Background/Rationale: Accumulating evidence suggests that the use of angiotensin-converting enzyme inhibitor (ACE-I) medication protects against cognitive decline in the elderly patients. We investigated whether ACE-I use was associated with higher plasma levels of amyloid-β (Aβ), possibly indicating improved Aβ clearance from brain to blood. Methods: We measured and compared plasma concentrations of Aβ42, Aβ40, and creatinine in cognitively impaired individuals with amnestic mild cognitive impairment, probable Alzheimer’s disease (AD) dementia, and mixed probable AD/vascular dementia. Results: Plasma Aβ42 levels and Aβ42/Aβ40 ratios of participants taking ACE-Is (n = 11) significantly exceeded ( t = 3.1, df = 19, P = .006; U = 24, P = .029, respectively) those not taking ACE-Is (n = 10). Conclusions: This study is the first to show an association between ACE-I use and increased plasma Aβ42 level and Aβ42/Aβ40 ratio in cognitively impaired individuals. Future investigations should assess whether a possible ACE-I-induced increase in plasma Aβ42 indicates improved Aβ42 clearance from brain that contributes to protection from cognitive decline.

IMPORTANCE:Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD.OBJECTIVE:To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor.DESIGN, SETTING, AND PARTICIPANTS:Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers.INTERVENTIONS:Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152).MAIN OUTCOMES AND MEASURES:Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures.RESULTS:Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants).CONCLUSIONS AND RELEVANCE:Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden.TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00235716.

Background: Alzheimer's disease (AD) has been associated with both oxidative stress and excessive glutamate activity. A clinical trial was designed to compare the effectiveness of (i) alpha-tocopherol, a vitamin E antioxidant; (ii) memantine (Namenda), an N-methyl-D-aspartate antagonist; (iii) their combination; and (iv) placebo in delaying clinical progression in AD.Methods: The Veterans Affairs Cooperative Studies Program initiated a multicenter, randomized, double-blind, placebo-controlled trial in August 2007, with enrollment through March 2012 and follow-up continuing through September 2012. Participants with mild-to-moderate AD who were taking an acetylcholinesterase inhibitor were assigned randomly to 2000 IU/day of alpha-tocopherol, 20 mg/day memantine, 2000 IU/day alpha-tocopherol plus 20 mg/day memantine, or placebo. The primary outcome for the study is the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory. Secondary outcome measures include the Mini-Mental State Examination; the Alzheimer's Disease Assessment Scale, cognitive portion; the Dependence Scale; the Neuropsychiatric Inventory; and the Caregiver Activity Survey. Patient follow-up ranged from 6 months to 4 years.Results: A total of 613 participants were randomized. The majority of the patients were male (97%) and white (86%), with a mean age of 79 years. The mean Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory score at entry was 57 and the mean Mini-Mental State Examination score at entry was 21.Conclusion: This large multicenter trial will address the unanswered question of the long-term safety and effectiveness of alpha-tocopherol, memantine, and their combination in patients with mild-to-moderate AD taking an acetylcholinesterase inhibitor. The results are expected in early 2013. (C) 2014 The Alzheimer's Association. All rights reserved.

Objectives: This study examines how surrogate decision makers for dementia patients developed an understanding of patient preferences about end-of-life (EOL) care and patient wishes. Methods: Semistructured interviews were conducted with 34 surrogate decision makers for hospice-eligible nursing home patients with dementia. The data were content analyzed. Results: Most surrogates reported that patients had previously completed an advance directive (59%), discussed preferences for EOL care (56%), or done both (38%). Catalysts for and barriers to completing an advance directive or having EOL care discussions included factors that were both intrinsic and extrinsic to the patient. The most commonly reported wish for EOL care was to not be kept alive by "machines" or "extraordinary measures." Discussion: Health care providers may be able to assist patients and families by normalizing discussions of dying, encouraging advance care planning, helping them identify goals for EOL care, and providing information to support treatment decisions consistent with patients' wishes.

To describe medication usage in nursing home residents with advanced dementia, to identify how this usage changed as patients advanced towards death, and to identify correlates of increased medication usage.

OBJECTIVETo determine rates of depression by dementia status in a statewide sample of nursing home admissions, and associations with medical comorbidity and physical functioning.METHODSTrained interviewers obtained information from nursing home residents, staff, significant others, and medical records.RESULTSA total of 22.3% were classified depressed in the nondemented status and 23.6% in the demented status. Depression status was significantly associated with more physical dependencies regardless of dementia status. In the nondemented, there was also a significant positive association with number of comorbidities. One interaction, dementia with comorbidity at the highest levels of comorbidity, was significant in looking at association with depression.CONCLUSIONThere is significant depressive symptomatology in nursing home admissions, which is also associated with difficulty in physical function and with the number of medical comorbidities in the nondemented. Application of the two measures used in this study represents a strategy to assess depression in all nursing home residents.

This study describes the health problems and comorbid illnesses of nursing home (NH) residents with advanced dementia (n=123) and identifies correlates of staff-identified pain. Study participants were residents of 3 NHs in Maryland, their surrogate decision makers and their physicians. Residents' cognitive function was assessed at study enrollment, and their medical records were reviewed to identify all health problems/illnesses and use of pain medications during the 6 months before their enrollment. The most prevalent health problems were skin problems (95%), nutrition/hydration problems (85%), psychiatric/behavioral problems (85%), gastrointestinal problems (81%), and infections (80%). Sixty-three percent of residents had recognized pain, and 95% of those residents received pain medications. In a multivariate regression analysis, staff-identified pain was associated with aspiration (P=0.008), peripheral vascular disease (P=0.021), musculoskeletal disorders (P=0.032), higher cognitive function (P=0.013), and use of pain medications, including nonopiates (P=0.004) and the combination of opiates and nonopiates (P=0.001). NH residents with advanced dementia experience a complex mixture of multiple chronic and acute comorbidities. These results suggest the need for clinicians in long-term care facilities to be vigilant in assessing and treating pain, particularly as cognitive function declines in those with advanced dementia.

OBJECTIVE:Despite the high rate of psychiatric disorders in nursing homes, research indicates that psychiatric consultation is requested infrequently. The authors sought to determine the rate of psychiatric consultation in a nursing home population and to assess what factors were related to a consultation request. METHODS:Subjects were recruited from a stratified random sample of 59 nursing homes across Maryland. All new admissions age 65 years and older from September 1992 through March 1995 were eligible for the study. A total of 2,285 subjects were included in the study. Variables examined were factor scores from the Cornell Scale for Depression in Dementia and the Psychogeriatric Dependency Rating Scale (Behavioral Subscale), nursing home characteristics, and whether the resident had a psychiatric consultation within 90 days of admission. RESULTS:Twenty percent of the residents (N=404) had a psychiatric consultation. There was no significant association with demographic variables. Behaviors that triggered a psychiatric consultation included agitation, physical/verbal abuse, wandering, and manic/destructive acts. A psychiatric consultation was also requested when residents displayed anxiety. Surprisingly, depression in retarded and psychotic residents did not trigger a psychiatric consult. CONCLUSION:As expected, behavioral problems and agitation are common reasons for a psychiatric consultation. However, the resident who is depressed, particularly the quiet or retarded depressed resident, may be overlooked. In this context, it is important for the nursing staff to recognize that lethargy and social withdrawal may be signs of depression, and a referral to a psychiatrist may be in order.

Adults with cognitive impairment are considered a vulnerable population. The conditions associated with cognitive impairment, such as dementia and delirium, cause great suffering to affected patients and their families. Improving clinical care for these conditions depends on research involving cognitively impaired participants. Cognitive impairment is at times associated with partial or full impairment of the capacity to consent to research. This both limits the ability of the individual to consent personally to research participation, and also increases pressure upon Institutional Review Boards (IRBs) and investigators to place additional safeguards for the appropriate participation of cognitively impaired individuals in research. While the ethical and legal principles permitting and safeguarding the participation of cognitively impaired persons in research are generally agreed upon, there are no specific methods that operationalize these principles in a language that can be used by IRBs and researchers to guide their day-to-day work in this area. This document contains recommendations that IRBs and investigators can use to operationalize the informed consent process for individuals with cognitive impairment. In situations in which IRBs might not have specific policies in this area, this guideline may also serve as the foundation for such policies. The recommendations discuss when to consider that cognitively impaired participants might be involved in a research project, the use of screening for cognitive impairment, the conduct of assessments evaluating capacity to consent to research, situations in which proxies might consent for research participation in the place of cognitively impaired participants, how to go about identifying appropriate proxies, and how to deal with the loss of consent capacity in the course of a research project.

Agitation is a serious problem for elderly individuals with dementia. It is often the major reason for admission to a restrictive environment such as a nursing home or hospital. The objectives of the current study were to (1) identify the components of agitation embedded in the Psychogeriatric Dependency Rating Scale (PGDRS) and (2) find race, gender, depression, and cognitive deficits associated with the factors extracted from the PGDRS in demographic variables and clinical variables. The study sample comprised 2285 subjects who were admitted to 59 nursing homes across Maryland. The factor analysis of the PGDRS confirmed that agitation is made up of a number of different elements ranging from physical and/or verbal aggression to wandering. Correlates of these elements varied, as did possible treatments. For example, physical and/or verbal aggression often accompanied severe depression, suggesting that treating the depression may alleviate this problem. However, wandering and psychotic behavior may be less amenable to existing treatments as these behaviors were associated with severe cognitive impairment. ( J Geriatr Psychiatry Neurol 2003; 16:4-7).

Editor Cornelia Cremens, MD Massachusetts General Hospital Boston, Massachusetts

Verbal and physical aggression are common behavior problems among nursing home residents with dementia. Depression among nursing home residents is also a common but underdiagnosed disorder.

Pilot studies indicate that dementia is under-diagnosed in primary care clinics. One reason for this under-diagnosis is the lack of a "gold standard" screening tool that is brief and easy to use in the primary care setting. The purpose of this study is to compare four different rating scales. Methods: 66 patients over age 65 were randomly recruited from a primary care clinic at the Baltimore VA. A trained research assistant completed four rating scales: the MMSE, the Blessed Orient-Memory-Concentration Test (BOMC), the Functional Activities Questionnaire (FAQ), and the Symptom Screen for Dementia (SSD). The first of these two scales (MMSE and BOMC) are patient-rated, and the other two (FAQ and SSD) are informant-rated. The BOMC and the FAQ are shorter forms than the MMSE and SSD. Results: There was a strong correlation (r=−0.674, P<0.0005) between scores on the MMSE and BOMC, the two patient-rated scales. There was also a strong correlation (r=0.895, P<0.005) between scores on the FAQ and SSD, the two informant rated scales. There was only a moderate correlation (r=−0.353, P<0.005) between the BOMC and FAQ. Only 6% of subjects tested positive for probable dementia as evidenced by a score of 10 or above on the BOMC, and a score of 9 or higher on the FAQ. Twenty six percent of subjects reached the cutoff score for one but not both of these measures. Conclusions: There were strong correlations between the BOMC and MMSE, and the FAQ and SSD suggesting that these shorter scales could be used for preliminary screening of cognitive impairment in primary care settings. The relatively low correlation between the BOMC and FAQ, as well as the large percentage of subjects who reached the cutoff score on one but not both of these scales, suggests that both patient-rated and informant-rated scales might be necessary to optimize identification of primary care patients with cognitive impairment. P33

The "Predictors Study" is a prospective cohort study of the natural history of Alzheimer disease (AD), the aim of which is to identify milestones in disease progression and to develop a model to predict disease course in individual patients. The empirical background to this study is based on previous reports that the presence of extrapyramidal signs (EPS), myoclonus, and psychosis in AD may signify greater disease severity at any given stage and a more rapid course of the disease over time. The present analyses were conducted to determine whether these independent "predictor" variables were associated with greater disease severity at baseline within a new cohort of 224 mild AD patients recruited from three different medical centers (in New York, Baltimore, and Boston). Measures of disease severity were provided by the modified Mini-Mental State Examination (mMMSE) and the Blessed Dementia Rating Scale (BDRS), which measures functional capacity. Independent variables were EPS, delusions, and slowing of the posterior dominant EEG rhythm. The frequency of myoclonus and hallucinations was too low to permit adequate statistical assessment of their effects at this time. EPS and EEG slowing were associated with low mMMSE scores, whereas delusions were primarily associated with impaired functional capacity. These effects were independent of the influence of age and disease duration. These results indicate that the effects of these independent variables can be detected at mild stages of AD and that these effects can be generalized across different geographical regions.

Clinicians should be able to provide the patient with Alzheimer disease (AD) and the family with an accurate prediction of what to expect, but the variability in the rate of disease progression precludes this. In several previous studies, specific clinical signs such as muscular rigidity, myoclonus, and hallucinations or delusions were associated with rapid progression to a more severe stage of dementia or death. The “Predictors Study,” a longitudinal study at three independent sites, was designed to develop a predictor model of the natural history of Alzheimer disease. The study was conducted at three study sites, New York, Baltimore, and Boston in a cohort of 224 patients with early probable AD. This article describes the design and implementation of the Predictors Study, and compares features of the study cohort at baseline across sites. Patients were all at the mild stage of disease at entry and were relatively comparable across sites. Extrapyramidal signs and delusions were common, but myoclonus was rarely observed.