PET studies of the dopamine system in relation to cognitive functions

The human brain is intricately designed to execute cognitive functions such as perception, attention, memory and learning. Deficits in cognitive functions accompany major psychiatric disorders such as schizophrenia, attention deficit hyperactivity disorder and Parkinson’s disease. The biological underpinnings of cognitive functions, is however poorly understood. One of the neurotransmitters proposed to play a central role in cognition is dopamine (DA). Positron emission tomography (PET) is a non-invasive molecular imaging technique by which biomarkers for neurotransmission systems can be examined in the human brain in vivo and related to higher brain functions. Development of new tests based on advances in cognitive science provides tools to identify basic elements of cognition. The first aim of the present thesis was to develop improved methodologies, both for molecular imaging and cognitive testing. The second aim was to apply these methods in a combined fashion with the intention to increase understanding of the organization of the DA system in the human brain and its role in cognitive functions. In the first study, a new selective radioligand for the dopamine transporter (DAT) was developed. [C]PE2I binding was characterized in four non-human primates and in one human control subject, showing better selectivity for the DAT when compared to previously developed radioligands. In addition, the distinctive contrast of this radioligand demonstrated sufficient signal not only in striatum, but also in substantia nigra. The relationship between the presynaptic DAT and the mainly postsynaptic DA D2 receptor was examined in a double-tracer PET study (Study II). The results from 17 human subjects demonstrated a lack of a correlation, suggesting independent regulation of the two DA biomarkers in the human striatum. The results suggest that these two biomarkers may not be mutually interchangeable when assessing the DAergic system in the healthy brain. Visuospatial working memory (VSWM) is commonly impaired in patients with schizophrenia resulting in disorganization in both thoughts and behavior. In Study III, a standard VSWM-test was modified to reduce ceiling effects among control subjects, thus allowing for a less biased comparison between patients with schizophrenia and controls. In addition, during high WM load the control group showed improved performance when the stimulus arrangement invited the use of cognitive strategies, as compared to an arrangement with random location of the target stimulus. This improvement was not present in the patient group. The results indicate that patients with schizophrenia do not make use of, or generate strategies to the same extent as control subjects. In the final study, the role of the DAT was examined in relation to cognitive aging. Cognitive performance was assessed in 12 human subjects, ranging from 34-81 years of age, and DAT density was quantified using PET. The results indicate that DAT may serve as a biomarker of age-related deficits in episodic memory and executive function, and that DAT is implicated in cognitive performance irrespective of age. In conclusion the present thesis, based on a combination of molecular imaging and cognitive assessment, corroborates a role for the DA system in higher brain functions in man. List of publications I. Halldin C. , Erixon-Lindroth N. , Pauli S. , Chou Y.H. , Okubo Y. , Karlsson P., Lundkvist C. , Olsson H. , Guilloteau D. , Emond P. and Farde L. [C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain. European Journal of Nuclear Medicine Molecular Imaging, 2003, 30: 1220-1230 II. Erixon-Lindroth N. , Jucaite A. , Bäckman L. , Halldin C. and Farde L. Density of preand postsynaptic dopaminergic markers in striatum are regulated by independent mechanisms – a PET study in human subjects. Manuscript submitted to Synapse III. Erixon-Lindroth N. , Baddeley A. , Magdalena Nord and Öhman A. An improved method for testing visuospatial working memory in patients with schizophrenia. Manuscript under revision in Schizophrenia Research IV. Erixon-Lindroth N. , Farde L. , Wahlin TB. , Sóvágó J., Halldin C. and Bäckman L. The role of the striatal dopamine transporter in cognitive aging. Psychiatry Research Neuroimaging, 2005, 138 (1): 1-12 All previously published papers were reprinted with kind permission from the publishers.