|Art der Förderung:||Standard Projekt|
|Institution:||J. W. Goethe-Universität Frankfurt/Main, Abteilung für klinische Neurophysiologie|
|Projektleiter:||Dr. Martin Jandl|
|Laufzeit:||01. November 2000 - 31. Oktober 2002|
Bislang existieren noch keine geeigneten Nachweismöglichkeiten, die Alzheimer-Erkrankung schon im frühen Stadium zu diagnostizieren. Das Ziel des Forschungsprojektes von Dr. Martin Jandl von der J.W. Goethe-Universität in Frankfurt ist es, diese Nachweismethoden zu entwickeln. Bei der Alzheimer-Erkrankung, so wie bei der vaskulären Demenz, sind nicht die gleichen Hirnregionen pathologisch betroffen. Dr. Jandl ist davon überzeugt, dass bei beiden Gedächtniserkrankungen unterschiedliche Hirnregionen betroffen sind. Diese Hypothese, wird durch die Ausfallerscheinungen von unterschiedlichen Gedächtnisleistungen, wie der Ziel- oder der Neuigkeitswahrnehmung, belegt.
Dr. Jandl geht dabei von zwei unterschiedlichen kortikalen Netzwerken in der Struktur des Gehirns aus. Bei Alzheimer-Patienten ist das Netzwerk für die Zielwahrnehmung stärker gestört, während bei der vaskulären Demenz das Netzwerk für die Neuigkeitswahrnehmung betroffen ist. Anhand von neurophysiologischen und bildgebenden Verfahren werden Informationen bereitgestellt, mit denen die Aktivitätsmuster einzelner Hirnregionen besser voneinander unterschieden werden können. Gleichzeitig wird mit diesen neuen Nachweismethoden der Verlauf der Krankheit schon in der frühen Phase verfolgt, um mögliche psychologische und medikamentöse Behandlungsstrategien gezielter einzusetzen.
A number of diseases related directly or indirectly to the brain can lead to relevant cognitive impairment. This group of diseases is called dementia. Dementia is commonly characterized by memory loss, deficits in attention, language, visuospatial abilities and in other higher cognitive functions. In consequence, the patients become disoriented relative to time, space, situations and even to themselves, which means an important impairment of life-quality and independence. This is why it is so important to recognize the beginning of such pathological processes as early as possible. In some diseases that cause dementia - like Alzheimer's disease (AD) - specific pathological processes concerning the cerebral tissue precede the onset of clinical symptoms. Furthermore, in many cases it is very difficult to assign mild cognitive impairments to a specific disease. An earlier diagnosis of dementia and recognition of the underlying pathological processes is essential for the development of specific and therefore effective treatment strategies in order to stop or at least to slow the underlying pathological processes.
Our objective is to establish new markers that will help to improve this early diagnosis and differential diagnosis of dementias. How can new markers be found and established? In order to understand possible ways to solve this problem it is necessary to have a look inside the brain. The human brain is a very complex network of billions of nerve cells, which are connected to each other in many different ways. Different arrays of nerve cells work synchronized in order to fulfil specific functions. This synchronized effort can be visualized by different methods of "neuroimaging". One of these methods is the measurement of electromagnetic fields over the scalp, generated by arrays of nerve cells firing synchronous electrical pulses. When these electromagnetic fields are related to specific events or cognitive processes, they are called 'event related potentials' (ERP). Increasing effort of nerve cells in different regions also leads to increasing blood flow within these regions, which in turn induces processes we can visualize by "functional magnetic resonance imaging" (fMRI). The great advantage of fMRI is its superb spatial resolution (around 1mm), which allows us to localize precisely the areas of the brain that are working on a specific task. By applying the same tasks during fMRI and ERP measurements, we can combine the specific advantages of both methods and thus establish patterns of functional activation. Alterations of these patterns should be very sensitive to early pathological processes of the brain and very specific for the different dementias.
In the last year we developed a paradigm that involves the processing of novel and target stimuli. This paradigm taps into two cognitive functions, encoding of new material into memory, and attention, that are impaired relatively early in the course of dementia. It also evokes one of the classic components of the ERP, the so-called P 300 (because it arises more than 300 milliseconds after the stimulus). We demonstrated with fMRI and ERP in a healthy control population that the brain mechanisms of target and novelty processing are indeed different. We then applied this paradigm to patients with various types of dementia and found that, as expected, the patterns of fMRI and ERP activation differed from those of the healthy controls. The "amplitude" (reflecting roughly how many neurons are activated at the same time) of the P300 was reduced, and its "latency" (reflecting roughly how long its takes until they are activated) was prolonged. This indicates that dementia patients recruit fewer neurons for target detection than healthy controls, and that they recruit them later, explaining why the patients are often slower and less accurate to respond even to relatively simple tasks.
Our initial hope that the ERP and fMRI measures of the P300 and its subcomponents could be established as a tool for the differential diagnosis of dementia were not confirmed. However, it seems that the combination of both ERP and fMRI with structural MRI will help our understanding of the functional and cognitive consequences of the pathological processes of AD and vascular dementia.
We are currently conducting a follow up study that aims to combine the elechophysiological data of the P300 with detailed cognitive assessment and structural MRI (looking at cortical thickness and, with diffusion tensor imaging, at the integrity of the fibre tracts linking cortical areas) in different patient groups with dementia.
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Bledowski, C., Prvulovic, D., Hoechstetter, K., Scherg, M., Wibral, M., Goebel, R. and Linden, D. E. J. (2004). Localizing P300 Generators in Visual Target and Distractor Processing: A Combined Event-Related Potential and Functional Magnetic Resonance Imaging Study. J. Neurosci., 24:9353-9360.
Van de Ven, V., Formisano, E., Prvulovic, D., Roeder, C. and Linden, D. (2004). Functional connectivity as revealed by spatial independent component analysis of fMRI measurements during rest. Human Brain Mapping, 22:3165-178.
Sack, A. T., Hubl, D., Prvulovic, D., Formisano, E., Jandl, M., Zanella, F. E., Maurer, K., Goebel, R., Dierks, T. and Linden, D. E. J. (2002). The experimental combination of rTMS and fMRI reveals the functional relevance of parietal cortex for visuospatial functions. Cognitive Brain Research, 13:85-93.