A Pragmatic, Investigator-Driven Process for Disclosure of Amyloid PET Scan Results to ADNI-4 Research Participants.

BACKGROUND: Prior studies of Alzheimer's disease (AD) biomarker disclosure have answered important questions about individuals' safety after learning and comprehending their amyloid PET results; however, these studies have typically employed highly structured disclosure protocols and focused on the psychological impact of disclosure (e.g., anxiety, depression, and suicidality) in homogeneous populations. More work is needed to develop flexible disclosure protocols and study outcomes in ethnoculturally representative samples. METHODS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is formally incorporating amyloid PET disclosure into the newest protocol (ADNI-4). Participants across the cognitive spectrum who wish to know their amyloid PET results may learn them. The pragmatic disclosure process spans four timepoints: (1) a pre-disclosure visit, (2) the PET scan and its read, (3) a disclosure visit, and (4) a post-disclosure check-in. This process applies to all participants, with slight modifications to account for their cognitive status. In designing this process, special emphasis was placed on utilizing investigator discretion. Participant measures include perceived risk of dementia, purpose in life, and disclosure satisfaction. Investigator assessment of the disclosure visit (e.g., challenges encountered, topics discussed, etc.) is also included. RESULTS: Data collection is ongoing. Results will allow for more robust characterization of the impact of learning amyloid PET results on individuals and describe the perspectives of investigators. CONCLUSION: The pragmatic design of the disclosure process in ADNI-4 coupled with the novel participant and investigator data will inform future disclosure practices. This is especially important as disclosure of biomarker results expands in research and care.

EU./U.S. CTAD Task Force on Alzheimer's Trial Populations.

Successful therapeutic trials require well-targeted populations to demonstrate the effectiveness of a drug candidate. Most trials in the field of Alzheimer's disease (AD) have been conducted in patients with mild to moderate dementia. However, the advent of amyloid PET imaging has demonstrated that a significant proportion of individuals enrolled in such studies do not have evidence of brain amyloidosis and may in fact not have Alzheimer's disease. Further, dementia represents an advanced stage of neurodegeneration, perhaps too late for significant benefits of disease-modifying interventions. The successful development of effective disease-slowing therapies requires a study population selected in accordance with the mechanism of the specific intervention. An international task force of investigators from academia, industry, non-profit foundations, and regulatory agencies met in San Diego, California, USA, on November 13, 2013, to address issues related to screening and identification of clinical trial participants, and the ramifications of decisions made in this regard for drug development in AD and other dementias.

Assessing mental capacity for everyday decision-making in the Chinese older population.

1. The abilities to make everyday decisions may be reliably measured in the local elderly population. 2. The Chinese version of the Assessment of Capacity for Everyday Decision-Making is a reliable tool to assess these abilities. 3. Significant proportion of participants with mild dementia was mentally incapable in making decisions on everyday tasks. Global cognitive functioning appeared to be an important prerequisite for intact mental capacity.

APOE ɛ4, an Alzheimer's disease susceptibility allele, and smoking cessation.

Possessing an apolipoprotein E (APOE) ɛ4 allele, advanced age and smoking are risk factors for Alzheimer's disease and cognitive decline. Deficits in cognitive function also increase risk for smoking relapse. Data from 917 adult smokers of European ancestry were pooled across three randomized trials of smoking cessation. We examined whether smokers who carry at least one ɛ4 allele (n=252) have more difficulty quitting smoking compared with noncarriers (n=665), and whether age moderated this association. The genotype by age interaction was significant for 7-day point-prevalence abstinence rates (P=0.04) and time to 7-day failure (P=0.03). Among smokers over age 60, ɛ4 carriers were less likely to quit (odds ratio=0.27, P=0.018) and relapsed more quickly (hazard ratio=3.38, P=0.001) compared with noncarriers. The genotype association with relapse was nonsignificant among younger smokers. An increased understanding of the underlying pathophysiological mechanisms of this association could facilitate the development of targeted therapies for smokers with increased risk for cognitive decline.

Mild cognitive impairment in clinical care: a survey of American Academy of Neurology members.

OBJECTIVE: To assess how neurologists view mild cognitive impairment (MCI) as a clinical diagnosis and how they treat patients with mild cognitive symptoms. METHODS: Members of the American Academy of Neurology with an aging, dementia, or behavioral neurology practice focus were surveyed by self-administered questionnaire. RESULTS: Survey respondents were 420 providers (response rate 48%), and 88% reported at least monthly encounters with patients experiencing mild cognitive symptoms. Most respondents recognize MCI as a clinical diagnosis (90%) and use its diagnostic code for billing purposes (70%). When seeing these patients, most respondents routinely provide counseling on physical (78%) and mental exercise (75%) and communicate about dementia risk (63%); fewer provide information on support services (27%) or a written summary of findings (15%). Most (70%) prescribe cholinesterase inhibitors at least sometimes for this population, with memantine (39%) and other agents (e.g., vitamin E) prescribed less frequently. Respondents endorsed several benefits of a diagnosis of MCI: 1) involving the patient in planning for the future (87%); 2) motivating risk reduction activities (85%); 3) helping with financial planning (72%); and 4) prescribing medications (65%). Some respondents noted drawbacks, including 1) too difficult to diagnose (23%); 2) better described as early Alzheimer disease (21%); and 3) diagnosis can cause unnecessary worry (20%). CONCLUSIONS: Patients with mild cognitive symptoms are commonly seen by neurologists, who view MCI as a useful diagnostic category. Information and treatments provided to patients with MCI vary significantly, suggesting a need for practice guidelines and further research on clinical decision-making with this population.

Surrogate consent for dementia research: a national survey of older Americans.

BACKGROUND: Research in novel therapies for Alzheimer disease (AD) relies on persons with AD as research subjects. Because AD impairs decisional capacity, informed consent often must come from surrogates, usually close family members. But policies for surrogate consent for research remain unsettled after decades of debate. METHODS: We designed a survey module for a random subsample (n = 1,515) of the 2006 wave of the Health and Retirement Study, a biennial survey of a nationally representative sample of Americans aged 51 and older. The participants answered questions regarding one of four randomly assigned surrogate-based research (SBR) scenarios: lumbar puncture study, drug randomized control study, vaccine study, and gene transfer study. Each participant answered three questions: whether our society should allow family surrogate consent, whether one would want to participate in the research, and whether one would allow one's surrogate some or complete leeway to override stated personal preferences. RESULTS: Most respondents stated that our society should allow family surrogate consent for SBR (67.5% to 82.5%, depending on the scenario) and would themselves want to participate in SBR (57.4% to 79.7%). Most would also grant some or complete leeway to their surrogates (54.8% to 66.8%), but this was true mainly of those willing to participate. There was a trend toward lower willingness to participate in SBR among those from ethnic or racial minority groups. CONCLUSIONS: Family surrogate consent-based dementia research is broadly supported by older Americans. Willingness to allow leeway to future surrogates needs to be studied further for its ethical significance for surrogate-based research policy.

How important is surrogate consent for stroke research?

BACKGROUND: Patients with stroke may have cognitive deficits that impact their capacity to provide informed consent for research. Some institutional review boards restrict surrogate consent to persons who have specific legal authority to provide it. We examined the importance of surrogate consent in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial, the study that led to the only US Food and Drug Administration-approved treatment for acute ischemic stroke. METHODS: The NINDS rt-PA Stroke Trial randomized subjects with ischemic stroke to treatment with recombinant tissue plasminogen activator (rt-PA) or placebo. We compared the baseline characteristics and clinical outcomes of subjects enrolled by self-consent with those of subjects enrolled by surrogate consent. RESULTS: Surrogate consent was used to enroll 439 of 624 (70%) subjects. Subjects enrolled by surrogate consent were older (68.5 vs 63.4 years, p < 0.001), had more severe strokes (median NIH Stroke Scale score 17 vs 9, p < 0.001), and were less likely to make a good recovery (p < 0.001 for all measures) than patients who provided their own consent. There was no interaction between method of consent and response to rt-PA. If the trial had used the same sample size and recruited at the same rate but excluded patients who could not provide their own consent, it would have taken 12.5 years to complete. CONCLUSIONS: The National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) Stroke Trial would not have been completed in a timely fashion without subjects enrolled by surrogate consent. Furthermore, exclusion of subjects who could not provide their own consent would have severely limited the generalizability and value of trial results.

Beneath the surface: discovering the unvoiced concerns of older adults with type 2 diabetes mellitus.

Emerging clinical guidelines recommend shared decision making to individualize drug regimens for older adults with Type 2 diabetes mellitus. While the current health education campaign for diabetes in the United States recommends physician-initiated medication-related discussions about adherence and side effects, little emphasis is placed on soliciting patient concerns. This study's aim was to explore the concerns of older adults with diabetes about the complexity of their drug regimens and to determine whether they discussed medication-related concerns with their physician. Twenty-two patients with Type 2 diabetes age 65 years and older who used five or more medications were selected from an urban academic geriatric medicine practice in the United States. In-depth semi-structured interviews were conducted to uncover participants' perceptions of multiple medication use and related discussions with providers. The predominant theme that emerged was the variability in medication-related topics that patients perceived they could discuss with their physician. While most participants described physician-initiated discussions about adherence and side effects, many did not bring up concerns about medication cost or their desire to reduce medication burden. In order to encourage greater patient involvement in medication decision making for diabetes treatment, educational messages promoting patient-physician dialogue need to take more account of patient concerns.

Factors associated with survival probability in autopsy-proven frontotemporal lobar degeneration.

OBJECTIVE: To examine the clinical and pathological factors associated with survival in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: The final analysis cohort included 71 patients with pathologically proven FTLD, excluding patients with clinical motor neuron disease (MND), evaluated at the University of Pennsylvania or at the University of California, San Francisco. We assessed clinical and demographic features; cognitive functioning at presentation; genetic markers of disease; and graded anatomical distribution of tau, ubiquitin and amyloid pathology. RESULTS: The tau-negative group (n = 35) had a median survival time of 96 months (95% CI: 72-114 months), whereas the tau-positive group (n = 36) had a median survival time of 72 months (95% CI: 60-84 months). Patients with tau-positive pathology across all brain regions had shorter survival than those with tau-negative pathology in univariate Cox regression analyses (Hazard ratio of dying = 2.003, 95% CI = 1.209-3.318, p = 0.007). CONCLUSIONS: Tau-positive pathology represents a significant risk to survival in FTLD, whereas tau-negative pathology is associated with a longer survival time when clinical MND is excluded.

The ability of persons with Alzheimer disease (AD) to make a decision about taking an AD treatment.

OBJECTIVE: To examine the severity of impairments in the decision-making abilities (understanding, appreciation, reasoning, and choice) and competency to make a decision to use an Alzheimer disease (AD)-slowing medication in patients with AD and the relationships between these impairments, insight, and overall cognition. METHODS: Semistructured in-home interviews were conducted with 48 patients with very mild to moderate AD and 102 family caregivers of patients with mild to severe AD recruited from the Memory Disorders Clinic of an AD center. The interview measured performance on the decision-making abilities and three expert psychiatrists' judgment of competency based on their independent review of the patient interviews. RESULTS: There was considerable variation in patients' performance on the measures of decision-making abilities. Three expert raters found 19 of 48 (40%) of the subjects competent. Competent patients were more likely to show awareness of their symptoms, prognosis, and diagnosis. A sensitivity analysis suggests that a MMSE score is helpful in discriminating capacity from incapacity only when below 19 or above 23. CONCLUSIONS: Persons with mild to moderate Alzheimer disease (AD) have notable impairments in their ability to make an AD treatment decision, especially persons with moderate AD and persons who lack awareness of symptoms, prognosis, or diagnosis.

Do persons with dementia vote?

To examine whether patients with dementia voted in the 2000 US Presidential Election, the authors surveyed 75 caregivers of patients with dementia. A substantial portion of patients with mild to moderate dementia voted on their own at a voting booth. Patients cared for by spouses were more likely to vote than patients cared for by adult children. Further research is needed to understand how persons with dementia and their caregivers decide what activities the person can and cannot continue and how well these decisions correspond to measures of competency.

The relationship between caregivers' global ratings of Alzheimer's disease patients' quality of life, disease severity, and the caregiving experience.

OBJECTIVES: To compare caregivers' ratings of Alzheimer's disease (AD) patients' global quality of life (QOL) using direct assessments and substituted judgments, and to identify qualities of the patients and their caregivers that are associated with these QOL assessments. DESIGN: Cross-sectional interviews. SETTING: A university-based Memory Disorders Clinic. PARTICIPANTS: Forty primary caregivers of AD patients. MEASUREMENTS: Direct scaling of overall quality of life (poor, fair, good, very good, or excellent) and measures of dementia severity, the caregiving experience, and patient and caregiver demographics. RESULTS: The majority of patients had mild (n = 20) or moderate (n = 11) AD. Caregivers' direct assessments of patient QOL were poor (5%, n = 2), fair (28%, n = 11), good (40%, n = 16), very good (20%, n = 8), and excellent (8%, n = 3). Twenty-one (52.5%) of the caregivers rated the patient's QOL the same as they thought the patient would; 12 (30.0%) rated the patient's QOL worse; and seven (17.5%) rated the patient's QOL better. Agreement between the two ratings was fair to moderate. Bivariate analyses showed that lower ratings of caregivers' direct assessments of patient QOL were associated with decreasing ratings of patient mental health and increasing dementia severity, caregiver burden, and caregiver depression. Multivariate models showed burden to be the significant predictor of caregivers' rating of patient QOL and the subscale measuring the caregivers' distress at controlling patient behavior had the strongest association with QOL. Lower ratings of substituted judgment assessments of patient QOL were associated with lower caregiver ratings of the patient's mental health. CONCLUSIONS: Nearly one-half of the caregivers of patients with predominantly mild to moderate AD assess a patient's QOL differently than they believe the patient would. Dementia severity and the caregiver's experiences of depression and burden negatively affect caregivers' assessments of QOL. These results provide a compelling reason why clinicians should take the time to screen for and address caregiver depression and burden and problematic patient behaviors.

Obtaining informed consent for clinical pain research: patients' concerns and information needs.

Investigators who conduct clinical pain research are required to obtain voluntary informed consent from patients. However, little is known about what information patients expect when they decide whether to enroll in such studies. It is important that investigators understand these information needs so they can effectively and clearly describe the research risks and potential benefits that matter to potential subjects. By understanding these needs for information, investigators may also be better able to anticipate patients' concerns and to recruit subjects more efficiently. This study was designed to define information needs that patients have when they decide whether to participate in clinical pain research. This paper describes these information needs, and identifies clinical and demographic variables associated with specific needs.

How do AD patients and their caregivers decide whether to enroll in a clinical trial?

To examine how patients and caregivers decide whether to enroll in a clinical trial, the authors conducted semi-structured interviews with 22 family caregivers of patients with mild to moderate AD who were recruited for a clinical trial. They found that a caregiver who enrolls a patient in research generally involves the patient in the decision-making process, reports that the patient shares in the decision, and regards the risks and benefits to the patient and to the caregiver as interdependent.

Addressing the ethical challenges of clinical trials that involve patients with dementia.

Research subjects face uncertainties, risks, burdens, and indignities, and research protocol requirements inhibit the physician's ability to make individualized treatment decisions. To address these problems, investigators and Institutional Review Boards (IRBs) should justify research risks using informed consent and the judgment that the risks of research are reasonable with respect to the potential benefits, if any, to subjects and to the expectation that the research will produce important knowledge. But clinical research in Alzheimer's disease (AD) presents investigators and IRBs with significant challenges to achieve these two requirements. Broadly, these challenges are the result of the impact of patients' cognitive impairment and the caregiving experience on decision making and the indeterminacy of defining clinically meaningful treatment benefits. In this article, we review the data that begin to answer whether and how patients' cognitive impairments and the caregiving experience impact on their decision making and what kinds of research results justify research risks. We will use these data to suggest changes to the design and conduct of clinical research in AD that can meet the challenge of justifying research risks.

Predictors of withdrawal from hospice.

CONTEXT: Hospice is designed to provide end-of-life care to patients who are terminally ill. However, some patients withdraw from hospice even though they are medically eligible. Little is known about these patients, and the factors associated with their withdrawal have not been described. OBJECTIVES: To identify predictors of withdrawal from hospice in a diverse cohort of hospice patients who are eligible to receive service. DESIGN: Retrospective cohort study. PATIENTS AND SETTING: Between January 1997 and January 1999 1,691 patients enrolled in an urban, nonprofit hospice program were identified and data were gathered until discharge or death. MAIN OUTCOME MEASURES: Time to discharge of eligible patients from hospice. RESULTS: Over the study period, 15% of patients were discharged from hospice while they still met medical eligibility criteria. Patients were more likely to withdraw if they were male, unmarried, and younger than 65, if they did not have cancer, and if they lacked a do-not-resuscitate order, intravenous access, and symptoms requiring intervention. CONCLUSIONS: A substantial proportion of hospice patients who meet medical criteria for services choose to withdraw. Further research is needed to define more clearly the reasons for withdrawal and to investigate whether withdrawal is consistent with patient preferences.

Designing pain research from the patient's perspective: what trial end points are important to patients with chronic pain?

OBJECTIVES: The goals of this study were to define the endpoints of pain research that are important to patients with chronic pain and to identify clinical and demographic variables that are associated with patients' choices of endpoints. PATIENTS & SETTING: Interviews were completed with 40 patients seen at the anesthesia pain clinic of an urban tertiary care medical center. DESIGN: Each patient was presented with 4 brief (3-4 sentences) fixed information vignettes describing studies in which new medications would be evaluated. For each, patients were asked to describe how the medication being studied might offer an improvement over their current therapy. OUTCOME MEASURES: Measures included structured qualitative analysis of responses, the Brief Pain Inventory, and Global Distress Index of the Memorial Symptom Assessment Scale. RESULTS: Patients described a total of 20 endpoints. Individually, patients cited between 2 and 9 endpoints each (mean 4.9, standard deviation 1.7). Of these, the most commonly cited were decrease pain, decrease opioid dose, decrease frequency of scheduled dose, increased ability to function, decrease frequency of breakthrough dose, and improve sleep. Patients with severe pain cited more endpoints than did those with mild or moderate pain (mean 5.5 vs. 4.3; Rank sum test p = 0.01). CONCLUSIONS: These data suggest that empirical research can provide data to guide the choice of endpoints in clinical studies of pain interventions.