Krista L. Lanctot - US grants

5-HT(1A) Receptor; 5-HT1A Receptor; Activities of Daily Living; Activities of everyday life; Age; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Animals; Area; Behavior; Bilateral; CRISP; Cognition; Communities; Computer Retrieval of Information on Scientific Projects Database; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Drugs; Dysfunction; Functional disorder; Funding; Grant; Human; Human, General; Injection of therapeutic agent; Injections; Institution; Investigators; Location; MR Imaging; MR Tomography; MRI; MRI Scans; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Man (Taxonomy); Man, Modern; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medical Imaging, Positron Emission Tomography; Medication; NIH; NMR Imaging; NMR Tomography; National Institutes of Health; National Institutes of Health (U.S.); Nuclear Magnetic Resonance Imaging; Numbers; Occipital lobe; PET; PET Scan; PET imaging; PETSCAN; PETT; Parietal; Participant; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiopathology; Play; Positron; Positron Emission Tomography Scan; Positron-Emission Tomography; Primary Senile Degenerative Dementia; Proton Magnetic Resonance Spectroscopic Imaging; Rad.-PET; Receptor Protein; Receptor, 5-Hydroxytryptamine 1A; Receptor, Serotonin, 5-HT1A; Recruitment Activity; Research; Research Personnel; Research Resources; Researchers; Resources; Role; Scans, MRI; Screening procedure; Serotonin 1A Receptor; Source; System; System, LOINC Axis 4; Therapeutic; Time; United States National Institutes of Health; Zeugmatography; brain atrophy; cerebral atrophy; cognitive function; cortical atrophy; daily living functionality; dementia of the Alzheimer type; drug/agent; functional ability; functional capacity; interest; intravenous injection; neuropsychiatric; neuropsychiatry; occipital cortex; pathophysiology; primary degenerative dementia; receptor; recruit; screening; screenings; senile dementia of the Alzheimer type; sex; social role; therapeutic target; tomography

DESCRIPTION (provided by applicant): Apathy in Alzheimer's dementia (AD) is a significant public health problem with serious adverse consequences for patients and caregivers. Apathy affects approximately 70% of AD patients, making it one of the most common neuropsychiatric symptoms (M. S. Mega, Cummings, Fiorello, &Gornbein, 1996;Steinberg et al., 2006;Steinberg et al., 2007). Despite the high prevalence of apathy in AD, there are no proven treatments for this condition. While non-pharmacologic treatments have been understudied, clinical experience suggests reliable but limited efficacy. Recent studies have begun to explore pharmacologic options, such as cholinesterase inhibitors (ChEIs). But ChEIs appear to be non-specific to apathy and findings regarding their efficacy have not been widely replicated. Antidepressant medications have also been considered as an option, but some evidence suggests that they could be detrimental rather than helpful in the treatment of apathy in AD. Therefore, better pharmacologic options are urgently needed for the treatment of apathy in AD. Dopaminergic agents show promise as treatments for apathy in AD. The rationale for their use is based on the strong tie between activity of the dopaminergic mesolimbic brain reward system and the expression of motivated behaviors in brain damaged populations. Evidence for the use of dopaminergic agents also comes from case reports and small open-label studies in nondemented populations. Preliminary data from a double blind, placebo controlled single-site crossover pilot study suggest that the dopamine agonist methylphenidate was superior to placebo for the treatment of apathy in AD (Lancttt, in press). The goal of the proposed Apathy in Dementia Methylphenidate Trial (ADMET) is to expand upon this encouraging preliminary work by evaluating methylphenidate for the treatment of AD patients with apathy. This study will employ a multi-site, parallel, randomized, double-blind, placebo-controlled design. It will bring together investigators who have collaborated successfully in the execution of the ongoing Depression in Alzheimer's Disease study (DIADS-2) and the completed Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE-AD). ADMET will examine the efficacy and safety of methylphenidate for the treatment of clinically significant apathy in AD patients. It will be a double-blind, 6 week, randomized, placebo-controlled trial involving 100 patients with AD. ADMET will enroll AD patients from outpatient, nursing home, and assisted living settings. This project is of great importance because it will explore the efficacy and safety of a promising dopamine agonist for treating apathy in AD, where there are no proven treatment options. Should methylphenidate be found effective, it will likely become a first line therapy for apathy in AD. In addition, by examining predictors of response, ADMET will lay the foundation for future studies to understand the mechanisms involved in the effects of methylphenidate and other dopamine agonists on apathy. PUBLIC HEALTH RELEVANCE: The 5 million Americans who suffer from Alzheimer's disease (AD) experience a lack of independence that contributes to the large emotional and economic costs of this disease. Apathy is one of the most common behavioral symptoms of AD and although it is thought to be one of the few potentially treatable causes of dependency in AD, currently there are no effective treatments for apathy. This study aims to develop a new treatment for apathy in AD that could decrease its debilitating consequences and reduce patients'dependency on caregivers, providing well-deserved relief to patients and their loved ones.

DESCRIPTION (provided by applicant): Apathy is defined as a loss of will and initiative, lack of interest in activities, lack of productivity, as well as limited affective response to positive r negative elements . Apathy is one of the most common neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD), affecting approximately 70% of AD patients and resulting in serious adverse consequences for patients and caregivers. Apathetic patients are also more likely to require institutionalization, the largest single driver of direct costs in AD. Despite the high prevalence of apathy in AD and its serious consequences, there are no proven treatments for this condition. Nonpharmacologic strategies appear to have limited effects on apathy in AD, as do current FDA-approved medications for AD such as cholinesterase inhibitors. Recently, new research has suggested the involvement of dopamine pathways in the biology of apathy in AD and the potential value of dopamine enhancers, such as methylphenidate, for the treatment of this condition. Moreover, we have recently reported the results of two six- week randomized controlled trials showing a clear benefit of methylphenidate over placebo in treating apathy in AD, as well as potential cognitive benefits of methylphenidate and a favorable safety/tolerability profile. [However, a number of key questions relevant for clinical practice were not answered by these studies. For example, is the treatment effective and safe beyond six weeks in a larger sample? Can the potential cognitive benefit of methylphenidate be reproduced and remain clinically significant in this population? Can the combination of a decrease in apathy and an improvement in cognition be translated to clinically significant functional change? Does the treatment of apathy in AD have an impact on subject quality of life and pharmacoeconomics? We propose to address these questions by conducting a multi-site, parallel, randomized, double-blind, placebo-controlled study evaluating methylphenidate for the treatment of apathy in AD patients (Apathy in Dementia Methylphenidate Trial-II (ADMET II)) in a larger sample, over a more extensive period of time and employing a concise battery of neuropsychological tests optimized for apathetic AD patients. The ultimate goal is to collect evidence strong enough to support a change in clinical practice. This trial will bring together a team of investigators who have collaborated successfully in the execution of the first ADMET study as well as other clinical trials exploring treatments for neuropsychiatric symptoms of dementia.]