Neuropsychopharmacology (2006) 31, S136-S197 © 2006 Nature Publishing Group All rights reserved 0893-133X/06 S136 www.neuropsychopharmacology.org Tuesday, December 5, 2006 2. Assessing Health Related Resource Use and Value of Time Poster Session II Among Healthy Elderly: Baseline Data from the ADCS Prevention Instrument Project Mary Sano*, Carolyn Zhu, Karen Messer, Brooke Sowell, Steven 1. Spatial Distribution of Glycolysis as Measured by PET Images of Edland, Aron Schwarcz, Alexandra Sacks and Frank Hwang, Glucose and Oxygen Metabolism in the Resting Healthy Human Brain Correlates with Distribution of Beta-Amyloid Plaques in Psychiatry, Mount Sinai School of Medicine, New York, NY, USA Alzheimers Disease Mark Mintun*, Dana Sacco, Abraham Z. Snyder, Lars Couture, Background: Resource utilization and costs for healthy, cogni- William J. Powers, Tom O. Videen, Lori McGee-Minnich, Robert H. tively intact elderly as they begin to demonstrate cognitive deterio- Mach,John C. Morris and Marc E. Raichle ration are not well understood. Also, value of time for participa- tion in work (volunteer or paid) is often disregarded in elderly Radiology, Washington Univ Med Ctr, St. Louis, MO, USA populations. The purpose of this study was to evaluate the utility of the Resource Use Inventory (RUI) developed by the Alzheimer’s β Background: The distribution of beta-amyloid (A ) plaques in indi- Disease Cooperative Study (ADCS) and assess resource and time viduals with dementia of the Alzheimer type (DAT) can be visualized use in a sample of non-demented elderly individuals living in the using PET and the tracer [11C]PIB (Klunk et al, Ann Neurol, 2004). community. β However, the distribution of A plaques is not uniform and may re- Methods: The RUI was administered either at home or in the late to underlying brain metabolism or function (Buckner et al, J clinic to 644 healthy, non-demented individuals age≥75 and their Neurosci, 2005). We and others have shown that physiologic neural study partners. The RUI quantified subjects’ use of direct medical activation in the human brain is associated with greater increase in care (e.g., hospitalizations), non-medical care (e.g., home health local consumption of glucose than oxygen, indicating a shift to gly- aides), time spent by paid and unpaid caregivers providing care to colysis (Fox et al., Science, 1988). We now argue that using PET meas- the subjects, and subjects’ participation in volunteer work and ures of cerebral metabolic rate of oxygen (CMRO2) and glucose paid employment. Assessment interval for each question was the (CMRGlu) obtained in the resting human brain reveals a spatial dis- past three months. Quantified measures of usage for each domain tribution of glycolysis that reflects baseline levels of neuronal activity. of care were converted into monetary values based on average β This study compares the spatial distribution of A plaques seen in prices reported from public sources. National average hourly earn- DAT subjects with the distribution of glycolysis in resting healthy ing for all private industries was used to estimate hourly wage rates subjects. of unpaid caregiving costs and time spent in volunteer or paid β Methods: We examined the spatial correlation between A plaques work. Subjects’ demographic characteristics included age, ± in 11 individuals with DAT (mean age = 79 5yrs)and glycolysis race/ethnicity, gender, and education. Clinical characteristics in- ± in a group of 16 healthy controls (mean age = 50 14 yrs). Images cluded baseline Clinical Dementia Rating (CDR), modified Mini- β representing the distribution of A plaques were created from PET Mental State Examination (mMMS), activities of daily living scans obtained from 30 to 60 minutes after injection of [11C]PIB. (ADL), and whether subjects demonstrated cognitive deterioration PET images were summed, normalized by cerebellar activity and over 24 months. Resource use and costs were compared by demo- then averaged in Talairach atlas space after normalization. Images graphic and clinical characteristics, and partner participation. representing the level of glycolysis at baseline were generated from Comparisons of utilization and costs were performed using t-tests sequential PET scans of three [15O] tracers (CO, O2 and H2O) and Wilcoxon ranksum tests. and [18F]FDG. CMRO2 and CMRGlu were estimated from the Results: Utilization of resources varied widely by type: 76.6% were [15O] tracers and the [18F]FDG, respectively, using a nonquanti- examined at least once by a doctor, 10% received non-paid care, and tative approach. Consumption of glucose in excess of that ex- 2% received paid care. Half of the subjects (51.6%) were engaged in pected by the level of oxygen consumption is a marker of glycoly- volunteer work and 14% in paid employment. Among the users of sis. Thus, individual images of glycolysis were calculated from the health care resources, the most costly resource items included hospi- pixel-by-pixel positive residual after regressing the estimates of the talizations ($15,970) and imputed cost of non-paid care ($2,688). glucose to the oxygen consumption. Similarly to the [11C]PIB The value of time spent by the subjects in paid and volunteer work data, the glycolysis images were then averaged in Talairach atlas were estimated at $3,204 and $1,135. For the sample as a whole, β space. Two different methods were then used to sample the A three-month total cost was estimated at $2,288 per person. The most plaque image and the glycolysis image for correlation analyses. costly resource item was hospitalizations ($571). The value of time First, the entire brain was exhaustively sampled using adjacent spent by the subjects in paid and volunteer work were estimated at non-overlapping 12 mm cubes. Second, a representative series of $423 and $634. Total cost was significantly higher for men than cortical spherical regions-of-interest were placed throughout both women ($2,843 vs. $1,890) and for subjects with higher education image sets. level than those with lower education ($2,697 vs $1,864). Hospitaliza- β Results: The mean images of A plaques and glycolysis were tion costs were not significantly different by demographic and clinical highly correlated as evaluated by either complete brain sampling characteristics measured. The dollar value of paid work was signifi- by non-overlapping 12 mm3 cubes (r = 0.669, p < 0.0001, n=729) cantly higher for men ($760 vs $215) and the value for volunteer or a set of cortical regions-of-interest spheres (r = 0.804, p < work was significantly higher for those with higher education ($725 0.001, n=50). vs $538), better CDR ($698 vs $417), better ADLs ($690 vs $439), and Discussion: Visually, glycolysis was low (i.e., there was little excess for subjects who did not demonstrate cognitive deterioration ($652 CMRGlu compared to CMRO2) in areas with low PIB binding (e.g., vs $300). cerebellum, insular cortex) while glycolysis was high in areas of high Discussion: Self-reported resource use in non-demented elders is PIB binding (e.g., precuneus, prefrontal cortex). This preliminary feasible for tracking resource and time use through transition from topographical relationship between resting glycolysis in controls and healthy aging to cognitive impairment. Results illustrate that value of β A plaques in DAT individuals implies a link between resting brain time for paid and volunteer activities are sensitive to cognitive metabolism and the later development of Alzheimer’s pathology. This changes even in elderly populations. research is support by grants from the NIH (NS006833, NS048056, AG026276, AG05681, AG03991). ACNP 2006 Annual Meeting S137 3. MEM 1003, a Novel, CNS-Selective L-Type Ca2+ Channel 4. Salvinorin A: Allosteric Interactions at the mu Opioid Receptor Blocker, Is a Potential Therapeutic Agent for CNS Disorders Richard B. Rothman*, Daniel L. Murphy, Heng Xu, Jonathan A. Michael De Vivo*, Crista Trippodi-Murphy, Jeffrey H. Kogan, Godin, Christina M. Dersch, John S. Partilla, Kevin Tidgwell, Geoffrey C. Tombaugh, Daguang Wang, Voon S. Ong, David A. Matthew Schmidt and Thomas E. Prisinzano Lowe, Eric R. Kandel, Jing Yang, Rosemary Ahrens, David Westaway and Paul Fraser Clinical Psychopharmacology Section, IRP, NIDA, NIH, Baltimore, MD, USA Memory Pharmaceuticals, Montvale, NJ, USA Background: Salvinorin A, a neoclerodane diterpene, is a kappa opi- Sponsor: Eric R. Kandel oid receptor agonist that lacks the usual basic nitrogen atom present in all other known opioid ligands. Our initial binding experiments Background: Neurons must maintain low intracellular concentra- indicated that Salvinorin A weakly inhibited mu receptor binding. tions of Ca2+ to function properly. Neurons lose this ability as they Additional experiments showed that Salvinorin A partially inhibited age or as they are affected by disease. An increase in intracellular mu receptor binding. We therefore hypothesized that Salvinorin A al- Ca2+ alters the activity of Ca2+-dependent signaling pathways which losterically modulates mu receptor binding. may adversely affect neuronal functions. One such Ca2+-mediated Methods: To test this hypothesis, we conducted opioid binding assays signal that may contribute to the decrease in cognitive performance and [35S]-GTP-γ-S binding assays using membranes prepared from associated with aging is an enlarged slow afterhypolarization (sAHP) CHO cells expressing the cloned human opioid mu receptors. due to the activation of Ca2+-dependent K+ conductance. Our re- Results: Salvinorin A partially inhibited [3H]DAMGO (0.5, 2.0 and cent findings demonstrated that sAHP amplitude co-varies with spa- 8.0 nM) binding with EMAX values of 78.6%, 72.1% and 45.7%, re- tial learning ability in aged rats. Excessive intracellular Ca2+ may be spectively and EC50 values of 955, 1124 and 4527 nM, respectively. exacerbated by an increase in density of L-type Ca2+-channels that Salvinorin A also partially inhibited [3H]diprenorphine (0.02, 0.1 reportedly occurs with aging and in Alzheimer’s disease. Blocking and 0.5 nM) binding with EMAX values of 86.2%, 64%, and 33.6%, voltage-regulated calcium channels facilitates the ability of neurons respectively and EC50 values of 1231, 866, 3078 nM, respectively.