Longitudinal Imaging Biomarkers Correlate with Progressive Motor Deficit in the Mouse Model of Charlevoix-Saguenay Ataxia.

Objective: In autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease, severity and age of onset vary greatly, hindering to objectively measure and predict clinical progression. Thickening of the retinal nerve fiber layer is distinctive of ARSACS patients, as assessed by optical coherence tomography, whereas conventional brain magnetic resonance imaging findings include both supratentorial and infratentorial changes. Because longitudinal imaging studies in ARSACS patients are not available to define these changes as biomarkers of disease progression, we aimed to address this issue in the ARSACS mouse model.

Stabilization of the retromer complex: Analysis of novel binding sites of bis-1,3-phenyl guanylhydrazone 2a to the VPS29/VPS35 interface.

The stabilization of the retromer protein complex can be effective in the treatment of different neurological disorders. Following the identification of bis-1,3-phenyl guanylhydrazone as an effective new compound for the treatment of amyotrophic lateral sclerosis, in this work we analyze the possible binding sites of this molecule to the VPS35/VPS29 dimer of the retromer complex. Our results show that the affinity for different sites of the protein assembly depends on compound charge and therefore slight changes in the cell microenvironment could promote different binding states.

Dual Functionalized Liposomes for Selective Delivery of Poorly Soluble Drugs to Inflamed Brain Regions.

Dual functionalized liposomes were developed to cross the blood−brain barrier (BBB) and to release their cargo in a pathological matrix metalloproteinase (MMP)-rich microenvironment. Liposomes were surface-functionalized with a modified peptide deriving from the receptor-binding domain of apolipoprotein E (mApoE), known to promote cargo delivery to the brain across the BBB in vitro and in vivo; and with an MMP-sensitive moiety for an MMP-triggered drug release. Different MMP-sensitive peptides were functionalized at both ends with hydrophobic stearate tails to yield MMP-sensitive lipopeptides (MSLPs), which were assembled into mApoE liposomes.

Topical nerve growth factor prevents neurodegenerative and vascular stages of diabetic retinopathy.

Specific and effective preventive treatment for diabetic retinopathy (DR) is presently unavailable, mostly because the early stages of the complication have been, until recently, poorly understood. The recent demonstration that the vascular phase of DR is preceded and possibly caused by the neurodegeneration of retinal ganglion cells suggests that DR could, at least theoretically, be prevented through an early neuroprotective approach. The aims of our study were to clarify the natural history of diabetes-driven retinal neurodegeneration and to verify the possibility to prevent DR using topical nerve growth factor (NGF).

Dose-dependent effect of myelin oligodendrocyte glycoprotein on visual function and optic nerve damage in experimental autoimmune encephalomyelitis.

Female Dark Agouti rats were immunized with increasing doses of myelin oligodendrocyte glycoprotein (MOG) to develop experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis. Typical EAE motor impairments were assessed daily and noninvasive visual evoked potentials (VEPs) were recorded at baseline and 5 weeks after immunization, with final histopathology of optic nerves (ONs). Immunized rats exhibited a relapsing-remitting clinical course.

Improving reproducibility of motor evoked potentials in mice.

Background: In preclinical research involving murine models of neurological diseases, Motor Evoked Potentials (MEPs) can detect pathological alterations in nerve conduction throughout the cortico-spinal tract. In mice, MEPs elicited by electrical stimulation of the motor cortex can be performed with epicranial or subdermal electrodes such as implanted screws or removable needles, which are associated with invasive surgery and variability in placement of the stimulating electrodes, respectively.

Methods: We compared MEPs induced by epicranial or subcutaneous stimulation with a non-invasive surface cup electrode over five recording sessions, in healthy C57BL/6 mice.

Non-invasive visual evoked potentials under sevoflurane ketamine-xylazine in rats.

Background: Visual Evoked Potential (VEP) quantifies electrical signals produced in visual cortex in response to visual stimuli. VEP elicited by light flashes is a useful biomarker to evaluate visual function in preclinical models and it can be recorded in awake or anaesthetised state. Different types of anaesthesia influence VEP properties, such as latency, which measures the propagation speed along nerve fibers, and amplitude that quantifies the power of electrical signal.

Peripheral Nerve Development and the Pathogenesis of Peripheral Neuropathy: the Sorting Point.

Nerve development requires a coordinated sequence of events and steps to be accomplished for the generation of functional peripheral nerves to convey sensory and motor signals. Any abnormality during development may result in pathological structure and function of the nerve, which evolves in peripheral neuropathy. In this review, we will briefly describe different steps of nerve development while we will mostly focus on the molecular mechanisms involved in radial sorting of axons, one of these nerve developmental steps.

Synthesis and Characterization of Novel Mono- and Bis-Guanyl Hydrazones as Potent and Selective ASIC1 Inhibitors Able to Reduce Brain Ischemic Insult.

Acid-sensitive ion channels (ASICs) are sodium channels partially permeable to Ca ions, listed among putative targets in central nervous system (CNS) diseases in which a pH modification occurs. We targeted novel compounds able to modulate ASIC1 and to reduce the progression of ischemic brain injury. We rationally designed and synthesized several diminazene-inspired diaryl mono- and bis-guanyl hydrazones.

Stroke and digital technology: a wake-up call from COVID-19 pandemic.

Introduction: The pandemic has implemented the need for new digital technologies as useful tools during the emergency and the long recovery phase that will follow. SARS-CoV-2 has strongly impacted stroke care with significant contraction in a number of patients treated.

Methods: This mini-review is an initiative of the "Digital Technologies, Web and Social Media Study Group" of the Italian Society of Neurology and briefly discusses digital tools for managing the acute phase and the rehabilitation after stroke, even considering the new apps that will improve the process of remote monitoring of patients after discharge at home.

The Danger of Walking with Socks: Evidence from Kinematic Analysis in People with Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is characterized by gait impairments and severely impacts the quality of life. Technological advances in biomechanics offer objective assessments of gait disabilities in clinical settings. Here we employed wearable sensors to measure electromyography (EMG) and body acceleration during walking and to quantify the altered gait pattern between people with progressive MS (PwPMS) and healthy controls (HCs).

Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker.

Repetitive Transcranial Magnetic Stimulation With H-Coil Coupled With Cycling for Improving Lower Limb Motor Function After Stroke: An Exploratory Study.

Background/objectives: Repetitive transcranial magnetic stimulation (rTMS) has been recognized as a promising intervention for the treatment of post-stroke motor deficits. Here, we explore safety, feasibility, and potential effectiveness of high-frequency rTMS (HF-rTMS) delivered with the Hesed coil (H-coil) during active cycling on paretic lower extremity (LE) motor function in chronic stroke.

Materials And Methods: Twelve subjects with a first-ever stroke were recruited in this double-blind, placebo controlled, crossover study.

The Use of Social Media and Digital Devices Among Italian Neurologists.

Digital devices and online social networks are changing clinical practice. In this study, we explored attitudes, awareness, opinions, and experiences of neurologists toward social media and digital devices. Each member of the Italian Society of Neurology (SIN) participated in an online survey (January to May 2018) to collect information on their attitude toward digital health.

Fifteen Years of Wireless Sensors for Balance Assessment in Neurological Disorders.

Balance impairment is a major mechanism behind falling along with environmental hazards. Under physiological conditions, ageing leads to a progressive decline in balance control per se. Moreover, various neurological disorders further increase the risk of falls by deteriorating specific nervous system functions contributing to balance.

Advances in physical rehabilitation of multiple sclerosis.

Purpose Of Review: Multiple sclerosis (MS) is a neurological disorder that heavily affects quality of life (QoL) and demands a multidisciplinary therapeutic approach. This includes multiple protocols and techniques of physical rehabilitation, ranging from conventional exercise paradigms to noninvasive brain stimulation (NIBS). Recently, studies showing the clinical efficacy of physical rehabilitation have remarkably increased, suggesting its disease-modifying potential.

Beyond rehabilitation in MS: Insights from non-invasive brain stimulation.

Although the number of disease-modifying treatments for people with multiple sclerosis (pwMS) has meaningfully increased in the past years, targeting repair or compensation for central nervous system damage associated with the disease process remains an important clinical goal. With this aim, neurorehabilitation is a powerful approach targeting central nervous system plasticity. Another driver of brain plasticity is non-invasive brain stimulation (NIBS), receiving recent attention in neurology, particularly for its potential synergy with neurorehabilitation and as add-on treatment for several neurological conditions, from pain to fatigue to sensorimotor and cognitive deficits.

Correction to: The Italian multiple sclerosis register.

Unfortunately in the original publication, the affiliation of the author Maria Pia Amato was incorrect. The author inadvertently missed out to include her second affiliation.

Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C.

The neuromuscular junction (NMJ) appears to be a site of pathology in a number of peripheral nerve diseases. Charcot-Marie-Tooth (CMT) 4C is an autosomal recessive, early onset, demyelinating neuropathy. Numerous mutations in the gene have been shown to underlie the condition often associated with scoliosis, foot deformities, and reduced nerve conduction velocities.

The Italian multiple sclerosis register.

The past decade has seen extraordinary increase in worldwide availability of and access to several large multiple sclerosis (MS) databases and registries. MS registries represent powerful tools to provide meaningful information on the burden, natural history, and long-term safety and effectiveness of treatments. Moreover, patients, physicians, industry, and policy makers have an active interest in real-world observational studies based on register data, as they have the potential to answer the questions that are most relevant to daily treatment decision-making.

No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a.

Background: No evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS).

Objective: The objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status.

Methods: NEDA was assessed in a modified intent-to-treat population ( = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β-1a; 44 μg).

TMS of primary motor cortex with a biphasic pulse activates two independent sets of excitable neurones.

Background: Biphasic pulses produced by most commercially available TMS machines have a cosine waveform, which makes it difficult to study the interaction between the two phases of stimulation.

Objective: We used a controllable pulse TMS (cTMS) device delivering quasi-rectangular pulse outputs to investigate whether monophasic are more effective than biphasic pulses.

Methods: Temporally symmetric ("biphasic") or highly asymmetric ("monophasic") charge-balanced biphasic stimuli were used to target the hand area of motor cortex in the anterior-posterior (AP) or posterior-anterior (PA) initial current direction.

Isolation and Characterization of Vessel-Associated Stem/Progenitor Cells from Skeletal Muscle.

More than 10 years ago, we isolated from mouse embryonic dorsal aorta a population of vessel-associated stem/progenitor cells, originally named mesoangioblasts (MABs ) , capable to differentiate in all mesodermal-derived tissues, including skeletal muscle. Similar though not identical cells have been later isolated and characterized from small vessels of adult mouse and human skeletal muscles. When delivered through the arterial circulation, MABs cross the blood vessel wall and participate in skeletal muscle regeneration , leading to an amelioration of muscular dystrophies in different preclinical animal models.