Olaf Lenz

Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene

A kindred from South Tyrol (northern Italy) with familial, adult‐onset parkinsonism of pseudo‐dominant inheritance and mutations in the parkin gene was recently described. To gain insight into basal ganglia dysfunction in this form of hereditary parkinsonism, positron emission tomography (PET) with 18‐fluorodopa (FDOPA) and 11C‐raclopride (RAC) was performed in 5 affected family members and 5 asymptomatic relatives with proven compound heterozygous or heterozygous parkin mutations. Results were compared to findings in healthy control subjects and patients with typical sporadic, idiopathic Parkinson‘s disease. Similar to findings in the sporadic Parkinson’s disease group, presynaptic striatal FDOPA storage was decreased in patients with compound heterozygous parkin mutations, with the most prominent reduction in the posterior part of the putamen. Along with the presynaptic lowered FDOPA uptake, we found a uniform reduction of the striatal 11C‐raclopride binding index in all affected family members as compared to asymptomatic family members carrying a heterozygous parkin mutation, sporadic Parkinsons disease, and control subjects. Our PET data provide evidence that parkinsonism in this family is associated with presynaptic dopaminergic dysfunction similar to idiopathic Parkinsons disease pathophysiology, along with alterations at the postsynaptic D2 receptor level. In asymptomatic carriers of a single parkin mutation with an apparently normal allele, we found a mild but statistically significant decrease of mean FDOPA uptake compared to control subjects in all striatal regions. These data indicate a preclinical disease process in these subjects. Ann Neurol 2001;49:367–376

In vivo study of acetylcholine esterase in basal forebrain, amygdala, and cortex in mild to moderate Alzheimer disease

It is currently unclear whether impairment of the cholinergic system is present in Alzheimer disease (AD) already at an early stage and to what extent it depends on degeneration of the nucleus basalis of Meynert (nbM). We examined acetylcholine esterase activity in vivo in the nbM, the amygdala, and cerebral neocortex. Measurements were performed in normal controls and in patients with mild to moderate AD with positron emission tomography (PET) and C-11-labeled N-methyl-4-piperidyl-acetate (MP4A) which is a specific substrate of AChE. AChE activity was reduced significantly in amygdala and cerebral cortex. In contrast, AChE activity and glucose metabolism appeared preserved or even increased in the nbM. The results support the concept that neocortical and amygdaloid functional changes of the cholinergic system are an early and leading event in AD, rather than the consequence of neurodegeneration of basal nuclei.

In-vivo measurements of regional acetylcholine esterase activity in degenerative dementia: comparison with blood flow and glucose metabolism

Summary. Memory and attention are cognitive functions that depend heavily on the cholinergic system. Local activity of acetylcholine esterase (AChE) is an indicator of its integrity. Using a recently developed tracer for positron emission tomography (PET), C-11-labeled N-methyl-4-piperidyl-acetate (C-11-MP4A), we measured regional AChE activity in 4 non-demented subjects, 4 patients with dementia of Alzheimer type (DAT) and 1 patient with senile dementia of Lewy body type (SDLT), and compared the findings with measurements of blood flow (CBF) and glucose metabolism (CMRGlc). Initial tracer extraction was closely related to CBF. AChE activity was reduced significantly in all brain regions in demented subjects, whereas reduction of CMRGlc and CBF was more limited to temporo-parietal association areas. AChE activity in SDLT was in the lower range of values in DAT. Our results indicate that, compared to non-demented controls, there is a global reduction of cortical AChE activity in dementia.

ESPResSo 3.1: Molecular Dynamics Software for Coarse-Grained Models

ESPResSo is a package for Molecular Dynamics (MD) simulations of coarse-grained models. We present the most recent version 3.1 of our software, highlighting some recent algorithmic extensions to version 1.0 presented in a previous paper (Limbach et al. Comput Phys Commun 174:704–727, 2006). A major strength of our package is the multitude of implemented methods for calculating Coulomb and dipolar interactions in periodic and partially periodic geometries. Here we present some more recent additions which include methods for systems with dielectric contrasts that frequently occur in coarse-grained models of charged systems with implicit water models, and an alternative, completely local electrostatic solver that is based on the electrodynamic equations. We also describe our approach to rigid body dynamics that uses MD particles with fixed relative positions. ESPResSo now gained the ability to add bonds during the integration, which allows to study e.g. agglomeration. For hydrodynamic interactions, a thermalized lattice Boltzmann solver has been built into ESPResSo, which can be coupled to the MD particles. This computationally expensive algorithm can be greatly accelerated by using Graphics Processing Units. For the analysis of time series spanning many orders of magnitude in time scales, we implemented a hierarchical generic correlation algorithm for user-configurable observables.

P3M algorithm for dipolar interactions.

An extension to the P(3)M algorithm for electrostatic interactions is presented that allows to efficiently compute dipolar interactions in periodic boundary conditions. Theoretical estimates for the root-mean-square error of the forces, torques, and the energy are derived. The applicability of the estimates is tested and confirmed in several numerical examples. A comparison of the computational performance of the new algorithm to a standard dipolar-Ewald summation methods shows a performance crossover from the Ewald method to the dipolar P(3)M method for as few as 300 dipolar particles. In larger systems, the new algorithm represents a substantial improvement in performance with respect to the dipolar standard Ewald method. Finally, a test comparing point-dipole-based and charged-pair based models shows that point-dipole-based models exhibit a better performance than charged-pair based models.

Simulation of charge reversal in salty environments : Giant overcharging?

Abstract.We have performed MD simulations of a highly charged colloid in a solution of 3:1 and additional 1:1 salt. The dependency of the colloids inverted charge on the concentration of the additional 1:1 salt has been studied. Most theories predict, that the inverted charge increases when the concentration of monovalent salt grows, up to what is called giant overcharging, while experiments and simulational studies observe the opposite. Our simulations agree with the experimental findings and shed light onto the weaknesses of the theories.

A generic model for lipid monolayers, bilayers, and membranes

We describe a simple coarse-grained model which is suited to study lipid layers and their phase transitions. Lipids are modeled by short semiflexible chains of beads with a solvophilic head and a solvophobic tail component. They are forced to self-assemble into bilayers by a computationally cheap ‘phantom solvent’ environment. The model reproduces the most important phases and phase transitions of monolayers and bilayers. Technical issues such as Monte Carlo parallelization schemes are briefly discussed.

PET measurement of cerebral acetylcholine esterase activity without blood sampling.

Abstract. Measurement of cerebral acetylcholine esterase (AChE) activity is of clinical interest for the differential diagnosis of memory disorders and dementia. We developed and tested a non-invasive method for quantitation of regional cortical AChE activity with carbon-11-labelled N-methyl-4-piperidyl acetate (11C-MP4A) that does not require arterial blood sampling. AChE activity was measured in terms of the rate constant for hydrolysis of 11C-MP4A (k3). The physiological model is based on the very high AChE activity in the basal ganglia, which are used as a reference structure. Non-invasive k3 was compared with k3 determined with a standard technique by fitting kinetic tissue and metabolite-corrected plasma data in nine subjects with and without dementia. Across all regional values, a very high correlation of 0.92 was found, with a tendency towards moderate underestimation of k3 by 5%–14% with the non-invasive technique as compared to the invasive technique. In addition to its advantages with respect to practicability, the new non-invasive technique overcomes problems of the invasive technique that are related to interindividual variation of delay times between cerebral and peripheral tracer arrival and measurement of very small amounts of non-hydrolysed tracer in plasma samples.

The optimal P3M algorithm for computing electrostatic energies in periodic systems.

We optimize Hockney and Eastwoods particle-particle particle-mesh algorithm to achieve maximal accuracy in the electrostatic energies (instead of forces) in three-dimensional periodic charged systems. To this end we construct an optimal influence function that minimizes the root-mean-square (rms) errors of the energies. As a by-product we derive a new real-space cutoff correction term, give a transparent derivation of the systematic errors in terms of Madelung energies, and provide an accurate analytical estimate for the rms error of the energies. This error estimate is a useful indicator of the accuracy of the computed energies and allows an easy and precise determination of the optimal values of the various parameters in the algorithm (Ewald splitting parameter, mesh size, and charge assignment order).

Simulational study of anomalous tracer diffusion in hydrogels

In this article, we analyze different factors that affect the diffusion behavior of small tracer particles (as they are used, e.g., in fluorescence correlation spectroscopy (FCS)) in the polymer network of a hydrogel and perform simulations of various simplified models. We observe, that under certain circumstances the attraction of a tracer particle to the polymer network strands might cause subdiffusive behavior on intermediate time scales. In theory, this behavior could be employed to examine the network structure and swelling behavior of weakly crosslinked hydrogels with the help of FCS.