Neurodegenerative Disorder

Parkinson's disease (PD) is the second most common neurodegenerative condition worldwide. It is a movement disorder characterised by tremor, rigidity, bradykinesia and postural instability. However, 78% of PD patients report visual problems such as dry eye, reduced visual acuity, visual field defects, impaired contrast sensitivity (CS), impaired eye movements, diplopia, convergence insufficiency, impaired colour vision, visual hallucinations and problems in visual-spatial orientation. In fact, visual dysfunction is one of the initial symptoms of PD. A recent study has found that dopaminergic neurons affected in PD show physiological dysfunctions, but do not die. Currently, there is no cure for PD; treatments consist of controlling symptoms, and the earlier the disease is detected and administered, the more effective they are. It is hypothesised that a programme of visual oculomotor therapy and/or visual perceptual learning (VPL) could slow or halt the deterioration of oculomotor ability and/or CS in these patients. Visual perceptual learning or VPL is a long-term improvement in performance on a visual task, any relatively permanent change in perception that arises from visual experience. Contrast Sensitivity or CS is the ability of the visual system to differentiate an object from the background in which it is located by the difference in contrast. It is the ability to detect differences in luminance between adjacent areas in an image. If the results confirm the hypothesis, this study will have a great impact on the PD population because it could slow down the deterioration of oculomotor ability that 75% of them suffer from. It could also slow down the decline in CS that they suffer, as demonstrated by several studies. Consequently, patients would also experience an improvement in their quality of life, as they would be able to continue to perform activities of daily living that are affected by visual impairment such as walking, reading, driving and cooking. This would have a major impact on society as PD affects many people worldwide. In Europe, the prevalence and incidence rates of PD are estimated to be approximately 108-257/100 000 and 11-19/100 000 per year, respectively. Furthermore, this project would expand scientific knowledge because to date there is no literature that has evaluated VPL in patients with PD. However, there is research on amblyopia, Stargardt's disease and other neural pathologies, such as Huntington's disease. Likewise, with regard to oculomotor therapy, there is still a lot of research to be done, as there are few studies on this subject. This is an analytical, longitudinal, prospective and observational study. In the first phase, to characterise the vision of the population with Parkinson's disease, non-invasive tests would be performed, such as measuring visual acuity, refraction, contrast sensitivity, colour vision, depth vision, the state of binocular vision and visual pathways and eye movements. Simultaneously, a control population will be measured to compare the data obtained in PD patients. In a second phase, visual oculomotor and/or perceptual exercises would be performed in a group of PD patients to assess whether there is stabilisation of the impairment and/or improvement of these visual skills. Finally, in the third phase, those visual skills that have been treated would be re-evaluated to assess possible changes, compared with a group of PD patients who have not undergone the visual exercises. The research will be carried out at the Laboratory of Vision and Colour Sciences of the Department of Optics, Optometry and Vision Sciences of the University of Valencia, at the Arnau de Vilanova Hospital and at the Parkinson's Association of Valencia. These are the institutions from which the participants who take part in the study will come. They will do so voluntarily, will not be coerced to participate in any way and will be free to choose whether they want to participate or not, after having been explained to them what this project consists of. Furthermore, they will be able to revoke their signed consent at any time, so that they will automatically be excluded from the study and their data will not be used in the study if the patient so wishes. Furthermore, this project does not harm the patient's health and does not bring any financial benefit to the patient. Only the members of the project will have access to the original study data. These data will be collected on paper, and the original source will be kept under lock and key in the laboratory of Vision and Colour Sciences of the Department of Optics, Optometry and Vision Sciences of the University of Valencia. For data analysis, the principal investigator will extract the data into a computer document in which each patient will be identified by a two-letter code (GP: control group; PD: Parkinson's patient) and three numbers. Not even the initials of the name will appear. Under this code, the data of each patient will be entered. This is the data that the rest of the group will see and have access to. Adverse event reporting and change management will be carried out through the Reservio platform, which will be used for appointment planning and online booking. Data analysis will be carried out using the SPSS (Statistical Package for Social Sciences) statistical software and the Matlab numerical calculation system. The statistical analysis plan is as follows: the mean, standard deviation and normality of the samples will be performed with the Shapiro-Wilk test. Statistical comparison between groups will be performed with Student's t-test if the data follow a normal distribution or with the U-Mann-Whitney test otherwise. The statistical test used for qualitative variables will be Pearson's chi-square test.

The 10,000 Step Club (10KSC) is a 6-month community walking program conducted at various local parks in Las Vegas (LV), Nevada for people with Parkinson's disease (PD). There will be three walking groups and each group will meet at a local park once weekly for a 60-minute walk. These walking groups will be led by UNLV physical therapy students who will organize, coordinate, and manage the different walking groups. Participants will be encouraged to attend at least one walking group per week in their area but will be permitted to participate at the other walking groups on different days if they desire to get in a second or third walk that week. Participants in the program will use Nordic walking poles to promote stability and upright posture, and to encourage full body movement and arm use. There will be three different walking groups throughout Las Vegas in areas with few PD exercise programs and higher proportions of people with Parkinson's disease in lower socioeconomic regions and historically underserved areas. The 10KSC program will be offered in both English and Spanish. Participants will be given a step watch to wear over the 6 months of the program and will be encouraged to build up their physical activity to eventually average 10,000 steps per day. The watches will be used to track step counts in real-time and there will be an incentive program to motivate participants and recognize achievements related to program goals. The program is designed to get people with Parkinson's disease out of their homes, cultivate a culture of connection with others with Parkinson's disease to decrease social isolation and loneliness, and to be collectively accountable for a common goal toward more physical activity. The 10KSC will be evaluated for effectiveness, feasibility, and safety. The program will target recruitment of 60 participants with Parkinson's disease. Participation will be free of charge and care partners will be encouraged to participate as well. The program inclusion criteria will be "pragmatic" which means that there will be few exclusion criteria and the only inclusion criterion will be a diagnosis of Parkinson's disease by a neurologist.

BACKGROUND AND RATIONALE 6-\[18F\]fluoro-dihydroxyphenylalanine (18F-DOPA) is a large neutral amino acid that resembles natural L-3.4-dihydroxyphenylalanine (L-DOPA) biochemically. L-DOPA is a precursor for dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline), collectively known as catecholamines. 18F-DOPA enters the biochemical pathway of L-DOPA both in the brain and peripherally, and can be imaged with a positron emission tomography / computed tomography (PET/CT) scanner. 18F-DOPA can therefore allow imaging of the L-DOPA metabolic pathway with a high target-to-background ratio providing valuable information for a number of diseases. While 18F-DOPA is an established diagnostic tracer at a number of different institutions globally, given the short half-life of 18F (110 minutes) this tracer cannot be imported for local use. The Edmonton PET Centre has recently developed a production method for this tracer allowing local access. An initial study at the University of Alberta (Pro00055342) has demonstrated this tracer to have an acceptable safety profile, an expected biodistribution (both physiologic and disease-related), and has established clinical efficacy of the tracer. In March, 2020 the University of Alberta Hospital (UAH) installed a new PET/CT scanner (GE Discovery MI) with a digital detector system and new iterative image reconstruction algorithms that represent a substantial technological improvement compared to the previously installed scanner. It is expected that this new system will reduce artifact and will increase the sensitivity for the detection of smaller lesions. Our initial study demonstrated rapid urinary excretion with intense collection of activity within the urinary bladder. While this physiology was expected, it did result in diminished image quality in the evaluation of the pelvis in some patients. Improved image reconstruction algorithms available on the new GE Discovery MI PET/CT system may improve imaged quality related to this problem. Based on our experience with 18F-fluorodeoxyglucose (FDG) PET/CT scans, the administration of intravenous furosemide prior to imaging can also substantially improve the image quality in the pelvis. These potential improvements have not yet been established with 18F-DOPA. A second observation from our initial study was that many participants demonstrated intense early activity at the gallbladder fundus. While biliary and gallbladder activity are described in the normal biodistribution of 18F-DOPA, the observed distribution suggests that the gallbladder fundus activity reflects primary uptake rather than reflux of activity within bile into the gallbladder. The rationale for this study is to explore the efficacy of these optimization parameters (new digital PET/CT camera system and use of intravenous furosemide) in the context of 18F-DOPA PET/CT imaging for patients with clinical indications for the scan. Imaging data from this study will be compared with data from the prior study (Pro00055342) to determine if the new digital detector PET/CT technology and preparatory furosemide administration improves image quality for these patients. A subgroup will also be scanned dynamically at the abdomen to better assess the pattern of gallbladder activity over time. This will include a mixture of clinical indications listed within the inclusion criteria. All patients will be screened for a history of previous gallbladder disease at the time of the scan by questionnaire. The intention of this sub-study is to better determine 18F-DOPA activity patterns associated with the gallbladder and to explore if there is a correlation between dopaminergic degeneration in the brain and the gallbladder. PURPOSE AND STUDY OBJECTIVE: Trial Type: Phase III non-randomized, non-blinded prospective cohort clinical trial of patients with a clinical indication for 18F-DOPA PET/CT imaging. The primary purpose of this study is to assess optimization parameters for 18F-DOPA PET CT imaging at UAH including the impact of new digital detector PET/CT technology as well as the impact of preparatory intravenous furosemide administration on image quality within the pelvis. A secondary purpose of this study is to better delineate the pattern of 18F-DOPA activity associated with the gallbladder and to explore if there is a relationship between dopaminergic denervation in the gallbladder and the brain. Only patient populations for which there are established clinical indications for the use of 18F-DOPA will be included in this study. Participation in this study will allow access to this tracer for patients in Alberta as there is no Health Canada approved similar tracer currently available. 18F-DOPA is an established clinical tracer at multiple institutions globally and has been approved for clinical use at multiple European centres for many (10+) years. Established clinical indications in the literature include: 1. Pediatric patients (less than 18 years old) with congenital hyperinsulinism. The 18F-DOPA scan is used to plan required surgical intervention for these patients. 2. Pediatric patients (less than 18 years old) with neuroblastoma. The 18F-DOPA scan is indicated for pre-operative assessment of a mass suspected to be a neuroblastoma, staging, re-staging, and assessment of recurrence in this patient group. 3. Pediatric (less than 18 years old) or Adult patients (18 or older) with known or clinically suspected neuroendocrine tumor. These include patients with carcinoid tumor, pheochromocytoma, paraganglioma, and medullary thyroid cancer. 18F-DOPA is indicated for metabolic assessment of a mass suspected to represent one of these tumor-types, for staging of a known tumor, for re-staging, and for assessment of recurrence in this patient group. 4. Adult patients (18 or older) with a clinical suspicion of Parkinson's disease or Lewy body dementia. 18F-DOPA is indicated to differentiate benign essential tremor from Parkinson's disease in this patient group \[22-26\]. 18F-DOPA may also be used to differentiate Lewy body dementia from other dementia types. 5. Pediatric (less than 18 years old) or Adult patients (18 or older) with brain tumors (primary or metastatic). 18F-DOPA is indicated for biopsy planning, radiation therapy planning, and post-therapy assessment to differentiate residual viable tumor from post-therapy necrosis in this patient population. When requested for patients falling into one of these diagnostic groups, an 18F-DOPA PET/CT scan will be performed and interpreted clinically with the results conveyed to the referring physician. Image optimization (the primary study objective) will be evaluated based on the following: * For patients with abnormal activity, the smallest 3 lesions will be recorded in terms of size (mm) and activity (SUVmax). For PET-avid lesions, the size measurement will be based on measuring the maximum dimension of the corresponding lesion on the CT scan component if possible. If not possible, a size measurement based on the PET images will be used. The minimum lesion size and average (3 smallest lesions) will be compared with a cohort of scans acquired on the previous non-digital PET/CT scanner (retrospective cohort of 50 positive patients, Pro00055342). * The SUVmax, SUVmean, and SUV standard deviation of urinary bladder activity will be measured and compared to a retrospective cohort of 50 patients from a previous study (Pro00055342) * A subjective score will be applied to the pelvis with respect to image artifact related to bladder activity (0 = no artifact, 1 = mild artifact, 2 = severe artifact). This will be compared to scoring of the previous study (retrospective cohort of 50 patients, Pro00055342) retrospectively. Gallbladder activity pattern (the secondary objective) will be evaluated based on the following: * SUVmax measurements of the gallbladder fundus, gallbladder neck, common bile duct, right and left main intrahepatic ducts, and liver parenchyma (right and left lobes, 3 cm diameter VOI) will be measured at 5 minute increments. These will be analyzed in total, and subgroups will be compared (32 PD vs. 32 non-PD participants). * All participants will be screened by questionnaire at the time of the scan as to whether there is a history of previous gallbladder disease. The positive response rate will be compared between three groups: non-PD patients, PD patients with objective evidence of dopaminergic denervation (positive FDOPA scan), PD patients without objective evidence of dopaminergic denervation (negative FDOPA scan). PATIENT POPULATION: A total of 800 patients who meet the inclusion criteria will be identified based on referrals from physicians who deem the imaging studies potentially useful for clinical care. It is anticipated that complete enrollment will take 5 years (approximately 160 scans per year). Sample size calculation is based on the following. There will typically be 5 participants total scanned per day. Dynamic imaging will be restricted to one patient per scanning day due to time constraints related to the scanner, as this requires the participant to lie quietly in the PET/CT scanner for up to one hour. Allowing for this restriction, it is estimated that the overall participation rate for dynamic scanning will be 10%. Based on a minimum total sample size of 64 participants for the secondary objective analysis, a total minimum study population of 640 is required. Allowing for some potential buffer for recruitment, a total of 800 participants is planned. The minimum sample size of 64 participants is based on the following estimations: gallbladder fundus SUVmax mean 10.9, SUVmax DS 4.6 (measured from cohort of 10 patients from the previous study), α = 0.05, and power = 0.80. Two groups of 32 participants (64 total) should allow for detection of a minimum 30% difference in SUVmax involving the gallbladder fundus between the two groups.

This is a study to investigate the long-term safety and tolerability of home peroneal eTNM® delivered by URIS I™ in subjects with PD or ET. The safety, tolerability and efficacy of the home-based peroneal eTNM® using URIS ITM neurostimulator in the treatment of symptoms related to movement disorders in subjects with PD and ET has been recently investigated in the study (NTC06036368). This 6-weeks, open-label, single-site pilot study enrolled 24 patients with either PD or ET and was completed in April 2024. This pilot study showed that home-based peroneal eTNM® was safe and well tolerated by patients. No adverse events related to treatment were observed during the study period. These data confirm the excellent safety profile of the peroneal eTNM® that has been observed in previous studies in the overactive bladder population. In addition, all patients were able to stimulate themselves at home without assistance. Adherence to the treatment was very high, reaching well over 90 %. Although this pilot study was not designed to demonstrate the efficacy of peroneal eTNM®, due to its pilot nature and the small sample size, the observed results suggest noteworthy positive effects on rest, postural and kinetic tremor as measured visually, by accelerometers and by validated MDS-UPDRS and TETRAS scales. Importantly, patients reported sustained improvement in tremor throughout the treatment and continuously for several weeks after conclusion of the 6 weeks stimulation period. Data obtained at EoS visit (6 weeks after the last stimulation) lend support for a long-lasting persistence of the effect. Based on these data, the present extension study is designed to evaluate the long-term safety, tolerability and efficacy of peroneal eTNM® in patients with PD and ET. The study will use the medical device URIS I™, which has been assessed for conformity and issued a declaration of conformity. This agent will be used for a different indication, or on a different group of patients, however, without any change in the procedure of use. The clinical trial will be conducted in accordance with clinical trial plan TS005.

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.

Cognitive impairment related to dementia is frequently under-diagnosed in primary care settings despite the increasing rates of patient cognitive complaints and the availability of numerous cognitive assessment tools. Missed detection delays treatment of reversible conditions as well as provision of support services and critical planning. This problem is more prevalent among older African-Americans and Hispanics than older whites, and more common in rural than urban populations. The investigators developed the 5-Cog brief cognitive assessment that is simple to use, standardized, takes \<5 minutes, does not require informants, and accounts for major technical, cultural, and logistical barriers of current assessments. The investigators are conducting a simple randomized clinical trial to examine the clinical efficacy of the 5-Cog paradigm (5-Cog brief cognitive assessment paired with a clinical decision-making tool) to improve dementia care in 1,200 predominantly minority sample of older adults with cognitive concerns presenting to a primary care clinic in the Bronx. Interim analysis revealed that the 5-Cog paradigm resulted in an over 8-fold increase in new cognitive impairment diagnoses and over 3-fold increase in improved dementia care actions by primary care physicians compared to an active control arm. Following up on these very promising results, the investigators propose a hybrid Type 1 effectiveness-implementation design in real-world settings to adapt and test the effectiveness of the 5-Cog paradigm to increase detection of cognitive impairment care in older adults presenting with cognitive concerns. The aim of the pragmatic cluster-randomized trial is to test the clinical effectiveness of the 5-Cog paradigm in increasing cognitive impairment detection and improving dementia care - ascertained via electronic medical record. Randomization will be at the clinic level, and select 22 primary care practices; 6 in Bronx and 18 in urban and rural Indiana. 300 participants per practice will be enrolled for a total of 6,600 older patients with cognitive concerns. Results will also be examined in NIH designated health disparity populations including underserved minority and socio-economically challenged populations. Outcomes are new cognitive impairment diagnoses (primary) and improved dementia care (secondary) in the 90-day period following presentation of cognitive concern to the primary care physician. * New cognitive impairment diagnoses (primary): New diagnosis of dementia or Mild Cognitive Impairment by primary care physicians. For patients with a previous diagnosis of Mild Cognitive Impairment in electronic medical record, only a new diagnosis of dementia will be considered as an incident outcome. * Improved dementia care (secondary): Any of the following: 1. Tests ordered for reversible causes of cognitive impairment as per published guidelines. 2. New cognitive enhancing medication prescriptions or deprescribing anti-cholinergic. 3. Referral for cognitive/dementia evaluation by specialists (Neurology, Geriatrics, Psychiatry). 4. Referral to social worker or community-based organizations. Implementation issues and cost-effectiveness of the 5-Cog paradigm will also be examined. This proposed study focuses on scalable approaches to address the unmet need of early detection of incident cognitive impairment, including in populations that experience health disparities.

Thirty to forty PD patients will be recruited who fulfill the U.K Parkinson's Disease Brain Bank Criteria for idiopathic PD. Patients with mild to moderate disease severity according to UPRS and Modified Hoehn and Yahr staging, age ranged from 55-70 years, duration of illness from two to five years will be included. The patients who will match our inclusion criteria will be assigned randomly into two equal groups; control group (G1) will receive a designed physical therapy program and study group (G2) will receive 12 sessions of (5Hz) rTMS over the primary motor cortex in addition to the same physical therapy program as in G1. The treatment will be conducted three times per week, over four weeks. Biodex balance system will be used to assess objectively balance indices (overall, anterio-posterior and medio-lateral balance index) and dynamic limit of stability (overall LOS score, time to complete test) pretreatment , posttreatment and one month later as a follow up.

In this study,we explored the imaging characteristics of PD. First, with the advantage of 7T, we detect the slight changes of PD with short diseases history compared with the healthy. Second, we investigate the different imaging characteristics in subtypes of PD, finding the effective neuroimaging biomarkers to distinguish different subtypes of PD. Finally, we take long time follow-up to evaluate the correlation between the imaging changes and clinical score alteration in PD.

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.