Prior research has demonstrated that radiation can reduce amyloid-like deposits in extra-cranial disease sites. In this study, researchers at William Beaumont Hospital compared the effects of three doses of radiation administered to 30-week-old male mice with a control group that received no radiation. Randomized groups of three to six mice were irradiated on the right side of their brain with a single 5, 10 or 15 Gy dose. A second series of experiments used fractionated lower-dose radiation of 1 or 2 Gy, delivered in five to 10 treatments (Radiother. Oncol. doi: 10.1016/j.radonc.2015.10.019).

After completion of irradiation, the mice were euthanized one day, or two, four or six weeks later for histopathology evaluation. The researchers analysed three stained coronal slices per mouse to compare the number and size of amyloid-β plaques in the irradiated and untreated sides of the brain. Because the number of plaques in each mouse's cortex varied considerably, the effect of the radiation was determined by the percentage change in absolute plaque number between the two sides, with each animal serving as its own control.

Lead author Brian Marples, radiobiologist and professor in Beaumont's department of radiation oncology, and colleagues, reported a statistically significant reduction in amyloid-β plaques after all single-dose treatments. The largest decrease in amyloid-β plaques after a single radiation exposure was seen with the highest dose and at the longest time post-treatment, at eight weeks.

Low-dose fractionated treatments produced greater reductions in amyloid-β plaques: 50.6% with ten 1 Gy treatments, 72% with five 2 Gy treatments and 78% with ten 2 Gy treatments. This compared with a 29.3% reduction seen after a single 5 Gy dose.

"A key aspect of this study is that lower-dose low-LET [linear energy transfer] radiation therapy produces an effect that is independent of the BBB," wrote the authors. "Treatment efficacy of established AD medications may be enhanced if given in combination with a course of fractionated, non-invasive radiation therapy treatments to further reduce the plaque burden."

The researchers also assessed the expression of genes associated with AD. After single dose treatments, there was a 2.4-fold decrease in presenilin 1 and a 4-fold increase in β-site APP-cleaving enzyme 2 within 48 hours.

The most notable change 24 hours after a low-dose fractionated treatment (five 2 Gy exposures) was a 1.48 fold reduction of Plakophilin 4. Reductions were also evident in plasminogen activators, growth associated protein 43 and protein kinase C theta. The researchers note that these data demonstrate the link between cranial radiation and changes in the expression of genes or factors involved in β-amyloid formation and degradation.

For cognitive testing, 33 mice were trained to locate a platform submerged in a pool of opaque water – a well-established behavioural test used to measure spatial memory function. Nineteen mice received whole-brain irradiation, 14 were controls. Prior to treatment, the two groups did not differ significantly in latency to find the platform. Eight weeks after irradiation, the radiation-treated group displayed significantly reduced latencies compared to the untreated group.

Clinical potential

Marples told medicalphysicsweb that he and his colleagues were encouraged with their findings, because evidence indicated that radiotherapy had an immediate effect on amyloid burden and could translate to an immediate benefit for patients. He stated that although the relationship between plaque reduction and cognitive improvement remains controversial, the application of modest-dose brain-targeted radiotherapy to reduce amyloid burden has the potential to offer a widely available, inexpensive new treatment option for all AD patients, irrespective of the extent of cognitive deficit.

The cognitive and behavioural effects of the amyloid reduction, as a key regulator of AD progression, need to be determined. Also, the underlying mechanism needs to be defined to ensure that this approach can be safely implemented.

"The goal of our future experiments is to determine the temporal dynamics and long-term persistence of the radiation effect, how often and at what dose intensity the radiation therapy needs to be given, and whether prophylactic irradiation can prevent the accumulation of insoluble amyloid burden in pre-symptomatic animals," said Marples. "We need to establish if the reduction in amyloid burden is simply a consequence of the repair and recovery of radiation-related events in the brain, and as such, the mechanism of amyloid clearance is independent of, and unrelated to, AD pathology."

The team is now conducting pre-clinical research to determine whether the reduction in amyloid could be a consequence of the brain responding to radiation-related chemical events, such as oxidative damage, or a cellular event such as radiation-mediated gliosis or cell death. The researchers are also investigating whether radiotherapy causes local production of cytokines that lead to brain inflammation and BBB disruption.

Marples says that a phase I human trial – called "Phase I feasibility study of low dose whole brain irradiation in the treatment of AD" – is also being developed. Its primary endpoint will be to assess the safety, toxicity and adverse events associated with the use of low-dose fractionated whole-brain irradiation in patients diagnosed with probable AD. The secondary endpoint will be to establish whether this intervention changes the recognized progression of AD through cognitive testing.

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