Language and Meaning: Asymptomatic Alzheimer's Disease in the Clinic and Society.

As the biological, biomarker-driven framework of Alzheimer's disease (AD) becomes formalized through revised, consensus clinical criteria, clinicians will confront more and more patients in the earliest, asymptomatic stages of disease. The language and diction used by practitioners to characterize these early patients, whether they are diagnosed with AD, and how their condition is documented in medical and legal records have important implications for both their care and their medical-legal status outside of the health system. Investigation is needed urgently to better understand clinicians' views and practices regarding early AD, as we adapt to new disease definitions in this unprecedented era of care.

Refinement of an Emergency Department-Based, Advance Care Planning Intervention for Patients With Cognitive Impairment and Their Caregivers.

BACKGROUND AND OBJECTIVES: Advance care planning (ACP) conversations are important to provide goal-concordant care (i.e., the care that matches the patient's previously stated goals) near end of life. While 31% of older adults presenting to the emergency department (ED) have dementia, only 39% have previously had ACP conversations. We refined and piloted an ED-based, motivational interview designed to stimulate ACP conversations (ED GOAL) for patients living with cognitive impairment and their caregivers. RESEARCH DESIGN AND METHODS: We systematically refined ED GOAL and then conducted an acceptability study in an urban, academic medical center. We prospectively enrolled adults aged 50+ with cognitive impairment and their caregivers. Trained clinicians conducted the intervention. We measured acceptability after the intervention and participants' ACP engagement at baseline and 1-month follow-up. RESULTS: Specific statements to address both the patient and caregiver were added to the ED GOAL script. Of 60 eligible patient/caregiver dyads approached, 26 participated, and 20 (77%) completed follow-up assessments. Patient mean age was 79 years (SD 8.5); 65% were female, 92.3% were White, 96.2% were non-Hispanic, and 69% had moderate dementia. Most patients/caregivers reported feeling completely heard and understood by the study clinician about their future medical care preferences (58%, 15/26). They also reported that the study clinician was very respectful (96%, 25/26) when eliciting those preferences. DISCUSSION AND IMPLICATIONS: Patients living with cognitive impairment and their caregivers found our refined ED GOAL acceptable and respectful. Future studies need to examine the effect of ED GOAL on ACP engagement among these dyads in the ED.

Centralizing prescreening data collection to inform data-driven approaches to clinical trial recruitment.

BACKGROUND: Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources. Collection and analysis of such prescreening data across sites could provide valuable information to improve understanding of recruitment intervention effectiveness, including whether traditionally underrepresented participants are lost prior to screening. METHODS: We developed an infrastructure within the National Institute on Aging (NIA) Alzheimer's Clinical Trials Consortium (ACTC) to centrally collect a subset of prescreening variables. Prior to study-wide implementation in the AHEAD 3-45 study (NCT NCT04468659), an ongoing ACTC trial recruiting older cognitively unimpaired participants, we completed a vanguard phase with seven study sites. Variables collected included age, self-reported sex, self-reported race, self-reported ethnicity, self-reported education, self-reported occupation, zip code, recruitment source, prescreening eligibility status, reason for prescreen ineligibility, and the AHEAD 3-45 participant ID for those who continued to an in-person screening visit after study enrollment. RESULTS: Each of the sites was able to submit prescreening data. Vanguard sites provided prescreening data on a total of 1029 participants. The total number of prescreened participants varied widely among sites (range 3-611), with the differences driven mainly by the time to receive site approval for the main study. Key learnings instructed design/informatic/procedural changes prior to study-wide launch. CONCLUSION: Centralized capture of prescreening data in multi-site clinical trials is feasible. Identifying and quantifying the impact of central and site recruitment activities, prior to participants signing consent, has the potential to identify and address selection bias, instruct resource use, contribute to effective trial design, and accelerate trial enrollment timelines.

Utility of Amyloid Positron Emission Tomography Imaging in Older Adults With Epilepsy and Cognitive Decline.

In older adults with cognitive decline and epilepsy, diagnosing the etiology of cognitive decline is challenging. We identified 6 subjects enrolled in the Imaging Dementia-Evidence of Amyloid Imaging Scanning (IDEAS) study and nonlesional epilepsy. Three cognitive neurologists reviewed each case to determine the likelihood of underlying Alzheimer's disease (AD) pathology. Their impressions were compared to amyloid PET findings. In 3 cases the impression was concordant with PET findings. In 2 cases "possibly suggestive," the PET reduced diagnostic uncertainty, with 1 having a PET without elevated amyloid and the other PET with intermediate amyloid. In the remaining case with lack of reviewer concordance, the significance of PET with elevated amyloid remains uncertain. This case series highlights that in individuals with a history of epilepsy and cognitive decline, amyloid PET can be a useful tool in evaluating the etiology of cognitive decline when used in an appropriate context.

Preclinical Alzheimer Disease and the Electronic Health Record: Balancing Confidentiality and Care.

Because information technologies are increasingly used to improve clinical research and care, personal health information (PHI) has wider dissemination than ever before. The 21st Century Cures Act in the United States now requires patient access to many components of the electronic health record (EHR). Although these changes promise to enhance communication and information sharing, they also bring higher risks of unwanted disclosure, both within and outside of health systems. Having preclinical Alzheimer disease (AD), where biological markers of AD are identified before the onset of any symptoms, is sensitive PHI. Because of the melding of ideas between preclinical and "clinical" (symptomatic) AD, unwanted disclosure of preclinical AD status can lead to personal harms of stigma, discrimination, and changes to insurability. At present, preclinical AD is identified mainly in research settings, although the consensus criteria for a clinical diagnosis may soon be established. There is not yet adequate legal protection for the growing number of individuals with preclinical AD. Some PHI generated in preclinical AD trials has clinical significance, necessitating urgent evaluations and longitudinal monitoring in care settings. AD researchers are obligated to both respect the confidentiality of participants' sensitive PHI and facilitate providers' access to necessary information, often requiring disclosure of preclinical AD status. The AD research community must continue to develop ethical, participant-centered practices related to confidentiality and disclosure, with attention to sensitive information in the EHR. These practices will be essential for translation into the clinic and across health systems and society at large.

Non-Pharmacological Treatments of Neuropsychiatric Symptoms in Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is a syndrome defined by objective cognitive deficits that do not impact functional independence. Individuals with MCI develop dementia at an annual rate of 10 to 15%. Neuropsychiatric symptoms (NPS) are common non-cognitive features of neurocognitive disorders and have a major impact on the wellbeing and quality of life of affected individuals and their families. Non-pharmacological interventions for NPS are considered the first-line treatment because of the limited efficacy and side-effect potential of current pharmacological agents. This article summarizes the literature on non-pharmacological treatments for NPS in MCI. The limited number of studies specific to individuals with MCI and its various etiologies, as well as the overall heterogeneity of research design and methodologies, make the evidence base inconclusive. Nevertheless, some studies support psychosocial interventions aimed at individuals with MCI and their caregivers.

Promoting Successful Cognitive Aging: A Ten-Year Update.

A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors.

Mindfulness and Cognitive Training Interventions in Mild Cognitive Impairment: Impact on Cognition and Mood.

With the lack of disease-modifying pharmacologic treatments for mild cognitive impairment and dementia, there has been an increasing clinical and research focus on nonpharmacological interventions for these disorders. Many treatment approaches, such as mindfulness and cognitive training, aim to mitigate or delay cognitive decline, particularly in early disease stages, while also offering potential benefits for mood and quality of life. In this review, we highlight the potential of mindfulness and cognitive training to improve cognition and mood in mild cognitive impairment. Emerging research suggests that these approaches are feasible and safe in this population, with preliminary evidence of positive effects on aspects of cognition (attention, psychomotor function, memory, executive function), depression, and anxiety, though some findings have been unclear or limited by methodological weaknesses. Even so, mindfulness and cognitive training warrant inclusion as current treatments for adults with mild cognitive impairment, even if there is need for additional research to clarify treatment outcomes and questions related to dose, mechanisms, and transfer and longevity of treatment effects.

The Brain Health Champion study: Health coaching changes behaviors in patients with cognitive impairment.

INTRODUCTION: Converging evidence suggests that increasing healthy behaviors may slow or prevent cognitive decline. METHODS: We piloted a six-month, randomized, controlled investigation of 40 patients with mild dementia, mild cognitive impairment, or subjective cognitive decline. The intervention consisted of weekly motivational interviewing phone calls and three visits with a "Brain Health Champion" health coach, who guided participants to achieve personalized goals. Changes in behavior were measured using validated questionnaires. RESULTS: Compared with the standard-of-care control group, Brain Health Champion participants had statistically significant and clinically meaningful increases in physical activity (Cohen's d = 1.37, P < .001), adherence to the Mediterranean diet (Cohen's d = 0.87, P = .016), cognitive/social activity (Cohen's d = 1.09, P = .003), and quality of life (Cohen's d = 1.23, P < .001). The magnitude of behavior change strongly predicted improvement in quality of life. DISCUSSION: Our results demonstrate the feasibility and potential efficacy of a health coaching approach in changing health behaviors in cognitively impaired and at-risk patients.

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial.

IMPORTANCE: Oligomeric amyloid-ß peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. OBJECTIVE: To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. DESIGN, SETTING, AND PARTICIPANTS: This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-ß peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. INTERVENTIONS: AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. MAIN OUTCOMES AND MEASURES: Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. RESULTS: Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. CONCLUSIONS AND RELEVANCE: Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02167256.

Dementia and Atrial Fibrillation: Pathophysiological Mechanisms and Therapeutic Implications.

Atrial fibrillation increases the risk of stroke by a factor of four- to fivefold, and dementia is a common consequence of stroke. However, atrial fibrillation has been associated with cognitive impairment and dementia, even in patients without prior overt stroke. Nonischemic mechanisms include cerebral hypoperfusion, vascular inflammation, brain atrophy, genetic factors, and shared risk factors such as age or hypertension. Critical appraisal of studies evaluating the association between atrial fibrillation and dementia in stroke-free patients reveals that several suffer from methodological issues, such as not including silent stroke or anticoagulation therapy in multivariate analyses. Some studies show a close relationship between atrial fibrillation and dementia due to silent stroke, in the absence of overt stroke. Evidence is accumulating that anticoagulation may be effective to decrease the risk of dementia in atrial fibrillation patients. Overall, the pathogenesis linking atrial fibrillation to dementia is likely multifactorial. Cerebral infarctions, including silent stroke, play a central role. These findings underscore the importance of stroke prevention measures in atrial fibrillation patients.

Dementia.

Dementia is any decline in cognition that is significant enough to interfere with independent, daily functioning. Dementia is best characterized as a syndrome rather than as one particular disease. The causes of dementia are myriad and include primary neurologic, neuropsychiatric, and medical conditions. It is common for multiple diseases to contribute to any one patient's dementia syndrome. Neurodegenerative dementias, like Alzheimer disease and dementia with Lewy bodies, are most common in the elderly, while traumatic brain injury and brain tumors are common causes in younger adults. While the recent decade has seen significant advancements in molecular neuroimaging, in understanding clinico-pathologic correlation, and in the development of novel biomarkers, clinicians still await disease-modifying therapies for neurodegenerative dementias. Until then, clinicians from varied disciplines and medical specialties are well poised to alleviate suffering, aggressively treat contributing conditions, employ medications to improve cognitive, neuropsychiatric, and motor symptoms, promote evidence-based brain-healthy behaviors, and improve overall quality of life for patients and families.