S1–03–05: Cellular prion protein as therapeutic target

not available. S1-03-06 TREATMENT OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES WITH DOXYCYCLINE Mario Salmona, Ada DeLuigi, Luisa Diomede, Laura Colombo, Claudia Manzoni, Raffaella Capobianco, Michela Mangieri, Claudia Miccolo, Gianluigi Forloni, Fabrizio Tagliavini, Mario Negri Institute of Pharmacological Research, Milan, Italy; Instituto Neurologico Nazionale Carlo Besta, Milan, Italy. Contact e-mail: salmona@marionegri.it Background: At present no effective treatment of prion diseases is available. Although several compounds have been found to antagonise prion propagation in animal or cellular models of disease, the suitability of these compounds for human therapy is limited, due to their poor ability to cross the blood-brain-barrier, the severity of their toxicity, and most importantly their ineffectiveness after the onset of the disease. Objectives: During the last 15 years we have been working on the identification of molecules with anti-prion activity and have shown that tetracyclines (i) interact with and revert the protease resistance of PrP extracted from scrapie-infected animals and patients with all forms of Creutzfeldt-Jakob disease (CJD), (ii) decrease the prion titre, and (iii) prolong survival of peripherally infected animals. In the last five years, a small series of CJD patients received compassionate treatment of doxycycline, and a retrospective analysis showed a significantly longer survival than untreated patients. On this ground a double-blind pilot clinical trial in CJD patients has been recently commenced in Italy. Methods: To extend the therapeutic potential of doxycycline, we are currently evaluating the efficacy of direct infusion of the compound into the brain of hamsters inoculated intracerebrally with the 263K scrapie agent, and treated in early or advanced stages of infection. Since intraventricular infusion of doxycycline solution caused overt acute toxicity to animals, we decided to entrap the drug into multilamellar vesicles (MLV) and preliminarily assess its effectiveness to revert the protease resistance of PrP extracted from scrapie-infected hamsters. The distribution of MLV loaded with doxycycline (25 g/animal) in the brain and cerebrospinal fluid (CSF) was evaluated by determining the fluorescence of brain sections after 1 and 4 days of intraventricular administration. Syrian hamsters were inoculated intracerebrally with 25 l of a 10 dilution of 263K-infected brain homogenate. Then a single intraventricular infusion of 25 g/animal of doxycycline entrapped into MLV was administered after 1 hour, 7 days and 30 days. At the time of writing, after one month of treatment, no death of animals caused by doxycycline toxicity was observed. Conclusion: Our data support the view that tetracyclines are potentially useful anti-prion drugs. SUNDAY, JULY 16, 2006 SYMPOSIA S1-04 OTHER DEMENTIAS S1-04-01 VASCULAR COGNITIVE IMPAIRMENT: TOWARD A COMMON APPROACH TO PREVENTABLE SENILITY Vladimar Hachinski, London Health Sciences Centre, London, ON, Canada. Contact e-mail: eva.newhouse@lhsc.on.ca Stroke and Alzheimer’s disease represent risks for each other. 64% of stroke patients over the age of 65 years will have some cognitive impairment and 24% of individuals over the age of 65 years with a cognitive impairment have had a stroke. Community based clinical pathological studies suggest that vascular lesions are as common a contributor to dementia as Alzheimer lesions. Moreover, strokes may trigger Alzheimer’s disease in susceptible individuals. About 25% of stroke patients have a significant cognitive impairment at three months, and about 2/3 continue to deteriorate, in a manner reminiscent of Alzheimer’s disease. The vascular risk factors that predispose people to stroke also make them prone to developing Alzheimer’s disease and hence, the need for a common approach. Stroke physicians do not routinely assess cognition nor do physicians interested in Alzheimer’s disease have sophistication in the management of vascular risk factors. A united, integrated and synergistic approach is likely to yield better and faster results than the increasingly fragmented approaches promoted by subspecialization. “La union hace la fuerza” (unity strengthens). S1-04-02 TREATMENT OF DEMENTIA ASSOCIATE TO PD Murat Emre, Istanbul Faculty of Medicine, Department of Neurology, 34390 Capa Istanbul, Turkey. Contact e-mail: muratemre@superonline.com Cognitive changes and dementia are frequently encountered in patients with Parkinson’s disease (PD). The incidence and prevalence of dementia are significantly higher in PD than expected; the prevalence in crosssectional studies is approximately 40%, in long-term studies up to 78% of patients were reported to develop dementia, the incidence is increased up to 6 folds as compared to controls. The treatment of dementia associated with PD (PDD) can be concieved as non-specific interventions such as treatment of psychosis and substitution therapy based on neurotransmitter deficits. Although deficits in several neurotransmitter systems have been reported to be associated with PDD, including those in dopaminergic, seretoninergic, noradrenergic and cholinergic innervation, the strongest evidence indicates an association with cholinergic impairment. PDD is characterized by a substantial loss of cholinergic neurones in basal forebrain and a reduction in cortical cholinergic markers which is correlated with the presence and severity of dementia. After cholinesterase inhibitors (ChE-I) became available for the treatment of Alzheimer disease, there have been attempts to use these agents also in the treatment of patients with PDD. A number of small, double-blind and open trials or case series with tacrine, donepezil, rivastigmine and galantamine were reported suggesting beneficial effects on cognition and behavioral symptoms without noteworthy worsening of motor features in the majority. Recently the first large, randomized, placebo controlled study with a ChE-I in PDD (EXPRESS) was published, reporting beneficial effects of rivastigmine. Patients on rivastigmine performed significantly better on both primary end-points (ADAS-cog and ADCS-CGIC). All secondary measures assessing attention, behavioral symptoms, executive function and activities of daily living also revealed significant differences in favor of rivastigmine. Main adverse effects were those related to the gastrointestinal system, nausea and vomiting being the most frequent ones. Worsening of tremor was reported in 10% of the patients as an adverse event. The objective assessment of motor functions with UPDRS part III, however, did not reveal any significant differences between rivastigmine and placebo. Taken together these results indicate that ChE-I such as rivastigmine can be beneficial in the treatment of patients with PDD. S1-04-03 SYNUCLEIN: AN UPDATE Isidro Ferrer, Institut Neuropatologia, Barcelona, Spain. Contact email: 8082ifa@comb.es Parkinson’s disease (PD) is pathologically defined by loss of neurons in selected nuclei of the brainstem, Meynert and amygdala, and by the presence of complex protein aggregates mainly composed of abnormal a-synuclein called Lewy bodies and aberrant neurites. Increased levels of a-synuclein, mutations in the a-synuclein gene and oxidative stress lead to a-synuclein aggregation. PD is considered to be within the spectrum of S6 Symposia S1-04: Other Dementias