FUNCTIONAL ACTIVATION STUDIES IN ALZHEIMER PATIENTS AND STRATEGIES IN DRUG EVALUATION Agneta Nordberg * 1. INTRODUCTION A great demand is presently put on available functional neuroimaging methods since they may provide a potential to reveal neuronal dysfunction before structural change may appear (Knopman et al. 2001). Positron emission tomography (PET), a non-invasive neuroimaging technique allows quantification and three-dimensional measures of distinct physiological variables such as glucose metabolism, cerebral blood flow, and neurotransmitter and receptor function (Nordberg 1999). Regional deficits in cerebral glucose metabolism (CMRGlu) in the parieto-temporal regions, assessed by [l8F] 2-Fluoro-2-deoxy- D-glucose (FDG) as tracer, have consistently been described in patients with Alzheimer's disease (AD). The fact that the metabolic impairment correlates to deficits in neuropsychological domains and increase with progression of the disease suggest that PET also may provide a sensitive marker of disease progression and severity (Nordberg 1993, Mielke et al. 1994). With the conservative diagnostic criteria for AD the diagnosis may often be given when the clinical symptoms of the disease are quite evident. While the present AD therapies have symptomatic effects with some slowing down of disease progression the drug therapies in the future will hopefully cure/prevent the AD disease (Nordberg and Svensson 1998, Giacobini 2001, Nordberg 2000a, Doody et al. 2001). An early diagnosis at preclinical stages of the disease will be a prerequisite for a successful therapy in the future for AD. The clinical symptoms of AD are probably preceded by a period of unknown duration during which neurophatological alterations may accumulate in the AD brain without detectable changes in cognition (Davis et al. 1999, Goldman et al. 2001). Neuropsychological studies suggest that mild cognitive impairment (MCI) is a condition characterised by subtle cognitive deficits before functional impairments are evident in the patient. MCI might therefore represent an early stage of AD (Almkvist et al. 1998, Petersen et al. 1999, Amaiz et al. 2000). Selective regional impairments of cortical glucose metabolism are found in MCI patients (Minoshima • A. Nordberg, Karolinska Institutet, NEUROTEC, Molecular Neuropharmacology, Huddinge University Hospital, 8-84, S-141 86 Stockholm. Sweden Mapping the Progress of Alzheimer's and Parkinson's Disease Edited by Mizuno et 01., Kluwer AcademiclPlenum Publishers, 2002 183