Friederike von Lewinski

Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS

Motoneurons are selectively damaged in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Although the underlying mechanisms are not completely understood, increasing evidence indicates that motoneurons are particularly sensitive to disruption of mitochondria and Ca(2+)-dependent signalling cascades. Comparison of ALS-vulnerable and ALS-resistant neurons identified low Ca(2+)-buffering capacity and a strong impact of mitochondrial signal cascades as important risk factors. Under physiological conditions, weak Ca(2+) buffers are valuable because they facilitate rapid relaxation times of Ca(2+) transients in motoneurons during high-frequency rhythmic activity. However, under pathological conditions, weak Ca(2+) buffers are potentially dangerous because they accelerate a vicious circle of mitochondrial disruption, Ca(2+) disregulation and excitotoxic cell damage.

Extensive exercise is not harmful in amyotrophic lateral sclerosis

Whether physical activity increases risk or promotes progression of motor neurone degeneration in amyotrophic lateral sclerosis (ALS) is still debated. Current pathophysiological hypotheses include excitotoxicity, oxidative stress and increased calcium loads as causes of selective degeneration of vulnerable motor neurones. Vigorous exercise might amplify these factors by increasing firing rates at motor neurones. To test this hypothesis, we constrained a transgenic mouse model of ALS overexpressing the mutant human form of the Cu/Zn superoxide dismutase‐1 (SOD‐1) to a lifetime exercise on motor‐driven running wheels for 10 h daily (active group, n = 12). Onset and progression of disease were assessed by grip strength, stride length and tight rope test. Data were compared with SOD‐1 mice placed in running wheels set to slow speed (sedentary group, n = 13). Untreated SOD‐1 mice were an additional control group (n = 12). We found no differences in disease onset, which was determined by a change‐point analysis using an iterative fitting of segmented linear regression models, or in disease progression. However, the running group showed a non‐significant 6‐day improvement in survival (133.7 ± 3.2 days) compared with the sedentary group (127.2 ± 3.2 days) and a 4‐day improvement compared with the control group (129.1 ± 2.5 days). We demonstrate that a lifetime of vigorous exercise does not promote onset or progression of motor degeneration in SOD‐1‐mediated ALS. Moreover, the results suggest that the level of excitatory input and calcium turnover at motor neurones, both of which should be increased by running activity, do not interfere with the pathophysiology of SOD‐1‐mediated ALS.

T2*-weighted MRI in diagnosis of multiple system atrophy : A practical approach for clinicians

BackgroundPutaminal iron deposition is a histopathological feature of multiple system atrophy (MSA), which is not observed in patients with idiopathic Parkinson’s disease (PD). T2*-weighted magnetic resonance imaging (MRI) gradient echo (GE) sequences are sensitive for paramagnetic susceptibility changes and therefore may support the clinical differential diagnosis between MSA and PD.MethodsWe evaluated putaminal signal intensities on 1.0 Tesla scans of 52 MSA patients, 88 patients with PD and 29 healthy control subjects.ResultsThe typical finding in T2* GE sequences of MSA patients was a signal loss of the dorsolateral putamen, which showed a high specificity (>0.91), but was present in only a subpopulation of patients (sensitivity 0.64–0.69). The combination of the latter with additional presence of a hyperintense lateral rim in fluid attenuated inversion recovery (FLAIR) sequences increased the specificity to 0.97. Using a quantitative evaluation of putaminal signal intensities in defined regions of interest MSA and PD could be discriminated with a diagnostic accuracy (r) of up to 0.82.ConclusionAlthough the separation of groups remains incomplete, the use of T2*-weighted GE sequences combined with FLAIR may be helpful for the differential diagnosis of MSA versus PD considering its fast application, easy evaluation, broad availability, the specificity of findings and the presence of putaminal signal loss already at early disease stages.

Low Ca2+ buffering in hypoglossal motoneurons of mutant SOD1 (G93A) mice.

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are associated with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by a selective degeneration of brainstem and spinal motoneurons. The pathomechanism of degeneration is still incompletely understood, but includes a disruption in cellular Ca2+ homeostasis. Here we report a quantitative microfluorometric analysis of the Ca2+ homeostasis in vulnerable hypoglossal motoneurons of neonatal mutant (G93A) SOD1 transgenic mice, a mouse model of human ALS. Ca2+ transient decay times (tau = 0.3 s), extrusion rates (gamma = 92 s(-1)) and exceptionally low intrinsic Ca2+ binding ratios (kappaS = 30) were found to be in the same range as compared to non-transgenic animals. Together with the previous observation of high Ca2+ binding ratios in ALS-resistant neurons (e.g. oculomotor), this supports the assumption that low Ca2+ buffering in vulnerable motoneurons represents a significant risk factor for degeneration. On the other hand, alterations in buffering properties by expression of mutant SOD1 are unlikely to be involved in disease initiation.

Towards physiological ankle movements with the ActiGait implantable drop foot stimulator in chronic stroke

Ahead of Print article withdrawn by publisher.

Impairment of brainstem implicit learning paradigms differentiates multiple system atrophy (MSA) from idiopathic Parkinson syndrome

Objectives Learning as measured by eyeblink classical conditioning is preserved in patients with idiopathic Parkinsons disease, but severely affected in patients with progressive supranuclear palsy. We here sought to clarify whether procedural learning is impaired in multiple system atrophy (MSA), and whether it may be helpful for the differentiation of parkinsonian syndromes. Design We investigated learning using (1) eyeblink classical conditioning with a delay (interstimulus interval 0 ms) and a trace (600 ms) paradigm and (2) a serial reaction time task. Setting Participants were recruited from academic research centres. Participants 11 patients with MSA and 11 healthy controls. Results Implicit learning in eyeblink classical conditioning (acquisition of conditioned responses) as well as the serial reaction time task measures of implicit learning (reaction time change) are impaired in patients with MSA as compared with controls, whereas explicit learning as measured by the sequence recall of the serial reaction time task is relatively preserved. Analysis We hypothesise that the learning deficits of patients with MSA are due to lesions of cerebellar and connected brainstem areas. Conclusions A retrospective synopsis of these novel data on patients with MSA and groups of patients with idiopathic Parkinsons disease and progressive supranuclear palsy studied earlier suggest that eyeblink classical conditioning may contribute to the early differentiation of atypical Parkinson syndromes from idiopathic Parkinsons disease. This hypothesis should be tested in a prospective trial.

Motoneuronerkrankungen und amyotrophe Lateralsklerose (ALS): von der molekularen Analyse der Ursachen zu neuen therapeutischen Ansätzen

Zusammenfassung Die amyotrophe Lateralsklerose (ALS) ist eine neurodegenerative Erkrankung, die durch eine selektive Zerstörung von Motoneuronen gekennzeichnet ist. Untersuchungen der letzten Jahre haben neue Einblicke in die molekularen und zellulären Ursachen der ALS ermöglicht, wobei die Analyse der familär bedingten Erkrankungsformen besonders wertvolle Erkenntnisse gebracht hat. Aus heutiger Sicht haben Störungen der glutamatergen synaptischen Übertragung, oxidativer Stress, mitochondriale Dysfunktion und eine gestörte Proteinfaltung eine zentrale Bedeutung für die Pathogenese der ALS-Erkrankung. Der vorliegende Artikel zeigt auf, wie das Zusammenspiel verschiedenartiger Störungen zur selektiven Degeneration von Motoneuronen führen kann. Trotz beeindruckender Fortschritte in der Grundlagenforschung haben klinische Studien bisher noch keine befriedigende medikamentöse Behandlung identifizieren können. Dabei zeichnet sich ab, dass eine effektive Therapie nicht durch einen einzelnen Wirkstoff, sondern erst durch eine Kombination verschiedenartiger neuroprotektiver Maßnahmen erreicht werden kann. Darüber hinaus versprechen gentherapeutische Ansätze und eine Stammzellbehandlung neue Therapiemöglichkeiten, die allerdings bisher auf vorklinische Studien beschränkt sind. Neben der Identifikation neuer therapeutischer Ansätze ist es wichtig, effiziente Marker für die ALS zu identifizieren, um schon im frühen Stadium der Erkrankung neuroprotektive Maßnahmen einleiten zu können.