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. Author manuscript; available in PMC: 2022 Sep 1.
Published in final edited form as: Cancer. 2021 Apr 29;127(17):3202–3213. doi: 10.1002/cncr.33624

Association between obesity and neurocognitive function in survivors of childhood acute lymphoblastic leukemia treated only with chemotherapy

Mayuko Iijima 1,2, Wei Liu 3, John C Panetta 4, Melissa M Hudson 1,5,6, Ching-Hon Pui 1, Deo Kumar Srivastava 3, Kevin R Krull 5,6,*, Hiroto Inaba 1,*
PMCID: PMC8355093  NIHMSID: NIHMS1705270  PMID: 33914910

Abstract

Background:

Neurocognitive impairment and obesity are common adverse sequelae in survivors of childhood acute lymphoblastic leukemia (ALL); however, the association has not been investigated.

Methods:

Neurocognitive function was evaluated once in survivors of ALL who were at least 8 years of age and 5 years from diagnosis. In cross-sectional analysis, the associations with body mass index (BMI) category and Z-score were examined. Longitudinal analysis employed the overweight/obesity area under the curve (AUC), determined by the trapezoidal rule by a sum of the integrals defined by the BMI Z-score at each time point and the time intervals of the BMI measurement.

Results:

For 210 survivors, the median BMI Z-score at diagnosis was 0.17, which increased to 0.54 at the end of induction and to 0.74 at neurocognitive assessment. In cross-sectional analysis, overweight/obese survivors scored significantly lower than others on the measures of executive function (cognitive flexibility, planning, verbal fluency, working memory, and spatial construction; all P < 0.05), attention (attention span and risk taking; all P < 0.05), and processing speed (visual motor coordination, visual speed, and motor speed; all P < 0.05). In longitudinal analysis, when the treatment period was subdivided into 4 time periods (induction/consolidation/early maintenance/late maintenance), a greater overweight/obesity AUC during induction therapy was associated with worse cognitive flexibility (P = 0.01) and slower motor speed (P = 0.02), which persisted throughout the treatment.

Conclusions:

Overweight/obesity was significantly associated with neurocognitive impairment during long-term follow-up, starting early in treatment for ALL. Novel early interventions to provide cognitive training and prevent weight gain are required for patients at risk.

Keywords: Acute lymphoblastic leukemia, children, neurocognitive function, obesity, body mass index, survivor

Precis

In a cohort of 210 children with acute lymphoblastic leukemia (ALL) at a median follow-up of 7.5 years from diagnosis, overweight/obese survivors scored significantly worse than others on measures of neurocognitive performance. This association with overweight/obesity status was already seen during induction therapy, which suggests that early multidisciplinary interventions should be implemented to prevent obesity and to alleviate adverse neurocognitive sequelae in survivors of ALL.

INTRODUCTION

Currently, the 5-year survival rates for pediatric patients with acute lymphoblastic leukemia (ALL), the most common cancer of childhood, exceed 90%.1,2 As the number of long-term survivors increases, close attention should be paid to their quality of life. Obesity is a major concern for patients with ALL during treatment as well as during survivorship. Their body mass index (BMI) increases immediately after diagnosis with induction therapy and continues to increase through early maintenance therapy, coinciding with glucocorticoid treatment.3 This rapid BMI gain caused by ALL treatment distinguishes patients with ALL from the general pediatric population, in which BMI Z-scores are remarkably stable over time.4 Lifestyle factors such as sedentary behavior and an unhealthy diet exacerbate unhealthy weight gain. Past research demonstrated that being overweight/obese could negatively influence survival and was more likely to cause treatment-related toxicities.5,6 Survivors of ALL experience another gain in BMI immediately after the completion of therapy, with 30%−50% of them becoming obese,7,8 which can further aggravate common adverse sequelae, such as metabolic syndrome and cardiovascular disease.9 Moreover, excessive adiposity is associated with neurocognitive impairment in children and adolescents without cancer.10,11 As obesity is a modifiable condition, developing a preventive intervention for use during and after ALL therapy is crucial to optimizing the subsequent quality of life of these patients.

Neurocognitive dysfunction after ALL therapy also has a serious impact on survivors. Although eliminating cranial radiation therapy has helped to preserve global cognitive abilities, CNS-directed chemotherapy, such as high-dose methotrexate (MTX), intrathecal therapy, and/or glucocorticoids, is still associated with impaired neurocognitive function.12–14

Based on the hypothesis that obesity contributes to the risk of neurocognitive impairment, we examined the association between obesity and neurocognitive function in survivors of ALL. It is challenging, however, to capture longitudinal changes in BMI Z-scores among survivors of ALL because of their unique pattern of fluctuation. For this purpose, we considered being overweight/obese as an exposure and employed an area under the curve (AUC) approach, in which the duration and extent of the exposure were represented as any positive area above the overweight threshold. Establishing a negative relation between obesity and neurocognitive function would be important for guiding multidisciplinary interventions for patients and their families to prevent obesity and to alleviate neurocognitive impairment.

PATIENTS AND METHODS

Patients

Survivors of childhood ALL treated on the St. Jude Total XV protocol1 who were 8 years of age or older and at least 5 years from diagnosis at follow-up were eligible for this study. Survivors who underwent hematopoietic stem cell transplantation (HCT); experienced relapse or developed a secondary cancer that required additional chemotherapy or cranial radiation therapy (CRT); had a pre-existing non–cancer-related neurodevelopmental or genetic disorder associated with cognitive impairment; had a moderate to severe brain injury unrelated to ALL that happened before, during, or after treatment; or were not fluent in English were excluded. This study was approved by the institutional review board at St. Jude Children’s Research Hospital, and informed consent and assent were obtained from the parents/guardians and/or patients as appropriate.

Treatment

Total XV therapy (ClinicalTrials.gov Identifier: NCT0013711) consisted of 3 treatment phases: induction (6 weeks), consolidation (8 weeks), and continuation (120 weeks for female patients, 146 weeks for male patients), as described previously.1 All patients received prednisone at 40 mg/m2/day for 28 days and dexamethasone at 8 mg/m2/day on days 1–8 and days 15–21 during reinduction I (weeks 7–9 after consolidation) and reinduction II (weeks 17–19 after consolidation), in addition to other chemotherapeutic agents. Oral dexamethasone pulses were administered for 5 days at 8 mg/m2/day for patients with low-risk (LR) ALL and at 12 mg/m2/day for patients with standard/high-risk (SR/HR) ALL, interrupting continuation every 4 weeks between week 1 and week 100 except during reinduction I and reinduction II. Patients with LR ALL received 13–18 intrathecal treatments and 4 doses of intravenous high-dose MTX with a target steady-state plasma concentration of 33 μM per dose with leucovorin rescue, and patients with SR/HR ALL were treated with 16–25 doses of intrathecal therapy and intravenous high-dose MTX targeted at 65 μM per dose for 4 doses with leucovorin rescue.

Neurocognitive Assessment

Neurocognitive assessments were administered by certified examiners under the supervision of a board-certified clinical neuropsychologist at a single time point during patient follow-up. Participants completed assessments according to standard clinical guidelines in a fixed order and on schedules designed to reduce the impact of fatigue and interferences. Neurocognitive assessments focused on executive function, attention, and processing speed. Measures of assessments included the Delis–Kaplan Executive Function System,15 the Wisconsin Card Sorting Test,16 the Rey Complex Figure Test,17 the Wechsler Abbreviated Scale of Intelligence,18 the Conners Continuous Performance Test,19 and the Grooved Pegboard Test.20 The subtests of the neurocognitive assessments and assigned cognitive domains are presented in the tables. Age-adjusted Z-scores were calculated based on population norms.

Body Mass Index

Height and weight data were collected at fixed time points from diagnosis to the end of treatment. The time points were as follows: the start of induction (± 3 days); day 19 of induction (± 3 days); the end of induction (± 7 days); continuation weeks 1 and 7 (± 14 days); and weeks 10, 17, 21, 48, 96, 120 (the end of therapy for female patients), and 146 (the end of therapy for male patients) (± 30 days). After treatment, measurements acquired at yearly follow-up visits to St. Jude were used for the period before the date of neurocognitive assessment. BMI was calculated as the patient’s weight in kilograms divided by the square of their height in meters for patients aged 2 years or older, and age- and sex-adjusted BMI Z-scores were calculated with the SAS program for the Centers for Disease Control and Prevention growth charts.21 For patients aged 20 years or older, Z-scores were calculated based on reference data for individuals aged 20 years. Weight for length was calculated for patients aged 1–2 years then converted to age- and sex-adjusted Z-scores. For analysis using BMI as a categorical variable, the BMI categories for patients younger than 20 years were as follows: underweight (less than the 5th percentile), normal to healthy weight (the 5th percentile to the <85th percentile), overweight (the 85th percentile to the <95th percentile), and obese (the 95th percentile or greater). The BMI categories for patients aged 20 years or older were determined according to the National Institutes of Health guidelines22 and were as follows: underweight (BMI < 18.5), healthy weight (BMI of 18.5–24.9), overweight (BMI of 25.0–29.9), and obese (BMI ≥ 30.0).

Statistical Analysis

Descriptive statistics were calculated for demographic variables and treatment factors. For cross-sectional analysis, the association between neurocognitive outcomes (age-adjusted Z-score) and BMI group (“underweight/healthy” vs. “overweight” and/or “obese”), as well as BMI Z-score, was determined using general linear modeling (GLM) analysis. For longitudinal analysis, the AUC was computed to demonstrate the dynamic transition of overweight/obesity. In this study, a total AUC was determined according to the trapezoidal rule by a sum of the integrals defined by the BMI Z-score at each time point and for each time interval of the BMI measurement. Overweight/obesity AUCs were defined as any positive areas above a BMI Z-score of 1.036 (corresponding to the >85th percentile) during the observational period, and their association with neurocognitive outcomes was examined by GLM. To examine the effects of time period, the analysis was first performed between “in treatment” and “off treatment.” “In treatment” was then subdivided into 4 time periods: induction, consolidation, early maintenance (weeks 1–48), and late maintenance (weeks 48–120). All statistical models were adjusted for sex, time since diagnosis, treatment risk (as an index of treatment intensity), and parents’ highest education level (in years). All statistical models were also adjusted with respect to BMI Z-score at diagnosis except for the “off treatment” analysis, which was adjusted with respect to BMI Z-score at the end of treatment. All analyses were conducted using SAS v9.4 (SAS Institute, Cary, NC).

RESULTS

Patient Characteristics

A total of 210 eligible survivors completed neurocognitive testing in the study (Figure 1); the patient demographics are presented in Table 1. Figure 2 shows the longitudinal changes in median, maximum, upper-quartile, and lower-quartile BMI Z-scores from diagnosis to the date of neurocognitive assessment. The median BMI Z-score increased from 0.17 (interquartile range [IQR], −0.46 to 1.02) at diagnosis to 0.54 (IQR, −0.38 to 1.37) at the end of induction. The median BMI Z-score increased until week 96 of continuation, reaching 0.94 (IQR, 0.09–1.58), and then declined to 0.67 (IQR, −0.25 to 1.27) by week 120. After the completion of treatment, the median BMI Z-score increased again to a peak value of 1.06 (IQR, 0.22–1.77) at 3 years off therapy; the median BMI Z score at the time of neurocognitive assessment was 0.74 (IQR, 0.04–1.62).

Figure 1.

Figure 1.

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Participant enrollment flow chart.

Abbreviations; CRT, cranial radiation therapy; HCT, hematopoietic cell transplant; SMN, secondary malignant neoplasm.

Table 1.

Patient Characteristics for Overall Group and for Each BMI Category*

Clinical Characteristics Overall (n = 210) Healthy/Underweight (n = 120) Overweight (n = 42) Obese (n = 48)
Median age at diagnosis in years (IQR) 5.0 (3.2–8.7) 5.0 (3.3–8.4) 5.0 (3.2–8.3) 5.3 (2.9–10.3)
Median age at assessment in years (IQR) 13.2 (10.5–17.6) 13.5 (10.5–17.3) 12.2 (10.0–17.8) 12.8 (10.7–18.5)
Median time since diagnosis in years (IQR) 7.5 (6.3–9.1) 7.7 (6.6–9.3) 7.2 (6.2–8.1) 7.3 (6.2–8.9)
Sex, n (%)
 Female 102 (48.6) 55 (45.8) 23 (54.8) 24 (50.0)
 Male 108 (51.4) 65 (54.2) 19 (45.2) 24 (50.0)
Race, n (%)
 White 155 (73.8) 92 (76.7) 31(73.8) 32 (66.7)
 Black 26 (12.40) 14 (11.7) 7 (16.7) 5 (10.4)
 Other† 29 (13.8) 14 (11.7) 4 (9.5) 11 (22.9)
Treatment risk, n (%)
 Low 121 (57.6) 68 (56.7) 25 (59.5) 28 (58.3)
 Standard/high 89 (42.4) 52 (43.3) 17 (40.5) 20 (41.7)
Lineage, n (%)
 B cell 181 (86.2) 103 (85.8) 38 (90.5) 40 (83.3)
 T cell 29 (13.8) 17 (14.2) 4 (9.5) 8 (16.7)
Median BMI Z-score at diagnosis (IQR) ‡ 0.17 (−0.46 to 1.02) −0.17 (−0.86 to 0.39) 0.27 (−0.32 to 0.98) 1.39 (0.85–1.95)
BMI category at diagnosis, n (%)
 Healthy/underweight 158 (75.2) 109 (90.8) 32 (76.2) 17 (35.4)
 Overweight 25 (11.9) 7 (5.8) 7(16.7) 11 (22.9)
 Obese 27 (12.9) 4 (3.3) 3 (7.1) 20 (41.7%)
Median BMI Z-score at assessment (IQR) 0.74 (0.04–1.62) 0.17 (−0.37 to 0.51) 1.36 (1.21–1.53) 2.20 (1.87–2.46)
Median highest education of parents in years (IQR) 14 (12–16) 15 (12–16) 14 (12–16) 14 (12–16)
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Abbreviation: BMI, body mass index; IQR, interquartile range.

*

BMI category at the time of neurocognitive assessment.

†

Other race includes Hispanic/Latino (n = 15 [7.1%]), Asian (n = 5 [2.4%]), and multiple races (NOS) (n = 9 [4.3%]).

‡

For survivors aged <2 years at diagnosis, the BMI Z-score was calculated as the weight-for-height Z-score.

Figure 2.

Figure 2.

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Longitudinal changes in body mass index Z-score.

Z-scores of 1.036 and 1.645 correspond to the 85th and 95th percentiles, respectively. Girls completed therapy in week 120 of maintenance therapy and boys did so in week 146.

Abbreviations; Dx, diagnosis; DOE, date of neurocognitive evaluation; EOI, end of induction; W, week.

Cross-Sectional Analyses of the Association Between BMI and Neurocognitive Function

Means, standard deviations, and percentages of patients exhibiting impairment on neurocognitive assessments for each BMI category are presented in Supplemental Table 1. We evaluated measurements that showed impairments in more than 25% of survivors for each BMI category. For executive function, 51.7% of healthy/underweight survivors had impairment in organization, whereas overweight survivors had impairment in cognitive flexibility (perseverative response: 25.0%), verbal fluency (letter fluency: 28.6%), organization (66.7%), and working memory (digit span backward: 26.2%), and obese survivors had impairment in cognitive flexibility (number-letter switching: 33.3%), verbal fluency (letter fluency: 27.1%), and organization (68.8%). With respect to attention measurements, only overweight survivors showed impairment in attention span (special span forward: 26.2%). For measures of processing speed, all groups exhibited impairments in motor speed (dominant hand: 37.1%, 47.6%, and 52.1%; non-dominant hand: 31.9%, 54.8%, and 56.3% for the healthy/underweight, overweight, and obese groups, respectively). Overweight survivors also had impairment in visual motor coordination (number sequencing: 26.2%; letter sequencing: 28.6%).

In the cross-sectional analysis, being overweight/obese at the time of neurocognitive assessment was associated with worse executive function, attention, and processing speed than were observed in healthy/underweight survivors (Table 2). With respect to executive function, scores for cognitive flexibility (letter switching: estimate [est] −0.526, P = 0.005), planning (est −0.284, P = 0.038), verbal fluency (letter fluency: est −0.388, P = 0.013; category fluency: est −0.620, P < 0.001), working memory (digit span backward: est −0.345, P = 0.034), and spatial construction (est −0.314, P = 0.047) were significantly worse in overweight/obese survivors than in healthy/underweight survivors.

Table 2.

Cross-Sectional Analysis of the Association of Body Mass Index Category with Neurocognitive Measurements

Cognitive Domain Measurement Overweight/Obese (n = 90) vs. Healthy/Underweight (n = 120)
Estimate SE P
Executive function
 Abstraction DKEFS Abstraction −0.058 0.169 0.732
 Inhibitory control DKEFS Inhibition −0.002 0.167 0.993
DKEFS Inhibition/switching −0.009 0.165 0.956
 Cognitive flexibility DKEFS Number-Letter Switching −0.526 0.187 0.005
WCST Perseverative Errors −0.316 0.253 0.213
WCST Perseverative Response −0.323 0.260 0.217
WCST Conceptual Level Response 0.001 0.190 0.994
 Planning DKEFS Tower −0.284 0.136 0.038
 Verbal fluency DKEFS Letter Fluency −0.388 0.155 0.013
DKEFS Category Fluency −0.620 0.168 <0.001
DKEFS Category Switching −0.273 0.150 0.071
 Organization Rey Complex Figure Copy −0.703 0.386 0.070
 Working memory WS Digit Span Backward −0.345 0.162 0.034
WS Spatial Span Backward −0.091 0.157 0.564
 Spatial construction WASI Block Design −0.314 0.157 0.047
Attention
 Attention span WS Digit Span Forward −0.314 0.158 0.048
WS Spatial Span Forward −0.269 0.150 0.075
 Risk taking CPT II Beta −0.409 0.159 0.011
 Commissions CPT II Commissions −0.094 0.193 0.626
 Detectability CPT II d Prime −0.226 0.192 0.239
 Omissions CPT II Omissions −0.405 0.247 0.102
 Perseveration CPT II Perseveration −0.461 0.299 0.125
 Response speed consistency CPT II Hit Reaction Time Standard Error −0.265 0.198 0.181
CPT II Variability of Standard Error −0.038 0.195 0.844
Processing speed
 Word reading DKEFS Word Reading 0.075 0.148 0.614
 Color naming DKEFS Color Naming −0.073 0.144 0.612
 Visual motor coordination DKEFS Motor Speed −0.144 0.153 0.348
DKEFS Number Sequencing −0.566 0.166 0.001
DKEFS Letter Sequencing −0.327 0.185 0.079
WS Digit Symbol −0.295 0.147 0.046
WS Processing Speed Index −0.419 0.152 0.007
 Visual speed CPT II Hit Reaction Time −0.359 0.179 0.047
WS Symbol Search −0.470 0.164 0.005
 Motor speed GPB Dominant Hand −0.466 0.244 0.058
GPB Non-Dominant Hand −0.673 0.249 0.007
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Abbreviations: SE, standard error; DKEFS, Delis–Kaplan Executive Function System; WCST, Wisconsin Card Sorting Test; WS, Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale; WASI, Wechsler Abbreviated Scale of Intelligence; CPT II, Conners’ Continuous Performance Test II; GPB, Grooved Pegboard Test

All models were adjusted for sex, time since diagnosis, Total XV treatment risk, parents’ highest education in years, and BMI Z-score at diagnosis.

With respect to attention, overweight/obese survivors had worse scores for attention span (digit span forward: est −0.314, P = 0.048) and risk taking (CPT II Beta: est −0.409, P = 0.011) when compared with healthy/underweight survivors.

With respect to processing speed, visual motor coordination (number sequencing: est −0.566, P = 0.001; digit symbol: est −0.295, P = 0.046), visual speed (hit reaction time: est −0.359, P = 0.047; symbol search: est −0.470, P = 0.005), and motor speed (non-dominant hand: est −0.673, P = 0.007) were significantly worse in overweight/obese survivors than in healthy/underweight survivors.

Although similar worse neurocognitive dysfunction was observed in both analyses when overweight and obese patients were compared separately with healthy/underweight patients (Supplemental Table 2), several measures of executive function (planning, letter fluency, digit span backward) and of attention (spatial span forward, risk taking, detectability, omissions) were significantly worse only in overweight survivors, whereas measures of spatial construction and motor speed were worse only in obese survivors.

When BMI Z-scores were evaluated as a continuous variable, a higher BMI Z-score at the time of neurocognitive assessment was associated with lower measured scores for executive function (cognitive flexibility, verbal fluency, and spatial construction), attention (detectability and perseveration), and processing speed (visual motor coordination, visual speed, and motor speed) (Supplemental Table 3).

Longitudinal Analysis of the Association Between Overweight/Obesity AUC and Neurocognitive Function

Longitudinal analysis demonstrated that a larger overweight/obesity AUC during treatment was negatively associated with measures of executive function (cognitive flexibility and spatial construction), attention (risk taking and omissions), and processing speed (visual motor coordination and motor speed) during treatment (Supplemental Table 4). In contrast, the overweight/obesity AUC after the treatment period was inversely associated with only a single measurement: cognitive flexibility.

Further analyses were conducted with the 4 phases of the treatment period (Table 3). During induction, negative associations with the overweight/obesity AUC were observed in measures of executive function, which includes cognitive flexibility (number-letter switching: standardized estimate −2.202, P = 0.029; perseverative errors: standardized estimate −2.467, P = 0.015; perseverative response: standardized estimate −2.492, P = 0.014; conceptual level response: standardized estimate −2.255, P = 0.025). Such negative associations with cognitive flexibility persisted during consolidation, early maintenance, and late maintenance, in addition to the negative associations with verbal fluency in late maintenance and with spatial construction in consolidation and early maintenance (P < 0.05 for all).

Table 3.

Longitudinal Analysis of the Association of Overweight/Obesity Area Under the Curve with Neurocognitive Measurements During Treatment

Cognitive Domain Measurement Induction Consolidation Early maintenance (Weeks 1–48) Late maintenance (Weeks 49–120)
Estimate SE Std. Est P Estimate SE Std. Est P Estimate SE Std. Est P Estimate SE Std. Est P
Executive function
 Abstraction DKEFS Abstraction −0.023 0.062 −0.372 0.710 −0.017 0.033 −0.514 0.610 −0.038 0.063 −0.601 0.550 −0.002 0.030 −0.065 0.950
 Inhibitory control DKEFS Inhibition −0.099 0.058 −1.702 0.091 −0.038 0.031 −1.219 0.220 −0.019 0.060 −0.313 0.750 −0.038 0.029 −1.331 0.180
DKEFS Inhibition/Switching 0.017 0.061 0.281 0.780 0.031 0.032 0.942 0.350 0.027 0.063 0.439 0.660 −0.022 0.030 −0.733 0.460
 Cognitive flexibility DKEFS Number-Letter Switching −0.144 0.065 −2.202 0.029 −0.072 0.034 −2.110 0.036 −0.141 0.066 −2.126 0.035 −0.092 0.032 −2.909 0.004
WCST Perseverative Errors −0.229 0.093 −2.467 0.015 −0.137 0.047 −2.917 0.004 −0.261 0.095 −2.760 0.006 −0.081 0.046 −1.783 0.076
WCST Perseverative Response −0.240 0.096 −2.492 0.014 −0.135 0.049 −2.756 0.007 −0.268 0.098 −2.729 0.007 −0.086 0.047 −1.821 0.070
WCST Conceptual Level Response −0.158 0.070 −2.255 0.025 −0.087 0.035 −2.465 0.015 −0.123 0.072 −1.704 0.090 −0.035 0.035 −1.012 0.310
 Planning DKEFS Tower 0.000 0.051 −0.006 0.990 0.009 0.026 0.338 0.740 0.018 0.052 0.340 0.730 −0.001 0.025 −0.036 0.970
 Verbal fluency DKEFS Letter Fluency −0.080 0.057 −1.395 0.160 −0.041 0.029 −1.386 0.170 −0.043 0.059 −0.735 0.460 −0.072 0.027 −2.637 0.009
DKEFS Category Fluency −0.066 0.063 −1.040 0.300 −0.040 0.033 −1.211 0.230 −0.093 0.064 −1.451 0.150 −0.052 0.031 −1.675 0.096
DKEFS Category Switching 0.010 0.054 0.191 0.850 0.017 0.028 0.586 0.560 0.020 0.055 0.356 0.720 0.001 0.026 0.046 0.960
 Organization Rey Complex Figure Copy −0.183 0.148 −1.232 0.220 −0.100 0.078 −1.282 0.200 −0.271 0.151 −1.795 0.074 −0.106 0.072 −1.466 0.140
 Working memory WS Digit Span Backward 0.004 0.061 0.072 0.940 0.019 0.031 0.601 0.550 −0.014 0.062 −0.217 0.830 0.000 0.030 0.015 0.990
WS Spatial Span Backward −0.033 0.058 −0.563 0.570 −0.001 0.030 −0.042 0.970 −0.042 0.059 −0.706 0.480 −0.040 0.028 −1.412 0.160
 Spatial construction WASI Block Design −0.093 0.058 −1.605 0.110 −0.069 0.030 −2.275 0.024 −0.130 0.059 −2.222 0.028 −0.049 0.028 −1.734 0.085
Attention
 Attention span WS Digit Span Forward −0.058 0.060 −0.958 0.340 −0.041 0.031 −1.323 0.190 −0.122 0.061 −1.993 0.048 −0.050 0.029 −1.718 0.088
WS Spatial Span Forward 0.010 0.057 0.179 0.860 0.017 0.030 0.590 0.560 0.003 0.058 0.057 0.950 0.009 0.028 0.328 0.740
 Risk taking CPT II Beta −0.082 0.051 −1.611 0.110 −0.047 0.025 −1.899 0.059 −0.092 0.053 −1.755 0.081 −0.062 0.025 −2.487 0.014
 Commissions CPT II Commissions 0.001 0.067 0.009 0.990 −0.017 0.035 −0.485 0.630 −0.034 0.069 −0.489 0.630 −0.008 0.033 −0.233 0.820
 Detectability CPT II d Prime −0.037 0.066 −0.562 0.570 −0.046 0.034 −1.360 0.180 −0.059 0.069 −0.863 0.390 −0.010 0.033 −0.315 0.750
 Omissions CPT II Omissions −0.124 0.088 −1.404 0.160 −0.107 0.047 −2.251 0.026 −0.165 0.091 −1.810 0.072 −0.063 0.043 −1.457 0.150
 Perseveration CPT II Perseveration −0.106 0.111 −0.957 0.340 −0.100 0.060 −1.670 0.097 −0.097 0.115 −0.845 0.400 −0.003 0.055 −0.053 0.960
 Response speed consistency CPT II Hit Reaction Time Standard Error −0.068 0.067 −1.017 0.310 −0.065 0.036 −1.826 0.070 −0.060 0.069 −0.864 0.390 −0.025 0.033 −0.742 0.460
CPT II Variability of Standard Error −0.049 0.067 −0.729 0.470 −0.048 0.035 −1.362 0.170 −0.041 0.069 −0.590 0.560 −0.010 0.033 −0.313 0.750
Processing speed
 Word reading DKEFS Word Reading 0.005 0.053 0.102 0.920 0.025 0.028 0.885 0.380 0.048 0.055 0.876 0.380 −0.033 0.026 −1.230 0.220
 Color naming DKEFS Color Naming −0.042 0.052 −0.802 0.420 −0.005 0.028 −0.193 0.850 0.018 0.053 0.332 0.740 −0.031 0.026 −1.205 0.230
 Visual motor coordination DKEFS Motor Speed −0.027 0.058 −0.471 0.640 −0.010 0.031 −0.318 0.750 −0.011 0.058 −0.188 0.850 −0.032 0.028 −1.126 0.260
DKEFS Number Sequencing −0.028 0.064 −0.445 0.660 −0.003 0.033 −0.093 0.930 −0.021 0.065 −0.328 0.740 −0.034 0.031 −1.094 0.280
DKEFS Letter Sequencing −0.044 0.069 −0.642 0.520 −0.023 0.035 −0.656 0.510 −0.035 0.070 −0.499 0.620 −0.050 0.034 −1.494 0.140
WS Digit Symbol −0.014 0.053 −0.261 0.790 0.001 0.028 0.026 0.980 −0.049 0.054 −0.907 0.370 −0.017 0.026 −0.672 0.500
WS Processing Speed Index −0.067 0.056 −1.209 0.230 −0.026 0.030 −0.873 0.380 −0.080 0.057 −1.401 0.160 −0.039 0.027 −1.422 0.150
 Visual speed CPT II Hit Reaction Time −0.087 0.060 −1.460 0.150 −0.053 0.032 −1.663 0.098 −0.057 0.062 −0.923 0.360 −0.060 0.029 −2.054 0.041
WS Symbol Search −0.103 0.062 −1.672 0.096 −0.045 0.033 −1.382 0.170 −0.093 0.063 −1.466 0.140 −0.053 0.030 −1.747 0.082
 Motor speed GPB Dominant Hand −0.192 0.091 −2.112 0.036 −0.092 0.048 −1.907 0.058 −0.052 0.094 −0.555 0.580 −0.037 0.045 −0.818 0.410
GPB Non-Dominant Hand −0.221 0.095 −2.323 0.021 −0.148 0.050 −2.953 0.004 −0.164 0.098 −1.670 0.097 −0.104 0.047 −2.218 0.028
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Abbreviations: SE, standard error; Std. Est, standard estimate, DKEFS, Delis-Kaplan Executive Function System; WCST, Wisconsin Card Sorting Test; WS, Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale; WASI, Wechsler Abbreviated Scale of Intelligence; CPT II, Conners’ Continuous Performance Test II; GPB, Grooved Pegboard Test

All periods were adjusted for sex, time since diagnosis, Total XV treatment risk, parents’ highest education in years, and body mass index Z-score at diagnosis.

Standard estimate was calculated as estimate divided by standard error.

Negative associations of attention measures with overweight/obesity AUC were seen for attention span in early maintenance, risk taking in late maintenance, and omissions in consolidation therapy (P < 0.05 for all) (Table 3).

For the measures of processing speed, larger overweight/obesity AUC was associated with lower scores for motor speed during induction (dominant hand: standardized estimate −2.112, P = 0.036; non-dominant hand: standardized estimate −2.323, P = 0.021) (Table 3). This association persisted during consolidation and late maintenance, and scores for visual speed were lower during late maintenance (P < 0.05 for all).

DISCUSSION

To our knowledge, this is the first study to investigate the association of obesity with neurocognitive function in pediatric ALL survivors. Our cross-sectional analyses revealed that not only being obese but also being overweight was negatively associated with neurocognitive performance in survivors of ALL. Moreover, greater exposure to overweight/obesity status starting during induction therapy, as indexed through AUC, was associated with neurocognitive impairment, adjusting for treatment risk (i.e., intensity).

It has long been recognized that survivors of ALL are at greater risk for obesity even without cranial irradiation.3,23,24 Our study cohort also demonstrated an acute increase in BMI Z-score during induction therapy and a subsequent gradual increase during and after therapy, with a short decline that coincided with the cessation of glucocorticoid treatment in the latter part of maintenance therapy. Treatment-induced neurocognitive impairment in survivors of ALL has been reported in previous studies.12–14 Higher-intensity CNS-directed therapy, especially with systemic methotrexate, intrathecal therapy, and glucocorticoids, all of which are associated with treatment risk status, can have a substantial neurotoxic effect on the cognitive performance of survivors of ALL, who are, therefore, highly susceptible to additional neurotoxic stress.25

Although a meta-analysis of the association between overweight/obesity and neurocognitive function in the non-cancer population indicated that the impact of overweight was quite limited when compared to the impact of obesity,11 our cross-sectional analysis demonstrated that even being overweight adversely affects neurocognitive function in survivors of ALL. In fact, when neurocognitive measurements of overweight and obese survivors were separately compared to those of healthy/underweight counterparts, overweight survivors scored significantly worse on more measurements than did obese survivors. Among overweight survivors at assessment, 76% were healthy/underweight at diagnosis, with a median BMI of 0.27, whereas among obese survivors, only 35% were healthy/underweight at diagnosis, with a median BMI of 1.39 (Table 1). Therefore, it appears that physiologic changes that result in a shift from the healthy to the “unhealthy” categories can influence neurocognitive function more adversely than simply remaining overweight/obese.

For the longitudinal analysis, analyzing AUC by time period, with adjustment for several important clinical factors, including BMI Z-score at diagnosis, revealed how the degree of exposure to overweight/obesity at each time point would influence the neurocognitive function of survivors of ALL. In this analysis, an overweight/obese AUC during induction therapy, when a remarkable gain in BMI Z-score was observed, was already associated with impaired cognitive flexibility and motor speed, indicating that a rapid trajectory of initial BMI gains from baseline might be critical to the impairment.

There are several possible explanations for the distinct effect of overweight/obesity on neurocognitive function in survivors of ALL. First, insulin resistance in obese individuals is considered a major contributor to neurocognitive decline, because insulin regulates memory and learning by promoting the survival of neurons through receptors in the brain.26,27 For patients with ALL, intensive glucocorticoid treatment is associated with insulin resistance,28 which can lead not only to increased BMI Z-scores but also to a decline in neurocognitive functions during induction therapy. Furthermore, given the heightened sensitivity of patients with ALL to neurotoxic stress, mild changes in glucose metabolism that are not yet manifested as insulin resistance could adversely influence neurocognitive function. Recent studies have suggested that hyperglycemia itself can cause cognitive impairment.29,30 Therefore, rigorous control of hyperglycemia, as well as ensuring appropriate dietary intake and exercise, especially during induction therapy, should be considered.

Chronic low-grade inflammation may also contribute to cognitive impairment. In obese individuals, an inflammatory cascade is activated early in adipose tissue expansion, and chronic obesity leads to a pro-inflammatory phenotype that is associated with poor cognitive performance.31 Chronic low-grade inflammation has been similarly observed in survivors of ALL32,33 and was significantly associated with impaired neurocognitive function in female patients.32 Treatment-related inflammation might be exacerbated by obesity-induced inflammation. Dietary intervention with exercise is beneficial for both obesity-induced inflammation34 and cancer-induced inflammation.35

The association of obesity with neurocognitive dysfunction is also promoted by neurobehavioral alterations. Past studies in non-cancer populations have demonstrated a bidirectional relation, implying that excessive adiposity has a direct adverse impact on neurocognitive function, and in turn, that impaired neurocognitive function predisposes individuals to obesity-related behavior.36,37 In our study, being overweight/obese during induction therapy was associated with decreased scores for cognitive flexibility. Cognitive flexibility represents the ability to accommodate appropriate behaviors in response to the changing environment.38 Patients with ALL have to maintain healthy behaviors during the periods of disrupted glucose metabolism, limited physical strength, and nutritional imbalance that are associated with leukemia and its treatment. Early onset of impaired cognitive flexibility during treatment might play a role in the development of subsequent obesity-related behaviors and obesity in later treatment phases.

This bidirectional relation is also observed for attention and processing speed. In our study, risk taking was significantly associated with being overweight/obese in both cross-sectional and longitudinal analyses. Risk taking is closely linked with impulsivity, a main component of attention problems, and individuals with a propensity for risk taking exhibit unhealthy eating behavior as a result of their difficulty in delaying gratification and suppressing urges.39,40 It is likely that this attention impairment, partly due to ALL treatment, promotes unhealthy eating behaviors after treatment that exacerbate the risk of obesity. Similarly, motor skill impairment was observed during induction therapy. As motor skills are an important component of physical activity,41 their impairment early in treatment might constitute a major obstacle to participation in physical activity, which, in turn, could contribute to later development of overweight/obesity.

These findings demonstrate that obesity among survivors of ALL is not merely a consequence of physiologic changes resulting from chemotherapy, unhealthy diet, or reduced physical activity; it can mutually associate with impaired neurocognitive function. However, how obesity influences specific domains of neurocognitive function remains unclear. Obesity among survivors of ALL can be influenced by various factors such as age at diagnosis,3 sex,42 and genetic variants.43 Past studies have demonstrated myriad factors that affect the neurocognitive function of survivors of ALL besides CNS-directed therapy; these include growth hormone deficiency,44 sepsis,45 and genetic factors.46 These sources of variability are intricately intertwined, further complicating the process of determining how specific domains are impaired. Moreover, although we employed AUC analysis, speculating that the degree and duration of overweight/obesity would be associated with neurocognitive function, the analysis for the whole period of observation demonstrated only a few significant associations. In the cross-sectional analysis, the degree of obesity did not appear to be a significant contributor to neurocognitive impairment. It is possible that if we were to focus on a limited time period (induction therapy) in which a major increase in BMI occurred, the association between overweight/obesity and neurocognitive function would be distinguished. However, over a longer time period, other sources of variability might have come into play.

Although we need to be aware of these other sources of variability, the significant association between obesity and neurocognitive function found in the current study suggests that focusing solely on weight control is not sufficient. Studies of obese children have demonstrated that interventions in executive function are effective at improving body composition as well as neurocognitive function.47 To prevent obesity and to alleviate adverse neurocognitive sequelae in survivors of ALL, multidisciplinary intervention involving oncologists, psychologists, nutritionists, endocrinologists, pharmacists, and nurses is crucial and should be started early after a diagnosis of ALL and continued after the completion of therapy.

Our study had several limitations. First, there was a lack of information on laboratory findings such as those pertaining to insulin levels, hyperglycemia, hyperlipidemia, or the presence of inflammatory markers (e.g., C-reactive protein and cytokines). Moreover, obesity-related behaviors, including physical activity or dietary patterns among the patients, were not examined in the study. Those factors were highly likely to influence the association between obesity and neurocognitive function and should be incorporated into future research. Second, the study did not have access to baseline neurocognitive data, although interpreting baseline assessments is challenging as cognitive skills of children aged 2 or 3 years are not directly comparable to those of adolescents. At best, baseline assessments can provide a crude indication of longitudinal attention and processing speed, although such assessments may be influenced by acute physical and psychologic conditions. Finally, the current study focused on the association between obesity and neurocognitive function and, therefore, although demographic and treatment-related risk factors were used as adjustment factors in our analysis, their respective impacts were not fully explored. Risk factors for neurocognitive function among the same cohort were already explored in a previous study.48 However, in future research, exploring the influence of demographic and treatment-related covariates on the association between obesity and neurocognitive function would be beneficial for tailoring effective interventions.

In conclusion, the results of the present study provide novel insights into the association between obesity and neurocognitive performance in survivors of ALL. Our findings indicate the need for interventional strategies that address this relation, such as early educational programs to promote healthy dietary intake and exercise to prevent weight gain, along with periodic assessment of cognitive function and neurocognitive training, especially for patients who are overweight/obese. The development of such novel interventions may be beneficial in reducing physiologic and neurologic sequelae in survivors of ALL and in improving their quality of life.

Supplementary Material

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Acknowledgements:

The authors thank Keith A. Laycock, PhD, ELS, for scientific editing of the manuscript

Funding sources: This work was supported by National Institutes of Health grants MH085849 and CA21765 and by ALSAC. The funding organizations had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Conflict of interest disclosures: The authors have declared no conflicts of interest.

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