Primary Lateral Sclerosis

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs due to retrograde axonal degeneration of the corticospinal tract. Baclofen is a selective GABA-B receptor agonist and is commonly used for the treatment of spasticity. Baclofen can be administered orally or intrathecally by the surgical implantation of a specialized pump. Intrathecal baclofen (ITB) is significantly more potent for the treatment of spasticity than the oral form. The goal of this clinical trial is to explore the efficacy and safety of ITB in the treatment of HSP patients. This study is prospective, open-label, single center, and this trial will last for 3 years. A total of 50 patients will participate. Twenty-five patients who will receive ITB and the other 25 control patients will receive oral baclofen. Patients with HSP aged 14 to 70 years, with a Modified Ashworth Scale score of ≥3 in ≥2 joints of lower limb, will be recruited. Patients who do not agree to undergo ITB and/or those who have an inadequate response during intrathecal baclofen test will receive oral baclofen therapy and undergo natural history observation. Professional clinical evaluations are conducted regularly for both groups.

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by axonal degeneration of the corticospinal tract. This degeneration often leads to foot deformities such as equinovarus, cavus foot, and Achilles tendon contracture, which result from lower limb spasticity and muscular imbalance. These deformities result in gait abnormalities, uneven plantar pressure distribution, and secondary osteoarticular damage, which significantly impair motor function and quality of life. Surgical correction serves as the primary intervention to address fixed deformities and delay disease progression.This prospective, open-label, single-center study aims to evaluate the long-term functional outcomes of surgical treatment for HSP-related foot deformities, determine the optimal timing for surgical intervention, and establish objective evaluation criteria. Over a 2-year period, 100 patients aged 10-45 years with HSP-confirmed isolated Achilles tendon contracture or equinovarus cavus foot deformity will be enrolled in the study. Eligible patients must exhibit progressive deformity refractory to conservative therapy, accompanied by walking pain, frequent falls, and significant quality-of-life impairment. They must also retain the ability to walk independently or with assistive devices for at least 10 meters. All participants will undergo regular clinical assessments.

Most people with ALS or MND who are seen clinically by the PI or PI designees at participating sites will be recruited into this study. This well-established framework provides an opportunity to offer to a large proportion of people with ALS/MND a chance to participate in a clinical research project. Upon obtaining consent, the following is done: People with ALS/MND are assigned a Neurological Global Unique Identifier (NeuroGUID) and its study-specific derivative, NeuroSTAmP, which is used to link this Study's information to biological samples, images, and clinical data obtained from those individuals in this Study and other studies/trials, in which these patients participate(d). The following information is captured in NeuroBANK platform: Baseline information * Longitudinal clinical and phenotypical data from routine clinical visits * Longitudinal clinical and historical phenotypical data transcribed from electronic health records and notes * Any other observational data that are of interest to the Investigator may be captured or linked to information in NeuroBANK. Other Key Features The site should track numbers of patients who declined participation. The site should have a mechanism in place to include an offer of participation to each patient in clinic (consenting does not require immediate data entry) Regular Data Quality checks may be performed at the site. Site personnel who intend to have access to NeuroBANK are trained and certified prior to given access. Several registries, both cross-sectional and longitudinal, currently exist in ALS. NeuroBANK is distinct from other current registries in that it is a patient-centered platform that is designed to function as a data repository of patient data from clinical visits and multiple clinical research projects as well as linking these data to biorepository for tissue, imaging, and other biological information. This natural history study can act as a clinical research framework that may link clinical and clinical research data from current and past studies with biological specimens and image collections. With obtained consents, biological specimens may be collected with bar-coded labels containing patient assigned study specific NeuroSTAmPs, printed from within NeuroBANK, and scanned into NeuroBANK's virtual distributed BioRepository module. Imaging studies are de-identified with NeuroSTAmPs and linked to clinical and phenotypical information. Anonymized clinical data obtained through this protocol are available to other researchers. Study Population Individuals who are seen during their clinical care visits are asked to allow their data to be uploaded and captured for clinical research. The NeuroBANK platform is located at and managed by the Center for Innovation and Bioinformatics (CIB), Neurological Clinical Research Institute (NCRI) of Massachusetts General Hospital (Boston, MA). Consent Process Every participant in the ALS clinic is approached to participate in this study. A signed informed consent form is obtained before any data are recorded for study purposes.

SPG56 is one of the complicated and early-onset HSP subtypes caused by genetic mutations in CYP2U1. So far, there is no standardized and specific clinical therapy for SPG56. The goal of this clinical trial is to explore the efficacy and safety of calcium folinate in the treatment of SPG56 patients. This study is prospective, open-label and single arm and this trial will last for 6 years. A total of 10 patients will participate and they will receive calcium folinate treatment and professional clinical evaluation regularly.

The study will consent patients with ALS or related disorders that are receiving care at a clinical center in the CReATe consortium that uses Epic as its electronic health record (EHR) system. The study aims to systematically gather a clinical dataset through the EHR using a standardized approach to characterize the natural history of ALS and related diseases.

In this observational study, participants with ALS and related disorders will be followed longitudinally over the course of a year to examine disease progression. Participants with ALS or a related disorder will have up to 5 in-person visits at screening, 0, 4, 8 and 12 months. Healthy controls are included as comparisons and will have 3 in-person visits at screening, 0 and 8 months. At each visit after screening, patients and healthy controls will undergo an MRI, neurocognitive and speech testing, clinical evaluations specific to ALS (ALSFRS-R, FVC, neurological exam, which are not completed by controls), answer questionnaires about their health and have biospecimens, including blood, saliva and optionally cerebrospinal fluid, collected.

ALS is a progressive neuromuscular disease that causes weakness and inevitably affecting multiple motor processes within the body. To assess changes in functional mobility, clinicians and clinical investigators often rely on the ALS Functional Rating Scale - Revised (ALSFRS-R), a standardized 12-item questionnaire that has been in use for decades. Although thoroughly validated, this scale has received criticism for providing a coarse reflection of a patient's disease, scaling non-linearly within and across functional domains, and without the sensitivity to reflect day-to-day variability or small but meaningful changes. This study includes collection of digital speech and fine motor control assessment data at a single study visit. Features extracted from this data will be compared with standard clinical disease outcome measures and also the features derived from control participant data. We will use these comparisons to explore the use of these digital assessments in capturing the range of functional changes that occur in ALS and the related motor neuron diseases of PLS and PMA that are regularly treated in the ALS clinic.

This single-arm pilot study aims to investigate the effects of a whole-body electrical muscle stimulation (WB-EMS) exercise program on neuromuscular and physical function in adults with neuromuscular disease (NMD). The background rationale is that individuals with NMD often experience significant barriers to traditional exercise due to impaired voluntary motor unit activation, leading to sedentary behavior, physical deconditioning, and worsened long-term health outcomes. WB-EMS may offer a therapeutic alternative by bypassing voluntary activation limits and directly stimulating muscle contractions through externally applied electrical currents. The intervention utilizes the Katalyst system, an FDA-cleared device being used off-label in this population, which delivers targeted stimulation to major muscle groups during synchronized exercise movements. Up to 50 adults diagnosed with various NMDs, including amyotrophic lateral sclerosis, spinal muscular atrophy, myasthenia gravis, and Charcot-Marie-Tooth disease, will be enrolled. Eligible participants must be at least 18 years old, able to stand continuously for 15 minutes with or without assistance, and have at least anti-gravity strength in major muscle groups. Key exclusion criteria include implanted electrical devices, unstable medical conditions, pregnancy, and conditions affecting muscle fiber structural integrity. The intervention consists of 20-minute supervised exercise sessions performed 1-2 times per week over 4-8 weeks, with real-time monitoring of pain, perceived exertion, and tolerability. Outcome measures include neural excitability assessed via transcranial magnetic stimulation, voluntary motor unit characteristics via decomposition electromyography, stimulated motor unit characteristics via compound muscle action potential nerve conduction study, functional performance tests (10-meter walk, timed up and go, five-time sit-to-stand, stair ascent/descent, broad jump, multidirectional lunge), and patient-reported outcomes evaluating fatigue, pain, and quality of life. This pilot study will generate critical preliminary data on the feasibility, safety, and efficacy of WB-EMS as a novel exercise modality for adults with NMD, with the goal of informing future large-scale clinical trials.

INTRODUCTION: Hereditary Spastic Paraplegia (HSP) is a heterogeneous group of inherited neurological disorders characterized by progressive weakness and spasticity in the lower limbs, which significantly impairs walking abilities (endurance and speed). Despite several specific interventions for particular deficits already having been studied, there is currently a lack of comprehensive and structured neurorehabilitation programs designed to improve walking function in these patients. Therefore, this protocol aims to explore the feasibility and effectiveness of a composite training approach focused on improving flexibility, muscle strength, motor control, balance, and aerobic capacity. STUDY OBJECTIVES: Primary endpoint: Feasibility of the study, assessed by the following: Sufficient recruitment rate, with 20 patients enrolled within 24 months from the study's initiation. Adequate adherence to the treatment plan, defined by the completion of at least 75% of the planned treatment sessions, with a minimum of 10 treatment sessions. Sufficient patient retention, defined as at least 75% of enrolled patients completing the study with adequate treatment adherence. Absence of serious adverse events related to patient participation in the study. Patient satisfaction with the healthcare received during the study. Secondary endpoint: Therapeutic efficacy of the study, assessed by: Improvement in walking endurance (6-Minute Walk Test). Improvement in walking speed (10-Meter Walk Test). Exploratory objectives: Improvement in overall functional condition (Spastic Paraplegia Rating Scale and the Hereditary Spastic Paraplegia - Self Notion and Perception Questionnaire). Improvement in passive joint range of motion in the lower limbs (goniometer). Improvement in lower limb muscle strength (5 Times Sit-to-Stand Test). Improvement in standing balance (Functional Reach Test and stabilometric platform). STUDY DESIGN: Open-label, non-randomized, uncontrolled interventional study. STUDY POPULATION: Hereditary Spastic Paraplegia patients SAMPLE SIZE: 20 patients ELIGIBILITY: Inclusion criteria: Adults diagnosed with Hereditary Spastic Paraplegia. Presence of any functional deficit in the lower limbs affecting walking, such as muscle weakness, hypertonia, or balance issues. Ability to walk independently, without physical assistance from another person, defined by a Functional Ambulation Category score of 3 or higher. Ability to understand simple instructions, comprehend the purpose of the study, willingness to participate, commitment to at least 10 treatment sessions, and suitability for signing the informed consent. Exclusion criteria: Use of botulinum toxin or surgery to treat lower limb hypertonia within six months prior to study enrollment. Contraindications for moderate physical activity, including stretching exercises, muscle strengthening, and aerobic training. Withdrawal Criteria: Voluntary withdrawal by the patient. Occurrence of adverse events or health issues that prevent continuation of the treatment plan. Patient Replacement: Recruitment will continue until 20 subjects are enrolled. Any patients who withdraw from the study will not be replaced. METHODS: Twenty adults diagnosed with HSP will participate in 10 to 16 therapist-guided sessions, each lasting 60 or 120 minutes, occurring once or twice a week depending on individual choice and capabilities. At the conclusion of the study, participants will receive an information package (manual and video tutorials) to support long-term home exercise. Evaluations will take place at three time points: before the intervention (T0), immediately after the intervention (T1), and three months post-intervention (T2). The primary objectives will focus on assessing the study's feasibility (recruitment, retention, adherence, absence of adverse events, and patient satisfaction). Secondary outcomes will evaluate improvements in walking ability and specific contributing factors, such as reduced spasticity, increased muscle strength, and improved balance. INTERVENTION: FRAME training is composed of four key components: Component 1: Flexibility. To decrease muscle tone and enhance mobility, the therapist will apply a combination of stretching exercises and electrical stimulation, targeting areas such as the triceps surae, adductors, rectus femoris, and hamstrings. Electrical stimulation will utilize biphasic, high-frequency sensory stimulation (100 Hertz, pulse width 200 µs, and intensity just below the motor threshold) for a duration of 30 minutes, combined with stretching activities. Component 2: Resistance Training (and Balance). The resistance training will focus on strengthening muscles typically weakened in individuals with Hereditary Spastic Paraplegia (HSP), especially the proximal muscles of the hip and trunk. To promote muscle engagement and improve balance and coordination, core stability and resistance exercises will be performed under conditions of mild instability. These exercises will be carried out in sitting or standing positions, rather than lying down, to optimize muscle activation. Component 3: Movement Execution (and Balance). Gait training will be based on motor learning principles such as repetitive, task-oriented practice, variable practice, and graded practice. Graded practice involves breaking down a complex movement into simpler segments, practicing each segment until proficiency is achieved, and then progressively combining them into more complex sequences. Patients will be challenged with standing balance exercises while working on specific gait impairments. Gait training will involve varying walking patterns, including fast, slow, sidewalk walking, walking backward, and stair climbing. Component 4: Aerobic Training via High-Intensity Interval Training (HIIT). HIIT consists of brief, intense aerobic efforts using large muscle groups, followed by rest periods of equal length. HIIT has been found to produce better cardiovascular results with a lower perceived level of effort compared to moderate-intensity aerobic exercise. In this protocol, patients will perform 30-second high-intensity intervals followed by 30 seconds of passive rest, repeated 10 times in two sets. Each session will begin with a 5-minute warm-up, include a 5-minute rest between sets, and conclude with a 5-minute cool-down. Patients will participate in the modality most suitable for consistent training, such as walking, running, cycling, or squatting. RELEVANCE: This protocol is significant for providing clinicians with valuable insights into the feasibility and potential effectiveness of a comprehensive, clinically-oriented program designed to improve walking ability in adults with Hereditary Spastic Paraplegia. It also aims to inform future translational research studies in the field.

Following the qualification of the 95th centile of stride velocity (SV95C) as a primary digital endpoint in Duchenne muscular dystrophy (DMD), there is growing interest in extending such digital assessments to other neurological and metabolic diseases that impair movement. Traditional in-clinic functional tests (e.g., 6-minute walk test, 10-meter walk/run) provide only limited snapshots of motor ability and are influenced by external factors such as motivation and fatigue. Similarly, motor function scales and biomarkers, while useful, often lack objectivity or established clinical relevance. The ActiLiège-Adult study aims to address these limitations by leveraging the Syde® device, a wearable magneto-inertial sensor worn on the wrist and/or ankle, to continuously monitor motor activity in daily life. This device has been previously validated in DMD and other neuromuscular conditions and has been used in both interventional and natural history studies. This academic study will enroll 300 ambulant adult patients, including 220 with neurological diseases and 20 with obesity, with a minimum of 20 patients per disease type. Ambulation is defined as the ability to walk 10 meters unaided. Patients who lose ambulation during the study will continue to be followed with adapted assessments. Participants will be monitored for up to two years (six months for diseases affecting the neuromuscular junction). Standardized clinical assessments-including timed tests, motor function evaluations, and strength measurements-will be conducted at baseline and every six months. These will be compared with continuous data collected by the Syde® device. Additionally, patients will complete a Patient Global Impression of Change (PGI-C) questionnaire every six months. The study's goal is to generate robust, real-world data to support the development of objective, sensitive, and clinically meaningful digital endpoints for use in future therapeutic trials targeting movement disorders.