Overview of Neuroimaging Studies
publicité
Overview of Neuroimaging Studies in Evaluating the PostPost-Chemo Brain International Cognition & Cancer Task Force Conference 15 15‐‐17 March 2012 Dan Silverman, MD, PhD Ahmanson Translational Imaging Division Dept. Molecular and Medical Pharmacology University of California, Los Angeles Studies of the PostPost-Chemo Brain • Scope • Differences in brain activation patterns • Differences observed in chemo-exposed vs. chemo-naive brains at rest • Mechanistic Considerations • Potential Implications for Clinical Decisions Studies of the PostPost-Chemo Brain: Scope Imaging studies of regional cerebral function after chemotherapy by structural and functional neuroimaging modalities, with focus upon: * human brain, * data published in peerpeer-reviewed literature Studies of the PostPost-Chemo Brain • Scope • Differences in brain activation patterns • Differences observed in chemo-exposed vs. chemo-naive brains at rest • Mechanistic Considerations • Potential Implications for Clinical Decisions PET Scan Protocol Inject 15O-water 2 min scan Inject Inject 15O-water 15O-water 2 min scan 2 min scan Baseline control task (read, repeat) 12 min. 12 min. Short-term Shortmemory recall task Long Long--term memory recall task 12 min. Inject 15O-water Inject 15O-water 2 min scan 2 min scan Baseline control task (read, repeat) 12 min. Short-term Shortmemory recall task Inject 15O-water 2 min scan 12 min. 30 min scan Inject 18FDG 45 min. uptake Resting metabolism Long Long--term memory recall task Cortical Activation in Chemotherapy‐Treated (left) and ‐Untreated (right) Subjects During Short‐Term Memory Task Color scale corresponds to voxels with significant activation (p<0.01). Peak activation occurring in the inferior frontal gyrus (bright yellow area in left image), was highly significant (p<0.0005 after correction for multiple comparisons, Z=5.95) in treated patients, but not in untreated patients, who showed more significant activation in the parietal cortex (bright yellow area in right image). See text for details. fMRI published studies Ferguson et al., 2007 Kesler et al., 2009 Cherrier et al. 2010 Cimprich et al., 2010 De Ruiter et al., 2011 Kesler et al., 2011 Scherling et al., 2011 Scherling et al., 2012 Reviewed in ICCTF Neuroimaging Workshop yesterday by Dr. Michiel de Ruiter Monozygotic Twins Study Monozygotic Twins Study Twin A: 60 y.o. woman who underwent adjuvant chemo for stage II breast cancer (doxorubicin, docetaxel, cyclophosphamide) 22 months previously, + ongoing tamoxifen Twin B: 60 y.o. woman without cancer from Ferguson et al., J Clin Oncol, 2007 Twin A: More frontal and parietal activation during working memory task by fMRI from Ferguson et al., J Clin Oncol, 2007 Monozygotic Twins Study: limitations to keep in mind Structural and functional brain differences between twins were observed, but •n = 1 per group • Twins A and B differ in chemo and cancer • Twin A still undergoing tamoxifen and cognitive cognitive--behavioral therapy from Ferguson et al., J Clin Oncol, 2007 Hypoactivation (fMRI) during Memory Encoding of Visual Paired Associates 10 Yrs after High High‐‐Dose Chemo + Tamoxifen Hypoactivation identified in parahippocampal gyrus (PHG) and posterior parietal cortex (PPC) De Ruiter et al. (2011) Human De Ruiter et al. (2011) Human Brain Mapping Posterior Hypo‐‐activation (fMRI) during Memory Posterior Hypo activation (fMRI) during Memory Encoding of Visual Paired Associates 10 Yrs after High High‐‐Dose Chemo + Tamoxifen De Ruiter et al. (2011) Chemo > Control Vs. Anterior Hyper‐‐activation ([O Anterior Hyper activation ([O‐‐15]Water) during Retrieval of Verbal Paired Associates 5‐ of Verbal Paired Associates 5‐10 Yrs after Standard Standard‐‐Dose Chemo Silverman et al. (2007) Posterior Hypoactivation (fMRI) during Memory Encoding of Visual Paired Associates 10 Yrs after High High‐‐Dose Chemo + Tamoxifen Ruiter et al. (2010) Chemo > Control Vs. Anterior Hyperactivation ( Hyperactivation ([O [O‐‐15]Water) during 15]Water) during Retrieval of of Verbal Verbal Paired Associates 5 Paired Associates 5‐‐10 Yrs after Standard Standard‐‐Dose Chemo Silverman et al. (2007) Studies of the PostPost-Chemo Brain • Scope • Differences in brain activation patterns • Differences observed in chemo-exposed vs. chemo-naive brains at rest • Mechanistic Considerations • Potential Implications for Clinical Decisions FDG‐PET Scans in Chemotherapy‐treated and Untreated Subjects at Rest Chemotherapy 55 y.o. female No Chemotherapy Breast Ca 55 y.o. female No Breast Ca 51 y.o. female Red arrows indicate location of superior frontal gyrus. Yellow arrows indicate location of Broca’s area and contralateral counterpart. (ROI analysis was performed by research personnel blinded to subjects’ therapy and disease status.) Short‐ Short‐term Visual Memory Test in Which Chemotherapy‐‐treated Patients Were Impaired: Chemotherapy Rey Osterrieth Complex Figure Delayed Recall • Visuoconstruction: Subject is required to reproduce this complex figure “as accurately as possible”. • Visual memory: subject must reproduce, uncued, the design from memory. Correlation of Short‐Term Recall Performance with Resting Metabolism in Chemotherapy‐Treated Subjects Sagittal ( left ) and transaxial ( right ) views of statistical parametric identifying areas where regional brain metabolism correlated with ROCF performance across chemotherapy-treated subjects. Voxels with correlative significance of p<0.01 are depicted in yellow, and superimposed upon an average MR T1-weighted image for anatomical reference. Red cursor lines intersect at the voxel of peak significance, located in the left inferior frontal cortex. maps Averaged l/r LN activity during FDG scan Lentiform Nucleus Resting Metabolic Activity Decreases in Patients Treated with Chemotherapy + Tamoxifen 1.2 1.15 * 1.1 1.05 * 1 0.95 0.9 Chemo + Tamoxifen Chemo only Breast Cancer, No Chemo Reference Controls Level of metabolism in lentiform nuclei measured in subjects undergoing chemotherapy+tamoxifen therapy tended to be lower (by 77-8%, p<0.01) than the level seen in all other control groups, including those subjects who received chemotherapy without tamoxifen, as well as those who received no chemotherapy for their breast cancer, and a reference group without chemotherapy or breast cancer. n=31 (11, 5, 5, 10) Structural MRI published studies Breast Cancer Survivors Saykin et al., 2003 (reduced GM and WM >5yrs) Eberling et al., 2004 Yoshikawa et al., 2005 Inagaki et al., 2007 de Ruiter et al., 2011 Koppelmans et al., 2012 Breast Cancer Prospective McDonald et al., 2010 Reviewed in ICCTF Neuroimaging Workshop yesterday by Dr. Brenna McDonald Breast Cancer Survivors Saykin et al., 2003 Breast cancer and leukemia survivors treated with chemotherapy and healthy controls (Ns=12 per group) >5 years post-diagnosis, various chemotherapy regimens VBM of gray and white matter Chemotherapy-treated patients showed reduced GM and WM Gray Matter Density (VBM) Decreases during First Month after Chemotherapy (within‐ (within‐group analysis) McDonald et al. (2010) Breast Cancer Res Treat. Breast Cancer Res Treat. Areas of Relatively Decreased Gray Matter Density (VBM) in Subjects with Breast Ca a) b) c) Chemo‐ Chemo‐Treated < Healthy Controls at 1 Month Non‐ Non‐Chemo Chemo‐‐Treated < Healthy Controls at 1 Month Chemo‐‐Treated < Healthy Controls at 1 Year Chemo McDonald et al. (2010) Breast Cancer Res Treat. Breast Cancer Res Treat. Demography and Therapy Effects of chemo vs. effects of more advanced cancer stage? (…not specific to this study… general problem of non‐‐randomization in human studies) specific to this study… general problem of non McDonald et al. (2010) Breast Cancer Res Treat. Breast Cancer Res Treat. DTI published studies Abraham, 2008 (reduced WM integrity in CC genu) Deprez, 2011 Deruiter, 2011 Deprez, 2012 Reviewed in ICCTF Neuroimaging Workshop yesterday by Dr. Sabine Deprez Abraham et al. 2008 “Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusion tensor imaging” - Clinical Breast Cancer Methods: • FA ROI analysis in genu and splenum of CC • Correlation with Processing speed Deprez et al., 2012 “Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning.” - J Clin Oncol • SPM VoxelVoxel-based whole brain analysis of FA • Correlation FA and neuropsychological tests Comparing Results Across Modalities and Activation vs. Cognitive Rest Designs Gray Matter Density (MRI) Decreases vs. Cerebral Blood Flow Increases (PET) Chemo Control Silverman et al. (2007) Breast Cancer Res Treat. Breast Cancer Res Treat. McDonald et al. (2010) Breast Cancer Res Treat. Breast Cancer Res Treat. Studies of the PostPost-Chemo Brain •Scope • Differences in brain activation patterns • Differences observed in chemo-exposed vs. chemo-naive brains at rest • Mechanistic Considerations • Potential Implications for Clinical Decisions Proposed Candidate Mechanisms from Ahles and Saykin, Nat Rev Cancer, 2007 Candidate Mechanisms: Cytokines •chemotherapy agents can boost cytokines •some cross the blood-brain barrier •some cause release of central cytokines through peripheral-to-central neuronal communication • can impair cognitive function • direct evidence for role in post-chemo brain remains to be established Implications for Novel Treatment Options I • • • • • • • • • • Etanercept (TNF‐receptor antagonists) Infliximab (Mab to TNF‐a) NSAIDS and Thalidomide Cytokine synthesis inhibitors Soluble Cytokine Receptors (competitors) Cytokine Receptor Antagonists Estrogen DHEA Fish Oils (inhibitors of TNF‐a, IL‐1b) Exercise Wilson, Finch, Cohen: Cytokines and Cognition JAGS 50:2041-2056 2002 Illman, Corringham et al: Are Inflammatory Cytokines the Common Link B/T CancerAssociated Cachexia and Depression? J Suppport Oncol 2005;3:37-50 Implications for Novel Treatment Options II • IL‐10 (suppresses production of PICs) – Being studied in RA, IBD, ARDS, HIV, Psoriasis – An MS trial was halted by manufacturer (??) • IL‐4 (anti‐allergic, anti‐inflammatory, anti‐tumor) – Used in Psoriasis, promising in leukemia – Negative MS trial (Bayer) Correlation Between Baseline Correlation Between Baseline Cytokine Levels and Baseline FDG Metabolism Baseline Inflammatory Cytokine Positive Correlations with Regional Brain Metabolism 1 year after Chemo IL1RA CRP IL6 TNF All color voxels are p<0.01. Baseline CRP Levels Negatively Correlate with Baseline Metabolism of Left Inferior Frontal Gyrus in Chemotherapy Subjects sVOI SPM IL1RA negatively correlated with baseline left GFi T=4.08, p<0.0005 Part of Largest Cluster (333 voxels) r=-0.52 p=0.03 All color voxels are p<0.05. At peak voxel in lGFi, p<0.0005. Slice view at ‐32,20,‐2. Studies of the PostPost-Chemo Brain • Scope • Differences in brain activation patterns • Differences observed in chemo-exposed vs. chemo-naive brains at rest • Mechanistic Considerations • Potential Implications for Clinical Decisions Potential Implications of Brain PET Imaging in Clinical DecisionDecision-Making • Search for baseline brain metabolic indicators of future vulnerability and image image--guided preventive/therapeutic strategies (e.g. (e.g.,, Does a patient having lower inferior frontal metabolism suggest being a potential candidate for cytokine cytokine--targeted manipulations manipulations?) ?) • Monitor cerebral response to potentially neurotoxic therapies -- analogously to using MUGA studies to monitor cardiac response to doxorubicin (Adriamycin) -- taking advantage of the typical lead time (2(2-10 years) of metabolic changes preceding neurologic symptoms. (This (This could be accomplished as simple ‘add‘add-on’ view to wholewhole-body PET studies performed for tumor assessments.) assessments.) Candidate Mechanisms • Direct chemotherapy toxicity possible • Most chemotherapy agents are thought to cross the blood-brain barrier in only low concentrations, however (some exceptions include 5-FU and methotrexate) J Label Compd Radiopharm 2005; 48: 635635-643. Comparing cyclophosphamide and fluorocyclophosphamide toxic behaviors against breast cancer cells Small animal PET and CT imaging with [F [F--18] fluorocyclophosphamide PET with [F PET with [F‐‐18]fluorocylophosphamide performed before performed before first course of chemotherapy predicts tumor volume changes predicts tumor volume changes measured 3 weeks later. JNM, 2007; 48:2021-2027 Comparing [F Comparing [F‐‐18]fluorocyclophosphamide biodistribution measured by small animal PET and by harvesting organs postmortem PET versions of the following drugs Paclitaxe 18F- l 5-Fluorouraci l 18F Inhibits cellular proliferation through stabilization of tubulin Antimetabolite, analog of pyrimidine, impairs pyrimidine synthesis Cyclophosphamid 18F- Alkylating agent, cross--links DNA cross Chemotherapy Group (n=20): Baseline Activation during Short‐ Short‐Term Memory Tasks Chemotherapy Group at Baseline: Activation in Inferior Frontal Gyrus during Short-Term Memory Task SPM Largest cluster: Left Inferior Frontal Gyrus (2581 contiguous voxels at p<0.01; peak voxel t = 5.72, p<0.0005) All color voxels are p<0.01. sVOI 0,014 Left Inferior Frontal Gyrus Metabolism (Av erage ± SEM) 1,11 Region that was most significantly activated during short-term memory task 0,012 0,01 1,105 0,008 0,006 (t=2.90 , p=0.01) 0,004 1,1 0,002 0 1,095 STM - Control 1,09 Control STM Chemotherapy Group at Baseline: Deactivation in Hindbrain during Short-Term Memory Task SPM Most significant cluster: R. ant. Cerebellum/post. Pons t = 7.03, p<0.0005 (pFWE FWE--corr=0.001) All color voxels are p<0.01. Pons Metabolism (Av erage ± SEM) sVOI 0 0,746 0,744 0,742 0,74 0,738 0,736 0,734 Region that was most significantly deactivated during short-term memory task ‐0,002 ‐0,004 ‐0,006 (t=-2.15 , p=0.05) ‐0,008 ‐0,01 STM - Control Control STM Comparison of Different Cytokine Batches Previous analyses have used batch 1 cytokine values. We have stopped using that batch and now use batches 2 and 3 instead for our analyses. The cytokine values are comparable, so the analysis results should not be substantially affected.
