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  • Review Article
  • Published:

Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours

Nature Reviews Neurology volume 13, pages 52–64 (2017)Cite this article

Subjects

Key Points

  • Intracranial radiotherapy leads to permanent and substantial cognitive disability in 50–90% of patients

  • The pathophysiology of radiotherapy-associated cognitive disability remains poorly understood and there are no effective preventive measures or long-term treatments

  • Historically, most research has addressed markers of damage and the cognitive decline that appears 6 months to 1 year or more after irradiation

  • More-sensitive imaging techniques have revealed subtle evidence of CNS damage much sooner than 6 months after radiation

  • These early forms of CNS damage can persist and synergize over time to cause long-term, irreversible deficits in neurons and supporting cell lineages that are vital to cognition

  • Consideration of early forms of radiation-induced CNS damage could help to identify early treatments that can reverse degenerative processes before they cause permanent disability

Abstract

Standard treatment of primary and metastatic brain tumours includes high-dose megavoltage-range radiation to the cranial vault. About half of patients survive >6 months, and many attain long-term control or cure. However, 50–90% of survivors exhibit disabling cognitive dysfunction. The radiation-associated cognitive syndrome is poorly understood and has no effective prevention or long-term treatment. Attention has primarily focused on mechanisms of disability that appear at 6 months to 1 year after radiotherapy. However, recent studies show that CNS alterations and dysfunction develop much earlier following radiation exposure. This finding has prompted the hypothesis that subtle early forms of radiation-induced CNS damage could drive chronic pathophysiological processes that lead to permanent cognitive decline. This Review presents evidence of acute radiation-triggered CNS inflammation, injury to neuronal lineages, accessory cells and their progenitors, and loss of supporting structure integrity. Moreover, injury-related processes initiated soon after irradiation could synergistically alter the signalling microenvironment in progenitor cell niches in the brain and the hippocampus, which is a structure critical to memory and cognition. Progenitor cell niche degradation could cause progressive neuronal loss and cognitive disability. The concluding discussion addresses future directions and potential early treatments that might reverse degenerative processes before they can cause permanent cognitive disability.

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Figure 1: Mechanisms of early CNS injury in brain tumour patients receiving radiotherapy.
Figure 2: Symptoms of radiation-induced CNS injury and cognitive decline.
Figure 3: Pathogenesis of radiation-induced long-term cognitive decline.
Figure 4: Vasculopathy and oligodendrocyte depletion underlie radiation-induced white matter damage.
Figure 5: The severity of radiation-induced white matter damage increases with age.
Figure 6: Dose-dependent cortical thinning.
Figure 7: Dose-dependent hippocampal atrophy.

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Acknowledgements

J.A.H.-G. has received funding from NIH (grants #1KL2TR001444 and #UL1TR000100), and has received the American Cancer Society Pilot Award ACS-IRG 70-002.

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Authors and Affiliations

  1. Department of Radiation Medicine and Applied Sciences, UC San Diego, 3855 Health Sciences Drive, La Jolla, 92093–0819, CA, USA

    Milan T. Makale & Jona A. Hattangadi-Gluth

  2. Department of Psychiatry, 9500 Gilman Drive, UC San Diego, La Jolla, 92093–0841, CA, USA

    Carrie R. McDonald

  3. Department of Translational Neuro-Oncology and Neurotherapeutics, John Wayne Cancer Institute at Providence Saint John's Health Center, 2200 Santa Monica Blvd., Santa Monica, 90404, California, USA

    Santosh Kesari

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  1. Milan T. Makale
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Contributions

M.T.M., C.R.M., and J.A.H.-G. contributed to researching the data, writing and reviewing of the manuscript. S.K. provided substantial contributions to the discussion of the content and revising of the manuscript.

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Correspondence to Milan T. Makale or Santosh Kesari.

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FURTHER INFORMATION

WHO description of health

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Glossary

Whole-brain radiotherapy

Entire brain and brainstem are irradiated to treat a tumour.

Partial-brain radiotherapy

Irradiation treatment of the tumour or tumour bed and surrounding margin; moreover, some healthy brain tissue is subject to incidental irradiation.

Diffusion tensor imaging

Models the motion of water as an ellipse, with derived metrics allowing the study of white matter integrity.

Delayed Match-to-Sample

A test used to assess non-verbal elements of short-term memory in humans and primates: the participant must recall whether a stimulus matches a previously presented 'sample' stimulus.

Homer1a

Homer1a is a protein expressed by neurons that selectively inhibits the binding of family 1 metabotropic glutamate receptor (mGluR) to the synapse.

Diffusion-weighted imaging

Measures and models the diffusion of water at the cellular level.

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Makale, M., McDonald, C., Hattangadi-Gluth, J. et al. Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours. Nat Rev Neurol 13, 52–64 (2017). https://doi.org/10.1038/nrneurol.2016.185

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