Givaudan-Roure Lecture - Association for Chemoreception Sciences

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192 Symposium [ ] Olfaction and Neurodegenerative Disorders OLFACTION AND NEURODEGENERATIVE DISORDERS Doty R. 1 1Smell and Taste Center, University of Pennsylvania, Philadelphia, PA Numerous major neurological disorders are associated with olfactory dysfunction. Indeed, the first clinical sign of such diseases as Alzheimer´s disease and idiopathic Parkinson´s disease appears to be decreased olfactory function. In the case of Parkinson's disease, the prevalence of smell loss is greater than the prevalence of tremor, and is essentially equivalent to that of the other major motoric signs of the disease. Importantly, not all neurological or neurodegenerative disorders are associated with smell loss. Hence, olfactory testing can aid in the differential diagnosis of a number of disorders commonly confused on initial presentation, including Alzheimer's disease vs. major affective disorder, and Parkinson's disease vs. progressive supranuclear palsy. The olfactory evaluation of at-risk individuals, including relatives, may prove to be of considerable clinical value for initiating neuroprotective therapy early in disease development. This symposium provides an up-to-date overview of relationships between olfactory function and four major neurological diseases. The participants and discussants represent active researchers in this field, and bring a variety of perspectives and a wealth of information to this topic. 193 Symposium [ ] Olfaction and Neurodegenerative Disorders LONGITUDAL EVALUATION OF OLFACTORY FUNCTION IN ALZHEIMER'S DISEASE Devanand D.P. 1, Tabert M.H. 1 1Psychiatry, Columbia University/NYSPI, New York, NY We evaluated the predictive utility of olfactory deficits in patients with minimal to mild cognitive impairment (MMCI). 150 outpatients presenting to a Memory Disorders Center were recruited and followed at 6-month intervals. 63 group-matched controls were followed annually. Patients had a mean age of 67 (SD 9.8) and mean education of 15 (SD 4.2) years. Mean age for controls was 65 (SD 9.3) and mean education was 16 (SD 2.6). UPSIT scores were lower in patients (mean 31 SD 6.4) than controls (mean 34 SD 4.2). Baseline UPSIT scores were lower in converters to Alzheimer´s Disease (AD; n=35, mean 26 SD 8.2) than non-converters (mean 33, SD 4.7) (mean follow-up=39 months). In Cox regression analyses, low olfaction scores predicted AD (Wald chi2=15.9, p < .0001). The UPSIT score remained a significant predictor (p < .0003, relative risk=0.9 per UPSIT point change) even when age, sex, and education were included as covariates, and when MMS was included as a covariate. ApoE e4 genotype did not differ between non-converters (22%) and converters (28%). UPSIT scores were correlated with right hippocampal volume (r=0.20, p < .03). In Cox regression analyses, low olfaction scores predicted outcome (Wald chi2=10.6, p < .002, relative risk=0.92 per point change) even when hippocampal volume, age, and gender were included. Olfactory deficits predicted conversion to AD in patients with MMCI, even after controlling for demographic, cognitive, and brain volumetric predictors. In addition, odor-induced fMRI activation is also being examined in controls and AD and MMCI patients. Grants: AG17761 (P.I. Devanand), K01AG21548 (P.I. Tabert) and from the Alzheimer´s Association (P.I. Devanand) 50 194 Symposium [ ] Olfaction and Neurodegenerative Disorders OLFACTORY SYSTEM DYSFUNCTION IN SCHIZOPHRENIA Moberg P.J. 1, Turetsky B.I. 1 1Psychiatry, University of Pennsylvania, Philadelphia, PA Psychophysical studies of olfaction have documented impairments in odor detection thresholds, identification, memory and hedonics in patients with schizophrenia. Similar deficits exist in non-ill family members. Despite evidence of behavioral impairment, there is little evidence that the neuroanatomical or neurophysiological substrates of olfaction are abnormal. We have conducted a series of studies examining the structural and functional integrity of the olfactory system in patients and their firstdegree relatives. 1)Using acoustic rhinometry, we have shown a reduction of the left-posterior nasal cavity in male patients. 2)Using high-resolution MRI, we found bilateral olfactory bulb volume reductions in patients, and unilateral right sided reductions in family members. 3)Following parcellation of the anterior ventromedial temporal lobe into perirhinal, entorhinal and temporal polar regions, patients exhibited selective gray matter volume reductions in the perirhinal and entorhinal areas bilaterally. 4)Using air-dilution olfactometry, both patients and non-ill family members were observed to exhibit dose-dependent abnormalities in the olfactory evoked potential. There are thus primary structural and functional abnormalities in the olfactory system, which underlie the behavioral deficits seen in schizophrenia. These abnormalities appear to denote an endophenotypic genetic vulnerability marker, rather than an index of either clinical disease status or treatment. A greater understanding of the neurobiology of these olfactory deficits could offer clues to both the basic neuropathology and the genetic precursors of this disorder. Supported by MH63381(PJM), MH59852(BIT), & NARSAD(PJM).
195 Symposium [ ] Olfaction and Neurodegenerative Disorders OLFACTORY DYSFUNCTION IN MULTIPLE SCLEROSIS Doty R.L. 1 1Smell and Taste Center, Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA For many years it was assumed that multiple sclerosis (MS) was unaccompanied by olfactory dysfunction. While several early studies, including a pioneering study by Ansari in 1976, failed to find any olfactory deficits in this disease, more recent studies from our group have clearly demonstrated that some MS patients exhibit olfactory loss. In 1984 we reported that 23% of a group of 31 MS patients exhibited smell dysfunction, as measured by the University of Pennsylvania Smell Identification Test (UPSIT). A decade later we presented clinical cases in which smell loss was a presenting sign of MS. In a subsequent series of studies in the late 1990´s, we demonstrated that such loss was correlated with the number of MS-related plaques in subtemporal and subfrontal brain regions, but not in other brain regions. Moreover, we showed that olfactory function waxes and wanes longitudinally in accordance with the number of active plaques in these brain regions. In this presentation, I review these studies, as well as initial results of a 5year-long study of 73 MS patients and controls, in which a range of sensory and neuropsychological tests were administered, including ones tapping olfactory (i.e., odor identification, detection & discrimination), gustatory (e.g., regional taste identification), auditory (e.g., pure tone thresholds, competing words, auditory figure-ground), vestibular (e.g., Rhomberg eyes open & closed tasks), and cognitive (e.g., Wechsler Memory Scale-Revised; National Adult Reading Test; Wisconson Card Sorting Test) functions. Supported by grant RO1 DC 02974 from the National Institute on Deafness and Other Communication Disorders. 196 Symposium [ ] Olfaction and Neurodegenerative Disorders OLFACTION IN PARKINSONISM Hawkes C. 1 1Essex Neuroscience Centre, Essex, United Kingdom There has been gradual increase of interest in olfaction since it was realised that anosmia was a common feature of idiopathic Parkinson's disease (IPD) and Alzheimer-type dementia (AD). It is an intriguing possibility that the first sign of a disorder hitherto regarded as one of movement or cognition may be that of disturbed smell sense. In this review of parkinsonian syndromes the following observations can be made: 1) olfactory dysfunction is frequent and often severe in IPD and may precede motor signs of IPD 2) normal smell identification in IPD is rare and should prompt review of diagnosis unless the patient is female with tremor dominant disease. 3) olfactory impairment in suspected progressive supranuclear palsy or corticobasal degeneration is atypical and should likewise provoke diagnostic review. 4) impaired smell sense is seen in some patients at 50% risk of parkinsonism 5) biopsy of olfactory nasal neurons reveals non-specific changes in IPD and at present will not aid diagnosis. 51 197 Poster [ ] Development of the Gustatory System EGF SIGNALING IN PATTERNING FUNGIFORM PAPILLAE IN EMBRYONIC RAT TONGUE Liu H. 1, Mistretta C. 1 1School of Dentistry, University of Michigan, Ann Arbor, MI In previous experiments to understand how papillae form in patterns on the embryonic tongue, we demonstrated roles for the morphogen, sonic hedgehog (Shh) in fungiform papilla development. Fungiform papillae form in doubled numbers and atypical posterior locations in tongue cultures when Shh signaling is selectively disrupted with the alkaloid, cyclopamine. To further understand molecular regulation and interactions in papilla formation, we are studying effects of epidermal growth factor, EGF. A polyclonal antibody to EGF receptor (EGFR) was used to immunolocalize EGFR in rat embryo tongues at gestational days (E) 13-18. Also, in whole tongue cultures begun at E14, we examined effects of exogenous EGF on fungiform papilla development and on the cyclopamine-induced change in papilla patterning. EGFR localized in all layers in the dorsal epithelium of embryonic rat tongue at all ages examined. Immunoproducts were weak and homogeneous in the tongue epithelium at E13-E14. Signals became progressively more intense in the inter-papilla space, but not within the papilla epithelium, in association with papilla development from E15-E18. In E14+2 day cultures, EGF dose-dependently decreased the number of fungiform papillae while stimulating epithelial proliferation. Moreover, preincubation with EGF, followed by culture with EGF plus cyclopamine, prevented the cyclopamine-induced change in papilla pattern. The data demonstrate that EGF signaling plays an important role in spacing of fungiform papillae in embryonic tongue, and interacts with Shh signaling in regulating development of papilla pattern. Supported by NIH NIDCD Grant DC000456 to CMM. 198 Poster [ ] Development of the Gustatory System TASTE BUD PRIMORDIA DEVELOP IN RODENT TONGUE CULTURES Walters E. 1, Mbiene J. 2 1Department of Biochemistry and Molecular Biology, Howard University, Washington, DC; 2Department of Biomedical Sciences, Texas A&M University System, Dallas, TX Lingual taste buds form within papillae in mammals. We are studying the molecular aspects of taste bud differentiation during development. Keratin 8 is expressed in epithelial cell clusters in distinctive patterns across the developing tongue in mouse embryos before the innervation of tongue epithelium. To learn whether keratin 8 expression proceeds in vitro as in vivo, we examined the expression patterns of keratin 8 in mouse tongue cultures. Tongue or lower jaw explants were taken from gestational days 11.5 and 12.5 mouse embryos and maintained at liquid-gas interface in conventional organ cultures. Explanted tongues were harvested after 1-6 days in culture and assayed for keratin 8 by immunocytochemistry. In E11.5 and 12.5 mouse tongue explants, keratin 8 is broadly expressed in the lingual epithelium, as in vivo. Over the next 24-48 hours, keratin 8 becomes restricted to clusters of cells located in the center of epithelial placodes. Surprisingly, keratin 8 continues to be expressed in few clusters after 6 days of culture. These results establish that much of taste bud development is nerve dependent in mammals. I am currently examining the gene repertoire expressed in tongue placodes that may possibly play a role in the determination of taste buds.Grant sponsor: NIDCD; Grant number: DC03503
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Page 17 and 18: 65 Slide [ ] Trigeminal Chemorecept
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Page 71 and 72: 273 Poster [ ] Accessory Olfactory
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Page 77 and 78: 294 Poster [ ] Sweet Taste BEHAVIOR
Page 79 and 80: 302 Poster [ ] Taste Psychophysics
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Page 83 and 84: 317 Poster [ ] Taste: Animal Behavi
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380 Slide [ ] Olfactory Development
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388 Poster [ ] Cell Biology of the
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410 Poster [ ] Multimodal Integrati
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418 Poster [ ] Taste: Umami POLYMOR
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Abou, Elizabeth, 309 Abraham, Micha
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Fadool, Debra, 34, 35, 64, 392, 393
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Kim, K-O, 297 Kim, Un-kyung, 191, 3
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Givaudan-Roure Lecture - Association for Chemoreception Sciences

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