A pilot study of neuropsychological functions, APOE and amyloid imaging in patients with gliomas

Abstract

Brain tumor patients treated with radiotherapy (RT) often develop cognitive dysfunction, and recent studies suggest that the APOE ε-4 allele may influence cognitive outcome. The ε-4 allele is known to promote beta (β) amyloid deposition in the cortex, and preliminary evidence suggests that RT may be associated with this process. However, it is unknown whether β-amyloid accumulation contributes to treatment neurotoxicity. In this pilot study, we assessed neuropsychological functions and β-amyloid retention using F-florbetaben (FBB) PET in a subset of brain tumor patients who participated in our study of APOE polymorphisms and cognitive functions. Twenty glioma patients treated with conformal RT ± chemotherapy participated in the study: 6 were APOE ε-4 carriers and 14 were non-ε-4 carriers. Patients completed a neuropsychological re-evaluation (mean time interval = 5 years, SD = 0.83) and brain MRI and FBB PET scans. Wilcoxon signed-rank test comparisons between prior and current neuropsychological assessments showed a significant decline in attention (Brief Test of Attention, p = 0.018), and a near significant decline in verbal learning (Hopkins Verbal learning Test-Learning, p = 0.07). Comparisons by APOE status showed significant differences over time in attention/working memory (WAIS-III digits forward, p = 0.028 and digits backward, p = 0.032), with a decline among APOE ε-4 carriers. There were no significant differences in any of the FBB PET analyses between APOE ε-4 carriers and non-ε-4 carriers. The findings suggest that glioma patients may experience worsening in attention and executive functions several years after treatment, and that the APOE ε-4 allele may modulate cognitive decline, but independent of increased β-amyloid deposition.

The APOE ε4 allele in relation to pre‐ and postsurgical cognitive functioning of patients with primary brain tumors

“…In addition, mean performances for Letter Fluency appeared higher in carriers than non-carriers at baseline, but similar at 12month follow-up, which indicates more improvement in non-carriers. These tests measure different facets of executive function, and a significant difference for Digit Span Backward was also found in previous research [36]. Future investigations may therefore focus primarily on executive measures.…”

“…We note some methodological differences between studies that might account for the different findings. The longitudinal study by Correa and colleagues [36] that reported a ε4-related risk for decline A longitudinal study by Ahles et al [50] investigating changes from pre-up to 18 months post-chemotherapy in breast cancer patients also found no main effect of APOE. Late cognitive effects of treatment-induced processes that continue >6 months after radiation, such as capillary loss [52] and apoptosis [53], may be captured better at later follow-ups than those in our study.…”

“…We note some methodological differences between studies that might account for the different findings. The longitudinal study by Correa and colleagues [36] that reported a ε4‐related risk for decline in Digit Span performance obtained cognitive measurements at later time points (first assessment 4 ± 3.4 years after completion of treatment and second assessment 5.2 ± 0.8 years after that). Similarly, a study by Ahles and colleagues included long‐term survivors of breast cancer 8.8 ± 4.3 years posttreatment [23].…”

“…Based on longitudinal research in treated (non-)CNS cancer patients, we expected ε4 carriers to show worse performances over time (ie, less recovery) compared to non-carriers on tests of executive functioning, (working) memory and processing speed [24,35,36,50,51]. A myriad of pathways [47], including vascular abnormalities, subefficient myelin regulation, increased oxidative stress and treatment-related toxicity [17,30,31,34], could contribute to this difference in cognitive outcome.…”

“…Correa and colleagues were the first to study the role of the APOE ε4 allele in cognitive functioning in patients treated for CNS tumors [5]. They found that ε4 carriers showed poorer verbal learning and recall [35] and were more susceptible to decline of attention and working memory [36] as compared to non-carriers years after treatment. Currently, the absence of prospective longitudinal assessment of cognitive function in the literature and a lack of investigations into other common primary brain tumors, such as meningioma, limit our understanding of the role of APOE ε4 in the course of cognitive functioning in this population.…”