LVR-Klinikum Düsseldorf Hospital of the Heinrich-Heine University ...

LVR-KLINIKUM DÜsseLDORF – hOsPITaL OF The heINRIch-heINe UNIVeRsITY DÜsseLDORF
Genetic principles of brain perfusion
in Alzheimer’s Dementia
C. Luckhaus, K. Fehsel in cooperation with H. J. Wittsack
(Institute for Radiology of the Heinrich-Heine University,
Düsseldorf) and the FMER-funded Competence Network on
Dementia
Project period: from 2007
Financing: Sub-project within the FMER-funded Competence
Network on Dementia (Funding No: 01GI0420)
In an ongoing functional neuroimaging study, we were able
to provide evidence for substantial changes of regional brain
perfusion already at the stage of mild cognitive impairment
(MCI), which appeared independently of regional atrophy
and of the APOE epsilon genotype. We are now looking
at the question of how far regional and global blood flow
values are associated with functional variants of relevant
candidate genes (endothelin 1, IL1beta, PP2A activator, NF
kappa B subunit B, KCNN3, NOS 3). Initial findings point to
a specific association of two variants of the NOS3 gene with
global brain perfusion in MCI and Alzheimer’s Dementia.
It is planned to confirm this association and to test other
associations with other candidate genes in a larger sample.
Establishing a murine neuronal lesion model in vitro:
investigations into the change of electrical spontaneous
activity of neuronal/glial networks through physical and
neurotoxic lesions
U. Henning, P. Görtz, Ch. Lange-Asschenfeldt and C. Luckhaus
Project period: from 2008
Financing: Departmental research budget
In relation to a possible regeneration of the central cellular
organisation, investigations were carried out, published in
the 1960s, into a paradigm shift proposing that neurons
were able to regenerate constantly in the brain. New animal
experiments show that neurogenesis can be stimulated by
activating the brain, as well as by drug components. It is
possible to measure the functional integrity of a neuronalglial
cell association in vitro using multi-electrode array
chip technology (MEA). The functional characteristic of
this cell model is the formation of electrical impulses, the
so-called “bursts”, which can be recorded using a special
recording system. These bursts are quantifiable in relation
to the number of bursts and their amplitude. This method
appears to be very suitable for investigating the integration
of embryonic stem cells (ES) into an electrophysiologically
active cell association. The integration and, thereby, the
differentiation of ES, which are experimentally added into
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the network, should influence the functional integrity of the
cell association and, thereby, the MEA-based recording of
network-evoked potentials (bursts).
Our approach to the investigation of functional neurogenesis
uses MEA technology to measure the activity of neuronal
networks before and after the induction of lesions. The
initial basic experiments will aim to define the threshold
concentrations at which cellular damage occurs. A second
phase will test whether drug components may prevent
damage or result in the restoration of neuronal activity.
Comorbidity of Alzheimer’s Dementia and Osteoporosis
C. Luckhaus, B. Mahabadi, T. Supprian, K. Fehsel in
cooperation with M. Jäger and H. Willenberg
Project period: from 2006
Financing: Departmental research budget
Epidemiological and clinical disease course studies not
only prove a comorbidity link between osteoporosis (Op) and
Alzheimer’s Dementia (AD), but also a link with prodromal
illness stages, such as cognitive decline und decline of
bone mineral density (BMD). In addition, several molecular
factors, such as oestrogen, NO, ROS and intracellular
signalling pathways, such as GSK-3, are documented as
pathogenetically relevant factors in both illnesses. In this
context, we are investigating biochemical factors of bone
metabolism – which are quantifiable in blood plasma –
in patients with Alzheimer’s Dementia, mild cognitive
impairment, osteoporosis and healthy controls. This
should lead to an answer to the question whether common
pathogenetic factors underlie these comorbidities. Initial
findings already indicate significant differences between the
diagnostic groups, which point to asymptomatic, vitamin
D-independent bone resorption and bone remodelling
processes at the MCI stage. Specific markers of bone
resorption will now be investigated. A cell-biological
approach will address the question of whether these and
additional plasma factors altered in AD have an influence
on the proliferation and differentiation of CD34-negative
mesenchymal stem cells.