Cranial irradiation causes brain degeneration

by Marcia Malory report
Reduced dendritic complexity of GCL neurons 30 d after irradiation. (A–C) Examples of deconvoluted EGFP+ GCL neurons showing dendrites orientated vertically and traversing the ML. (D–F) Deconvoluted 3D reconstructed images of A–C, respectively, with dendrites containing spines projecting into the ML (sky blue, cell body; green, dendrites; blue, branch points; red, spines). Credit: PNAS, Published online before print July 15, 2013, doi: 10.1073/pnas.1307301110

(Medical Xpress)—Cranial irradiation saves the lives of brain cancer patients. It slows cancer progression and increases survival rates. Unfortunately, patients who undergo cranial irradiation often develop problems with cognitive functioning. To determine how radiation affects cognition, Vipan Parihar and Charles Limoli of the University of California, Irvine studied cranial irradiation in mice. They found that exposure to radiation causes degenerative changes to brain architecture similar to those observed in people with neurodegenerative conditions such as Alzheimer's disease and Huntington's disease. Their research appears in the Proceedings of the National Academy of Sciences.

Radiation therapy is the routine frontline treatment for almost all forms of pediatric and cancer because of its ability to forestall tumor growth. While it increases the lifespans of people diagnosed with brain cancer, cranial irradiation can reduce quality of life by causing irreversible cognitive impairment. Central nervous system (CNS) exposure to radiation causes problems with memory, learning, attention, processing speed and executive function.

To understand how reduces cognitive ability, Parihar and Limoli exposed mice to either 1 or 10 Gy of radiation, doses much lower than the maximum dose the CNS can withstand before tissue damage occurs. After 10 or 30 days, the researchers killed the mice and dissected their brains. They then examined the hippocampus, which is associated with learning and memory.

Parihar and Limoli observed dose-dependent reductions in the area, length and branching of dendrites, projections on neurons that send and receive signals to and from other neurons. These reductions persisted after 30 days. The number and density of dendritic spines, bulbous extensions on dendrites, also decreased. Dendritic spines regulate CNS connectivity, are associated with memory storage and play an important role in mediating . There is a positive correlation between number of dendritic spines and synaptic density, which in turn correlates with cognitive ability. The researchers also identified significant changes in levels of pre and post-synaptic proteins.

Reduced dendritic complexity is a characteristic of Alzheimer's disease, Huntington's disease, recurrent depressive illness and epilepsy. Dendritic spine abnormalities are associated with Huntington's disease, temporal lobe epilepsy, AIDS-related dementia, Down syndrome, Rett syndrome and Fragile-X syndrome.

Parihar and Limoli state that the reduction in dendritic spine density and the persistence of degenerative changes after one month is consistent with the irreversible reduction in cognitive functioning experienced by brain cancer survivors who have had cranial radiotherapy.

More information: Cranial irradiation compromises neuronal architecture in the hippocampus, PNAS, Published online before print July 15, 2013, doi: 10.1073/pnas.1307301110

Abstract
Cranial irradiation is used routinely for the treatment of nearly all brain tumors, but may lead to progressive and debilitating impairments of cognitive function. Changes in synaptic plasticity underlie many neurodegenerative conditions that correlate to specific structural alterations in neurons that are believed to be morphologic determinants of learning and memory. To determine whether changes in dendritic architecture might underlie the neurocognitive sequelae found after irradiation, we investigated the impact of cranial irradiation (1 and 10 Gy) on a range of micromorphometric parameters in mice 10 and 30 d following exposure. Our data revealed significant reductions in dendritic complexity, where dendritic branching, length, and area were routinely reduced (>50%) in a dose-dependent manner. At these same doses and times we found significant reductions in the number (20–35%) and density (40–70%) of dendritic spines on hippocampal neurons of the dentate gyrus. Interestingly, immature filopodia showed the greatest sensitivity to irradiation compared with more mature spine morphologies, with reductions of 43% and 73% found 30 d after 1 and 10 Gy, respectively. Analysis of granule-cell neurons spanning the subfields of the dentate gyrus revealed significant reductions in synaptophysin expression at presynaptic sites in the dentate hilus, and significant increases in postsynaptic density protein (PSD-95) were found along dendrites in the granule cell and molecular layers. These findings are unique in demonstrating dose-responsive changes in dendritic complexity, synaptic protein levels, spine density and morphology, alterations induced in hippocampal neurons by irradiation that persist for at least 1 mo, and that resemble similar types of changes found in many neurodegenerative conditions.

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baudrunner
1 / 5 (1) Jul 16, 2013
"..cranial irradiation can reduce quality of life by causing irreversible cognitive impairment."


So much for the brain's elasticity. Some cognitive impairment probably occurs after these treatments, but they are not irreversible, if conventional thinking on the subject of the brain's ability to regenerate neurons and form new neural networks is correct.
MrVibrating
1 / 5 (1) Jul 16, 2013
@baudrunner - i'm no expert but presumably the widespread dieback causes some kind of cascade of necrosis?
dollymop
5 / 5 (1) Jul 16, 2013
Some years ago my mother was paralyzed from the waist down by radiation scatter from radiation too close to her spine during treatment for metastasized breast cancer. The paralysis began 30 days after her second radiation treatment. It took that long for the nerves in her lower spinal cord to die. It lasted until her death, 3 years later. The neurosurgeon who diagnosed her, was very angry at the common use of radiation to treat cancers - and the lack of information given to patients about side effects. He told us that he had diagnosed many patients who had undergone radiation on their brains, and all of them suffered later from severe brain damage. Radiation damages nervous tissue badly, often irrevocably. Of course he saw the worst cases. Perhaps other cases aren't so severe. He felt that people should be informed ahead of time so they could chose - and this rarely happens. This is the first time I have seen an article on the subject.
baudrunner
not rated yet Jul 19, 2013
@dollymop: It's a sensitive topic. The illusion is that all medical school grads are infallible and created equal once they've been given their walking papers. I've been saying all along that they are just people with jobs. Furthermore, how many patients expire prematurely because HMO's do not want to continue prolonging their lives at their expense? I once saw a documentary in which a young cancer patient with brain cancer who could easily communicate and get around like the rest of us most of the time but required regular hospital stays for treatments died a few days after his HMO decided that the doctors should perform a biopsy on the affected area of the brain, effectively removing a chunk the size of half a mandarin orange. That's the sad state of American medicine. You are at the mercy of HMO's, insurers, and their re-insurers. The skills and potential capabilities are there for the most part, but they are never applied carte blanche to save lives.