Down Syndrome Memantine Follow-up Study

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ClinicalTrials.gov Identifier: NCT02304302

Recruitment Status : Completed

First Posted : December 1, 2014

Results First Posted : April 5, 2022

Last Update Posted : April 5, 2022

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

Alana USA Foundation

Information provided by (Responsible Party):

Dr. Alberto Costa, University Hospitals Cleveland Medical Center

Study Description

Brief Summary:

The purpose of this research study is to learn if the medication Memantine Hydrochloride (the study medication) can help adolescents and young adults with Down syndrome. Dr. Alberto Costa and his research team want to see if a 16-week treatment with this medication can improve the participant's ability to learn and remember things. In this study, memantine hydrochloride will be used. Thus, the researchers want to learn whether the study drug can help improve memory in young adults with Down syndrome. To test the effect of the study medicine, half of the people in the study will receive the study medicine and half will receive a placebo (an inactive substance). Memantine is an approved medication to treat memory and thinking problems in persons with Alzheimer disease. However, little is known about the effect of this medication in persons with Down syndrome and it has not been approved for use in persons with Down syndrome.

Condition or disease	Intervention/treatment	Phase
Down Syndrome Intellectual Disability	Drug: Memantine Drug: Placebo	Phase 2

Show detailed description

Detailed Description:

This study seeks to investigate if the medication Memantine Hydrochloride can help young adults with Down syndrome. Two hundred persons with Down syndrome from both genders and between 15 and 32 years of age will be recruited from two sites: Cleveland, OH, USA and São Paulo, SP, Brazil. Participants will be assigned randomly to either a placebo group or a group taking the active medication with a 50% probability of being on either group. Neither the participants nor the investigators will know who will be taking the study medication and who will be taking the placebo during the study. Only the investigational pharmacist will have access to this information.

Up to 60 people with Down syndrome of the recruited study participants will take part on an optional magnetic resonance imaging (MRI) study. This investigation is aimed at helping to make the EEG study more precise and to find out whether the study medication has any significant effect on the structure of the brain.

Additionally, we will recruit a control group of 60 age- and gender-matched participants without Down syndrome. The goal is to investigate how different groups of people activate their brains when they hear or see something, and if he can use high-density EEG and MRI to see how this study medication works in persons with Down syndrome. In other words, this additional control group should help us ascertain which parts of the test results are due to a person having Down syndrome and which ones are not. Persons without Down syndrome will only come for one EEG visit and one MRI visit, and not be asked to take the study medication.

The visits for the participants with Down syndrome will be as follows:

Screening visit (approximately 2-hour long). The subject will be asked about his/her health, medical history, social background, and work background, as well as some simple questions to determine performance on tests of memory and function that are part of this study. Informed consent and assent will be obtained in this visit. At the end of this visit, an EEG machine will be used to access brain responses to different auditory and visual stimuli. Some will be asked if they would be willing to have an MRI performed, but this portion is not imperative.

A urine sample will be collected and used to obtain cells that will be kept frozen for potential future studies. If the date of the screening visit is not convenient, this sample can be collected during any of the next five visits.

Visit 1 (approximately 1 hour). Pulse, blood pressure, and an electrocardiogram (ECG) will be taken. At the end of the visit, urine and blood samples will be taken. Pregnancy will also be checked.

Visit 2 (2-3 hours). Tests of memory, learning, and reasoning skills will be conducted before the start of the study medicine or placebo. At the end of this visit, a 60-day supply of either the study medicine or the placebo will be given. This will need to be taken for 16 weeks.

Visit 3 (approximately 30 minutes). Eight weeks after the beginning of the treatment, the participant will return to assess how she/he is doing under the treatment. Pulse, blood pressure, a physical exam, and pregnancy will be checked. At this visit, another supply of study medicine will be given.

Visit 4 (2-3 hours). Sixteen weeks after starting the medicine, the participant will take a second series of tests in learning, memory, and reasoning skills to find out whether there were any changes in these skills.

Visit 5 (approximately 1 hour). In the 16th or 17th week after starting the medicine, the participant will meet one more time with the doctor from visits 1 and 3. Vital signs, a physical exam, and an ECG will be taken, as well as a blood sample to ensure nothing has changed with the participant's general health. For women, a pregnancy test will be performed.

If for some reason the subject withdraws from this study prior to Visit 5, he/she will be asked to return to the clinic for a "Treatment Discontinuation Visit." In addition, if the participant discontinues the medication prior to the end of the study, he/she will be asked to complete a "Retrieved Dropout Visit" on the date that should have represented Visit 5. Study medication will not be provided beyond the study period.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	160 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Phase II Multicenter 16-Week Randomized Double Blind Placebo-Controlled Evaluation of the Efficacy, Tolerability and Safety of Memantine Hydrochloride on Enhancing the Cognitive Abilities of Adolescents and Young Adults With Down Syndrome
Study Start Date :	October 2014
Actual Primary Completion Date :	July 22, 2020
Actual Study Completion Date :	July 22, 2020

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: CASK-related intellectual disability Down syndrome SYNGAP1-related intellectual disability

MedlinePlus related topics: Down Syndrome

Drug Information available for: Memantine Memantine hydrochloride

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo Identically-looking placebo pills to memantine will be dispensed in a 66-day supply (56 days plus 10 extra days) by the study coordinator to participants receiving the placebo at the end of visits 2 and 3.	Drug: Placebo Identically looking placebo capsules bid (after a four-week regimen designed to mimic standard dose titration protocol) Other Name: Inactive Capsules
Experimental: Memantine Memantine will be dispensed in a 66-day supply (56 days plus 10 extra days) by the study coordinator to participants receiving the placebo at the end of visits 2 and 3.	Drug: Memantine Encapsulated Namenda 10 mg bid (after four-week standard dose titration protocol) Other Name: Namenda

Outcome Measures

Primary Outcome Measures :

Efficacy of the Drug Memantine as Assessed by Change in Score on the California Verbal Learning Test-II (CVLT-II) Short Form Total Free Recall [ Time Frame: baseline and 16 weeks from start of treatment ]
The primary efficacy measure is focused on episodic memory. The CVLT-II short form assesses supraspan word learning ability as an index of episodic verbal long-term memory. We hypothesize that treatment with memantine will produce significant improvements in this test. The main dependent variable selected, based on prior literature was the total number of target items correct summed across learning trials 1-4. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2). Scale Range: from 0 to 36; higher scores represent better outcomes.

Secondary Outcome Measures :

Efficacy of the Drug Memantine as Assessed by Change in Score on the Paired Associates Learning (PAL) From the Cambridge Neuropsychological Test Automated Battery (CANTAB) [ Time Frame: baseline and 16 weeks from start of treatment ]
This is a measure of non-verbal memory that requires the participant to learn associations between an abstract visual pattern and its location. Two dependent variables have been selected: Total number of items correct on the first trial of each stage, and total number of stages completed. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2). The minimum value of the PAL Memory Score Scale is 0 and the maximum value is 21; higher scores mean better outcomes.
Efficacy of the Drug Memantine as Assessed by Change in Score on the Recall of Digits Forward (From the Differential Ability Scales; DAS-II) [ Time Frame: baseline and 16 weeks from start of treatment ]
This is a measure of rote short-term verbal memory. Total number of items correct were used as the dependent variable. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2). The minimum value for this scale is 0 and the maximum value is 38; higher scores mean a better outcome.
Efficacy of the Drug Memantine as Assessed by Change in Score on the Pattern Recognition Memory (PRM; Part of the Cambridge Neuropsychological Test Automated Battery -- CANTAB) [ Time Frame: baseline and 16 weeks from start of treatment ]
This is a measure of non-verbal memory. Total number correct across the two series of items presented was used as the dependent variable. We used the PRM total scale in this study, which represents the sum of the PRM correct scores (ranging from 0 to 24) and the PRM delayed scores (ranging from 0 to 24). Therefore, the range of the PRM total scale is from 0 to 48; higher values mean better outcomes.
Efficacy of the Drug Memantine as Assessed by Change in Score on the Spatial Working Memory (Part of the Cambridge Neuropsychological Test Automated Battery -- CANTAB) [ Time Frame: baseline and 16 weeks from start of treatment ]
The test requires participants to search under a series of colored boxes to locate a "blue token" hidden underneath one of them. During a series of trials, the participant is told that the token will be in a new location each time and that they should not go back to a location he or she has looked in previously. The main dependent variable was the total number of errors ("between errors"), which indexes the number of times a participant went back to a box where a token had already been found, lower scores mean better performance. The minimum value of the Spatial Working Memory scale is 0 and the maximum value is 137 (which was computed as the equivalent to -4 standard deviations from the mean of this measure); higher scores mean worse outcomes. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2).
Efficacy of the Drug Memantine as Assessed by Change in Score on the Spatial Span (Part of the Cambridge Neuropsychological Test Automated Battery -- CANTAB) [ Time Frame: baseline and 16 weeks from start of treatment ]
This measure is a computerized version of the Corsi Blocks task, a long-standing neuropsychological test. The main dependent variables selected for this test was the span length, which is the longest sequence of numbers recalled accurately. The minimum value of the Spatial Span Length Score Scale is 0 and the maximum value is 9; higher scores mean better outcomes. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2).
Efficacy of the Drug Memantine as Assessed by Change in Score on the The Go - No Go Task [ Time Frame: baseline and 16 weeks from start of treatment ]
This is a measure of inhibitory control, often used as a marker for prefrontal-striatal function integrity. Specifically, it measures the participant's ability to inhibit pre-potent behavioral responses that have been established by provision of prior "go" or "no-go" cues in a classical conditioning paradigm. The main dependent variables selected was speed of response of execution to Go targets. The minimum value of the speed of response of execution to Go targets is 280 milliseconds (ms) and the maximum value is 1000 ms; higher scores mean worse outcomes. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2).
Safety and Tolerability of the Drug Memantine as Assessed by Change in QTc Interval [ Time Frame: baseline and 16 weeks from start of treatment ]
Incidence of adverse events was monitored by clinical history, physical examinations, electrocardiograms (ECGs), clinical laboratory tests, the Screen for Childhood Anxiety Related Emotional Disorders (SCARED). Here, we report the analysis of the effect of memantine treatment on QTc intervals because of its clinical importance for this analysis for potential drug toxicity. QTc intervals ≥ 450 ms are generally considered long, and drug-induced QTc interval prolongations ≥ 60 ms are generally considered clinically relevant.

Other Outcome Measures:

Intellectual Functioning of the Participants as Assessed by Change in Score on the Matrices Subtest of the Differential Ability Scales-II (DAS-II) [ Time Frame: baseline and 16 weeks from start of treatment ]
This test provides a measure of non-verbal reasoning ability that requires subjects to visually inspect a matrix of 4 or 9 pictures that has a missing piece. Participants have to infer a rule or pattern in the stimuli and select the appropriate response from a range of 4-6 possibilities. Since age norms are not available for individuals older than 17y11m, the ability score will be used as the dependent variable. This is an intermediate score based on Rasch modeling that corrects for different items set being administered to participants. The minimum value of the DAS-II Rasch Score Scale is 0 and the maximum value is 153; higher scores mean better outcomes. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2).
Linguistic Functioning of the Participants as Assessed by Change in Score on the Test for Reception of Grammar 2nd Edition (TROG-II) [ Time Frame: baseline and 16 weeks from start of treatment ]
This is a measure of receptive syntax skills (Bishop, 1983). Participants are asked to point to a picture (out of 4) that corresponds to a phrase or sentence spoken by the examiner. The total number of items correct (rather than blocks passed) will be used as the dependent variable, following the administration manual's ceiling rule. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2). The minimum value of the scores is 0 and the maximum value is 40; with higher scores considered to be a better outcome.
Linguistic Functioning of the Participants as Assessed by Change in Score on the Peabody Picture Vocabulary Test-IV (PPVT-IV) [ Time Frame: baseline and 16 weeks from start of treatment ]
This is a measure of receptive semantics, whereby the participant is asked to point to a picture (out of 4) that corresponds to a word spoken by the examiner. As this test has a 0.85 correlation with composite measures of Verbal IQ (i.e. from the Wechsler Intelligence Scale series), it can be used in conjunction with the Matrices subtest to estimate overall intellectual functioning. The total number of items correct was used as the dependent variable, following the administration manual's rules for basals and ceilings. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2). The minimum value for this scale is 0 and the maximum value is 192, higher scores mean a better outcome.
Adaptive/Behavioral Functioning of the Participants as Assessed by Change in Score on the Scales of Independent Behavior-Revised (SIB-R) [ Time Frame: baseline and 16 weeks from start of treatment ]
This is a measure of adaptive functioning that integrates information from 13 different domains (e.g., gross motor, social interaction, eating, toileting, dressing, personal self-care, etc.). It is in a questionnaire format, which a caregiver can complete while the participant is being tested. Standard scores for all indices will be derived from age norms that extend from birth to age 80, as these were used as dependent variables. We report here on the Broad Independence Score recorded as change in score from baseline (T1) to after the treatment (T2). The minimum value of the SIB-R Score Scale in this study was -24 (this number is below 0 because -24 was the minimum value for the worst performing participant in the trial) and the maximum value of this scale is 153; higher scores mean better outcomes.
Exploratory Study of Electroencephalographic (EEG) Recordings of Evoked Potentials as Potential Biomarkers for the Severity of the Cognitive Disability Associated to Down Syndrome and for the Efficacy of the Memantine Treatment [ Time Frame: baseline and 16 weeks from start of treatment ]
Auditory and visual evoked potential experiments will search for significant differences in peak amplitude and latency of MMNs in persons with Down syndrome in relation to typically developing persons without Down syndrome, and in participants with Down syndrome before and after memantine treatment. As of this report date, the analysis of this exploratory measure has not yet been performed.
Exploratory Study of Magnetic Resonance Imaging (MRI) as Potential Biomarkers for the Severity of the Cognitive Disability Associated to Down Syndrome and for the Efficacy of the Memantine Treatment [ Time Frame: baseline and 16 weeks from start of treatment ]
MRI studies will be to provide precise source localization for the high-density EEG recordings of evoked potentials in a subset of 30-60 participants of this trial. In addition, these experiments will also produce high resolution sagittal slice images of the hippocampus and simple connectivity data sets. We were not able to collect data from enough participants of this study to perform any meaningful statistical analysis related to this exploratory measure.

Eligibility Criteria

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Ages Eligible for Study:	15 Years to 32 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Cytogenetically documented Trisomy 21 or Complete Unbalanced Translocation of Chromosome 21. Mosaic Trisomy 21 and partial translocations will be excluded from the study
No pregnancy by serum testing at screening. Females of child-bearing potential, sexually active must be practicing a reliable method of birth control. Urine pregnancy tests will be done at the 2 follow-up medical visits
Laboratory findings within normal limits or judged clinically insignificant at baseline
Vital signs within normal limits for age. Stable, medically treated hypotension will be allowed
ECG must demonstrate predominately normal sinus rhythm. Minor abnormalities documented as clinically insignificant will be allowed
Participants and their authorized representatives will provide written informed consent
Participants who have received any experimental drug for Down syndrome must undergo a washout
All participants must: Be in general good health as judged by the investigators; Be able to swallow oral medication; Have a reliable caregiver or family member who agrees to accompany participant to all visits, provide information about the participant as required by the protocol, and ensure compliance with the medication schedule; Be sufficiently proficient in English (USA) or Portuguese (Brazil) to reliably complete the study assessments
Age and gender matching participants without Down syndrome, must be: Males or females without Down syndrome aged-matching (within 3 years) participants with Down syndrome whom they are expected to serve as controls

Exclusion Criteria:

Participant weighing less than 40 kg
Current psychiatric or neurologic diagnosis other than Down syndrome (e.g., major depressive disorder, schizophrenia, bipolar disorder, autism, Alzheimer disease)
Current treatment with psychotropic drugs
Drug or alcohol abuse or dependence
Significant suicide risk or who would require treatment with electro-convulsive therapy or with psychotropic drugs during the study or who have received treatment with a depot neuroleptic drug within 6 months of entering the study.
Current or expected (within the next 6 months) hospitalization or residence in a skilled nursing facility (may reside in group homes or other residential settings with no skilled nursing)
Active or clinically significant conditions affecting absorption, distribution, or metabolism of study drug (e.g. inflammatory bowel disease or celiac disease)
Significant allergies to or other significant intolerance of memantine therapy, its ingredients, or with contraindications to memantine therapy as stated in the prescribing information
Participants who are expected to require general anesthetics during the course of the study
Presence or recent history of seizure disorder (< 3 years).
Clinically significant and/or clinically unstable systemic disease. (Those with controlled hypothyroidism must be on a stable dose of medication for at least 3 months prior to screening and have normal serum T-4 and TSH at screening; and those with controlled diabetes mellitus must have an HbA1c of < 8.0% and a random serum glucose value of < 170 mg/dl)
Severe infections or a major surgical operation within 3 months prior to screening
History of persistent cognitive deficits immediately following head trauma.
Donation of blood or blood products less that 30 days prior to screening, while participating in the study, or four weeks after completion of the study
Inability to comply with the protocol or perform the outcomes measures due to significant hearing or visual impairment or other issues judged relevant by the investigators
Exclusion criteria for controls without Down syndrome: History of substance abuse, major psychiatric disorder, attention deficit disorder, or learning disability; Beck Depression Score greater than 10; Exclusion criteria specific to MR scanning; Pregnancy; Neurologic history

Contacts and Locations

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): NCT02304302

Locations

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United States, Ohio
University Hospitals Case Medical Center
Cleveland, Ohio, United States, 44106
Brazil
Sociedade Beneficente Israelita Brasileira Albert Einstein
São Paulo, SP, Brazil, 05652- 900

Sponsors and Collaborators

University Hospitals Cleveland Medical Center

Alana USA Foundation

Investigators

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Principal Investigator:	Alberto C Costa, MD, PhD	University Hospitals Cleveland Medical Center
Study Director:	Stephen L Ruedrich, MD	University Hospitals Cleveland Medical Center

Study Documents (Full-Text)

Documents provided by Dr. Alberto Costa, University Hospitals Cleveland Medical Center:

Study Protocol and Statistical Analysis Plan [PDF] June 6, 2021

More Information

Publications of Results:

Costa ACS, Brandao AC, Boada R, Barrionuevo VL, Taylor HG, Roth E, Stasko MR, Johnson MW, Assir FF, Roberto MP, Salmona P, Abreu-Silveira G, Bederman I, Prendergast E, Huls A, Abrishamcar S, Mustacchi Z, Scheidemantel T, Roizen NJ, Ruedrich S. Safety, efficacy, and tolerability of memantine for cognitive and adaptive outcome measures in adolescents and young adults with Down syndrome: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2022 Jan;21(1):31-41. doi: 10.1016/S1474-4422(21)00369-0.

Other Publications:

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Retraction in: J Alzheimers Dis. 2016 Nov 1;55(1):445

Chez MG, Burton Q, Dowling T, Chang M, Khanna P, Kramer C. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol. 2007 May;22(5):574-9. doi: 10.1177/0883073807302611.

Costa AC, Scott-McKean JJ. Prospects for improving brain function in individuals with Down syndrome. CNS Drugs. 2013 Sep;27(9):679-702. doi: 10.1007/s40263-013-0089-3.

Costa AC, Scott-McKean JJ, Stasko MR. Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology. 2008 Jun;33(7):1624-32. doi: 10.1038/sj.npp.1301535. Epub 2007 Aug 15.

Danysz W, Parsons CG. Alzheimer's disease, beta-amyloid, glutamate, NMDA receptors and memantine--searching for the connections. Br J Pharmacol. 2012 Sep;167(2):324-52. doi: 10.1111/j.1476-5381.2012.02057.x.

Erickson CA, Mullett JE, McDougle CJ. Open-label memantine in fragile X syndrome. J Autism Dev Disord. 2009 Dec;39(12):1629-35. doi: 10.1007/s10803-009-0807-3. Epub 2009 Jul 16.

Erickson CA, Posey DJ, Stigler KA, Mullett J, Katschke AR, McDougle CJ. A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl). 2007 Mar;191(1):141-7. doi: 10.1007/s00213-006-0518-9. Epub 2006 Oct 3.

Fernandez G, Weyerts H, Schrader-Bolsche M, Tendolkar I, Smid HG, Tempelmann C, Hinrichs H, Scheich H, Elger CE, Mangun GR, Heinze HJ. Successful verbal encoding into episodic memory engages the posterior hippocampus: a parametrically analyzed functional magnetic resonance imaging study. J Neurosci. 1998 Mar 1;18(5):1841-7. doi: 10.1523/JNEUROSCI.18-05-01841.1998.

Findling RL, McNamara NK, Stansbrey RJ, Maxhimer R, Periclou A, Mann A, Graham SM. A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type. J Child Adolesc Psychopharmacol. 2007 Feb;17(1):19-33. doi: 10.1089/cap.2006.0044.

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Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, Corbett A, Lawrence D, Yu LM, Tyrer S, Francis PT, Johnson T, Bullock R, Ballard C; MEADOWS trial researchers. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet. 2012 Feb 11;379(9815):528-36. doi: 10.1016/S0140-6736(11)61676-0. Epub 2012 Jan 10.

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Jarrold C, Baddeley AD, Hewes AK. Verbal short-term memory deficits in Down syndrome: a consequence of problems in rehearsal? J Child Psychol Psychiatry. 2000 Feb;41(2):233-44.

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Layout table for additonal information

Responsible Party:	Dr. Alberto Costa, MD, PhD, Professor of Pediatric Neurology, University Hospitals Cleveland Medical Center
ClinicalTrials.gov Identifier:	NCT02304302
Other Study ID Numbers:	121971
First Posted:	December 1, 2014 Key Record Dates
Results First Posted:	April 5, 2022
Last Update Posted:	April 5, 2022
Last Verified:	April 2022

Keywords provided by Dr. Alberto Costa, University Hospitals Cleveland Medical Center:


Memantine Episodic Memory CVLT Hippocampus dependent memory Short-term memory

Additional relevant MeSH terms:

Layout table for MeSH terms

Down Syndrome Intellectual Disability Syndrome Disease Pathologic Processes Neurobehavioral Manifestations Neurologic Manifestations Nervous System Diseases Abnormalities, Multiple Congenital Abnormalities Chromosome Disorders Genetic Diseases, Inborn	Neurodevelopmental Disorders Mental Disorders Memantine Antiparkinson Agents Anti-Dyskinesia Agents Dopamine Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Excitatory Amino Acid Antagonists Excitatory Amino Acid Agents

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