Inflammation is an important candidate mechanism underlying cancer and cancer treatment-related cognitive impairment. We investigated levels of blood cell-based inflammatory markers in breast cancer ...survivors on average 20 years after chemotherapy and explored the relation between these markers and global cognitive performance.
One hundred sixty-six breast cancer survivors who received post-surgical radiotherapy and six cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy on average 20 years before enrollment were compared with 1344 cancer-free women from a population-based sample (50-80 years old). Breast cancer survivors were excluded if they used adjuvant hormonal therapy or if they developed relapse, metastasis, or second primary malignancies. Systemic inflammation status was assessed by the granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). Cognitive performance was assessed using an extensive neuropsychological test battery from which the general cognitive factor was derived to evaluate global cognitive performance. We examined the association between cancer, the general cognitive factor, and inflammatory markers using linear regression models.
Breast cancer survivors had a lower general cognitive factor than non-exposed participants from the comparator group (mean difference = -0.21; 95% confidence interval (CI) -0.35 to -0.06). Inflammatory markers were higher in cancer survivors compared with non-exposed participants (mean difference for log(GLR) = 0.31; 95% CI 0.24 to 0.37, log(PLR) = 0.14; 95% CI 0.09 to 0.19, log(SII) = 0.31; 95% CI 0.24 to 0.39). The association between higher levels of inflammatory markers and lower general cognitive factor was statistically significant in cancer survivors but not among non-exposed participants. We found a group-by-inflammatory marker interaction; cancer survivors showed additional lower general cognitive factor per standard deviation increase in inflammatory markers (P for interaction for GLR = 0.038, PLR = 0.003, and SII = 0.033).
This is the first study to show that (1) cancer survivors have increased levels of inflammation on average 20 years after treatment and (2) these inflammatory levels are associated with lower cognitive performance. Although this association needs verification by a prospective study to determine causality, our findings can stimulate research on the role of inflammation in long-term cognitive problems and possibilities to diminish such problems.
Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk ...factors on this risk.
Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam Study aged 45 years and older who were free from NCDs at baseline for incident stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease. We quantified occurrence/co-occurrence and remaining lifetime risk of any NCD in a competing risk framework. We additionally studied the lifetime risk of any NCD, age at onset, and overall life expectancy for strata of 3 shared risk factors at baseline: smoking, hypertension, and overweight. During 75,354 person-years of follow-up from a total of 9,061 participants (mean age 63.9 years, 60.1% women), 814 participants were diagnosed with stroke, 1,571 with heart disease, 625 with diabetes, 1,004 with chronic respiratory disease, 1,538 with cancer, and 1,065 with neurodegenerative disease. NCDs tended to co-occur substantially, with 1,563 participants (33.7% of those who developed any NCD) diagnosed with multiple diseases during follow-up. The lifetime risk of any NCD from the age of 45 years onwards was 94.0% (95% CI 92.9%-95.1%) for men and 92.8% (95% CI 91.8%-93.8%) for women. These risks remained high (>90.0%) even for those without the 3 risk factors of smoking, hypertension, and overweight. Absence of smoking, hypertension, and overweight was associated with a 9.0-year delay (95% CI 6.3-11.6) in the age at onset of any NCD. Furthermore, the overall life expectancy for participants without these risk factors was 6.0 years (95% CI 5.2-6.8) longer than for those with all 3 risk factors. Participants aged 45 years and older without the 3 risk factors of smoking, hypertension, and overweight at baseline spent 21.6% of their remaining lifetime with 1 or more NCDs, compared to 31.8% of their remaining life for participants with all of these risk factors at baseline. This difference corresponds to a 2-year compression of morbidity of NCDs. Limitations of this study include potential residual confounding, unmeasured changes in risk factor profiles during follow-up, and potentially limited generalisability to different healthcare settings and populations not of European descent.
Our study suggests that in this western European community, 9 out of 10 individuals aged 45 years and older develop an NCD during their remaining lifetime. Among those individuals who develop an NCD, at least a third are subsequently diagnosed with multiple NCDs. Absence of 3 common shared risk factors is associated with compression of morbidity of NCDs. These findings underscore the importance of avoidance of these common shared risk factors to reduce the premature morbidity and mortality attributable to NCDs.
Cancer and dementia: Two sides of the same coin? Willik, Kimberly D.; Schagen, Sanne B.; Ikram, M. Arfan
European journal of clinical investigation,
November 2018, Volume:
48, Issue:
11
Journal Article
Peer reviewed
Open access
Noncentral nervous system cancer and the brain share an interesting and complex relation, with an emerging body of evidence showing that cancer patients are at an increased risk of developing ...cognitive problems. In contrast, population‐based studies consistently find an inverse link between cancer and dementia, that is patients with dementia having a lower risk of subsequently developing cancer, and cancer patients being less often diagnosed with dementia. Different biological processes such as inversely activated cell proliferation and survival pathways have been suggested to have an important role underlying this inverse association. However, the effect of methodological biases including surveillance or survival bias has not been completely ruled out, calling into question the inverse direction of the association between cancer and dementia. In fact, emerging evidence now suggests that cancer and dementia might share a positive association. This narrative review summarises the current literature on cancer, cognitive problems and dementia. Moreover, different strategies will be discussed to reduce the impact of potential methodological biases on the association between cancer and dementia, trying to reveal the true direction of this link.
Immunity has been suggested to be important in the pathogenesis of dementia. However, the contribution of innate versus adaptive immunity in the development of dementia is not clear. In this study, ...we aimed to investigate (1) the association between components of innate immunity (granulocytes and platelets) and adaptive immunity (lymphocytes) with risk of dementia and (2) the association between their derived ratios (granulocyte-to-lymphocyte ratio GLR, platelet-to-lymphocyte ratio PLR, and systemic immune-inflammation index SII), reflecting the balance between innate and adaptive immunity, with risk of dementia.
Blood cell counts were measured repeatedly between 2002 and 2015 in dementia-free participants of the prospective population-based Rotterdam Study. Participants were followed-up for dementia until 1 January 2016. Joint models were used to determine the association between granulocyte, platelets, and lymphocyte counts, and their derived ratios with risk of dementia.
Of the 8313 participants (mean standard deviation age 61.1 7.4 years, 56.9% women), 664 (8.0%) developed dementia during a median follow-up of 8.6 years. Doubling of granulocyte and platelet counts tended to be associated with an increased risk of dementia (HR 95%CI 1.22 0.89-1.67 and 1.45 1.07-1.95, respectively). Doubling of the derived ratios GLR, PLR, and SII were all associated with an increased dementia risk (HR 95%CI 1.26 1.03-1.53, 1.27 1.05-1.53, and 1.15 0.98-1.34, respectively).
GLR, PLR, and SII are associated with an increased risk of dementia in the general population. This supports the role of an imbalance in the immune system towards innate immunity in the pathogenesis of dementia.
Atherosclerotic cardiovascular disease (ASCVD) is driven by multifaceted contributions of the immune system. However, the dysregulation of immune cells that leads to ASCVD is poorly understood. We ...determined the association of components of innate and adaptive immunity longitudinally with ASCVD, and assessed whether arterial calcifications play a role in this association.
Granulocyte (innate immunity) and lymphocyte (adaptive immunity) counts were determined 3 times (2002-2008, mean age 65.2 years; 2009-2013, mean age 69.0 years; and 2014-2015, mean age 78.5 years) in participants of the population-based Rotterdam Study without ASCVD at baseline. Participants were followed-up for ASCVD or death until 1 January 2015. A random sample of 2,366 underwent computed tomography at baseline to quantify arterial calcification volume in 4 vessel beds. We studied the association between immunity components with risk of ASCVD and assessed whether immunity components were related to arterial calcifications at baseline. Of 7,730 participants (59.4% women), 801 developed ASCVD during a median follow-up of 8.1 years. Having an increased granulocyte count increased ASCVD risk (adjusted hazard ratio for doubled granulocyte count 95% CI = 1.78 1.34-2.37, P < 0.001). Higher granulocyte counts were related to larger calcification volumes in all vessels, most prominently in the coronary arteries (mean difference in calcium volume mm3 per SD increase in granulocyte count 95% CI = 32.3 9.9-54.7, P < 0.001). Respectively, the association between granulocyte count and incident coronary heart disease and stroke was partly mediated by coronary artery calcification (overall proportion mediated 95% CI = 19.0% -10% to 32.3%, P = 0.08) and intracranial artery calcification (14.9% -10.9% to 19.1%, P = 0.05). A limitation of our study is that studying the etiology of ASCVD remains difficult within an epidemiological setting due to the limited availability of surrogates for innate and especially adaptive immunity.
In this study, we found that an increased granulocyte count was associated with a higher risk of ASCVD in the general population. Moreover, higher levels of granulocytes were associated with larger volumes of arterial calcification. Arterial calcifications may explain a proportion of the link between granulocytes and ASCVD.
Complete and accurate registration of cancer is needed to provide reliable data on cancer incidence and to investigate aetiology. Such data can be derived from national cancer registries, but also ...from large population‐based cohort studies. Yet, the concordance and discordance between these two data sources remain unknown. We evaluated completeness and accuracy of cancer registration by studying the concordance between the population‐based Rotterdam Study (RS) and the Netherlands Cancer Registry (NCR) between 1989 and 2012 using the independent case ascertainment method. We compared all incident cancers in participants of the RS (aged ≥45 years) to registered cancers in the NCR in the same persons based on the date of diagnosis and the International Classification of Diseases (ICD) code. In total, 2,977 unique incident cancers among 2,685 persons were registered. Two hundred eighty‐eight cancers (9.7%) were coded by the RS that were not present in the NCR. These were mostly nonpathology‐confirmed lung and haematological cancers. Furthermore, 116 cancers were coded by the NCR, but not by the RS (3.9%), of which 20.7% were breast cancers. Regarding pathology‐confirmed cancer diagnoses, completeness was >95% in both registries. Eighty per cent of the cancers registered in both registries were coded with the same date of diagnosis and ICD code. Of the remaining cancers, 344 (14.5%) were misclassified with regard to date of diagnosis and 72 (3.0%) with regard to ICD code. Our findings indicate that multiple sources on cancer are complementary and should be combined to ensure reliable data on cancer incidence.
What's new?
While national cancer registries and population‐based cohort studies are the primary sources of data on cancer risk and incidence, the degree to which these data sets are concordant remains unknown. In this investigation, the authors evaluated concordance between the population‐based Rotterdam Study and the Netherlands Cancer Registry. The two data sets were highly concordant for pathology‐confirmed cancers and cancer site. Non‐pathology‐confirmed cancers, however, were under‐registered in the Netherlands Cancer Registry, potentially resulting in underestimation of cancer incidence. The findings highlight the important role that different sources of cancer diagnosis registration serve in providing reliable estimates of cancer incidence.
Objective
Clinical studies showing that non‐central nervous system cancer patients can develop cognitive impairment have primarily focused on patients with specific cancer types and intensive ...treatments. To better understand the course of cognitive function in the general population of cancer patients, we assessed cognitive trajectories of patients before and after cancer diagnosis in a population‐based setting.
Methods
Between 1989 and 2014, 2211 participants from the population‐based Rotterdam study had been diagnosed with cancer of whom 718 (32.5%) had undergone ≥1 cognitive assessment before and after diagnosis. Cognition was measured every 3 to 6 years using a neuropsychological battery. Linear mixed models were used to compare cognitive trajectories of patients before and after diagnosis with those of age‐matched cancer‐free controls (1:3).
Results
Median age at cancer diagnosis was 70.3 years and 47.1% were women. Most patients (68.1%) had received local treatment only. Cognitive trajectories of patients before and after cancer diagnosis were largely similar to those of controls. After diagnosis, the largest difference was found on a memory test (patients declined with 0.14 units per year on the Word Learning Test: delayed recall 95% CI = −0.35; 0.07 and controls with 0.09 units 95% CI = −0.18;‐0.00, p for difference = .59).
Conclusions
In this longitudinal cohort, cancer did not appear to alter the trajectory of change in cognitive test results over time from that seen in similar individuals without cancer, although most cancer patients did not receive systemic therapies. Future studies should focus on identifying subgroups of patients who are at high risk for developing cognitive impairment.
Abstract
Background
An emerging body of research suggests that noncentral nervous system cancer may negatively impact the brain apart from effects of cancer treatment. However, studies assessing ...cognitive function in newly diagnosed cancer patients cannot exclude selection bias and psychological effects of cancer diagnosis. To overcome these limitations, we investigated trajectories of cognitive function of patients before cancer diagnosis.
Methods
Between 1989 and 2013, a total of 2059 participants from the population-based Rotterdam Study were diagnosed with noncentral nervous system cancer. Cognitive assessments were performed every 3 to 5 years using a neuropsychological battery. The general cognitive factor was composed of individual cognitive tests to assess global cognition. Using linear mixed models, we compared change in cognitive function of cancer case patients before diagnosis with cognitive change of age-matched cancer-free control subjects (1:2). In addition, we performed sensitivity analyses by discarding assessments of control subjects 5 years before the end of follow-up to exclude effects from potential undiagnosed cancer. All statistical tests were two-sided.
Results
The Word Learning Test immediate recall declined faster among case patients than among control subjects (−0.05, 95% confidence interval = −0.09 to −0.01 vs 0.01, 95% confidence interval = −0.01 to 0.03; P for difference = .003). However, this difference was not statistically significant in sensitivity analyses. Furthermore, no statistically significant differences were observed in change of other individual cognitive tests and of the general cognitive factor.
Conclusions
In this study, we evaluated cognitive function in a large group of cancer patients prior to diagnosis, thereby excluding the psychological impact of cancer diagnosis and biased patient selection. In contrast to previous studies shortly after cancer diagnosis, we found no difference in change of cognitive function between cancer patients and control subjects.
Purpose
Breast cancer treatment has been associated with vascular pathology. It is unclear if such treatment is also associated with long-term cerebrovascular changes. We studied the association ...between radiotherapy and chemotherapy with carotid pathology and brain perfusion in breast cancer survivors.
Methods
We included 173 breast cancer survivors exposed to radiotherapy and chemotherapy, assessed ± 21.2 years after cancer diagnosis, and 346 age-matched cancer-free women (1:2) selected from the population-based Rotterdam Study. Outcome measures were carotid plaque score, intima-media thickness (IMT), total cerebral blood flow (tCBF), and brain perfusion. Additionally, we investigated the association between inclusion of the carotid artery in the radiation field (no/small/large part), tumor location, and these outcome measures within cancer survivors.
Results
Cancer survivors had lower tCBF (− 19.6 ml/min, 95%CI − 37.3;− 1.9) and brain perfusion (− 2.5 ml/min per 100 ml, 95%CI − 4.3;− 0.7) than cancer-free women. No statistically significant group differences were observed regarding plaque score or IMT. Among cancer survivors, a large versus a small part of the carotid artery in the radiation field was associated with a higher IMT (0.05, 95%CI0.01;0.09). Also, survivors with a right-sided tumor had lower left carotid plaque score (− 0.31, 95%CI − 0.60;− 0.02) and higher brain perfusion (3.5 ml/min per 100 ml, 95%CI 0.7;6.2) than those with a left-sided tumor.
Conclusions
On average two decades post-diagnosis, breast cancer survivors had lower tCBF and brain perfusion than cancer-free women. Also, survivors with a larger area of the carotid artery within the radiation field had a larger IMT. Future studies should confirm if these cerebrovascular changes underlie the frequently observed cognitive problems in cancer survivors.
Several observational studies have described an inverse association between cancer diagnosis and subsequent dementia risk. Multiple biologic mechanisms and potential biases have been proposed in ...attempts to explain this association. One proposed explanation is the opposite expression of Pin1 in cancer and dementia, and we use this explanation and potential drug target to illustrate the required assumptions and potential sources of bias for inferring an effect of Pin1 on dementia risk from analyses measuring cancer diagnosis as a proxy for Pin1 expression.
We used data from the Rotterdam Study, a population-based cohort. We estimate the association between cancer diagnosis (as a proxy for Pin1) and subsequent dementia diagnosis using two different proxy methods and with confounding and censoring for death addressed with inverse probability weights. We estimate and compare the complements of a weighted Kaplan-Meier survival estimator at 20 years of follow-up.
Out of 3634 participants, 899 (25%) were diagnosed with cancer, of whom 53 (6%) had dementia, and 567 (63%) died. Among those without cancer, 15% (411) were diagnosed with dementia, and 667 (24%) died over follow-up. Depending on the confounding and selection bias control, and the way in which cancer was used as a time-varying proxy exposure, the risk ratio for dementia diagnosis ranged from 0.71 (95% confidence interval CI = 0.49, 0.95) to 1.1 (95% CI = 0.79, 1.3).
Being explicit about the underlying mechanism of interest is key to maximizing what we can learn from this cancer-dementia association given available or readily collected data, and to defining, detecting, and preventing potential biases.
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