim that head trauma can be studied experimentally in mice. (LLM, conf=0.94)

  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

In the paper

“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]”

What the sources say

• Supported

  The Results section (‘Differential accumulation of VLCFA in brain cell types derived from AMN-IPSC or cALD-IPSC’) reports higher VLCFA levels in AMN iPSC-derived OLs than in control OLs, with the highest levels in cALD OLs. This supports the comparison attributed to this paper; the sentence’s ‘two studies’ refers to its two citations, not to a claim that this paper conducted two studies. (LLM, conf=0.94)

  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
• ?Could not verify

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“Those iPSC-derived astrocytes accumulated VLCFAs”

What the sources say

• Supported

  Results §2.5 reports significantly increased VLCFA (C26:0) levels in AMN iPSC-derived astrocytes versus controls, with a further increase in cALD astrocytes. The Discussion states that the present study generated astrocytes from two male patients each with AMN and cALD. (LLM, conf=0.93)

  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

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [403] Maguire, 2023, Human iPSC-derived glia models for the study of neuroinflammation, J. Neuroinflammation sourceExperimental — accuracy not yet measured