Lucy Y. Wang

Prazosin for the Treatment of Behavioral Symptoms in Patients With Alzheimer Disease With Agitation and Aggression

OBJECTIVES Agitation/aggression in Alzheimer disease (AD) is a major cause of patient distress, caregiver burden, and institutionalization. Enhanced behavioral responsiveness to central nervous system norepinephrine (NE) release may contribute to the pathophysiology of agitation/aggression in AD. Prazosin, a nonsedating generic medication used for hypertension and benign prostatic hypertrophy, antagonizes NE effects at brain postsynaptic alpha-1 adrenoreceptors. This pilot study examined the efficacy and tolerability of prazosin for behavioral symptoms in patients with agitation/aggression in AD. DESIGN Double-blind, placebo controlled, parallel group study. SETTING A university AD center and a nursing home in Seattle, WA. PARTICIPANTS Twenty-two nursing home and community-dwelling participants with agitation/aggression and probable or possible AD (mean age: 80.6 +/- 11.2). INTERVENTION Randomization to placebo (N = 11) or prazosin (N = 11). Medication was initiated at 1 mg/day and increased up to 6 mg/day using a flexible dosing algorithm. MEASUREMENTS The Brief Psychiatric Rating Scale (BPRS) and Neuropsychiatric Inventory (NPI) at Weeks 1, 2, 4, 6, and 8. The Clinical Global Impression of Change (CGIC) at Week 8. RESULTS Participants taking prazosin (mean dose: 5.7 +/- 0.9 mg/day) had greater improvements than those taking placebo (mean dose: 5.6 +/- 1.2 mg/day) on the NPI (mean change: -19 +/- 21 versus -2 +/- 15, chi = 6.32, df = 1, p = 0.012) and BPRS (mean change: -9 +/- 9 versus -3 +/- 5, chi = 4.42, df = 1, p = 0.036) based on linear mixed effects models and the CGIC (mean: 2.6 +/- 1.0 versus 4.5 +/- 1.6, z = 2.57, p = 0.011 [Mann-Whitney test]). Adverse effects and blood pressure changes were similar between prazosin and placebo groups. CONCLUSION Prazosin was well tolerated and improved behavioral symptoms in patients with agitation/aggression in AD.

ABCB1 Genotype and CSF β-Amyloid in Alzheimer Disease

The ABCB1 gene, coding for the efflux transporter P-glycoprotein (PGP), is a candidate gene for Alzheimer disease (AD). P-glycoprotein is heavily expressed at the blood—brain barrier, where it mediates the efflux of β-amyloid (Aβ) from the brain. In this study, we investigated a possible association between 2 common ABCB1 polymorphisms, G2677T/A (Ala893Ser/Thr) and C3435T, AD, and cerebrospinal fluid (CSF) levels of Aβ. No strong evidence for association was found.

Common Psychiatric Problems in Cognitively Impaired Older Patients Causes and Management

Although dementias are defined by their cognitive and functional deficits, psychiatric problems are common, contribute to patient distress and caregiver burden, and precipitate institutionalization. Successful treatment involves understanding that physiologic, psychological, and environmental factors can contribute to the development of these symptoms. By carefully assessing each of these factors, clinicians can individualize treatment and flexibly use nonpharmacologic and pharmacologic approaches tailored to patients and the context of care. Although there exist limitations to many treatment options, clinicians can still adapt current knowledge to develop a multifaceted treatment approach that improves the quality of life for patients and their caregivers.

Cognitive Impairment in Older Adults Without Dementia: Clinical and Pathologic Outcomes in a Community-Based Sample

This study examines clinical and neuropathologic characteristics of 37 participants in a community-based dementia series who had cognitive complaints at enrollment but did not meet dementia criteria. Participants had neuropsychological testing, were followed until death, and underwent autopsy. Twenty-four participants progressed to dementia, and their baseline characteristics were analyzed. Of the 24, 13 met criteria for neuropathologic Alzheimer disease (AD). The 13 participants who progressed to neuropathologic AD (mean intake age 78.5 ± 7.7, mean enrollment 6.4 ± 2.1 years) performed worse than the 11 who progressed to neuropathologic non-AD dementias (mean intake age 79.0 ± 6.0, mean enrollment 6.0 ± 3.2 years) on baseline Wechsler Memory Scale (WMS) delayed logical memory (3.4 ± 2.9 vs 6.3 ± 3.9, P = .05) and delayed visual reproduction (1.4 ± 2.1 vs 3.1 ± 2.7, P = .02). These observations are consistent with the view that nondemented patients with underlying AD may be more likely to present with memory than nonmemory cognitive impairment.

Antipsychotic drugs for psychosis and agitation in dementia: efficacy, safety, and a possible noradrenergic mechanism of action.

The first patient described by Alzheimer in 1907 had both progressive cognitive deterioration and prominent comorbid signs and symptoms of psychosis and agitation (Alzheimer, 1907, 1987). In this editorial, we use “psychosis” to denote delusions and hallucinations and “agitation” to denote irritability, aggression, pressured motor activity, and active resistance to necessary care. Although advances have been made in the treatment of these non-cognitive symptoms, these psychosis and agitation symptoms continued to be burdensome and costly for dementia patients, caregivers, and society. Among the pharmacologic treatments available for psychosis and agitation, antipsychotic drugs are the drug class most consistently demonstrated effective for psychosis and agitation in dementia (Lyketsos et al ., 2006; APA Work Group on Alzheimers Disease and Other Dementias et al ., 2007). These are widely prescribed for these behavioral problems, but their use remains controversial and their mechanism of action unclear.

Blood Pressure and Brain Injury in Older Adults: Findings from a Community-Based Autopsy Study: BLOOD PRESSURE AND DEMENTIA NEUROPATHOLOGY

OBJECTIVES: To examine correlations between blood pressure (BP) and dementia‐related pathological brain changes in a community‐based autopsy sample.

Blood pressure and brain injury in older adults

OBJECTIVES: To examine correlations between blood pressure (BP) and dementia‐related pathological brain changes in a community‐based autopsy sample.

Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia

This study evaluated the effects of Alzheimer disease (AD) on the relationship between the brain noradrenergic system and hypothalamic pituitary adrenocortical axis (HPA). Specifically, relationships between cerebrospinal fluid (CSF) norepinephrine (NE) and CSF cortisol were examined in cognitively normal participants and participants with AD dementia and amnestic mild cognitive impairment (aMCI). We hypothesized that there would a positive association between these 2 measures in cognitively normal controls and that this association would be altered in AD.

CSF F2-ISOPROSTANES, NOREPINEPHRINE, AND COGNITIVE FUNCTION IN COGNITIVELY NORMAL ADULTS

COGNITIVE FUNCTION IN COGNITIVELY NORMAL ADULTS Elaine R. Peskind, Ge (Gail) Li, Charles W. Wilkinson, Jane Shofer, Lucy Y. Wang, Carl Sikkema, Joseph F. Quinn, Douglas Galasko, Murray A. Raskind, Thomas J. Montine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington, United States; University of Washington, School of Medicine, Seattle, Washington, United States; University of Washington, Seattle, Washington, United States; VA Puget Sound Health Care System, Seattle, Washington, United States; 5 Oregon Health and Sciences University and Portland VA Medical Center, Portland, Oregon, United States; University of California San Diego, La Jolla, California, United States. Contact e-mail: gli@u.washington.edu

P2-277: Prazosin for treatment of disruptive agitation in Alzheimer's disease

component in studying AD. Not much is known about the effects of inclusion of lumbar punctures (LP) in clinical trials on the recruitment of participants, especially those who are asymptomatic. Evaluating recruitment efforts for trials with LPs is essential in determining if a protocol that includes CSF analysis can be accomplished. Objective: To discuss recruitment results for a clinical trial in which lumbar puncture procedures are part of study participation. Reasons for declining participation are described. Methods: Cognitively healthy, middle-aged adult children (ages 35-69) of persons with AD were contacted to participate in this 9 month clinical trial with 5-7 study visits. Study participation involves evaluating the effects of the study medication, simvastatin, on blood, CSF, MRI and cognitive biomarkers of AD. Individuals were recruited through the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study, community outreach, memory clinics, internet postings, mailings, and newsletters. Chi-square tests were used to assess differences between groups. Re ults: Currently, 90 individuals of the targeted 100 have been enrolled. 108 individuals declined. Leading reasons for declining participation included the following: did not meet study inclusion criteria (n 43 [40%]); declined LP (n 18 [17%]); inconvenience (time and travel) (n 15 [14%]). The number of persons declining LP was significantly less than the number not meeting study inclusion criteria (p 0.0001), yet similar to the number of persons who did not want to participate due to the inconvenience (p 0.705). More women (n 74) than men (n 34) demonstrated interest in research (p 0.001). There were no differences in reasons for declining participation between women and men. Conclusions: Lumbar puncture procedures are not a significant barrier to successful recruitment of research participants into clinical trials aimed at studying biomarkers for AD prevention in asymptomatic adults at risk for disease. While women were more likely to express interest in participating in clinical trials, reasons for declining participation were similar between both groups of men and women.