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Monday, December 4, 2006 Poster Session I Neuropsychopharmacology (2006) 31, S70-S135 © 2006 Nature Publishing Group All rights reserved 0893-133X/06 S70 www.neuropsychopharmacology.org Monday, December 4, 2006 pared to placebo, with a similar incidence of AEs (78.1% vs. 76.0%). Poster Session I No trend in type of AEs was observed across trials. Compared to placebo, donepezil treatment was associated with a greater rate of dis- continuation in most individual trials (overall: 23.0% vs. 19.8%), a 1. Neuropsychological Performance and Vascular Function in higher rate of discontinuations due to AEs (14.0% vs. 8.8%), and Patients with Atherosclerotic Vascular Disease higher incidence of AEs (80.8% vs. 73.5%). Diarrhea was associated David J. Moser*, Robert G. Robinson, Stephanie M. Hynes, Rebecca with donepezil treatment across trials, as was vomiting in two of the L. Reese, Stephan Arndt, Jane S. Paulsen and William G. Haynes four studies. Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Discussion: In treatment of patients with moderate to severe AD, IA, USA donepezil use was associated with gastrointestinal symptoms. No such trends were seen in the treatment of patients with memantine. Sponsor: Past Travel Awardee, Young Investigator Memorial, 2004 Given the low number of trials and limitations of comparing treat- Background: Forearm vascular function is reflective of general vas- ments between separate trials, prospective studies directly comparing cular health in patients with atherosclerotic vascular disease (AVD). memantine and donepezil would be required to properly address tol- Indeed, all known risk factors for AVD are also associated with re- erability differences between the two drugs. duced vascular function. We previously reported preliminary data (N = 14) that demonstrated a significant relationship between forearm 3. White Matter Integrity in Aging – Linking Vascular Risk and vascular function and neuropsychological performance in individu- Cognition to the Brain als with AVD. The current study was conducted to confirm and ex- Kelvin O. Lim*, Laura S. Hemmy, Lars Bäckman, Lars-Olof tend those findings in a much larger, non-overlapping sample. Wahlund, Yi Zhang, Huxin Wang, Åsa Livner, Anders Frank, Stuart Methods: Participants were 82 individuals with AVD, with no history MacDonald and Laura Fratiglioni of stroke, cardiac surgery, or dementia. Forearm vascular function was measured before and after brachial artery infusion of vasoactive GRECC, VA Medical Center, Minneapolis, MN, USA agents (acetylcholine, nitroprusside, verapamil). Neuropsychological functioning was assessed with the Repeatable Battery for the Assess- Background: While the relationship of vascular risk factors (VRF) ment of Neuropsychological Status. Statistical analysis included mul- and vascular diseases to cognitive impairment, cognitive decline, and tiple regression and partial correlations, controlling for education. dementia is well established, the mechanisms linking vascular risk Results: Vascular function was significantly associated with global factors, vascular brain injury (VBI) and cognitive impairment are neuropsychological performance [R Square Change = .116, F Change not well understood. We investigated the relationship between vascu- (3,74) = 3.72, p = .015]. Follow-up analyses indicated that smooth lar risk factors, vascular brain injury and cognitive impairment using muscle function was the aspect of vascular function most strongly as- asubsample of the community based study, the Swedish National sociated with neuropsychological performance. Delayed memory and study of Aging and Care in Kungsholmen (SNACK). semantic fluency were the aspects of neuropsychological perform- Methods: The SNACK is a multidisciplinary, longitudinal study of ance most strongly associated with vascular function. Individual vas- aging targeting the age 60+ population (n = 3363). Baseline imaging cular risk factors (e.g. glucose level, blood pressure, etc.) were not sig- data were available on a subset of 552 subjects ranging from 60 to 93 nificantly associated with neuropsychological performance when years-old. The following preliminary findings are derived from an controlling for vascular function. initial analysis of a random sampling of one quarter of the 552. VRFs Discussion: Forearm vascular function is significantly associated included life habits (diet/body mass index, alcohol, smoking), hyper- with neuropsychological performance in individuals with AVD. With tension, ischemic diseases (both heart and cerebral), and diabetes additional research, measures of vascular function might be useful in and obesity as part of the metabolic syndrome. VBI, as measured by the early identification of individuals who are at greatest risk for de- Diffusion Tensor Imaging(DTI), includes measures of mean diffusiv- veloping vascular cognitive impairment. ity (MD) and fractional anisotropy (FA) of white matter in the fol- lowing brain regions: centrum semiovale, frontal, and occipital. Hip- pocampal volume measures were also obtained as measures of 2. A Review of the Safety and Tolerability of Treatments for neurodegeneration. Five major domains of cognitive functioning Moderate to Severe Alzheimer’s Disease were evaluated: episodic memory, executive functioning, processing Jeffrey Cummings*, Martin Farlow, George Grossberg, Patti Green, speed, verbal knowledge, and visuospatial skill. Michael Tocco, E. Malca Resnick, Jason Olin and Stephen Graham Results: Significant relationships were observed between VRF and cognitive functioning,VRF and DTI brain measures and DTI and cog- University of California, Los Angeles, Alzheimer’s Disease Center, Los nitive functioning. When DTI indices were entered into a prediction Angeles, CA, USA model along with demographic factors (e.g., age, gender, and educa- Background: Safety concerns play a prominent role in selecting an tion) and the composite of vascular burden, in each case the individual appropriate Alzheimer’s disease (AD) treatment. Memantine, an an- contribution of the vascular burden score to cognitive performance tagonist of N-methyl-D-aspartate receptors, is approved for treat- was reduced (by .032 for frontal FA and .052 for centrum semiovale ment of moderate to severe AD in the US and Europe. Donepezil, a MD) and the total variance accounted for by the prediction model was cholinesterase inhibitor, is approved for treatment of mild to moder- improved (by .036 for frontal FA and .028 for centrum semiovale ate AD and is under review for approval in severe AD. This analysis MD). Hippocampal volume measurements were significant predictors compares the safety and tolerability of memantine and donepezil in of episodic memory performance, independent of age, gender, and ed- the treatment of patients with moderate to severe AD. ucation. No other significant relationships were found between hip- Methods: Relevant databases and conference procedings were pocampal volume and measures of cognitive performance (including searched for randomized, placebo-controlled clinical trials of me- speed, visuospatial, and executive functioning). In contrast, indices of mantine and donepezil involving patients with moderate to severe MD and FA correlated with visuospatial function but not memory. AD, with a minimum duration of 24 weeks. Trends from each study Discussion: These preliminary results provides support for our model and pooled analysis were examined. of white matter integrity (brain) mediating the relationship between Results: Three memantine and four donepezil trials fulfilled the VRF and cognition. Given the well established role of medial-tempo- search criteria. Memantine treatment was associated with a lower rate ralregions as early markers of neurodegeneration, these findings lend of discontinuations (overall: 20.3% vs. 27.9%) and a lower rate of dis- partial support to a hypothesized differentiation between microvascu- continuations due to adverse events (AEs) (9.9% vs. 14.0%) com- lar, subcortical pathology and neurodegenerative pathology. ACNP 2006 Annual Meeting S71 4. Systematic Review and Meta-Analysis of Cholinesterase was tested in a double-blind placebo-controlled study for the treat- Inhibitors and Memantine for Moderate to Severe Alzheimer’s ment of methamphetamine dependence. Disease Methods: 151 participants with DSM-IV diagnosis of methampheta- Lon S. Schneider*, Karen Dagerman, Zakaria Shaikh and Rupert mine dependence were consented and enrolled. 72 participants were McShane assigned to placebo and 79 to Bupropion SR 150mg BID. Patients were University of Southern California, Los Angeles, CA, USA required to come to the clinic three times per week for assessments, urine drug screens, and group psychotherapy. The primary outcome Background: Context: Cholinesterase inhibitors are FDA-approved was the change in proportion of participants having a methampheta- for mild to moderate Alzheimer’s disease and not for severe AD mine-free week. Secondary outcomes included Addiction Severity (donepezil is currently under FDA review for this indication). Me- Index (ASI), craving, and quantitative urine methamphetamine. mantine, a non-competitive, NMDA-antagonist, is FDA- approved Results: Analysis of the primary outcome showed a trend toward sig- for the treatment of moderate to severe AD and but not for mild. nificance for the total sample (p=0.09), favoring bupropion. Baseline Cholinergic neurons in the nucleus basalis are decreased in AD pa- use in the 30 days prior to screening, using time-line follow back, dif- tients along with
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