Complaints of reduced cognitive abilities are frequent following chemotherapy. Research in the breast cancer population has revealed some patients may experience treatment-related decline in cognitive domains such as executive function, information processing speed, memory and learning, attention and concentration, and working memory. The extent and mechanism of action of this phenomenon remain poorly understood. Neuroimaging research can characterize the neural underpinnings of chemotherapy-related cognitive impairment; however, with few longitudinal studies, more prospective studies are needed to elucidate this important topic. The aim of this thesis was to use magnetic resonance imaging and contemporary analysis techniques to better understand the influence chemotherapy exerts on both the brain and cognition. This was achieved in two studies that measured cognitive function and brain structure and function at three time points: pre-treatment, one month post-chemotherapy, and at one-year follow-up. In the first study, the association between regions of brain structural changes and cognitive function was examined. The second study took a narrower approach and investigated the functional profile of brain activity during a working memory task. Patients had more pronounced structural and functional disruptions shortly after treatment, relative to both pre-treatment and one-year post-chemotherapy intervals. Regions of structural compromise were largely associated with information processing speed. Functional disruptions occurred in a frontoparietal network. Overall, this thesis provides more evidence of the injurious role chemotherapy plays on cognition, particularly in the short term. This thesis also provides the first longitudinal neuroimaging study to illustrate a complete resolution of working memory related brain disruption one year post-treatment.

OBJETIVOS: Evidências consistentes sugerem que a quimioterapia (QT) sistêmica para o tratamento do câncer pode apresentar efeitos deletérios na cognição levando a prejuízos de memória, atenção, velocidade de processamento e função executiva. A maioria dos estudos anteriores, entretanto, foi realizada em mulheres com câncer de mama, o que levanta a possibilidade de que o déficit possa ter sido causado por alterações hormonais e/ou menopausa precoce induzidas pela QT. Pouco se sabe sobre a toxicidade da QT na cognição de pacientes portadores de câncer coloretal (CCR). O objetivo do estudo foi avaliar os efeitos cognitivos da QT adjuvante baseada em fluorouracil (5FU) associado ou não a oxaliplatina (FLOX) em pacientes portadores de CCR estádios II e III , em comparação a indivíduos com câncer de cólon estádio II de baixo risco não submetidos à QT. METODOLOGIA: Estudo de coorte prospectivo, não intervencionista, unicêntrico, onde os pacientes com CCR foram submetidos a uma avaliação neuropsicológica detalhada, além da avaliação de queixas subjetivas de memória e de sintomas depressivos antes do início da quimioterapia (t1) e após 12 meses de seguimento (t2). Avaliamos ainda o papel da apoliproteína E como preditor de risco para disfunção cognitiva e a presença de lesão de substância branca por ressonância magnética (RM) de crânio. RESULTADOS: Num período de 2 anos, de dezembro de 2012 a dezembro de 2014, 85 pacientes foram recrutados e completaram a avaliação inicial (t1): 26 no grupo controle (sem quimioterapia= QT-) e 59 no grupo casos (quimioterapia= QT+). Dentre os 85 pacientes que participaram da avaliação inicial, 16 foram excluídos da análise do desfecho principal. A maioria dos pacientes era do sexo masculino (60,3%), idosos com idade média de 62,5 anos (DP 9,4) e escolaridade média de 7,6 anos (DP 3,7). Considerando o desfecho primário do escore composto global e também os domínios cognitivos de memória e atenção, não econtramos diferença significativa de desempenho no t1 e t2 entre os grupos. Com relação a função executiva, os pacientes que realizaram QT apresentaram melhor desempenho no t1, entretanto, evoluíram com maior declínio e pior desempenho que os controles no t2 após ajuste para idade, sexo, escolaridade e sintomas depressivos no baseline (beta -1,80; 95%CI -3,50; -0,11, p=0,04). Um subgrupo de 32 pacientes foram submetidos a RM de crânio que não mostrou alterações significativas de substância branca pela técnica de imagem de tensor de difusão (DTI) no seguimento. A presença do alelo ?4 da apolipoproteína E não foi diferente entre os grupos. CONCLUSÃO: Pacientes portadores de câncer colorretal que receberam quimioterapia adjuvante com esquema FLOX apresentaram declínio no desempenho cognitivo no domínio função executiva em comparação a pacientes com doença localizada que não receberam QT após 12 meses de seguimento / PURPOSE: Cognitive dysfunction may occur after chemotherapy in cancer survivors, especially in those that received chemotherapy for breast cancer. The frequency and to which extent such toxicity develops in colorectal cancer (CRC) survivors is unknown. This prospective study evaluated the effects of adjuvant chemotherapy on the cognitive performance of patients with localized CRC in comparison with a control group who did not receive chemotherapy. METHODS: Consecutive patients with localized stages II and III CRC completed neuropsychological assessments, self-reported cognitive complaints questionnaires, and depressive symptoms evaluation before starting fluoropyrimidine-based adjuvant chemotherapy (t1) and after 12 months (t2). Control group was assessed at matching intervals. Blood was collected for apolipoprotein E (APOE) genotyping. Clinical and demographic data were also collected. Diffusion tensor imaging (DTI) data was acquired from a subset of participants at both time-points. RESULTS: From December 2012 to December 2014, 137 patients were approached and 85 patients were recruited: 59 received chemotherapy (CTh+) and 26 did not (CTh-), based on standard recommendation for adjuvant therapy for CRC. The mean age was 62.5 years (SD 9.4), 60% were male, and the mean years of education was 7.6 (SD 3.7). No difference was found on global composite score (p=0.38), attention (p= 0.84) or memory (p= 0.97) between the two groups during the followup (mean 375 days, SD 29). However there was a significant difference on executive function domain, after adjustment for age, sex, education, and depressive symptoms at baseline (beta - 1.80; 95%CI -3.50; -0.11, p=0.04), suggesting worse performance for the CTh+ group. In 32 patients who underwent MRI, there was no significant differences for all DTI indices in any white matter regions between CTh+ and CTh- groups during follow-up. APOE polymorphisms were not predictive of cognitive dysfunction. CONCLUSION: After adjusting for confounding factors, patients with CRC who received adjuvant fluorouracil with or without oxaliplatin presented cognitive decline on executive function after 12 months in comparison with patients with localized disease that did not receive chemotherapy

OBJETIVOS: Evidências consistentes sugerem que a quimioterapia (QT) sistêmica para o tratamento do câncer pode apresentar efeitos deletérios na cognição levando a prejuízos de memória, atenção, velocidade de processamento e função executiva. A maioria dos estudos anteriores, entretanto, foi realizada em mulheres com câncer de mama, o que levanta a possibilidade de que o déficit possa ter sido causado por alterações hormonais e/ou menopausa precoce induzidas pela QT. Pouco se sabe sobre a toxicidade da QT na cognição de pacientes portadores de câncer coloretal (CCR). O objetivo do estudo foi avaliar os efeitos cognitivos da QT adjuvante baseada em fluorouracil (5FU) associado ou não a oxaliplatina (FLOX) em pacientes portadores de CCR estádios II e III , em comparação a indivíduos com câncer de cólon estádio II de baixo risco não submetidos à QT. METODOLOGIA: Estudo de coorte prospectivo, não intervencionista, unicêntrico, onde os pacientes com CCR foram submetidos a uma avaliação neuropsicológica detalhada, além da avaliação de queixas subjetivas de memória e de sintomas depressivos antes do início da quimioterapia (t1) e após 12 meses de seguimento (t2). Avaliamos ainda o papel da apoliproteína E como preditor de risco para disfunção cognitiva e a presença de lesão de substância branca por ressonância magnética (RM) de crânio. RESULTADOS: Num período de 2 anos, de dezembro de 2012 a dezembro de 2014, 85 pacientes foram recrutados e completaram a avaliação inicial (t1): 26 no grupo controle (sem quimioterapia= QT-) e 59 no grupo casos (quimioterapia= QT+). Dentre os 85 pacientes que participaram da avaliação inicial, 16 foram excluídos da análise do desfecho principal. A maioria dos pacientes era do sexo masculino (60,3%), idosos com idade média de 62,5 anos (DP 9,4) e escolaridade média de 7,6 anos (DP 3,7). Considerando o desfecho primário do escore composto global e também os domínios cognitivos de memória e atenção, não econtramos diferença significativa de desempenho no t1 e t2 entre os grupos. Com relação a função executiva, os pacientes que realizaram QT apresentaram melhor desempenho no t1, entretanto, evoluíram com maior declínio e pior desempenho que os controles no t2 após ajuste para idade, sexo, escolaridade e sintomas depressivos no baseline (beta -1,80; 95%CI -3,50; -0,11, p=0,04). Um subgrupo de 32 pacientes foram submetidos a RM de crânio que não mostrou alterações significativas de substância branca pela técnica de imagem de tensor de difusão (DTI) no seguimento. A presença do alelo ?4 da apolipoproteína E não foi diferente entre os grupos. CONCLUSÃO: Pacientes portadores de câncer colorretal que receberam quimioterapia adjuvante com esquema FLOX apresentaram declínio no desempenho cognitivo no domínio função executiva em comparação a pacientes com doença localizada que não receberam QT após 12 meses de seguimento / PURPOSE: Cognitive dysfunction may occur after chemotherapy in cancer survivors, especially in those that received chemotherapy for breast cancer. The frequency and to which extent such toxicity develops in colorectal cancer (CRC) survivors is unknown. This prospective study evaluated the effects of adjuvant chemotherapy on the cognitive performance of patients with localized CRC in comparison with a control group who did not receive chemotherapy. METHODS: Consecutive patients with localized stages II and III CRC completed neuropsychological assessments, self-reported cognitive complaints questionnaires, and depressive symptoms evaluation before starting fluoropyrimidine-based adjuvant chemotherapy (t1) and after 12 months (t2). Control group was assessed at matching intervals. Blood was collected for apolipoprotein E (APOE) genotyping. Clinical and demographic data were also collected. Diffusion tensor imaging (DTI) data was acquired from a subset of participants at both time-points. RESULTS: From December 2012 to December 2014, 137 patients were approached and 85 patients were recruited: 59 received chemotherapy (CTh+) and 26 did not (CTh-), based on standard recommendation for adjuvant therapy for CRC. The mean age was 62.5 years (SD 9.4), 60% were male, and the mean years of education was 7.6 (SD 3.7). No difference was found on global composite score (p=0.38), attention (p= 0.84) or memory (p= 0.97) between the two groups during the followup (mean 375 days, SD 29). However there was a significant difference on executive function domain, after adjustment for age, sex, education, and depressive symptoms at baseline (beta - 1.80; 95%CI -3.50; -0.11, p=0.04), suggesting worse performance for the CTh+ group. In 32 patients who underwent MRI, there was no significant differences for all DTI indices in any white matter regions between CTh+ and CTh- groups during follow-up. APOE polymorphisms were not predictive of cognitive dysfunction. CONCLUSION: After adjusting for confounding factors, patients with CRC who received adjuvant fluorouracil with or without oxaliplatin presented cognitive decline on executive function after 12 months in comparison with patients with localized disease that did not receive chemotherapy

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.