In this study, we observed that white matter fiber integrity is compromised ensuing a course of RT in normal appearing tissue of cerebral tumor patients. DTI results indicated a substantial increase in λ
but only a mild increase in λ
following RT, suggesting demyelination is the predominant effect on white matter fibers 28
. The increases in λ
diffusivities occurred gradually and persisted until shortly after RT, albeit the magnitudes of increase were different. Furthermore, the increases in diffusivities were dose-dependent starting as early as 3 weeks from the start of RT. The dose-dependent increase in λ
were not sustained later than 32 weeks after the start of RT, indicating that demyelination is not limited to regions receiving high radiation doses but becomes diffuse over time. The comprehensive analysis of our longitudinal DT imaging studies elucidates white matter sequelae that include dose-dependent demyelination during RT and acutely up to three months after RT with subsequent mild axonal degradation and diffuse demyelination subacutely, four to six months post RT. These findings suggest a window of opportunity in which treatment could be administered to arrest or retard degradation of white matter.
Demyelination and axonal damage are the hallmarks of white matter injury, each playing a different role in neurological function; thus a distinction between the two pathologies is important. White matter in the brain is known to be highly vulnerable to radiation 1, 2, 29
. In primates, post-radiation responses included perivascular and diffuse demyelination manifest in degeneration of myelin accompanied by degeneration of axonal fibers, in the later stages 11, 30
. There is no noninvasive biological marker that can differentiate between the white matter pathologies of demyelination and axonal damage. Studies suggest that among the indices that can be measured with DTI, comparison of the parallel (λ
) and perpendicular (λ
) components of diffusivity is useful to distinguish between myelin dysfunction and axonal degradation. A DTI study of myelin-deficient/absent Shiverer mice validated that an elevation in λ
with unchanged λ
was caused by demyelination 26
. Conversely in an animal model of axonal loss from the optic nerve after retinal injury, an unaltered λ
accompanied with a change in λ
was confirmed histologically to be due to axonal degeneration without demyelination19
. Our observation of the substantial increase in λ
with a smaller increase in λ
over a 45-weeks period suggests that demyelination is the predominant early response of NAWM to RT. Also, neither remyelination, more severe demyelination, or radiation necrosis were evident up to 45 weeks after the start of RT in the normal-appearing genu and splenium. Remyelination would be indicated by renormalization or decrease in λ 31, 32
. More severe demyelination would be evident as hyperintense signal on T2 images 33
, while radiation necrosis could be indicated by alterations in both T1 and T2 33
. However, these developments did not present in our data.
Radiation response of cerebral white matter tissue appears to be progressive with dose-dependent demyelination early in regions receiving high radiation doses, followed by dose-independent demyelination not limited to high dose regions and mild axonal degradation, four to six months after completion of RT. Both early and diffuse pathological changes have been reported in animal and post-mortem human studies 13, 34, 35
, with myelin breakdown detected within weeks of irradiation 11
. In monkeys treated with neutron irradiation progressive demyelination was documented, but the demyelination was not accompanied by axonal, glial, neuronal or inflammatory responses 30
. In a post-mortem study of glioma patients, radiation was shown to produce selective demyelination in tissue adjacent to the neoplasm 13
. Our observations concur with the above reports; radiation-induced abnormalities in NAWM were continuous, progressing from early (during and up to three months after RT) dose-dependent demyelination, to ongoing demyelination that became dose-independent subacutely (four to six months after completion of RT), indicative of diffuse demyelination. To avoid radiation injury to critical white matter fibers that connect the large neuronal network diffuse demyelination poses a major challenge in the treatment planning paradigm. The current finding of the progressive but mild demyelination initially and latency in degradation of axonal structures up to several months opens a window of opportunity during which interventional therapies can be implemented to salvage, arrest or retard further deterioration of white matter structures and thereby minimize neurocognitive dysfunction.
Cerebral white matter plays a vital role in carrying action potentials from one gray matter region to another. The primary effect of demyelination is to slow transmission from one region to another, while injury to axons causes more severe disruption of transmission. Clinical evidence suggests that limited RT-induced demyelination is associated with minimal or mild neurocognitive deficits, while more extensive demyelination, termed RT encephalopathy or RT leukoencephalopathy is associated with more severe cognitive dysfunction as well as motor and possibly visual deficits 14 36 37 38 39
. The patterns of neurocognitive impairments include decline or loss of memory, attention, learning, and executive functions 40 41
, sometimes severe enough to meet the definition of dementia. The most common motor manifestation is gait impairment, sometimes termed gait apraxia 41
. In a rodent model, neurological deficits included paralysis 4 to 7 months post irradiation 42
. A study of the relationship between radiation-induced white matter injury and compromised neurocognitive functions demonstrated a significant correlation between the DTI fractional anisotropy index and cognitive decline months to years after whole brain radiation in children with medulloblastoma and acute lymphoblastic leukemia pediatric patients 43
. Whether the early changes we demonstrated in white matter after cranial irradiation are predictive of delayed neurological dysfunction will be tested in a future study.
Our study aimed to characterize the temporal changes before, during and after RT, thus providing information on the time-sequence of structural changes in normal-appearing white matter, and allowed us to use patients' as their own control and eliminated the need to use a control population. Therefore, factors such as patient age, disease grade and tumor pathology were not relevant. By using quantitative DTI indices, absolute values were calculated to evaluate changes over time.