Multiple System Atrophy (MSA)

Patients hospitalized in CRCU will be informed of the research. Those who do not object to participating in the research and who meet the eligibility criteria will be included. Their participation will begin with an initial functional and joint assessment of the patient's hand by an occupational therapist to determine the diameter of cutlery handles best suited to the patient's grip (25, 30, 35 or 40 mm). The patient's autonomy ("Eating" criterion on the Katz scale) will be assessed by the same ergotherapist, and the quantity of food ingested will be measured by a dietician at 3 points: * During a lunch before using the adapted cutlery handles (Day0); * At lunch when the adapted cutlery handles are used for the first time (Day1); * At lunch after 3 days' use of the adapted cutlery handles (Day3), corresponding to the learning phase in the use of the technical aid. Lunches will be similar over the 3 days. These are standard lunches predefined by the unit's dietician. On Day0 and Day3, the ergotherapist will carry out an ecological assessment of meals. Ecological assessment is used in ergotherapy to observe and analyze the patient's interactions with his environment and their repercussions on his ability to perform a task. The aim here is to assess whether the patient exhibits compensation of the upper limb (such as shoulder elevation or trunk inclination) during the meal performed without technical aids (Day0) and that performed after the learning phase of using the adapted handle (Day3). The patient's participation will end at the end of the Day3 assessments.

This is a prospective cohort study that will enroll patients who are about to or have already undergone DBS electrode placement for a variety of disorders including, but not limited to Parkinson's disease, essential tremor, dystonia, depression, epilepsy, neuropathic pain and Alzheimer's disease. This eligible patient population is broad but unified by the fact that they will all undergo DBS to treat specific circuit dysfunctions. Pre-operative DBS patients and patients with externalized leads or internalized IPG may be included. We propose to study patients with externalized leads or internalized IPG programmed at either 'switched off' (IPG at 0 volt and off state) and 'switched on' settings We have already performed phantom safety testing for these experimental conditions and found it to be safe. We propose to perform the following scans: 1. Structural 1.5Tesla or 3Tesla MRI with 8 channel coil/or transmit-receive head coil - 3D FSPGR, standard FRFSE T2 scan, standard DTI scan (white matter tracts) and standard QSM (Quantitative Susceptibility Mapping) scan (Iron quantification). 2. Resting state and task based functional MRI with 8 channel coil Further, we propose to assess whether the aforementioned scans can be used as an adjunct to improve current DBS post-operative follow up.

Study Rationale: This prospective study, to be conducted in two centers (UZ Leuven and UZ Gent), aims to validate cardiac \[18F\]-MFBG PET in distinguishing Parkinson's disease (PD) from multiple system atrophy (MSA-P) and differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Both PD and DLB, caused by alpha-synuclein deposits (Lewy bodies), exhibit not only nigrostriatal dopaminergic deficits but also early peripheral changes in myocardial norepinephrine (NE) innervation. These defects can be visualized and quantified using NE transporter tracers. \[18F\]-MFBG was developed several years ago with high-yield production and has already been employed in multiple centers worldwide, mainly in the context of imaging neuroendocrine tumors. \[18F\]-MFBG offers logistical, technical, and pharmacological advantages, including faster scanning, high spatial resolution, and improved quantification compared to the existing method using \[123I\]-MIBG SPECT. Participant Population: The study will include 28 healthy volunteers (CON), of which 3 will participate in \[18F\]-MFBG PET dosimetry (part 1) and 25 in the main study for optimization/age-dependence of cardiac \[18F\]-MFBG parameters (part 2). In part 3, 40 PD, 15 MSA-P, 15 DLB, and 15 AD patients with biomarker-confirmed diagnoses will be included. Total: 113 subjects. Intervention: All subjects will undergo three examinations in the main work packages (parts 2 and 3) dynamic cardiac \[18F\]-MFBG PET, with dynamic \[123I\]-MIBG SPECT as a comparator, as well as cerebral \[18F\]-PE2I PET. Endpoints: Primary: Non-inferiority in discriminating populations using \[18F\]-MFBG; Secondary: effect size, relationship between myocardial uptake and cerebral dopamine active transporter (DAT) changes, autonomic dysfunction, regional myocardial variation. Secondary: 1. Determine the effect size (ES) of the reduction in myocardial uptake of \[18F\]-MFBG in PD and DLB compared to \[123I\]-MIBG SPECT and \[123I\]-MIBG planar scintigraphy. 2. Identify any significant correlation between the reduction in myocardial uptake of \[18F\]-MFBG in PD and DLB and the reduction in \[18F\]-PE2I binding in early to moderate disease stages. 3. Assess the relationship between the reduction in myocardial uptake of \[18F\]-MFBG in PD and DLB and measures of autonomic dysfunction. 4. Examine the regional pattern of reduced \[18F\]-MFBG uptake in PD/DLB compared to controls, with an endpoint considered met if different regional segment scores are evident between PD/MSA-P or DLB/AD or subtypes of PD.

This is an open-label, first in human (FiH) positron emission tomography (PET) microdose study in patients with suspected α-synuclein pathology and healthy volunteers (HVs) using \[18F\]ACI-15916 as a novel radioligand. This study will be dedicated to qualification of the ligand \[18F\]ACI-15916 to measure α-synuclein pathology using PET investigations, including estimation of effective dose and test-retest reliability. The study consists of four parts in which a total of up to 46 participants may be included: * Part 1: Up to 5 HVs and up to 5 patients with Parkinson's Disease (PD) will be included. * Part 2: Up to 30 additional subjects including: HV cases (maximum 10) and patients with α-synucleinopathies such as PD, Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). * Part 3: Up to 10 participants from Part 1 and/or Part 2 will have a second PET measurement within one month after their initial PET measurement to evaluate test-retest variability and reproducibility. * Part 4. Up to 6 HVs (3 female and 3 male) will undergo a whole-body PET-CT examination to estimate the effective dose after one administration of \[18F\]ACI-15916. The four study parts can overlap. The study consists of a screening period of up to 60 days to assess participants' eligibility, a PET scan with \[18F\]ACI-15916 along with arterial blood sampling, and a safety phone call following the scanning visit. For participants in Part 3, a second PET scan with \[18F\]ACI-15916 will be performed up to one month after the first scan to evaluate test-retest variability and reproducibility, followed by a new safety phone call. For subjects in Part 4 (dosimetry), no arterial blood sampling will be performed. The total study duration will be up to 10 weeks for Part 1, 2 and 4 participants and up to 14 weeks for Part 3 participants.

Alpha-synucleinopathies refer to age-related neurodegenerative and dementing disorders, characterized by the accumulation of alpha-synuclein in neurons and/or glia. The anatomical location of alpha-synuclein inclusions (Lewy Bodies) and the pattern of progressive neuronal death (e.g. caudal to rostral brainstem) give rise to distinct neurological phenotypes, including Parkinson's disease (PD), Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB). Common to these disorders are the involvement of the central and peripheral autonomic nervous system, where Pure Autonomic Failure (PAF) is thought (a) to be restricted to the peripheral autonomic system, and (b) a clinical risk factor for the development of a central synucleinopathy, and (c) an ideal model to assess biomarkers that predict phenoconversion to PD, MSA, or DLB. Such biomarkers would aid in clinical trial inclusion criteria to ensure assessments of disease- modifying strategies to, delay, or halt, the neurodegenerative process. One of these biomarkers may be related to the neurotransmitter dopamine (DA) and related changes in the substantia nigra (SN) and brainstem. \[18F\]F-DOPA is a radiolabeled substrate for aromatic amino acid decarboxylase (AAADC), an enzyme involved in the production of dopamine. Use of this radiolabeled substrate in positron emission tomography (PET) may provide insight to changes in monoamine production and how they relate to specific phenoconversions in PAF patients. Overall, this study aims to identify changes in dopamine production in key regions including the SN, locus coeruleus, and brainstem to distinguish between patients with PD, MSA, and DLB, which may provide vital information to predict conversion from peripheral to central nervous system disease.

In the field of diagnosing brain neurodegenerative diseases, it is now a well-established practice to inject positron-emitting tracers into the human body. These tracers bind to specific target proteins, allowing their distribution to be visualized via PET imaging. Currently, several research groups worldwide are engaged in developing and clinically validating their own tau imaging agents. This clinical research project aims to visualize abnormal tau pathology in the living human brain using \[18F\]NIDF PET imaging. \[18F\]NIDF is a 2-arene-azaindole-based tracer that offers stronger binding affinity to tau neurofibrillary tangles and reduced non-specific/off-target binding compared to existing tau-PET imaging agents. The study primarily focuses on evaluating the safety and diagnostic efficacy of \[18F\]NIDF PET imaging in human subjects.

2\. INTERVENTION The first phase of the intervention will last four weeks and will be done in the hospital. After this intervention, if the patients meet the inclusion criteria, they will be enrolled in the second phase, which will be done at the patient's home for two additional weeks. Three assessments will be performed during the study: The first one ("Day 0") will be assessed before starting the treatment, the second one will be done ("Week 4") directly after the intervention at a hospital setting, and the last one ("Week 6"), after the home intervention. The intervention will be conducted in 1-hour sessions three times a week for four weeks, performing different exercises using an augmented reality platform accessed through RGSweb. If the patients continue the intervention at home, a three-session training for two weeks will be conducted in the presence of a patient's relative, who will accept to be the training partner. 3\. EQUIPMENT AND TECHNICAL SPECIFICATIONS. RGSweb can be used with any computer or device with a camera. However, our target users are patients who might have visibility issues due to old age. Therefore, bigger screens will be used to enhance the patients'; visibility. Additional screen support will be required to hold the monitor. There are three protocols in RGSweb: Twister Buddy: It has been developed for balance training, which involves a series of levels intended to strengthen the muscles crucial for maintaining upright posture, notably those in the legs. The aim is to improve stability and help prevent falls. Levels The user will have to shift their weight from one leg to the other while doing different exercises, such as touching targets with their hands and feet or taking steps. All levels will start with a calibration phase to ensure the user is in the correct position. Level 1 -Balance: In this level, two colored columns will be displayed on the screen, while user motion trackers will also be reflected on the screen. The goal is to align the trackers with the same color column. Level 2 - Balance + Hands: In addition to the balance movement from Level 1, a target will be displayed on the screen. The user must maintain balance on the highlighted column while reaching the target with their hand. Level 3 - Side Steps: To initiate, the user must have their feet on a square-like target at the bottom center of the screen. After that, a target will appear adjacent to the square. The user's task is to adjust their foot position so that both the toe and heel are inside this target area. Once achieved, the user must return their foot to the original position within the square, prompting the appearance of the next target for the opposite foot. Level 4 - Front steps: Similar to level 4, the user begins by positioning both feet on the square target. Then, an arrow will appear above one of the user's feet, indicating the direction of the step (either forward or backward). Once the user moves the designated foot past a predefined threshold value, currently indicated by a slider, the arrow will disappear, prompting the user to return both feet to the square. Subsequently, an arrow will appear above the other foot, indicating the direction for the next step. The direction of the steps is randomized for each interaction. Level 5 -- Balance + Hands + Feet: This is the next step from level 4. It starts with Balance, then the target for the hand, and finally, the target for the opposite foot. Like level 2, the user must maintain only the bottom part (hip and under) inside the column while reaching the target with their hand and foot. Costume Party: This protocol's main focus is sit-to-stand. The levels of this exercise follow different steps to stand up from a chair, starting with leaning forward. Levels All levels will start with a calibration phase to ensure the user is in the correct position. The objective is to dress up for a costume party using a reference shown at the bottom right of the screen. Various costume parts will appear on a bar and move across the screen. The user needs to catch the right parts for their costume and put them on. Once the costume is complete, there will be a few seconds to admire it before the process starts over with a new costume reference. Level 1-Lean Forward: In this level, the costume elements move from one side of the screen to another at the user's eye level. To grab the element, they must lean forward enough to surpass a threshold value defined by a slider. Level 2-Flex Knees: The user starts the motion of standing up by flexing the knees and rising slightly from the chair. The elements will appear close to the user's head, and leaning forward is unnecessary. Level 3-Stand Up: This level is similar to level 2, but the elements are positioned higher, requiring the user to stand up to reach them. Gentle Giant: This exercise targets less-impaired patients who can perform sit-to-stand and balance training exercises. Levels: The aim is to allow the elements to move from one platform to another following color coding. To do so, the user will act as a bridge between the different floors. All levels will start with a calibration phase to ensure the user is in the correct position. Level 1-Squats: In this level, the user must move the elements from one platform to another by moving the bridge up and down, that is, by squatting to go down and standing again to come up. Level 2-Tip-Toe: In this level, one platform will be higher than the user's height. The aim is similar, though: The user must stand in a tip-toe position to move the bridge higher and connect the platforms.

The use of deep brain stimulation (DBS) has expanded to include multiple conditions in children including dystonia, epilepsy, Tourette syndrome and mood disorders. Despite its growing application, DBS remains a low-volume procedure in most pediatric centers, which limits opportunities for large-scale research studies. To overcome this challenge, an international data-sharing platform is essential for advancing knowledge about DBS in pediatric patients, particularly concerning surgical techniques and patient outcomes across various conditions. This study aims to establish a multicenter pediatric DBS registry. With limited data on pediatric DBS outcomes and a small number of cases at individual centers, there is a need for a comprehensive registry to enable large-scale, well-powered analyses of DBS safety and effectiveness. The primary goals of this study are to: * Establish and implement a multi-center pediatric DBS registry * Facilitate large-scale analyses of DBS safety and effectiveness in children * Refine DBS as a treatment option for dystonia and other hyperkinetic movement disorders in children. Secondary objectives include: * Identifying which patients benefit most from DBS * Determining clinical variables that influence DBS responsiveness * Identifying optimal implant sites for specific conditions * Understanding the long-term effects of DBS in children * Assessing the impact of DBS on the quality of life in pediatric patients The study will involve both prospective and retrospective data collection from pediatric DBS patients.

The purpose of the study is to evaluate 2 doses of YA-101 compared to placebo in MSA patients, including: 1) safety and tolerability, 2) pharmacokinetics, and 3) potential efficacy of YA-101.

A Phase 2a Study of Foralumab Nasal in Patients with Multiple System Atrophy (MSA)