Alzheimer Disease: Auff E

Bauer M, Langer O, Dal-Bianco P, Karch R, Brunner M, Abrahim A, Lanzenberger R, Hofmann A, Joukhadar C, Carminati P, Ghirardi O, Piovesan P, Forloni G, Corrado ME, Lods N, Dudczak R, Auff E, Kletter K, Müller M. · Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, University of Vienna, Vienna, Austria. · Clin Pharmacol Ther. · Pubmed #16952488 No free full text.

Abstract: This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9-17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3-2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid-beta-rich and -poor regions, with slow washout of radioactivity (half-life, 82-185 minutes). In conclusion, these data provide important information on the blood-brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET microdosing approach is a useful method to describe the target-organ pharmacokinetics of radiolabeled drugs in humans.

Lehrner J, Gufler R, Guttmann G, Maly J, Gleiss A, Auff E, Dal-Bianco P. · University Clinic of Neurology, Medical University of Vienna, Vienna, Austria. · Wien Klin Wochenschr. · Pubmed #16416345 No free full text.

Abstract: OBJECTIVE: The goals of this study were to determine the annual conversion rate to Alzheimer disease (AD) among patients reporting memory problems, including a subgroup with amnestic mild cognitive impairment (aMCI), and to investigate the predictive value of neurocognitive testing for future dementia. METHODS: A prospective study was carried out in an outpatient memory clinic. One hundred and seven patients underwent a clinical examination and completed a battery of standard cognitive tests at study entry and two years later. The conversion rate to clinically manifested AD two years later was investigated and sensitivity, specificity, receiver operating characteristics (AUC), positive predictive value and negative predictive value for each neuropsychological test were determined. RESULTS: We found an annual rate of conversion to AD of 6.5% among patients reporting memory decline in the setting of our clinic. Specifically, patients with aMCI had an annual conversion rate of approximately 20%. The annual conversion rate for patients reporting memory problems but showing no memory deficit at memory testing was approximately 3%. Receiver operating characteristics (AUC) of the neuropsychological tests ranged from 0.60 to 0.94. CONCLUSIONS: Patients with aMCI have 8.6-fold higher odds of developing AD compared with patients without evident memory impairment on neuropsychological testing. Although the risk of developing AD among patients without objective memory decline is small, some patients in this group still convert to AD and therefore close clinical monitoring of patients is necessary.