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

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01785628

Enrollment

Registered

2013-02-07

Start date

2010-08-31

Completion date

2012-07-31

Last updated

2013-08-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Parkinson's Disease With Dementia

Keywords

Parkinson's disease, dementia, NMDA, event related potential, Bereitschaftspotential

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).

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

Interventions

DIETARY_SUPPLEMENTSarcosine Capsule

Sarcosine is a glycine transporter-1 (GlyT-1) inhibitor. By blocking glycine uptake, sarcosine increases synaptic glycine concentration to enhance NMDA receptor function.

DIETARY_SUPPLEMENTPlacebo Capsule

Placebo is dextrin composition.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

SUPPORTIVE_CARE

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks.	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

Measure	Time frame	Description
Change in Cognitive Abilities Screening Instrument (CASI) From Baseline to 8 Weeks.	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.
Change in Clinical Dementia Rating (CDR) From Baseline to 8 Weeks.	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.
Change in Neuropsychiatry Inventory (NPI) From Baseline to 8 Weeks.	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.
Change in Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) From Baseline to 8 Weeks.	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.
Change in Beck Depression Inventory-II (BDI-II) From Baseline to 8 Weeks.	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.
Change in The 39-item Parkinson's Disease Questionnaire (PDQ-39) From Baseline to 8 Weeks.	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.
Change in Hamilton Depression Rating Scale (HAM-D) From Baseline to 8 Weeks.	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.

Other

Measure	Time frame	Description
Change in Brain Imaging by 18F-FDG PET From Baseline to 8 Weeks.	baseline to 8 weeks	18F-FDG PET scan : 8 patients for treatment and placebo groups,respectively.
Change in Brain Imaging by [99mTc]TRODAT-1 From Baseline to 8 Weeks.	baseline to 8 weeks	\[99mTc\]TRODAT-1 : 7 patients for treatment and placebo groups, respectively.

Countries

Taiwan

Participant flow

Recruitment details

Date of recruitment period: 05-Aug-2010 to 08-Jun-2012 Type of location: Hospital, Medical China Universities, Neurology clinic.

Pre-assignment details

The diagnosis of PD-D was based on the criteria proposed by 2007 movement disorders PD-D task force. 30 patients were enrolled.

Participants by arm

Arm	Count
Sarcosine Capsule Oral capsules of Sarcosine (0.5g capsule) 1g / bid for 8 weeks.	15
Placebo Capsule Oral capsules of Placebo (Dextrin 0.5g capsule) 1g / bid for 8 weeks.	15
Total	30

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	2	3

Baseline characteristics

Characteristic	Placebo Capsule	Sarcosine Capsule	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	15 Participants	14 Participants	29 Participants
Age, Categorical Between 18 and 65 years	0 Participants	1 Participants	1 Participants
Age Continuous	77.3 years STANDARD_DEVIATION 6.6	76.3 years STANDARD_DEVIATION 5.3	76.8 years STANDARD_DEVIATION 5.9
Region of Enrollment Taiwan	15 participants	15 participants	30 participants
Sex: Female, Male Female	4 Participants	7 Participants	11 Participants
Sex: Female, Male Male	11 Participants	8 Participants	19 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	1 / 15	1 / 15
serious Total, serious adverse events	0 / 15	0 / 15

Outcome results

Primary

Change in Unified Parkinson's Disease Rating Scale (UPDRS) From 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.

Time frame: baseline to 8 weeks.

Population: The Intent-to-Treat (ITT) Population comprised all randomised patients who took at least one dose of study medication or placebo and who had a valid baseline efficacy measure and at least one post-baseline efficacy measure.

Arm	Measure	Group	Value (MEAN)	Dispersion
Sarcosine Capsule	Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks.	baseline	71.6 Scores on a scale	Standard Deviation 21.8
Sarcosine Capsule	Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks.	V1(2-week)	67.9 Scores on a scale	Standard Deviation 20.9
Sarcosine Capsule	Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks.	V2(4-week)	69.3 Scores on a scale	Standard Deviation 22.5
Sarcosine Capsule	Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks.	V3(8-week)	71.3 Scores on a scale	Standard Deviation 25.1
Placebo Capsule	Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks.	V3(8-week)	68.3 Scores on a scale	Standard Deviation 21.7
Placebo Capsule	Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks.	baseline	66.7 Scores on a scale	Standard Deviation 23.1
Placebo Capsule	Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks.	V2(4-week)	67.6 Scores on a scale	Standard Deviation 22.4
Placebo Capsule	Change in Unified Parkinson's Disease Rating Scale (UPDRS) From Baseline to 8 Weeks.	V1(2-week)	65.2 Scores on a scale	Standard Deviation 24

Secondary

Change in Beck Depression Inventory-II (BDI-II) From 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.