Neuropsychiatric Symptom Profile in Alzheimer's Disease and Their Relationship With Functional Decline.

OBJECTIVE: Understanding the course of individual neuropsychiatric symptoms (NPS) and their relationship with function is important for planning targeted interventions for preventing and delaying functional decline. This study aims to disentangle relative contributions of individual NPS on functional decline. METHODS: Longitudinal study of 9,358 well-characterized participants with baseline diagnoses of Mild Cognitive Impairment or AD in the National Alzheimer's Coordinating Center Uniform Data Set. Function was measured using the Functional Assessment Questionnaire (FAQ). Clinician judgment of seven common behavioral symptoms were examined simultaneously: apathy-withdrawal, depressed mood, visual or auditory hallucinations, delusions, disinhibition, irritability, and agitation. RESULTS: Apathy was the most common NPS at baseline (33.7%) and throughout follow-up, endorsed by clinicians in 63.7% of visits. Apathy was the most persistent with 36.7% of participants having clinician-endorsed apathy in ≥50% of their visits. Apathy strongly correlated with faster rate of functional decline. Compared to those who never had apathy, baseline FAQ was worse in those with intermittent or persistent/always apathy (intermittent: estimated coefficient ±SE=1.228±0.210, 95% CI=[0.817, 1.639]; persistent/always: 2.354±0.244 (95% CI=[1.876, 2.832], both p <0.001). Over time, rate of functional decline was faster in those with intermittent and persistent/always apathy (intermittent: 0.454±0.091, 95% CI=[0.276, 0.632]; persistent/always: 0.635±0.102, 95% CI=[0.436, 0.835], both p <0.001). Worse agitation, delusions, and hallucinations also correlated with functional decline, but magnitudes of the estimates were smaller. CONCLUSION: Individual NPS may be sensitive targets for tracking longitudinal change in function. The study raises awareness of the need for more comprehensive assessment of functional decline in AD patients with noncognitive symptoms.

Evaluating memory testing to distinguish dementia severity among White, Black, and Spanish-speaking individuals in the Uniform Data Set (UDS).

INTRODUCTION: Little work has compared the effectiveness of using multiple types of memory tests alone or in combination to distinguish dementia severity in diverse research cohorts including Black individuals and Spanish speakers. Here we evaluate word list and paragraph recall tests to distinguish cognitively normal, mild cognitively impaired, and those with Alzheimer's disease in diverse cohorts. METHODS: Using Uniform Data Set (UDS) and site-specific supplemental data, logistic regression models and receiver operating characteristic-area under the curve were used to compare paragraph recall versus word list in differentiating among Clinical Dementia Rating (CDR) scale level. RESULTS: Results reveal high discriminability for all groups and no difference between either test in distinguishing between CDR levels. Combining tests improved discriminability for the whole group but did not for Black individuals or Spanish speakers. DISCUSSION: Our findings indicate that using multiple memory tests may not improve differentiation between cognitive impairment levels for diverse cohorts. The burden of added testing may be a barrier for maximizing inclusion of under-represented groups in research.

Agitation in Cognitive Disorders: Use of the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS) to Evaluate International Psychogeriatric Association Definition.

OBJECTIVE: Consensus-based definition of agitation by the International Psychogeriatric Association (IPA) has not been evaluated in community-based samples who are not preselected for behavioral disturbances. Here, we use a well-characterized cohort of community-dwelling older adults with cognitive impairment to assess the IPA criteria associated with agitation to evaluate the construction of this diagnostic entity. METHODS: We used the National Alzheimer Coordinating Center Unified Data Set (NACC-UDS) to construct the IPA consensus-based provisional definition of agitation in cognitive impairment (N = 19,424). We used clinician diagnosis of agitation as a gold standard in those with mild cognitive impairment and dementia and used the Neuropsychiatric Inventory-Questionnaire to define agitation symptoms and standardized assessments of function (including the Functional Assessment Scale and Clinical Dementia Rating Scale Sum of Boxes) to assess "excess disability." We also examined patterns of psychiatric comorbidities to determine if they were consistent with IPA criteria. RESULTS: There was agreement between the selected NPI measure of agitation and clinician judgment (sensitivity = 0.79, specificity = 0.69, Cohen's Kappa = 0.304). More than 84% of those with clinician judgment of agitation and 74% of those meeting the scale-based definition of agitation demonstrated excess social/functional disability. Comorbid psychiatric symptoms were present in 38% of the sample without agitation and higher in those with agitation by either definition. CONCLUSION: Agitation ranges between 15% and 48% in those with cognitive impairment. The pattern of level of excess disability and the presence of comorbid psychiatric symptoms is consistent with the profile of published definitions.

Adapting Alzheimer Disease and Related Dementias Clinical Research Evaluations in the Age of COVID-19.

In March 2020, the novel coronavirus (COVID-19) became a global pandemic that would cause most in-person visits for clinical studies to be put on pause. Coupled with protective stay at home guidelines, clinical research at the Icahn School of Medicine at Mount Sinai Alzheimer's Disease Research Center (ISMMS ADRC) needed to quickly adapt to remain operational and maintain our cohort of research participants. Data collected by the ISMMS ADRC as well as from other National Institute on Aging (NIA) Alzheimer Disease centers, follows the guidance of the National Alzheimer Coordinating Center (NACC). However, at the start of this pandemic, NACC had no alternative data collection mechanisms that could accommodate these safety guidelines. To stay in touch with our cohort and to ensure continued data collection under different stages of quarantine, the ISMMS ADRC redeployed their work force to continue their observational study via telehealth assessment. On the basis of this experience and that of other centers, NACC was able to create a data collection process to accommodate remote assessment in mid-August. Here we review our experience in filling the gap during this period of isolation and describe the adaptations for clinical research, which informed the national dialog for conducting dementia research in the age of COVID-19 and beyond.

Relapse risk after discontinuation of risperidone in Alzheimer's disease.

BACKGROUND: Among patients with Alzheimer's disease who have had a response to antipsychotic medication for psychosis or agitation-aggression, the risk of a recurrence of symptoms after discontinuation of the medication has not been established. METHODS: Patients with Alzheimer's disease and psychosis or agitation-aggression received open-label treatment with risperidone for 16 weeks. Those who had a response to risperidone therapy were then randomly assigned, in a double-blind fashion, to one of three regimens: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), or placebo for 32 weeks (group 3). The primary outcome was the time to relapse of psychosis or agitation. RESULTS: A total of 180 patients received open-label risperidone (mean dose, 0.97 mg daily). The severity of psychosis and agitation were reduced, although there was a mild increase in extrapyramidal signs; 112 patients met the criteria for response to treatment, of whom 110 underwent randomization. In the first 16 weeks after randomization, the rate of relapse was higher in the group that received placebo than in the groups that received risperidone (60% [24 of 40 patients in group 3] vs. 33% [23 of 70 in groups 1 and 2]; P=0.004; hazard ratio with placebo, 1.94; 95% confidence interval [CI], 1.09 to 3.45; P=0.02). During the next 16 weeks, the rate of relapse was higher in the group that was switched from risperidone to placebo than in the group that continued to receive risperidone (48% [13 of 27 patients in group 2] vs. 15% [2 of 13 in group 1]; P=0.02; hazard ratio, 4.88; 95% CI, 1.08 to 21.98; P=0.02). The rates of adverse events and death after randomization did not differ significantly among the groups, although comparisons were based on small numbers of patients, especially during the final 16 weeks. CONCLUSIONS: In patients with Alzheimer's disease who had psychosis or agitation that had responded to risperidone therapy for 4 to 8 months, discontinuation of risperidone was associated with an increased risk of relapse. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00417482.).

The antipsychotic discontinuation in Alzheimer disease trial: clinical rationale and study design.

OBJECTIVES: : Research studies on the effects of discontinuing antipsychotic medications in patients with dementia have not identified specific target symptoms or response to antipsychotics prior to discontinuation. The Antipsychotic Discontinuation in Alzheimer Disease (ADAD) trial addresses these issues in a randomized, double-blind, placebo-controlled, multicenter risperidone treatment and discontinuation trial. In Phase A, AD patients with psychosis or agitation receive open treatment with risperidone for 16 weeks. Responders are randomized, double-blind, to one of three arms in Phase B: 1) continuation risperidone for the next 32 weeks, 2) risperidone for the next 16 weeks followed by placebo for 16 weeks, or 3) placebo for the next 32 weeks. METHODS: : Several design features provide unique strengths to this trial: identification of target symptoms and systematic open antipsychotic treatment with only responders randomized in the discontinuation trial, use of a single antipsychotic medication, two clinically relevant time-points for discontinuation to evaluate the impact of duration of treatment on relapse, exclusion of patients at increased risk of stroke, assessment of several affected symptom domains, and state-of-the-art approaches to assess relapse and handle dropout. CONCLUSIONS: : This study will provide clinically relevant data on the likelihood and time to relapse, and predictors of relapse, in patients switched from risperidone to placebo after response to risperidone treatment. Given the warnings about antipsychotic use in patients with dementia, studies of this type are essential to determine the optimal duration of treatment that confers the greatest benefit to risk ratio and to improve evidence-based treatment strategies.

Effect of Social Determinants of Health on Cognition and Risk of Alzheimer Disease and Related Dementias.

Social determinants of health are the conditions in which people are born, work, live, and age and the wider set of forces and systems that shape the conditions of daily life. They affect every area of life, particularly health and health care. There is increasing focus on modifiable factors that affect cognition and risk of Alzheimer disease and related dementias (ADRDs). This article examines the impact of various social determinants of health, which are potentially reversible, on the incidence, prevalence, and risk of ADRDs and cognition. Various social determinants of health affect cognition and risk of ADRDs. Lower socioeconomic status (SES) and less education are associated with a higher incidence of ADRDs, whereas higher SES and education level appear to be protective, leading to a deceleration of time to diagnosis. In terms of employment, manual labor is associated with a higher risk of ADRDs. Higher body mass index in midlife and a decreasing body mass index in old age are associated with a higher risk of ADRDs. Furthermore, lower food security in early and late life is associated with a higher risk of ADRD diagnosis. Neighborhoods that are economically disadvantaged with fewer physical resources are associated with a higher risk of ADRDs. Higher levels of social engagement have a protective effect on diagnosis of ADRDs. Higher levels of stress are associated with a higher likelihood of developing ADRDs. Early-life adversity is associated with an increased risk of ADRDs, and further work in this area will be illuminating. Racial discrimination also leads to higher risk of ADRDs through the direct effect of discrimination and indirectly through lower SES, educational level, employment, and residential segregation. With an aim of reducing of ADRDs, future work in enhancing education, improving socioeconomic conditions, work, and neighborhood environments, and eliminating racial discrimination could potentially have a drastic impact.

Analyzing Individual-Level Secondary Data with Instrumental Variable Methods Is Useful for Studying the Effects of Air Pollution on Dementia.

We hypothesize that analyzing individual-level secondary data with instrumental variable (IV) methods can advance knowledge of the long-term effects of air pollution on dementia. We discuss issues in measurement using secondary data and how IV estimation can overcome biases due to measurement error and unmeasured variables. We link air-quality data from the Environmental Protection Agency's monitors with Medicare claims data to illustrate the use of secondary data to document associations. Additionally, we describe results from a previous study that uses an IV for pollution and finds that PM2.5's effects on dementia are larger than non-causal associations.

Prevalent, persistent, and impairing: Longitudinal course and impact of apathy in Alzheimer's disease.

INTRODUCTION: Understanding of the natural history of apathy and its impact on patient function is limited. This study examines, in a large, national sample of Alzheimer's disease (AD) patients with long follow-ups: (1) prevalence, incidence, and persistence of apathy, and (2) impact of apathy on function across dementia severity. METHODS: A longitudinal study of 9823 well-characterized AD patients in the National Alzheimer's Coordinating Center Uniform Data Set. RESULTS: Apathy was highly prevalent across disease severity with cumulative prevalence of 48%, 74%, and 82% in Clinical Dementia Rating (CDR) 0.5, 1.0, and 2.0, respectively. Persistence of apathy from clinician judgment varied from visit to visit at earlier disease stages but remained high at moderate dementia. Independent of cognition, persistent apathy was strongly associated with accelerated rate of functional decline. DISCUSSION: Findings point to important targets for the treatment and management of apathy, include functional outcomes, and study designs that account for variable persistence of the apathy syndrome.

Design Considerations for Mobile Health Applications Targeting Older Adults.

Mobile technologies are becoming ubiquitous in the world, changing the way we communicate and provide patient care and services. Some of the most compelling benefits of mobile technologies are in the areas of disease prevention, health management, and care delivery. For all the advances that are occurring in mobile health, its full potential for older adults is only starting to emerge. Yet, existing mobile health applications have design flaws that may limit usability by older adults. The aim of this paper is to review barriers and identify knowledge gaps where more research is needed to improve the accessibility of mobile health use in aging populations. The same observations might apply to those who are not elderly, including individuals suffering from severe mental or medical illnesses.

Longitudinal Cognitive Profiles in Diabetes: Results From the National Alzheimer's Coordinating Center's Uniform Data.

BACKGROUND: Diabetes is a risk factor for the development of cognitive impairment and possibly for accelerated progression to Alzheimer disease (AD) and other dementias, though the trajectory of cognitive decline in general and in specfic cognitive domains by diabetes is unclear. METHODS: Using the National Alzheimer's Coordinating Center's Uniform Data Det (NACC-UDS) to identify cohorts of elders with normal cognition (N = 7,663) and mild cognitive impairment (MCI, N = 4,114), we compared overall cognitive composite and domain specific sub-scores and their progression over time between diabetic and non-diabetic subjects. RESULTS: Diabetes was more common among those with MCI (14.7%) than among subjects who were cognitively normal (11.7%). In subjects who were cognitively normal, baseline cognitive composite scores, attention, and executive function sub-scores were lower in diabetics than non-diabetics (by 0.098, 0.066, and 0.015 points, respectively). Over time, cognitive composite score showed subtle worsening in non-diabetics (0.025 points every 6 months), with an additional worsening of 0.01 points every 6 months in diabetics compared to non-diabetics. In the MCI groups, baseline cognitive composite as well as attention and executive domain sub-scores were lower in diabetics than non-diabetics (by 0.078, 0.092, and 0.032 points, respectively). Over time, cognitive composite (by 0.103 points every 6 months) and all domain specific sub-scores showed subtle worsening in non-diabetics, but diabetics had significantly slower worsening than non-diabetics on both cognitive composite (by 0.028 points) and domain specific sub-scores. DISCUSSION: Among elders, diabetes may be associated with lower cognitive performance, primarily in non-memory domains. However it is not associated with continued worsening, suggesting a static deficit with minimal memory involvement. This data suggest that diabetes may contribute more to a vascular profile of cognitive impairment than a profile more typical of AD.

Cognitive performance of older adults in a specialized diabetes clinic.

BACKGROUND: Diabetes mellitus is a risk factor for cognitive changes, but assessment for cognitive disorders in this population is performed infrequently. The present study examined the frequency of cognitive disorders and patterns of deficit in patients enrolled in a specialized clinic for diabetes. METHODS: A cross-sectional study was conducted to assess cognition in Mount Sinai Diabetes Center patients. Thirty eligible subjects aged ≥50 years were assessed and compared with non-diabetic cognitively normal control subjects, as well as non-diabetic subjects with mild cognitive impairment (MCI). The main outcome(s) and measure(s) were obtained through cognitive assessment and diagnosis using the Alzheimer's Disease Centers' uniform data set. RESULTS: Forty percent of subjects were newly diagnosed with a cognitive disorder: 10% were diagnosed with dementia and 30% with MCI. Diabetic subjects performed worse on the Mini-Mental State Examination (27.2 vs 28.4; P = 0.0132), list generation (9.5 vs 12.2; P = 0.0190), Trail Making Test, Parts A (70.1 vs 43.0; P < 0.0001) and B (197.2 vs 123.6; P < 0.0001), and the Digit Symbol test (12.7 vs 40.1; P < 0.0001) than cognitively normal individuals. Compared with subjects with MCI (amnestic type), diabetic subjects performed better on tasks of immediate and delayed recall (11.2 vs 7.3 [P = 0.0048] and 8.4 vs. 4.1 [P = 0.0003], respectively). CONCLUSIONS: Undiagnosed cognitive disorders are common and underappreciated in patients being treated in a specialized diabetes clinic. It may be important to make cognitive assessment a standard part of patient assessments.

Prediction of Relapse After Discontinuation of Antipsychotic Treatment in Alzheimer's Disease: The Role of Hallucinations.

OBJECTIVE: In Alzheimer's disease, antipsychotic medications are often used for a period, with relief of symptoms, and then discontinued, after which relapse may occur. The authors sought to determine which neuropsychiatric symptoms predict relapse. METHOD: In the Antipsychotic Discontinuation in Alzheimer's Disease trial, 180 patients with Alzheimer's disease and symptoms of agitation or psychosis were treated with risperidone for 16 weeks, after which patients who responded (N=110) were randomly assigned to continue risperidone for 32 weeks, to continue risperidone for 16 weeks followed by switch to placebo for 16 weeks, or to receive placebo for 32 weeks. As reported previously, discontinuation of risperidone was associated with a two- to fourfold increased risk of relapse over 16-32 weeks. In planned post hoc analyses, the authors examined associations between the 12 symptom domains in the Neuropsychiatric Inventory (NPI) and relapse in the first 16-week phase after randomization. RESULTS: Compared with patients with mild hallucinations or no hallucinations, patients with severe hallucinations as a presenting symptom at baseline had a higher likelihood of relapse (hazard ratio=2.96, 95% CI=1.52, 5.76). This effect was present for the subgroup with auditory hallucinations, but not the subgroup with visual hallucinations. Among patients with baseline hallucinations, 13 of 17 (76.5%) who discontinued risperidone relapsed, compared with 10 of 26 (38.5%) who continued risperidone (p<0.02). This group difference remained significant for severe (77.8%) compared with mild (36%) hallucinations. NPI domain scores after the initial open-treatment phase were not associated with relapse. CONCLUSIONS: Patients with severe baseline hallucinations were more likely to relapse after randomization, and the presence of baseline hallucinations was associated with a higher risk of relapse after discontinuation of risperidone compared with continued risperidone treatment. For patients with hallucinations, particularly auditory hallucinations, antipsychotic discontinuation should be approached cautiously because of high relapse risk.

Disability reduction in elderly patients with schizophrenia.

This article reviews a frequently overlooked subject, the topic of schizophrenia in late life. By examining the available literature on schizophrenia in this particular population, we hope to provide clinicians with a better understanding of the distinguishing characteristics, course, and optimal treatments of this disease in elderly patients. The validity of the concept of symptom "burn out" is discussed and the cognitive changes seen in schizophrenia as patients age are examined. Similarities and differences between late-onset schizophrenia and early-onset schizophrenia in aging patients are compared. The similarities and differences between schizophrenia and dementia in the elderly are also discussed. Finally, treatments for the illness, including both typical and atypical antipsychotic treatments, as well as nonpharmacological intervention strategies, along with their advantages and disadvantages, are reviewed.

Cognition in non-demented diabetic older adults.

Evidence links diabetes mellitus to cognitive impairment and increased risk of Alzheimer's disease (AD) and suggests that insulin therapy improves cognition. With an increasing percentage of the US elderly population at high risk for diabetes and AD, the evidence of an association between diabetes and poor cognition in non-demented elderly may have implications for diagnosis, prevention and treatment of cognitive decline including AD. In our study, we hypothesized that diabetic elders with normal cognition would demonstrate poorer cognitive outcomes than non-diabetic elders and that diabetic elders receiving diabetes treatment would demonstrate better outcomes than those not receiving treatment. Data were evaluated from the National Alzheimer's Coordinating Center's Uniform Data Set (UDS). The UDS consists of clinical and neuropsychological assessments of a sample of elderly research subjects recruited from thirty-one Alzheimer's Disease Centers nationwide. The UDS provides a unique opportunity to study cognition in a nationally recruited sample with structured neuropsychological tests. We examined the impact of diabetes and diabetes treatment on cognitive measures in 3421 elderly research subjects from 2005-2007 with normal cognition. We performed linear regression analyses to compare cognitive scores between diabetic subjects and non-diabetic subjects. Diabetic subjects had lower scores than non-diabetic subjects including attention, psychomotor function and executive function, but no differences in memory or semantic memory language. There was no association between diabetes treatment and cognitive scores. These subtle but significant cognitive deficits in diabetic subjects compared to non-diabetic subjects may contribute to difficulty with compliance with complex diabetes medication regimens. A specific role of diabetes as a risk for cognitive impairment will require longitudinal study.

Update on neuropsychiatric symptoms of dementia: antipsychotic use.

Antipsychotic medications have a modest effect on the neuropsychiatric symptoms of dementia, but product labels warn of the excess risk of death and morbidity associated with their use in older patients. As such, these agents should not be the first choice for the treatment of behavioral and psychotic symptoms of dementia. Nevertheless, a trial of these agents may be indicated in instances in which the severity of symptoms is extreme, or symptoms do not respond to nonpharmacologic methods or other medications. Most clinical trials in which the efficacy of these agents was studied for the treatment of neuropsychiatric symptoms were of short duration, and thus may not be representative of true efficacy over the long term. There is no evidence to suggest differences in effectiveness between atypical and conventional antipsychotics; therefore, the choice of an antipsychotic for neuropsychiatric symptoms often relies on side effect profile and individual patient circumstances. Extrapyramidal symptoms and QTc prolongation are concerns with conventional antipsychotic agents. The incidence of cerebrovascular events with either atypical or conventional antipsychotics appears increased compared with placebo. A discussion of the risk-benefit ratio of antipsychotics with the patient's family and/or caregivers should precede the decision to use these agents.