Access the full text.
Sign up today, get DeepDyve free for 14 days.
(2004)
Effect of low doses of ionising radiation in infancy on cognitive function in adulthood: Swedish population based cohort studyBMJ, 328
Compromised quality of life in adult patients who have received a radiation dose towards the basal part of the brain. A case–control study in long-term survivors from cancer in the head and neck region
Radiat Oncol
(2008)
Cranial radiation therapy and damage to hippocampal neurogenesisDev Disabil Res Rev, 14
(2009)
Defining the human hippocampus in cerebral magnetic resonance images–an overview of current segmentation protocolsNeuroImage, 47
(2006)
Early patterns of verbal memory impairment in children treated for medulloblastomaNeuropsychology, 20
(2008)
Small baseline volume of left hippocampus is associated with subsequent conversion of MCI into dementia: the Goteborg MCI studyJ Neurol Sci, 272
(2009)
Hypopituitarism following radiotherapyPituitary, 12
C Tomasi, R Manduchi (1998)
Bilateral filtering for gray and color images
(1989)
Anterior temporal lobes and hippocampal formations: normative volumetric measurements from MR images in young adultsRadiology, 172
(2009)
Brain damage from anticancer treatments in adultsCurr Opin Oncol, 21
(2001)
Amygdalar and Hippocampal Volumetry in Control Participants: Differences Regarding HandednessAJNR Am J Neuroradiol, 22
(1988)
Effects of low-dose cranial radiation on growth hormone secretory dynamics and hypothalamic-pituitary functionAm J Dis Child, 142
(2005)
MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disordersMol Psychiatry, 10
(2006)
Sex and symmetry differences in hippocampal volumetrics: before and beyond the opening of the crus of the fornixHippocampus, 16
(1997)
Specific hippocampal volume reductions in individuals at risk for Alzheimer's diseaseNeurobiol Aging, 18
(2007)
Impaired human hippocampal neurogenesis after treatment for central nervous system malignanciesAnn Neurol, 62
(2009)
Adult hippocampal neurogenesis: Regulation, functional implications, and contribution to disease pathologyNeurosci Biobehav Rev, 33
(2005)
MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employedMol Psychiatry, 10
(2009)
CNS complications of radiotherapy and chemotherapyLancet, 374
(2004)
A critical review of the clinical effects of therapeutic irradiation damage to the brain: the roots of controversyNeuropsychol Rev, 14
(2005)
Preservation of hippocampal volume throughout adulthood in healthy men and womenNeurobiol Aging, 26
(2007)
Hippocampal volume is as variable in young as in older adults: implications for the notion of hippocampal atrophy in humansNeuroImage, 34
(2007)
Single extreme low dose/low dose rate irradiation causes alteration in lifespan and genome instability in primary human cellsBr J Cancer, 96
(1999)
Hippocampal layers on high resolution magnetic resonance images: real or imaginary?J Anat, 195
(1990)
The Nottingham Health Profile–a measure of health-related quality of lifeScand J Prim Health Care Suppl, 1
(2002)
Pathogenesis of cognitive decline following therapeutic irradiation for head and neck tumorsActa Oncol, 41
(1984)
The Psychological General Well-Being (PGWB) IndexAssessment of Quality of Life in Clinical Trials of Cardiovascular Therapies
(1997)
A nonlinear gaussian filter applied to images with discontinuitiesJournal of Nonparametric Statistics, 8
HJ Dupuy (1984)
Assessment of Quality of Life in Clinical Trials of Cardiovascular Therapies
(1982)
A short questionnaire for the measurement of habitual physical activity in epidemiological studiesAm J Clin Nutr, 36
H Duvernoy (2005)
The Human Hippocampus
(2009)
Irradiation to the immature brain attenuates neurogenesis and exacerbates subsequent hypoxic-ischemic brain injury in the adultJ Neurochem, 111
(2004)
A Bayesian Framework for Image DenoisingThesis
(2012)
Cranial irradiation alters dendritic spine density and morphology in the hippocampusPLoS One, 7
(2004)
Abnormal hippocampal development in children with medulloblastoma treated with risk-adapted irradiationAJNR Am J Neuroradiol, 25
A Wrangsjö (2004)
Thesis
(2003)
Radiological and clinical assessment of long-term brain tumour survivors after radiotherapyRadiother Oncol, 69
(2009)
Differential recovery of neural stem cells in the subventricular zone and dentate gyrus after ionizing radiationStem Cells, 27
(2011)
Consistent neuroanatomical age-related volume differences across multiple samplesNeurobiol Aging, 32
(2005)
Age-dependent sensitivity of the developing brain to irradiation is correlated with the number and vulnerability of progenitor cellsJ Neurochem, 92
Background: An earlier study from our group of long time survivors of head and neck cancer who had received a low radiation dose to the hypothalamic-pituitary region, with no signs of recurrence or pituitary dysfunction, had their quality of life (QoL) compromised as compared with matched healthy controls. Hippocampal changes have been shown to accompany several psychiatric conditions and the aim of the present study was to test whether the patients’ lowered QoL was coupled to a reduction in hippocampal volume. Methods: Patients (11 men and 4 women, age 31–65) treated for head and neck cancer 4–10 years earlier and with no sign of recurrence or pituitary dysfunction, and 15 matched controls were included. The estimated radiation doses to the basal brain including the hippocampus (1.5 – 9.3 Gy) had been calculated in the earlier study. The hippocampal volumetry was done on coronal sections from a 1.5 T MRI scanner. Measurements were done by two independent raters, blinded to patients and controls, using a custom method for computer assisted manual segmentation. The volumes were normalized for intracranial volume which was also measured manually. The paired t test and Wilcoxon’s signed rank test were used for the main statistical analysis. Results: There was no significant difference with respect to left, right or total hippocampal volume between patients and controls. All mean differences were close to zero, and the two-tailed 95% confidence interval for the difference in total, normalized volume does not include a larger than 8% deficit in the patients. Conclusion: The study gives solid evidence against the hypothesis that the patients’ lowered quality of life was due to a major reduction of hippocampal volume. Background recently emerged as one possible such region. Cognitive Side effects of high dose radiation therapy directed to impairment and lowered quality of life are significant the CNS is a well-known concern [1,2]. Less is known sequels in patients irradiated for head and neck tumors about the effects on the brain of low radiation doses, and vascular damage resulting in hypoxia in the medial which may result from treatment of cancers outside the temporal lobe is a possible cause [7,8]. Further, the CNS, although there is some clinical and laboratory evi- hippocampus is a neurogenic region of the brain, with dence of such effects [3,4]. No studies have as yet with the presence of both progenitor cells and a microenvir- certainty identified human brain regions that are more onment suitable for production of new neurons [9]. sensitive to radiotherapy [5,6] but the hippocampus has Children with a slowed cognitive development after adapted radiotherapy treatment of medulloblastoma also had a delayed development of their hippocampi [10,11]. * Correspondence: helge.malmgren@filosofi.gu.se Animal studies have shown that when brains of young Department of Philosophy, Linguistics and Theory of Science, University of rats are unilaterally irradiated, the volume of the Gothenburg, Gothenburg, Sweden Full list of author information is available at the end of the article © 2012 Olsson et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Olsson et al. Radiation Oncology 2012, 7:202 Page 2 of 8 http://www.ro-journal.com/content/7/1/202 irradiated hippocampus is reduced compared to the concomitant somatic disease. For details of the selection non-irradiated side, corresponding to an apoptosis- process see our companion paper [18]. Median time induced loss of proliferating neural stem and progenitor from radiation treatment to the performance of the cells [12,13]. A post-mortem study on patients treated study was 6 years (range 4–10 years). None of the with chemotherapy and cranial irradiation, some with selected 15 patients had a significant growth hormone reported memory deficits, showed profoundly reduced deficiency or other endocrine disturbance but 6 had hippocampal neurogenesis. This further supports the hy- thyroxin substitution since at least 6 months at the time pothesis that neurocognitive impairment after CNS- of the study. Fifteen healthy controls matched for age, directed therapy to some degree is due to a hampered sex and BMI were recruited. Relatives or close friends hippocampal neurogenesis [14,15]. A recent laboratory were selected in the first place in order to adjust for so- study of 10 Gy radiation to the rodent hippocampus cial status. The anamnestic investigation of both patients showed significant changes in spine density and morph- and controls included an estimation of lifetime smoking. ology in cornu ammonis 1 beside the changes in the One male and one female patient, both in the orophar- neurogeneous gyrus dentatus [16]. There is also experi- ynx cancer group, were left-handed as were two male mental evidence that late effects involve yet other areas; controls. Patients and controls all underwent an MRI one study found that mice with radiation damage to the examination of the brain on a Philips Gyroscan Intera neurogenic zones had impaired recovery from later is- 1.5 T scanner. Written informed consent was received chemic damage [17]. from all participants in the study. The study was Radiotherapy to patients with cancer in the head and approved by the Ethics Committee of the University of neck region will result in a low dose to the basal parts of Gothenburg (dnr S644-01). the brain. In a recent retrospective study from our group [18] fifteen long-term survivors of such treatment, with Radiation treatment and dose to the basal brain no sign of recurrence or pituitary dysfunction, were All patients had received external-beam radiotherapy identified and compared with 15 controls matched for (EBRT) with a beam quality of 4–6 MV from linear age, sex, BMI and social status. Several quality of life accelerators (Varian) using CT-assisted 3-D dose plan- dimensions were significantly compromised in patients ning (Cadplan System). Thirteen of the patients had also compared to controls, an observation which might be received a brachytherapy boost after the external ther- related to a negative effect on the CNS of the radiation apy. For dosage and other details see [18]. In that study, therapy. Hippocampal volumetry has proven to be a the dose to the pituitary and hypothalamus, including sensitive indicator of several CNS disorders, including the contribution from the external radiotherapy as well Alzheimer’s disease and its precursor states [19,20]. as from the brachytherapy, was calculated in detail from However, to our knowledge no volumetric study of the the CT dose plans. The calculations showed that for the hippocampi has been performed in patients who have 13 patients with cancer of the oropharynx, the median received low-dose radiation to the basal brain at adult accumulated dose to the hypothalamus was 1.9 Gy age. The purpose of the present study is to test the hy- (range 1.5-2.2 Gy) and the median dose to the pituitary pothesis that the lowered quality of life of the patients is gland 2.4 Gy (range 1.8-3.3 Gy). The two patients with due to a substantial reduction in hippocampal volume. epipharynx cancer received 9.3/6.0 Gy in the hypothal- amus and 46.1 Gy/ 33.5 Gy in the pituitary region. The Methods hippocampi were not clearly demarcated on the CT dose Patients plans and therefore no separate calculation for the dose In 2002, 101 individuals treated for head and neck ma- to the hippocampi was performed. Instead the hippo- lignancies were identified from the local database of the campi were assumed to receive a similar dose as the Department of Oncology. They had received radiother- hypothalamus since these structures are at a similar dis- apy to the neck and base of the skull during 1992 to tance from the field border. 1998 due to cancer in the epipharynx or oropharynx. Out of these 101, fifteen patients (11 men and 4 women, Quality of life mean age 56 years, range 31–65) with no sign of recur- In [18], quality of life was assessed using three generic self- rence participated in a final intensive study. Thirteen of rating questionnaires: the Nottingham Health Profile these were treated for cancer of the oropharynx and two (NHP I) [21], the Psychological General Well-Being for cancer of the epipharynx; the two latter received (PGWB) index [22], the Symptom Checklist-90 (SCL-90 R) higher radiation doses to the brain (see below). In order [23] and the Baecke Questionnaire [24]. The patients to eliminate several confounders, patients included were selected had a lower quality of life, with more anxiety and highly selected well functioning patients without hypo- depressiveness and lower vitality, than the matched pituitarism due to the radiotherapy and without controls. Olsson et al. Radiation Oncology 2012, 7:202 Page 3 of 8 http://www.ro-journal.com/content/7/1/202 Hippocampal volumetry The study was done while a custom method for com- puter assisted manual volumetry was being developed using the present sample and three other datasets. Only the results from the fully developed method will be reported here. For details about the method see also [19]. The segmentation was performed on interactive Wacom PL400 and PL700 screens in the Hipposegm routine – a software developed in Matlab . Before seg- mentation the MR images were preprocessed using image intensity normalization and Bayesian noise reduc- tion [25]. The noise reduction was performed using bi- lateral filtering [26,27] with Gaussian kernels. Figure 1 Segmentation of the hippocampal body, including the parts of subiculum contiguous with the hippocampus. The hippocampal segmentation was done on T1 weighted coronal slices scanned perpendicularly to the hippocampal principal axis. The main scan parameters means of the landmark setting and noise reduction, the for this series and the sagittal series used for ICV seg- whole hippocampus including the tail [31] could be seg- mentation (see below) are presented in Table 1. mented without ad hoc determination of the most anter- Anatomical definitions of the hippocampus and the ior and the most posterior slice [33,34]. See Figure 2. hippocampal formation are given in Duvernoy’s sectional A 3D-visualisation was done after the preliminary seg- anatomy of the hippocampus [28] which is the basis for mentation of the hippocampus to check for deviations the segmentation protocol used. Our protocol is partly from anatomical and curvature expectations. similar to that of Convit [29,30] and only the part of the Two raters, EO and CE, both segmented the whole ma- subiculum inferior of and contiguous with the hippo- terial using the fully developed method. Both raters were campus was included (Figure 1). The fimbria and fornix blind for group belonging, patient ID, and other patient were excluded, and the hippocampal tail segmentation data. Because of EO’s greater experience with the method, was based on Maller [31]. Since limited resolution makes we have chosen to present the results from his measure- it difficult to demarcate the alveus from other parts of ment. (CE’s measurements gave quite similar results). the hippocampus on 1.5 T scanners [32], it was included in the segmentation. Intracranial volume estimation and normalization Table 2 summarizes the rules adhered to in the present To reduce the variance in hippocampal volumes by study. normalization to skull size, intracranial volumes (ICV) The segmentation process consisted of two steps: 1. were measured for all subjects. Since we were at the time Pointwise landmark setting was done in the reformatted developing and validating a quick algorithm for estimating sagittal view of the coronal images where the demarcation ICV, the same two raters (EO and CE) did a full manual in the original coronal images is indiscernible or difficult segmentation of ICV in the whole material, using the Hip- to interpret. 2. Segmentation of the hippocampus in the posegm software on 5 mm T2 sagittal slices. The mean of coronal images was done by continuous pen drawing. By these measurements was used as the value of ICV. The main scan parameters for the ICV segmentation are sum- Table 1 Scan parameters marized in Table 1 above. No results from the ICV meas- Acquisition sequence 3D T1 FFE T2 W/TSE urement are presented here except its inter-rater reliability. Orientation Coronal Sagittal We then calculated the regression of left and right hip- pocampal volumes on ICV in the whole material. To get Slice thickness mm 2.4 5 a normalized volume V from an absolute volume norm Slice center-to-center distance mm 1.2 6 V , we used the formula [35]: abs Repetition time ms 25 5834 Echo time ms 4.6034 110 V ¼ V –k ðÞ ICV –MeanðÞ ICV norm abs Flip angle ° 30 90 Field of view mm 230 250 where ICV is the current ICV estimate, k is the detected regression coefficient and Mean(ICV) refers to the mean Acquisition voxel size (AP * LR * FH) mm 2.4*0.72*0.57 1.12*5.0*0.89 estimated ICV in the material. Mean normalized volume Reconstruction matrix size 512*512 256*256 in the whole sample therefore equals mean absolute Reconstruction pixel size mm 0.45*0.45 0.98*0.98 volume. Olsson et al. Radiation Oncology 2012, 7:202 Page 4 of 8 http://www.ro-journal.com/content/7/1/202 Table 2 Definitions of hippocampal segmentation borders Anterior border Landmark setting where the uncal recess of the temporal horn or the alveus is visible in the sagittally reformatted image Posterior Landmark setting between the gray matter of the hippocampal tail and the surrounding white matter in the sagittally reformatted border image Medial border Border between the hippocampal body and the transverse fissure; border between the hippocampal head and the crural cistern Lateral border Medial wall of the temporal horn Inferior border Border between the gray matter of the subiculum and the white matter in the parahippocampal gyrus Statistics Levene’s test of equality of variances. Beside the paired and Interrater reliability for the hippocampal segmentation unpaired comparisons, hippocampal and intracranial by the two raters was calculated using raw correlation volumes were correlated with age. For correlations, Pear- (Pearson’s r) and intraclass correlation (ICC, two-way son’s r and Spearman’s ρ were used. mixed model, single measure reliability, both absolute Since the results using parametric and non-parametric agreement and consistency versions). methods were generally in very good agreement, only Interrater reliability for the intracranial volume segmen- those from the parametric methods are reported. tation by the two raters was calculated using Pearson’sr Calculations were done on the whole sample of 30 and ICC (two-way mixed model, average measure reliabil- subjects and, in order to maximize the homogeneity of ity, absolute agreement). the sample, also on a restricted group that did not in- Pairwise comparisons of normalized hippocampal clude the two patients with epipharyngeal cancer (and in volumes (left and right side separately, as well as total the pairwise comparisons, their controls). volumes) between patients and their matched controls were The main calculations were made using StatView 5.0 performed using both parametric and non-parametric for Macintosh. For the reliability analysis, SPSS 19 for methods: paired t test (two-tailed) with 95% confidence Macintosh was also used. intervals and Wilcoxon’s signed rank test. Hippocampal volumes on the right and the left side were compared for Results all subjects using the same tests. Groupwise comparisons Reliability between male and female subjects with respect to both ab- The raw correlation (Pearson’s r) between the two raters’ solute and normalized hippocampal volumes were also per- measurements of intracranial volume was 0.987 and the formed. For these, the unpaired t test (two-tailed) was used absolute agreement intraclass correlation (ICC; two-way together with Mann-Whitney’s U test. Before the unpaired mixed model, average measure reliability) was 0.992. t test the homogeneity of variances was tested with Figure 2 Landmark setting. A1. Landmarks set in the reformatted sagittal slice of the hippocampal region. Yellow line shows the position of the coronal slice to in A2. Red crosses used for anterior and posterior limits. Green crosses used for other limits. A2. Landmarks transformed into the coronal view to guide the segmentation (red line) in the anterior hippocampal head. B1. Landmarks set in the reformatted sagittal slice of the hippocampal region. Yellow line showing the position of the coronal slice in B2. B2. Landmarks (crosses) transformed into the coronal view to guide the segmentation (red line) in the most difficult parts of the hippocampal tail. Olsson et al. Radiation Oncology 2012, 7:202 Page 5 of 8 http://www.ro-journal.com/content/7/1/202 The raw correlation (Pearson’sr) between EO’sand CE’s are not shown in Table 4 but the L/R difference was measurements of total hippocampal volumes was 0.854; somewhat higher in the control group (8.5%) and smal- the absolute agreement intraclass correlation (ICC; two- ler (5.5%) but still highly significant among the patients. way mixed model, single measure reliability) was 0.764. Also not shown is that among the 24 right-handed sub- Consistency ICC (two-way mixed model, single measure jects in the restricted sample the L/R difference was reliability) was 0.852. 6.7%, and among the four left-handed subjects it was 9.5% (the right hippocampus still the bigger one). Main results It should be noted that patient 4 had a very small ICV Table 3 shows the results of a pairwise comparison of compared to patient 6. In terms of normalized volumes, normalized hippocampal volumes between patients and the left hippocampus of both patients deviate somewhat controls in the restricted homogeneous sample of 13 from the mean of the restricted sample (cf. Table 3). Pa- pairs. A negative difference means that the patient mean tient 4 lies one SD above the group mean, while patient is below the control mean. 6 lies one and a half SD below the mean and has the The comparison does not reveal any significant differ- next to lowest normalized left hippocampal volume in ence in any of the measures of normalized hippocampal the whole sample of 30. Their right hippocampal volumes. The observed small mean patient/control vol- volumes are close to the restricted group mean. ume differences – at most 3% of a mean volume – go both ways. The two-tailed 95% confidence interval for The hippocampus and age the difference in total normalized hippocampal volume, The correlation between age and total normalised hippo- expressed as a percentage of the volume mean, ranges campal volume in the whole sample is negative (−0.457) from 7.5% on the negative side (corresponding to smal- and significant (p = 0.0103). In the restricted sample of ler patient volumes) to 9.0% on the positive side (corre- 28 it is still significant (p = 0.0221). If the restricted sam- sponding to larger patient volumes). Adding the two ple is split according to gender, the correlation becomes epipharynx patients (see Table 4) to the sample does not −0.500 (p = 0.0198) in the male group, but is close to change the results notably except that it further com- zero (actually weakly positive) among the females. The presses the confidence interval. A statistical subgroup correlation is essentially the same among the male analysis based on gender is not meaningful because of patients (−0.499) and the male controls (−0.513). The the low number of female participants. age change in the male group corresponds to an annual 0.5% decrease in volume. Comparisons of men and women, and left vs right hippocampus Discussion The mean absolute and normalized hippocampal This is to our knowledge the first study on hippocampal volumes in the restricted group of 28 subjects, split on volumes after low dose radiation to the basal part of the men and women, are presented in Table 4. Since the adult human brain. Although the dose to the hippocam- results of these calculations were similar in patients and pus could not be calculated directly, the estimates of ra- controls, they are not presented separately. The last two diation dose to relevant areas are probably more exact rows of Table 4 present the corresponding results from than in any previous study. The small study size is an ef- Patient 4 (man) and Patient 6 (woman), both with fect of our ambitions to minimize the influence of con- former epipharyngeal cancer. Note that the measure of founding factors in an original sample of 101 patients. variation is 2 standard deviations. Moreover, the patient sample is homogeneous in terms There is a nearly significant difference, in the order of of treatment with the exception of two patients who 10%, between men and women regarding total absolute received a higher radiation dose; these were treated sep- volumes. The difference is eradicated when the volumes arately in the statistical analysis. are normalized. There is also a highly significant abso- Automatic methods for hippocampal volumetry are lute volume difference of 7.1% between left and right rapidly gaining acceptance. They have undisputed advan- hippocampus in the group of 28. Patients vs control data tages in terms of cost, inter-rater reliability and 3 2 Table 3 Normalized right, left and total hippocampal volumes (mm ) in 13 patients and their controls Pat mean Cont mean Diff DF t value p 95% CI Right 2454.8 2476.1 −21.3 12 −0.186 0.839 −244.4 < D < 201.9 Left 2324.5 2265.8 58.7 12 0.774 0.525 −136.4 < D < 253.9 Total 4779.3 4741.8 37.4 12 0.272 0.840 −357.5 < D < 432.5 Pat mean: Patient mean normalized volume. Cont mean: Control mean normalized volume. Diff: difference between patient and control mean. DF: degrees of freedom. p: significance level of patient/control difference, paired t test (two-tailed). CI: Confidence interval for difference between patient and control mean. Olsson et al. Radiation Oncology 2012, 7:202 Page 6 of 8 http://www.ro-journal.com/content/7/1/202 Table 4 Mean absolute and normalized hippocampal volumes (mm ) in the restricted group of 28 subjects, split on men and women, and of the two epipharynx patients Right abs Left abs Total abs Rightnorm Leftnorm Total norm R/L p All (n = 28) 2472.2 ± 676.9 2301.1 ± 622.7 4773.3 ± 1261.5 2466.7 ± 519.8 2296.1 ± 456.0 4762.7 ± 924.6 <0.0001 Men (n = 21) 2530.9 ± 689.3 2364.9 ± 659.6 4895.8 ± 1310.4 2458.7 ± 519.6 2299.5 ± 500.5 4758.2 ± 968.3 Women (n = 7) 2296.0 ± 534.2 2109.8 ± 258.6 4405.9 ± 773.4 2490.4 ± 559.0 2285.9 ± 316.7 4776.3 ± 848.6 M/W p 0.028* 0.931 Pat 4 W 2167.3 2268.7 4436.0 2430.4 2507.1 4937.5 Pat 6 M 2463.1 2009.6 4472.6 2355.1 1911.8 4266.8 Group results are presented plus minus 2 standard deviations. Right abs: absolute volume of right hippocampus, etc. Rightnorm: normalized volume of right hippocampus, etc. R/L p: significance level of the difference between right and left volumes (paired t test). M/W p: significance level of the differences between. comparability between studies. However, for small-scale It could be argued that the sample is small and that the studies involving only intra-study comparisons, we study therefore has insufficient power. This argument would argue that manual segmentation is still superior. would have had a point if our only result had been that This is even more so since the issue of ICV the mean volume difference between patients and controls normalization has not been satisfactorily resolved for the was not significantly different from zero. However, all most used automatic method [36]. observed mean volume differences were close to zero, and The reliability results for the volumetric method are the 95% confidence interval for the difference in total nor- acceptable. Since the main results in the study are based malized volume does not include larger deficits in the pa- on differences between patients or groups, the most tient group than 8% of the group mean. Using the data relevant measure when comparing the results of the two from the second rater would have given very similar raters is consistency ICC which does not take systematic results. Hence our results constitute solid positive evi- (non-random) differences between the raters into ac- dence that low dose radiation to the basal brain in adults count. Importantly, consistency ICC was considerably does not cause a lasting, major volume reduction of the higher than absolute measure ICC which reflects that hippocampi. The lowered quality of life in our patient the latter was strongly influenced by such a systematic group stands in need of some other explanation. difference. When interpreting the reliability figures, one The neurogenic cells in the gyrus dentatus are the most should also bear in mind that the method included seg- radiosensitive elements of the hippocampus and a sub- mentation of the hippocampal tail, which is the most dif- region analysis would have added important information. ficult part and adds variation in comparison with not However, such an analysis is not feasible on 1.5 T data. including the tail (data not shown). Further, experimental and clinical evidence support the The size of the observed interindividual variation in hip- thought that the cognitive effects seen long after low dose pocampal volumes as reported in Table 4 accords with re- radiation to the brain are at least partly mediated by indir- cently published data from healthy subjects [37]. Other ect effects on other structures than the gyrus dentatus [40]. facts that speak in favour of the validity of our measure- The method described in this work may be of value in ments are that the observed volumetric differences between the future considering the change in radiation treatment left and right hippocampal volumes and between men and techniques that are being introduced, such as IMRT (in- women, as well as the negative correlation with age in the tensity modulated radiation therapy) and SRT (stereotac- male group, are in general accord with main trends among tic radiation therapy). The radiation dose will be better earlier findings [31,36,38,39]. The L/R difference and the targeted and controlled with these techniques, but the age correlation were similar in patients and controls. The areas receiving low dose will be much larger than after influence of handedness could not be tested properly since the traditional methods used in our study. It is not the number of left-handed subject was too low to admit known what this means biologically and clinically, and it any statistically meaningful subgroup calculation. has to be studied and documented carefully. Our study Intracranial volume, ICV, was measured with a highly re- should be seen as a part of this work. liable manual method. Normalization of hippocampal volumes with respect to ICV eliminated the gender differ- Endnote ences and reduced the overall variance. Somewhat surpris- In two subjects the scans were incomplete at the level ingly, the latter does not hold for the female group. This is of the tail and mean tail values had to be imputed. probably a statistical artifact since there were only seven Competing interests females while the normalization was based on a regression The authors have no conflict of interest that could be perceived as in the whole sample of 30 subjects. prejudicing the impartiality of the research reported. Olsson et al. Radiation Oncology 2012, 7:202 Page 7 of 8 http://www.ro-journal.com/content/7/1/202 Authors' contributions 13. Hellstrom NA, Bjork-Eriksson T, Blomgren K, Kuhn HG: Differential recovery EO, CE, EL, GJ, SE and HM contributed to the conception and the design of of neural stem cells in the subventricular zone and dentate gyrus after the trial and drafted the first version of the manuscript. All authors ionizing radiation. Stem Cells 2009, 27:634–641. contributed to the collection of data, data interpretation and critical revision 14. Monje M: Cranial radiation therapy and damage to hippocampal of the manuscript and have reviewed the final version for publication. neurogenesis. Dev Disabil Res Rev 2008, 14:238–242. 15. Monje ML, Vogel H, Masek M, Ligon KL, Fisher PG, Palmer TD: Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies. Ann Neurol 2007, 62:515–520. Acknowledgements 16. Chakraborti A, Allen A, Allen B, Rosi S, Fike JR: Cranial irradiation alters The work was supported by grants from the University of Gothenburg, the dendritic spine density and morphology in the hippocampus. PLoS One King Gustav V Jubilee Clinic Cancer Research Foundation, Gothenburg, and 2012, 7:e40844. the Swedish Research Council (grant # 2002–5462). No actual or potential 17. Zhu C, Huang Z, Gao J, Zhang Y, Wang X, Karlsson N, Li Q, Lannering B, Bjork- conflicts of interest exist. Eriksson T, Georg Kuhn H, Blomgren K: Irradiation to the immature brain attenuates neurogenesis and exacerbates subsequent hypoxic-ischemic Author details braininjuryinthe adult. JNeurochem 2009, 111:1447–1456. Institute of Neuroscience and Physiology; Sahlgrenska University Hospital, 18. Löfdahl E, Berg G, Johansson K-A, Leonsson-Zachrisson M, Malmgren H, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Mercke C, Olsson E, Wiren L, Johansson G: Compromised quality of life in Department of Oncology, Sahlgrenska University Hospital, Sahlgrenska adult patients who have received a radiation dose towards the basal Academy, University of Gothenburg, Gothenburg, Sweden. Department of part of the brain. A case–control study in long-term survivors from Biomedical Engineering, Linköping University, Linköping, Sweden. cancer in the head and neck region. Radiat Oncol, in press. Department of Imaging Sciences, University of Rochester Medical Center, 19. Eckerstrom C, Olsson E, Borga M, Ekholm S, Ribbelin S, Rolstad S, Starck G, Rochester, N.Y, USA. Department of Endocrinology, Sahlgrenska University Edman A, Wallin A, Malmgren H: Small baseline volume of left Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, hippocampus is associated with subsequent conversion of Sweden. Department of Radiation Physics, Sahlgrenska University Hospital, MCI into dementia: the Goteborg MCI study. J Neurol Sci 2008, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 272:48–59. Department of Medical Physics and Biomedical Engineering, Sahlgrenska 20. Geuze E, Vermetten E, Bremner JD: MR-based in vivo hippocampal University Hospital, Sahlgrenska Academy, University of Gothenburg, volumetrics: 2. Findings in neuropsychiatric disorders. Mol Psychiatry Gothenburg, Sweden. Department of Philosophy, Linguistics and Theory of 2005, 10:160–184. Science, University of Gothenburg, Gothenburg, Sweden. 21. Wiklund I: The Nottingham Health Profile–a measure of health-related Received: 22 June 2012 Accepted: 25 November 2012 quality of life. Scand J Prim Health Care Suppl 1990, 1:15–18. Published: 29 November 2012 22. Dupuy HJ: The Psychological General Well-Being (PGWB) Index.In Assessment of Quality of Life in Clinical Trials of Cardiovascular Therapies. Edited by Wenger NK, Mattson ME, Furburg CD, Elinson J. New York: Le Jacq Publishing; 1984:170–183. References 23. Symptom Checklist-90 Revised. http://psychcorp.pearsonassessments.com/ 1. Darzy KH, Shalet SM: Hypopituitarism following radiotherapy. Pituitary HAIWEB/Cultures/en-us/Productdetail.htm?Pid=PAg514. 2009, 12:40–50. 24. Baecke JA, Burema J, Frijters JE: A short questionnaire for the 2. Ricard D, Taillia H, Renard JL: Brain damage from anticancer treatments in measurement of habitual physical activity in epidemiological studies. Am adults. Curr Opin Oncol 2009, 21:559–565. J Clin Nutr 1982, 36:936–942. 3. Hall P, Adami HO, Trichopoulos D, Pedersen NL, Lagiou P, Ekbom A, Ingvar 25. Wrangsjö A: A Bayesian Framework for Image Denoising.In Thesis. M, Lundell M, Granath F: Effect of low doses of ionising radiation in Linköping: Linköping University; 2004. infancy on cognitive function in adulthood: Swedish population based 26. Godtliebsen F, Spjotvoll E, Marron JS: A nonlinear gaussian filter applied to cohort study. BMJ 2004, 328:19. images with discontinuities. Journal of Nonparametric Statistics 1997, 4. Okada M, Okabe A, Uchihori Y, Kitamura H, Sekine E, Ebisawa S, Suzuki M, 8:21–43. Okayasu R: Single extreme low dose/low dose rate irradiation causes 27. Tomasi C, Manduchi R: Bilateral filtering for gray and color images, alteration in lifespan and genome instability in primary human cells. Proceedings of the Sixth International Conference on Computer Vision. Br J Cancer 2007, 96:1707–1710. Washington DC: IEEE Computer Society; 1998:839–846. 5. Armstrong CL, Gyato K, Awadalla AW, Lustig R, Tochner ZA: A critical review of the clinical effects of therapeutic irradiation damage to the 28. Duvernoy H: The Human Hippocampus. Thirdth edition. Berlin: Springer; 2005. brain: the roots of controversy. Neuropsychol Rev 2004, 14:65–86. 29. Convit A, De Leon MJ, Tarshish C, De Santi S, Tsui W, Rusinek H, George A: Specific hippocampal volume reductions in individuals at risk for 6. Costin G: Effects of low-dose cranial radiation on growth hormone Alzheimer's disease. Neurobiol Aging 1997, 18:131–138. secretory dynamics and hypothalamic-pituitary function. Am J Dis Child 30. Harmonization of protocols for the manual tracing of the hippocampus - an 1988, 142:847–852. EADC-ADNI joint effort AUTHOR-CERTIFIED PROTOCOL FEATURES AND TRACINGS. 7. Abayomi OK: Pathogenesis of cognitive decline following therapeutic http://www.hippocampal-protocol.net/public/file/convit-protocol.pdf. irradiation for head and neck tumors. Acta Oncol 2002, 41:346–351. 31. Maller JJ, Reglade-Meslin C, Anstey KJ, Sachdev P: Sex and symmetry 8. Johannesen TB, Lien HH, Hole KH, Lote K: Radiological and clinical differences in hippocampal volumetrics: before and beyond the opening assessment of long-term brain tumour survivors after radiotherapy. of the crus of the fornix. Hippocampus 2006, 16:80–90. Radiother Oncol 2003, 69:169–176. 9. Balu DT, Lucki I: Adult hippocampal neurogenesis: Regulation, functional 32. Wieshmann UC, Symms MR, Mottershead JP, MacManus DG, Barker GJ, Tofts implications, and contribution to disease pathology. Neurosci Biobehav PS, Revesz T, Stevens JM, Shorvon SD: Hippocampal layers on high Rev 2009, 33:232–252. resolution magnetic resonance images: real or imaginary? J Anat 1999, 10. Nagel BJ, Delis DC, Palmer SL, Reeves C, Gajjar A, Mulhern RK: Early patterns 195(Pt 1):131–135. of verbal memory impairment in children treated for medulloblastoma. 33. Geuze E, Vermetten E, Bremner JD: MR-based in vivo hippocampal Neuropsychology 2006, 20:105–112. volumetrics: 1. Review of methodologies currently employed. 11. Nagel BJ, Palmer SL, Reddick WE, Glass JO, Helton KJ, Wu S, Xiong X, Kun LE, Mol Psychiatry 2005, 10:147–159. Gajjar A, Mulhern RK: Abnormal hippocampal development in children 34. Konrad C, Ukas T, Nebel C, Arolt V, Toga AW, Narr KL: Defining the human with medulloblastoma treated with risk-adapted irradiation. AJNR Am J hippocampus in cerebral magnetic resonance images–an overview of Neuroradiol 2004, 25:1575–1582. current segmentation protocols. NeuroImage 2009, 47:1185–1195. 12. Fukuda A, Fukuda H, Swanpalmer J, Hertzman S, Lannering B, Marky I, Bjork- 35. Jack C Jr, Twomey C, Zinsmeister A, Sharbrough F, Petersen R, Cascino G: Eriksson T, Blomgren K: Age-dependent sensitivity of the developing Anterior temporal lobes and hippocampal formations: normative brain to irradiation is correlated with the number and vulnerability of volumetric measurements from MR images in young adults. Radiology progenitor cells. J Neurochem 2005, 92:569–584. 1989, 172:549–554. Olsson et al. Radiation Oncology 2012, 7:202 Page 8 of 8 http://www.ro-journal.com/content/7/1/202 36. Walhovd KB, Westlye LT, Amlien I, Espeseth T, Reinvang I, Raz N, Agartz I, Salat DH, Greve DN, Fischl B, et al: Consistent neuroanatomical age-related volume differences across multiple samples. Neurobiol Aging 2011, 32:916–932. 37. Lupien SJ, Evans A, Lord C, Miles J, Pruessner M, Pike B, Pruessner JC: Hippocampal volume is as variable in young as in older adults: implications for the notion of hippocampal atrophy in humans. NeuroImage 2007, 34:479–485. 38. Sullivan EV, Marsh L, Pfefferbaum A: Preservation of hippocampal volume throughout adulthood in healthy men and women. Neurobiol Aging 2005, 26:1093–1098. 39. Szabo CA, Xiong J, Lancaster JL, Rainey L, Fox P: Amygdalar and Hippocampal Volumetry in Control Participants: Differences Regarding Handedness. AJNR Am J Neuroradiol 2001, 22:1342–1345. 40. Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D, Delattre JY: CNS complications of radiotherapy and chemotherapy. Lancet 2009, 374:1639–1651. doi:10.1186/1748-717X-7-202 Cite this article as: Olsson et al.: Hippocampal volumes in patients exposed to low-dose radiation to the basal brain. A case–control study in long-term survivors from cancer in the head and neck region. Radiation Oncology 2012 7:202. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit
Radiation Oncology – Springer Journals
Published: Nov 29, 2012
You can share this free article with as many people as you like with the url below! We hope you enjoy this feature!
Read and print from thousands of top scholarly journals.
Already have an account? Log in
Bookmark this article. You can see your Bookmarks on your DeepDyve Library.
To save an article, log in first, or sign up for a DeepDyve account if you don’t already have one.
Copy and paste the desired citation format or use the link below to download a file formatted for EndNote
Access the full text.
Sign up today, get DeepDyve free for 14 days.
All DeepDyve websites use cookies to improve your online experience. They were placed on your computer when you launched this website. You can change your cookie settings through your browser.