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Growing evidence suggests an unusual epidemiologic association between cancer and certain neurological conditions, particularly age-related neurodegenerative diseases. Cancer survivors have a 20–50 % lower risk of developing Parkinson’s and Alzheimer’s disease, and patients with these neurodegenerative conditions have a substantially lower incidence of cancer. We review the epidemiologic evidence for this inverse co-morbidity and show that it is not simply an artifact of survival bias or under-diagnosis. We then review the potential biological explanations for this association, which is intimately linked to the very different nature of dividing cells and neurons. The known genetic and metabolic connections between cancer and neurodegeneration generally fall within two categories. The first includes shared genes and pathways such as Pin1 and the ubiquitin proteasome system that are dysregulated in different directions to cause one disease or the other. The second includes common pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress and DNA damage that drive both conditions, but with different cellular fates. We discuss examples of these biological links and their implications for developing new approaches to prevention and treatment of both diseases.

Objective To appraise the existing literature on cancer risk among patients with Parkinson's disease (PD), determine the overall cancer risk ratio among patients with PD, explore reasons for variations in study results, and assess the potential for publication bias. Methods Studies reporting cancer risk in patients with PD were identified by searching electronic databases through 18 November 2009 using the terms PARKINSON DISEASE, NEOPLASM, and CANCER. Reviewers individually performed data extraction and scored each study using a quality assessment instrument. Cancer risk in all patients with PD was calculated overall, and after excluding melanoma and other skin cancers. We tested for heterogeneity and publication bias, and stratified for gender, smoking-related versus non-smoking-related cancers, and study quality. We pooled effect sizes using fixed-effects and random-effects models. Results We included 29 studies in the overall analysis for a total of 107,598 patients with PD. Compared to controls, the aggregate risk for cancer in patients with PD was 0.73 (95% confidence interval [CI], 0.63-0.83), and after excluding skin tumors, 0.69 (95% CI, 0.62-0.78). These risks varied by gender (males, RR = 0.71, 95% CI, 0.57-0.88; females, RR = 0.82; 95% CI, 0.68-0.98). After strictly excluding skin tumors, both smoking-related (RR = 0.61; 95% CI, 0.58-0.65) and non-smoking-related cancer rates (RR = 0.76; 95% CI, 0.65-0.89) were significantly lower among patients with PD . Conclusions Studies on cancer risk among patients with PD collectively show significantly reduced cancer risk ratios. Further research to explain the biological mechanisms, particularly for the association with non-smoking-related cancers, appears warranted.

BackgroundEvidence for the benefit of implantable cardioverter defibrillators (ICD) in preventing sudden cardiac death (SCD) in older adults is mixed; age alone may not predict benefit. Frailty may help identify patients in whom an ICD does not improve overall mortality risk.MethodsStructured search of PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials on 1/31/2019, without language restriction, with terms for ICD, frailty, and mortality. Frailty was defined broadly using any validated single component (e.g., walking speed, weight loss) or multi-component tool (e.g., cumulative deficit index). Each study was assessed for quality and risk of bias.ResultsWe identified and screened 2649 titles, reviewed 280 abstracts, and extracted 71 articles. Nine articles, including two RCTs, one prospective cohort, and six retrospective cohort studies met all criteria. The most common reason for exclusion was a lack of frailty definition. Frailty definitions were heterogeneous, including cumulative deficit models, low weight, and walking speed. Follow-up time for mortality differed: from days to > 6 years. All studies indicated that mortality was higher amongst individuals identified as frail, regardless of definition. In one RCT, slow walkers did not benefit from ICD therapy after 3 years. A cohort of 83,792 Medicare beneficiaries in an ICD registry reported higher 1-year mortality following ICD in those with frailty or dementia. Four studies reported an association between being underweight and increased mortality following ICD placement.ConclusionExisting literature suggests that individuals with frailty may not benefit from ICD placement for primary prevention of SCD.

Background Over-/undertreatment are pervasive in older adults with cancer, and challenges arise in applying the principles of bioethics: beneficence, nonmaleficence, justice, and patient autonomy. The objective of this study was to determine whether these ethical principles relate to over-/undertreatment for older adults, and how tensions among the principles may contribute. Methods We conducted a modified Delphi study with 13 experts in biomedical ethics for iterative rounds of data collection. In the first round, we presented via electronic questionnaire our previously published definitions of over-/undertreatment in older adults with cancer. We then asked which ethical principles related to each definition, followed by how over-/undertreatment might arise from conflicts among different ethical principles. Consensus for each question was defined as ≥ 75% of experts answering “agree” or “strongly agree”. The second round consisted of a virtual discussion with nine of the panel experts led by a qualitative researcher to summarize round one results and review questions that did not reach consensus, followed by a second questionnaire including those questions. Findings Experts reached consensus that beneficence, non-maleficence, and autonomy were related to over-/undertreatment in older adults with cancer. Consensus was reached (92%) that overtreatment can occur when oncologists overemphasize beneficence valuing the potential benefit of cancer treatments, while underemphasizing non-maleficence with respect to treatment toxicities. Consensus was also reached (85%) that undertreatment reflects a lack of justice in equitable consideration of cancer treatments that could provide similar net benefits in older adults compared to younger adults. Lastly, consensus was reached that, in most cases, it is unethical to make a treatment recommendation without (1) formal assessment of patient frailty (e.g., via a geriatric assessment) or (2) the opportunity for the patient to share their values, goals, and preferences. Interpretation Our findings elucidate the ethical principles underpinning over- and undertreatment in older adults with cancer.

The Age-Friendly Health System (AFHS) movement has spread widely in recent years, with nearly 5000 healthcare organizations across the country recognized as Age-Friendly. Despite this broad recognition, there is little focus on how AFHS are implemented and the impact of implementation. The objectives of this study were to describe the strategies employed to support AFHS implementation in outpatient settings and to identify the measures used to evaluate implementation and effectiveness. We conducted a systematic review of literature from multiple databases spanning 2015 to March 2024, identified eligible studies using predefined inclusion/exclusion criteria, and extracted key data (eg, study design, study population, implementation strategies, outcomes/measures). We identified ten eligible studies from primary care clinics (N = 8), convenient care clinics (N = 1) and a cancer center (N = 1). The studies employed over 65 implementation strategies and 98 outcomes or measures. The vast majority of measures mapped to components of the 4Ms (Mobility, Mentation, Medication, What Matters), with up to ten measures per M category. Five of ten studies had reporting discrepancies and four did not fully define outcomes. The ten included studies serve as clear examples for the need for more evidence to support AFHS implementation in outpatient settings. Existing research lacks strategy specification and standardization of measures. We present gaps and opportunities to advance from AFHS “recognition” to impact.

OBJECTIVE:--To evaluate the association between type 2 diabetes and newly reported Parkinson's disease. RESEARCH DESIGN AND METHODS--Our study included 21,841 participants in the Physicians' Health Study, a cohort of U.S. male physicians. Diabetes and Parkinson's disease were self-reported via questionnaire. We used time-varying Cox regression to calculate adjusted relative risk (RR) for Parkinson's disease. RESULTS:--Over 23 years, 556 individuals with Parkinson's disease were identified. Subjects with diabetes had an increased Parkinson's disease risk (multivariable-adjusted RR 1.34 [95% CI 1.01-1.77]). The association remained significant after exclusion of those with known vascular disease. The diagnosis of diabetes was clustered around the diagnosis of Parkinson's disease and was more apparent among men with short diabetes duration and those without complications from diabetes. CONCLUSIONS:--Results of this large prospective study in men do not suggest that diabetes is a preceding risk factor for Parkinson's disease. Whether the positive association may be explained by ascertainment bias or a common underlying biological mechanism remains to be established.

Background Older patients with non‐small cell lung cancer (NSCLC) are a heterogeneous population with varying degrees of frailty. An electronic frailty index such as the Veterans Affairs Frailty Index (VA‐FI) can potentially help identify vulnerable patients at high risk of poor outcomes. Methods NSCLC patients ≥65 years old and diagnosed in 2002–2017 were identified using the VA Central Cancer Registry. The VA‐FI was calculated using administrative codes from VA electronic health records data linked with Medicare and Medicaid data. We assessed associations between the VA‐FI and times to mortality, hospitalization, and emergency room (ER) visit following diagnosis by Kaplan–Meier analysis and multivariable stratified Cox models. We also evaluated the change in discrimination and calibration of reference prognostic models after adding VA‐FI. Results We identified a cohort of 42,204 older NSCLC VA patients, in which 55.5% were classified as frail (VA‐FI >0.2). After adjustment, there was a strong association between VA‐FI and the risk of mortality (HR = 1.23 for an increase of four deficits or, equivalently, an increase of 0.129 on VA‐FI, p < 0.001), hospitalization (HR = 1.16 for four deficits, p < 0.001), and ER visit (HR = 1.18 for four deficits, p < 0.001). Adding VA‐FI to baseline prognostic models led to statistically significant improvements in time‐dependent area under curves and did not have a strong impact on calibration. Conclusion Older NSCLC patients with higher VA‐FI have significantly elevated risks of mortality, hospitalizations, and ER visits following diagnosis. An electronic frailty index can serve as an accessible tool to identify patients with vulnerabilities to inform clinical care and research. Older non‐small cell lung cancer patients with higher values of an electronic frailty index have elevated risks of mortality and acute care utilization following diagnosis. Such an electronic index can help identify vulnerable patients to inform clinical decision‐making and research.

Background The association between cancer and multiple sclerosis has long been investigated. Several studies and reviews have examined the risk of cancer among patients with multiple sclerosis treated with disease-modifying therapies (DMTs) but with conflicting results. This study will aim to investigate the association between DMTs for multiple sclerosis and subsequent cancer risk using research synthesis methods. Methods/design We designed and registered a study protocol for a systematic review and meta-analysis. We will include randomised and non-randomised trials, prospective or retrospective cohort studies, and case–control studies of treatment with DMTs compared with placebo, no treatment, or another active agent. The primary outcome will be the risk of cancer (all-malignant neoplasms) in association with the exposure of DMTs. Secondary outcomes will include site-specific cancers (e.g. breast cancer). Literature searches will be conducted in multiple electronic databases (from their inception onwards), including the following: PubMed/MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Two researchers will screen all citations, full-text articles, and abstract data independently. The risk of bias (quality) of individual studies will be appraised using an appropriate tool. If feasible, we will use a two-stage approach to evidence synthesis: (1) Peto’s method for meta-analysis of data from randomised trials alone; and (2) Random-effects model for meta-analysis adding data from non-randomised studies. We will calculate odds ratios and their associated 95% confidence intervals. Potential sources of heterogeneity will be explored in additional analyses (e.g. subgroups considering different DMTs individually, mechanism of action, type of control, length of follow-up, mode of treatment). Discussion This systematic review and meta-analysis of randomised and non-randomised studies will provide an updated synthesis of the risk of cancer associated with DMTs for adult patients with multiple sclerosis. This study will also examine some factors that may explain potential variations across studies. The findings will be published in a peer-reviewed journal. Systematic review registration Open Science Framework ( https://osf.io/v4sez ).

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer’s disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro , neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term ‘cistauosis’, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer’s disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury. Here the cis form of tau protein, which disrupts axonal microtubules and transport, spreads to other neurons, and leads to apoptosis in vitro and in vivo , is found to be produced by neurons immediately after traumatic brain injury (TBI); treating TBI mice with cis antibody blocks early production of cis tau, prevents tauopathy and spread and restores brain structural and functional outcomes, and may be further developed to treat TBI and to prevent neurodegeneration after injury. cis P-tau tauopathy in traumatic brain injury The symptoms of traumatic brain injury (TBI), a common condition in players of contact sports and in the military, are associated with acute neurological dysfunction and TBI is a major risk factor for Alzheimer's disease. Tauopathy associated with the aggregation of phosphorylated tau protein (P-tau) in the brain is a defining feature of the neurodegeneration associated with chronic traumatic encephalopathy and Alzheimer's but it has not been observed in the early stages of TBI. Here Kun Ping Lu and colleagues show that tauopathy caused by cis P-tau, but not trans P-tau, is an early driver of brain injury in patients with TBI and in mouse models. Treating TBI mice with cis antibody blocks early production of cis P-tau and prevents further tauopathy and spread, and may be further developed to treat TBI after injury.

IntroductionHealth services generate large amounts of routine health data (eg, administrative databases, disease registries and electronic health records), which have important secondary uses for research. Increases in the availability and the ability to access and analyse large amounts of data represent a major opportunity for conducting studies on the possible relationships between complex diseases. The objective of this study will be to evaluate the design, methods and reporting of studies conducted using observational routinely collected health data for investigating the link between cancer and neurodegenerative diseases.Methods and analysisThis is the protocol for a meta-research study. We registered the study protocol within the Open Science Framework: https://osf.io/h2qjg. We will evaluate observational studies (eg, cohort and case–control) conducted using routinely collected health data for investigating the associations between cancer and neurodegenerative diseases (such as Alzheimer’s disease, amyotrophic lateral sclerosis/motor neuron disease, Huntington’s disease, multiple sclerosis and Parkinson’s disease). The following electronic databases will be searched (from their inception onwards): MEDLINE, Embase and Web of Science Core Collection. Screening and selection of articles will be conducted by at least two researchers. Potential discrepancies will be resolved via discussion. Design, methods and reporting characteristics in each article will be extracted using a standardised data extraction form. Information on general, methodological and transparency items will be reported. We will summarise our findings with tables and graphs (eg, bar charts, forest plots).Ethics and disseminationDue to the nature of the proposed study, no ethical approval will be required. We plan to publish the full study in an open access peer-reviewed journal and disseminate the findings at scientific conferences and via social media. All data will be deposited in a cross-disciplinary public repository.