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Three Part Question

In [a patient with brain tumor requiring cranial irradiation with pre-exisiting Alzheimer’s disease] would [cranial radiation be safely delivered] without [aggravating Alzheimer’s disease]?

Clinical Scenario

It is rare for Alzheimer’s disease patient to present with brain tumor. You are working in a Radiation Oncology Clinic when the nurse informs you that a patient with CNS Lymphoma and Alzheimer’s disease has arrived. You wonder the safety of cranial irradiation in an Alzheimer’s disease patient and the management of this clinical challenge.

Search Strategy

(Brain RT or cranial irradiation or whole brain RT) and (Alzheimer’s disease) in pubmed interface in World Wide Web was searched using the terms above. Limit was set to human species and English Language. No other limits were set. Search date - 25/11/10.
We used the following keywords in pubmed search:
Alzheimer’s disease and whole brain radiation.
Alzheimer’s disease and brain radiation.
Radiation and Alzheimer’s disease.
Radiation and Alzheimer’s.

Search Outcome

A total of 860 results were obtained. Only five literature were relevant clinically in human population. In addition we did the “related articles search” for that single relevant article, but found no further article of relevance.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Momcilović B Sep 11, 2006 Croatia	86-year-old deceased woman who had suffered from Alzheimer's disease.	This is a case report on distribution of naturally occurring environmental radon daughters (RAD) polonium-210 (210Po; alpha particle emitter) and bismuth-210 (210Bi; beta particle emitter) in nine different brain regions of an 86-year-old deceased woman, who was a resident of North Dakota who suffered from Alzheimer’s diseases (AD) at old age and with otherwise uneventful medical history.	This postmortem case report on an AD patient shows that there was accumulation of natural radioisotopes and their daughters especially Radon at selective loci of brain resulting in high radiation exposure to those loci. More specifically, this study has reported that highest radon daughters (RAD) irradiation (mSv•year-1) occurred in the decreasing order of magnitude: amygdale (Amy) >> hippocampus (Hip) > temporal lobe (Tem) ~ frontal lobe (Fro) > occipital lobe (Occ) ~parietal lobe (Par) > substantia nigra (SN) >> locus ceruleus (LC) ~ nucleus basalis (NB); generally more RAD accumulated in the proteins than lipids of gray and white (gray > white) brain matter. Amy and Hip are particularly vulnerable brain structure targets to significant RAD internal radiation damage in AD (5.98 and 1.82 mSv•year-1, respectively). Naturally occurring RAD radiation occurs for Tem and Fro, then Occ and Par, and SN was in an order of magnitude higher than that in LC and NB; the later was within RAD observed previously in the healthy control brains.	This literature attempts to correlate natural irradiation and enhanced Alzheimer’s disease (AD) deterioration. It tries to establish the inability of AD neural structures to cope up environmental radiation induced free radical injury. It also tries to establish the potential of such radiation accumulation at select locations of brain to induce and/or hasten the process of progressive neuronal degeneration.	This literature is a post-mortem study in single patient and the result cannot be assumed to be universal truth. There could be several reasons for selective accumulation of the daughter radon nuclei at specific loci in brain. The correlation does not mean causation. This natural irradiation being alpha and beta particle having higher biologically effective dose and internally located cannot be compared with external radiation which are gamma rays or X-rays.
Shaw EG March 2006. USA	Thirty-five cranially irradiated patients.	This prospective phase II study evaluated the improvement of cognitive function, mood and health-related QOL in 35 cranially irradiated patients. Thirty-five patients were enrolled between 2001 and 2003, including 23 glioma patients (about half low-grade, half high grade), four meningioma patients, seven with other primary brain tumor histology and one with metastatic disease. Eleven patients went off-study before 24 weeks for various reasons. Twenty-four patients remained on-study for the 24 weeks and completed all assessments. All 24 patients had a primary brain tumor, mostly low-grade glioma; their median age was 45 years, 46% were female, 92% were white, and 8% were black. Cognitive function was measured on several cognitive domains including attention/concentration (Digit Span Test Total), verbal memory (California Verbal Learning Test-II), figural memory (Modified Rey-Osterrieth Figure Test recall) and verbal fluency (Controlled Oral Word Association Test). Mood was evaluated by Profile of mood states (POMS) and Health Related Quality of Life (HRQOL) by FACT-Br total and brain-specific concerns subscale scores.	A significant improvement in the above parameters after 24 weeks course of acetylcholinesterase inhibitor was observed. This study attempts to state that increasing the cerebral acetylcholine activity tends to reverse or nullify the radiation induced cognitive dysfunction, similar to Alzheimer’s Disease (AD) induced cognitive dysfunction. This potentially means that both AD and radiation induce similar cognitive dysfunction.	Increasing the cerebral acetylcholine activity tends to reverse or nullify radiation induced dysfunction similar to that of AD.	The limitation of this study is the lack of suitable control group, lack of blinding and randomization process. While, radiation could have potentially reduced the cholinergic activity of brain similar to AD, there also occurs a possibility that radiation could have caused a different effect which was partially or fully restored by improved cerebral cholinergic level.
Riudavets 2005 Sep-Oct USA	20 cranially irradiated patients who had both pre-radiation (biopsy) and post-radiation (autopsy) specimen for examination.	This study is aimed at investigating radiation induced neurodegenerative changes in a large series of patients receiving radiation for brain tumors. It examined 485 patients with primary or metastatic brain tumor, who received radiation therapy between initial and subsequent pathological study. 20 patients had both biopsy and autopsy specimen for examination. The study included five females and 15 males with a median age of 50 years (range – 33-75 years), and a median interval of 18 months (range = 5-96 months) between the initial biopsy (7cases) and subsequent autopsy (13 cases).	In the autopsy cases examined, none fulfilled either Braak [Braak and Braak 1991] or CERAD [Mirra et al. 1993] criteria for the diagnosis of Alzheimer’s disease. There did not appear to be any significant interval change in the degree of neurodegenerative change in these cases. The remaining 14 (70%) cases did not show any neuro-pathological Alzheimer-related changes (ie. Neuritic plaques, diffuse plaques, neurofibrillary tangles, amyloid) It identified Alzheimer-type neuropathological changes in six cases (30%), including neurofibrillary tangles (fewer than 5 per 10 hpl) sparsely distributed in the cerebral cortex on both the initial and subsequent sample. Neither senile plaques nor amyloid angiopathy were identified. In this study, examination of the preradiation specimens provided important and unique control data. In contrast to previous studies, which only had post-radiation specimens available, additional pre-radiation data allow more meaningful conclusions about the causal relationship between radiation and neurodegenerative changes. In only 6 of the 20 cases isolated, sparse neurofibrillary tangles were found on both the first and second specimen; therefore the presence of neurodegenerative features in these cases do not support the hypothesis that radiation could have produced those changes. None of the cases in this study showed tangles, diffuse or senile plaques and/or A- β amyloid deposition on the post-radiation specimen alone, or an increase in these changes between the pre- and post-radiation sample.	There is no evidence that radiation induces Alzheimer-like neurodegenerative changes in patients receiving therapeutic radiation for brain tumors. This study did not identify neurodegenerative changes typical of Alzheimer's disease such as the formation of neuritic or diffuse plaques and tangles as a consequence of radiation therapy. The neurodegenerative changes of radiation therapy are different from that of Alzheimer’s disease. The clinically observed radiation dementia syndrome characterized by cognitive impairment include memory loss, etc. might have been related more with subtle subcortical features, ie., axonal and myelin loss with white matter necrosis and spongiosis rather than cortical morphologic changes such as tangles or plaques.	The mean interval between the two samples may not have been long enough for the development of neurogdegenerative changes visible at the light microscopic level. The radiation may have induced focal cortical changes, depending on the radiotherapy modality, that were not sampled in this study.
Boerrigter ME 1993 Jan Netherland	43 Alzheimer's Disease (AD) patients and 48 controls.	An exploratory assessment found no significant age-related differences in the percentage SSB disappearance with different repair incubations after exposure of Peripheral Blood Lymphocytes (PBL) to the three different DNA-damaging agents ie. ENU, MMS or Gamma-radiation. The second stage of the study was carried out in a blinded fashion with 43 AD patients and 48 controls without age matching.	Alzheimer’s disease (AD) patients who had no or only one first-degree relative with dementia (sporadic AD), had a mean percentage of SSB disappearance of 42.5 |+ or -~ 8.2% and 43.0 |+ or -~ 4.4%, respectively, which was not significantly different from that found in the control subjects. However, AD patients with at least two first-degree relatives with dementia (considered as familial AD) had a significantly lower percentage SSB disappearance (23.6% |+ or -~ 5.8%) than controls (p |is less than~ 0.01) or AD patients with no or only one first-degree relative with dementia (p |is less than~ 0.02). There was no statistically significant age-related difference in the percentage SSB disappearance at 1 h after exposure to ENU for either the AD groups, the control groups, or all groups combined. The amount of SSB disappearance was not associated with the age of onset, the degree or the duration of the disease. Also, no differences were observed between males and females of either group.	This set of data on large group of Alzheimer’s disease (AD) patients and matched control subjects considerably extends earlier findings and confirms the existence of a DNA repair defect in familial, but not in sporadic AD.	The insignificant SSB in PBL need not necessarily mean the same in neurons. The neurons, being late reacting normal tissue have higher DNA repair capacity and higher radiation tolerance. This study has not measured DSB which are lethal on cells.
Sugihara S 1995 Japan	136 unselected patients with no signs of dementia (90 males and 46 females) at their middle ages (30 and 59 years).	136 unselected patients with no signs of dementia (90 males and 46 females) who died in the Gunma Cancer Center and its associated hospitals at ages between 30 and 59 years were examined from autopsied brains. A-β and tau deposits in the 123 brains of the subjects who died with malignant tumors (123 of 136) were studied. There were 17 in their fourth decades (30-39 years old, 30s groups), 41 in their fifth decades (40-49 years old, 40s group) and 65 in their sixth decades (50-59 years old, 50s group). Tissue samples from the frontal lobe and the temporal lobe (including the hippocampal area) after suitable processing were immunolabelled with Aβ antiserum. The interrelationship between cerebral A-β deposition and clinico-pathological features such as brain metastasis and brain radiation therapies was statistically analyzed in 106 cancer-bearing subjects aged between 40 and 59 using t-test and comparison of two proportions. Of the 106 brains, 41 were found to have brain metastases; 18 patients had received radiation therapy for metastatic and invasive tumors.	Out of the total 106 subjects, 18 had A-β deposits. Of the 18 Aβ-positive cases, 5 had received brain radiation therapy, 3 of which had whole brain radiation therapy and 2 had irradiation of the skull base for invasive tumors. The prevalence of A-β was 27.8% (5 of 18) in the brains from subjects treated with radiation therapy, and approximately double that in subjects without brain radiation therapy (13 or 88, 14.8%). In the frontal lobe, the prevalence of the amyloid angiopathy of the irradiated group (4 of 18, 22.2%) was nearly three times higher than that of the non-radiated group (7 of 88, 8.0%), showing significant increase (P<0.05). Capillary amyloid was found in six cases, and was prominent in those with brain radiation therapy. The amount of irradiation and the duration from the end of radiation therapy to death (survival time) were not significantly different between cases with and without cerebral A-β depositions. Brain radiation had no effect on tau accumulation. Among the 106 subjects, 4 out of 18 irradiated brains (22.2%) showed marked vacular hyalinosis, whereas 2 of 88 non-radiated brains (2.3%) had vascular hyalinosis (P<0.001). In the 88 subjects without brain radiation therapy, the prevalence of A-β deposition in the subjects with brain metastasis/invasion (3 of 23, 13.0%) was similar to that in the subjects without brain metastasis/invasion (10 of 65, 15.4%).	The prevalence of cerebral A-β deposits was about two times higher in patients who had received brain radiation therapy (27.8%) compared to non-radiated patients (14.8%). Amyloid angiopathy was much more prominent (P < 0.05) with radiation therapy (22.2%) than without (8.0%). It was found that cerebral A-β deposition is dependent on aging, even in patients with malignant tumors and at beginning in their forties, and that brain radiation therapy is a possible risk factor of A-β deposition, especially in the form of amyloid angiopathy.	Although amyloid angiopathy is frequently associated with Alzheimer’s disease, it is less specific to Alzheimer’s disease than senile plaques. Arteriovenous malformation promotes A-β immunoreactive amyloid angiopathy.

Comment(s)

Alzheimer's disease (AD) neural structures may have the inability to cope up with natural radiation [Momcilović B et al]. There exist DNA repair defects in familial AD, but not in sporadic AD [Boerrigter ME et al.]. Cranial radiation is a risk factor for A-β amyloid deposition and amyloid angiopathy in Brain. Radiation injures endothelial cells, breaks the blood-brain barrier and could be an enhancing factor of A-β deposition, although further study is necessary [Sugihara S et al.]. Changes typical of AD such as the formation of neuritic or diffuse plaques and tangles were not identified as a consequence of cranial irradiation. Although the neurodegenerative changes of radiation therapy are different from that of AD [Riudavets et al.], both have similar effect on cognitive function of neuronal structures [Shaw EG et al.]. Further studies with larger case sample that includes longer post-treatment intervals are needed to improve the understanding of the consequences and mechanisms leading to radiation-induced neuro-degeneration [Riudavets et al.]. These literatures can be considered as theoretical evidence to state that cranial irradiation can potentiate the neuronal degeneration of AD. The logical conclusion can be that cranial radiation can potentiate the cognitive dysfunction and neurodegeneration of AD. However, this does not constitute satisfactory evidence to neither suggest that radiation aggravates the pre-existing AD nor recommend safe cranial radiation in AD patients. There exists a need for clinical reports in the form of case reports, case series and well designed clinical studies of varying dimensions to ascertain the safety of cranial irradiation in AD patients.

Clinical Bottom Line

Radiation having the potential to induce/hasten neuronal degeneration and AD neuronal structure having got the susceptibility, external cranial radiation used to cure brain tumors, can potentially aggravate cognitive dysfunction of AD. Caution need to be exercised while cranial irradiation of elderly patients with AD and patients with familial AD. Radiation induced changes being similar to AD, neurocognitive changes can accumulate. However this cannot be considered as Level1 evidence to draw evidence based treatment decision over the effect of cranial irradiation on cognitive function of AD patients.

References

1. Momcilović B, Lykken GI, Cooley M. Natural distribution of environmental radon daughters in the different brain areas of an Alzheimer disease victim. Mol Neurodegener 2006 Sep 11;1:11.
2. Shaw EG Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol 2006 Mar 20;24(9):1415-20.
3. Riudavets Relationship between radiation injury and Alzheimer-related neurodegenerative changes. Clin Neuropathol. 2005 Sep-Oct;24(5):236-8.
4. Boerrigter ME Studies on DNA repair defects in degenerative brain disease. Age Ageing. 1993 Jan;22(1):S44-52.
5. Sugihara S Cerebral beta amyloid deposition in patients with malignant neoplasms: its prevalence with aging and effects of radiation therapy on vascular amyloid. Acta Neuropathol. 1995;90(2):135-41.