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The Impact of Pharmacological and Electric Modulation of NMDA Pathway on the Cognitive Flexibility and Volitional Movement Preparation in Patients With Parkinson's Disease

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ClinicalTrials.gov Identifier: NCT01785628
Recruitment Status : Completed
First Posted : February 7, 2013
Results First Posted : August 22, 2013
Last Update Posted : August 22, 2013
Sponsor:
Collaborator:
National Science Council, Taiwan
Information provided by (Responsible Party):
Chon-Haw Tsai, China Medical University Hospital

Brief Summary:
The project will investigate the effect of pharmacological and electric modulation of N-methyl-D-aspartate (NMDA) pathway on the cognitive flexibility and volitional movement preparation in patients with Parkinson's disease (PD).

Condition or disease Intervention/treatment Phase
Parkinson's Disease With Dementia Dietary Supplement: Sarcosine Capsule Dietary Supplement: Placebo Capsule Not Applicable

Detailed Description:
Sarcosine (also called N-methylglycine) is an endogenous GlyT-1 inhibitor. By blocking glycine uptake, sarcosine increases synaptic glycine concentration to enhance NMDA receptor function. NMDA receptor, a subtype of ionotropic glutamate receptors, serves important functions in the brain, including learning, memory, cognition, and neural plasticity under physiological conditions and contributes to neurodegeneration in pathophysiological processes. NMDA receptor represents collectively a group of heteromeric tetramers. Every NMDA receptor is a protein complex, typically composed of two NR1 subunits and two NR2 subunits that together form the NMDA receptor ion channel. It requires two receptor agonists (glutamate for the NR2 binding site and glycine for the NR1 binding site) to open the ion channel for NMDA receptor activation. Clinically, modulation through the NMDA-NR1-glycine site is preferred to avoid the excitotoxicity associated with the glutamate site activation.8 In addition, recent animal studies have shown that dopamine secretion can be enhanced by either blocking the striatal NR2 or by activation of the NMDA-receptor glycine site. In the project, we will focus on pharmacological enhancement of NMDA-glycine receptor function based on increasing synaptic glycine concentration by sarcosine administration to examine whether enhancing NMDA-glycine receptor activity can improve the neuropsychiatric symptoms, cognition and hopefully motor function in PD-D patients

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Study Start Date : August 2010
Actual Primary Completion Date : June 2012
Actual Study Completion Date : July 2012

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sarcosine capsule
Oral capsules of Sarcosine (0.5g capsule) 1g / bid for 8 weeks.
Dietary Supplement: Sarcosine Capsule
Sarcosine is a glycine transporter-1 (GlyT-1) inhibitor. By blocking glycine uptake, sarcosine increases synaptic glycine concentration to enhance NMDA receptor function.

Placebo Comparator: Placebo capsule
Oral capsules of Placebo (Dextrin 0.5g capsule) 1g / bid for 8 weeks.
Dietary Supplement: Placebo Capsule
Placebo is dextrin composition.




Primary Outcome Measures :
  1. Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks. ]
    Outcome is defined as change in total Unified Parkinson's Disease Rating Scale (UPDRS) between the baseline to 8 weeks. The UPDRS score has three parts, part I (Mentation, Behavior and Mood), Part II (Activities of Daily Living) and Part III (Motor Examination). Each consisting of questions answered on a 0-4 point scale. The minimum total score possible is 0 and the maximum total score possible is 176. Higher scores indicating more severe symptoms.


Secondary Outcome Measures :
  1. Change in Cognitive Abilities Screening Instrument (CASI) From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks ]
    The Cognitive Abilities Screening Instrument (CASI) has a score range of 0 to 100 and provides quantitative assessment on attention, concentration, orientation, short-term memory, long-term memory, language abilities, visual construction, list-generating fluency, abstraction, and judgment. With a higher score indicating Symptom improvement.

  2. Change in Clinical Dementia Rating (CDR) From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks ]
    The CDR is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. With a higher score indicating more severe symptoms.

  3. Change in Neuropsychiatry Inventory (NPI) From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks ]
    The NPI scale has 12 domains: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. The total score ranges from 0 to 144, where the score for a domain is defined as the product of frequency (range: 1-4) and severity (range: 1-3). Each domain has a maximum score of 12 and with a higher score indicating more severe symptoms.

  4. Change in Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks ]
    The Behave-AD includes the assessment of symptoms and a global rating of caregiver distress. A total of 25 symptoms in 7 clusters are rated: paranoid and delusional ideation, hallucinations, aggressiveness, activity disturbances, diurnal rhythm disturbances, affective disturbances and anxieties, and phobias. Caregivers rate behavioral symptoms over the preceding 2 weeks on a 0 to 3 scale. The caregiver also determines a global assessment of caregiver distress on a scale of 0 to 3. The maximum score is 75 and with a higher score indicating more severe symptoms.

  5. Change in Hamilton Depression Rating Scale (HAM-D) From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks ]
    The HAM-D is a 21-item rating scaled which includes an emphasis on behavioral symptoms and somatic complaints that neglects self-reported feelings of distress; and an intermingling of frequency and intensity of symptoms. The total score ranges from 0 to 64: ten items are ranked on a scale from 0 to 4; 9 items are ranked 0 to 2; and 2 items are ranked 0 to 3. With a higher score indicating more severe symptoms.

  6. Change in Beck Depression Inventory-II (BDI-II) From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks ]
    The BDI-II is a 21-item self-report questionnaire assessing the current severity of depression symptoms. Each item is scored on a scale of 0 to 3 and the total score ranges from 0 to 63. With a higher score indicating more severe symptoms.

  7. Change in The 39-item Parkinson's Disease Questionnaire (PDQ-39) From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks ]
    The PDQ-39 contains 39-items covering 8 discrete dimensions: mobility, activities of daily living, emotional well-being, stigma, social support, cognitions, communication, and bodily discomfort. Each question is scored on a 5-point scale and recoded to 0 to 4 for the analysis. The total score can range from 0 to 132 and with a higher score indicating more severe symptoms.


Other Outcome Measures:
  1. Change in Brain Imaging by 18F-FDG PET From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks ]
    18F-FDG PET scan : 8 patients for treatment and placebo groups,respectively.

  2. Change in Brain Imaging by [99mTc]TRODAT-1 From Baseline to 8 Weeks. [ Time Frame: baseline to 8 weeks ]
    [99mTc]TRODAT-1 : 7 patients for treatment and placebo groups, respectively.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The diagnosis of PD-D will be based on the criteria proposed by 2007 movement disorders PD-D task force. (Emre M et.al. Mov Disord 2007; 22:1689-1707)

Exclusion Criteria:

  • Acute confusion due to systemic illnesses or drug intoxication.
  • Major depression
  • Features compatible with "Probable Vascular dementia.
  • Patient who is pregnant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01785628


Locations
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Taiwan
China Medical University Hospital/Neuro Depart.
Taichung, Taiwan
Sponsors and Collaborators
China Medical University Hospital
National Science Council, Taiwan
Investigators
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Principal Investigator: Chon-Haw Tsai, MD, PHD Department of Neurology, China Medical University Hospital, Taichung, Taiwan

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Chon-Haw Tsai, The Chief, Department of Neurology, China Medical University Hospital
ClinicalTrials.gov Identifier: NCT01785628     History of Changes
Other Study ID Numbers: DMR98-IRB-296
First Posted: February 7, 2013    Key Record Dates
Results First Posted: August 22, 2013
Last Update Posted: August 22, 2013
Last Verified: August 2013
Keywords provided by Chon-Haw Tsai, China Medical University Hospital:
Parkinson's disease
dementia
NMDA
event related potential
Bereitschaftspotential
Additional relevant MeSH terms:
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Parkinson Disease
Dementia
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders