NAinPD: The Role of the Noradrenergic System in the Nonmotor Symptoms of Parkinson's Disease
Study Details
Study Description
Brief Summary
The purpose of the study is to learn about the role of noradrenergic system in the non-motor symptoms of Parkinson's disease. In particular, researchers hope to better understand what role the noradrenergic system may play in the regulation of blood pressure, cognition and mood symptoms in patients with Parkinson's disease. With this information, future research may explore treatments that target the noradrenergic system in order to better treat the non-motor symptoms of Parkinson's disease.
The experimental drug used in some of the study assessments, yohimbine hydrochloride, is not being tested as a potential treatment for Parkinson's disease. Yohimbine hydrochloride will be used to manipulate the noradrenergic system during some of the assessments. By measuring the amounts of hormones and neurotransmitters the body produces before and after yohimbine hydrochloride administration, researchers can assess how well the noradrenergic system is functioning.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Early Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Yohimbine The first visit in the study has no interventional drug. Yohimbine (5mg) is administered orally during visit two, during a head up tilt test, to manipulate the noradrenergic system to determine the association between OH and NP symptoms in those with PD. Yohimbine is not administered as a treatment in this study, but as a pharmacologic tool to study the adrenergic system. |
Drug: Yohimbine HCl
Yohimbine hydrochloride will be used to manipulate the noradrenergic system during some of the assessments. By measuring the amounts of hormones the body produces before and after yohimbine hydrochloride administration, researchers can assess how well the noradrenergic system is functioning
|
Outcome Measures
Primary Outcome Measures
- Difference in fatigue (measured with the self-reported Fatigue Severity Scale) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment]
The Fatigue Severity Scale (FSS) measures average fatigue experienced over the previous week. The FSS questionnaire contains nine statements that rate the severity of fatigue symptoms. A low value indicates strong disagreement with the statement, a high value indicates strong agreement. A total score of 36 or more suggests presence of fatigue.
Secondary Outcome Measures
- Difference in apathy (measured with the self-reported Apathy Evaluation Scale) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment]
Apathy Evaluation Scale (AES) measures apathy over the previous month. The AES questionnaire contains 18 statements that each rAll measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment ate the severity of apathy on a scale from 1 to 4. A total score ranges from 18 to 72, with higher scores indicating more apathy.
- Difference in self-reported depression (measured with the Geriatric Depression Scale - short form) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment]
The Geriatric Depression Scale - short form measures depression over the previous week. This questionnaire contains 15 questions that are answered by either indicating "Yes" or "No" to the questions. The total score ranges from 0 to 15, with higher scores indicating more depression.
- Difference in self-reported anxiety (measured with the Geriatric Anxiety Inventory) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment]
The Geriatric Anxiety Inventory measures anxiety over the previous week. This questionnaire contains 20 questions that are answered by indicating either "Yes" or "No" to the questions. The total score ranges from 0 to 20, with higher scores indicating more anxiety.
- Difference in neurocognition (measured with average composite z-score on a neurocognitive battery) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment]
Neurocognition will be measured with the following battery, adjusting for age, gender, education level, and premorbid functioning. Digit Span subtest from the Wechsler Adult Intelligence Scale - IV; Symbol Digit Modalities Test; Trail Making Test; California Verbal Learning Test - II; Rey Complex Figure Test; DKEFS Color-Word Interference Test; Phonemic and Semantic Verbal Fluency; Behavior Rating Inventory of Executive Function - Adult Outcome. An average composite z-score will calculated and compared between groups.
- Difference in informant-reported anxiety (measured by an informant-reported Neuropsychiatric Inventory Questionnaire) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH). [All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment]
The NPI-Q measures 12 psychiatric symptoms, and each symptom (ie anxiety) is scored as absent or present.
- Difference in informant-reported apathy (measured by an informant-reported Neuropsychiatric Inventory Questionnaire) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH) [All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment]
The NPI-Q measures 12 psychiatric symptoms, and each symptom (ie apathy) is scored as absent or present.
- Difference in informant-reported depression (measured by an informant-reported Neuropsychiatric Inventory Questionnaire) in patients with Parkinson's disease with and without orthostatic hypotension (PD+OH v PD-OH). [All measurements for this study will be obtained during one of the two study visits that each subject will undergo. These two visits will be completed within 6 months of subject enrollment]
The NPI-Q measures 12 psychiatric symptoms, and each symptom (ie depression) is scored as absent or present
- Change in serum catecholamine levels (supine and orthostatic) before and after yohimbine administration [Baseline (supine position), after 5 minutes of head-up tilt, 60 minutes after yohimbine administration (supine position), and 5 minutes after that with repeat head-up tilt.]
Change in serum catecholamine levels will be measured from blood samples collected from participants upon lying face up and 5 minutes after head-up tilt, before and after yohimbine administration
- Change in serum desmopressin levels (supine and orthostatic) before and after yohimbine administration [Baseline (supine), after 15 minutes of head-up tilt, 60 minutes after yohimbine administration (supine position) and 15 minutes after that with repeat head-up tilt]
Change in serum desmopressin levels 15 minutes after head-up tilt before and after yohimbine administration
Other Outcome Measures
- Between group (Parkinson patients with and without orthostatic hypotension (PD+OH v PD-OH) change in self-reported anxiety before and after yohimbine administration [Baseline and 45 minutes after yohimbine administration]
Change in self-reported anxiety levels before and after yohimbine administration measured with an 11-point visual analogue scale (0-10), where a higher score indicate more anxiety and fatigue
- Between group (Parkinson patients with and without orthostatic hypotension (PD+OH v PD-OH) change in self-reported mood before and after yohimbine administration [Baseline and 45 minutes after yohimbine administration]
Change in self-reported mood before and after yohimbine administration measured with an 11-point visual analogue scale (0-10), where a higher score indicate more anxiety and fatigue
- Between group (Parkinson patients with and without orthostatic hypotension (PD+OH v PD-OH) change in self-reported fatigue before and after yohimbine administration [Baseline and 45 minutes after yohimbine administration]
Change in self-reported fatigue levels before and after yohimbine administration measured with an 11-point visual analogue scale (0-10), where a higher score indicate more anxiety and fatigue
- Between group (PD+OH v PD-OH) change in diastolic blood pressure before and after yohimbine [Baseline (after resting 30 minutes supine) and 45 minutes after yohimbine administration]
Change in diastolic blood pressure (measured in mmHg, supine after 30 min rest) before and after yohimbine administration in Parkinson's patient with and without orthostatic hypotension
- Between group (PD+OH v PD-OH) change in time until pupillary redilation before and after yohimbine [Baseline (after resting 30 minutes supine) and 45 minutes after yohimbine administration]
Change in time until pupillary redilation (measure in seconds after brief light stimulus using a NeuroOptics pupilometer) before and 45 minutes after yohimbine administration
- Between group (PD+OH v PD-OH) difference in change in time to recovery of BP after 60 degree head-up tilt before and after yohimbine administration [Baseline tilt test before yohimbine and second tilt 60 minutes after yohimbine administration]
Change in time to recovery of systolic blood pressure (measured in seconds back to baseline) after 60 degree head-up tilt before and after yohimbine administration
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Participant able to provide informed consent
-
Diagnosis of Parkinson's disease confirmed by a DH neurologist according to Movement Disorder Society criteria, with the exception that "Red flag" 5a will not be used (severe autonomic failure within five years of disease onset).
-
All subjects must have CMP and CBC drawn within 6 months of study visit 1, with results in the normal range or with abnormal results not considered to be clinically significant in the investigator's opinion.
-
Female patients must be post-menopausal (at least one year) or not planning to get pregnant and have negative pregnancy test.
Exclusion Criteria:
-
Diagnosis or previous history of diabetes of any kind
-
Known autonomic neuropathy unrelated to PD
-
History of or current cardiac, liver or renal disease that, in the opinion of the investigator, may put the patient at risk because of participation in the study
-
Known condition that in the investigator's opinion would be a contraindication to HUT testing or yohimbine challenge (e.g. decompensated cardiac disease, severe positional vertigo; severe anxiety, known panic disorder69)
-
Current use of catecholaminergic medications (e.g. stimulants, droxidopa, midodrine) that cannot be held for at least three half-lives
-
Inability to hold PD medications for at least 12 hours
-
History of major depressive or bipolar disorder preceding the diagnosis of PD,69 or diagnosis or previous history of psychiatric illness that in the investigator's opinion would affect the subject's ability to successfully participate in the study.
-
Any history (other than PD) that could significantly and adversely affect neurocognitive function, such as history of traumatic brain injury (head injury with loss of consciousness > 1 hour), known dementia unrelated to Parkinson's or related diseases; developmental delay, multiple sclerosis or epilepsy with cognitive impairment, intellectual deficit, diagnosed and untreated sleep apnea; untreated syphilis; HIV with HAND; or other conditions that, based on the investigators opinion, could interfere with neurocognitive evaluation.
-
Known ophthalmologic disease such as untreated cataract, glaucoma, optic neuritis, orbital trauma, or other neuroretinal disease that might impact pupillary function
-
Severe illness within 30 days prior to enrollment.
-
Use of opiate, procholinergic, or other medications influencing pupillary function that cannot be held for three half-lives
-
In the Investigator's opinion, subject would be unable to successfully participate in the study for any reason.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Dartmouth-Hitchcock | Lebanon | New Hampshire | United States | 03756 |
Sponsors and Collaborators
- Nathaniel M. Robbins
Investigators
- Principal Investigator: Nathaniel M Robbins, MD, Dartmouth-Hitchcock Medical Center
Study Documents (Full-Text)
More Information
Publications
None provided.- D19090