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

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

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Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * Department of Psychiatry, 9500 Gilman Drive, UC San Diego, La Jolla, 92093–0841, CA, USA Carrie R. McDonald * 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

Authors * Milan T. Makale View author publications You can also search for this author inPubMed Google Scholar * Carrie R. McDonald View author publications You can also search for this

author inPubMed Google Scholar * Jona A. Hattangadi-Gluth View author publications You can also search for this author inPubMed Google Scholar * Santosh Kesari View author publications You

can also search for this author inPubMed Google Scholar 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. CORRESPONDING AUTHORS Correspondence to Milan T. Makale or Santosh Kesari. ETHICS

DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS FURTHER INFORMATION WHO description of health POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG.

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FOR TABLE 1 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. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 16 December 2016 * Issue Date: January 2017 * DOI:

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