S5–01–02: Clinical criteria of AD—can we make a diagnosis earlier

not available. S5-01-04 CAN CSF BIOMARKERS PREDICT AD? Tuula Pirttilä, Kuopio University Hospital, Kuopio, Finland. Contact e-mail: tuula.pirttila@uku.fi Abstract not available.not available. S5-01-05 PATHOLOGICAL CORRELATES OF DEMENTIA IN A LARGE POPULATION-BASED COHORT Paul Geoffrey Ince, MRC CFAS, University of Sheffield, Newcastle, United Kingdom. Contact e-mail: paul.g.ince@sth.nhs.uk Background: Conventional views of the pathological substrates of cognitive decline are challenged by the findings of population-based cohorts. Disorders conforming to ‘pure’ consensus guidelines are infrequent and mixed pathologies predominate. Objective(s): Characterization of pathologies underlying cognitive decline in the first 456 deaths within the MRC Cognitive Function and Ageing Study. Comprehensive data on degenerative and vascular pathologies will be analyzed in relationship to cognitive status, genetic risk factors and self-reported risk factors. Methods: Prospective longitudinal assessment of respondents in a population-based cohort linked to a brain donation program. Conventional neuropathology was supplemented by post-mortem brain imaging and genetic analyses. Conclusions: Data from the first 209 brains within the study showed that the burden of brain pathology is linked to cognitive decline but does not permit the definition of thresholds for any specific brain lesion (e.g. Alzheimer’s pathology, synucleinopathy etc). Mixed pathologies including vascular brain disease were the most frequent finding. Prediction of cognitive status from a global assessment of significant pathological variables is accurate in 4 out of 5 cases. Incorrect predictions include both demented individuals with low pathology burden and cognitively intact individuals with high pathology burden. The findings will be updated based on analysis of data collected from 456 brains up to July 2005. The implications for understanding the interaction of pathology and brain function will be addressed. S5-01-06 CLINICAL CORRELATION OF ALPHA SYNUCLEIN PATHOLOGY Irina I. Alafuzoff, Neuropathology, Kuopio, Finland. Contact e-mail: irina.alafuzoff@uku.fi Background: Intracytoplasmic aggregates of alpha-synuclein protein as Lewy bodies in brainstem neurons is considered diagnostic for Parkinson’s disease, whereas if this process also occurs in the cortical neurons it is considered pathognomonic for dementia with Lewy bodies. The reported link between alpha-synuclein inclusions, neuronal dysfunction and clinical symptoms is based on numerous clinico-pathological studies. Most of these studies have one common feature, they are carried out on material selected based on the clinical findings. However, it has been previously shown that the prevalence of alpha-synuclein pathology is highly dependent on the case selection. Methods: To further assess the clinico-pathological link between alphasynuclein pathology and clinical symptoms we investigated 904 autopsy cases. The cases included in this study were selected based on their alpha-synuclein pathology in dorsal motor nucleus of vagus, substatia nigra and basal forebrain. Results: It was noted that the prevalence of alpha-synuclein pathology in the 210 out of 904 subjects clearly depended on the case selection. Our clinical retrospective assessment of the 210 alpha-synuclein positive cases revealed that only 30% of them were diagnosed with a neurodegenerative disorder. Cognitive impairment was not blindly predictable by neuropathological investigation i.e. based on the load or distribution of alpha-synuclein pathology. Some unimpaired subjects had a significant burden of alpha-synuclein pathology in both brainstem and cortical areas. Conclusions: Our results indicate that alphasynuclein positive structures as such are not definite markers of neuronal dysfunction and cannot be used to predict disease status reliably. THURSDAY, JULY 20, 2006 SYMPOSIA S5-02 DISEASE MECHANISMS (OTHERS) S5-02-01 P53, APOPTOSIS Frederic Checler, Institut de Pharmacologie Moleculaire et Cellulaire, Valbonne, France. Contact e-mail: checler@ipmc.cnrs.fr Abstract not available.not available. S5-02-03 EXPRESSION STUDIES Bruce A. Yankner, Children’s Hospital, Boston, MA, USA. Contact e-mail: Bruce.Yankner@childrens.harvard.edu Abstract not available.not available. S5-02-04 CELL CYCLE RE-ENTRY MEDIATES ALZHEIMER-TYPE CHANGES IN NEURONS IN VITRO Mark A. Smith, Hyoung-gon Lee, Inez Vincent, Nancy J. Linford, Jens-Oliver Funk, Robert A. Shapiro, Andrew McShea, Case Western Reserve University, Cleveland, OH, USA; University of Washington, Seattle, WA, USA; Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany; Oregon Health & Science University, Portland, OR, USA; CombiMatrix Corporation, Mukilteo, WA, USA. Contact e-mail: mark.smith@case.edu There is now considerable evidence for the aberrant re-expression of a series of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease (AD). That a mitotic cell cycle-related mechanism may play an important role in disease pathogenesis is highlighted by the earlier occurrence of cell cycle proteins compared to abnormal tau in AD. That cell cycle proteins are representative of a true cell cycle, rather than being an epiphenomena of other processes, is evident from recent evidence showing that, in AD and other neurodegenerative diseases, there is a true mitotic alteration that leads to DNA replication (i.e., S phase). These findings led us to develop a novel hypothesis that neurodegeneration in AD, like cancer, is a disease of inappropriate cell cycle control. In support of this notion, this study shows that the expression of a powerful cell cycle inducer, MYC, drives primary neurons to re-enter the cell cycle and, moreover, that oncogene-induced cell cycle re-entry leads to tau phosphorylation. Specifically, we used adenoviral-mediated expression of c-myc and ras oncogenes to drive postmitotic primary S91 Symposia S5-02: Disease Mechanisms (Others)