GPR109A and Parkinson's Disease: Role of Niacin in Outcome Measures

Not Applicable

Completed

• Conditions: Parkinson's Disease
• Interventions: Dietary Supplement: niacin; Other: placebo

• Registration Number: NCT03462680
• Lead Sponsor: VA Office of Research and Development

Brief Summary

Inflammation plays a central role in Parkinson's disease. The use of anti-inflammatory drugs was found to reduce the risk of PD . Niacin may play an important role in reducing inflammation in PD. The investigators also found that individuals with PD have a chronic niacin deficiency .

The purposes of this study are to (1) examine the blood, urine and spinal fluid of persons with Parkinson's to look for evidence of inflammation and; (2) whether 6 months of vitamin B3 supplements may reduce the inflammation and/or improve symptoms.

Detailed Description

Inflammation plays a central role in Parkinson's disease (PD) pathology \[1\] as evidenced by the presence of microglia in the substantia nigra in post-mortem samples \[2\] as well as activated microglia and cytokines in clinical and animal studies \[3\]. The use of non-aspirin non-steroidal anti-inflammatory drugs was found to reduce the risk of PD \[4\]. The investigators recently identified an anti-inflammatory receptor GPR109A that is upregulated in PD \[5\]. Niacin has a high affinity for this receptor, suggesting that it (niacin) may play an important role in reducing inflammation in PD. The investigators also found that individuals with PD have a chronic niacin deficiency \[5\]. Using seed funding from the local PD chapter, the investigators obtained pilot data which suggested that restoring the deficiency via over-the-counter (OTC) supplementation reduced inflammation and decreased the severity of the disease symptoms \[6\]. In this VA-funded study, the investigators will determine the effect of 6 months' OTC niacin supplementation on inflammation (as assessed in the blood and spinal fluid) and severity of the PD symptoms.

Study Timeline

• Study Start: 2016-09-28
• Study First Submitted: 2018-02-22
• Study First Submitted QC: 2018-03-05
• Study First Posted: 2018-03-12
• Primary Completion: 2020-04-23
• Study Completion: 2020-04-23
• Results First Submitted: 2021-07-21
• Status Verified: 2021-10
• Results First Submitted QC: 2021-10-18
• Last Update Submitted: 2021-10-18
• Results First Posted: 2021-11-17
• Last Update Posted: 2021-11-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 47

Inclusion Criteria

• PD subjects will be adult men and women diagnosed with idiopathic mild to moderately severe PD defined as modified Hoehn & Yahr Stages I-III (while "On").

  • PD is defined according to the United Kingdom Brain Bank Criteria made at least six months prior to recruitment to the study.
  • PD features include the presence of at least two of the four cardinal clinical manifestations of the disease, which are tremor, rigidity, bradykinesia, and disturbances of posture or gait, without any other known or suspected cause of Parkinsonism.

• Subjects should be stabilized on PD medication for at least 3 months before enrollment into the study.

• Subjects' PD drug prescriptions will not be altered nor withheld during the study, i.e., they will be tested while "On."

• The patient will have signed informed consent.

• Subjects who do not have PD (i.e., healthy or have other medical conditions such as traumatic brain injury (TBI), stroke, or other syndromes in which inflammation plays a role in the condition) will also be recruited as control subjects.

• This will allow us to estimate whether these other conditions show similar or unique inflammatory profile.

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Exclusion Criteria

• Subjects will be excluded if they had previous brain surgery or other severe neurological problems

  • intracerebral hemorrhage
  • traumatic brain injury
  • central nervous system malignancy
  • active central nervous system (CNS) infection
  • significant stroke
  • Alzheimer disease or any type of implanted stimulator including but not limited to Deep Brain Stimulator (DBS) or pacemaker

• All subjects must be without evidence of dementia, defined as a score > 24 the Mini-Mental State Examination and able to understand test instructions

• Subjects must not have functional blindness (inability to participate in gait and visuomotor assessments) or lower limb amputation higher than the forefoot or any orthopedic problem that precludes performance of physical tests

• Allergic to niacin

• Significant cardiac, pulmonary, hepatic, gastrointestinal, or renal disease

  • e.g., New York Heart Association Class III or IV congestive heart failure
  • endocarditis
  • pulmonary insufficiency symptomatic at rest or with mild physical exertion
  • acute or chronic hepatitis
  • renal failure requiring dialysis
  • second and third degree atrioventricular block or sick sinus syndrome), or diabetes are also exclusionary factors

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
niacin	niacin	Niacin 250 mg is compared to placebo tablet.
placebo	placebo	placebo

Primary Outcome Measures

Name	Time	Method
Unified Parkinson's Disease Rating Scale (UPDRS) Change	at the recruitment and after 6 months	This is the Unified Parkinson's disease rating scale assessment. The investigators assess I, II, III and V components of the UPDRS. UPDRS 3 is motor skills. Higher scores mean worse outcome. A 0 is minimum and 120 is the maximum.
REM Sleep Pattern	baseline and after 6 months	This requires an instrument Zeo sleep monitor. Subjects are given instructions how to use it. Sleep sensor patches are supposed to be applied on forehead before going to sleep and the data of quality of sleep is captured overnight. The reported data captures the rapid eye movement (REM) sleep as a percentage.
Deep Sleep	At baseline and after 6 months	This requires an instrument Zeo sleep monitor. Subjects are given instructions how to use it. Sleep sensor patches are supposed to be applied on forehead before going to sleep and the data of quality of sleep is captured overnight. The reported data captures the deep sleep percentage.
Light Sleep	baseline and 6 months	This requires an instrument Zeo sleep monitor. Subjects are given instructions how to use it. Sleep sensor patches are supposed to be applied on forehead before going to sleep and the data of quality of sleep is captured overnight. The reported data captures the light sleep percentage.
Sleep Time - Awake	at baseline and 6 months	This requires an instrument Zeo sleep monitor. Subjects are given instructions how to use it. Sleep sensor patches are supposed to be applied on forehead before going to sleep and the data of quality of sleep is captured overnight. The reported data captures the awake time during night sleep percentage.
Mini-Mental State Examination (MMSE) Change	at baseline and after 6 months of treatment	It captures mental status and awareness of time, place and surrounding. A zero is minimum and 30 is maximum. Higher score indicates better cognition.
Stroop Test Change	at the baseline and after 6 months of intervention	It captures understanding of color and its description within a certain time frame when letters and colors do not match. There are only two choices to pick from and the correct choices should be made to proceed to the next one. Correct choices are given one point and incorrect choices delete one point. Maximum number of correct choices per unit time are recorded. Three initial trials are given to understand the test. No minimum or maximum values. Higher numbers indicate better cognition.
Fatigue Severity Scale	at baseline and after 6 months	Fatigue was rated from 0-7 in a fatigue questionnaire. A 0 being the least and 7 being the highest level of fatigue.

Secondary Outcome Measures

Name	Time	Method
Cerebrospinal Fluid Changes - Interleukin 6 (IL6)	at baseline and after 6 months	IL-6 cytokine levels will be tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention.
Cerebrospinal Fluid Changes - Interleukin 10 (IL-10)	at baseline and after 6 months	IL-10 will be tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention.
Niacin Metabolite in Urine - Niacin	at baseline and after 6 months	Plasma and urine samples will be tested to report levels of niacin and its metabolites. Higher value indicates higher niacin levels
Niacin Metabolites in Urine - NAM Nicotinamide	at baseline and 6 months	Plasma and urine samples will be tested to report levels of niacin and its metabolites. Higher value indicates higher niacin levels
Niacin Changes in Plasma - Niacin	baseline and 6 months	Plasma and urine samples will be tested to report levels of niacin and its metabolites. Higher value indicates higher niacin levels.
Niacin Changes in Plasma - NUA Nicotinuric Acid	at baseline and 6 months	Plasma and urine samples will be tested to report levels of niacin and its metabolites. Higher value indicates higher niacin levels
Cerebrospinal Fluid Changes - Interleukin 8 (IL8)	at baseline and after 6 months	IL-8 cytokine levels will be tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention.
Niacin Metabolite in Urine - Nicotinuric Acid NUA	at baseline and after 6 months	Plasma and urine samples will be tested to report levels of niacin and its metabolites. Higher value indicates higher niacin levels
CSF Fluid Changes - Interleukin 1B (IL-1B)	at baseline and 6 months	IL-1beta levels were tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention.
Cerebrospinal Fluid (CSF) Changes - Macrophage Inflammatory Protein 1 Beta (MIP 1 Beta)	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention. We are reporting levels of MIP-1 beta here.
Macrophage Changes	at baseline and after 6 months	The blood is tested to report G-protein coupled receptor 109A (GPR109A) levels in macrophages in M1 and M2 populations.
Niacin Metabolite Changes in Plasma - Nicotinamide (NAM)	at baseline and after 6 months	Plasma and urine samples will be tested to report levels of niacin and its metabolites. Higher value indicates higher niacin levels.
CSF Changes in Interferon Gamma (IF-gamma)	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention. We are reporting levels of IF-gamma beta here.
CSF Changes - Tumor Necrosis Factor - Alpha (TNF-alpha)	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention. We are reporting levels of TNF-alpha here.
Cerebral Spinal Fluid Changes - Interferon Gamma Induced Protein -10 (IP-10)	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention. We are reporting levels of IP-10 here.
Cerebral Spinal Fluid (CSF) Changes - Monocyte Chemoattractant Protein 4 (MCP4)	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention. We are reporting levels of MCP4 here.
Cerebral Spinal Fluid (CSF) Changes - MIP1-alpha	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in cerebral spinal fluid (CSF) at baseline and 6 months after intervention. We are reporting levels of MIP1-alpha here.
Plasma Cytokines - IF Gamma	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of IF-gamma here.
Plasma Cytokines - IL-10	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of IL-10 here.
Plasma Cytokines - IL1-B	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of IL-1B here.
Plasma Cytokines - IL-8	at baseline and after 6 Months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of IL-8 here.
Plasma Cytokines - TNF-alpha	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of TNF-alpha here.
Plasma Cytokines - IP-10	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of IP-10 here.
Plasma Cytokines - MCP-4	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of MCP-4 here.
Plasma Cytokines - MIP1-alpha	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of MIP1-alpha here.
Plasma Cytokines - MIP1-beta	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of MIP1-beta here.
Plasma Levels - Serotonin	at baseline and after 6 months	Plasma serotonin levels
Plasma Cytokines - IL-6	at baseline and after 6 months	Inflammatory and non-inflammatory cytokines levels will be tested in plasma at baseline and 6 months after intervention. We are reporting levels of IL-6 here.

Trial Locations

Locations (1)

Charlie Norwood VA Medical Center, Augusta, GA; 🇺🇸 Augusta, Georgia, United States