Rate of radiation-induced microbleed formation on 7T MRI relates to cognitive impairment in young patients treated with radiation therapy for a brain tumor

Abstract

Background: Radiation therapy (RT) is essential to the management of many brain tumors, but has been known to lead to cognitive decline and vascular injury in the form of cerebral microbleeds (CMBs).

Purpose: In a subset of children, adolescents, and young adults recruited from a larger trial investigating arteriopathy and stroke risk after RT, we evaluated the prevalence of CMBs after RT, examined risk factors for CMBs and cognitive impairment, and related their longitudinal development to cognitive performance changes.

Methods: Twenty-five patients (mean 17 years, range: 10-25 years) underwent 7-Tesla MRI and cognitive assessment. Nineteen patients were treated with whole-brain or focal RT 1-month to 20-years prior, while 6 non-irradiated patients with posterior-fossa tumors served as controls. CMBs were detected on 7T susceptibility-weighted imaging (SWI) using semi-automated software, a first use in this population.

Results: CMB detection sensitivity with 7T SWI was higher than previously reported at lower field strengths, with one or more CMBs detected in 100% of patients treated with RT at least 1-year prior. CMBs were localized to dose-targeted brain volumes with risk factors including whole-brain RT (p = 0.05), a higher RT dose (p = 0.01), increasing time since RT (p = 0.03), and younger age during RT (p = 0.01). Apart from RT dose, these factors were associated with impaired memory performance. Follow-up data in a subset of patients revealed a proportional increase in CMB count with worsening verbal memory performance (r = -0.85, p = 0.03).

Conclusions: Treatment with RT during youth is associated with the chronic development of CMBs that evolve with memory impairment over time.

Keywords: Brain tumors; Cerebral microbleeds; Cognitive outcome; Radiation therapy; Ultra-high field magnetic resonance imaging.

Figure 1.. Risk factors for the development of CMBs after RT.

Patients treated with whole brain RT presented with significantly more CMBs than patients treated with focal RT including whole ventricular RT (A). When comparing two age-matched patients, one treated with whole brain RT 15 years prior, and the other treated with focal RT 13 years prior, striking differences in CMB burden are seen (B). A composite of patients’ CMBs in (C) (excluding some patients with many CMBs for better visualization), illustrates localization of CMBs to the dose-targeted brain areas.In addition to treatment strategy, greater dose, younger age during RT, and greater time since RT contributed to the most severe cases of chronic CMB development (D).

Figure 2.. Risk factors for memory impairment after RT.

Performance on a verbal memory task different significantly between patients treated without RT versus with focal or whole brain RT (A). The most severe memory impairments were observed in patients treated at younger ages, and imaged further out from treatment (B). Cognitive domains: attention (IDN), association learning and visual memory (CPAL), psychomotor function (DET), executive function (GML), verbal memory and learning (ISL, ISRL), working memory (ONB).

Figure 3.. Serial changes in CMB burden and cognitive performance.

Of the 10 patients imaged serially (8 treated with RT, 2 treated without RT), 6 RT-treated patients had usable imaging data, and presented with new CMBs at follow-up (A). All but one patient treated with whole brain RT at the age of 12, worsened in global performance (denoted by the arrows and annotations) (B). The remaining patients treated with focal RT or no RT (not shown) performed better or slightly worse at follow-up (B). The rate of change in global performance, and performance on memory-domain tasks, correlated with and the rate of increase in CMB development (C-F). Cognitive domains: association learning and visual memory (CPAL), verbal memory and learning (ISL, ISRL).