Extracellular Vesicle Delivery of Neferine for the Attenuation of Neurodegenerative Disease Proteins and Motor Deficit in an Alzheimer’s Disease Mouse Model

Exosomes are nano-extracellular vesicles with diameters ranging from 30 to 150 nm, which are secreted by the cell. With their role in drug cargo loading, exosomes have been applied to carry compounds across the blood–brain barrier in order to target the central nervous system (CNS). In this study, high-purity exosomes isolated by the ultra-high-speed separation method were applied as the natural compound carrier, with the loading efficiency confirmed by UHPLC-MS analysis. Through the optimization of various cargo loading methods using exosomes, this study compared the efficiency of different ways for the separation of exosomes and the exosome encapsulation of natural compounds with increasing molecular weights via extensive in vitro and in vivo efficacy studies. In a pharmacokinetic study, our data suggested that the efficiency of compound’s loading into exosomes is positively correlated to its molecular weight. However, with a molecular weight of greater than 1109 Da, the exosome-encapsulated natural compounds were not able to pass through the blood–brain barrier (BBB). In vitro cellular models confirmed that three of the selected exosome-encapsulated natural compounds—baicalin, hederagenin and neferine—could reduce the level of neurodegenerative disease mutant proteins—including huntingtin 74 (HTT74), P301L tau and A53T α-synuclein (A53T α-syn)—more effectively than the compounds alone. With the traditional pharmacological role of the herbal plant Nelumbo nucifera in mitigating anxiety, exosome-encapsulated-neferine was, for the first time, reported to improve the motor deficits of APP/PS1 (amyloid precursor protein/ presenilin1) double transgenic mice, and to reduce the level of β-amyloid (Aβ) in the brain when compared with the same concentration of neferine alone. With the current trend in advocating medicine–food homology and green healthcare, this study has provided a rationale from in vitro to in vivo for the encapsulation of natural compounds using exosomes for the targeting of BBB permeability and neurodegenerative diseases in the future.

Efficiency and Stability of Step-To Gait in Slow Walking

As humans, we constantly change our movement strategies to adapt to changes in physical functions and the external environment. We have to walk very slowly in situations with a high risk of falling, such as walking on slippery ice, carrying an overflowing cup of water, or muscle weakness owing to aging or motor deficit. However, previous studies have shown that a normal gait pattern at low speeds results in reduced efficiency and stability in comparison with those at a normal speed. Another possible strategy is to change the gait pattern from normal to step-to gait, in which the other foot is aligned with the first swing foot. However, the efficiency and stability of the step-to gait pattern at low speeds have not been investigated yet. Therefore, in this study, we compared the efficiency and stability of the normal and step-to gait patterns at intermediate, low, and very low speeds. Eleven healthy participants were asked to walk with a normal gait and step-to gait on a treadmill at five different speeds (i.e., 10, 20, 30, 40, and 60 m/min), ranging from very low to normal walking speed. The efficiency parameters (percent recovery and walk ratio) and stability parameters (center of mass lateral displacement) were analyzed from the motion capture data and then compared for the two gait patterns. The results suggested that step-to gait had a more efficient gait pattern at very low speeds of 10–30 m/min, with a larger percent recovery, and was more stable at 10–60 m/min in comparison with a normal gait. However, the efficiency of the normal gait was better than that of the step-to gait pattern at 60 m/min. Therefore, step-to gait is effective in improving gait efficiency and stability when faced with situations that force us to walk slowly or hinder quick walking because of muscle weakness owing to aging or motor deficit along with a high risk of falling.

Cerebrospinal fluid evaluation in patients with progressive motor impairment due to critical central nervous system demyelinating lesions

Background Elevated intrathecal immunoglobulin G (IgG; oligoclonal bands (OCBs)) or IgG in people with progressive motor impairment due to “critical” demyelinating lesions are of uncertain significance. Objective Compare clinical/radiological features of people with “critical” demyelinating lesion-induced progressive motor impairment with/without elevated intrathecal IgG synthesis. Methods A total of 133 people with progressive motor impairment attributable to “critical” demyelinating lesions (corticospinal tract location, consistent with the progressive motor deficit) were compared regarding clinical and radiological presentation with and without ≥2 unique cerebrospinal fluid (CSF) OCB and/or IgG index ≥0.85. Results Ninety-eight (74%) had CSF-elevated OCB and/or IgG index, higher with increased magnetic resonance imaging-lesion burden. No differences were found with/without CSF abnormalities in sex (46 of 98 female (47%) vs. 22 of 35 (63%), p = 0.11), onset-age (median 49 vs. 50 years, p = 0.5), progression from onset (62 of 98 (63%) vs. 25 of 35 (71%)), progression post-relapse (36 of 98 (37%) vs. 10 of 35 (29%), p = 0.4), and duration between demyelinating disease onset and CSF examination (30 (0–359) vs. 48 (0–323) months p = 0.7). “Critical” lesions were radiologically similar, most commonly cervical spine located (72 of 98 (74%) vs. 19 of 35 (54%), p = 0.18) both with/without CSF abnormalities. Conclusions People with “critical” demyelinating lesion-induced progressive motor impairment typically have elevated intrathecal IgG (OCB and/or IgG) and similar clinical and radiological presentation regardless of CSF findings, therefore representing valid presentations of progressive demyelinating disease.

Exploration of the Mechanism Underlying the Association of Incident Microinfarct and Motor Deficit: A Preliminary Functional MRI Study

Background: Cerebral microinfarcts (CMIs) might cause measurable disruption to brain connections and are associated with cognitive decline, but the association between CMIs and motor impairment is still unclear. Objective: To assess the CMIs effect on motor function in vivo and explore the potential neuropathological mechanism based on graph-based network method. Methods: We identified 133 non-demented middle-aged and elderly participants who underwent MRI scanning, cognitive, and motor assessment. The short physical performance battery (SPPB) assessed motor function, including balance, walking speed, and chair stand. We grouped participants into 34 incident CMIs carriers and 99 non-CMIs carriers as controls, depending on diffusion-weighted imaging. Then we assessed the independent CMIs effects on motor function and explored neural mechanisms of CMIs on motor impairment via mapping of degree centrality (DC) and eigenvector centrality (EC). Results: CMIs carriers had worse motor function than non-carriers. Linear regression analyses showed that CMIs independently contributed to motor function. CMIs carriers had decreased EC in the precuneus, while increased DC and EC in the middle temporal gyrus and increased DC in the inferior frontal gyrus compared to controls (p < 0.05, corrected). Correlation analyses showed that EC of precuneus was related to SPPB (r = 0.25) and balance (r = 0.27); however, DC (r = –0.25) and EC (r = –0.25) of middle temporal gyrus was related with SPPB in all participants (p < 0.05, corrected). Conclusion: CMIs represent an independent risk factor for motor dysfunction. The relationship between CMIs and motor function may be attributed to suppression of functional hub region and compensatory activation of motor-related regions.

Clinical Features and Ultrasound Findings of a Rare Musculoskeletal System Disease--neuromuscular Choristomas

Background: Neuromuscular choristomas (NMCs) as exquisitely rare developmental lesions have previously been established associated with recurrent fibromatosis after surgery, led to multiple operations, or even amputation. Yet, the report about ultrasound imaging features and clinical conditions of NMCs was rare. The purpose of this study was to describe the ultrasound features and clinical analysis of NMCs to provide suggestions to the optimal management strategy.Methods: From 2020 September to 2021 September, 7 patients with a confirmed diagnosis of NMC who underwent ultrasound examination in our department were enrolled into our study. Physical examinations were performed to detect motor deficit, sensory deficit, neuropathic pain, limb undergrowth, muscular atrophy, cavus foot and bone dysplasia. Ultrasound imaging were performed and investigated in both involved nerve and neuromuscular choristomas associated desmoid-type fibromatosis (NMC-DTF). All patients had a definite history and regular follow up. The clinical course, physical examinations, ultrasound features and pathologic results of NMC patients were analyzed.Results: Seven patients with an average age of 7.0±7.2 years (range: 2-22 years) were enrolled into our study. Nerves involved included the sciatic nerve (6 cases) and the brachial plexus (1 case). 6 patients (85.7%) presented with manifestations of limb undergrowth, 6 (85.7%) with muscular atrophy, and 5 (71.4%) with cavus foot deformity. Based upon ultrasound findings, all visible involved nerve segments presented with hypoechoic and fusiform enlargement with intraneural skeletal muscle elements. Five patients (71.4%) had NMC-DTFs at the site of the affected nerve. All NMC-DTFs were shown as hypoechoic solid lesion adjacent to the nerve and well-circumscribed. In the subset of surgery group, all 5 patients presented with progression to NMC-DTFs at the site of the NMCs. No fibromatosis was detected in the other two non-surgery patients. Conclusions: Understanding of the typical ultrasound features and clinical associated conditions would help to early diagnose the rare disease. When a potential diagnosis is made, invasive procedure like biopsy or resection might be not a good choice given frequent complication by aggressive recurrence.

Efficacy of Action Observation for Upper Limb Motor Deficit in Acute Stroke Participants

Introduction: Action Observation (AO) is a multisensory approach encompassing motor, somatosensory and cognitive rehabilitation. Several Studies have proved the effects of action observation on recovery of motor functions in chronic stroke survivors. However, the effect of action observation strategy on acute stroke participants remains unclear. The objective of this study was to find out the effectiveness of action observation to improve upper limb function in acute stroke. Methods: 28 acute stoke participants were selected based on inclusion and exclusion criteria and randomly assigned into two groups based on computer generated randomization. Action observation training group (AO) received action observation training and conventional group received conventional physiotherapy. Both the groups received 45 minutes session per day for the total duration of 10 days. Results: Upper limb functions were measured using Fugl Myer upper limb component (FMA) and action research arm test (ARAT)at the baseline and after the intervention. Compared with the conventional training group, AO group showed significant improvement in ARAT but no significant difference between the groups in FMA. Conclusion: In conclusion Action observation treatment may become a useful strategy in rehabilitation of acute stroke participants.

Paediatric Spinal Tumours: Profile and Treatment Outcome in A Nigerian Tertiary Institution

Introduction Paediatric spinal tumours are rare, accounting for 1-10% of all childhood central nervous system tumours. There is a paucity of information on spinal tumours in Sub-Saharan Africans. This is particularly so in the Nigerian paediatric population where neuro-oncologic data is limited. Indeed, there is no previously published work on the profile of paediatric spinal tumours in the Nigerian neurosurgical literature. The authors aim to document the profile of paediatric spinal tumours in a Nigerian tertiary institution and to contribute to the available data on paediatric central nervous system tumours in West Africa. Methods We retrospectively evaluated data on paediatric patients who underwent surgery for spine tumours over a 20-year-period at our institution. Results A total of 12 patients were managed for paediatric spine tumours during the study period. These had a male: female ratio of 1:1.4 and their ages ranged between 3 and 18 years (mean: 12.83 ± 4.75 years). The highest incidence (6/12) was seen in the 15-18 years age group. The mean duration of symptoms was 10.2 months. More than half (7/12) of the patients presented with symptoms with duration of at least 6 months. Motor deficit was present in all patients at presentation. Two-thirds of the tumours were in the thoracic region, 1 was located in the cervical region, while the remaining 3 tumours were cervicothoracic. The tumour was extradural in location in 8 of our patients and intramedullary in the remaining 4. Astrocytoma (intramedullary in all cases) was the most predominant histological tumour type in (3/12) in our series. Postoperative neurological improvement occurred in 7 of the patients while 5 remained the same. There was no permanent postoperative neurological deterioration or perioperative mortality. Conclusion Paediatric spinal tumours mostly affected older children in our study group and were predominantly astrocytic in nature. The most common tumour location was extradural, involving mostly the thoracic spinal level. The preoperative neurological status correlates with the postoperative functional outcome. Therefore, the need for early diagnosis and treatment of these tumours cannot overemphasized.

A Novel Mutation Diagnosing in Allan–Herndon–Dudley's Syndrome

Allan–Herndon–Dudley's syndrome (AHDS) is a rare X-linked recessive disease that causes abnormal serum thyroid function tests, severe hypotonia, intellectual disability, and motor deficit due to a mutation in the monocarboxylate transporter 8, which is a thyroid hormone transporter. A 6-month-old male patient presented to our outpatient clinic with a serious hypotonia complaint. With a preliminary diagnosis of AHDS, a molecular genetic examination was performed. The molecular genetic analysis detected a new previously unidentified variant in the SLC16A2 gene. This case has been presented to report the AHDS, which is a rare cause of hypotonia in patients presenting/consulting with severe hypotonia, global developmental delay, and abnormal thyroid function test results. Besides, a novel pathogenic mutation in the SLC16A2 gene has been described in the present article.

Rhythmic tapping difficulties in adults who stutter: a deficit in Central Clock and/or Motor Implementation?

The study aims to better understand the origin of increased tapping variability and inaccuracy in people who stutter during paced and un-paced tapping. The overall question is to what extent these timing difficulties are related to a central clock deficit, a deficit in motor execution, or both.Finger tapping behavior of 16 adults who stutter (PWS) with different levels of musical training was compared with performance of 16 matching controls (PNS) in three finger tapping synchronization tasks ― a simple 1:1 isochronous pattern, a complex non-isochronous pattern, and a 4 tap:1 beat isochronous pattern ―, a continuation task (without external stimulation), and a reaction task involving aperiodic and unpredictable patterns. The results show that PWS exhibited larger negative asynchrony (expressed as phase angles), and increased synchronization variability (expressed as phase locking values) in paced tapping tasks, and that these differences from the PNS group were modulated by rhythmic complexity and musical training. The tapping asynchrony with a simple isochronous pattern correlated significantly with the average inter-tap duration, and with tap reaction times during the reaction task. The synchronization variability with a simple isochronous pattern correlated significantly with both the central clock and motor implementation variances as extracted during un-paced tapping, according to the Wing and Kristofferson’s model of timing.The results support the idea that increased tapping variability of PWS is associated with both a central clock and a motor execution deficit. The greater Negative Mean Asynchrony of PWS does not appear to be attributable to a deficit in time estimation but rather to a motor deficit. Several models and theories related to deficits in sensorimotor integration were considered to explain the interactions with beat strength, pattern complexity, and musical training.

α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson's disease

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the brain in a prion-like manner. While rodent models have recapitulated gut-to-brain α-synuclein transmission, animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first C. elegans models in which feeding with α-synuclein pre-formed fibrils (PFFs) induced prion-like dopamine neuron degeneration and seeding of aggregation of human α-synuclein expressed in the host. PFF acceleration of α-synuclein aggregation in C. elegans muscle cells was associated with a progressive motor deficit, whereas feeding with α-synuclein monomer produced much milder effects. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, and enzymes involved in heparan sulfate proteoglycan biosynthesis, afforded protection from PFF-induced seeding of aggregation and toxicity, as well as dopaminergic neurodegeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.