Abstract
Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy-only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution and sex-stratified multivariable linear regression models were used to test associations between Brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared to controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (p’s<0.005), hippocampal sub-regions (p’s<0.03), temporal lobe regions (p’s <0.03), frontal lobe regions (p’s<0.04), and parietal lobe regions (precuneus; p’s<0.002). Long-term problems with learning may be related to residual post-treatment brain differences.
Keywords: Childhood leukemia, dexamethasone exposure, hippocampus
Introduction
Glucocorticoids (hydrocortisone, dexamethasone and prednisone) remain an essential part of acute lymphoblastic leukemia (ALL) therapy. Dexamethasone is frequently used in young children with ALL because of better CNS penetrance, longer plasma and biological half-life, anti-inflammatory properties, and improved anti-leukemia outcome.1,2 However, dexamethasone has increasingly come under scrutiny because of uncertainty as to its optimal dose and the prevalence of associated adverse effects.3,4 We previously reported that adult survivors of childhood ALL treated with chemotherapy-only had smaller hippocampal volumes compared to survivors treated with combined cranial radiotherapy and chemotherapy.5 However, that study did not distinguish between survivors treated with dexamethasone or prednisone, which may account for observed differences in neurocognitive outcomes.6–8
Dexamethasone can exacerbate neuronal injury by provoking an energy crisis and increased intracellular peroxide.9,10 Evidence of oxidative injury during chemotherapy-only treatment for ALL has been previously described11. Cerebrospinal fluid (CSF) levels of oxidized phosphatidylcholine (a sensitive marker for oxidative stress) significantly increased from diagnosis through induction and consolidation, with the most dramatic increase during consolidation treatment in the high-risk group. Elevations of CSF concentration of oxidized phospholipids were associated with neurocognitive deficits in working memory, organization and attention two years after completion of therapy.12
In the current study, we hypothesized that regions of the brain with higher concentrations of glucocorticoid receptors would demonstrate smaller volumes in survivors compared to community controls and these volume differences would be associated with treatment exposure.
Methods
In this retrospective cross-sectional study, survivors were eligible for participation if they were treated on a risk-stratified institution-based chemotherapy-only protocol (TOTXV) and were ≥5 years from cancer diagnosis and ≥8 years of age.13 Exclusions included secondary cancers or relapse requiring cranial radiation or additional chemotherapy, unrelated central nervous system injury/disease, and no longer eligible for pediatric follow-up. Of the 408 potential participants, 302 eligible survivors were identified, of which 218 (72.2%) participated in the study. Eighty-two community controls were recruited from Shelby county, Tennessee. The protocol was approved by the institutional review board at St. Jude Children’s Research Hospital, and all participants/guardians gave written informed assent/consent, as appropriate.
While undergoing active therapy, blood samples were drawn prior to high-dose intravenous methotrexate (HDMTX) infusion, and then again at 6, 23 and 42 hours after the start of each HDMTX course. Blood samples for dexamethasone were collected prior to administration and 1, 2, 4 and 8 hours after the morning dose on days 1 and 8 of reinduction I (corresponding to weeks 7 and 8 of continuation therapy). Serum dexamethasone and methotrexate levels were quantified as area under the curve (AUC), as previously described.14
After completion of therapy, survivors were assessed once during long-term follow up between 5 and 10 years after initial diagnosis and controls were assessed at a similar age. Structural MRI’s were obtained during the >5-year follow-up and included a T1-weighted sagittal 3D MPRAGE sequence (TR/TE/TI = 1980/2.32/1100ms) with a resolution of 1.0 mm isotropic. Cortical reconstruction and volumetric segmentation were performed using freesurfer image analysis suite (https://surfer.nmr.mgh.harvard.edu/), which have been described previously.14 The automatically segmented and labeled brain areas permit detection of submillimeter differences between groups because they are not restricted to the voxel resolution of the original data. These procedures have been validated against histological studies and manual measurements.15,16
Eighteen regions of interest were identified a priori based on glucocorticoid receptor distribution.17,18 We predicted five of these regions (caudate, putamen, pallidum, entorhinal, and parahippocampal cortex) would be spared treatment induced changes based on reduced regional specific glucocorticoid receptor density. For example, the entorhinal cortex has lower expression of glucocorticoid receptors in layer II, III, and V and has no layer IV, which contains the highest expression in other temporal lobe structures.17 Two-sample t-test were used to compare brain morphology between survivors and controls. Among survivors, sex-stratified multivariable linear regression models were used to test associations between significant ROI’s and serum concentration of dexamethasone and methotrexate, respectively, adjusting for age at diagnosis and intracranial volume. Probability levels less than 0.05 were deemed significant. All analyses were conducted using software R (v3.3.2).
Results
Survivors (51% female; median (range) age 6.8 years (1–18) at diagnosis; 14.5 years (8–27) at evaluation) did not differ significantly from controls (45% female; 13.8 years (8–26) at evaluation). There was no significant difference in intracranial volumes between survivors and controls (Table 1). Survivors had smaller hippocampal (Cornu Ammonis (CA)1, CA2–3, CA4-Dentate Gyrus (DG) and fimbria) and cerebellar volumes compared to controls. Survivors also had significantly thinner cortex in the parahippocampal, fusiform gyrus, caudal middle frontal, superior frontal, rostral middle frontal, rostral anterior cingulate, and precuneus compared to that of controls, regardless of sex.
TABLE 1.
Comparison of region of interest measurements between control and survivors, controlling for intracranial volume and age at diagnosis. Regions predicted to have no differences are denoted with †.
| Female | |||||
| Intracranial Volume (mm3) | 1 520 000 | (149 000) | 1 480 000 | (133 000) | 0.1 |
| Cerebellum | |||||
| L Cerebellum (mm3) | 75 100 | (6030) | 70 600 | (6540) | 0.002 |
| R Cerebellum (mm3) | 75 200 | (7530) | 70 500 | (6390) | 0.002 |
| Deep Grey Nuclei | |||||
| L Thalamus (mm3) | 7658 | (870) | 7457 | (801) | 0.14 |
| R Thalamus (mm3) | 7812 | (805) | 7546 | (971) | 0.09 |
| †L Caudate (mm3) | 3916 | (422) | 3844 | (510) | 0.25 |
| †R Caudate (mm3) | 3761 | (452) | 3839 | (497) | 0.23 |
| †L Putamen (mm3) | 5550 | (551) | 5516 | (636) | 0.40 |
| †R Putamen (mm3) | 5321 | (555) | 5316 | (663) | 0.48 |
| †L Pallidum (mm3) | 1703 | (208) | 1756 | (256) | 0.12 |
| †R Pallidum (mm3) | 1512 | (184) | 1675 | (286) | 0.002 |
| Hippocampus | |||||
| L CA1 (mm3) | 2529 | (391) | 2409 | (314) | 0.06 |
| R CA1 (mm3) | 2575 | (376) | 2451 | (347) | 0.06 |
| L CA2–3 (mm3) | 7487 | (1055) | 7076 | (975) | 0.03 |
| R CA2–3 (mm3) | 8162 | (1076) | 7351 | (1085) | 0.002 |
| L CA4-Dentate Gyrus (mm3) | 4246 | (588) | 4006 | (512) | 0.02 |
| R CA4-Dentate Gyrus (mm3) | 4484 | (604) | 4113 | (572) | 0.002 |
| L Fimbria (mm3) | 667 | (179) | 528 | (137) | 0.002 |
| R Fimbria (mm3) | 521 | (179) | 428 | (147) | 0.002 |
| Temporal lobe | |||||
| †L Entorhinal (mm) | 3.40 | (0.53) | 3.07 | (0.48) | 0.002 |
| †R Entorhinal (mm) | 3.57 | (0.57) | 3.34 | (0.53) | 0.03 |
| L Fusiform (mm) | 2.80 | (0.22) | 2.71 | (0.20) | 0.02 |
| R Fusiform (mm) | 2.86 | (0.23) | 2.71 | (0.20) | 0.002 |
| L Inferior Temporal (mm) | 3.00 | (0.27) | 3.03 | (0.23) | 0.34 |
| R Inferior Temporal (mm) | 3.09 | (0.25) | 3.07 | (0.25) | 0.34 |
| †L Parahippocampal (mm) | 2.76 | (0.40) | 2.51 | (0.37) | 0.002 |
| †R Parahippocampal (mm) | 2.79 | (0.38) | 2.48 | (0.35) | 0.002 |
| Parietal lobe | |||||
| L Precuneus (mm) | 2.65 | (0.22) | 2.48 | (0.35) | 0.002 |
| R Precuneus (mm) | 2.70 | (0.17) | 2.59 | (0.17) | 0.002 |
| Frontal lobe | |||||
| L Caudal Middle Frontal (mm) | 2.90 | (0.16) | 2.80 | (0.20) | 0.03 |
| R Caudal Middle Frontal (mm) | 2.91 | (0.15) | 2.80 | (0.22) | 0.002 |
| L Rostral Ant. Cingulate (mm) | 3.30 | (0.35) | 3.03 | (0.31) | 0.002 |
| R Rostral Ant. Cingulate (mm) | 3.36 | (0.31) | 3.13 | (0.29) | 0.002 |
| L Rostral Middle Frontal (mm) | 2.81 | (0.20) | 2.72 | (0.20) | 0.03 |
| R Rostral Middle Frontal (mm) | 2.79 | (0.18) | 2.71 | (0.21) | 0.03 |
| L Superior Frontal (mm) | 3.20 | (0.23) | 3.12 | (0.22) | 0.04 |
| R Superior Frontal (mm) | 3.22 | (0.21) | 3.13 | (0.24) | 0.03 |
| Males | |||||
| Intracranial Volume (mm3) | 1 670 000 | (166 000) | 1 660 000 | (152 000) | 0.63 |
| Cerebellum | |||||
| L Cerebellum (mm3) | 80 600 | (7380) | 77 400 | (6030) | 0.005 |
| R Cerebellum (mm3) | 80 600 | (7460) | 77 200 | (6390) | 0.004 |
| Deep Grey Nucleus | |||||
| L Thalamus (mm3) | 8171 | (1002) | 8001 | (829) | 0.17 |
| R Thalamus (mm3) | 8344 | (917) | 8142 | (907) | 0.13 |
| †L Caudate (mm3) | 4147 | (556) | 4085 | (560) | 0.29 |
| †R Caudate (mm3) | 4041 | (521) | 4115 | (583) | 0.25 |
| †L Putamen (mm3) | 6019 | (541) | 5913 | (692) | 0.20 |
| †R Putamen (mm3) | 5806 | (594) | 5791 | (629) | 0.45 |
| †L Pallidum (mm3) | 1903 | (254) | 1924 | (367) | 0.38 |
| †R Pallidum (mm3) | 1635 | (212) | 1845 | (358) | 0.002 |
| Hippocampus | |||||
| L CA1 (mm3) | 2752 | (406) | 2584 | (375) | 0.01 |
| R CA1 (mm3) | 2764 | (331) | 2592 | (359) | 0.004 |
| L CA2–3 (mm3) | 8145 | (907) | 7694 | (1102) | 0.01 |
| R CA2–3 (mm3) | 8578 | (1050) | 7907 | (1173) | 0.002 |
| L CA4-Dentate Gyrus (mm3) | 4596 | (536) | 4352 | (579) | 0.01 |
| R CA4-Dentate Gyrus (mm3) | 4744 | (568) | 4395 | (641) | 0.002 |
| L Fimbria (mm3) | 755 | (163) | 630 | (149) | 0.002 |
| R Fimbria (mm3) | 627 | (175) | 524 | (131) | 0.002 |
| Temporal lobe | |||||
| †L Entorhinal (mm) | 3.24 | (0.52) | 3.08 | (0.51) | 0.05 |
| †R Entorhinal (mm) | 3.41 | (0.54) | 3.23 | (0.63) | 0.05 |
| L Fusiform (mm) | 2.79 | (0.21) | 2.72 | (0.18) | 0.03 |
| R Fusiform (mm) | 2.82 | (0.22) | 2.70 | (0.18) | 0.002 |
| L Inferior Temporal (mm) | 2.98 | (0.22) | 3.00 | (0.19) | 0.29 |
| R Inferior Temporal (mm) | 3.08 | (0.23) | 3.04 | (0.20) | 0.17 |
| †L Parahippocampal (mm) | 2.70 | (0.38) | 2.53 | (0.33) | 0.006 |
| †R Parahippocampal (mm) | 2.67 | (0.31) | 2.40 | (0.30) | 0.002 |
| Parietal lobe | |||||
| L Precuneus (mm) | 2.73 | (0.20) | 2.60 | (0.18) | 0.002 |
| R Precuneus (mm) | 2.71 | (0.17) | 2.57 | (0.17) | 0.002 |
| Frontal lobe | |||||
| L Caudal Middle Frontal (mm) | 2.90 | (0.18) | 2.78 | (0.20) | 0.002 |
| R Caudal Middle Frontal (mm) | 2.91 | (0.21) | 2.78 | (0.19) | 0.002 |
| L Rostral Ant. Cingulate (mm) | 3.30 | (0.34) | 3.03 | (0.29) | 0.002 |
| R Rostral Ant. Cingulate (mm) | 3.34 | (0.32) | 3.15 | (0.29) | 0.002 |
| L Rostral Middle Frontal (mm) | 2.87 | (0.22) | 2.72 | (0.19) | 0.002 |
| R Rostral Middle Frontal (mm) | 2.82 | (0.23) | 2.72 | (0.18) | 0.002 |
| L Superior Frontal (mm) | 3.22 | (0.21) | 3.09 | (0.19) | 0.002 |
| R Superior Frontal (mm) | 3.21 | (0.22) | 3.08 | (0.17) | 0.002 |
Abbreviations: Left (L), Right (R), Cornu Ammonis (CA), millimeters cubed (mm3), millimeters (mm).
Bolded indicates significance p<0.05
Higher dexamethasone exposure was associated with thinner frontal, temporal and parietal lobe cortices (Table 2). Thinner left entorhinal, right caudal middle frontal gyrus, left rostral middle frontal, left superior frontal gyrus and bilateral fusiform gyrus and precuneus were associated with higher dexamethasone in female survivors. Age at diagnosis was associated with bilateral precuneus and rostral middle frontal cortical thickness in females. Among survivors, no significant association was seen between methotrexate AUC and any region of interest. Additionally, no association was found between dexamethasone AUC and bilateral cerebellar or hippocampal subfield volumes.
TABLE 2.
Brain volumes, that were significantly smaller in survivors compared to controls, associated with Dexamethasone area under the curve (AUC) and Methotrexate AUC.
| Dexamethasone AUC | Methotrexate AUC | Age at Diagnosis | ||||
|---|---|---|---|---|---|---|
| Female | ||||||
| Cerebellum | ||||||
| L Cerebellum | −1.04a | 0.82 | −43.7a | 0.70 | 150c | 0.58 |
| R Cerebellum | −0.88a | 0.82 | −14.1a | 0.89 | 71.6c | 0.78 |
| Hippocampus | ||||||
| L CA2–3 | −0.38a | 0.54 | −0.03a | 0.45 | 54.65d | 0.07 |
| R CA2–3 | −0.23a | 0.77 | 0.032a | 0.45 | 63.38d | 0.06 |
| L CA4-Dentate Gyrus | −0.15a | 0.70 | −0.019a | 0.45 | 23.79d | 0.13 |
| R CA4-Dentate Gyrus | −0.0053a | 0.98 | −0.016a | 0.45 | 29.47d | 0.09 |
| L Fimbria | −0.051a | 0.63 | −0.0017a | 0.70 | 0.23d | 0.94 |
| R Fimbria | −0.12a | 0.14 | −0.0048a | 0.45 | −2.50 | 0.66 |
| Temporal lobe | ||||||
| L Entorhinal Cortex | −0.00052b | 0.04 | −0.010b | 0.45 | 0.0068 | 0.66 |
| R Entorhinal Cortex | −0.00013b | 0.77 | −0.00065b | 0.92 | 0.0045 | 0.81 |
| L Fusiform Gyrus | −0.00021b | 0.04 | −0.0019b | 0.60 | −0.0069 | 0.29 |
| R Fusiform Gyrus | −0.00018b | 0.12 | −0.0028b | 0.45 | −0.0074 | 0.26 |
| L Parahippocampal | −0.00028b | 0.14 | −0.0041b | 0.50 | 0.0057 | 0.66 |
| R Parahippocampal | −0.000088b | 0.77 | −0.0042b | 0.45 | −0.0050 | 0.66 |
| Parietal lobe | ||||||
| L Precuneus | −0.00018b | 0.04 | −0.0024b | 0.45 | −0.013 | 0.01 |
| R Precuneus | −0.00017b | 0.07 | −0.0014b | 0.60 | −0.015 | 0.02 |
| Frontal lobe | ||||||
| L Caudal Middle Frontal | −0.00017b | 0.14 | −0.0024b | 0.50 | −0.001 | 0.87 |
| R Caudal Middle Frontal | −0.00028b | 0.04 | −0.0046b | 0.45 | −0.0056 | 0.46 |
| L Rostral Ant. Cingulate | −0.000029b | 0.85 | −0.0014b | 0.70 | −0.01 | 0.26 |
| R Rostral Ant. Cingulate | −0.00033b | 0.04 | 0.0014b | 0.70 | −0.013 | 0.14 |
| L Rostral Middle Frontal | −0.00017b | 0.12 | −0.0034b | 0.45 | −0.015 | 0.02 |
| R Rostral Middle Frontal | −0.00013b | 0.28 | −0.0018b | 0.60 | −0.014 | 0.03 |
| L Superior Frontal Gyrus | −0.00026b | 0.04 | −0.004b | 0.45 | −0.0098 | 0.17 |
| R Superior Frontal Gyrus | −0.0002b | 0.14 | −0.002b | 0.60 | +0.013 | 0.07 |
| Male | ||||||
| Cerebellum | ||||||
| L Cerebellum | 0.98a | 0.69 | −23.3a | 0.83 | 44.5c | 0.86 |
| R Cerebellum | 1.26a | 0.52 | −17.3a | 0.86 | 48.9c | 0.86 |
| Hippocampus | ||||||
| L CA1 | 0.062a | 0.88 | 0.0031a | 0.85 | 6.54 | 0.80 |
| R CA1 | 0.23a | 0.52 | 0.01a | 0.78 | 19.04 | 0.16 |
| L CA2–3 | 0.27a | 0.69 | 0.0058a | 0.89 | 27.80 | 0.66 |
| R CA2–3 | 0.47a | 0.78 | 0.014a | 0.83 | 66.43 | 0.13 |
| L CA4-Dentate Gyrus | 0.19a | 0.85 | 0.0095a | 0.83 | 6.04 | 0.86 |
| R CA4-Dentate Gyrus | 0.11a | 0.88 | 0.0079a | 0.83 | 32.43 | 0.73 |
| L Fimbria | 0.074a | 0.69 | −0.0018a | 0.83 | 4.41 | 0.59 |
| R Fimbria | 0.044a | 0.85 | −0.0015a | 0.83 | 8.60 | 0.13 |
| Temporal lobe | ||||||
| L Entorhinal | −0.00052b | 0.09 | −0.01.0b | 0.52 | −0.011 | 0.86 |
| R Entorhinal | −0.00013b | 0.88 | −0.00065b | 0.94 | −0.021 | 0.86 |
| L Fusiform Gyrus | 0.000028b | 0.88 | 0.0017b | 0.83 | 0.0024 | 0.86 |
| R Fusiform Gyrus | −0.000023b | 0.88 | 0.001b | 0.83 | −0.025 | 0.59 |
| L Parahippocampal | −0.000048b | 0.88 | 0.0078b | 0.26 | 0.0067 | 0.73 |
| R Parahippocampal | −0.00014b | 0.78 | 0.0013b | 0.83 | 0.017 | 0.86 |
| Parietal lobe | ||||||
| L Precuneus | −0.000029b | 0.88 | 0.00068b | 0.83 | −0.0057 | 0.56 |
| R Precuneus | 0.0000061b | 0.93 | 0.00011b | 0.94 | −0.018 | 0.13 |
| Frontal lobe | ||||||
| L Caudal Middle Frontal | −0.00017b | 0.26 | −0.0024b | 0.83 | 0.014 | 0.86 |
| R Caudal Middle Frontal | −0.00028b | 0.08 | −0.0046b | 0.52 | −0.010 | 0.80 |
| L Rostral Ant. Cingulate | 0.000027b | 0.88 | −0.0033b | 0.78 | −0.024 | 0.86 |
| R Rostral Ant. Cingulate | 0.000034b | 0.88 | 0.0023b | 0.83 | −0.024 | 0.59 |
| L Rostral Middle Frontal | −0.00017b | 0.26 | −0.0034b | 0.62 | −0.0033 | 0.56 |
| R Rostral Middle Frontal | −0.00013b | 0.52 | −0.0018b | 0.83 | −0.0056 | 0.13 |
| L Superior Frontal Gyrus | −0.00026b | 0.09 | −0.0040b | 0.62 | 0.012 | 0.59 |
| R Superior Frontal Gyrus | −0.0002b | 0.26 | −0.002b | 0.83 | −0.0017 | 0.66 |
Abbreviations: Left (L), Right (R), Cornu Ammonis (CA).
Bolded indicates significance p <0.05
Indicates SEst = mm/(g*hr/L).
Indicates SEst = mm3/(g*hr/L).
Indicates SEst=mm3/year.
Indicates Sest =mm/year
Discussion
Our study provides insight as to why adult survivors of pediatric ALL demonstrate significantly poorer performance in working memory and have higher rates of learning problems.19–21 Hippocampal volume loss is persistent, and previous studies have shown significant correlations between hippocampal volume and semantic memory, verbal learning and verbal recall.22,23 This implies that survivors with smaller hippocampi after therapy may have reduced capacity for learning new information. Additionally, our results suggest that dexamethasone exposure impacts male and female brains differently, with female survivors having more areas of volume loss associated with higher dexamethasone exposure. These findings are in agreement with long-term outcomes studies, which demonstrated that female survivors have traditionally completed fewer years of schooling and have higher unemployment compared to their siblings.24,25 Finally, in a previous study of adult survivors treated on an earlier chemotherapy-only protocol at St. Jude, global average grey matter volume and brain fraction (volume/total intracranial volume) was reportedly greater than healthy controls.5 Our results demonstrate that the effects of chemotherapy are targeted rather than global.
We did not find the expected dose-response association between dexamethasone AUC and cerebellar and hippocampal subfield volumes. It is possible that the linear exposure-response relationship modeled here may not be suitable to detect these changes or that dexamethasone has a ceiling effect such that increasing doses result in progressively smaller effects. Another, limitation of this study was that we are unable to exclude oxidative injury related to disease or inflammatory changes, which could mimic the results presented here. Finally, this study is a single institution cross-sectional analysis and is not representative of all dexamethasone inclusive chemotherapy-only ALL therapies.
This study highlights that differences in glucocorticoid receptor rich brain regions exist between survivors and healthy controls after completion of therapy. Dexamethasone exposure is associated with brain morphology differences in survivors, particularly within the female sex. One clinical implication of this study would be to investigate if children in the most vulnerable populations, such as younger female patients, would benefit from a lower dose of dexamethasone. Additionally, our oxidative injury model would predict that early interventions, during therapy, with a N-methyl-D-aspartate (NMDA) receptor antagonist, such as Memantine, could reduce glutamatergic excitotoxicity associated with glucocorticoid receptor activation and provide some protection against the indirect oxidative injury.26 And although the use of NMDA receptor antagonist in children is limited, one published study using Memantine in 61 children diagnosed with autism reported one serious adverse effect (mood disorder judged to be unrelated to the study medication) and only seven participants discontinued treatment because of an adverse effect (placebo n=4 [6.6%], memantine, n=3 [5.0%]) suggesting that safety concerns should not discourage its evaluation as a potential therapeutic approach.27 Moreover, N-acetylcysteine might rescue the brain’s antioxidant system and reduce or prevent CNS insult.28 Such approaches would obviously require steps to ensure efficacy of cancer therapy is not compromised. Finally, this study has clear implications for other patient populations treated with dexamethasone and warrants further investigation.
Acknowledgments:
We would like to thank the survivors, volunteers and their families for participating in this study.
Funding: This study was supported (in part) by research funding from the National Institute of Mental Health (MH085849 to K.R. Krull), National Cancer Institute (CA195547 to M.M. Hudson and L.L. Robison; CA21765 to C. Roberts), National Institute of Child Health and Human Development (HD049888 to R.J. Ogg).
Abbreviations:
- ALL
Acute lymphoblastic leukemia
- AUC
Area under the curve
- CA
Cornu Ammonis
- CNS
Central nervous system
- CSF
Cerebrospinal fluid
- DG
Dentate gyrus
- HDMTX
High dose Methotrexate
- MPRAGE
Magnetization prepared rapid acquisition gradient echo
- NMDA
N-methyl-D-aspartate
- ROI
Region of interest
- TE
Echo time
- TI
Inversion time
- TR
Repetition time
Footnotes
Portions of the results in this manuscript were presented at the American Society of Clinical Oncology meeting, June 2018 as “Subcortical brain volumes and neurocognitive function in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.” Journal of Clinical Oncology 2017 35:15_suppl, 10517–10517
Disclosure of Conflict of Interest: No author of this manuscript has any conflicts of interest to disclose.
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