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Cited by 1,728Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction

Open access
Nation, Daniel A., Sweeney, Melanie D., Montagne, Axel, Sagare, Abhay P., D’Orazio, Lina M., Pachicano, Maricarmen, Sepehrband, Farshid, Nelson, Amy R. +11 more·2019·Nature Medicine
DOI 10.1038/s41591-018-0297-yPMC PMC6367058
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Abstract

Vascular contributions to cognitive impairment are increasingly recognized1–5 as shown by neuropathological6,7, neuroimaging4,8–11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer’s disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)3,11,14, and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood–brain barrier (BBB) breakdown14–16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8–10,12,13, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8–10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer’s Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau. Neuroimaging and cerebrospinal fluid analyses in humans reveal that loss of blood–brain barrier integrity and brain capillary pericyte damage are early biomarkers of cognitive impairment that occur independently of changes in amyloid-β and tau.

AI snapshot

Written from the paper’s full text.

TL;DR

This study reports that older adults with early cognitive impairment show signs of brain capillary pericyte injury and blood-brain barrier leakage, especially in hippocampus and parahippocampal regions, even when amyloid and tau biomarkers are normal. The authors conclude that BBB breakdown may be an early biomarker of cognitive dysfunction independent of classic Alzheimer’s disease pathology.

Key findings

  • CSF sPDGFRβ, a pericyte injury marker, increased with greater CDR impairment (CDR 1 > 0.5 > 0) and was higher in CDR 0.5 than CDR 0 regardless of Aβ1–42 or pTau status; it remained predictive after adjustment for Aβ/pTau, with partial eta squared values of .10–.12.
  • DCE-MRI in 73 participants showed higher BBB permeability (Ktrans) in hippocampus, CA1, CA3, dentate gyrus, and parahippocampal gyrus in CDR 0.5 versus CDR 0, but not in frontal/temporal cortex, subcortical white matter, corpus callosum, internal capsule, thalamus, or striatum; effects were independent of Aβ/pTau and had partial eta squared values of .09–.28.
  • Similar patterns appeared using neuropsychological domain impairment: elevated CSF sPDGFRβ and regional BBB permeability in medial temporal regions in impaired versus unimpaired participants, independent of Aβ/pTau and vascular risk factor burden; several glial, inflammatory, and neuronal degeneration CSF markers did not differ.
  • Findings persisted after controlling for hippocampal/parahippocampal volumes and were not correlated with age; the authors interpret BBB breakdown as independent of Aβ/tau and normal aging.

Methods

  • Observational biomarker study at two sites (USC/HMRI and Washington University) including 161 participants for CSF studies, 35 for PiB-PET, and 73 for DCE-MRI; participants were ≥45 years, stratified by CDR and neuropsychological domain impairment, and classified by CSF Aβ1–42 (<190 pg/mL positive) and pTau181 (>78 pg/mL positive) cutoffs.
  • CSF sPDGFRβ was measured by quantitative Western blot; other CSF markers by ELISA/MSD; BBB permeability was measured by DCE-MRI Ktrans using Patlak modeling; hippocampal/parahippocampal volumes came from FreeSurfer; analyses used ANCOVA and hierarchical logistic regression with covariates and FDR correction.

Limitations

  • The authors state that because vascular dementia, vascular cognitive impairment, and substantial cerebrovascular pathology were excluded, the independence from traditional vascular risk factors may not extend to populations with more severe vascular lesions; interactive or synergistic effects were not ruled out.
  • The authors note uncertainty about whether medial temporal BBB pathology can explain impairment in cognitive domains supported by brain regions outside the medial temporal lobe, since those regions did not show BBB breakdown in this cohort.
  • Evident from the text: DCE-MRI and PiB-PET findings come from smaller subsets (73 and 35), and the cross-sectional design cannot establish that BBB breakdown precedes or causes cognitive decline.

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

Integrity signals

Registry

Crossref · 10.1038/s41591-018-0297-y

Cites

59 of 59 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 26 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    CSF amyloid-beta and tau oligomer levels do not differ between CDR 0 and CDR 0.5 groups.

    “we found no differences in CSF Aβ and tau oligomers levels between CDR 0 and CDR 0.5 groups”
    Quote in the paperSubstantial claim
  • Findingown data

    CSF sPDGFRβ remains significantly increased in domain analysis after statistical control for CSF tau oligomers.

    “CSF sPDGFRβ remained significantly increased in domain analysis after statistically controlling for CSF tau oligomers in ANCOVA models”
    Quote in the paperSubstantial claim
  • Findingown data

    CSF sPDGFRβ increases remain significant after statistical control for hippocampal and parahippocampal gyrus volumes.

    “CSF sPDGFRβ increases remained significant after controlling for HC and PHC volumes”
    Quote in the paperSubstantial claim
  • Findingown data

    CSF amyloid-beta and tau oligomer levels do not differ between participants with impairment in one or more cognitive domains and those without cognitive impairment.

    “There was no difference in CSF Aβ and tau oligomers between participants with impairment in 1 or more cognitive domains and those without cognitive impairment”
    Quote in the paperSubstantial claim
  • Findingown data

    Higher CSF sPDGFRβ remains a significant predictor of cognitive impairment after statistical control for CSF amyloid-beta 1-42 and pTau, with medium-to-large incremental effect sizes (partial eta squared .10-.12).

    “Higher CSF sPDGFRβ remained a significant predictor of cognitive impairment after statistically controlling for CSF Aβ1–42 and pTau, as shown by estimated marginal means from ANCOVA models (Figure 1f) indicating medium-to-large incremental effect sizes with η2partial range = .10–.12”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Statistical control for amyloid-beta, pTau, vascular risk factors, and brain volumes adequately removes confounding, so remaining associations indicate independence.
  • May combine two claims. 22
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    In domain analysis, participants with one or more cognitive domains impaired versus zero domains impaired show no significant hippocampal volume change but a significant parahippocampal gyrus volume decrease.

    “there were no significant changes in HC volume, but a significant decrease in PHC volume, in participants with 1+ cognitive domains impaired compared to 0 domains impaired”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    CSF sPDGFRβ increases correlate positively with DCE-MRI measures of blood-brain barrier permeability in hippocampus and parahippocampal gyrus in all studied participants, but not in other studied brain regions.

    “we also observed a significant positive correlation between increases in CSF sPDGFRβ and DCE-MRI measures of BBB permeability in the HC and PHC in all studied participants”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Increased DCE-MRI blood-brain barrier permeability in medial temporal lobe structures is associated with worse CDR scores and impairment in multiple cognitive domains.

    “An increase in DCE-MRI BBB permeability in several medial temporal lobe structures that sub serve episodic memory (e.g., HC, PHC, and CA1, CA3 and dentate gyrus HC subfields) was associated with worse CDR scores (CDR 0 vs. 0.5) and with impairment in multiple cognitive domains”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In CDR 0.5 versus CDR 0 participants, hippocampal volume does not change significantly, but parahippocampal gyrus volume decreases significantly.

    “In participants with CDR 0.5 vs. CDR 0, we found no significant changes in HC volume, but a significant decrease in PHC volume”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Vascular risk factor burden does not influence blood-brain barrier permeability changes in hippocampus and parahippocampal gyrus in CDR 0.5 versus CDR 0 participants, nor blood-brain barrier integrity in other studied brain regions.

    “the VRF burden did not influence BBB permeability changes in the HC and PHC in individuals with CDR 0.5 compared to CDR 0, and also had no effect on BBB integrity in other studied brain regions”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    DCE-MRI shows higher blood-brain barrier permeability to gadolinium in the hippocampus, its CA1, CA3 and dentate gyrus subfields, and parahippocampal gyrus in CDR 0.5 versus CDR 0 participants, but not in other studied brain regions.

    “The DCE-MRI analysis of regional BBB permeability in a subset of 73 participants with CDR 0.5 compared to those with CDR 0, indicated increased BBB permeability to gadolinium-based contrast agent in the hippocampus (HC) and its CA1, CA3 and dentate gyrus subfields, and parahippocampal gyrus (PHC), but not in other studied brain regions”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither CSF sPDGFRβ nor regional blood-brain barrier permeability in hippocampus and parahippocampal gyrus correlates with age in either CDR 0 or CDR 0.5 groups.

    “Neither CSF sPDGFRβ (Extended Data Figure 10a-b) nor regional BBB permeability HC and PHC values (Extended Data Figure 10c-f) were correlated with age in either the CDR 0 or CDR 0.5 groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ADAM10 mediates sPDGFRβ shedding in human pericytes but not smooth muscle cells.

    “we found that ADAM10 mediates sPDGFRβ shedding in human pericytes but not SMCs (Extended Data Fig. 1)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Hippocampal and parahippocampal gyrus volumes do not differ between CSF amyloid-beta-positive and -negative or pTau-positive and -negative participants in either CDR 0 or CDR 0.5 groups.

    “HC or PHC volumes did not statistically differ between participants that were CSF Aβ+ vs. Aβ- (Figure 2c) or pTau+ vs. pTau- (Figure 2d) in either CDR 0 or CDR 0.5 groups.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Hippocampal and parahippocampal gyrus volumes do not differ between CSF amyloid-beta-positive and -negative or pTau-positive and -negative participants in domain analysis.

    “which did not statistically differ between participants that were CSF Aβ+ vs. Aβ- or pTau+ vs. pTau-”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Human brain vascular smooth muscle cells released very little sPDGFRβ, and ionomycin did not significantly raise it.

    “Compared to pericytes, SMCs shed extremely low levels of sPDGFRβ, which was not significantly increased by IM.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Marimastat and ADAM10 siRNA each significantly decreased ionomycin-stimulated sPDGFRβ shedding, by over 90% and 75% respectively.

    “Both pharmacologic (MM) and genetic (siRNA) inhibition of ADAM10 significantly reduced sPDGFRβ shedding activated by IM by > 90% and 75%, respectively.”
    Quote in the paperSubstantial claim

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

    Findingown data

    No statistically significant between-subject variation was found in the measured vp.

    “A statistically significant intersubject variability in the measurement of vp was not observed.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Tissue tracer concentration follows the Patlak model equation with Ktrans and vp.

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

    Findingown data

    At Washington University, Aβ42 but not pTau changed.

    “whereas Aβ42, but not pTau, was altered at Washington University site”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Ktrans does not increase with CDR in superior frontal and inferior temporal cortex, subcortical white matter fibers, corpus callosum, internal capsule, thalamus, caudate nucleus, or striatum.

    “but not in other brain regions including superior frontal cortical gyrus (Sup Front) and inferior temporal cortical gyrus (Inf Temp), white matter regions including subcortical white matter fibers (white matter, WM), corpus callosum (CC), and internal capsule (IC), and deep gray matter regions including thalamus (Thal), caudate nucleus (Caud) and striatum (b)”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The tracer diffuses across the blood-brain barrier in only one direction during the acquisition period.
    • The authors state this as an assumption: Tissue tracer concentration follows the Patlak model equation with Ktrans and vp.

  • May combine two claims.

    Findingown data

    Human brain pericytes released high baseline sPDGFRβ, and ionomycin, which activates ADAM10, increased it more than fivefold.

    “Pericytes shed high basal levels of sPDGFRβ that was significantly increased by > 5-fold by treatment with IM, which activated ADAM10.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Blood-brain barrier breakdown is an independent, early biomarker of cognitive impairment unrelated to amyloid-beta and tau.

    “suggesting that BBB breakdown is an independent, early biomarker of cognitive impairment unrelated to Aβ and tau”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The cross-sectional group differences reflect an early pathological process that precedes or is independent of cognitive dysfunction, rather than a consequence of it.

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

    Premisecitation

    Prior studies established improved sensitivity and specificity of the neuropsychological criteria relative to single-test-score criteria, and adaptability to various neuropsychological batteries.

    “Prior studies have established improved sensitivity and specificity of these criteria relative to those employing a single test score, as well as adaptability of this diagnostic approach to various neuropsychological batteries21,41,42.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Bondi, M. W. et al. Neuropsychological criteria for mild cognitive impairment improves diagnostic precision, biomarker associations, and progression rates. J. Alzheimers Dis. 42, 275–289 (2014). source

      Not checked in the free run.

    • cites [41] Jak, A. J. et al. Quantification of five neuropsychological approaches to defining mild cognitive impairment. Am. J. Geriatr. Psychiatry 17, 368–375 (2009). source

      Not checked in the free run.

    • cites [42] Jak, A. J. et al. Neuropsychological criteria for mild cognitive impairment and dementia risk in the Framingham Heart Study. J. Int. Neuropsychol. Soc. 22, 937–943 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human brain pericytes, but not smooth muscle cells, shed sPDGFRβ in culture, and shedding increases with hypoxia or injurious stimuli.

    “Human brain pericytes, but not SMCs, shed sPDGFRβ in the culture media, which is increased by hypoxia or injurious stimuli8,18.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Montagne, A. et al. Blood–brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015). source

      Not checked in the free run.

    • cites [18] Sagare, A. P., Sweeney, M. D., Makshanoff, J. & Zlokovic, B. V. Shedding of soluble platelet-derived growth factor receptor-β from human brain pericytes. Neurosci. Lett. 607, 97–101 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PDGFRβ is primarily expressed in the brain by vascular mural cells, capillary pericytes and smooth muscle cells, and not by neurons, astrocytes, endothelial cells, oligodendrocytes, or microglia.

    “PDGFRβ is primarily expressed in brain by vascular mural cells – capillary pericytes and vascular smooth muscle cells (SMCs), but not by neurons, astrocytes, endothelial cells, oligodendrocytes and/or microglia22–25.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [22] Bell, R. D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010). source

      Not checked in the free run.

    • cites [23] Lindahl, P., Johansson, B. R., Levéen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997). source

      Not checked in the free run.

    • cites [24] Winkler, E. A., Bell, R. D. & Zlokovic, B. V. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol. Neurodegener. 5, 32 (2010). source

      Not checked in the free run.

    • cites [25] Vanlandewijck, M. et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature 554, 475–480 (2018). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The imaging protocol was designed to identify subtle blood-brain barrier changes in cognitively impaired patients.

    “The imaging protocol performed was developed to detect subtle BBB changes in patients with cognitive impairment and is detailed in Montagne et al. 20158.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Montagne et al. 2015 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Individuals diagnosed with vascular dementia, vascular cognitive impairment, and other disorders that might account for cognitive impairment were excluded.

    “Individuals diagnosed with vascular dementia and vascular cognitive impairment, and other disorders that might account for cognitive impairment were excluded”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The USC Institutional Review Board approved the study.

    “The study was approved by the USC Institutional Review Board.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Older adults with Alzheimer's disease and two or more vascular risk factors are more likely to have occult cerebrovascular disease at autopsy, whereas a single vascular risk factor is common and not necessarily associated with increased cerebrovascular disease.

    “We have previously shown that older adults with AD exhibiting two or more VRFs are more likely to exhibit occult cerebrovascular disease at autopsy, whereas a single VRF is common and not necessarily associated with increased cerebrovascular disease in this population44,45.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Nation, D. A. et al. Antemortem pulse pressure elevation predicts cerebrovascular disease in autopsy-confirmed Alzheimer’s disease. J. Alzheimers Dis. 30, 595–603 (2012). source

      Not checked in the free run.

    • cites [45] Bangen, K. J. et al. Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy-confirmed Alzheimer’s disease. Alzheimers Dement. 11, 394–403.e1 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Participants were stratified using accepted cutoff values for CSF amyloid-beta 1-42 and pTau181.

    “using the accepted cutoff values19–21”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Pan, C. et al. Diagnostic values of cerebrospinal fluid t-tau and Aβ42 using meso scale discovery assays for Alzheimer’s disease. J. Alzheimers Dis. 45, 709–719 (2015). source

      Not checked in the free run.

    • cites [20] Roe, C. M. et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology 80, 1784–1791 (2013). source

      Not checked in the free run.

    • cites [21] Bondi, M. W. et al. Neuropsychological criteria for mild cognitive impairment improves diagnostic precision, biomarker associations, and progression rates. J. Alzheimers Dis. 42, 275–289 (2014). source

      Not checked in the free run.

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

    Study design and conductreasoning

    APOE-ε4 carrier status was omitted as a covariate from site-specific and interaction analyses to preserve statistical power.

    “Site-specific analyses and interaction effect analyses did not include APOE-ε4 carrier status as a covariate to conserve statistical power.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Missing data for all other CSF biomarkers and clinical measures was limited to less than 10%.

    “the extent of missing data was capped at < 10% for all other CSF biomarkers and clinical measures”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The siRNA knockdown of ADAM10 achieved 85% efficiency in this study.

    “The siRNA ADAM10 knockdown efficiency in this study was 85% as shown by Western analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    All ANCOVA omnibus p-values were corrected for multiple comparisons using the Benjamini-Hochberg false discovery rate method.

    “false discovery rate (FDR)-correction was applied to all ANCOVA omnibus p-values using the Benjamini-Hochberg method60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Glickman, M. E., Rao, S. R. & Schultz, M. R. False discovery rate control is a recommended alternative to Bonferroni-type adjustments in health studies. J. Clin. Epidemiol. 67, 850–857 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    Patlak linearized regression produced Ktrans maps with high spatial and temporal resolution, enabling simultaneous regional permeability measurements in white and gray matter and accurate values in small structures like hippocampal subdivisions.

    “The Patlak linearized regression mathematical analysis was used to generate the BBB permeability Ktrans maps8,49,50 with high spatial and temporal resolutions allowing not only simultaneous measurements of the regional BBB permeability in different white (WM) and gray matter (GM) regions, but also accurate calculations of the Ktrans values in anatomical regions as small as the subdivisions of the”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Montagne, A. et al. Blood–brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015). source

      Not checked in the free run.

    • cites [49] Barnes, S. R. et al. ROCKETSHIP: a flexible and modular software tool for the planning, processing and analysis of dynamic MRI studies. BMC Med. Imaging 15, 19 (2015). source

      Not checked in the free run.

    • cites [50] Patlak, C. S. & Blasberg, R. G. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J. Cereb. Blood Flow Metab. 5, 584–590 (1985). source

      Not checked in the free run.

    • The authors state this as an assumption: The tracer diffuses across the blood-brain barrier in only one direction during the acquisition period.
    • The authors state this as an assumption: Tissue tracer concentration follows the Patlak model equation with Ktrans and vp.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All biomarker assays and quantitative MRI scans were conducted by investigators blinded to participant clinical status.

    “All biomarker assays and quantitative MRI scans were conducted by investigators blinded to the clinical status of the participant.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Continuous variables were screened for outliers and non-normality, and log10 transformations were applied when distributions departed from normality before parametric testing.

    “All continuous variables were screened for outliers (+/− 3 SDs from mean) and evaluated for departures from normality through quantitative examination of skewness and kurtosis, as well as visual inspection of frequency distributions. Where departures of normality were identified, log10-transformations were applied, and distribution normalization was confirmed prior to parametric analyses.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Every participant had complete primary outcome data for CSF sPDGFRβ and DCE-MRI.

    “all participants had complete data for primary outcomes (CSF sPDGFRβ and DCE-MRI)”
    Quote in the paperNot a substantial claim
33 of 33

  • The paper relies on this without support.

    The cross-sectional group differences reflect an early pathological process that precedes or is independent of cognitive dysfunction, rather than a consequence of it.

    “suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau”

  • The paper relies on this without support.

    The study sample of older adults with CDR 0.5 or domain impairment is representative of the broader population with early cognitive dysfunction, so findings generalize.

    “older adults with early cognitive dysfunction develop brain capillary damage associated with mural cell pericyte injury and BBB breakdown in the HC irrespective of Aβ and/or tau changes”

  • The paper relies on this without support.

    The selected CSF glial/inflammatory and neuronal markers are representative of glial/inflammatory response and neuronal degeneration, so no differences indicate no involvement.

    “as illustrated with a few representative biomarkers out of 20 studied”

  • The paper relies on this without support.

    Statistical control for amyloid-beta, pTau, vascular risk factors, and brain volumes adequately removes confounding, so remaining associations indicate independence.

    “after statistically controlling for CSF Aβ1–42 and pTau”

  • The authors state this as an assumption.

    The tracer diffuses across the blood-brain barrier in only one direction during the acquisition period.

    “The present analysis requires that the tracer’s diffusion across the BBB remains unidirectional during the acquisition time.”

  • The paper relies on this without support.

    Individual arterial input function measurements are important when the population varies by age because blood volume and flow changes can affect AIF and Ktrans values.

    “Individual AIF measurements are important particularly if the studied population diverges by age as changes in blood volume and flow may affect AIF and the Ktrans measurements.”

  • The authors state this as an assumption.

    Tissue tracer concentration follows the Patlak model equation with Ktrans and vp.

    “The total tracer concentration in the tissue, Ctissue (t), can be described as a function of the blood concentration, CAIF (t), the intravascular blood volume, vp, and a blood-to-brain transfer constant, Ktrans, that represents the flow from the intravascular to the extravascular extracellular space using equation below: Ctissue(t)=Ktrans∫0tCAIF(u)du+vpAIF(t)”
7 of 7

Claims other papers make about this one

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

  • Cerebrovascular dysfunction is an early pathological event in Alzheimer's disease and contributes significantly to permanent loss of neuronal function.

    “Increasing evidence demonstrates that cerebrovascular dysfunction is an early pathological event in AD and contributes significantly to the permanent loss of neuronal function.[ 3 ]”

    From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [3]

    The Introduction says neurovascular dysfunction and blood–brain barrier breakdown develop early in AD, and suggests they may contribute to cognitive and functional decline. It does not establish a significant contribution to permanent loss of neuronal function; the study reports no detectable neuronal degeneration associated with the early damage it observed. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Altered morphology of cerebral vasculature and reduced CBF are critical pathological changes in Alzheimer's disease.

    “Altered morphology of cerebral vasculature and reduced CBF are critical pathological changes in AD.[ 3 , 30 ]”

    From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [3]

    The Introduction describes vascular changes and early neurovascular dysfunction in Alzheimer’s disease, and reports brain capillary damage and blood–brain barrier breakdown in people with early cognitive dysfunction. It does not establish altered cerebral vessel morphology or reduced cerebral blood flow as the two critical pathological changes claimed; the paper’s cited reference on blood-flow regulation is not evidence that this study found reduced flow. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Breakdown of the blood-brain barrier plays a critical role in the progression of Alzheimer's disease.

    “The breakdown of the blood–brain barrier (BBB) plays a critical role in the progression of AD [29].”

    From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [29]

    The Introduction (page unavailable) reports that BBB breakdown develops early in AD and is associated with early cognitive dysfunction, including in people with AD biomarker positivity. It describes neurovascular dysfunction as a possible contributor to decline, but does not establish that BBB breakdown plays a critical causal role in AD progression. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In patients and mouse models of AD, fibrinogen extravasates in the brain at sites of impaired blood-brain barrier integrity and cerebrovascular dysfunction, which are early features of AD pathogenesis.

    “In patients and mouse models of AD, fibrinogen extravasates in the brain at sites of impaired blood-brain barrier integrity and cerebrovascular dysfunction, which are early features of AD pathogenesis.21,39-42”

    From Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models (2024) · cites this paper as [40]

    The Introduction describes neurovascular dysfunction and BBB breakdown as early features of AD. It also reports that CSF fibrinogen correlates with a marker of BBB breakdown, as shown in Extended Data Figure 2 (no page number provided). Neither passage establishes fibrinogen extravasation at impaired brain sites in AD patients or mouse models. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Increasing evidence shows BBB breakdown is among early markers in AD development.

    “Actually, there are increasing evidence showing that BBB breakdown is among the early markers in AD development.140,141”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [141]

Self-check

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

  • DCE-MRI voxel dimensions do not match the stated field of view and matrix

    Minor

    Dividing the stated 188 × 180 mm field of view by the 160 × 160 matrix gives in-plane dimensions of 1.175 × 1.125 mm, not 0.625 × 0.625 mm. No reconstruction or resampling step is stated to account for the difference.

    Reported 0.625 · recomputed 1.175

1 of 1

Cites

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Authors
Nation, D. A., Sweeney, M. D., Montagne, A., Sagare, A. P., D’Orazio, L. M., Pachicano, M., Sepehrband, F., Nelson, A. R., Buennagel, D. P., Harrington, M. G., Benzinger, T. L. S., Fagan, A. M., Ringman, J. M., Schneider, L. S., Morris, J. C., Chui, H. C., Law, M., Toga, A. W., & Zlokovic, B. V.
Affiliations
  • University of Southern California (US)
  • Huntington Medical Research Institutes (US)
  • Washington University in St. Louis (US)
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-01-14
Volume
25
Issue
2
Pages
270-276
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-018-0297-y
PMC
PMC6367058
OpenAlex
W2911147760
Semantic Scholar
2d4c2320820f57ab71715ec28ba9a3be66d05e1e
Cited by
1,728
References
59
Citations by year
2026: 212 · 2025: 256 · 2024: 257 · 2023: 241 · 2022: 203 · 2021: 230 · 2020: 231 · 2019: 93 · 2018: 4 · 2012: 1
FWCI
83.57
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute on Aging (R01AG023084, R01AG039452, R21AG055034, R01AG055770, P50AG005681, P50AG005142, K99AG058780, P01AG003991, RF1AG039452, R00AG058780, R01AG054434, P01AG052350, P01AG026276)
  • National Institute of Neurological Disorders and Stroke (R01NS100459, R01NS090904, R01NS034467)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
blood-brain barrier disruption, cognitive impairment, Alzheimer's disease, cerebrospinal fluid biomarkers, PDGFRβ, pericytes, blood-brain barrier permeability, dynamic contrast-enhanced MRI, amyloid-beta, tau protein, hippocampus
MeSH terms
Blood-Brain Barrier, Humans, Biomarkers, Amyloid beta-Peptides, tau Proteins, Receptor, Platelet-Derived Growth Factor beta, Imaging, Three-Dimensional, Cognitive Dysfunction

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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

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

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