title: Impaired brain metabolism and neurocognitive function in childhood leukemia survivors despite complete hormone supplementation in adulthood.
abstract: Cranial radiotherapy is a known risk factor for neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia (ALL). Understanding the nature of cognitive dysfunction during adulthood in ALL survivors is important as it has an impact on major life situations. Thirty-eight (21 women) ALL survivors were investigated 34 years after diagnosis. Median-age was 38 (27-46) years. All were treated with a CRT dose of 24Gy and 11 years (3-13) of complete hormone supplementation. Comparisons were made to 29 matched controls. Assessments of magnetic resonance spectroscopy (white and grey matter metabolic alterations), brain volume and neuropsychological tests were performed. ALL survivors demonstrate a generally lower performance in neuropsychological tests. ALL survivors scored lower than controls in vocabulary (p<0.001), memory (p<0.001), learning capacity (p<0.001), spatial ability (p<0.001), executive functions and attention (p<0.001) 34 years after ALL treatment. Compared to controls ALL survivors had reduced white matter (WM) (492 vs 536cm3, p<0.001) and grey matter (GM) volumes (525 vs 555cm3, p=0.001). ALL survivors had lower levels of WM N-acetyl aspartate/creatin (NAA/Cr) (1.48 vs 1.63, p=0.004), WM NAA+NAAG (N-acetylaspartylglutamate)/Cr (1.61 vs 1.85, p<0.001) and lower levels of GM NAA/Cr (1.18 vs 1.30, p=0.001) and GM NAA+NAAG/Cr (1.28 vs 1.34, p=0.01) compared to controls. ALL survivors had higher levels in WM MI (Myoinositol)/NAA (0.65 vs 0.56, p=0.01) concentrations compared to controls. There was a significantly negative correlation of years since ALL diagnosis to WM NAA+NAAG/Cr (r=-0.4, p=0.04) in ALL survivors. The present study shows impaired brain metabolism detected by MRS, reduced brain volumes and neurocognitive impairment in childhood ALL survivors treated with cranial radiotherapy and chemotherapy, despite complete hormone substitution. We also report an impairment of metabolites correlated to time since treatment and a progressive impairment in sustained attention, suggesting an accelerated aging in the irradiated brain. Following these survivors many decades, or throughout life, after treatment with cranial radiotherapy and chemotherapy is highly warranted for a broader understanding of long-term outcome in this patient group.
authors: Department of Endocrinology, Skåne University Hospital and IKVL, Lund University, Lund, Sweden. Electronic address: Cecilia.follin@med.lu.se.
authors: Cecilia
authors: C
authors: Follin
authors: Department of Endocrinology, Skåne University Hospital and IKVL, Lund University, Lund, Sweden.
authors: Eva Marie
authors: EM
authors: Erfurth
authors: Department of Psychiatry, Clinical Sciences, Lund University, Lund, Sweden.
authors: Aki
authors: A
authors: Johansson
authors: Department of Diagnostic Radiology, Skåne University Hospital and Clinical Sciences, Lund University, Sweden.
authors: Jimmy
authors: J
authors: Lätt
authors: Department of Diagnostic Radiology, Skåne University Hospital and Clinical Sciences, Lund University, Sweden.
authors: Pia C
authors: PC
authors: Sundgren
authors: Department of Psychology, Lund University, Lund, Sweden.
authors: Kai
authors: K
authors: Österberg
authors: Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
authors: Gabriella
authors: G
authors: Spulber
authors: Department of Diagnostic Radiology, Skåne University Hospital and Clinical Sciences, Lund University, Sweden.
authors: Peter
authors: P
authors: Mannfolk
authors: Department of Diagnostic Radiology, Skåne University Hospital and Clinical Sciences, Lund University, Sweden; Lund University Bioimaging Centre (LBIC), Lund University, Sweden.
authors: Isabella M
authors: IM
authors: Björkman-Burtscher
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D060825:Cognitive Dysfunction / Q000209:etiology / Q000503:physiopathology*; D016371:Cranial Irradiation / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000473:pathology; D020249:Hormone Replacement Therapy; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000532:radiotherapy*; D017741:Survivors; D013997:Time Factors; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology
keywords: Acute lymphoblastic leukemia; Brain metabolism; Childhood leukemia; Cranial radiotherapy; MR-spectroscopy; Magnetic resonance spectroscopy; Neurocognitive function; Neuropsychology