ABSTRACT
Introduction: Ultrasound can be used to visualize peripheral nerve abnormality. Our objective in this study was to prove whether nerve ultrasound can differentiate between axonal and ...demyelinating polyneuropathies (PNPs). Methods: Systematic ultrasound measurements of peripheral nerves were performed in 53 patients (25 with demyelinating, 20 with axonal, 8 with mixed neuropathy) and 8 healthy controls. Nerve conduction studies of corresponding nerves were undertaken. Results: Analysis of variance revealed significant differences between the groups with regard to motor conduction velocity, compound muscle action potential amplitude, and cross‐sectional area (CSA) of different nerves at different locations. Receiver operating characteristic curve analysis revealed CSA measurements to be well suited for detection of demyelinating neuropathies, and boundary values of peripheral nerve CSA could be defined. Conclusions: Systematic ultrasound CSA measurement in different nerves helped detect demyelination, which is an additional cue in the etiological diagnosis of PNP, along with nerve conduction studies and nerve biopsy. Muscle Nerve 50: 976–983, 2014
In contrast to the programmed nature of development, it is still a matter of debate whether aging is an adaptive and regulated process, or merely a consequence arising from a stochastic accumulation ...of harmful events that culminate in a global state of reduced fitness, risk for disease acquisition, and death. Similarly unanswered are the questions of whether aging is reversible and can be turned into rejuvenation as well as how aging is distinguishable from and influenced by cellular senescence. With the discovery of beneficial aspects of cellular senescence and evidence of senescence being not limited to replicative cellular states, a redefinition of our comprehension of aging and senescence appears scientifically overdue. Here, we provide a factor-based comparison of current knowledge on aging and senescence, which we converge on four suggested concepts, thereby implementing the newly emerging cellular and molecular aspects of geroconversion and amitosenescence, and the signatures of a genetic state termed genosenium. We also address the possibility of an aging-associated secretory phenotype in analogy to the well-characterized senescence-associated secretory phenotype and delineate the impact of epigenetic regulation in aging and senescence. Future advances will elucidate the biological and molecular fingerprints intrinsic to either process.
In the aftermath of an acute stroke, numerous signaling cascades that reshape the brain both in the perilesional zone as well as in more distal regions are activated. Despite continuous improvement ...in the acute treatment of stroke and the sustained research efforts into the pathophysiology of stroke, we critically lag in our integrated understanding of the delayed and chronic responses to ischemic injury. As such, the beneficial or maladaptive effect of some stroke-induced cellular responses is unclear, restricting the advancement of therapeutic strategies to target long-term complications. A prominent delayed effect of stroke is the robust increase in adult neurogenesis, which raises hopes for a regenerative strategy to counter neurological deficits in stroke survivors. In the adult brain, two regions are known to generate new neurons from endogenous stem cells: the subventricular zone (SVZ) and the dentate subgranular zone (SGZ) of the hippocampus. While both niches respond with an increase in neurogenesis post-stroke, there are significant regional differences in the ensuing stages of survival, migration, and maturation, which may differently influence functional outcome. External interventions such as rehabilitative training add a further layer of complexity by independently modulating the process of adult neurogenesis. In this review we summarize the current knowledge regarding the effects of ischemic stroke on neurogenesis in the SVZ and in the SGZ, and the influence of exogenous stimuli such as motor activity or enriched environment (EE). In addition, we discuss the contribution of SVZ or SGZ post-stroke neurogenesis to sensory, motor and cognitive recovery.
Spatial smoothing of functional magnetic resonance imaging (fMRI) data can be performed on volumetric images and on the extracted surface of the brain. Smoothing on the unfolded cortex should ...theoretically improve the ability to separate signals between brain areas that are near together in the folded cortex but are more distant in the unfolded cortex. However, surface-based method approaches (SBA) are currently not utilized as standard procedure in the preprocessing of neuroimaging data. Recent improvements in the quality of cortical surface modeling and improvements in its usability nevertheless advocate this method. In the current study, we evaluated the benefits of an up-to-date surface-based smoothing in comparison to volume-based smoothing. We focused on the effect of signal contamination between different functional systems using the primary motor and primary somatosensory cortex as an example. We were particularly interested in how this signal contamination influences the results of activity and connectivity analyses for these brain regions. We addressed this question by performing fMRI on 19 subjects during a tactile stimulation paradigm and by using simulated BOLD responses. We demonstrated that volume-based smoothing causes contamination of the primary motor cortex by somatosensory cortical responses, leading to false positive motor activation. These false positive motor activations were not found by using surface-based smoothing for reasonable kernel sizes. Accordingly, volume-based smoothing caused an exaggeration of connectivity estimates between these regions. In conclusion, this study showed that surface-based smoothing decreases signal contamination considerably between neighboring functional brain regions and improves the validity of activity and connectivity results.
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•Treatment with PLX5622 leads to a dose-dependent depletion of microglia.•Treatment with PLX5622 differentially affected cytokines in young and aged mice.•Low doses lead to reduction ...in inflammation circumventing the astrocyte activation.•Depletion of microglia led to decreased expression of the senescence marker p16.•Brain inflammation can be reduced by reducing the microglial cell population.
Chronic macrophage activation was implicated as one of the main culprits for chronical, low-grade inflammation which significantly contributes to development of age-related diseases. Microglia as the brain macrophages have been recently implicated as key players in neuroinflammation and neurodegeneration in the aged brain. Microglial cell functions are indispensable in early development, however, activation or senescence of microglia in aging cells may be detrimental. Depletion of microglia using genetical or pharmacological approaches leads to opposite results regarding effects on brain cognition. In this study we pharmacologically depleted microglia using orally delivered low and high doses of the CSF1R inhibitor PLX5622 and assessed the expression levels of known inflammation markers (TNF-α, IL1-β, IL-6, IL-10), glia markers (Iba-1 and Gfap) and specific senescence marker p16Ink4a in the aged murine brain. Our results indicate that treatment with low and high doses of PLX5622 leads to a dose-dependent depletion of microglial cells with similar levels in young and aged mice. We also show that treatment with low and high PLX5622 differentially affected cytokine levels in young and old brains. By using low doses we could achieve reduction in inflammation circumventing the astrocyte activation. Removal of microglia cells led to decreased expression of the senescence marker p16Ink4a in the aged brain, indicating a relevant contribution of these cells to the expression of this marker and their senescent status in the healthy aging brain. Our results indicate that increased and detrimental brain inflammation in aged murine brain can be impaired by selectively reducing the microglial cell population.
Capturing disease progression in amyotrophic lateral sclerosis (ALS) is challenging and refinement of progression markers is urgently needed. This study introduces new motor unit number index ...(MUNIX), motor unit size index (MUSIX) and compound muscle action potential (CMAP) parameters called M50, MUSIX200 and CMAP50. M50 and CMAP50 indicate the time in months from symptom onset an ALS patient needs to lose 50% of MUNIX or CMAP in relation to the mean values of controls. MUSIX200 represents the time in months until doubling of the mean MUSIX of controls. We used MUNIX parameters of Musculi abductor pollicis brevis (APB), abductor digiti minimi (ADM) and tibialis anterior (TA) of 222 ALS patients. Embedded in the D50 disease progression model, disease aggressiveness and accumulation were analyzed separately. M50, CMAP50 and MUSIX200 significantly differed among disease aggressiveness subgroups (p < 0.001) regardless of disease accumulation. ALS patients with a low M50 had a significantly shorter survival compared to high M50 (median 32 versus 74 months). M50 preceded the loss of global function (median of about 14 months). M50, CMAP50 and MUSIX200 characterize the disease course in ALS in a new way and may be applied as early measures of disease progression.
The pathophysiology of amyotrophic lateral sclerosis （ALS） is particularly challenging due to the heteroge- neity of its clinical presentation and the diversity of cellular, molecular and genetic ...peculiarities involved. Molecular insights unveiled several novel genetic factors to be inherent in both familial and sporadic dis- ease entities, whose characterizations in terms of phenotype prediction, pathophysiological impact and putative prognostic value are a topic of current researches. However, apart from genetically well-defined high-confidence and other susceptibility loci, the role of DNA damage and repair strategies of the genome as a whole, either elicited as a direct consequence of the underlying genetic mutation or seen as an autono- mous parameter, in the initiation and progression of ALS, and the different cues involved in either process are still incompletely understood. This mini review summarizes current knowledge on DNA alterations and counteracting DNA repair strategies in ALS pathology and discusses the putative role of unconventional DNA entities including transposable elements and extrachromosomal circular DNA in the disease process. Focus is set on SODl-related pathophysiology, with extension to FUS, TDP-43 and C90RF72 mutations. Advancing our knowledge in the field will contribute to an improved understanding of this relentless dis- ease, for which therapeutic options others than symptomatic approaches are almost unavailable.
•We determined microglia expression of critical metabolic rate limiting enzymes.•We found different metabolic changes occurring in senescent vs. aged microglia cells.•Senescent microglia display ...glycolysis activation and hypermetabolic state.•Aged microglia are rather in a state of hypometabolism.•Metabolic changes in aged microglia may present a novel therapeutical target.
Microglia, the resident immune cells of the central nervous system, are critically involved in maintaining brain homeostasis. With age, microglia display morphological and functional alterations that have been associated with cognitive decline and neurodegeneration. Although microglia seem to participate in an increasing number of biological processes which require a high energy demand, little is known about their metabolic regulation under physiological and pathophysiological conditions and during aging/senescence. Here, we determined mRNA expression levels of critical rate limiting enzymes in several key metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis in association with oxidative phosphorylation in microglia, both under aging and senescent conditions. We found strong evidence for different metabolic changes occuring in senescent vs. aged microglia cells. While senescent microglia display a hypermetabolic state as indicated by increased expression of key enzymes involved in glycolysis and pentose phosphate pathway, aging microglia are rather in a state of hypometabolism. Our findings indicate that studies involving aging and senescent microglia require a clear differentiation between these microglial states due to profound metabolic differences observed here. Understanding metabolic changes in senescent and aged microglia may lead to novel strategies to decrease over-activation of these cells due to aging, which is associated to the process of inflamm-aging and neurodegeneration.
Visually induced motion sickness (VIMS) is a relevant limiting factor in the use of virtual reality (VR) devices. Understanding the origin of this problem might help to develop strategies to ...circumvent this limitation. Previous studies have attributed VIMS to a mismatch between visual, and vestibular information, causing ambiguity of the position of the body in relation to its surrounding. Studies using EEG have shown a shift of the power spectrum to lower frequencies while VIMS is experienced. However, little is known about the relationship between the intensity of the VIMS and the changes in these power spectra. Moreover, the effect of different varieties of VIMS on the causal relationship between brain areas is largely unknown. Here, we used EEG to study 14 healthy subjects in a VR environment who were exposed to increasing levels of mismatch between vestibular and visual information. The frequency power and the bivariate transfer entropy as a measure for the information transfer were calculated. We found a direct association between increasing mismatch levels and subjective VIMS. With increasing VIMS, the proportion of slow EEG waves (especially 1–10 Hz) increases, especially in temporo-occipital regions. Furthermore, we found a general decrease in the information flow in most brain areas but especially in brain areas involved in the processing of vestibular signals and the detection of self-motion. We hypothesize that the general shift of frequency power and the decrease in information flow while experiencing high intensity VIMS represent a brain state of a reduced ability to receive, transmit and process information. We further hypothesize that the mechanism of reduced information flow is a general reaction of the brain to an unresolvable mismatch of information. This reaction aims on transforming a currently unstable model with a high prediction error into a stable model in an environment of minimal contradictory information.
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