Outcomes with spinal versus general anesthesia for patients with and without preoperative cognitive impairment: Secondary analysis of a randomized clinical trial.

INTRODUCTION: The effect of spinal versus general anesthesia on the risk of postoperative delirium or other outcomes for patients with or without cognitive impairment (including dementia) is unknown. METHODS: Post hoc secondary analysis of a multicenter pragmatic trial comparing spinal versus general anesthesia for adults aged 50 years or older undergoing hip fracture surgery. RESULTS: Among patients randomized to spinal versus general anesthesia, new or worsened delirium occurred in 100/295 (33.9%) versus 107/283 (37.8%; odds ratio [OR] 0.85; 95% confidence interval [CI] 0.60 to 1.19) among persons with cognitive impairment and 70/432 (16.2%) versus 71/445 (16.0%) among persons without cognitive impairment (OR 1.02; 95% CI 0.71 to 1.47, p = 0.46 for interaction). Delirium severity, in-hospital complications, and 60-day functional recovery did not differ by anesthesia type in patients with or without cognitive impairment. DISCUSSION: Anesthesia type is not associated with differences in delirium and functional outcomes among persons with or without cognitive impairment.

Effectiveness and Ethics of Incentives for Research Participation: 2 Randomized Clinical Trials.

Importance: Incentivizing research participation is controversial and variably regulated because of uncertainty regarding whether financial incentives serve as undue inducements by diminishing peoples' sensitivity to research risks or unjust inducements by preferentially increasing enrollment among underserved individuals. Objective: To determine whether incentives improve enrollment in real randomized clinical trials (RCTs) or serve as undue or unjust inducements. Design, Setting, and Participants: Two RCTs of incentives that were embedded in 2 parent RCTs, 1 comparing smoking cessation interventions (conducted at smoking cessation clinics in 2 health systems) and 1 evaluating an ambulation intervention (conducted across wards of the Hospital of the University of Pennsylvania) included all persons eligible for the parent trials who did not have prior knowledge of the incentives trials. Recruitment occurred from September 2017 to August 2019 for the smoking trial and January 2018 through May 2019 for the ambulation trial; data were analyzed from January 2020 to July 2020. Interventions: Patients were randomly assigned to incentives of $0, $200, or $500 for participating in the smoking cessation trial and $0, $100, or $300 for the ambulation trial. Main Outcomes and Measures: The primary outcome of each incentive trial was the proportion of people assigned to each recruitment strategy that consented to participate. Each trial was powered to test the hypotheses that incentives served neither as undue inducements (based on the interaction between incentive size and perceived research risk, as measured using a 10-point scale, on the primary outcome), nor unjust inducements (based on the interaction between incentive size and participants' self-reported income). Noninferiority methods were used to test whether the data were compatible with these 2 effects of incentives and superiority methods to compare the primary and other secondary outcomes. Results: There were a total of 654 participants (327 women [50.0%]; mean [SD] age, 50.6 [12.1] years; 394 Black/African American [60.2%], 214 White [32.7%], and 24 multiracial individuals [3.7%]) in the smoking trial, and 642 participants (364 women [56.7%]; mean [SD] age, 46.7 [15.6] years; 224 Black/African American [34.9%], 335 White [52.2%], and 5 multiracial individuals [0.8%]) in the ambulation trial. Incentives significantly increased consent rates among those in the smoking trial in 47 of 216 (21.8%), 78 of 217 (35.9%), and 104 of 221 (47.1%) in the $0, $200, and $500 groups, respectively (adjusted odds ratio [aOR] for each increase in incentive, 1.70; 95% CI, 1.34-2.17; P < .001). Incentives did not increase consent among those in the ambulation trial: 98 of 216 (45.4%), 102 of 212 (48.1%), and 92 of 214 (43.0%) in the $0, $100, and $300 groups, respectively (aOR, 0.88; 95% CI, 0.64-1.22; P = .45). In neither trial was there evidence of undue or unjust inducement (upper confidence limits of ORs for undue inducement, 1.15 and 0.99; P < .001 showing noninferiority; upper confidence limits of ORs for unjust inducement, 1.21 and 1.26; P = .01 and P < .001, respectively). There were no significant effects of incentive size on the secondary outcomes in either trial, including time spent reviewing the risk sections of consent forms, perceived research risks, trial understanding, perceived coercion, or therapeutic misconceptions. Conclusions and Relevance: In these 2 randomized clinical trials, financial incentives increased trial enrollment in 1 of 2 trials and did not produce undue or unjust inducement or other unintended consequences in either trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02697799.

"I Don't Have Time to Sit and Talk with Them": Hospitalists' Perspectives on Palliative Care Consultation for Patients with Dementia.

BACKGROUND/OBJECTIVES: Specialty palliative care for hospitalized patients with dementia is widely recommended and may improve outcomes, yet rates of consultation remain low. We sought to describe hospitalists' decision-making regarding palliative care consultation for patients with dementia. DESIGN: Descriptive qualitative study. SETTING: Seven hospitals within a national nonprofit health system. PARTICIPANTS: Hospitalist physicians. MEASUREMENTS: Individual semistructured interviews. We used thematic analysis to explore factors that influence hospitalists' decision to consult palliative care for patients with dementia. RESULTS: A total of 171 hospitalists were eligible to participate, and 28 (16%) were interviewed; 17 (61%) were male, 16 (57%) were white, and 18 (64%) were in practice less than 10 years. Overall, hospitalists' decisions to consult palliative care for patients with dementia were influenced by multiple factors across four themes: patient, family caregiver, hospitalist, and organization. Consultation was typically only considered for patients with advanced disease, particularly those receiving aggressive care or with family communication needs (navigating conflicts around goals of care and improving disease and prognostic understanding). Hospitalists' limited time and, for some, a lack of confidence in palliative care skills were strong drivers of consultation. Palliative care needs notwithstanding, most hospitalists would not request consultation if they perceived families would be resistant to it or had limited availability or involvement in caregiving. Additional barriers to referral at the organization level included a hospital culture that conflated palliative and end-of-life care and busy palliative care teams at some hospitals. CONCLUSION: Hospitalists described a complex consultation decision process for involving palliative care specialists in the care of patients with dementia. Systematic identification of hospitalized patients with dementia most likely to benefit from palliative care consultation and strategies to overcome modifiable family and organization barriers are needed. J Am Geriatr Soc 68:2365-2372, 2020.

Ethical issues in the neurology of aging and cognitive decline.

Caring for persons with Alzheimer's disease presents neurologists with ethical challenges. Some of these, such as end-of-life care or research participation, are well known and have significant overlap with challenges in other areas of medicine or other neurologic diseases, such as cancer or traumatic brain injury, while others, such as the rise of biomarker-based diagnostics, are more novel and reflect the impact of developments in the science and clinical care of Alzheimer's disease. A thoughtful and systematic approach to these challenges, from the preclinical to the late symptomatic stage of this disease, is required and will help clinicians be better advocates and stewards of their patients. This chapter addresses a number of the most pressing ethical problems facing patients, caregivers, and clinicians during this disease, including early and presymptomatic testing, assessment of decision-making capacity for treatment or research participation, restriction of driving, remote monitoring, assisted suicide, and treatment of disruptive behaviors.

Cognitive impairment and PD patients' capacity to consent to research.

OBJECTIVE: To examine how cognitive impairment affects Parkinson disease (PD) patients' research consent capacity. METHODS: A cross-sectional study of 90 patients with PD, divided using Mattis Dementia Rating Scale-2 scores into 3 groups of 30 (normal, borderline, and impaired), and 30 neurologically normal older adults completed 2 capacity interviews (an early-phase randomized and controlled drug trial and a sham-controlled surgical implantation of genetic tissue) using the MacArthur Competence Assessment Tool for Clinical Research. Expert clinicians used the interviews to classify the patients as either capable or not capable of providing their own informed consent. These judgments were compared with performance on the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). RESULTS: Cognitively normal PD patients typically scored well on the capacity measures. In contrast, patients with impaired cognition were not capable of providing their own informed consent: 17% (5/30) on the drug trial and 3% (1/30) on the surgery trial were judged capable. Patients with borderline impairment showed adequate performance on measures of appreciation and reasoning, but impaired performance on understanding the drug trial compared with normal controls and normal PD patients, and on understanding the surgery trial compared with normal controls. Sixty-seven percent (20/30) on the drug trial and 57% (17/30) on the surgery trial were judged capable of consent. Receiver operating characteristic analyses showed that the MMSE and MoCA could detect the likelihood of impaired capacity, with the MoCA demonstrating greater sensitivity. CONCLUSIONS: PD patients with borderline cognitive impairment have impairments in their decisional capacity. The MoCA may be useful to identify the patients at risk of impaired capacity.

Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease.

OBJECTIVES: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aß42 levels and t-tau/Aß42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. CONCLUSION: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.

Screening questionnaires for parkinsonism: a systematic review.

Parkinson's disease (PD) is a common, treatable movement disorder that often remains undiagnosed despite clinically manifest symptoms. Screening for parkinsonism could lead to improved detection and earlier treatment, and facilitate research studies of PD prevalence. In order to determine the feasibility of screening, this study evaluated the validity of previously developed screening questionnaires. We systematically searched online databases PubMed and EMBASE for English-language studies published between 1980 and 2009. In each database a "Parkinson(s) disease" or "parkinsonism" term was combined with a screening term ("screening instrument," "screening questionnaire," "screen" or "prevalence survey") and a validity term ("validation," "sensitivity" and "specificity"). Included studies reported the psychometric properties of at least one self-report questionnaire for parkinsonism. Twenty-seven studies met the inclusion criteria. From these studies, 9 screening questionnaires were identified. Sensitivity and specificity estimates varied widely. Sensitivity estimates were as high as 100% when questionnaires were tested among previously diagnosed PD patients and included a high number of parkinsonism specific items, but were as low as 48% when tested among early cases in a community-based sample. Specificity estimates were lower, ranging from 22 to 100%. An older sample, presence of multiple co-morbid conditions and lower literacy led to lower specificity estimates. Higher specificity estimates were seen when the screening questionnaires were administered by a physician. Screening questionnaires can detect symptomatic parkinsonism. However, the performance of these questionnaires varied based on the individual items, study sample, and method of administration. The performance of screening questionnaires in the detection of early or mild parkinsonism was modest.

Countrywide strategic plans on Alzheimer's disease: developing the framework for the international battle against Alzheimer's disease.

As the world's population ages, countries must prepare for the significant impact Alzheimer's disease will have on their health systems, their economies, and their citizens. In anticipation of major global demographic changes, many countries in the G-20 since 2000 have begun to develop and enact plans to address Alzheimer's disease as a national priority. However, even with nearly half of these participating countries having plans in place, there has been little research done to quantify the value of enacting a countrywide plan on this disease. In this review, we summarize recent national plans (from the year 2000 and beyond) and any results stemming from their respective recommendations and activities.

Design of comprehensive Alzheimer's disease centers to address unmet national needs.

The problem of Alzheimer's disease (AD) exemplifies the challenges of dealing with a broad range of aging-related chronic disorders that require long-term, labor-intensive, and expensive care. As the baby boom generation ages and brain diseases become more prevalent, the need to confront the pending health care crisis is more urgent than ever before. Indeed, there is now a critical need to expand significantly the national effort to solve the problem of AD, with special focus on prevention. The Campaign to Prevent Alzheimer's Disease by 2020 (PAD2020) aims to create a new paradigm for planning and supporting the organization of worldwide cooperative research networks to develop new technologies for early detection and treatments of aging-related memory and motor impairments. PAD 2020 is developing an implementation plan to justify (1) increasing the federal budget for research, (2) developing novel national resources to discover new interventions for memory and motor disorders, and (3) creating innovative and streamlined decision-making processes for selecting and supporting new ideas. Since 1978 the National Institute on Aging or National Institute of Health (NIH) established an extensive national network of AD research facilities at academic institutions including AD Centers (ADCs), Consortium to Establish a Registry for AD, AD Cooperative Study (ADCS), AD Drug Discovery Program, National Alzheimer's Coordinating Center, National Cell Repository for AD, and AD Neuroimaging Initiative. However, despite the success of these programs and their critical contributions, they are no longer adequate to meet the challenges presented by AD. PAD 2020 is designed to address these changes by improving the efficiency and effectiveness of these programs. For example, the ADCs (P30s and P50s) can be enhanced by converting some into Comprehensive Alzheimer's Disease Centers (CADCs) to support not only research, but also by being demonstration projects on care/treatment, clinical trials, and education as well as by seamlessly integrating multisite collaborative studies (ADCS, AD Neuroimaging Initiative, Patient Registries, Clinical Data Banks, etc) into a cohesive structure that further enhances the original mission of the National Institute on Aging ADCs. Regional CADCs offer greater efficiency and cost savings while serving as coordinating hubs of existing ADCs, thereby offering greater economies of scale and programmatic integration. The CADCs also broaden the scope of ADC activities to include research on interventions, diagnosis, imaging, prevention trials, and other longitudinal studies that require long-term support. Thus, CADCs can address the urgent need to identify subjects at high risk of AD for prevention trials and very early in the course of AD for clinical trials of disease modification. The enhanced CADCs will allow more flexibility among ADCs by supporting collaborative linkages with other institutions and drawing on a wider expertise from different locations. This perspective article describes the University of Pennsylvania (Penn) CADC Model as an illustrative example of how an existing ADC can be converted into a CADC by better utilization of Penn academic resources to address the wide range of problems concerning AD. The intent of this position paper is to stimulate thinking and foster the development of other or alternative models for a systematic approach to the study of dementia and movement disorders.

The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts.

Previously we have shown that the H1c haplotype on the background of the H1 clade of haplotypes at the MAPT locus is associated with increased risk for progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer's disease (AD). Here we replicated the association with AD in an additional autopsy confirmed series. We show that this haplotype increases both the expression of total MAPT transcript as well as specifically increasing the proportion of 4 microtubule binding repeat containing transcripts. We discuss these findings both in terms of the problems facing the dissection of the etiologies of complex traits and the pathogenesis of the tauopathies.

Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations.

Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.

Are depressed patients more likely to share health care decisions with others?

OBJECTIVES: To determine whether psychological variables, particularly depression, influence patients' willingness to share medical decisions with family members or friends. DESIGN: Cross-sectional interviews. SETTING: Oncology and general geriatrics outpatient clinics of an urban VA medical center. PARTICIPANTS: Ninety-five patients with a Charlson comorbidity index score greater than 5. MEASUREMENTS: Subjects described the way that they make health care decisions with friends or family as a dichotomous variable ("shared" versus "not shared") and as a 5-point ordinal variable (the degree to which they share decisions). Patients also completed the 15-item version of the Geriatric Depression Scale (GDS), the Global Distress Index of the Memorial Symptom Assessment Scale, and selected tests of cognitive function and health literacy. RESULTS: Patients with a GDS score higher than 5 were more likely to share decision-making (16/26 versus 26/69; odds ratio 2.58; p = 0.040), as were patients who were married (23/35 versus 19/60; odds ratio 3.63; p = 0.001). In multivariable regression models, a short form GDS score higher than 5 was independently associated with a willingness to share decision with others. CONCLUSION: These results suggest that depression may have a clinically significant influence on patients' willingness to share health care decisions with others. Health care providers should be alert to this possibility, particularly when the decision at hand is significant.

Identifying ambulatory cancer patients at risk of impaired capacity to consent to research.

Ethicists and others have expressed concerns that some patients with cancer might lack adequate decision-making capacity to give consent for research. Although this concern is plausible, it is not known what patient characteristics might be used to identify those patients who are at risk and who therefore should undergo a formal assessment of decision-making capacity. Forty-five patients with cancer were presented with a description of a randomized controlled trial, accompanied by an Institutional Review Board-approved consent form. Two raters who were blind to all patient characteristics assessed decision-making capacity using the MacArthur Competency Assessment Tool for Clinical Research. These scores were summarized in overall capacity judgments using criteria established by a panel of experts. Subjects also completed a symptom rating scale and a battery of neuropsychiatric tests. No relationship was observed between symptom severity and any domain of decision-making capacity (understanding, appreciation, reasoning, ability to express a choice) or summary judgments. However, several other patient characteristics, including age, education, and selected neuropsychiatric test results, were found to be strongly associated with capacity scores. These data suggest that several patient characteristics, such as age, education, and tests of cognitive functions, may help investigators to identify patients with impaired capacity to give consent for research.

Must patients with advanced cancer choose between a Phase I trial and hospice?

BACKGROUND: Phase I oncology trials offer no meaningful chance for direct medical benefit and they may prevent patients with advanced cancer from receiving palliative care in a hospice program. However, it is not known whether dual enrollment in a Phase I trial and hospice is feasible. METHODS: Five hundred thirty-four Phase I trials were identified in a national online database, of which 179 (34%) accepted patients with a life expectancy of less than 6 months. Of these, 50 were selected randomly. Their principal investigators were surveyed by fax, with follow-up telephone calls and e-mails. Ninety-two hospices were selected randomly from a national database. Surveys were conducted by telephone with intake coordinators. Principal investigators were asked whether patients enrolled in hospice could also enroll in their trials if they were eligible in all other respects. Hospice intake coordinators were asked whether a patient with advanced cancer who met hospice eligibility criteria could also enroll in a Phase I trial. RESULTS: Surveys were completed by 45 of 50 principal investigators (90%) and by 89 of 92 hospices (97%). Although both groups were in favor of dual enrollment, principal investigators (41 of 45; 91%) were more likely to support dual enrollment than hospices (60 of 89; 67%; chi-square test, P = 0.004). Most hospices that did not support dual enrollment cited reasons that were based on concerns about payment or misunderstandings about the nature of Phase I trials. CONCLUSIONS: Most hospices and Phase I principal investigators believe that eligible patients should be allowed to enroll simultaneously in hospice and Phase I trials. These results suggest that the choice between hospice and a Phase I trial is a false dilemma and that greater collaboration in this area is needed.

Are hospices ready to participate in palliative care research? Results of a national survey.

BACKGROUND: Improvements in end-of-life care will require an active program of research, and this research will need to involve patients in hospice. However, it is not known whether hospices are prepared to participate in research, nor is it known what barriers may prevent hospices from becoming involved in research. METHODS: This nationwide telephone survey was conducted with a random sample of hospice organizations taken from a national database. Questions elicited the research activities in which hospices are involved, the resources that hospices have available for the ethical review of research, and perceived barriers to research participation. RESULTS: Of 88 hospices identified, 17 (19%) reported that they had participated in research in the past year. Hospices that participated in research were more likely to be urban, affiliated with an academic institution, and were more likely to have an inpatient unit. Hospices cited several barriers to research participation, including time commitments, staffing resources, ethical concerns, and burdens to patients and families. The most important concern was lack of staffing resources. Hospices indicated that they would be most willing to support research regarding pain management and timing of referral to hospice.

Obtaining informed consent for cancer pain research: do patients with advanced cancer and patients with chronic pain have different concerns?

To explore the factors that patients with malignant and nonmalignant pain consider when deciding whether to enroll in pain research studies, determine whether their views are different, and determine whether willingness to enroll in research is associated with pain severity, semi-structured interviews were conducted with 80 patients (cancer pain: n = 40; chronic nonmalignant pain: n = 40). The risks and potential benefits that were important to patients with cancer were the same as those that were important to patients with chronic pain. Willingness to enroll in research was associated with pain severity (Spearman rho = 0.33; P = 0.041) in patients with chronic pain, but not in patients with cancer pain. Patients with cancer pain do not have different concerns than chronic pain patients do. Although chronic pain patients' willingness to enroll in research was related to pain severity and a desire for better pain management, cancer patients' willingness to enroll was not.