Quality of Life in Amyotrophic Lateral Sclerosis Patients and Care Burden of Caregivers in Sardinia during COVID-19 Pandemic.

Amyotrophic Lateral Sclerosis (ALS) is a rare neurogenerative disorder whose median survival ranges from 2 to 4 years after symptomatic onset. Therefore, the global Quality of Life (QoL) assessment in these patients should be carefully evaluated to guarantee an adequate care level, particularly during the COVID-19 pandemic period, given the increased social isolation and the pressure on healthcare services. Caregiving has been recognized as an important source of physical and psychological burden, with a possible QoL impairment. The purpose of this study was to evaluate the QoL of ALS patients and the burden of their caregivers across Sardinia, Italy. The ALS Specific QoL Instrument-Short Form (ALSSQOL-SF) and the Zarit Burden Inventory (ZBI) tools were used to assess patient's QoL and the burden on their caregivers, respectively. The questionnaires were supplemented with items specific for the COVID-19 period. Sixty-six family units of patients with advanced ALS were interviewed between June and August 2021 across Sardinia. Patients' psychological and social well-being were found to significantly affect the patients' QoL, regardless of their physical condition. In addition, the caregiver burden resulted as being inversely proportional to the patient's perceived QoL. Lack of adequate psychological support was reported among the caregivers during the emergency period. Providing adequate psychological and social support might be useful to improve QoL in middle and late stages of ALS patients and to decrease caregivers' perceived home care burden.

Bulbar Onset Amyotrophic Lateral Sclerosis in a COVID-19 Patient: A Case Report.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with a largely unknown etiology. In this case, we are presenting an 84-year-old male patient who was admitted for acute hypoxemic respiratory failure secondary to coronavirus disease 2019 (COVID-19) infection. He was neurologically intact. His infection improved and oxygen requirement was gradually weaned off allowing for discharge. However, he was admitted again a month later with progressive dysphagia and aspiration that were confirmed on videofluoroscopic study. He was also found to have mild dysarthria, bulbar muscle weakness, bilateral lower motor neuron facial nerve palsy, diffuse hyporeflexia on four extremities with intact sensory function. Diagnosis of ALS was suspected after extensive workup was pursued and ruled out nutritional, structural, autoimmune, infectious and inflammatory disorders. This case is only the third reported case in medical literature to suggest COVID-19 infection as a triggering/accelerating factor of ALS progression.

British Neuropsychiatry Annual Meeting 2021

The proceedings contain 40 papers. The topics discussed include: sex, bugs microwave attacks: how bad science, mating insects psychogenic illness created an international incident with Cuba;Covid-19 and neuropsychiatry;clinical update on delirium;fibromyalgia and myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS): an interoceptive predictive coding model of pain and fatigue expression;when the spark goes out: the neurology of apathy and motivation;is subjective cognitive decline (SCD) a better marker of susceptibility to functional cognitive disorder (FCD) than to neurodegeneration?: the caerphilly prospective study;temporal and spectral dynamics of reward and risk processing in the amygdala revealed with stereo-EEG recordings in epilepsy;a systematic review of extra-motor symptom evaluation in clinical trials for amyotrophic lateral sclerosis;and stimulation of the ventrolateral prefrontal cortex speeds up evidence accumulation in conflictual-uncertain environments.

Roads to Remote Monitoring of Als

Monitoring disease progression in ALS is fundamental to both routine clinical care and outcome measure- ment in clinical trials. The ALS Functional Rating Scale (ALSFRS) has for decades provided a simple summary of disability progression but has well-recognised limitations. Rasch Overall ALS Disability Scale (ROADS) is a novel, mathematically designed, yet simple scale proposed to improve reporting of functional decline due to ALS. ROADS is, thus far, not widely validated or broadly applied in clinical practice. We describe the introduction of ROADS to patients attending an NHS trust, while gathering descriptive qualitative feedback on the questionnaire acceptability and utility. Remote data collection and self-completion was mandated by the Covid-19 pandemic. The results from the ROADS questionnaire are contrasted with ALSFRS scores, appraising the pattern of disability for each patient on both rating scales and highlighting additional information provided by ROADS to further inform clinical management. We encourage review of ROADS scores alongside objective respiratory measures and King's staging.

Experience with telemedicine in neuromuscular clinic during COVID-19 pandemic.

Objectives: The aim of the present study was to evaluate the feasibility and acceptability of telehealth for the care of neuromuscular patients during the COVID-19 pandemic. Methods: Neuromuscular patients or their caregivers, as well as health care providers (HCPs), who completed a televisit during the pandemic received an online survey, assessing satisfaction with the visit, quality of care, and experience with the televisit interference. Results: Surveys from 46 neuromuscular patients (including 18 with motor neuron disease [MND])/caregivers and 7 HCPs were completed. Several aspects of televisits including good communication, adequate time to discuss concern, provision of equal care, and telemedicine interference were rated favorably among participants. Telehealth was strongly satisfactory in 30 (65.22%) and satisfactory in 15 (32.61%) neuromuscular patients/caregivers. In 18 MND patients, this was 10 (55.56%) and 7 (38.89%), respectively. Moreover, 24 (52.17%) neuromuscular patients/caregivers would strongly agree and 18 (39.13%) would agree to participate again in televisits. This was 10 (55.56%) and 4 (33.33%) for MND cases, respectively. Various medical issues were addressed during the televisits including medication management, ordering tests/referrals, discussion of goals of care, and research. The predictive stepwise logistic model found younger age as a predicting factor for higher satisfaction from, or participation again in, televisits in neuromuscular patients. Limb onset location was also a predicting factor for strong satisfaction from televisits in MND cases. Conclusions: Telemedicine is feasible and highly effective at achieving personalized care that was rated satisfactory by the majority of neuromuscular patients/caregivers and HCPs during the COVID-19 pandemic.

Ultrasound-guided glenohumeral joint injections for shoulder pain in ALS: A case series.

Introduction: Shoulder pain is a common secondary impairment for people living with ALS (PALS). Decreased range of motion (ROM) from weakness can lead to shoulder pathology, which can result in debilitating pain. Shoulder pain may limit PALS from participating in activities of daily living and may have a negative impact on their quality of life. This case series explores the efficacy of glenohumeral joint injections for the management of shoulder pain due to adhesive capsulitis in PALS. Methods: People living with ALS and shoulder pain were referred to sports medicine-certified physiatrists for diagnostic evaluation and management. They completed the Revised ALS Functional Rating Scale and a questionnaire asking about their pain levels and how it impacts sleep, function, and quality of life at baseline pre-injection, 1-week post-injection, 1 month post-injection, and 3 months post-injection. Results: We present five cases of PALS who were diagnosed with adhesive capsulitis and underwent glenohumeral joint injections. Though only one PALS reported complete symptom resolution, all had at least partial symptomatic improvement during the observation period. No complications were observed. Conclusions: People living with ALS require a comprehensive plan to manage shoulder pain. Glenohumeral joint injections are safe and effective for adhesive capsulitis in PALS, but alone may not completely resolve shoulder pain. Additional therapies to improve ROM and reduce pain should be considered.

Physical therapy follow-up before and during COVID-19 pandemic of patients with amyotrophic lateral sclerosis

Introduction: Amyotrophic lateral sclerosis (ALS) is marked by a gradual decline in functional capacity and increased morbidity from respiratory infections due to progressive loss of muscle strength. The regular monitoring by a multidisciplinary team, adjustments in ventilatory parameters, and maintenance of NIV are essential for disease management. This study aimed to monitor functional progression of patients with ALS during COVID-19 pandemic using telemedicine. Method(s): This is longitudinal case series with patients with ALS. Five assessments were performed, being two occurred in-person and three were performed remotely during the COVID-19 pandemic. First assessments included pulmonary function, respiratory muscle strength, functionality (ALSFRS-R), rate of disease progression, and disease staging. The further assessments included a clinical evaluation form, use and parameters of NIV. Result(s): We followed 11 patients for 30 months. Most patients had spinal onset ALS (72.7%), were male (72.7%), had a median age of 51 years. Total ALSFRS-R (P < 0.01) and motor domain (P < 0.01) scores reduced during the pandemic. However, total and domain scores were not different between patients with spinal and bulbar onset. According to ALSFRS-R, 90.9% of patients presented a slow disease progression. Most patients used NIV at night and during a half-day shift. Conclusion(s): The telemedicine facilitates monitoring clinical and seems to influence functional progression of patients with ALS during COVID-19 pandemic. Patients with ALS have a slow rate of disease progression and a functional decrease during 14 months follow-up period.

Proactive dysphagia management of patients with neurodegenerative diseases: Early identification and intervention

Patients with neurodegenerative diseases (ND) frequently experience concomitant impairments in pulmonary, cough, and swallow function. These impairments can lead to accelerated morbidity and mortality due to adverse events (e.g. aspiration pneumonia, respiratory failure, malnutrition/dehydration). Historically, exercise-based interventions have been avoided in patients with ND due to fear that they may lead to faster disease progression and increased fatigue, yet, emerging evidence has revealed moderate exercise training in patients with ND may prolong function, life, and quality of life. This has led to the proposal of a paradigm shift from reactive to proactive management of these patients. Therefore, there is high demand for noninvasive, portable methods for continuously monitoring pulmonary and swallow function in patients with ND to proactively implement palliative interventions and mitigate adverse events. Yet, few exist. Gold standard assessments (e.g. spirometry, videofluoroscopy) require in-person clinic visits, which can be challenging for patients with ND to attend due to physical mobility impairments, transportation issues, multifactorial health problems, and compromised immune systems (e.g. COVID-19 pandemic). Therefore, this dissertation examined: 1) The safety, tolerability, and impact of exercise-based interventions on function and quality of life in patients with amyotrophic lateral sclerosis (PALS);and 2) The ability of a novel, non-invasive, sensor-based technology (high-resolution cervical auscultation [HRCA]) to characterize swallow function in patients with ND. To examine Aim 1, the first experiment examined the impact of respiratory interventions on pulmonary, cough, and surrogates of swallow function in PALS and the second experiment investigated the impact of exercise-based interventions on function and quality of life in PALS via a systematic review. To investigate Aim 2, the third experiment explored HRCA's ability to differentiate between swallows from patients with ND and healthy age-matched adults and the fourth experiment compared temporal and spatial swallow kinematic measures between patients with ND and healthy adults and investigated HRCA's ability to annotate specific swallow kinematic events in patients with ND. Findings revealed: 1) Exercise-based interventions are well-tolerated and may be beneficial for PALS with mild-moderate disease severity, and 2) HRCA has high potential as a noninvasive, accurate method for characterizing swallow function in patients with ND. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

Facing amyotrophic lateral sclerosis under lockdown: The experiences of minors

Purpose: The purpose of this study is to assess the effect of social isolation of minors with a parent or grandparent suffering from amyotrophic lateral sclerosis (ALS) and to determine whether the psychological support offered by an Italian no-profit association helped them to manage stress. Methodology: This study followed a qualitative research design. The participants responded to in-depth interviews that were processed with inductive thematic analysis. Findings: Five themes emerged: feedback on the psychological intervention;learning and changes after the intervention;discourses on illness and death in the family;experiences and difficulties during the lockdown and suggestions for other peers who might face the same situation. Social Implications: Psychological support is necessary for these minors, and it helped them to manage both the stress of living with ALS and the limitations of social relationships during the pandemic. It showed the importance of authentic and honest communication about illness and death that allowed minors to manage anxiety and fear. Positive reinterpretation of these experiences by transforming them into opportunities was also revealed. Originality: Studies on families with ALS patients are numerous, but studies on children of these patients are still rare, and no study has investigated the impact of the COVID-19 pandemic on these children. This research investigated a topic that has not been covered previously and it also provided the opportunity to know how these children, preadolescents and adolescents living in an already complex environment, have experienced lockdown and restrictions. The study also enriched the literature on this important issue. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

Real-World Experience in Conducting Adaptive Platform Trials

Platform trials like RECOVERY, SOLIDARITY, REMAP-CAP, TOGETHER, PRINCIPLE, and many others have dominated the COVID clinical trial effort, changing clinical practice with multiple results in The Lancet, New England Journal of Medicine, and the Journal of the American Medical Association. These large-scale international efforts have enrolled tens of thousands of patients and explored dozens of potential therapies for mild, moderate, and severe COVID-19. These trials are the result of a decade of theory and practice building on the experience of oncology platform trials such as I-SPY2. In addition to COVID-19 and oncology, platform trials are now used or planned in Alzheimer's disease, amyotrophic lateral sclerosis (ALS), antibiotics, psychiatry, and many other clinical areas. Conducting a large-scale platform trial is daunting. While recent platform trial review papers have hundreds of references on the theoretical design issues and research potential of these trials, there is no substitute for the actual real-world experience of implementing an adaptive platform trial, made all the more challenging within a fast-moving global pandemic. This proposed session will investigate the challenges and solutions for successfully executing a platform trial. The proposed speakers bring decades of combined expertise from executing platforms such as ISPY-2, GBM-AGILE, REMAP-CAP, TOGETHER, PRINCIPLE, ANTICOV, HEALEYALS, Precision Promise, and others. They will describe many of the challenges specific to these large global platform trials, and the infrastructure and process needs that underpin these complex trials. The session will consist of 4 speakers with integrated 20-min talks, followed by a question-and-answer period as time allows. Dr. Ed Mills will provide an overview of platform trials and their challenges in relation to simpler clinical trials. Dr. Michelle Detry will sharpen the focus on the complexities specific to trial execution and the interactions between various stakeholders, including publication plans that must account for the perpetual nature of many platform trials. Dr. Anna McGlothlin will then discuss the specific requirements and role of the committee performing the actual interim analyses, and, finally, Dr. Hong Yu will discuss these challenges in the context of the HEALEY-ALS platform trial. All speakers will include examples from their rich realworld experience in implementing complex adaptive platform trials. Speakers (in proposed order) Ed Mills, Cytel COVID-19 has exemplified the utility of platform trials for making clinical and public health decisions in a timely manner. The most useful trials that emerged during the pandemic have been from platform trials. However, with the enthusiasm for platform trials comes the concern that trials should be implemented using methods that many groups are unfamiliar with, such as advanced statistical approaches and implementation of quick changes to the protocols. Challenges exist in interactions with funders, partners managing data sets, and clinical users. This session will use real-world experiences of platform trials in the pandemic to exemplify the utility and challenges of this new approach to clinical evaluation. This talk is for any audience with an interest in clinical trials and will address strategies to promote the use of platform trials while also highlighting the concerns about the quick adoption of this method. Michelle Detry, Berry Consultants Adaptive platform trial designs include interim analyses for pre-specified adaptations, sharing of control arm information, and a perpetual design where investigational agents enter and leave the trial at different time points. This talk will discuss the infrastructure considerations for a perpetual platform trial, ongoing statistical support from both blinded and unblinded statistical teams, setting clear communication channels and firewalls between blinded and unblinded teams, and the role of Data and Safety Monitoring Committee (DSMC) and their interaction with the independent Statistical Analysis Committe that implements the protocol-specified interim analyses. In addition, ongoing platform trials face unique challenges in determining ''who knows what, when.'' Dr. Detry will discuss planning for public releases of results, and data sharing in situations where an investigational arm may complete their trial arm participation, but the control arm data will still be used for ongoing investigational arms. Anna McGlothlin, Berry Consultants A Statistical Analysis Committee (SAC) is a team of unblinded statisticians tasked with performing the interim analyses for an adaptive trial. The unblinded SAC must have expertise in the statistical methodology being utilized and in the complexities of adaptive designs. This talk will describe the role of the SAC during the preparation and conduct of a platform trial. Responsibilities of the SAC include performing analyses in accordance with the pre-specified design, monitoring each analysis to ensure that the adaptive algorithm is performing as intended, building semi-automated reproducible reports to facilitate quick turnaround of interim results, and partnering with the Data and Safety Monitoring Board (DSMB) to aid in the interpretation of interim results. In addition, platform trials may have the unique aspect that arms may complete their final read out while other arms continue in the trial. In some cases, the fully unblinded SAC may be the only group that has complete access to the necessary data to perform the final analysis for an arm while other arms continue. Hong Yu, Massachusetts General Hospital A complex adaptive platform trial requires complex infrastructure, and many of the challenges are not revealed when conceiving or planning the trial, but only in the face of actual implementation. In this talk, we will discuss real-world experiences in developing infrastructure for adaptive platform trials, particularly the HEALEY-ALS platform. The specific challenges to be investigated are the required personnel to implement a platform, the system architecture required to support a perpetual trial design beyond the initial set of therapies, and the monitoring and management plans required to maintain robust data throughout multiple interim analyses and periodic reporting of results. Platform trials must be nimble to fulfill their goal of efficiently exploring multiple therapies as quickly as possible. These infrastructure solutions allow the trial to adapt to changing arms, maintain data quality as well as trial integrity, and support multiple sets of results and publications throughout the trial's duration.

Saliva and Saliva Extracellular Vesicles for Biomarker Candidate Identification-Assay Development and Pilot Study in Amyotrophic Lateral Sclerosis.

Saliva is gaining increasing attention as a source of biomarkers due to non-invasive and undemanding collection access. Extracellular vesicles (EVs) are nano-sized, cell-released particles that contain molecular information about their parent cells. In this study, we developed methods for saliva biomarker candidate identification using EV-isolation and proteomic evaluation. We used pooled saliva samples for assay development. EVs were isolated using membrane affinity-based methods followed by their characterization using nanoparticle tracking analysis and transmission electron microscopy. Subsequently, both saliva and saliva-EVs were successfully analyzed using proximity extension assay and label-free quantitative proteomics. Saliva-EVs had a higher purity than plasma-EVs, based on the expression of EV-proteins and albumin. The developed methods could be used for the analysis of individual saliva samples from amyotrophic lateral sclerosis (ALS) patients and controls (n = 10 each). The starting volume ranged from 2.1 to 4.9 mL and the amount of total isolated EV-proteins ranged from 5.1 to 42.6 µg. Although no proteins were significantly differentially expressed between the two groups, there was a trend for a downregulation of ZNF428 in ALS-saliva-EVs and an upregulation of IGLL1 in ALS saliva. In conclusion, we have developed a robust workflow for saliva and saliva-EV analysis and demonstrated its technical feasibility for biomarker discovery.

Neuromuscular disease: 2023 update.

This review highlights ten important advances in the neuromuscular disease field that were reported in 2022. As with prior updates in this article series, the overarching topics include (i) advances in understanding of fundamental neuromuscular biology; (ii) new / emerging diseases; (iii) advances in understanding of disease etiology and pathogenesis; (iv) diagnostic advances; and (v) therapeutic advances. Within this general framework, the individual disease entities that are discussed in more detail include neuromuscular complications of COVID-19 (another look at the topic first covered in the 2021 and 2022 reviews), DNAJB4-associated myopathy, NMNAT2-deficient hereditary axonal neuropathy, Guillain-Barré syndrome, sporadic inclusion body myositis, and amyotrophic lateral sclerosis. In addition, the review highlights a few other advances (including new insights into mechanisms of fiber maturation during muscle regeneration and fiber rebuilding following reinnervation, improved genetic testing methods for facioscapulohumeral and myotonic muscular dystrophies, and the use of SARM1 inhibitors to block Wallerian degeneration) that will be of significant interest for clinicians and researchers who specialize in neuromuscular disease.

Impact of the covid-19 pandemic on amyotrophic lateral sclerosis care in the UK.

The Covid-19 pandemic has impacted healthcare. Our aim was to identify how amyotrophic lateral sclerosis (ALS) care in the UK has been affected by the pandemic by exploring the experiences of people living with ALS (plwALS), healthcare professionals (HCPs) working with plwALS, and ALS care centers. Three surveys were carried out to explore the experiences of plwALS, HCPs and ALS care centers during the pandemic. Quantitative data were analyzed using descriptive and inferential statistics and triangulated with the qualitative data which were analyzed thematically. Responses from 53 plwALS, 73 HCPs and 23 ALS care centers were analyzed. Five main themes were identified: keeping safe, losses, negative emotions, delivering care and alternative care delivery in a pandemic. PlwALS and HCPs felt that care was sub-optimal as a result of the pandemic. Changes to care included longer waiting times and face-to-face appointments being canceled or replaced by virtual consultations. While benefits of virtual consultations were reported, concerns were raised about incomplete clinical assessments and the disruption of provision of testing and interventions. ALS care has changed as a result of the pandemic. Patients have had a lack of face-to-face contact with HCPs and have experienced delays to investigations and treatments. PlwALS and HCPs were concerned about the impact of this change, but the long-term implications remain unclear. We propose recommendations for HCPs caring for plwALS, that will promote continuity of evidenced based care in the context of a pandemic.

Virus exposure and neurodegenerative disease risk across national biobanks.

With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis and growing concerns regarding the neurological impact of the coronavirus pandemic, we examined potential links between viral exposures and neurodegenerative disease risk. Using time series data from FinnGen for discovery and cross-sectional data from the UK Biobank for replication, we identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease and replicated 22 of these associations. The largest effect association was between viral encephalitis exposure and Alzheimer's disease. Influenza with pneumonia was significantly associated with five of the six neurodegenerative diseases studied. We also replicated the Epstein-Barr/multiple sclerosis association. Some of these exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. As vaccines are currently available for some of the associated viruses, vaccination may be a way to reduce some risk of neurodegenerative disease.

At-home telespirometry (AHT) in amyotrophic lateral sclerosis (ALS): Digital health technology and quality control

Background: Smart phone mobile application (Breathe Easy app) with data dashboard (https://www.zephyrx.com/) receive and display results of remote FVC accelerated in use during COVID-19 pandemic. Objective(s): We assessed the reliability of FVC as reported with in-clinic Conventional (Viaire and Vyasis, USA) and inclinic portable and at-home portable (MIR Spirobank Smart, Italy) spirometers that calculated FVC as percentage of predicted values based on GLI (Global Lung Index)-2012 reference standard. Method(s): In this retrospective study, twenty-two ALS patients were analyzed from a total of 95 ALS patients seen in clinic between July 2020 and June 2021. Independent analysis of FVC % predicted values acquired with portable spirometer was performed using GLI-2012 online calculator equations based on age, height, gender and ethnicity. To confirm that the same reference standard GLI-2012 was displayed by the software application, a web-based tool was used to calculate % predicted FVC to confirm that spirometric values were standardized according to GLI-2012 (glicalculator. ersnet.org). Result(s): A third of dashboard-reported measurements were found to be 1% less than calculated measurements (29 out of 87 portable spirometry measurements) and appeared to be a fairly consistent difference in the first 1/3 of FVC followed longitudinally. Query was brought to the attention of the ZephyRx software development team. Dashboard algorithm was assessed to investigate for possible systematic error to account for the difference. The automated dashboard reporting of age using exact birth date to one decimal place on the day of testing as opposed to birth year used with manual calculations was confirmed to result in the 1% predicted difference in manually calculated FVC. Discussion(s): Reported difference in spirometric values can be due to systematic difference in spirometric reference standards or a true difference in pulmonary function (1). ALS-specific digital health technology require vetting by independent ALS neuromuscular and pulmonary researchers and quality testing needs to occur within the clinical realm (2).

At-home telespirometry (AHT) in amyotrophic lateral sclerosis

Background: COVID-19 pandemic presents new opportunities to augment respiratory monitoring complementary to remote telehealth services. Stratification of vital capacity may allow for characterization of FVC and disease trajectory clusters (1). Objective(s): In this implementation science study, we assessed the feasibility of measuring FVC in seated upright and supine positions obtained with in-clinic-conventional (Viaire and Vyasis, USA), in-clinic-portable and at-home-portable (MIR Spirobank Smart, Italy) spirometers with respiratory therapist coaching. Method(s): Electronic health records of 22/95 ALS clinic patients (23%) from single-center in Central New York that launched AHT between July 2020 and June 2021 was reviewed in this IRB-approved retrospective study. Mean age of patients was 65 years old and 9 were males. Patients were stratified according to baseline seated FVC % predicted by conventional method: Group A, FVC >80%, Group B, 60-80%, Group C <60% predicted. Patients unable to come to clinic received spirometers by mail followed with remote training with respiratory therapists without conventional spirometry. Result(s): Pearson correlation coefficient was used to evaluate the correlation between FVC measurement using conventional and portable spirometry by position. Bland-Altman analysis was performed to evaluate the mean difference (conventional - portable) with 95% limits of agreement. Measurement of seated FVC acquired during the same clinic visit (N=13) were highly correlated in liters (R2=0.95, p<0.0001) and % predicted (R2=0.952, p<0.0001). Bland- Altman analysis showed good agreement with a mean difference of 0.147L, 0.345 to 0.639L);4.154% predicted, (8.004 to 16.311%). In-clinic supine FVC (N=4) were highly correlated in liters (R2=0.987, p=0.007) and % predicted (R2=0.987, p=0.007) with a mean difference of =0.33L, (0.101 to 0.761L);8.5% predicted, (0.043-17.043%). Supine vital capacity measurements were more frequently obtained with AHT 35/52 (67.31%) vs. 9/21(42.86%) with Conventional spirometry. Safety concerns associated with patient transfers were the most frequently encountered barrier in performing supine testing in clinic. Reason for drop out for 2/22 patients with no remote AHT was attributed to perceived aggravation of anxiety from readily viewing FVC results on smartphone and low baseline FVC (<50% predicted). AHT led to prompt initiation of NIV in 5/22 patients, of which 3 were homebound, had low FVC at initial AHT (12-48% predicted), low ALS FRSR (14-28 out of 48) and received remote AHT training without conventional spirometry. An ongoing slow vital capacity (NCT05106569) prospective clinical study in ALS will determine if frequent respiratory surveillance from home using AHT leads to better outcomes in relation to use of NIV.

Suppressing neuroinflammation: regulatory T lymphocyte immunomodulatory therapy for ALS

Neuroinflammation plays a prominent role in promoting the disease progression of ALS, mediated in part by the interaction of injured motoneurons with surrounding glia and dysregulated central and peripheral immunomodulatory cells. Prominent among such immunomodulatory cells are the CD4+ CD25highFOXP3+ T-lymphocytes that mediate neuroprotection by suppressing proinflammatory responses. However, Treg suppressive functions are impaired in ALS, but are restored and even enhanced following expansion ex vivo. Autologous infusions of these expanded T regs together with subcutaneous IL- 2 injections formed the basis of two ALS clinical trials. In a Phase 1 pilot study of 3 ALS patients, infusions were safe and well-tolerated and slowed progression rates during early and later stages of the disease. Treg numbers and suppressive function increased after each infusion and correlated with slowing of disease progression. However, the duration of the clinical benefit was limited, possibly related to the serum biomarkers of oxidative stress, 4-hydroxynonenal, and oxidized LDL These lipid peroxide biomarkers were increased prior to Treg infusions, fell with Treg infusions and slowing of disease progression, rose again as disease progression accelerated in the absence of infused Tregs, then fell again when Tregs were reinfused. Thus, the levels of 4-HNE and ox- LDL were effectively responsive to Treg infusions and mirrored the stabilization or deterioration of the subject's clinical status. A Phase 2A study of autologous infusion of expanded Tregs in combination with subcutaneous IL-2 injections was undertaken at Houston Methodist and Massachusetts General Hospitals. The study was planned for 12 ALS pts enrolled in a 24-week randomized control trial (RCT) followed by a 24- week open label extension (OLE). In the RCT Treg/IL-2 treatments were safe and well-tolerated;with increased Treg suppressive function in the active group. Evaluation of relative progression rates in the RCT was precluded by the COVID pandemic which decreased the number of participants. However, 8 ALS patients did complete the 24-week OLE;Treg/IL-2 treatments were safe and well-tolerated, and Treg suppressive function and numbers were increased. Six patients showed slow to no progression in the OLE (mean change of -2.7 points on ALSFRS-R) Two patients progressed rapidly;they were unresponsive to Treg infusions and had elevated markers of peripheral inflammation (IL-17C and IL-17F) as well as elevated markers of oxidative stress (OLR1 and oxidized-LDL). The 6 participants in the slow progressing group had normal levels. Whether Treg/IL-2 treatments can slow disease progression in ALS requires a large double-blind randomized controlled study. Nevertheless, our open-label studies, albeit in a limited population, suggest that Treg therapy is safe and well tolerated, and a promising approach to slowing ALS progression;lipid peroxide biomarkers may not only reflect a heightened pro-inflammatory milieu but may also be useful in monitoring clinical responsiveness to therapy.

Psychological Support for Family Caregivers of Patients With Amyotrophic Lateral Sclerosis at the Time of the Coronavirus Disease 2019 Pandemic: A Pilot Study Using a Telemedicine Approach.

The coronavirus disease 2019 (COVID-19) pandemic confined most of the population to homes worldwide, and then, a lot of amyotrophic lateral sclerosis (ALS) centers moved to telemedicine services to continue to assist both patients with ALS and their caregivers. This pilot, randomized, controlled study aimed to explore the potential role of psychological support interventions for family caregivers of patients with ALS through resilience-oriented sessions of group therapy during the COVID-19 pandemic. In total, 12 caregivers agreed to be remotely monitored by our center since March 2020 and underwent scales for global burden (i.e., Caregiver Burden Inventory, CBI), resilience (i.e., Connor Davidson Resilience Scale, CD-RISC), and perceived stress (i.e., Perceived Stress Scale, PSS) at two-time points (i.e., at pre-treatment assessment and after 9 months or at post-treatment assessment). They were randomized into two groups: the former group underwent resilience-oriented sessions of group therapy two times a month for 3 months, while the latter one was only remotely monitored. No significant differences were found in CBI, CD-RISC, and PSS during the 9-month observation period in the treated group compared with the control group, suggesting a trend toward stability of caregiver burden together with resilience and perceived stress scores in all the subjects monitored. The lack of differences in caregivers' burden, resilience, and perceived stress scores by comparing the two groups monitored during 9 months could be due to the co-occurrence of the COVID-19 pandemic with the stressful events related to caring for patients with ALS that might have hindered the detection of significant benefits from short-lasting psychological support.