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Abstract Background Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP), amyotrophic lateral sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE) are associated with deposition of cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons. One complexity of this process lies in the ability of TDP-43 to form liquid-phase membraneless organelles in cells. Previous work has shown that the recombinant, purified, prion-like domain (PrLD) forms liquid droplets in vitro, but the behaviour of the complementary fragment is uncertain. Methods We have purified such a construct without the PrLD (PrLD-less TDP-43) and have induced its phase separation using a solution-jump method and an array of biophysical techniques to study the morphology, state of matter and structure of the TDP-43 assemblies. Results The fluorescent TMR-labelled protein construct, imaged using confocal fluorescence, formed rapidly (

Abstract Background Amyloid-β42 (Aβ42) aggregation consists of a complex chain of nucleation events producing soluble oligomeric intermediates, which are considered the major neurotoxic agents in Alzheimer’s disease (AD). Cerebral lesions in the brain of AD patients start to develop 20 years before symptom onset; however, no preventive strategies, effective treatments, or specific and sensitive diagnostic tests to identify people with early-stage AD are currently available. In addition, the isolation and characterisation of neurotoxic Aβ42 oligomers are particularly difficult because of their transient and heterogeneous nature. To overcome this challenge, a rationally designed method generated a single-domain antibody (sdAb), named DesAb-O, targeting Aβ42 oligomers. Methods We investigated the ability of DesAb-O to selectively detect preformed Aβ42 oligomers both in vitro and in cultured neuronal cells, by using dot-blot, ELISA immunoassay and super-resolution STED microscopy, and to counteract the toxicity induced by the oligomers, monitoring their interaction with neuronal membrane and the resulting mitochondrial impairment. We then applied this approach to CSF samples (CSFs) from AD patients as compared to age-matched control subjects. Results DesAb-O was found to selectively detect synthetic Aβ42 oligomers both in vitro and in cultured cells, and to neutralise their associated neuronal dysfunction. DesAb-O can also identify Aβ42 oligomers present in the CSFs of AD patients with respect to healthy individuals, and completely prevent cell dysfunction induced by the administration of CSFs to neuronal cells. Conclusions Taken together, our data indicate a promising method for the improvement of an early diagnosis of AD and for the generation of novel therapeutic approaches based on sdAbs for the treatment of AD and other devastating neurodegenerative conditions.

Abstract Background Treadmill based Robotic-Assisted Gait Training (t-RAGT) provides for automated locomotor training to help the patient achieve a physiological gait pattern, reducing the physical effort required by therapist. By introducing the robot as a third agent to the traditional one-to-one physiotherapist-patient (Pht-Pt) relationship, the therapist might not be fully aware of the patient’s motor performance. This gap has been bridged by the integration in rehabilitation robots of a visual FeedBack (FB) that informs about patient’s performance. Despite the recognized importance of FB in t-RAGT, the optimal role of the therapist in the complex patient-robot interaction is still unclear. This study aimed to describe whether the type of FB combined with different modalities of Pht’s interaction toward Pt would affect the patients’ visual attention and emotional engagement during t-RAGT. Methods Ten individuals with incomplete Spinal Cord Injury (C or D ASIA Impairment Scale level) were assessed using eye-tracking (ET) and high-density EEG during seven t-RAGT sessions with Lokomat where (i) three types of visual FB (chart, emoticon and game) and (ii) three levels of Pht-Pt interaction (low, medium and high) were randomly combined. ET metrics (fixations and saccades) were extracted for each of the three defined areas of interest (AoI) (monitor, Pht and surrounding) and compared among the different experimental conditions (FB, Pht-Pt interaction level). The EEG spectral activations in theta and alpha bands were reconstructed for each FB type applying Welch periodogram to data localised in the whole grey matter volume using sLORETA. Results We found an effect of FB type factor on all the ET metrics computed in the three AoIs while the factor Pht-Pt interaction level also combined with FB type showed an effect only on the ET metrics calculated in Pht and surrounding AoIs. Neural activation in brain regions crucial for social cognition resulted for high Pht-Pt interaction level, while activation of the insula was found during low interaction, independently on the FB used. Conclusions The type of FB and the way in which Pht supports the patients both have a strong impact on patients’ engagement and should be considered in the design of a t-RAGT-based rehabilitation session.

Abstract Background Electroencephalography (EEG)-based brain-computer interfaces (BCIs) allow to modulate the sensorimotor rhythms and are emerging technologies for promoting post-stroke motor function recovery. The Promotoer study aims to assess the short and long-term efficacy of the Promotoer system, an EEG-based BCI assisting motor imagery (MI) practice, in enhancing post-stroke functional hand motor recovery. This paper details the statistical analysis plan of the Promotoer study. Methods The Promotoer study is a randomized, controlled, assessor-blinded, single-centre, superiority trial, with two parallel groups and a 1:1 allocation ratio. Subacute stroke patients are randomized to EEG-based BCI-assisted MI training or to MI training alone (i.e. no BCI). An internal pilot study for sample size re-assessment is planned. The primary outcome is the effectiveness of the Upper Extremity Fugl-Meyer Assessment (UE-FMA) score. Secondary outcomes include clinical, functional, and user experience scores assessed at the end of intervention and at follow-up. Neurophysiological assessments are also planned. Effectiveness formulas have been specified, and intention-to-treat and per-protocol populations have been defined. Statistical methods for comparisons of groups and for development of a predictive score of significant improvement are described. Explorative subgroup analyses and methodology to handle missing data are considered. Discussion The Promotoer study will provide robust evidence for the short/long-term efficacy of the Promotoer system in subacute stroke patients undergoing a rehabilitation program. Moreover, the development of a predictive score of response will allow transferring of the Promotoer system to optimal clinical practice. By carefully describing the statistical principles and procedures, the statistical analysis plan provides transparency in the analysis of data. Trial registration ClinicalTrials.gov NCT04353297 . Registered on April 15, 2020.

Abstract Background Traumatic cervical spinal cord injury (SCI) results in reduced sensorimotor abilities that strongly impact on the achievement of daily living activities involving hand/arm function. Among several technology-based rehabilitative approaches, Brain-Computer Interfaces (BCIs) which enable the modulation of electroencephalographic sensorimotor rhythms, are promising tools to promote the recovery of hand function after SCI. The “DiSCIoser” study proposes a BCI-supported motor imagery (MI) training to engage the sensorimotor system and thus facilitate the neuroplasticity to eventually optimize upper limb sensorimotor functional recovery in patients with SCI during the subacute phase, at the peak of brain and spinal plasticity. To this purpose, we have designed a BCI system fully compatible with a clinical setting whose efficacy in improving hand sensorimotor function outcomes in patients with traumatic cervical SCI will be assessed and compared to the hand MI training not supported by BCI. Methods This randomized controlled trial will include 30 participants with traumatic cervical SCI in the subacute phase randomly assigned to 2 intervention groups: the BCI-assisted hand MI training and the hand MI training not supported by BCI. Both interventions are delivered (3 weekly sessions; 12 weeks) as add-on to standard rehabilitation care. A multidimensional assessment will be performed at: randomization/pre-intervention and post-intervention. Primary outcome measure is the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) somatosensory sub-score. Secondary outcome measures include the motor and functional scores of the GRASSP and other clinical, neuropsychological, neurophysiological and neuroimaging measures. Discussion We expect the BCI-based intervention to promote meaningful cortical sensorimotor plasticity and eventually maximize recovery of arm functions in traumatic cervical subacute SCI. This study will generate a body of knowledge that is fundamental to drive optimization of BCI application in SCI as a top-down therapeutic intervention, thus beyond the canonical use of BCI as assistive tool. Trial registration Name of registry: DiSCIoser: improving arm sensorimotor functions after spinal cord injury via brain-computer interface training (DiSCIoser). Trial registration number: NCT05637775; registration date on the ClinicalTrial.gov platform: 05-12-2022.