PET studies of the dopamine system in relation to cognitive functions
Author: Erixon-Lindroth, Nina
Date: 2007-10-12
Location: Föreläsningssalen, Magnus Huss, hus M4:00, Karolinska Universitetssjukhuset, Solna, Stockholm
Time: 09.30
Department: Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
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thesis.pdf (970.6Kb)
Abstract
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. [11C]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 papers:
I. Halldin C, Erixon-Lindroth N, Pauli S, Chou YH, Okubo Y, Karlsson P, Lundkvist C, Olsson H, Guilloteau D, Emond P, Farde L (2003). "[(11)C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain." Eur J Nucl Med Mol Imaging 30(9): 1220-30. Epub 2003 Jun 13
Pubmed
II. Erixon-Lindroth N, Jucaite A, Bäckman L, Halldin C, Farde L (2007). "Density of pre- and postsynaptic dopaminergic markers in striatum are regulated by independent mechanisms a PET study in human subjects." Synapse (Submitted)
III. Erixon-Lindroth N, Baddeley A, Magdalena Nord, Öhman A (2007). "An improved method for testing visuospatial working memory in patients with schizophrenia." Schizophrenia Research (Manuscript)
IV. Erixon-Lindroth N, Farde L, Wahlin TB, Sovago J, Halldin C, Bäckman L (2005). "The role of the striatal dopamine transporter in cognitive aging." Psychiatry Res 138(1): 1-12
Pubmed
I. Halldin C, Erixon-Lindroth N, Pauli S, Chou YH, Okubo Y, Karlsson P, Lundkvist C, Olsson H, Guilloteau D, Emond P, Farde L (2003). "[(11)C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain." Eur J Nucl Med Mol Imaging 30(9): 1220-30. Epub 2003 Jun 13
Pubmed
II. Erixon-Lindroth N, Jucaite A, Bäckman L, Halldin C, Farde L (2007). "Density of pre- and postsynaptic dopaminergic markers in striatum are regulated by independent mechanisms a PET study in human subjects." Synapse (Submitted)
III. Erixon-Lindroth N, Baddeley A, Magdalena Nord, Öhman A (2007). "An improved method for testing visuospatial working memory in patients with schizophrenia." Schizophrenia Research (Manuscript)
IV. Erixon-Lindroth N, Farde L, Wahlin TB, Sovago J, Halldin C, Bäckman L (2005). "The role of the striatal dopamine transporter in cognitive aging." Psychiatry Res 138(1): 1-12
Pubmed
Issue date: 2007-09-21
Rights:
Publication year: 2007
ISBN: 978-91-7357-302-3
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