Biomedical Engineering Reference
In-Depth Information
community. Quantitative readouts are essential for DDD, where the efi cacy of various drug candi-
dates have to be compared in relevant animal models of human disease and ultimately in patients
(see Section 7.2.1). Noninvasiveness enables to monitor changes longitudinally in comparison to a
baseline state, which signii cantly reduces the intra-individual variability and thereby increases the
statistical power of the experiment.
An important advantage of using imaging readouts is the fact that tissue is analyzed in its host
environment with all regulatory processes in place. Any artifacts due to tissue collection and
processing, for example, for subsequent histological analysis, are therefore largely reduced. For
example, tissue collection is invariably linked to a period of global ischemia for a specimen, which
will at least transiently affect metabolite levels. Similarly, histological processing of tissue may
lead to morphological distortions that will affect any morphometric measurements.
Undisputed imaging applications are those providing information that could not be gained other-
wise. In vivo mapping of physiological parameters in a temporospatially resolved manner falls in this
category. An illustrative example is functional analysis of the heart. Dynamic cardiac MRI provides
cardiac functional parameters such as diastolic and systolic ventricular volumes, stroke volume, and
ejection fraction. Moreover, advanced techniques allow analyzing myocardial wall dynamics, wall
stress, as well as hemodynamic l ow characteristics. The method has been applied to characterize
animal models of cardiac hypertrophy and myocardial infarction and to evaluate potential thera-
peutic interventions. Similarly, imaging-based studies of brain function are of considerable interest
for the characterization of CNS disorders and for the evaluation of therapeutic interventions. The
functional CNS response can be recorded with a temporal resolution of seconds, which enables cor-
relative studies to identify networks involved in signal processing and alteration of connectivity in a
pathological condition or due to drug administration. Complementing receptor occupancy informa-
tion with evidence of functional activity opens new perspective for the development of CNS drugs.
7.5 IMAGING IN DDD: CHALLENGES
The various imaging modalities have undergone tremendous development over the last two decades;
yet signii cant advances are required to fully exploit their potential for biomedical applications in
general and DDD in particular.
Imaging technologies
: Diagnostic applications require efi cient 3-dimensional coverage of the
whole body or selected body regions (e.g., whole brain imaging). For example, whole-body FDG
scans allow the detection of the metastatic burden in tumor patients. Similarly, in order to analyze
brain connectivity the whole brain has to be scanned with high temporal resolution to enable cor-
relation of signal response in various brain regions and to analyze how drugs might interfere with
this network.
Diagnostic specii city and sensitivity can be improved by characterizing a given state using mul-
tiple parameters, i.e., by measuring a i ngerprint rather than changes in a single parameter. For
example, it has been shown that combining various MRI readouts such as water diffusion proper-
ties, tissue perfusion status, and microscopic changes as rel ected by altered relaxation rates to
characterize brain tissue in stroke patients allows predicting the outcome for this patient. Such
prognostic data, once validated, could potentially be used to evaluate the efi cacy of therapeutic
interventions. Multivariate tissue analysis requires the development of hybrid imaging technolo-
gies, which, for example, combine structural and physiological or metabolic information (CT/PET,
MRI/PET). Combined techniques can also be used to improve the reconstruction of physiological
data by using prior structural information. Multimodality imaging strategies combining imaging
data at various time and length scales would be crucial in providing information for elucidating the
mechanism underlying the signal changes detected macroscopically.
Also the efi ciency of imaging procedures should be improved to cope with the increasing
number of potential targets that are investigated. For structural phenotyping the time required
