Characterizing CRT-Induced Vascular Injury in the Developing Brain
Melanie A Morrison1, Erin Felton2, Angela Jakary1, Andrew Leynes1, Peder Larson1, Sabine Mueller2, and Janine Lupo1

1Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States, 2Neurology, University of California San Francisco, CA, United States


In the treatment of pediatric medulloblastomas, cranial radiation therapy (CRT) may induce long-term effects including CRT-induced vascular injury and cognitive impairments. 7T Susceptibility-weighted MRI was used to characterize CRT-induced injury in the form of cerebral microbleeds (CMBs) as potential markers of cognitive deficits. The majority of CMBs were located in the frontal lobe, which develop late in the adolescent brain. CMB density was associated with deficits in working and visual memory as a function of time since CRT. This work supports a modification of future standards for defining radiation target volumes, with evidence for early intervention with cognitive rehabilitation strategies.


With brain tumors now the leading cause of cancer-related deaths in children under the age of 20, there is a pressing need for more research to evaluate current treatment strategies. Pediatric medulloblastomas, typically arising in the cerebellum and posterior fossa, are the most common malignant brain tumors in children. Although cranial radiation therapy (CRT) remains an integral role in the treatment of medulloblastomas, it is often associated with significant long-term side effects including vascular injury, hormonal deficiencies, and cognitive decline.1,2 Current treatment strategies have significantly improved the prognosis of medulloblastomas; the 5-year survival rate is now at 70-80% in average-risk disease.3 Thus the impact of treatment on development and quality of life are important considerations for this group, such that they can maximize their cognitive potential and go on to lead independent lives.

Manifestation of CRT-induced vascular injury have been detected with Susceptibility-Weighted Imaging (SWI) as early as 8 months following treatment on a 3T scanner.4 This includes hemosiderin deposits in the form of cerebral microbleeds, CMBs, which can vary in size, and/or changes in the white matter pathways and cortical thickness.4,5 Similar vascular injuries have previously been related to the cognitive decline experienced by stroke and vascular dementia patients6, however, the underlying mechanism driving CRT-associated cognitive decline still remain unclear. With the emergence of ultra-high field MR imaging offering improved visualization of vascular injury over clinical field strengths7, there is a unique opportunity to thoroughly characterize CRT-induced injury with respect to its distribution in the brain, and its relation to clinical variables, cognitive performance measures, and connectivity within cerebral networks.


Seven patients (3 male, 4 female; mean age 15.1 ± 5.6) treated with whole-brain uniform CRT with a boost to the posterior fossa 8 months to 15 years prior for a pediatric medulloblastoma, as well as two, nonirradiated, control patients (2 female; mean age 14.5 ± 0.7) treated for pediatric low-grade gliomas (Figure 1) were scanned on a 7T scanner with a 32-channel phase array coil. High-resolution SWI data were acquired8 along with T1-weighted images of brain anatomy. Cognitive performance measures were acquired via a computerized cognitive battery (Cogstate, Newhaven, CT) designed to assess multiple domains of cognitive function. CMBs were detected using an in-house automated CMB detection algorithm9, recently updated to perform CMB volume quantification10. The distribution of CMBs was evaluated to identify regions of the brain most susceptible to CRT-induced vascular injury. Associations between CMB presence, radiation dose, time since CRT, and cognitive function were explored.


As predicted, patients in the control group did not develop any CMBs. The number and mean volume of CMBs, ranging between 5 and 342 CMBs, and 0.53 and 2.39 mm3 respectively, were positively correlated with time since CRT (Figure 2). This trend, however, was modulated by radiation dose; when comparing two patients treated 5 and 6 years prior, the patient who received a greater total dose presented with 3 times as many CMBs (Figure 3). The majority of CMBs were located in the frontal lobes, followed by the insular and cingular cortices, temporal lobes, and posterior fossa (Figure 4). Global cognitive performance scores (z-score units) were predominately worse for the irradiated patients when compared with one control (patient 8), though no correlations with CMB presence or time since CRT were observed. Domain specific scores, however, revealed similar cognitive deficits in the working memory and visual memory of patients treated either 1-2 years or > 2 years’ prior (thus having either low or high CMB density), respectively (Figure 5).


The existing goal of this study is to characterize CRT-induced vascular injury towards modifying future standards for defining radiation target volumes, and provide evidence for early intervention with cognitive rehabilitation strategies. Preliminary findings suggest that the effects of radiation dose with respect to CRT-induced vascular injury, become most apparent approximately 5 years post-CRT, and that the frontal lobe, which has been show to mature late in the developing brain11, is most susceptible to CRT-induced vascular injury.12 A measure of CMB density in the frontal lobe or other radio-sensitive brain areas may serve as a marker of domain-specific cognitive impairment. The present cohort augmented by four additional patients who have enrolled and consented to participate in a scan in the next 3 months, will enable a more thorough investigation of this association to determine its statistical significance. This will include an evaluation of CMB characteristics within specific brain structures, and their relation to distinct cognitive processes as well as the integrity of adjacent white matter pathways.


The study was supported by NIH grant RO1HD079568.


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Patient Demographics

Number of CMBs (above) and mean CMB volume (below) as functions of time since RT. The influence of radiation dose on CMB presence becomes evident at 5 and 6 years post-treatment, as indicated by the red arrows above and illustrated in Figure 3.

Influence of radiation dose on CMB presence. Scanned at 6 and 5 years post-CRT respectively, patient 1 (left) who received a total dose of 7740 cGy presented with fewer CMBs than patient 4 (right) who received a total dose of 9100 cGy. The red arrows indicate CMBs detected by the algorithm. Automated segmentation of individual CMBs (red outline) is shown within the regions of interest outlined by the blue boxes.

Regional distribution of CMBs in the developing brain. The majority of CMBs were detected in the frontal lobe (bright blue), followed by the insular cingular gyri (burgundy), posterior fossa (red), and temporal lobe (dark blue).

Patient cognitive performance scores against normative samples in z-score units. Patients treated 1-2 years prior exhibited the most cognitive impairment in working memory (burgundy), while patients treated >2 years exhibited the greatest magnitude of deficit in visual memory (with the exception of patient 4). Normative samples in the age bracket of patients 5,8, and 9 were unavailable for the verbal memory tasks (yellow, red). Nonirradiated, control patient 9 presented with substantial ventricular enlargement which may have an independent influence on cognition.

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)