Myelinated Fibers Research Articles

Understanding neuropathic pain: the role of neurophysiological tests in unveiling underlying mechanisms

AbstractNeuropathic pain, arising from lesions of the somatosensory nervous system, presents with diverse symptoms including ongoing pain, paroxysmal pain, and provoked pain, usually accompanied by sensory deficits. Understanding the pathophysiological mechanisms behind these symptoms is crucial for targeted treatment strategies. Neurophysiological techniques such as nerve conduction studies, reflexes, and evoked potentials help elucidate these mechanisms by assessing large myelinated non-nociceptive fibres and small nociceptive fibres. This argumentative review highlights the importance of tailored neurophysiological assessments for improving our understanding of the pathophysiological mechanisms behind neuropathic pain symptoms.

Contribution of remote Pacinian corpuscles to flutter-range frequency discrimination in humans.

Among the various classes of fast-adapting (FA) tactile afferents found in hairy and glabrous skin, FA2 afferents, associated with Pacinian corpuscles (PC), preferentially signal high-frequency sinusoidal events corresponding with vibration percepts, in contrast to other classes associated with lower frequency flutter percepts. The FA2-PC complex is also uniquely sensitive to distant sources of vibration mechanically transmitted through anatomical structures. In the present study, we used a pulsatile waveform to assess the contribution of FA2 afferents to the perception of flutter-range frequency stimuli (~ 20Hz) in combination with two methods to abolish local FA inputs and force a dependence on FA2 via transmission from adjacent structures. Firstly, we examined frequency discrimination and perception of vibration applied to the hairy skin overlying the ulnar styloid before and during the blockade of intradermal receptors by local anaesthesia. Secondly, we tested frequency discrimination on the digital glabrous skin before and during the blockade of myelinated fibres by ulnar nerve compression. Despite reliance on vibration transmission to activate remote PCs, we found that flutter-range frequency discrimination was unimpeded across both skin types. Comparisons with stimuli applied to the contralateral side also indicated that perceived frequency was unaffected. This confirms that flutter-range frequency perception can be encoded by the FA2-PC system. Our results demonstrate that input from receptors specialised for low-frequency signalling is not mandatory for flutter-range frequency perception. This explains how the constancy of frequency perception might be achieved across different skin regions, irrespective of the afferent type activated for transmitting these signals.

Effect of Forward and Reverse Suturing on Nerve Regeneration Following Facial Nerve Axotomy

Background/Objectives: When the facial nerve is severed and a nerve graft is required, motor nerves are typically connected in the forward direction, while sensory nerves are connected in the reverse direction. However, there is limited research on the effects of reversing this connection, and no studies have been conducted using the same facial nerve. This study aimed to investigate the effects of forward and reverse suturing on nerve regeneration following facial nerve axotomy. Methods: The facial nerve trunk of male Sprague Dawley rats was incised to induce facial nerve injury, and autografts were sutured using both forward and reverse methods. Behavioral tests, including whisker reflex and eye blink tests, were conducted. Histological analyses, including toluidine blue staining and transmission electron microscopy (TEM), were performed to evaluate axon recovery. Results: Behavioral experiments showed signs of recovery at 3–4 weeks in both the forward and reverse suture groups, with no significant differences between the two methods (p < 0.01). Histological analysis showed partial recovery by 8 weeks in both groups. Toluidine blue staining indicated a reduction in the number of axons at 4 weeks, with partial recovery at 8 weeks (p < 0.001) in both groups. TEM analysis revealed that myelin fiber thickness was restored in both the forward and reverse suture groups, though it remained thinner compared to normal (p < 0.01). Conclusions: Our results suggest that the direction of nerve suturing (forward vs. reverse) does not significantly impact nerve regeneration or functional recovery. Both suturing methods demonstrated similar recovery effects, with no significant differences in microstructural regeneration. Future studies should investigate the molecular mechanisms underlying nerve regeneration and extend the observation period to provide a more comprehensive understanding of this process.

Ultrathin visible-light OCT endomicroscopy for in vivo ultrahigh-resolution neuroimaging in deep brain

Deep-brain neuroimaging, a task that demands high-resolution imaging techniques for visualizing intricate brain structures, assessing deep-seated disease histopathology, and offering real-time intervention guidance, is challenged by the resolution-depth trade-off of current methods. We propose an optical coherence tomography (OCT) endomicroscopy device for high-resolution in vivo imaging of deep brain microstructures and histopathology. A unique liquid shaping technique enables the direct fabrication of a microlens on the fiber tip of the imaging probe, optimizing imaging performance parameters, such as longitudinal focal shift, focused spot size, and working distance. In addition, a broadband visible-light source enhances axial resolution and OCT imaging contrast. As a result, the first monolithic visible-light OCT (vis-OCT) endomicroscope, with a submillimeter outer diameter (∼0.4 mm), is presented, achieving an ultrahigh resolution of 1.4 μm axial × 4.5 μm transverse in air. This compact probe allows minimally invasive in vivo deep-brain imaging in mice at a depth of 7.2 mm. Key regions in the mouse deep brain, such as the isocortex, corpus callosum, and caudate putamen, were successfully identified using our vis-OCT endomicroscope. In addition, we examined the myeloarchitectures and cytoarchitectures in the isocortex. Our findings demonstrate that the vis-OCT endomicroscope offers enhanced visualization of myelinated axon fibers and nerve fiber bundles compared to its 800 nm counterpart. This vis-OCT endomicroscope, overcoming resolution and imaging depth limitations of conventional methods, offers a novel tool for minimally invasive, ultrahigh-resolution in vivo deep brain neuroimaging.

First-in-human microelectrode recordings from the vagus nerve during clinical vagus nerve stimulation.

Vagus nerve stimulation (VNS) is an effective treatment for people with drug-resistant epilepsy. However, its mechanisms of action are poorly understood, including which nerve fibers are activated in humans during VNS in typical clinical settings and which are required for clinical efficacy. In particular, there have been no intraneural recordings of vagus nerve fiber activation in awake humans undergoing chronic VNS. In this study, for the first time, we report recordings from the vagus nerve in this setting. The recordings were performed using a sterile tungsten microelectrode inserted percutaneously into the cervical vagus nerve under ultrasound guidance. The clinical VNS systems were used to deliver stimulation while activity in the vagus nerve was recorded. In addition to activating myelinated axons at low currents, we provide evidence that VNS can also activate unmyelinated C fibers in the vagus nerve at currents <1 mA. These results add to our understanding of how VNS exerts its beneficial effects in drug-resistant epilepsy. Here we describe for the first time, electrical recordings from the vagus nerve in awake drug-resistant epilepsy patients with an implanted vagus nerve stimulation (VNS) device. We found that the VNS device was able to activate both myelinated and unmyelinated fibers within the vagus nerve, whichcontributes to our understanding of how VNS works in the context of drug-resistant epilepsy.

Diffusion kurtosis imaging, MAP-MRI and NODDI can selectively track gray matter myelin density in the primate cerebral cortex

Abstract Diffusion magnetic resonance imaging (dMRI) has been widely used to model the trajectory of myelinated fiber bundles in the white matter. Increasingly, it is also used to evaluate the microstructure of the cerebral cortex gray matter. For example, in diffusion tensor imaging (DTI) of the cortex, fractional anisotropy (FA) correlates strongly with the anisotropy of cellular anatomy, while radial diffusivity (RD) tracks the anisotropy of myelinated fibers. However, no DTI parameter shows specificity to gray matter myelin density. Here we show that three higher order diffusion parameters - the mean diffusion kurtosis (MK), the Neurite Density Index (NDI) from NODDI, and the Non-Gaussian (NG) parameter from MAP-MRI— each track the laminar and regional myelin density of the primate cerebral cortex in fine detail. We carried out ultra-high resolution, multi-shelled dMRI in ex-vivo marmoset monkey brains. We compared the spatial mapping of the MK, NDI, and ND diffusion parameters to the cortical myelin distribution of these brains, with the latter obtained in two ways: First, using histological sections finely co-registered to the MRI, and second using magnetization transfer ratio MRI scans (MTR), an established non-diffusion method for imaging myelin density. We found that, in contrast to DTI parameters, each of these higher order diffusion measures captured the spatial variation of myelin density in the cortex. The demonstration that diffusion parameters exhibit both sensitivity and specificity for gray matter myelin density will allow dMRI to more effectively track human disease, in which myelinated and non-myelinated tissue compartments are affected differentially.

Camillo Golgi's contributions to the anatomic basis of sensitivity in tendons.

Between 1878 and 1880 Camillo Golgi, professor of Histology and General Pathology at the University of Pavia, studied the termination of the nerves inside the tendons, near their muscular insertion. He defined two fundamental categories of corpuscles. The first type, which he called muscle-tendon terminal organs, was morphologically characterized by spindle structures which at one end seemed to relate to the muscle fibers while at the other end they gradually merged with the tendon bundles. Golgi discovered that these structures received from one to four myelinated nerve fibers, which lost their myelin sheath as they entered the bundle, within which they divided dichotically, ending in a large number of terminal arborizations that had the appearance of reticular intertwines. In the superficial thickness of the tendon, near the muscle, Golgi also noticed a second category of corpuscles, which he described as claviform bodies or formations similar to Pacinian bodies. In 1890 Vittorio Mazzoni precisely defined their morphological characteristics. These corpuscles were later called Golgi muscle-tendon organs and Golgi-Mazzoni corpuscles. On the basis of their position and histological appearance, Golgi also correctly hypothesized their physiological role: to be receptors of muscular tension for the muscle-tendon organs and transducers of sensitivity to touch and pressure for the Golgi-Mazzoni corpuscles.

Hypertension is associated with the reduction in epidermal small fibres independently of sural nerve inflammation in type 2 diabetic subjects.

Diabetic polyneuropathy (DPN) is a multifactorial disease associated not only with hyperglycaemia but also with circulatory disturbances such as hypertension. A close interaction between the immune system and hypertension is known. It remains unclear whether the inflammatory response is associated with hypertension in the pathology of human DPN. Autopsied patients were evaluated: 7 non-diabetic patients (nDM), 11 non-diabetic patients with hypertension (nDMHT), 6 patients with diabetes (DM) and 9 patients with hypertension and diabetes (DMHT). Intraepidermal nerve fibre density (IENFD) was examined by immunofluorescent staining. Dissected sural nerve (SNs) were morphometrically quantified. Dermal and endoneurial macrophage infiltration was evaluated by double immunostaining using anti-CD68 and anti-CD206 antibodies. IENFD was significantly decreased in DM compared to nDM (p < 0.05) and was further decreased in DMHT (p < 0.05). Myelinated nerve fibre density (MNFD) in the SN was significantly decreased in DM compared with nDM (p < 0.05) and further decreased in DMHT (p < 0.01 vs. DM). The infiltration of CD206-/CD68+ proinflammatory macrophages in the SN was significantly increased in DM compared to nDM (p < 0.05), whilst the number of CD206+/CD68+ anti-inflammatory macrophages was decreased in DM (p < 0.05). Hypertension had no impact on macrophage infiltration. The ratio of CD206- and CD206+ macrophage was negatively correlated with MNFD (r = 0.42, p < 0.05) but not IENFD (r = 0.30, p = 0.09). Dermal CD206+ macrophage infiltration was similar amongst all groups. Diabetes complicated by hypertension significantly increased the total diffusion barrier thickness (p < 0.01 vs. DM). Total diffusion barrier thickness was inversely correlated with both IENFD (r = -0.59, p < 0.01) and MNFD (r =-0.62, p < 0.01). Our results suggest that vascular factors and inflammation might be synergistically involved in pathological changes in human diabetic patients through different mechanisms.

Monitoring Myelin Lipid Composition and the Structure of Myelinated Fibers Reveals a Maturation Delay in CMT1A.

Findings accumulated over time show that neurophysiological, neuropathological, and molecular alterations are present in CMT1A and support the dysmyelinating rather than demyelinating nature of this neuropathy. Moreover, uniform slowing of nerve conduction velocity is already manifest in CMT1A children and does not improve throughout their life. This evidence and our previous studies displaying aberrant myelin composition and structure in adult CMT1A rats prompt us to hypothesize a myelin and axon developmental defect in the CMT1A peripheral nervous system. Peripheral myelination begins during the early stages of development in mammals and, during this process, chemical and structural features of myelinated fibers (MFs) evolve towards a mature phenotype; deficiencies within this self-modulating circuit can cause its blockage. Therefore, to shed light on pathophysiological mechanisms that occur during development, and to investigate the relationship among axonal, myelin, and lipidome deficiencies in CMT1A, we extensively analyzed the evolution of both myelin lipid profile and MF structure in WT and CMT1A rats. Lipidomic analysis revealed a delayed maturation of CMT1A myelin already detectable at P10 characterized by a deprivation of sphingolipid species such as hexosylceramides and long-chain sphingomyelins, whose concentration physiologically increases in WT, and an increase in lipids typical of unspecialized plasma membranes, including phosphatidylcholines and phosphatidylethanolamines. Consistently, advanced morphometric analysis on more than 130,000 MFs revealed a delay in the evolution of CMT1A axon and myelin geometric parameters, appearing concomitantly with lipid impairment. We here demonstrate that, during normal development, MFs undergo a continuous maturation process in both chemical composition and physical structure, but these processes are delayed in CMT1A.

The concept of the Schwann cell by Louis Ranvier and his school: The ‘interannular segment’ as a cell unit

ABSTRACT The hundredth anniversary of the death of French histologist Louis Ranvier (1835‒1922) is an opportunity to reexamine his elaboration of the first concept of the Schwann cell. A loyal supporter of Theodor Schwann and his discoveries, and an attentive reader of the work of Albert von Kölliker, Ranvier studied the anatomic details of the myelinated nerve fiber with picrocarminate staining. The diffusion of the dye into the nerve fiber at the cut ends and at the sites of the annular constrictions (Ranvier’s nodes) set him on the path to defining a new cellular entity surrounding the axon, the “interannular segment,” comprising a Schwann nucleus, myelin, and cytoplasm. Ramón y Cajal recognized in 1913 that this concept of the Schwann cell according to Ranvier and his pupil William Vignal had been a brilliant intuition, but it was widely rejected until it was rediscovered using electron microscopy in the 1950s. The article reconstructs the steps of Ranvier and Vignal in building this Schwann cell concept, as well as establishing bridges with the discoveries of the 1950s.

Progressive maculopathy in a child resulting from vitreopapillary traction on a congenitally anomalous nerve.

To present a case of worsening maculopathy and vision loss due to vitreopapillary traction associated with an anomalous optic nerve head in a pediatric patient successfully managed with pars plana vitrectomy. Retrospective case report. A 13-year-old boy presented with unilateral maculopathy that slowly progressed over a four-year period. As his visual acuity declined, he became increasingly symptomatic. The macular pathology occurred in the setting of vitreopapillary traction overlying multiple congenital optic nerve abnormalities, including a myelinated nerve fiber layer and a Bergmeister papilla. Following pars plana vitrectomy to alleviate the traction, the patient's macular appearance improved, and his vision slowly recovered to baseline. There are limited reports of congenital optic nerve anomalies associated with vitreopapillary traction and maculopathy among any age group. This report illustrates a pediatric case in which removal of traction on the nerve head by pars plana vitrectomy was the key therapeutic intervention to alleviate the maculopathy.

Loss of C1q alters the auditory brainstem response.

Neural circuits in the auditory brainstem compute interaural time and intensity differences used to determine the locations of sound sources. These circuits display features that are specialized for these functions. The projection from the ventral cochlear nucleus (VCN) to the medial nucleus of the trapezoid (MNTB) body travels along highly myelinated fibers and terminates in the calyx of Held. This monoinnervating synapse emerges during development as multiple inputs are eliminated. We previously demonstrated that elimination of microglia with a colony stimulating factor-1 inhibitor results in impaired synaptic pruning so that multiple calyceal terminals reside on principal cells of MNTB. This inhibitor also resulted in impaired auditory brainstem responses (ABRs), with elevated thresholds and increased peak latencies. Loss of the microglial fractalkine receptor, CX3CR1, decreased peak latencies in the ABR. The mechanisms underlying these effects are not known. One prominent microglial signaling pathway involved in synaptic pruning and plasticity during development and aging is the C1q-initiated compliment cascade. Here we investigated the classical complement pathway initiator, C1q, in auditory brainstem maturation. We found that C1q expression is detected in the MNTB by the first postnatal week. C1q levels increased with age and were detected within microglia and surrounding the soma of MNTB principal neurons. Loss of C1q did not affect microglia-dependent calyceal pruning. Excitatory and inhibitory synaptic markers in the MNTB and LSO were not altered with C1q deletion. ABRs showed that C1q KO mice had normal hearing thresholds but shortened peak latencies. Altogether this study uncovers the developmental time frame of C1q expression in the sound localization pathway and shows a subtle functional consequence of C1q knockdown.

Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aβ production in COS cells transfected with wild-type or mutant PSEN1. The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aβ42 in PSEN1 G266S-transfected cells significantly increased. Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Proteo-transcriptomic profiles reveal genetic mechanisms underlying primary hair follicle development in coarse sheep fetal skin

Long hair trait represents a valuable genetic asset in Qinghai Tibetan sheep, with its quality and yield being contingent upon the characteristics of hair follicles (HFs). This study aims to elucidate the genetic mechanism underlying primary hair follicles (PFs) formation through an integrated analysis of proteomics and transcriptomics. Samples were collected at key stages of fetal HF formation (E65 and E85) for histological observation, revealing significant alterations in the microstructure of PF (E65) during the developmental process. In this study, a comprehensive analysis revealed a total of 217 overlapping genes that exhibited concordant expression patterns at both the proteomic and transcriptomic levels. Furthermore, to ensure the reliability of our findings, we employed parallel response monitoring (PRM) to validate the obtained proteomic data. The protein-protein interaction (PPI) network diagram highlights five hub core proteins (TTN, IGTA2, F2, EGFR, and MYH14). These differentially expressed proteins (DEPs) play crucial roles in metabolic processes, cell adhesion, and diverse biological processes. The potential synergy between transcriptional regulation and post-translational modifications plays a pivotal role in governing the initiation PF development. The findings presented in this study offer innovative insights into the molecular mechanisms underlying HFs generation and establish a robust foundation for targeted breeding strategies aimed at augmenting wool traits in sheep. SignificanceThe composition of coarse hair primarily consists of long, myelinated fibers originating from primary hair follicles. Sheep fetal skin initiates the formation of primary hair follicles around E65, followed by the development of secondary hair follicles around E85. Conducting differential proteomic and transcriptomic analyses during these developmental stages enhances our understanding of the molecular mechanisms underlying primary hair follicle development and offers valuable insights for sustainable utilization of high-quality germplasm resources.

Electroacupuncture alleviates sciatic nerve injury and inhibits autophagy in rats.

Sciatic nerve injury is a common form of peripheral nerve injury (PNI). It has been suggested that electroacupuncture (EA) stimulation at GB30 and ST36 can improve nerve dysfunction post-PNI. Autophagy is an important factor in the regeneration of sciatic nerves and recovery of motor function. Therefore, we investigated the biological effects of EA and examined whether these were mediated by autophagy in sciatic nerve injury. Mechanical clamping of the sciatic nerve in Sprague-Dawley rats was performed to establish an experimental model of sciatic nerve injury. EA stimulation was administered once daily for 15 min for seven consecutive days beginning 1 week after successful modeling. The recovery of sciatic nerve function was examined via the sciatic functional index (SFI) test. Morphometric analysis was conducted by staining nerve samples with toluidine blue. Autophagy-associated protein levels were measured via Western blotting. EA stimulation at GB30 and ST36 significantly increased the number of myelinated fibers, axonal and fiber diameters, and the thickness of the myelin sheath in our rat model of sciatic nerve injury. In addition, EA stimulation greatly facilitated nerve regeneration following sciatic nerve injury. Moreover, sciatic nerve injury-induced autophagy was inhibited by EA stimulation. EA facilitates recovery of injured sciatic nerves and inhibits autophagy in a rat model.

Neurologic Clinical, Electrophysiologic, and Pathologic Characteristics of Primary vs Secondary Neurolymphomatosis.

Neurolymphomatosis (NL) is characterized by lymphomatous infiltration of the peripheral nervous system presenting as the initial manifestation of a lymphoma (primary NL [PNL]) or in relapse of a known lymphoma (secondary NL [SNL]). This report details and compares the neurologic clinicopathologic characteristics of these 2 groups. This retrospective study was performed on patients diagnosed with pathologically confirmed NL in nerve between January 1, 1992, and June 31, 2020. Patient clinical characteristics, neurologic examination, imaging studies, EMG, and nerve biopsy data were collected, analyzed, and compared between PNL and SNL. A total of 58 patients were identified (34 PNL and 24 SNL). Time from neurologic symptom onset to diagnosis was longer in PNL at 18.5 months compared with 5.5 months in SNL (p = 0.01). Neurologic symptoms were similar in both patient groups and included primarily sensory loss (98%), severe pain (76%), and asymmetric weakness (76%). A wide spectrum of EMG-confirmed different neuropathy patterns were observed, but patients with SNL had increased numbers of mononeuropathies (n = 8) compared with PNL (n = 1, p = 0.01). MRI studies detected NL more frequently (86%) compared with fluorodeoxyglucose (FDG)-PET CT imaging studies (60%) (p = 0.007). Nerve biopsies revealed B-cell lymphoma (PNL n = 32, SNL n = 22), followed by T-cell lymphoma (PNL n = 2, SNL n = 2), with increased demyelination in both groups and increased axonal degeneration (p = 0.01) and multifocal myelinated fiber loss (p = 0.04) significant in SNL vs PNL. Identifying SNL resulted in patient treatment modifications but a worse prognosis compared with PNL (p = 0.025). While PNL and SNL are both primarily painful and asymmetric neuropathies with axonal and demyelinating features on EMG and nerve biopsy, SNL presents somewhat differently than PNL with fulminant, asymmetric often mononeuropathies better detected on MRI than FDG-PET/CT. The focal pattern of SNL is likely a result of residual cancer cells that evaded initial chemotherapy, which does not cross the blood-nerve barrier, and these cells can later recur and result in fulminant disease. Although still resulting in a poorer prognosis, identifying SNL is important because this changed treatment and management in every SNL case.

Clinical and biochemical characterization of asymptomatic carriers and symptomatic patients with hereditary transthyretin amyloidosis caused by TTR V30L mutation.

Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by amyloid fibril deposition. The TTR c.148G > T mutation (V30L) in ATTR is rarely reported, and its biochemical properties are unknown. Seven patients and two asymptomatic carriers from two unrelated families diagnosed with V30L variant of ATTR were included. Data on clinical manifestations, laboratory examination, electrophysiology, ophthalmological corneal confocal microscopy (CCM), pathology and molecular biological experiments was collected and analyzed. Most patients initially experienced paresthesia, with varying degrees of peripheral neuropathy, autonomic dysfunction, and cardiac involvement. Nerve conduction studies showed extensive motor and sensory nerve involvement in upper and lower limbs. CCM revealed reduced corneal nerve density and fiber length. Sural nerve biopsies indicated loss of myelinated nerve fibers, with neurogenic patterns in gastrocnemius muscle biopsies. Asymptomatic carriers had nearly normal electrophysiology but mild reductions in corneal nerve fiber density and length. Sural nerve biopsies in carriers showed mild reductions in small myelinated nerve fibers. V30L mutation impaired thermodynamic and kinetic stability of the mutant protein. Plasma TTR tetramer concentration was lower in ATTR V30L patients compared to healthy donors. Small molecule stabilizers failed to exhibit satisfactory inhibition on fibril formation of V30L mutation in vitro. This study highlights the multisystem involvement in ATTR V30L patients, including neuropathy and cardiac issues. Both patients and carriers showed abnormalities in nerve conduction, corneal microscopy, and pathology. The V30L mutation impaired protein stability and reduced plasma TTR tetramer levels. Small molecule stabilizers were ineffective, indicating a need for alternative treatments.

Microglial process convergence onto injured axonal swellings, a human postmortem brain tissue study

Traumatic brain injury (TBI) affects millions globally, with a majority of TBI cases being classified as mild, in which diffuse pathologies prevail. Two of the pathological hallmarks of TBI are diffuse axonal injury (DAI) and microglial activation. While progress has been made investigating the breadth of TBI-induced axonal injury and microglial changes in rodents, the neuroinflammatory progression and interaction between microglia and injured axons in humans is less well understood. Our group previously investigated microglial process convergence (MPC), in which processes of non-phagocytic microglia directly contact injured proximal axonal swellings, in rats and micropigs acutely following TBI. These studies demonstrated that MPC occurred on injured axons in the micropig, but not in the rat, following diffuse TBI. While it has been shown that microglia co-exist and interact with injured axons in humans post-TBI, the occurrence of MPC has not been quantitatively measured in the human brain. Therefore, in the current study we sought to validate our pig findings in human postmortem tissue. We investigated MPC onto injured axonal swellings and intact myelinated fibers in cases from individuals with confirmed DAI and control human brain tissue using multiplex immunofluorescent histochemistry. We found an increase in MPC onto injured axonal swellings, consistent with our previous findings in micropigs, indicating that MPC is a clinically relevant phenomenon that warrants further investigation.

Beyond pain: Using Unsupervised Machine Learning to Identify Phenotypic Clusters of Small Fiber Neuropathy.

Small fiber neuropathy (SFN) is characterized by dysfunction and loss of peripheral unmyelinated and thinly myelinated nerve fibers, resulting in a phenotype that includes varying combinations of somatosensory and dysautonomia symptoms, which can be profoundly disabling and lead to decreased quality of life. Treatment aimed mainly at pain reduction, which may not target the underlying pathophysiology, is frequently ineffective. Another impediment to the effective management of SFN may be the significant between-patient heterogeneity. Accordingly, we launched this study to gain insights into the symptomatic variability of SFN and determine if SFN patients can be sub-grouped based on clinical characteristics. To characterize the phenotype and investigate how patients with SFN differ from those with large fiber involvement, 105 patients with skin-biopsy proven SFN and 45 with mixed fiber neuropathy (MFN) were recruited. Using unsupervised machine learning, SFN patients were clustered based upon symptom concurrence and severity. Demographics, clinical data, symptoms, and skin biopsy- and laboratory findings were compared between the groups. MFN- as compared to SFN patients, were more likely to be male, older, had a lower intraepidermal nerve fiber density at the ankle and more frequent abnormal immunofixation. Beyond these differences, symptom prevalence and intensities were similar in the two cohorts. SFN patients comprised three distinct phenotypic clusters, which differed significantly in symptom severity, co-occurrence, localization, and skin biopsy findings. Only one subgroup, constituting about 20% of the patient population, was characterized by intense neuropathic pain, which was always associated with several other SFN symptoms of similarly high intensities. A pauci-symptomatic cluster comprised patients who experienced few SFN symptoms, generally of low to moderate intensity. The largest cluster was characterized by intense fatigue, myalgias and subjective weakness, but lower intensities of burning pain and paresthesia. This data-driven study introduces a new approach to subgrouping patients with SFN. Considering both neuropathic pain and pernicious symptoms beyond pain, we identified three clusters, which may be related to distinct pathophysiological mechanisms. Although additional validation will be required, our findings represent a step towards stratified treatment approaches and, ultimately, personalized treatment.

Morphometrical analysis of myelinated nerve fibers: is there a room for improvement?

Despite advancements in automatic approaches for histomorphometry analysis of peripheral nerves, manual and semi-automated methods are widely utilized. Standard software functions are often unsuitable for analysis due to their irregular shapes, especially in pathological conditions. This study aims to assess the reproducibility of nerves morphometric analysis and compare results obtained using both default and new alternative algorithms. Sciatic nerves from Wistar rats (untreated and after administration of intraperitoneal hydrargyrum chloride), previously embedded in resin, were used. Morphometric analysis (diameters, myelin thickness, g-ratio, and circularity) was conducted using ImageJ on semithin sections, with axon and myelin boundaries manually outlined. Default diameters were calculated as the mean of Feret diameters, with subsequent calculations for myelin thickness and g-ratio. The alternative approach estimated diameters based on the geometric center of axons, iterating through selected coordinates; myelin thickness was obtained using line equations. In the control group, inter-rater agreement was higher or within expected reliability (0.8 ± 0.05). However, in the experimental group, myelin thickness, g-ratio, and axon circularity showed lower agreement (0.66, 0.58, and 0.68, respectively) without visible patterns on Bland-Altman plots. The alternative approach did not reveal significant differences between approaches, except for g-ratio in the control group and fiber diameter in the experimental group (p < 0.05), with effect sizes of 0.29-0.30 and 0.19-0.20, respectively. This study highlights reduced agreement among investigators analyzing nerve fibers under pathological conditions, raising concerns about the current standard measurement methods. The proposed approach, based on a single geometric center, provides more natural estimations for irregular fibers, and can be implemented in automated nerve fibers acquisition systems.