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Imaging subtle leaks in the blood–brain barrier in the aging human brain: potential pitfalls, challenges, and possible solutions

Abstract

Recent studies using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium-based contrast agents (GBCA) have demonstrated subtle blood–brain barrier (BBB) leaks in the human brain during normal aging, in individuals with age-related cognitive dysfunction, genetic risk for Alzheimer’s disease (AD), mild cognitive impairment, early AD, cerebral small vessel disease (SVD), and other neurodegenerative disorders. In these neurological conditions, the BBB leaks, quantified by the unidirectional BBB GBCA tracer’s constant Ktrans maps, are typically orders of magnitude lower than in brain tumors, after stroke and/or during relapsing episodes of multiple sclerosis. This puts extra challenges for the DCE-MRI technique by pushing calculations towards its lower limits of detectability. In addition, presently, there are no standardized multivendor protocols or evidence of repeatability and reproducibility. Nevertheless, subtle BBB leaks may critically contribute to the pathophysiology of cognitive impairment and dementia associated with AD or SVD, and therefore, efforts to improve sensitivity of detection, reliability, and reproducibility are warranted. A larger number of participants scanned by different MR scanners at different clinical sites are sometimes required to detect differences in BBB integrity between control and at-risk groups, which impose additional challenges. Here, we focus on these new challenges and propose some approaches to normalize and harmonize DCE data between different scanners. In brief, we recommend specific regions to be used for the tracer’s vascular input function and DCE data processing and how to find and correct negative Ktrans values that are physiologically impossible. We hope this information will prove helpful to new investigators wishing to study subtle BBB damage in neurovascular and neurodegenerative conditions and in the aging human brain.

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Acknowledgements

We thank Drs. Joanna Wardlaw and Michael Thrippleton for their most helpful comments and discussion.

Funding

The work of B.V.Z. is supported by the National Institutes of Health (grant nos. R01AG023084, R01NS090904, R01NS034467, R01AG039452, 1R01NS100459, 5P01AG052350, and P30AG06653), in addition to the Alzheimer’s Association (strategic 509279 grant) and the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease (reference no. 16 CVD 05). The work of A.M. is supported by the UK Dementia Research Institute (MRC, Alzheimer’s Society, ARUK) and the UKRI Medical Research Council (Career Development Award MR/V032488/1). The work of D.A.N. is supported by the National Institutes of Health (grant nos. P01AG052350, R01AG064228, R01AG060049, P30AG066519) and Alzheimer’s Association (grant AARG-17–532905). The work of A.W.T. is supported by the National Institutes of Health (grant nos. P01AG052350, P41EB015922 and P30AG066530).

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Contributions

A.M., S.R.B., and B.V.Z. performed literature search and designed the study. A.M. and S.R.B. performed MRI data analyses and interpreted the data. D.A.N. helped with statistical analyses. A.W.T. provided critical reading and additional information of the manuscript. K.K. helped with manuscript writing. A.M. and S.R.B. contributed to manuscript writing, and B.V.Z. supervised all data analysis and interpretation and wrote the manuscript.

Corresponding authors

Correspondence to Axel Montagne, Samuel R. Barnes or Berislav V. Zlokovic.

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Supplementary Fig. 1. Representative SPGR- and VIBE-derived T1 mapping and dynamic contrast-enhanced MRI datasets.

(a) Representative unenhanced coronal fast spoiled gradient echo (SPGR) T1 variable flip angle (2°, 5°, and 10°) and its associated T1 map before administration of a gadolinium-based contrast agent (GBCA). (b) Histogram illustrating the distribution of the T1 values within the whole brain (blue line) of a SPGR subject. (c) Representative unenhanced coronal volumetric interpolated breath-hold examination (VIBE) T1 variable flip angle (2°, 5°, 10°, 12°, and 15°) and its associated T1 map before administration of a GBCA. (d) Histogram illustrating the distribution of the T1 values within the whole brain (red line) of a VIBE subject. (e) Representative 64-frame SPGR DCE (yellow dot represents the GBCA injection time), maximum intensity projection (MIP) of the 64 frames, and its associated BBB Ktrans map. (f) Representative 64-frame VIBE DCE (yellow dot represents the GBCA injection time), maximum intensity projection (MIP) of the 64 frames, and its associated BBB Ktrans map. (a-d) Linked to main Fig. 1a-c; (e,f) Linked to main Fig. 1d-f.

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Montagne, A., Barnes, S.R., Nation, D.A. et al. Imaging subtle leaks in the blood–brain barrier in the aging human brain: potential pitfalls, challenges, and possible solutions. GeroScience 44, 1339–1351 (2022). https://doi.org/10.1007/s11357-022-00571-x

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Keywords

  • Blood–brain barrier permeability
  • Aging population
  • Cognitive impairment
  • Alzheimer’s disease
  • Dementia
  • Small vessel disease
  • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)