Overview. 1.Introduction 22/11/2011. Longitudinal assessment of chemotherapyinduced structural changes in cerebral white

Transcription

1 22/11/2011 Subtle cognitive after chemotherapy Longitudinal assessment of chemotherapyin patients with breast cancer: evidence from induced structural in cerebral white a combined neuropsychological and medical matter andimaging its correlation study with impaired cognitive functioning in breast cancer patients S. Deprez, F. Amant, J. Verhoeven, A. Smeets, M-R. Christiaens, A. Leemans, R. S. Deprez, F. Amant, J. Verhoeven, A. Smeets, M-R. Christiaens, A. Leemans, R. Peeters, W. Van hecke, J. Vandenberghe, M. Vandenbulcke, chemotherapy-induced and structural S. Sunaert in cerebral white matter Peeters, W. Van hecke, J. Vandenberghe, M. Vandenbulcke, and S. Sunaert 1.Introduction Breast cancer incidence in Western countries is 1 in 8 Survival rate is increasing 10-40% suffer mild cognitive impairment after systemic adjuvant treatment Longitudinal assessment of chemotherapyinduced structural in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients So-called Chemobrain Impact on quality of life The pathophysiology is still unclear S. Deprez, F. Amant, J. Verhoeven, A. Smeets, M-R. Christiaens, A. Leemans, R. Peeters, W. Van hecke, J. Vandenberghe, M. Vandenbulcke, and S. Sunaert Ik stel op het werk een vraag en krijg als antwoord : Heb ik je net gezegd, weet je dat niet meer?" Soms weet ik midden in een gesprek niet meer waar het over gaat of wat ik wilde zeggen. Longitudinal assessment of chemotherapyinduced structural in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients Je bent met iets bezig en plots weet je niet meer wat je aan het doen was. S. Deprez, F. Amant, J. Verhoeven, A. Smeets, M-R. Christiaens, A. Leemans, R. Peeters, W. Van hecke, J. Vandenberghe, M. Vandenbulcke, and S. Sunaert Velen zeggen : jamaar je word ook een dag ouder hé, maar bij het ouder worden gaat dat geleidelijk aan, en bij ons is dat ineens gekomen Veel mensen begrijpen dat niet, sommige reageren soms boos zelfs, ook mijn huisgenoten Longitudinal assessment of chemotherapyinduced structural in cerebral white matter and its correlation with impaired cognitive functioning in breast Ik ben ondertussen 18 maand na mijn laatste chemo: m'n cancer patients geheugen is nog niet echt spectaculair verbeterd, MAAR: via trucjes lukt het: Alarm zetten om de wasmachine niet te vergeten. overal briefjes leggen... S. Deprez, F. Amant, J. Verhoeven, A. Smeets, M-R. Christiaens, A. Leemans, R. Peeters, W. Van hecke, J. Vandenberghe, M. Vandenbulcke, and S. Sunaert 1

2 Candidate mechanism Research methods Induced hormonal Genetic predisposition (APOE E4 allele?) Immune dysregulation Changes in: cognition brain structure function Direct neurotoxicity Oxidative stress and DNA damage TA Ahles and AJ Saykin, 2007 Mostly: 1. Neuropsychological testing 2. Self-rated subjective questionaires Recently also: 3. Animal research 4. Advanced medical imaging Neuropsychological tests Animal Research Chemotherapy-treated (C+) patients perform worse then C- patients or healthy controls on neuropsychological tests Effects are modest, within normal limits Deficits in working memory, executive function, information processing, attention, Effects remain after controlling for factors like fatigue, mood, anxiety (Schagen et al, 2001, Ahles et, 2002, Matsuda et al, 2005, Castellon et al, 2004, Jansen et al, 2008, Ahles et al, 2011 ) Animal experiments learning deficits after administration chemotherapeutic agents (Foley et al., 2008; Macleod et al., 2007). Treatment in mouse with chemotherapeutic agent (5-FU) resulted in damage to white mater myelin of CNS (Han, 2008, Mustafa et al., 2008) Electron micrographs of longitudinal sections of axons Brain Imaging studies Very few imaging studies have been done sofar Structural Imaging studies Functional Imaging studies MR VBM Inagaki et al, 2006 Mc Donald, 2010 PET Silverman et al, 2006 MR DTI 2 pilot studies: Abraham et al, 2008 Deprez et al, 2010 fmri Ferguson et al, 2007 De Ruiter et al, 2010 Both structural and functional in the brain were detected 2

3 microscopy of white matter Gray Matter White Matter Pictures by courtesy of G. Bartzokis Our Research question Potential mechanism = direct neurotoxicty Diffusion Tensor Imaging MR Imaging technique Enabling the visualisation AND quantification of white matter architecture and integrity Based on the measurement of diffusion of water molecules in the brain Possible white matter (WM) injury? Changes in WM microstructure measurable with MR Diffusion Tensor Imaging (DTI)? Damage to the WM will change quantitative DTI parameters such as FA: Fractional Anisotropy 2. Cross-sectional pilot study Evaluate possible differences in WM integrity and link with cognitive function of C+ vs controls DTI Neuropsychological tests Self-rated subjective questionnaires Are there differences in WM integrity? Attention / Concentration Processing speed Memory Executive functioning Cognitive functioning Depression Anxiety 3

4 Cross-sectional pilot study DTI analysis Neuropsychological assessment Neuropsychological tests covering: Attention (Bourdon-Wiersma, Every Day Attention (TEA), Digit span, CORSI block span) Psychomotor speed (WAIS digit symbol, 9 hole Pegboard test (9HPT)) Memory (AVLT, RVLT) Executive funtioning (Stroop, Trail Making Test, COWAT) Verbal IQ Regions where FA value in patients < healthy controls (pcorr < 0.05) Frontal, Temporal Regions where MD value in patients > healthy controls (pcorr < 0.05) - Frontal Deprez et al, Human Brain Mapping, 2010 Self-rated subjective questionnaires: Cognitive Failure Questionnaire (CFQ) Spielberger State-Trait Anxiety Inventory (STAY) Beck Depression Inventory (BDI) WM integrity affected in chemotherapy treated patients Example: WAIS Digit Symbol Neuropsychological assessment Cross-sectional pilot study Correlation analysis correlations between FA and neuropsych tests E.g. WAIS digit symbol score (p=0.04)* * P corrected for multiple comparisons Aim of present LONGITUDINAL study Evaluate possible in WM integrity and link with cognitive functioning DTI Neuropsychological tests Self-rated subjective questionnaires Are there in WM structure PRE vs POS? Attention / Concentration Processing speed Memory Executive functioning Cognitive functioning Depression Anxiety 4

5 Subjects Subjects Subjects (age 35-50y): 34 C+ breast cancer patients 16 C- breast cancer patients 19 matched healthy controls surgery t1 9 months chemotherapy t2 AT BASELINE (t1) C+ Patients (n=34) C- Patients (n=16) Healthy controls (n=19) MEAN SD MEAN SD MEAN SD F p ANOVA Age (years) Depression BDI Anxiety STAI Verbal IQ MR DTI Imaging Neuropsych. Test battery MR DTI Imaging Neuropsych. Test battery No significant differences in age, IQ, anxiety Significant difference in depression score Include as covariate in statistical analysis Significant decreased FA at t2 vs t1 in C+ patients A Assessment of FA : RESULTS in control groups L L 4 3 <2 T > 6 NO significant differences in WM integrity were found for BOTH control groups C- and HC L 2 1 B Neuropsychological assesment PAIRED T-tests t1 vs t2 Correlation analysis C+ Sign t2 vs t1 Attention and concentration WAIS letter number sequencing (p=0.01) Psychomotor speed 9PEG (p=0.03 and p=0.007); WAIS digit/symbol (p=0.04) Verbal memory AVLT (p=0.02 and p=0.04) C- Sign t2 vs t1 Attention and concentration Bourdon Wiersma (p=0.01); Everyday attention (p=0.04) Memory Verbal memory (p=0.004); Visual memory (p=0.01) HC Sign t2 vs t1 Attention and concentration WAIS digit span (p=0.01); Every day attention (p=0.001) Psychomotor speed 9PEG (p=0.04) Verbal memory AVLT (p<0.006) 5

6 Summary C+ C- HC DTI FA analysis FA Sign No sign No sign Neuro psych. analysis Sign or = Sign or = Sign or = Correlation between FA and performance for C+ Conclusion Chemotherapy seems to affect white matter integrity This decrease in white matter integrity could be linked with a decrease in performance on memory and attention tests DTI WM parameters have the required sensitivity to quantify chemotherapyinduced Conclusion This is study is adding to the Growing support for chemo brain in scientific community Growing body of scientific evidence Growing public awareness and concern Future: More studies are needed: Larger longitudinal imaging studies to confirm findings Is there different impact of different treatments? To give better information to patients about possible cognitive problems in relation to cancer and cancer treatment Thanks to Patients and volunteers FWO and Stichting tegen Kanker Colleagues of UZ Leuven: Radiology Multidisciplinary Breast Center Neuropsychiatry 6