Association of anemia and cognitive dysfunction in patients with acute myelogenous leukemia and myelodysplastic syndrome
Authors: Susan M. Wood, Christina A. Meyers, Stefan Faderl, Hagop M. Kantarjian, Sherry A. Pierce, Guillermo Garcia‐Manero
Journal: American Journal of Hematology (2011)

Anemia is a symptom associated with cognitive dysfunction and is diagnosed if the hemoglobin level of a blood sample is too low. The clinical impact of chronically low hemoglobin level may be insufficient brain oxygenation, which may result in a decline in cognitive functioning. Previous studies have provided evidence of decrements in cognitive functioning associated with anemia across various disease processes, but few have investigated the association between cognitive dysfunction and hemoglobin level in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). As this population is inherently anemic, studying these patients allowed for an exploration of cognitive changes at mild, moderate, and severe levels of anemia. This investigation explored cutoff points for hemoglobin at which cognitive decline may occur. Findings showed decrements in cognitive functioning occurring at hemoglobin levels of 10 g/dL or below. Performance on measures of word retrieval, attention, and fine motor function was most affected which suggests fronto-temporal lobe dysfunction. Results provided evidence as to a hemoglobin cutoff point below which cognitive function may be affected in patients with AML and MDS. This cutoff value may provide a clinical marker at which cognitive testing and therapeutic interventions could be utilized to improve patients' cognitive function, level of fatigue and overall quality of life. Anemia is a symptom associated with cognitive dysfunction and reported fatigue across numerous cancers, and as a side effect of various cancer treatments. Other studies have investigated the association between cognitive dysfunction and biomarkers of anemia in various types of disease processes and as associated with chemotherapy treatment, but few have explored the association in untreated patients with AML and MDS whose hemoglobin level often falls in the moderate to severe range. Prior research has provided evidence of specific differences between cancer patients with hemoglobin values greater than 12 g/dL and patients with values less than or equal to 12 g/dL. Patients reported significantly less fatigue, fewer nonfatigue anemia symptoms, better physical well-being, better functional well-being, and higher general quality of life at higher levels [1]. Jacobsen et al. [2] examined the relationship between changes in hemoglobin levels and changes in reported fatigue and cognitive functioning prior to and after chemotherapy treatment in patients with various types of cancer. They found that in only a smaller subset of patients whose hemoglobin levels dropped to less than or equal to 12 g/dL was cognitive impairment associated with decreased hemoglobin levels. The decline was limited to poorer performances on measures of attention, executive function, and visual memory. Other studies have proposed that difficulty concentrating and slowed processing speed may occur at a hemoglobin level lower than 8 g/dL [3, 4]. These findings suggest that below normal hemoglobin levels may impact cognitive functioning. The current cross-sectional study investigated the association between hemoglobin and cognitive dysfunction in a patient population that is inherently anemic, thus allowing for the examination of a range of lower biomarker levels and their relationship to cognitive impairment in patients with blood cancers. Some studies that have examined the relationship between hemoglobin level and cognitive dysfunction have explored hemoglobin as a continuous variable, which may not allow for elucidation of the true relationship [5]. Various cutoff points have been proposed in the previous literature as discussed above but have not been examined, per se. This study investigated the level at which hemoglobin must decline to contribute to cognitive dysfunction using cutoff values of 12, 10, or 8 g/dL, which were suggested in the previous literature. In particular, the cognitive domains of processing speed, fine motor dexterity, and executive function were hypothesized to be most affected. Another aim was to examine whether patients who were cognitively impaired (as defined by evidencing impaired performance on three or more cognitive measures) would fall within a particular hemoglobin group. As cognitive dysfunction in this population is not generally an imminent concern for physicians, a hemoglobin cutoff level may provide a clinical marker at which cognitive testing and therapeutic interventions may be utilized to improve patients' quality of life. Our investigation was carried out with 88 adult patients with AML or MDS divided into three groups by hemoglobin level at time of testing. Demographic variables and clinical diagnosis were not significantly different between the groups. Overall, more participants in the study were male, had a diagnosis of MDS, and were predominantly Caucasian and right-handed. The demographic characteristics of the participants are reported in Table I and clinical characteristics are reported in Table II. Group results of the patients' cognitive testing are provided in Table III. A one-way between-group multivariate analysis of covariance (MANCOVA) was performed to investigate how differences in hemoglobin level were related to performance on measures of cognitive functioning. There was a significant difference between hemoglobin groups and their performance on the collective cognitive measures (P = 0.026); however, when considering the cognitive measures separately, there were no significant differences. A discriminant function analysis revealed a subset of measures that was able to explain 69.2% of the variance between the groups (P = 0.038). These findings indicate that group differences as shown in the MANCOVA analysis can be explained in terms of one underlying dimension principally consisting of the contributions from the cognitive tests measuring word retrieval, fine motor function, and attention. The findings also revealed that the collective performance on these measures was able to discriminate the moderate and severe hemoglobin groups from the mild hemoglobin group. Another aim of this study was to investigate not only whether blood groups differed statistically on particular cognitive characteristics, but also whether the degree of clinical cognitive impairment differed between the groups. A final set of analyses was conducted to judge whether not only statistically significant, but clinically meaningful, cognitive impairment was evident in the patient groups. Although there were no significant differences between the groups (P = 0.746), the findings revealed a percentage of cognitive impairment in each group (Mild Hg group = 25%, Moderate Hg group = 35%, and Severe Hg group= 33%). When using hemoglobin level as the indicator of anemia severity, the results showed that anemia severity is associated with differences in cognitive performance. However, differences in cognitive function between the mild, moderate, and severe groups could not be explained in terms of separate performance on cognitive tests. Rather, the results of this study suggest that the group differences are better explained in terms of the combined contributions of the tests. The largest contributors to this combination were those tests which measured immediate and delayed word retrieval (Hopkins Verbal Learning Test–Revised), divided attention and working memory (Trails B and Digit Span), and fine motor dexterity (Grooved Pegboard). These findings are similar to those reported by Jacobsen and associates [2], in that, aspects of fronto-temporal lobe function [6, 7] appear to be affected at hemoglobin levels below 12 g/dL. Cognitive functioning in the moderate and severe hemoglobin groups was more affected than the functioning in the mild hemoglobin group. This finding suggests that a hemoglobin level of 10 g/dL or below (cutoff point for the moderate group) is associated with a change in cognitive functioning. These results help to elucidate the mixed findings in previous studies in which hemoglobin level was not grouped according to severity but investigated as a continuous variable to be compared with performance on cognitive tests. An interesting finding from this study was that only a subset of patients in each group evidenced significant cognitive impairment, per se. In the mild hemoglobin group, 25% of the patients showed significant cognitive impairment on at least three of the cognitive measures, while in the moderate and severe group a third or more of the patients showed cognitive impairment (33 and 35% respectively). Although these differences were not statistically significant between groups, this finding suggests that between one-fourth and one-third of patients with AML or MDS experience cognitive impairment when hemoglobin level falls below 12 g/dL. It is unclear as to what factors may contribute to this decline in only a subset of this population and further research may help elucidate these findings. Although IPSS guidelines currently indicate that a hemoglobin level of less than 10 g/dL is indicative of cytopenia, the clinical guideline for the level at which physicians typically transfuse is 8 g/dL [8]. Our finding of the level at which low hemoglobin may affect cognitive functioning may facilitate an improvement in patient care by providing physicians with a higher biologic marker at which intervention strategies for supportive care may be implemented. An earlier intervention for anemia in these patients may improve cognitive function, level of fatigue and overall quality of life. In addition, more cognitive screening may be warranted as part of a current trend involving implementation of more aggressive treatments for this patient population. Eighty-eight outpatient participants were recruited in conjunction with a protocol approved by the institutional review board at the University of Texas M.D. Anderson Cancer Center in Houston, Texas. To be eligible to participate, patients had to be: (1) at least 18 years of age, (2) diagnosed with either AML or MDS, and (3) fluent in spoken and written English. Also they (4) may not have received previous or current chemotherapy treatment, nor (5) have a history of psychiatric illness or head injury with an alteration of consciousness. They must (6) have completed at least 8 years of formal education, and (7) be able to give written informed consent before study entry. Patients who were in contact isolation due to fever or infection were not offered participation in this study. Demographic information was obtained through patient self-report during a brief clinical interview at the time of testing. Patients were evaluated using a battery of neuropsychological tests that were selected based on their sensitivity and suitability for use as a brief assessment. These measures were also chosen for their ability to measure cognitive functions often affected by anemia, including mental processing speed, attention, executive function, verbal memory consolidation, and fine motor speed and dexterity. The tests administered were (1) Digit Span subtest from either the Wechsler Adult Intelligence Scale-Revised (WAIS-R) or the Wechsler Adult Intelligence Scale-III (WAIS-III) [9] to assess auditory attention span and working memory; (2) Digit Symbol Coding subtest from either the WAIS-R or the WAIS-III as a measure of psychomotor processing speed and sustained attention; (3) HVLT-R to assess verbal learning and memory, including immediate recall, delayed recall, and recognition memory [10]; (4) Trail Making Test Part A to assesses visual scanning ability, simple attention and psychomotor processing speed; (5) Trail Making Test Part B to assess divided attention/executive function [11]; (6) Controlled Oral Word Association Test to assess phonemic verbal fluency [12]; and (7) fine motor speed and dexterity were assessed using the Grooved Pegboard task [13]. Medical records were accessed in order to obtain laboratory values within one day of time of testing for hemoglobin level, as well as information regarding patient diagnosis, type of treatment received, and transfusion dates. A MANCOVA was selected as the statistical method for comparing differences between hemoglobin level and test performance. Participants were divided into a severe group with hemoglobin level less than or equal to 8 g/dL (n = 21); a moderate group with levels between 8.1 and 10 g/dL (n = 51); and a mild group with levels between 10.1 and 12.5 g/dL (n = 16). Baseline data were collected on 88 participants who met study criteria. The alpha level used for significance was P ≤ 0.05. A preliminary analyses of variance (ANOVA) was conducted to compare the mean differences for hemoglobin level between groups of participants to ensure that the cutoff points chosen on the basis of the literature produced groups with significantly different levels of hemoglobin and that the sample sizes were reasonably large. In addition, an analysis was conducted to assess whether there was a significant difference between the groups in diagnosis type, race, sex, age, and education using separate ANOVA and Pearson chi-square procedures. A MANCOVA was conducted using hemoglobin level as the independent variable on the three groups: mild, moderate, and severe. The dependent variables were the standard scores on the administered cognitive measures. Covariates included in this analysis were age and education level, as these variables have been shown to be related to cognitive performance and may not have been completely controlled as different norms were used for different tests. Significant effects were followed by univariate ANOVA tests to further elucidate the findings, and other post-hoc procedures were used as deemed appropriate. A final analysis was performed to determine if there was a difference between the groups in the number of patients who were cognitive impaired. Impairment was defined as a z-score ≤ 1.50 on three or more of the cognitive measures. A Pearson chi-square analysis was performed on the frequencies of impaired versus nonimpaired patients between hemoglobin groups to assess differences. Susan M. Wood [email protected]*, Christina A. Meyers*, Stefan Faderl , Hagop M. Kantarjian , Sherry A. Pierce , Guillermo Garcia-Manero , * Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas.