Psychosis in Alzheimer disease: towards an integrated research agenda

Featured Research Session F1-02: Neuropsychiatric Symptoms in Neurodegenerative Disease Juvenile or early forms dementia do not differ histologically from diffuse forms of senile dementia except that cotton wool plaques can be found in a subset. However brain weight is lower, the spinal cord can be affected as well and the parietal cortex is more prominently affected in AD cases with early onset.

SUNDAY, JULY 17, 2011 FEATURED RESEARCH SESSION F1-02 NEUROPSYCHIATRIC SYMPTOMS IN NEURODEGENERATIVE DISEASE Chairs: David Miller, United BioSource Corporation, Wayne, Pa., United States Constantine Lyketsos, Johns Hopkins Bayview Medical Center, Baltimore, Md., United States F1-02-01

PSYCHOSIS IN ALZHEIMER DISEASE: TOWARDS AN INTEGRATED RESEARCH AGENDA

Robert Sweet, University of Pittsburgh, Pittsburgh, Pa., United States. Background: The Alzheimer’s Association established a PIA to facilitate discourse on neuropsychiatric syndromes (NPS). Alzheimer’s disease with Psychosis (AD+P) is a major focus of care and of research on NPS. Methods: An expert panel on psychosis in AD reviewed research progress to date and outlined a future research agenda. Results: Previous studies have evaluated instruments assessing psychosis and its clinical correlates in AD. Widely replicated associations of AD+P include greater cognitive burden, more rapid cognitive deterioration, excess disability, and increased aggressive behavior. Additional associations with increased institutionalization and caregiver distress are documented. “Psychosis in Alzheimer’s Disease” criteria have been proposed (Jeste and Finkel 2000), but require validation. The efficacy of pharmacotherapy for AD+P is not established yet evidence for toxicity is clear. Strong evidence indicates that AD+P is familial, with three independent replications. Limited evidence estimates the heritability of psychosis in AD at 61%. No genetic loci are clearly linked or associated with AD+P, though substantial evidence suggests APOE e4 alleles are not associated. Structural brain imaging studies have implicated frontal, parietal and temporal lobe abnormalities in white and gray matter, as well as possible asymmetries in frontal and temporal volumes in AD+P. Functional imaging has suggested reduced blood flow in frontal and parietal regions. Magnetic resonance spectroscopy may also be an avenue for future work. Neuropathologic studies have not found associations between AD+P and aggregated beta-amyloid, though increased hyperphosphorylated tau has been reported. AD+P has been associated with reciprocal changes in neocortical pre- and post-synaptic muscarinic receptors. Single studies have found excess synaptic disruption in neocortex and other monoamine receptors in neocortex and striatum. Numerous, mainly small, cohort studies and RCTs have demonstrated the value of psychological and other non-pharmacological treatments for NPS in AD. However, few analyses specifically address the treatment of psychosis, which could be remedied via more extensive analysis of already completed trials. Conclusions: Research is needed to characterize the neurobiology of AD+P through integration of genetic, neuroimaging, and postmortem approaches, leveraging the rapid advances in knowledge of the neurobiology of AD. Concurrently, better assessment tools for late-stage illness and new non-pharmacologic treatment strategies are needed. F1-02-02

SLEEP IN ALZHEIMER’S DISEASE: TOWARDS AN INTEGRATED RESEARCH AGENDA

Sonia Ancoli-Israel, University of California, San Diego, La Jolla, Calif., United States.

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Background: The Alzheimer’s Association has established a Professional Interest Area (PIA) as a platform for scientific discourse on the topic of neuropsychiatric syndromes (NPS) in neurodegenerative diseases. The focus of this workgroup is sleep, one of the more common NPS among patients with Alzheimer’s disease (AD). Methods: A panel of experts in sleep and dementia was assembled to discuss research progress to date and outline a future research agenda. Results: There is agreement in the field of sleep medicine that patients with AD have many sleep disorders including insomnia, sleep disordered breathing (SDB), restless legs syndrome/periodic limb movements in sleep and circadian rhythm disturbances; however much of these data are from cross-sectional studies. While there are treatments available for many of these sleep disorders in the general population, few have been tested in patients with AD. A handful of recent studies have been conducted on the relationship between poor sleep and cognitive function and on behavioral treatments of some sleep disorders. However, the treatment studies all suffer from similar limitations such as small sample sizes. Sedative/hypnotic medications known to improve sleep in non-demented elderly populations have not been adequately tested in AD. A research agenda that attempts to identify promising behavioral and pharmaceutical treatments in randomized clinical trials needs to be developed. In addition, longitudinal studies of sleep disorders and cognitive impairment need to be conducted to better define causal pathways. The panel of experts will review the research to date in terms of identification and treatment of sleep problems in patients with AD, including diagnosis, clinical assessment and treatment. It will also define the future direction of the study of sleep disorders in AD. Conclusions: Much research is still needed in all areas of sleep disorders in AD. The research agenda to be outlined by this panel of experts will help guide future studies and facilitate a better understanding of this NPS in AD.

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DEPRESSION IN THE MILD BEHAVIORAL IMPAIRMENT (MBI), MILD COGNITIVE IMPAIRMENT (MCI), ALZHEIMER’S DISEASE (AD) SPECTRUM: PRIORITIES FOR CLINICAL AND NEUROBIOLOGICAL RESEARCH

Gwenn Smith, Johns Hopkins University, Baltimore, Md., United States. Background: The importance of improving diagnostic criteria and outcome measures for depressive symptoms (DS), for understanding the neurobiological substrates, and for developing more effective treatments has been an increasing focus of clinical and neurobiological research for the past decade. The public health significance of DS is underscored by the observations of the high prevalence of DS in MCI and AD; the prognostic significance of DS in normal aging and MCI and the limited efficacy of using approved treatments developed to treat DS in younger individuals. Methods: To continue the productive discussion following the 2010 Alzheimer’s Association Research Roundtable on neuropsychiatric symptoms (NPS), a Professional Interest Area (PIA) was established and five workgroups organized for specific NPS. The depression workgroup included participants with diverse expertise in psychiatry, clinical trials, psychopharmacology and neuroscience (animal models/neuroimaging/ neuropathology), who were affiliated with academia, government (NIH) and the pharmaceutical industry. Results: The following areas for interdisciplinary research were identified: 1) Is the construct of depression stable or dynamic over time? Can the same criteria be applied and assessment instruments used in normal aging, MCI and AD? 2) Should depression be considered a syndrome or will a dimensional approach to study depression across multiple levels of analysis (genes, circuits, behavior) be more useful, as outlined in the NIMH Research Domain Criteria project (RDoC)? 3) Do the same neurobiological mechanisms underlie DS in normal aging, MCI and AD? How can an understanding of alterations in affective neural circuitry, neurotransmitter modulation, synaptic plasticity and relationship to AD pathology inform the development of more effective treatments, such as combination pharmacologic treatments (e.g. targeting multiple monoamine