Neurons must maintain appropriate ion gradients in order to functionproperly; as they age, or are affected by toxins such as beta amyloidpeptides, neurons lose this ability. An increase in Ca2� entry into the cellalters activity of Ca2�-dependent proteins such as ion channels and pro-teolytic enzymes which may adversely affect many cell functions. Exces-sive Ca2� entry may be exacerbated by an increase in density of L-typeCa2�-channels reported to occur in aging and in Alzheimer’s disease.Blocking voltage-regulated calcium channels may facilitate the ability ofneurons to maintain appropriate calcium levels and function properly.Memory Pharmaceuticals is developing MEM1003, a dihydropyridine(DHP) Ca2� channel modulator, for Alzheimer’s disease. MEM1003 isequipotent to nimodipine, another DHP, in blocking L-type Ca2�currentsin CA1 hippocampal neurons, but it is 4 to 15-fold less potent in relaxingrat thoracic smooth muscle when compared to other DHPs like nimodipine,nitrendipine or felodipine. This suggests that MEM1003 may have asuperior safety profile. MEM1003 is a single enantiomer, unlike nimodip-ine and many other DHP drugs, and may lack potential off-target pharma-cological activities present in racemic mixtures. We will present datashowing the effectiveness of MEM1003 in improving cognitive perfor-mance in multiple preclinical behavior models at plasma exposure levelsconsistent with its affinity for the DHP binding site. One proposed mech-anism for the procognitive effects of MEM1003 is that it mediates areduction in the slow afterhypolarization (sAHP) of CA1 pyramidal neu-rons. An enlarged sAHP, functionally linked to L-type Ca2� channels, mayinterfere with cognitive behaviors. Our recent findings have demonstratedthat sAHP amplitude co-varies with spatial learning ability in aged rats(Tombaugh et al., 2005). The pharmacokinetic and safety profiles ofMEM1003 were recently studied in double-blind, randomized, placebo-controlled Phase 1A and Phase 1B clinical trials. MEM1003 was welltolerated up to the highest dose tested of 180 mg twice daily. The safetydata and pharmacokinetics of MEM1003 in these studies will be presentedand the relevance of the exposure levels to preclinical animal efficacymodels and toxicology studies will be discussed. MEM1003 is currently ina Phase 2A clinical trial for Alzheimer’s disease.

P4-438 HISTAMINE H3 RECEPTOR ANTAGONISTSELICIT PROCOGNITIVE EFFECTS ON EPISODICAND SPATIAL REFERENCE MEMORIES OFYOUNG AND AGED ANIMALS

Wayne Rowe, Rachael Di Somma, Cathleen Hsu, Ken Solomon,Patrick Callahan, Daguang Wang, David Lowe, MemoryPharmaceuticals, Montvale, NJ, USA. Contact e-mail:Rowe@memorypharma.com

Histamine H3 receptors are located on presynaptic terminals in key brainareas important for learning and memory. Blockade of the histamine H3receptor via an antagonist leads to enhanced histamine release as well asenhanced neurotransmitter release of acetylcholine, dopamine and nor-adrenaline. Such neurochemical actions are implicated in cognitive pro-cesses and thus, histamine H3 antagonists may represent a novel drug classwith therapeutic potential against neurodegenerative diseases like Alzhei-mer’s disease, schizophrenia and attentional deficit hyperactive disorder.The present study assessed the possible procognitive effects associatedwith the histamine H3 antagonist thioperamide (1-10 mg/kg, ip; 30 min) onepisodic and spatial reference memories in young and aged rodents. In anobject recognition model of episodic memory, young Sprague-Dawley ratsshowed a significant and dose-dependent improvement in object recogni-tion memory at the 48hr test delay interval. In the rat Morris water-mazemodel of spatial reference memory, aged Fischer 344 rats are screened andclassified as either aged cognitively-impaired or aged cognitively-unim-paired based upon their water-maze performance to that of young Fischer344 rats, Approximately 40% of the aged rats are considered performanceimpaired (�2 STDs from young rat performance) whereas 25% of the agedrats are not significantly different from young controls. Following classi-fication, aged-impaired rats were given thioperamide during 3 additionaldays of water-maze performance assessment. Thioperamide significantly

reversed the aged-related spatial reference memory deficit. Both latency toplatform and probe trial (e.g., % time in quadrant, entry to first annulus-40and time in annulus-40) performance were significantly enhanced by theH3 receptor antagonist compared to aged-impaired controls. These resultssuggest that histamine H3 receptor antagonists may be a viable therapeuticdrug target for the treatment of Alzheimer’s disease and other neurode-generative disorders.

SATURDAY, JULY 15, 2006ALZHEIMER’S IMAGING CONSORTIUM PRESENTATIONS

PLENARYIC-PL

IC-PL-01 AGING OF THE BRAIN: NEUROBIOLOGY ANDIMAGING

Naftali Raz1,2, 1Institute of Gerontology, Detroit, MI, USA; 2WayneState University, Detroit, MI, USA. Contact e-mail: nraz@wayne.edu

Background: To comprehend causes and mechanisms of age-related de-generative brain disease we need to understand the course of the normaland successful aging. Objective: Summarize neuroimaging findings per-taining to normal brain aging. Methods: Narrative and quantitative reviewof the literature. Results: In vivo cross-sectional studies suggest differentialbrain aging with the prefrontal cortex more affected than the rest of theneocortex. Smaller age differences are observed in temporal, parietal andoccipital cortices. The volumes of the hippocampus, amygdala, striatumand cerebellum show moderately negative association with age; the ento-rhinal cortex shows little age-related differences. The white matter volumeincreases throughout development, remains stable in the middle-aged, andis reduced in the older people. White matter integrity indices (white matterhyperintensities, WMH; fractional anisotropy, FA) are compromised onlyin older individuals, especially in the anterior regions. Longitudinal studiesconfirm the notion of differential aging. Association cortices (prefrontal,parietal, and temporal) tend to shrink faster than the sensory regions(primary visual). However, the neostriatum and the cerebellum exhibit assignificant a change as the association cortices. The shrinkage of thehippocampus is minimal in the middle age but accelerates during the laterpart of the lifespan. Entorhinal cortex maintains stable volume during mostof adulthood but begins to shrink significantly in the sixth decade of life.Shrinkage rates and increase in WMH burden in some regions depend onage-associated pathological factors (vascular risk and vascular disease).The prefrontal cortices, the hippocampus and the white matter are vulner-able to such negative modifiers. However, the prefrontal cortices and thewhite matter may be responsive to positive modifying intervention such asaerobic exercise. Although cognitive performance is differentially compro-mised in older adults, the magnitude of declines may depend on differentialshrinkage of specific brain regions (e.g. entorhinal) and presence of vas-cular risk factors. Conclusions: Although brain exhibits regional shrinkageeven in successful aging, its magnitude and relation to cognition areaffected by concomitant subclinical pathology, which can be prevented,delayed or modified.

IC-PL-02 UPDATE ON PATHOLOGY OF THE DEMENTIAS,AND WHAT SHOULD/COULD IMAGERS BEIMAGING

Dennis W. Dickson, Mayo Clinic, Jacksonville, FL, USA. Contacte-mail: dickson.dennis@mayo.edu

Neuropathology provides information about the structural and molecularpathology of diseases and has led to a rational classification of neurode-generative disorders, including amyloidoses, tauopathies, synucleinopa-thies, ubiquitinopathies, neurofilament-opathies, prion-opathies and trinu-cleotide repeat disorders. Clinical syndromes reflect distribution ofpathology and are rarely specific for the underlying pathology. Imaging hasthe prospect of providing more specific biomarkers, but structural imaging,

S647Alzheimer’s Imaging Consortium Presentations Imaging Consortium Plenary IC-PL:: Plenary