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44/100

✓ Peer-reviewed alzhub usefulness score 44 out of 100. Mild cognitive impairment

Topic: Brain proteins, microglia and lab models

Background The blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer's disease (AD) that precedes the hallmarks of amyloid beta (amyloid β) plaque deposition and neuronal neurofibrillary tangle (NFT) formation. A damaged BBB correlates directly with neuroinflammation involving microglial activation and reactive astrogliosis, which is associated with increased expression and/or release of high-mobility group box protein 1 (HMGB1) and thrombin. However, the link between the presence of these molecules, BBB damage, and progression to neurodegeneration in AD is still elusive. Therefore, we aimed to profile and validate non-invasive clinical biomarkers of BBB dysfunction and neuroinflammation to assess the progression to neurodegeneration in mild cognitive impairment (MCI) and AD patients. Methods We determined the serum levels of various proinflammatory damage-associated molecules in aged control subjects and patients with MCI or AD using validated ELISA kits. We then assessed the specific and direct effects of such molecules on BBB integrity in vitro using human primary brain microvascular endothelial cells or a cell line. Results We observed a significant increase in serum HMGB1 and soluble receptor for advanced glycation end products (sRAGE) that correlated well with amyloid beta levels in AD patients (vs. control subjects). Interestingly, serum HMGB1 levels were significantly elevated in MCI patients compared to controls or AD patients. In addition, as a marker of BBB damage, soluble thrombomodulin (sTM) antigen, and activity were significantly (and distinctly) increased in MCI and AD patients. Direct in vitro BBB integrity assessment further revealed a significant and concentration-dependent increase in paracellular permeability to dextrans by HMGB1 or α-thrombin, possibly through disruption of zona occludins-1 bands. Pre-treatment with anti-HMGB1 monoclonal antibody blocked HMGB1 effects and leaving BBB integrity intact. Conclusions Our current studies indicate that thrombin and HMGB1 are causal proximate proinflammatory mediators of BBB dysfunction, while sTM levels may indicate BBB endothelial damage; HMGB1 and sRAGE might serve as clinical biomarkers for progression and/or therapeutic efficacy along the AD spectrum.

Key findings

A damaged BBB correlates directly with neuroinflammation involving microglial activation and reactive astrogliosis, which is associated with increased expression and/or release of high-mobility group box protein 1 (HMGB1) and thrombin.
Results We observed a significant increase in serum HMGB1 and soluble receptor for advanced glycation end products (sRAGE) that correlated well with amyloid beta levels in AD patients (vs. control subjects).
Interestingly, serum HMGB1 levels were significantly elevated in MCI patients compared to controls or AD patients.
In addition, as a marker of BBB damage, soluble thrombomodulin (sTM) antigen, and activity were significantly (and distinctly) increased in MCI and AD patients.
Direct in vitro BBB integrity assessment further revealed a significant and concentration-dependent increase in paracellular permeability to dextrans by HMGB1 or α-thrombin, possibly through disruption of zona occludins-1 bands.

Why it matters

This study found higher blood levels of HMGB1 and sRAGE in people with Alzheimer's disease that tracked with amyloid beta levels, and it examined how these molecules affect the blood-brain barrier in cells in the laboratory. These are proposed biomarkers of inflammation and barrier damage, not a treatment, and the work is early and laboratory-based.

Study details

Evidence strengthLow

How this study scored 44/100

Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.

Component	Points	Why
Journal tier	7 / 10	Tier 3 — peer-reviewed journal (Journal of neuroinflammation)
Journal's citation record	2 / 4	Journal of Neuroinflammation: journal h-index 216 (OpenAlex, 2026-10-29)
Study design	0 / 12	No study design recorded — scores zero, not guessed (not stated in the record — scored 0)
Strength of evidence	1 / 5	Rated “low” in our summary
Peer-review validation	10 / 10	Peer-reviewed. Published as an article in a named peer-reviewed journal.
How recent	1 / 5	2016 — within 20 year(s) of the newest study here
Sample size	0 / 4	Participant count not stated — scores zero (not stated in the record — scored 0)
Effect reported	0 / 3	No effect size reported — scores zero (not stated in the record — scored 0)
Studied in people	0 / 3	Not stated whether this was studied in people — scores zero (not stated in the record — scored 0)
Randomised / blinded	0 / 2	No randomisation or blinding stated — scores zero (not stated in the record — scored 0)
Times cited	5 / 7	Cited 211 times (OpenAlex, 2026-10-10)
Citations per year	3 / 5	17.6 citations a year over 12 year(s) since 2016
Impact for its field and year	3 / 6	Cited 7.9× the average for papers of its field and year (OpenAlex FWCI)
Cited by studies here	1 / 6	Cited by 1 other studies in this library
Still being cited	3 / 4	Cited 62 times in 2024–2026 (2026 still in progress; OpenAlex)
Senior author's track record	3 / 4	Last-listed author Luca Cucullo: h-index 52 (OpenAlex, whole career)
Institution's track record	0 / 3	University of Kansas Medical Center: institution h-index 578 (OpenAlex)
Multi-centre collaboration	1 / 3	OpenAlex lists 3 institution(s) in 2 countries
Indexed in PubMed	2 / 2	Indexed in PubMed (PMID 27553758)
Free to read	2 / 2	Free to read
Total	44 / 100	—

What each of these 20 components measures, and what this score is not →

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Cite this study APA, Vancouver, BibTeX · download .bib or .ris

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APA 7th

Festoff, B. W., Sajja, R. K., van Dreden, P., & Cucullo, L. (2016). HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease. Journal of neuroinflammation. https://doi.org/10.1186/s12974-016-0670-z

Vancouver

Festoff BW, Sajja RK, van Dreden P, Cucullo L. HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease. Journal of neuroinflammation. 2016. doi:10.1186/s12974-016-0670-z. PMID: 27553758.

BibTeX

@article{festoff2016-27553758,
  author  = {Festoff, B. W. and Sajja, R. K. and van Dreden, P. and Cucullo, L.},
  title   = {{HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease}},
  journal = {Journal of neuroinflammation},
  year    = {2016},
  doi     = {10.1186/s12974-016-0670-z},
  pmid    = {27553758},
  url     = {https://doi.org/10.1186/s12974-016-0670-z}
}

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