Deleterious effects of whole- body vibration on the spine: A review of in vivo,ex vivo,and in vitro models

Occupational exposure to whole- body vibration is associated with the develop-ment of musculoskeletal, neurological, and other ailments. Low back pain and other...     

Clinical and neuroimaging findings in MOGAD–MRI and OCT

Myelin oligodendrocyte glycoprotein antibody‐associated disorders (MOGAD) are rare in both children and adults, and have been recently suggested to be an autoimmune neuroinflammatory group of disorders that are different from aquaporin‐4 autoantibody‐associated neuromyelitis optica spectrum disorder and from classic multiple sclerosis. In‐vivo imaging of the MOGAD patient central nervous system has shown some distinguishing features when evaluating magnetic resonance imaging of the brain, spinal cord and optic nerves, as well as retinal imaging using optical coherence tomography. In this review, we discuss key clinical and neuroimaging characteristics of paediatric and adult MOGAD. We describe how these imaging techniques may be used to study this group of disorders and discuss how image analysis methods have led to recent insights for consideration in future studies.     

In vivo and ex vivo range of motion in the fire salamander Salamandra salamandra

Joint range of motion (RoM) analyses are fundamental to our understanding of how an animal moves throughout its ecosystem. Recent technological advances allow for more detailed quantification of this RoM (e.g. including interaction of degrees of freedom) both in ex vivo joints and in vivo experiments. Both types of data have been used to draw comparisons with fossils to reconstruct locomotion. Salamanders are often used as analogues for early tetrapod locomotion; testing such hypotheses requires an in‐depth analysis of salamander joint RoM. Here, we provide a detailed dataset of the ex vivo ligamentous rotational joint RoM in the hindlimb of the fire salamander Salamandra salamandra, using a new method for collecting and visualising joint RoM. We also characterise in vivo joint RoM used during walking, via scientific rotoscoping and compare the in vivo and ex vivo data. In summary, we provide (1) a new method for joint RoM data experiments and (2) a detailed analysis of both in vivo and ex vivo data of salamander hindlimbs, which can be used for comparative studies.     

Cultured dissociated primary dorsal root ganglion neurons from adult horses enable study of axonal transport

Neurological disorders are prevalent in horses, but their study is challenging due to anatomic constraints and the large body size; very few host‐specific in vitro models have been established to study these types of diseases, particularly from adult donor tissue. Here we report the generation of primary neuronal dorsal root ganglia (DRG) cultures from adult horses: the mixed, dissociated cultures, containing neurons and glial cells, remained viable for at least 90 days. Similar to DRG neurons in vivo, cultured neurons varied in size, and they developed long neurites. The mitochondrial movement was detected in cultured cells and was significantly slower in glial cells compared to DRG‐derived neurons. In addition, mitochondria were more elongated in glial cells than those in neurons. Our culture model will be a useful tool to study the contribution of axonal transport defects to specific neurodegenerative diseases in horses as well as comparative studies aimed at evaluating species‐specific differences in axonal transport and survival.     

Comparison of 1540-nm laser-induced injuries in ex vivo and in vitro rabbit corneal models

Despite the increasing use of infrared lasers in medical, industrial, and military settings, data on threshold radiant exposures and median effective dose (ED(50)) as they relate to laser-tissue interaction are limited. Our goals were to determine the ED(50) for single-pulse, 1540-nm laser exposures in ex vivo and in vitro rabbit corneal models and to characterize the histopathological changes associated with the laser-tissue interaction. An erbium-glass laser was used to deliver single, 1540-nm wavelength pulses to 27 ex vivo and 24 in vitro rabbit corneal models. The ex vivo model was exposed to single pulses of 0.8-ms duration and radiant energies ranging from 17.61 J/cm(2) to 42.26 J/cm(2). The in vitro corneal models were exposed to single pulses of 0.8 ms duration and had radiant exposures ranging from 14.87 to 29.72 J/cm(2). Tissue exposure sites were observed for presence of a lesion immediately post-exposure and 24 h after exposure. Histopathological evaluations of tissue exposure sites were conducted 24 h after exposure. The ED(50) was determined to be 21.24 J/cm(2) for the in vitro rabbit corneal models and 30.86 J/cm(2) for the ex vivo corneal models. Both the in vitro and ex vivo models displayed similar histopathological responses of tissue necrosis and epithelial cell proliferation.     

Growth and development of trabecular structure in the calcaneus of Japanese macaques (Macaca fuscata) reflects locomotor behavior,life history,and neuromuscular development

Bone structure dynamically adapts to its mechanical environment throughout ontogeny by altering the structure of trabecular bone, the three‐dimensional mesh‐like structure found underneath joint surfaces. Trabecular structure, then, can provide a record of variation in loading directions and magnitude; and in ontogenetic samples, it can potentially be used to track developmental shifts in limb posture. We aim to broaden the analysis of trabecular bone ontogeny by incorporating interactions between ontogenetic variation in locomotor repertoire, neuromuscular maturation, and life history. We examine the associations between these variables and age‐related variation in trabecular structure in the calcaneus of Japanese macaques (Macaca fuscata). We used high‐resolution micro‐computed tomography scanning to image the calcaneus in a cross‐sectional sample of 34 juvenile M. fuscata aged between 0 and 7 years old at the Primate Research Institute, Japan. We calculated whole bone averages of standard trabecular properties and generated whole‐bone morphometric maps of bone volume fraction and Young’s modulus. Trabecular structure becomes increasingly heterogeneous in older individuals. Bone volume fraction (BV/total volume [TV]) decreases during the first month of life and increases afterward, coinciding with the onset of independent locomotion in M. fuscata. At birth, primary Young’s modulus is oriented orthogonal to the ossification center, but after locomotor onset bone structure becomes stiffest in the direction of joint surfaces and muscle attachments. Age‐related variation in bone volume fraction is best predicted by an interaction between the estimated percentage of adult brain size, body mass, and locomotor onset. To explain our findings, we propose a model where interactions between age‐related increases in body weight and maturation of the neuromuscular system alter the loading environment of the calcaneus, to which the internal trabecular structure dynamically adapts. This model cannot be directly tested based on our cross‐sectional data. However, confirmation of the model by longitudinal experiments and in multiple species would show that trabecular structure can be used both to infer behavior from fossil morphology and serve as a valuable proxy for neuromuscular maturation and life history events like locomotor onset and the achievement of an adult‐like gait. This approach could significantly expand our knowledge of the biology and behavior of fossil species.     

Alleviation of extensive visual pathway dysfunction by a remyelinating drug in a chronic mouse model of multiple sclerosis

Visual deficits are among the most prevalent symptoms in patients with multiple sclerosis (MS). To understand deficits in the visual pathway during MS and potential treatment effects, we used experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The afferent visual pathway was assessed in vivo using optical coherence tomography (OCT), electroretinography (ERG), and visually evoked cortical potentials (VEPs). Inflammation, demyelination, and neurodegeneration were examined by immunohistochemistry ex vivo. In addition, an immunomodulatory, remyelinating agent, the estrogen receptor β ligand chloroindazole (IndCl), was tested for its therapeutic potential in the visual pathway. EAE produced functional deficits in visual system electrophysiology, including suppression of ERG and VEP waveform amplitudes and increased signal latencies. Therapeutic IndCl rescued overall visual system latency by VEP but had little impact on amplitude or ERG findings relative to vehicle. Faster VEP conduction in IndCl‐treated mice was associated with enhanced myelin basic protein signal in all visual system structures examined. IndCl preserved retinal ganglion cells (RGCs) and oligodendrocyte density in the prechiasmatic white matter, but similar retinal nerve fiber layer thinning by OCT was noted in vehicle and IndCl‐treated mice. Although IndCl differentially attenuated leukocyte and astrocyte staining signal throughout the structures analyzed, axolemmal varicosities were observed in all visual fiber tracts of mice with EAE irrespective of treatment, suggesting impaired axonal energy homeostasis. These data support incomplete functional recovery of VEP amplitude with IndCl, as fiber tracts displayed persistent axon pathology despite remyelination‐induced decreases in latencies, evidenced by reduced optic nerve g‐ratio in IndCl‐treated mice. Although additional studies are required, these findings demonstrate the dynamics of visual pathway dysfunction and disability during EAE, along with the importance of early treatment to mitigate EAE‐induced axon damage.     

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change and microvascular pathologies in community‐dwelling older persons

Limbic‐predominant age‐related transactive response DNA‐binding protein 43 (TDP‐43) encephalopathy neuropathologic change (LATE‐NC) and microvascular pathologies, including microinfarcts, cerebral amyloid angiopathy (CAA), and arteriolosclerosis are common in old age. A relationship between LATE‐NC and arteriolosclerosis has been reported in some but not all studies. The objectives of this study were to investigate the frequency of co‐occurring LATE‐NC and microvascular pathologies and test the hypothesis that arteriolosclerosis, specifically, is related to LATE‐NC in brains from community‐dwelling older persons. Analyses included 749 deceased participants with completed data on LATE‐NC and microvascular pathology from 3 longitudinal clinical pathologic studies of aging. Given the specific interest in arteriolosclerosis, we expanded the examination of arteriolosclerosis to include not only the basal ganglia but also two additional white matter regions from anterior and posterior watershed territories. Ordinal logistic regression models examined the association of microvascular pathology with LATE‐NC. LATE‐NC was present in 409 (54.6%) decedents, of which 354 (86.5%) had one or multiple microvascular pathologies including 132 (32.3%) with moderate‐severe arteriolosclerosis in basal ganglia, 195 (47.6%) in anterior watershed, and 144 (35.2%) in posterior watershed; 170 (41.5%) with moderate‐severe CAA, and 150 (36.6%) with microinfarcts. In logistic regression models, only posterior watershed arteriolosclerosis, but not other regions of arteriolosclerosis was associated with a higher odds of more advanced LATE‐NC stages (Odds Ratio = 1.12; 95% Confidence Interval = 1.01–1.25) after controlling for demographics, AD, and other age‐related pathologies. Capillary CAA, but not the severity of CAA was associated with an increased odds of LATE‐NC burden (Odds Ratio = 1.71; 95% Confidence Interval = 1.13–2.58). Findings were unchanged in analyses controlling for APOE ε4, vascular risk factors, or vascular diseases. These findings suggest that LATE‐NC with microvascular pathology is a very common mixed pathology and small vessel disease pathology may contribute to LATE‐NC in the aging brain.     

Ermin deficiency leads to compromised myelin,inflammatory milieu,and susceptibility to demyelinating insult

Ermin is an actin‐binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here, we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de‐compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin‐deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune‐mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near‐exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling “inside‐out” model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability‐targeted therapies.     

Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants

Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP‐43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP‐43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP‐43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer’s disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non‐FTLD related findings can influence the cognitive status, particularly in older age groups.     

FUS‐Immunoreactive Intranuclear Inclusions in Neurodegenerative Disease

Neuronal intranuclear inclusions (NIIs) are a histopathological hallmark of several neurodegenerative disorders. However, the role played by NIIs in neurodegenerative pathogenesis remains enigmatic. Defining their molecular composition represents an important step in understanding the pathophysiology of these disorders. Recently, a nuclear protein, “fused‐in‐sarcoma” (FUS) was identified as the pathological protein in two forms of frontotemporal lobar degeneration (FTLD‐IF, formerly known as neuronal intermediate filament inclusion disease, and FTLD‐UPS, formerly known as atypical FTLD‐U), both of which are characterized by the presence of NII. The objective of the present study was to determine the range of neurodegenerative disorders characterized by FUS‐positive NIIs. Immunostaining for FUS revealed intense reactivity of NIIs in FTLD‐IF and FTLD‐UPS as well as in Huntington''s disease, spinocerebellar ataxias 1 and 3, and neuronal intranuclear inclusion body disease. In contrast, there was no FUS staining of NIIs in inherited forms of FTLD‐TDP caused by GRN and VCP mutations, fragile‐X‐associated tremor ataxia syndrome, or oculopharyngeal muscular dystrophy. In a cell culture model of Huntington''s disease, NIIs were intensely FUS‐positive. NII‐bearing cells displayed loss of the normal diffuse nuclear pattern of FUS staining. This suggests that sequestration of nuclear FUS by NIIs may interfere with its normal nuclear localization.     

Consequences of Making Weight: A Review of Eating Disorder Symptoms and Diagnoses in the United States Military

Eating disorders are serious psychiatric illnesses associated with health problems. Such problems may compromise military performance, highlighting the need to establish the level of eating pathology that exists in military samples. This article qualitatively reviews prevalence estimates of eating disorder symptoms and diagnoses in military samples, providing nonmilitary estimates for context. Findings suggest that eating disorder symptoms are prevalent in cadets and active duty service members, especially when using self‐report measures. The increased salience of weight in the military and increased exposure to trauma may influence risk for eating disorders. Alternatively, individuals at risk for eating disorders may self‐select into the military. Overall, this review suggests that eating disorder symptoms are common in military samples and that further research is warranted.     

Distinct and dementia‐related synaptopathy in the hippocampus after military blast exposures

Explosive shockwaves, and other types of blast exposures, are linked to injuries commonly associated with military service and to an increased risk for the onset of dementia. Neurological complications following a blast injury, including depression, anxiety, and memory problems, often persist even when brain damage is undetectable. Here, hippocampal explants were exposed to the explosive 1,3,5‐trinitro‐1,3,5‐triazinane (RDX) to identify indicators of blast‐induced changes within important neuronal circuitries. Highly controlled detonations of small, 1.7‐gram RDX spherical charges reduced synaptic markers known to be downregulated in cognitive disorders, but without causing overt neuronal loss or astroglial responses. In the absence of neuromorphological alterations, levels of synaptophysin, GluA1, and synapsin IIb were significantly diminished within 24 hr, and these synaptic components exhibited progressive reductions following blast exposure as compared to their stable maintenance in control explants. In contrast, labeling of the synapsin IIa isoform remained unaltered, while neuropilar staining of other markers decreased, including synapsin IIb and neural cell adhesion molecule (NCAM) isoforms, along with evidence of NCAM proteolytic breakdown. NCAM₁₈₀ displayed a distinct decline after the RDX blasts, whereas NCAM₁₄₀ and NCAM₁₂₀ exhibited smaller or no deterioration, respectively. Interestingly, the extent of synaptic marker reduction correlated with AT8‐positive tau levels, with tau pathology stochastically found in CA1 neurons and their dendrites. The decline in synaptic components was also reflected in the size of evoked postsynaptic currents recorded from CA1 pyramidals, which exhibited a severe and selective reduction. The identified indicators of blast‐mediated synaptopathy point to the need for early biomarkers of explosives altering synaptic integrity with links to dementia risk, to advance strategies for both cognitive health and therapeutic monitoring.     

A Zika virus primary isolate induces neuroinflammation,compromises the blood‐brain barrier and upregulates CXCL12 in adult macaques

Zika virus (ZIKV) is a flavivirus that can cause neuropathogenesis in adults and fetal neurologic malformation following the infection of pregnant women. We used a nonhuman primate model, the Indian‐origin Rhesus macaque (IRM), to gain insight into virus‐associated hallmarks of ZIKV‐induced adult neuropathology. We find that the virus causes prevalent acute and chronic neuroinflammation and chronic disruption of the blood‐brain barrier (BBB) in adult animals. ZIKV infection resulted in specific short‐ and long‐term augmented expression of the chemokine CXCL12 in the central nervous system (CNS)of adult IRMs. Moreover, CXCL12 expression persists long after the initial viral infection is apparently cleared. CXCL12 plays a key role both in regulating lymphocyte trafficking through the BBB to the CNS and in mediating repair of damaged neural tissue including remyelination. Understanding how CXCL12 expression is controlled will likely be of central importance in the definition of ZIKV‐associated neuropathology in adults.     

Reduction in miR‐219 expression underlies cellular pathogenesis of oligodendrocytes in a mouse model of Krabbe disease

Krabbe disease (KD), also known as globoid cell leukodystrophy, is an inherited demyelinating disease caused by the deficiency of lysosomal galactosylceramidase (GALC) activity. Most of the patients are characterized by early‐onset cerebral demyelination with apoptotic oligodendrocyte (OL) death and die before 2 years of age. However, the mechanisms of molecular pathogenesis in the developing OLs before death and the exact causes of white matter degeneration remain largely unknown. We have recently reported that OLs of twitcher mouse, an authentic mouse model of KD, exhibit developmental defects and endogenous accumulation of psychosine (galactosylsphingosine), a cytotoxic lyso‐derivative of galactosylceramide. Here, we show that attenuated expression of microRNA (miR)‐219, a critical regulator of OL differentiation and myelination, mediates cellular pathogenesis of KD OLs. Expression and functional activity of miR‐219 were repressed in developing twitcher mouse OLs. By using OL precursor cells (OPCs) isolated from the twitcher mouse brain, we show that exogenously supplemented miR‐219 effectively rescued their cell‐autonomous developmental defects and apoptotic death. miR‐219 also reduced endogenous accumulation of psychosine in twitcher OLs. Collectively, these results highlight the role of the reduced miR‐219 expression in KD pathogenesis and suggest that miR‐219 has therapeutic potential for treating KD OL pathologies.     

Distinct neuronal excitability alterations of medial prefrontal cortex in early‐life neglect model of rats

ObjectEarly‐life neglect has irreversible emotional effects on the central nervous system. In this work, we aimed to elucidate distinct functional neural changes in medial prefrontal cortex (mPFC) of model rats.MethodsMaternal separation with early weaning was used as a rat model of early‐life neglect. The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole‐cell patch clamp.ResultsGlutamatergic and GABAergic neurons of mPFC were distinguished by typical electrophysiological properties. The excitation of mPFC glutamatergic neurons was significantly increased in male groups, while the excitation of mPFC GABAergic neurons was significant in both female and male groups, but mainly in terms of rest membrane potential and amplitude, respectively.ConclusionsGlutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early‐life neglect, which can contribute to distinct mechanisms for emotional and cognitive manifestations.     

General Aspects and Neuropathology of X‐Linked Adrenoleukodystrophy

X‐adrenoleukodystrophy (X‐ALD) is a metabolic, peroxisomal disease affecting the nervous system, adrenal cortex and testis resulting from inactivating mutations in ABCD1 gene which encodes a peroxisomal membrane half‐adenosine triphosphate (ATP)‐binding cassette transporter, ABCD1 (or ALDP), whose defect is associated with impaired peroxisomal β‐oxidation and accumulation of saturated very long‐chain fatty acids (VLCFA) in tissues and body fluids. Several phenotypes are recognized in male patients including cerebral ALD in childhood, adolescence or adulthood, adrenomyeloneuropathy (AMN), Addison''s disease and, eventually, gonadal insufficiency. Female carriers might present with mild to severe myeloneuropathy that resembles AMN. There is a lack of phenotype–genotype correlations, as the same ABCD1 gene mutation may be associated with different phenotypes in the same family, suggesting that genetic, epigenetic, environmental and stochastic factors are probably contributory to the development and course of the disease. Degenerative changes, like those seen in pure AMN without cerebral demyelination, are characterized by loss of axons and secondary myelin in the long tracts of the spinal cord, possibly related to the impaired lipid metabolism of VLCFAs and the associated alterations (ie, oxidative damage). Similar lesions are encountered following inactivation of ABCD1 in mice (ABCD1 ^‐). A different and more aggressive phenotype is secondary to cerebral demyelination, very often accompanied by inflammatory changes in the white matter of the brain and associated with activation of T lymphocytes, CD1 presentation and increased levels of cytokines, γ‐interferon, interleukin (IL)‐1α, IL‐2 and IL‐6, Granulocyte macrophage colony‐stimulating factor (GM‐CSF), tumor necrosis factor‐α, chemokines and chemokine receptors.     

Magnetic resonance imaging correlates of neuro‐axonal pathology in the MS spinal cord

In people with multiple sclerosis (MS), the spinal cord is the structure most commonly affected by clinically detectable pathology at presentation, and a key part of the central nervous system involved in chronic disease deterioration. Indices, such as the spinal cord cross‐sectional area at the level C₂ have been developed as tools to predict future disability, and—by inference—axonal loss. However, this and other histo‐pathological correlates of spinal cord magnetic resonance imaging (MRI) changes in MS remain incompletely understood. In recent years, there has been a surge of interest in developing quantitative MRI tools to measure specific tissue features, including axonal density, myelin content, neurite density, and orientation, among others, with an emphasis on the spinal cord. Quantitative MRI techniques including T₁ and T₂, magnetization transfer and a number of diffusion‐derived indices have all been applied to MS spinal cord. Particularly diffusion‐based MRI techniques combined with microscopic resolution achievable using high magnetic field scanners enable a new level of anatomical detail and quantification of indices that are clinically meaningful.