Clinical Laboratory Evaluation of Chronic Autonomic Failure
Açar sözlər
Mücərrəd
Təsvir
Objective:
In dysautonomias, altered functions of one or more components of the autonomic nervous system adversely affect health. A subset of dysautonomias consists of chronic autonomic failure (CAF) syndromes. A key sign of CAF is orthostatic hypotension (OH) due to sympathetic neurocirculatory failure (neurognic OH, or nOH). Primary CAF has been classified based on clinical manifestations into three forms-pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson s disease with OH (PD+OH). All three forms involve deposition of the protein, alpha-synuclein (AS), in neurons (PD, PAF) or glial cells (MSA) and therefore are called autonomic synucleinopathies. Clinical assessment alone often is inadequate for distinguishing among these conditions in individual patients. Dementia with Lewy bodies (DLB) is another form of autonomic synucleinopathy. This observational study continues and expands on Protocol 03-N-0004, Clinical Laboratory Evaluation of Primary Chronic Autonomic Failure. The objective is to conduct multi-modality testing of catecholaminergic and autonomic systems in patients with neurodegenerative chronic
autonomic failure (CAF). The goals are to: (a) build up rosters of well characterized patients for future experimental therapeutic trials; (b) test predictions derived from the catecholaldehyde hypothesis for the pathogenesis of autonomic synucleinopathies; (c) follow the natural history of neurodegenerative chronic autonomic failure (CAF); and (d) discover new clinical entities involving catecholaminergic neurodegeneration.
Study Population:
The study population consists of patients with neurodegenerative chronic autonomic failure (neurodegenerative CAF) identified by on site screening at the NIH Clinical Center. Comparison groups include a group on control patients with iatrogenic CAF (e.g., status-post cardiac transplantation, pre/post renal sympathetic ablation, pre/post bilateral thoracic sympathectomies) or PD and without OH (PD No OH), and a group of Healthy Volunteers (HVs), some of whom have genetic abnormalities known to increase the risk of developing PD. A group of MSA patients is included, to build up a subject roster for a planned clinical trial.
Design:
This is an observational pathophysiology/natural history study with a planned duration of 3 years. Descriptive statistics will be done in diagnostic groups with neurodegenerative CAF.
Outcome Measures:
The primary outcome measure is results of clinical laboratory research tests in neurodegenerative CAF patients. Neuroimaging data are from MRI and from 18F-DOPA and 18F-dopamine PET scanning. Neurochemical data are from assays of catechols in plasma and cerebrospinal fluid. Immunofluorescence microscopy data are from analyses of immunoreactive tyrosine hydroxylase and AS in skin biopsy samples. Neurobehavioral rating scale data are from the University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Uniform Parkinson s Disease Rating Scale (UPDRS). Correlation analyses will be done among individual values for outcome measures. A secondary outcome measure is estimated extraneuronal binding of 11C-methylreboxetine, based on studies of patients with iatrogenic CAF and desipraminetreated HVs.
Tarixlər
| Son Doğrulandı: | 01/21/2020 |
| İlk təqdim: | 08/23/2018 |
| Təxmini qeydiyyat təqdim edildi: | 08/24/2018 |
| İlk Göndərmə: | 08/27/2018 |
| Son Yeniləmə Göndərildi: | 06/18/2020 |
| Son Yeniləmə Göndərildi: | 06/21/2020 |
| Həqiqi Təhsilin Başlama Tarixi: | 09/05/2018 |
| Təxmini İlkin Tamamlanma Tarixi: | 12/30/2021 |
| Təxmini İşin Tamamlanma Tarixi: | 12/30/2025 |
Vəziyyət və ya xəstəlik
Müdaxilə / müalicə
Drug: 18F-Dopa
Drug: 11C-methylreboxetine
Drug: 13N-Ammonia
Drug: 18F-Dopamne
Drug: Healthy Volunteers
Faza
Qol Qrupları
| Qol | Müdaxilə / müalicə |
|---|---|
| Active Comparator: Control patients (iatrogenic CAF) Patients with iatrogenic chronic autonomic failure (CAF) (e.g., status-post cardiac transplantation, pre/post renal sympathetic ablation, pre/post bilateral thoracic sympathectomies) | |
| Active Comparator: Control patients (PD No OH) Patients with Parkinson's disease (PD) without orthostatic hypotension (PD no OH) | |
| Active Comparator: Healthy Volunteers Despiramine | Drug: Healthy Volunteers Desipramine (DMI) is an approved tricyclic antidepressant. The drug inhibits neuronal uptake of catecholamines. DMI treatment is used to test for effects of NET inhibition on results of 11C-MRB or 18F-dopamine PET scans. The subject receives a single dose of DMI by mouth (about 125 mg per 70 kg body mass) about 2-3 hours before the subject receives the PET imaging agent. |
| Active Comparator: Healthy Volunteers as Controls Healthy Volunteers | |
| Experimental: Healthy Volunteers with genetic risk of PD Healthy Volunteers with genetic risk of PD | |
| Experimental: Patients with neurodegenerative chronic autonomic failure (CAF Includes patients with orthostatic hypotension (OH) due to sympathetic neurocirculatory failure (nOH), and people with multiple system atrophy (MSA). |
Uyğunluq Kriteriyaları
| Təhsil üçün uyğun yaşlar | 18 Years Üçün 18 Years |
| Təhsilə Uyğun Cinslər | All |
| Nümunə götürmə metodu | Non-Probability Sample |
| Sağlam Könüllüləri qəbul edir | Bəli |
| Kriteriyalar | - INCLUSION CRITIERIA: Inclusion Critieria: Patients referred for orthostatic hypotension. This is the main subject cohort. - Previously studied and diagnosed with one of the forms of nOH or else newly accrued with a referral diagnosis of orthostatic hypotension, and - 18 years or older, and - Able to provide own consent to participate or have an existing Legally Authorized Representative (LAR). If a patient has already been diagnosed as having neurodegenerative CAF under NIH Clinical Protocol 03-N-0004, this satisfies the inclusion criteria for that patient. Previous enrollment in NIH Clinical Protocol 03-N-0004 is not required for enrollment in this study. We do plan to recruit participation intothis study from NIH Clinical Protocol 03-N-0004 which has been closed. If a patient has been referred for OH, then the patient gives consent at the NIH Clinical Center (and therefore is accrued) and then has screening testing at the NIH Clinical Center to confirm that the OH is neurogenic. We anticipate that all patients referred for OH will be shown to have nOH upon screening testing at the NIH Clinical Center. At the time of screening, exclusionary abnormal laboratory test results (e.g., high serum creatinine indicating renal failure) may come to light, in which case they will be withdrawn from the study; however, the patient would have been accrued. Inclusion criteria: Control patients with iatrogenic CAF - Patients with heart transplants, pre or post bilateral endoscopic thoracic sympathectomies, or pre or post-renal sympathetic ablation, and - 18 years or older, and - Able to provide own consent to participate. Inclusion criteria: Cotrol patients with PD No OH: -Patients with PD and no OH who have (a) already been evaluated under other protocols of the AMS and are undergoing follow-up; (b) have already been evaluated under another intramural NINDS protocol; or (c) have cardiac symptoms, signs, or laboratory findings that in the opinion of the PI make it likely there is a cardiac sympathetic lesion, and - 18 years or older, and - Able to provide own consent to participate. Inclusion criteria: Healthy Volunteers: - Age 18 years or older and - Able to provide own informed consent to participate NIH employees may participate. There is no direct solicitation of employees/staff by supervisors. Co-workers will not solicit co-workers. NIH employees are required to abide by NIH Policy Manual 2300-630-3, Leave Policy for NIH Employees Participating in NIH Medical Research Studies. EXCLUSION CRITIERIA: Patient Group Referred for Orthostatic Hypotension - A medical condition that in the judgment of the Principal Investigator would place the subject at substantially increased acute medical risk, or - A disqualifying condition such as: hepatic or renal failure, symptomatic congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, currently symptomatic coronary heart disease, cerebrovascular disease with current symptoms (e.g., recent transient ischemic attacks), diabetes or - Secondary form of CAF, such as diabetic autonomic neuropathy, or - Being treated currently (within 2 weeks of anticipated protocol participation) with a medication known to interfere with the cell membrane norepinephrine transporter, which would obviate obtaining scientifically valid results (e.g., tricyclic antidepressant). - Condition that may cause difficulty or inability to insert a catheter into a vein, or - Unable to tolerate lying still for up to 1 hour during the procedures, or - Refusal to undergo certain procedures. These include: (1) IV catheter and blood drawing; (2) DNA extraction, storage, and analysis; (3) PET scanning; and (4) skin biopsies, or - History of keloid, or - Unable to travel safely to the NIH CC, or - Lacking consent capacity, unless a Durable Power of Attorney (DPA) is in place. - Subordinates of study investigators or relatives of the PI or AIs. Patient Control Group with Iatrogenic CAF or PD no OH - A medical condition which in the judgment of the Principal Investigator would place the subject at substantially increased acute medical risk, or - A disqualifying condition such as: hepatic or renal failure, symptomatic congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, currently symptomatic coronary heart disease, cerebrovascular disease with current symptoms (e.g., recent transient ischemic attacks), or diabetes or - Being treated currently (within 2 weeks of anticipated protocol participation) with a medication that would obviate obtaining scientifically valid results (e.g., tricyclic antidepressant). - Condition that may cause difficulty or inability to insert a catheter into a vein, or - Unable to tolerate lying still for up to 1 hour during the procedures, or - Refusal to undergo certain procedures. These include: (1) IV catheter and (2) PET scanning, or - Unable to travel safely to the NIH CC, or - Lacking consent capacity, or - Subordinates of study investigators or relatives of the PI or AIs. Healthy Volunteer Group - A medical condition which in the judgment of the Principal Investigator would place the subject at substantially increased acute medical risk, or - A disqualifying condition such as: hepatic or renal failure, symptomatic congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, currently symptomatic coronary heart disease, cerebrovascular disease with current symptoms (e.g., recent transient ischemic attacks), diabetes or - Being treated currently (within 2 weeks of anticipated protocol participation) with a medication that would obviate obtaining scientifically valid results (e.g., tricyclic antidepressant). - Condition that may cause difficulty or inability to insert a catheter into a vein, or - Unable to tolerate lying still for up to 1 hour during the procedures, or - Refusal to undergo certain procedures. These include: (1) IV catheter and (2) PET scanning, or - Unable to travel safely to the NIH CC, or - Lacking consent capacity, or - Subordinates of study investigators or relatives of the PI or AIs. |
Nəticə
İlkin nəticə tədbirləri
1. Pathophysiological classification based on clinical laboratory test results [Initial Visit and on an approximately biennial basis]
İkincili Nəticə Tədbirləri
1. Estimated non-specific binding of 11C-methylreboxetine [Initial Visit]
