Aims of the work
Current research activities
Main results of previous studies
Research program for doctoral theses
Aims of the work
The purpose of the neurological project is to study normal ageing, cognitive brain functions and the etiology and pathophysiology and treatment of neurodegenerative diseases. In normal human brain the effect of ageing on neurotransmitter systems and especially the role of brain dopaminergic system in memory and language functions in investigated. Of the neurodegenerative diseases main focus is on Parkinson´s disease and Alzheimer´s disease.
Current research activities
The main research interest is brain neurotransmission in health and disease. In healthy subjects ur focus is in dopaminergic system. The role of dopaminergic system in various cognitive functions will be explored by using PET to reflect release of dopamine during cognitive tasks. Our preliminary results (Aalto et al. Journal of Neuroscience 2005) suggest that cortical dopamine levels change during cognitive performance. A project to further validate and develop methods to evaluate more precisely and accurately cortical dopamine release during human behaviour is ongoing. We also plan to validate the cortical dopamine release measurement with PET by using drug induced dopamine release. This research line has been accepted as part of the Nordic Centers of Excellence (NoCE) for research in cognitive control. In addition Functional Neuroimaging is one of the key research areas of Turku University Hospital. Neurodegenerative diseases, especially Alzheimer´s disease (AD) and Parkinson´s disease (PD) are the main disease interest areas, especially the cognitive impairment in these disorders. In AD the earliest changes is being explored by a) examining both mono- and dizygotic twins discordant for AD, b)studying a follow up cohorts of subjects with MCI. These studies will exploit the amyloid tracer 11C-PIB which enables to visualise the key pathophysiological mechanism of AD in vivo in living subjects. These studies have importance to both development of early diagnostic methods and to attempts to develop methods to evaluate possible disease modifying therapies in AD. Supporting these efforts we also participate in EU projects (ADIT, Framework 6, NAD, Framework 7) where the main aim is to develop and validate the use of small molecules for the early detection and treatment of AD (ADIT) and to investigate nanoparcticles as possible diagnostic and therapeutic agents (NAD). In PD the focus is on the progression of dopaminergic hypofunction during the course of the disease and its relationship to motor and especially to cognitive impairment. The role of amyloid accumulation in cognitive impairment in PD is being explored. New line of research investigates the role dopaminergic function in relation to cognitive performance and personality traits of the patients. In all of the analyses mentioned above, the PET imaging data will be combined with clinical, neuropsychological and brain MRI data, brain metabolism (FDG) and to genetic analyses (apoE genotype, butyrylcholinesterase gene polymorphism, dopamine receptor gene and COMT gene polymorphisms). These factors may affect the outcome measure or treatment effects and could help to understand differences in imaging analysis and treatment responses between individuals.
Main results of previous studies
The main findings include that we were the first to demonstrate that there is supersensitivity of striatal dopamine receptors in early PD. This finding has impact on the differential diagnosis of parkinsonian syndromes, since in the other parkisonian syndromes a reduced striatal D2 receptor binding is seen. Second important finding is that with fluorodopa- and diprenorphine-PET it was possible to show that patients with sporadic olivo-pontocerebellar atrophy (OPCA) actually have similar impairment of the brain dopaminergic and opioid systems as is seen in MSA suggesting that these two clinical entities represent different ends of a clinical picture in one single disease. Fluorine labelled tropane derivative, FCFT and other dopamine transporter ligands were shown in our PET studies to be sensitive markers for dopaminergic hypofunction in PD and to correlate with the clinical severity of the disease. Combined fluorodopa and dopamine receptor studies have shown the importance of both pre and postsynaptic dopaminergic system in the pathogenesis of fluctuations in PD. We were also able to demonstrate with PET the effects of a new antiparkinsonin drug, entacapone. The enhancement of dopaminergic function in PD patients after entacapone was related to improvement in patients´ clinical condition. The progression studies indicate that the preclinical period in PD is shorter than previously expected. Recent findings in longitudinal follow-up of fluorodopa uptake indicate that the impairment of dopaminergic hypofunction is not linear, but is faster in the beginning of the disease.
In addition, latest results show that brain dopaminergic function and brain atrophy is involved in cognitive symptoms of the patients and is related to harm avoidance personality score. Further studies in these fields are ongoing.
Ageing and dementia
Our previous results show that during ageing the number of striatal dopamine D2 and D1 receptors decline, and interestingly, males and females seem to differ in this respect. In addition, we found that the dopamine receptor gene allele A1 predicts low D2 receptor availability. We have also been able to demonstrate with a high affinity dopamine D2/D3 receptor PET ligand [11C]FLB ageing and Parkinson´s disease related changes in extrastriatal dopamine D2/D3 receptors. It was and found that ageing effects are regionally different and different between women and men. In addition to dopamine receptors, dopamine transporter function declines clearly with age as shown by us with [11C]CFT. In twins discordant for AD we demonstrated that there is a slight reduction in cortical and hippocampal glucose metabolism in the cognitively healthy co-twins. In AD the severity of extrapyramidal symptoms was found to be related to reduced striatal dopamine transporter function and not with D1 and D2 receptors. Studies on the role of extrastriatal dopamine D2/D3 receptors in AD show that hippocampal dopamine receptor availability is associated with cognitive functions in AD.
Also new ligands to study brain acetylcholine system (MP4A for acetylcholinesterase activity, MP4B for butyrylcholinesterase) have been used in healthy controls and people with mild cognitive impairment and AD. It seems that neither of the cholinesterase ligands are suitable for early diagnosis of AD, but are useful in exploring the effect of Alzheimer drugs on brain cholinergic system.
More recently we began to conduct studies with the new amyloid imaging agent 11C-PIB. Our aim is to study subjects with AD, MCI and healthy controls. In addition we will explore Alzheimer component in patients with dementia with Lewy bodies or Parkinson´s disease related dementia or patients with normal pressure hydrocephalus. We have found that 11C-PIB uptake is increased in patients with AD, in subjects with MCI (especially in those who later convert to AD) and also in great proportion of patients with dementia with Lewy bodies. Patients with PD have normal 11C-PIB uptake and only occasionally increased uptake is seen in demeted PD patients. Comparion of brain 11C-PIB uptake and beta-amyloid load in brain biopsy in patients with suspected NPH has revealed a good correlation between in vivo and in vitro estimates of beta-amyloid load.
Our activation studies have also demonstrated changes in cerebral blood flow by mobile phone induced electromagnetic field. Further studies in this field are ongoing. In addition to classical blood flow activation studies we have used a dopamine D2/D3 receptor ligand [11C]FLB with competition principle to reflect changes in cortical dopamine levels during cognitive performance. 11C-raclopride PET has been used to investigate the placebo effects of caffeine in coffee drinkers, and currently studies exploring the effects of intravenous glucose or its expectation on striatal and thalamic dopamine release in obese and lean humans is ongoing. Further validation and development of more sensitive methods are being developed to explore changes in cortical dopaminergic activity during cognitive performance.
Anna Brück, MD, PhD
Valtteri Kaasinen, MD, PhD
Nina Kemppainen, MD, PhD
Juho Joutsa, MD, PhD
Toivo Haltia, MD
Pekka Jokinen, MD
Jaana Koivunen ,BM
Noora Scheinin, MD
Timo Suotunen, BM
Terhi Tuokkola, MD
Jere Virta, MD
Jyri Virta, BM
We have domestic collaboration with the different University Hospitals in Finland. We also have collaboration with different faculties of Turku University and Åbo Akademi University (Departments of biology, pathology, pharmacology, psychology etc.). International collaboration has been established with several laboratories. We are one site in a collaborative project in memory and language that has been accepted as part of the Nordic Centers of Excellence (NoCE) in research in cognitive contrl. We also participate in EU projects in which brain imaging and PET is one part of the project.
Academy of Finland
Turku University Foundation
Turku University Hospital Clinical Funds (EVO)
Sigrid Juselius Foundation
Collaborative projects with drug industry
EU (Framework 6 program project “Design of small molecule therapeutics for the treatment of Alzheimer´s disease based on the discovery of innovative drug targets” ADIT, see www.aditproject.org and Framework 7 program project “Nanoparticles for therapy and diagnosis of Alzheimer´s disease” NAD)
Research programme for doctoral thesis
This project has published doctoral thesis by Hanna Ruottinen, Valtteri Kaasinen, Salla Lamusuo Elina Nurmi, Nina Kemppainen, Tarja Järvenpää, Anna Brück. The neurological research group belongs to the Finnish Graduate School for Neuroscience (FGSN).