Grazyna Debska-Vielhaber

Subfield-specific loss of hippocampal N-acetyl aspartate in temporal lobe epilepsy.

Purpose: In patients with mesial temporal lobe epilepsy (MTLE) it remains an unresolved issue whether the interictal decrease in N‐acetyl aspartate (NAA) detected by proton magnetic resonance spectroscopy (1H‐MRS) reflects the epilepsy‐associated loss of hippocampal pyramidal neurons or metabolic dysfunction.

Metabolic progression markers of neurodegeneration in the transgenic G93A-SOD1 mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. Visualizing corresponding metabolic changes in the brain of patients with ALS with proton magnetic resonance spectroscopy (1H‐MRS) may provide surrogate markers for an early disease detection, for monitoring the progression and for evaluating a treatment response. The primary objective of our study was to evaluate whether modifications in MR metabolite levels occur before clinical disease onset, and whether these changes are directly linked to a distinct spatial progression pattern in the CNS. Therefore, age‐dependent alterations in the cerebral and spinal metabolic profile in the mouse model of ALS overexpressing the mutated human G93A‐superoxide dismutase 1 (G93A‐SOD1) were determined by high‐resolution MRS of tissue extracts at 14.1u2003Tesla. Both non‐transgenic mice (control mice) and transgenic mice overexpressing the non‐mutated human SOD1 (tg‐SOD1) served as controls. In the spinal cord of G93A‐SOD1 mice significantly decreased levels of N‐acetyl aspartate were already detected 34u2003days postpartum, i.e. about 60u2003days before the average disease onset caused by motor neuron decline. In addition, glutamine and γ‐aminobutyric acid concentrations were significantly diminished at Day 75, which is still in the presymptomatic phase of the disease. These metabolic changes were further progressive in the course of the disease and started to involve the brainstem at Day 75. Overall, high‐resolution 1H‐MRS allows a sensitive spatial and temporal metabolite profiling in the presymptomatic phase of ALS even before significant neuronal cell loss occurs.

Mitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion

Charcot–Marie–Tooth neuropathy type 2A (CMT2A) is associated with heterozygous mutations in the mitochondrial protein mitofusin 2 (Mfn2) that is intimately involved with the outer mitochondrial membrane fusion machinery. The precise consequences of these mutations on oxidative phosphorylation are still a matter of dispute. Here, we investigate the functional effects of MFN2 mutations in skeletal muscle and cultured fibroblasts of four CMT2A patients applying high-resolution respirometry. While maximal activities of respiration of saponin-permeabilized muscle fibers and digitonin-permeabilized fibroblasts were only slightly affected by the MFN2 mutations, the sensitivity of active state oxygen consumption to azide, a cytochrome c oxidase (COX) inhibitor, was increased. The observed dysfunction of the mitochondrial respiratory chain can be explained by a twofold decrease in mitochondrial DNA (mtDNA) copy numbers. The only patient without detectable alterations of respiratory chain in skeletal muscle also had a normal mtDNA copy number. We detected higher levels of mtDNA deletions in CMT2A patients, which were more pronounced in the patient without mtDNA depletion. Detailed analysis of mtDNA deletion breakpoints showed that many deleted molecules were lacking essential parts of mtDNA required for replication. This is in line with the lack of clonal expansion for the majority of observed mtDNA deletions. In contrast to the copy number reduction, deletions are unlikely to contribute to the detected respiratory impairment because of their minor overall amounts in the patients. Taken together, our findings corroborate the hypothesis that MFN2 mutations alter mitochondrial oxidative phosphorylation by affecting mtDNA replication.

Interaction of mitochondrial potassium channels with the permeability transition pore

Three types of potassium channels cooperate with the permeability transition pore (PTP) in the inner mitochondrial membranes of various tissues, mtK(ATP), mtBK, and mtKv1.3. While the latter two share similarities with their plasma membrane counterparts, mtK(ATP) exhibits considerable differences with the plasma membrane K(ATP)‐channel. One important function seems to be suppression of release of proapototic substances from mitochondria through the PTP. Open potassium channels tend to keep the PTP closed thus acting as antiapoptotic. Nevertheless, in their mode of action there are considerable differences among them. This review introduces three K+‐channels and the PTP, and discusses known facts about their interaction.

Genetic Variation of the Serotonin 2a Receptor Affects Hippocampal Novelty Processing in Humans

Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing.

Brain 1H magnetic resonance spectroscopic differences in myotonic dystrophy type 2 and type 1

To evaluate cerebral metabolism and intergroup differences in closely matched patients with myotonic dystrophy type 2 (DM2, n = 15) and type 1 (DM1, n = 14), we performed 1H magnetic resonance spectroscopic (MRS) analyses of the occipital and temporoparietal cortical regions as well as of subcortical frontal white matter. Relative to healthy subjects, the concentration of N‐acetylaspartate was significantly reduced in all tested brain regions in both disease groups. In the DM1 patients we also observed a concomitant depletion of creatine and choline levels, particularly in the frontal white matter. A discriminant analysis based on the 1H‐MRS data distinguished between the DM2, DM1, and control groups with an overall accuracy of 88%. 1H‐MRS indicates that neurochemical alterations involving gray and white matter occur in patients with DM2 and DM1. Although structural abnormalities (cerebral atrophy, white matter lesions) are similar in DM2 and DM1, changes in cerebral metabolites can differentiate these disease groups, suggesting that the diseases differ in their neurocellular pathology. Muscle Nerve, 2006

24-Months results in two adults with Pompe disease on enzyme replacement therapy

OBJECTIVEnLate-onset Pompe disease is a slowly progressive disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Since 2006, an intravenous enzyme replacement therapy (ERT) with Myozyme™ (alglucosidase alfa) is available but long-term experience with ERT in late-onset Pompe disease is still limited.nnnMETHODSnTwo adult patients with impaired walking ability and disease duration of 10 and 13 years, respectively received ERT over a period of 24 months. Clinical and functional parameters including dynamometer-based assessment of proximal muscle strength were registered longitudinally.nnnRESULTSnIn both patients some gain in function and physical endurance could be observed which was collaborated by stable dynamometer tests. No serious adverse events occurred and no patient required de novo ventilation.nnnCONCLUSIONnThe clinical results from our data base imply that long term enzyme replacement therapy seems to somewhat affect functionality and quality of life and can stabilize the otherwise progressive disease course in patients with late-onset Pompe disease.

Peripheral nerve ultrasound in amyotrophic lateral sclerosis phenotypes

Introduction: In this study we sought to determine the cross‐sectional area (CSA) of peripheral nerves in patients with distinct subtypes of amyotrophic lateral sclerosis (ALS). Methods: Ulnar and median nerve ultrasound was performed in 78 ALS patients [classic, nu2009=u200921; upper motor neuron dominant (UMND), nu2009=u200914; lower motor neuron dominant (LMND), nu2009=u200920; bulbar, nu2009=u200915; primary lateral sclerosis (PLS), nu2009=u20098] and 18 matched healthy controls. Results: Compared with controls, ALS patients had significant, distally pronounced reductions of ulnar CSA (forearm/wrist level) across all disease groups, except for PLS. Median nerve CSA (forearm/wrist level) did not differ between controls and ALS. Conclusion: Ulnar nerve ultrasound in ALS subgroups revealed significant differences in distal CSA values, which suggests it has value as a marker of LMN involvement. Its potential was particularly evident in the UMND and PLS groups, which can be hard to separate clinically, yet their accurate separation has major prognostic implications. Muscle Nerve 51:669–675, 2015

6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson’s disease: respirometric, histological, and behavioral analyses

Mitochondrial defects have been shown to be associated with the pathogenesis of Parkinson’s disease (PD). Yet, experience in PD research linking mitochondrial dysfunction, e.g., deregulation of oxidative phosphorylation, with neuronal degeneration and behavioral changes is rather limited. Using the 6-hydroxydopamine (6-OHDA) rat model of PD, we have investigated the potential role of mitochondria in dopaminergic neuronal cell death in the substantia nigra pars compacta by high-resolution respirometry. Mitochondrial function was correlated with the time course of disease-related motor behavior asymmetry and dopaminergic neuronal cell loss, respectively. Unilateral 6-OHDA injections (>2.5xa0μg/2xa0μl) into the median forebrain bundle induced an impairment of oxidative phosphorylation due to a decrease in complex I activity. This was indicated by increased flux control coefficient. During the period of days 2–21, a progressive decrease in respiratory control ratio of up to −58xa0% was observed in the lesioned compared to the non-lesioned substantia nigra of the same animals. This decrease was associated with a marked uncoupling of oxidative phosphorylation. Mitochondrial dysfunction, motor behavior asymmetry, and dopaminergic neuronal cell loss correlated with dosage (1.25–5xa0μg/2xa0μl). We conclude that high-resolution respirometry may allow the detection of distinct mitochondrial dysfunction as a suitable surrogate marker for the preclinical assessment of potential neuroprotective strategies in the 6-OHDA model of PD.

Quantifying disease progression in amyotrophic lateral sclerosis using peripheral nerve sonography

Introduction: In this study we investigated whether peripheral nerve sonography could be used as a biomarker to monitor disease progression in amyotrophic lateral sclerosis (ALS). Methods: In 37 patients, ulnar and median nerve cross‐sectional area (CSA) was determined in at least 2 ultrasound sessions; mean follow‐up was 14.5 months. Linear mixed‐effects models were conducted to analyze time effects on CSA. Results: Ulnar nerve CSA declined significantly at a monthly rate of –0.04 mm2 (forearm) and –0.05 mm2 (wrist); the decrease was more pronounced when baseline CSA was greater. To detect a 50% treatment effect on ulnar nerve CSA, 332 patients would need to be entered in a hypothetical randomized, controlled clinical trial. Time had no significant impact on median nerve CSA. Conclusions: Distal ulnar nerve ultrasound may be a useful biomarker to monitor disease progression in ALS, especially as hypothetical treatment effects on CSA seem to be detectable in manageable cohort sizes. Muscle Nerve 54: 391–397, 2016