Dataset Information

White Matter is the Predilection Site of Late-Delayed Radiation-Induced Brain Injury in Non-Human Primates.

ABSTRACT: Fractionated whole-brain irradiation for the treatment of intracranial neoplasia causes progressive neurodegeneration and neuroinflammation. The long-term consequences of single-fraction high-dose irradiation to the brain are unknown. To assess the late effects of brain irradiation we compared transcriptomic gene expression profiles from nonhuman primates (NHP; rhesus macaques Macaca mulatta) receiving single-fraction total-body irradiation (TBI; n = 5, 6.75-8.05 Gy, 6-9 years prior to necropsy) to those receiving fractionated whole-brain irradiation (fWBI; n = 5, 40 Gy, 8 × 5 Gy fractions; 12 months prior to necropsy) and control comparators (n = 5). Gene expression profiles from the dorsolateral prefrontal cortex (DLPFC), hippocampus (HC) and deep white matter (WM; centrum semiovale) were compared. Stratified analyses by treatment and region revealed that radiation-induced transcriptomic alterations were most prominent in animals receiving fWBI, and primarily affected white matter in both TBI and fWBI groups. Unsupervised canonical and ontologic analysis revealed that TBI or fWBI animals demonstrated shared patterns of injury, including white matter neuroinflammation, increased expression of complement factors and T-cell activation. Both irradiated groups also showed evidence of impaired glutamatergic neurotransmission and signal transduction within white matter, but not within the dorsolateral prefrontal cortex or hippocampus. Signaling pathways and structural elements involved in extracellular matrix (ECM) deposition and remodeling were noted within the white matter of animals receiving fWBI, but not of those receiving TBI. These findings indicate that those animals receiving TBI are susceptible to neurological injury similar to that observed after fWBI, and these changes persist for years postirradiation. Transcriptomic profiling reaffirmed that macrophage/microglial-mediated neuroinflammation is present in radiation-induced brain injury (RIBI), and our data provide novel evidence that the complement system may contribute to the pathogenesis of RIBI. Finally, these data challenge the assumption that the hippocampus is the predilection site of injury in RIBI, and indicate that impaired glutamatergic neurotransmission may occur in white matter injury.

SUBMITTER: Andrews RN

PROVIDER: S-EPMC6422025 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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White Matter is the Predilection Site of Late-Delayed Radiation-Induced Brain Injury in Non-Human Primates.

Andrews Rachel N RN Dugan Gregory O GO Peiffer Ann M AM Hawkins Gregory A GA Hanbury David B DB Bourland J Daniel JD Hampson Robert E RE Deadwyler Samuel A SA Clinea J Mark JM

Radiation research 20190129 3

Fractionated whole-brain irradiation for the treatment of intracranial neoplasia causes progressive neurodegeneration and neuroinflammation. The long-term consequences of single-fraction high-dose irradiation to the brain are unknown. To assess the late effects of brain irradiation we compared transcriptomic gene expression profiles from nonhuman primates (NHP; rhesus macaques Macaca mulatta) receiving single-fraction total-body irradiation (TBI; n = 5, 6.75-8.05 Gy, 6-9 years prior to necropsy) ...[more]

PMID: 30694733

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Project description:PurposeOur purpose was to investigate the association between imaging biomarkers of radiation-induced white matter (WM) injury within perisylvian regions and longitudinal language decline in patients with brain tumors.Methods and materialsPatients with primary brain tumors (n = 44) on a prospective trial underwent brain magnetic resonance imaging, diffusion-weighted imaging, and language assessments of naming (Boston Naming Test [BNT]) and fluency (Delis-Kaplan Executive Function System Category Fluency [DKEFS-CF]) at baseline and 3, 6, and 12 months after fractionated radiation therapy (RT). Reliable change indices of language function (0-6 months), accounting for practice effects (RCI-PE), evaluated decline. Bilateral perisylvian WM regions (superficial WM subadjacent to Broca's area and the superior temporal gyrus [STG], inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus [IFOF], and arcuate fasciculus) were autosegmented. We quantified volume and diffusion measures of WM microstructure: fractional anisotropy (FA; lower values indicate disruption) and mean diffusivity (MD; higher values indicate injury). Linear mixed-effects models assessed mean dose as predictor of imaging biomarker change and imaging biomarkers as longitudinal predictors of language scores.ResultsDKEFS-CF scores declined at 6 months post-RT (RCI-PE, -0.483; P = .01), whereas BNT scores improved (RCI-PE, 0.262; P = .04). Higher mean dose to left and right regions was predictive of decreased volume (left-STG, P = .02; right-ILF and IFOF, P = .03), decreased FA (left-WM tracts, all P < .01; right-STG and IFOF, P < .02), and increased MD of left-WM tracts (all P < .03). Volume loss within left-Broca's area (P = .01), left-ILF (P = .01), left-IFOF (P = .01), and left-arcuate fasciculus (P = .04) was associated with lower BNT scores. Lower FA correlated with poorer DKEFS-CF and BNT scores within left-ILF (P = .02, not significant), left-IFOF (P = .02, .04), and left-arcuate fasciculus (P = .01, .01), respectively. Poorer DKEFS-CF scores correlated with increased MD values within the left-arcuate fasciculus (P = .03). Right-sided biomarkers did not correlate with language scores.ConclusionsPatients with primary brain tumors experience language fluency decline post-RT. Poorer fluency and naming function may be explained by microstructural injury to left-sided perisylvian WM, representing potential dose-avoidance targets for language preservation.

Project description:White matter disruption is an important determinant of cognitive impairment after brain injury, but conventional neuroimaging underestimates its extent. In contrast, diffusion tensor imaging provides a validated and sensitive way of identifying the impact of axonal injury. The relationship between cognitive impairment after traumatic brain injury and white matter damage is likely to be complex. We applied a flexible technique-tract-based spatial statistics-to explore whether damage to specific white matter tracts is associated with particular patterns of cognitive impairment. The commonly affected domains of memory, executive function and information processing speed were investigated in 28 patients in the post-acute/chronic phase following traumatic brain injury and in 26 age-matched controls. Analysis of fractional anisotropy and diffusivity maps revealed widespread differences in white matter integrity between the groups. Patients showed large areas of reduced fractional anisotropy, as well as increased mean and axial diffusivities, compared with controls, despite the small amounts of cortical and white matter damage visible on standard imaging. A stratified analysis based on the presence or absence of microbleeds (a marker of diffuse axonal injury) revealed diffusion tensor imaging to be more sensitive than gradient-echo imaging to white matter damage. The location of white matter abnormality predicted cognitive function to some extent. The structure of the fornices was correlated with associative learning and memory across both patient and control groups, whilst the structure of frontal lobe connections showed relationships with executive function that differed in the two groups. These results highlight the complexity of the relationships between white matter structure and cognition. Although widespread and, sometimes, chronic abnormalities of white matter are identifiable following traumatic brain injury, the impact of these changes on cognitive function is likely to depend on damage to key pathways that link nodes in the distributed brain networks supporting high-level cognitive functions.

Project description:PurposeThe corpus callosum (CC) and intrahemispheric white matter tracts (IHWM) subserve critical aspects of attention and processing speed. We analyzed imaging biomarkers of microstructural injury within these regions and association with attention and processing speed performance before and after radiation therapy in primary brain tumor patients.Methods and materialsIn a prospective clinical trial, 44 primary brain tumor patients underwent cognitive testing and magnetic resonance imaging/diffusion-weighted imaging at baseline (pre-radiation therapy) and 3-, 6-, and 12-months post-radiation therapy. CC (subregions, total) and IHWM tracts (left/right without CC, total) were autosegmented; tumor, tumor bed, and edema were censored. Biomarkers included volume changes (cm3), mean diffusivity ([MD]; higher values indicate white matter injury), fractional anisotropy ([FA]; lower values indicate white matter injury). Reliable-change indices measured changes in attention (Weschler Adult Intelligence Scale [WAIS-IV] digits-forward; Delis-Kaplan Executive Function System Trail Making [D-KEFS-TM] visual-scanning), and processing speed (WAIS-IV coding; D-KEFS-TM number-sequencing, letter-sequencing), accounting for practice effects. Linear mixed-effects models evaluated associations between mean radiation dose and biomarkers (volume, MD, FA) and imaging biomarkers and neurocognitive performance. Statistics were corrected for multiple comparisons.ResultsProcessing speed declined at 6 months following radiation therapy (number sequencing, letter sequencing; P < .04). Seizures and antiepileptic drug therapy were associated with lower visual-scanning attention reliable-change indices at 6 months (P = .039). Higher radiation dose correlated with smaller midanterior CC volume (P = .023); lower FA in posterior CC, anterior CC, and total CC (all P < .03); and higher MD in anterior CC (P = .012). Smaller midanterior CC and left IHWM volume correlated with worse processing speed (coding, letter-sequencing, number-sequencing; all P < .03). Higher FA in right, left, and total IHWM correlated with better coding scores (all P < .01). Lower FA in total IHWM (P = .009) was associated with worse visual-scanning attention scores. Higher FA in midposterior CC (P = .029) correlated with better digits-forward attention scores.ConclusionsThe CC demonstrated radiation dose-dependent atrophy and WM injury. Microstructural injury within the CC and IHWM was associated with attention and processing speed decline after radiation therapy. These areas represent possible avoidance regions for preservation of attention and processing speed.

Dataset Information

White Matter is the Predilection Site of Late-Delayed Radiation-Induced Brain Injury in Non-Human Primates.

Publications

White Matter is the Predilection Site of Late-Delayed Radiation-Induced Brain Injury in Non-Human Primates.

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