The efficacy of Memantine combined with Speech language therapy for post stroke non-fluent aphasia rehabilitation: A randomized controlled clinical study

The efficacy of Memantine combined with Speech language therapy for post stroke non-fluent aphasia rehabilitation: A randomized controlled clinical study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The efficacy of Memantine combined with Speech language therapy for post stroke non-fluent aphasia rehabilitation: A randomized controlled clinical study Chaojinzi Li, Haixia Mi, Yuanyuan Tao, Xingxing Lei, Rong Sun, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4020634/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Aphasia is a common complication after stroke, and traditional speech or language therapy has a limited effect on post-stroke aphasia. This randomized, controlled, open-label study aimed to evaluate the effectiveness of intensive speech and language therapy together with memantine on speech and cognitive function in patients with non-fluent aphasia after stroke. Methods Fifty post stroke non-fluent aphasia patients with unilateral left hemispheric infarction or hemorrhage were recruited and randomly divided into speech language therapy (SLT) group or Memantine group. The SLT group will receive only SLT treatment and placebo, while Memantine group will receive memantine combined with SLT treatment. Primary outcome measure will include the Western Aphasia Battery (WAB)-Aphasia Quotient from baseline to endpoint, Secondary outcomes measure will include Mini-Mental State Examination score. Assessment data were collected at baseline, Week4(Visit 1), Week 8 (Visit 2), Week 12 (Visit 3), and Week 16 (Visit 4). Results On the basis of consistent baseline data, the language function of the two groups improved after treatment (p < 0.001). Compared with the control group, the memantine group had significant benefits in auditory comprehension-AQ at week 4 (p = 0.04), WAB-AQ (p = 0.04) and spontaneous speech-AQ(p = 0.006) at week 8, WAB-AQ(p = 0.01) and spontaneous speech-AQ(p < 0.001), auditory comprehension-AQ(p = 0.03) at week 12, WAB-AQ (p = 0.01) and spontaneous speech-AQ(p < 0.001), auditory comprehension-AQ(p = 0.04) at week 16. The increase in the change of MMSE scores was higher in Memantine group at week 8 (p = 0.04) and week 12(p = 0.048). Conclusion Memantine combined with SLT are useful for improving non-fluency aphasia after stroke, especially spontaneous speech and auditory comprehension. Cognitive function has also improved. Trial registration: www.clinicaltrials.gov ; TRN: NCT00196703; stroke non-fluent aphasia memantine speech language therapy Figures Figure 1 Figure 2 Figure 3 Introduction Stroke is one of the leading causes of disability worldwide and aphasia is common among survivors. Post-stroke aphasia (PSA) is an acquired neurological disorder of language processing that affects listening, speaking, writing, reading and gesturing. Approximately 30–35% of acute stroke patients suffer from aphasia[ 1 ], which is associated with their life dependence, less social participation, poorer rehabilitation outcomes and worsen quality of life[ 2 – 4 ]. Various methods of rehabilitation have been used to treat patients with stroke-related aphasia, speech language therapy is a conventional intervention for aphasia, has been proposed to be beneficial for improving language functions of stroke patients at acute and sub-acute phases, in addition to the spontaneous recovery[ 5 ].Preliminary data reveals that combining neuroscience based intensive aphasia techniques (constraint-induced aphasia therapy) and drugs acting on cholinergic and glutamatergic neurotransmitter systems are associated with better outcomes than other strategies and long-term maintenance of benefits[ 6 ]. Memantine is a non-competitive, use-dependent N-methyl-D-aspartate receptor antagonist, which has been proved to reduce infarct volume[ 7 ] and to improve function[ 8 ] by blocking the excitability of glutamate toxicity[ 9 ][ 14 ]. Recently, a few clinical researches had shown memantine in conjunction with constraint-induced aphasia therapy had promising effects on improving language and cognitive function in chronic post stroke aphasia[ 10 , 11 ]. In this study, we identify whether subacute PSA can be improved more substantially by conjoined application of intensive SLT together with drug treatment. Subjects and Methods Patients Patients were recruited from China Rehabilitation Research Center. Inclusion criteria were: (1) age between 18 and 70 years, (2) unilateral cortical-subcortical or subcortical lesions caused by a single infarction or hemorrhage diagnosed as stroke by CT/MRI, (3) aphasia diagnosis according to the Western Aphasia Battery (WAB), Fluency ≤ 6 was classified as non-fluency aphasia. (4) presence of aphasia for 4 weeks to 6 months prior to the Screening visit, (5) Patients and caregivers are given written informed consent to participate in this trial. Exclusion criteria were: (1) Presence of a severe language deficit (mutism, recurrent utterances in aphasia, neologistic jargon aphasia, or WAB comprehension score < 4), (2) history of any other neurological or psychiatric disease impairing language and communicative ability (eg, dementia), (3) severe visual agnosia (eg, inability to identify visually presented objects),(4) severe limb apraxia (eg, inability to manipulate objects) and severe speech apraxia (difficulty executing or sequencing oral-motor movements, or both), (5) severe depression,(6) epilepsy,(7) pregnancy, (8) recent myocardial infarction, (9) uncompensated congestive heart failure, (10) uncontrolled hypertension, (11) hypersensitivity toward memantine, and (12) ongoing medication with agents interfering with memantine (including amantadine, dextromethorphan, or ketamine).Any concomitant medication was kept unchanged during the study. The study was undertaken during 2017–2019. The study is registered with EudraCT(2004-002337-39), and the protocol for the study was filed with the open clinical trial registry ( www.clinicaltrials.gov ; Identification No. NCT00196703). Study Design This study is designed as a randomized controlled, single-blinded, open-labled 16-week clinical study. All the scales will be evaluated by the same raters who is blinded to the patient’s group. A database will need to be established to collect clinical and rehabilitative information of patients with post stroke aphasia. Patients were randomized divided into the speech language therapy (SLT) group or Memantine group respectively in a ratio of 1:1 with random number table (Fig. 1 ). The SLT group received treatment with SLT and placebo while the Memantine group received memantine and SLT simultaneously. Blinding was established with identical film-coated tablets for oral intake containing either memantine (5 mg) or placebo. Tablets were dispensed into patient-coded containers by a nonblinded pharmacist. Researchers, as well as patients and their caregivers, were unaware of and could not determine the study drug assignment by appearance or otherwise. The outcome measures are the mean score change of the Aphasia Quotient (AQ) of the WAB from baseline to endpoints. The study evaluations will take place on the baseline(Day1),week4(Visit 1), week 8(Visit 2), week 12 (Visit 3), week 16 (Visit 4) respectively. The study design is shown in Fig. 1 . Drug Treatment All patients underwent a 3-week up-titration phase of either memantine or placebo. memantine was titrated in 5mg weekly increments from a starting dose of 5 to 20mg/day. After the dose-escalation phase, patients receive a fixed treatment dose of memantine (20mg once daily) during the next 9 weeks (week 4th -12nd ) followed by a 4-week period of drug washout (weeks 13rd -16th ). During the drug washout period, all patients continue speech language therapy. Speech and Language therapy All SLT was performed by the experienced therapist, 30min/each time, one language therapy/day, 5 times/week, totally 12 weeks. The SLT plan is made according to the patient’s language function, including understanding, orofacial movement, pronounce, reading, naming, writing et al. Homework that matched with SLT after training are requested to finish by the patients. Outcome Measure To detect the possible correlation between cognitive function and aphasia severity. The primary outcome measures were set as the mean score change from baseline to end points in the Aphasia Quotient (AQ) of the Western Aphasia Battery(WAB)[ 12 ] at week 16 (drug washout). The Chinese version of the Mini-Mental State Examination (MMSE) score was evaluated at baseline, Week 4,8,12 and 16. Sample size The sample size is determined using the treatment effect size from literature[ 13 ]. A two-group T-test with a 0.050 two-sided significance level will have 85% power to detect a difference in means of 5,000 in AQ of the WAB, assuming that the common SD is 4,000 when the sample size in each group is 20. Statistical Analysis Categorical variables (sex, risk factors and handedness) will be analyzed using Chi-Square Test. Numeric variables (age, duration of disease) will be analyzed by using an independent T-test. Statistical analysis will be performed using SPSS software, V.16.0 (Statistical Product and Service Solutions Inc).The curative effect was evaluated according to the change of each score and baseline value in two groups at each time point. Using paired T-tests to compare the baseline with the score of each time point within group. Calculating the least-square mean of difference (LSM) and 95% confidence interval (mean,95%CI) for the change of the same outcome measure at the same time point. Then using T-test to compare LSM of two groups and correcting the values with the baseline value (Analysis of Covariance) of sex, age, education, duration, stroke types, type of aphasia. This is an exploratory RCT study firstly to observe the effect of memantine on non-fluent aphasia patients, the number of 60 patients planned to recruit is actually more than the sample size calculated with statistical method(Power Analysis and Sample Size11, PASS11). Results Patient characteristics A total of 60 patients were included ,50 of them were no-fluent aphasia, 49 of them completed the trial. The CONSORT diagram showing the flow of participants is shown in Fig. 2 . Baseline characteristics of memantine and as are shown in Table 1. Groups were well matched with respect to baseline demographic and clinical characteristics. The analyses were adjusted for these baseline characteristics. All patients had lesions in the left perisylvian region. No patients developed adverse events to memantine or placebo treatments. Table 1 Baseline characteristics of the Memantine group and SLT group. Outcome measure: Aphasia severity Within-group comparisons between baseline and the end of up-titration phase assessment (week 4) demonstrated a significant increase in WAB-AQ and subtests in both the Memantine group and SLT group(p<0.001 or p = 0.001). But there’s no positive changes in WAB-AQ scores were observed in the Memantine group compared with SLT group at this time point (mean difference 1.5, 95%CI -0.6 to 3.6, p = 0.31), while the change of auditory comprehension improvement in the Memantine group compared with SLT group was significant (mean difference 0.4, 95%CI 0.0 to 0.8, p = 0.04). (Table 2) Within-group comparisons between baseline and the drug/placebo maintenance period demonstrated a significant increase in WAB-AQ scores and all the WAB subtests in both the Memantine group and SLT group at the drug/placebo maintenance period (week 4 to week 12, p＜0.001). A significant improvement in WAB-AQ scores was observed in the Memantine group compared with SLT group at the drug/placebo maintenance period.（week 8:mean difference 5.6,95%CI 1.4 to 9.8,p=0.04;week 12: mean difference 8.0,95%CI 2.9 to 13.0,p=0.01）.Positive changes were also observed in WAB subtests-spontaneous speech at week 8 (mean difference 1.7,95%CI 0.7 to 2.7,p=0.006) and week 12（mean difference 2.5,95%CI 1.4 to 3.5,p＜0.001）,auditory comprehension（mean difference 1.3 , 95%CI 0.3 to 2.4,p=0.03）at week12. (Table 2) During the drug washout period, both groups showed a significant improvement on WAB-AQ and WAB subtests over the baseline(p＜0.001), and a significant between-group difference also emerged when comparing improvements between week 12 （mean difference 8.0 ,95%CI 2.9 to 13.0，p=0.01）and week 16（mean difference 9.3 , 95%CI 3.4 to 15.1，p=0.01）, indicating that a significant improvement in WAB-AQ scores was observed in the Memantine group during washout period, thus we can infer that the effect of memantine was still continued. (Table 2)（Fig. 3）. A significant increase in MMSE score was found in both the Memantine group and SLT group at all the time points compared with baseline. A significant improvement of MMSE between-group was observed only at weeks 8 and12, reflecting the effect of memantine on cognition (Table 2). Table 2 Within-group and between-group comparisons between baseline and scores on each time point from visit 1 to 4 Discussion In this study, the significant improvement on language and cognitive function over continuous 16 weeks period could been observed in both SLT group and Memantine group. It is notable that after 8 to 12 weeks of treatment, the WAB-AQ scores increased more significantly in Memantine group, that represented the speech and recognition improvement in PSA patients. Memantine combined with SLT is an effective method in post-stroke aphasia. The manifestations of aphasia is closely related to the location of ischemia or hemorrhage damage and the dominant hemisphere. From the pathophysiological mechanism, due to ischemia and hypoxia in the local brain tissue after ischemia and hemorrhage, edema, a large number of harmful substances are produced, such as free radicals and excitatory amino acids that was the primary mechanism for neuron death. The FDA approved memantine in 2003 for its use in moderate to severe Alzheimer’s disease. In the treatment of Alzheimer's disease in recent years, it has shown a relatively good effect, memantine can enhance neuronal synaptic plasticity in the brain, improve memory, and act as a neuroprotectant against the destruction of neurons caused by excitatory neurotransmitters [ 15 ]. Not only that, memantine hydrochloride has also shown good curative effects in basic studies of stroke animal models [ 16 ] [ 17 ].In stroke studies, memantine has been proven to provide post-ischemic neuroprotection via multiple mechanisms, including inhibition of apoptosis [ 18 ], NMDA inhibition mediated excitotoxicity [ 19 ], preserving intracellular ATP stores [ 18 ], and increasing tissue concentration of neuron-specific growth factors [ 20 ]. The main performance of aphasia is difficulty in comprehension and expression, their abilities of communicating are limited, which decrease the effectiveness of rehabilitation training. Aphasia examination mainly includes six basic aspects: oral comprehension, spontaneous language expression, repeating, naming, reading, and writing. For many years an effort has been made to target language therapy techniques that help the recovery of patients with aphasia [ 21 ]. Treatment guidelines for aphasia recommend intensive speech and language therapy for aphasia after stroke [ 22 ][ 23 ],but also with neuromodulation technology combined with speech therapy, Repetitive Transcranial Magnetic Stimulation(rTMS) and transcranial Direct Current Stimulation(tDCS) [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 28 ]. Drug treatment of large-scale, class 1 randomized controlled trials specifically for aphasia after stroke are scarce. In this study, we investigated the effects of SLT, memantine combined with SLT in patients with subacute PSA. The results showed that the mean WAB-AQ increased from visit 1 to visit 4, indicating both methods can improve overall language function after 4–16 weeks. But the improvement is more significant in Memantine group at week 8 to week 16. The effect of memantine was still continued during medicine washout period. The results of WAB-AQ subitem analysis showed that compared with SLT group, significant improvement in auditory comprehension-AQ at visit 1, auditory comprehension-AQ and spontaneous speech-AQ at visit 2,3,4 was observed in Memantine group. In the four follow-ups, the increase in MMSE scores was more obvious in the Memantine group, and there was a statistical difference compared with the control group at the second and third follow-up. We considered that there was no difference between groups in WAB-AQ at week 4 because the effect of memantine on aphasia recovery during a 3-week up-titration phase was unstable. These findings suggest that memantine combined with intensive speech and language therapy have a positive effect on the recovery of aphasia after subacute stroke, especially after eight weeks of continuous treatment. Studies on stroke at different stages have shown controversial effects of drug therapy. In acute stroke studies, a case series study has shown that intravenous thrombolysis or endovascular therapy result in improvement of acute aphasia recovery[ 29 ]. A study consisted of 33 subacute stroke patients suggests that speech and language therapy, 30–60 minutes per day, 2 days a week, for 8 successive weeks, are effective in the treatment of subacute-stroke aphasic [ 30 ]. In chronic phase of stroke recovery, no study has provided evidence that pharmaceutical intervention results in significant improvement in chronic post-stroke aphasia in the absence of SLT [ 31 ]. However, several trials have provided primary evidence that some medications may augment the effects of speech therapy. A plausible mechanism is that language recovery depends on neuroplasticity. Medications that alter the availability of neurotransmitters could enhance neuroplasticity [ 32 ].In a study of 27 patients with chronic post-stroke aphasia, constraint-induced aphasia therapy was beneficial when used combined with memantine 10 mg twice daily [ 33 ]. Meanwhile, no insufficient evidence to recommend an optimal dosage that would result in maximum treatment outcome. [ 34 ]. In this RCT study, SLT was performed 30min/each time, once/day, 5 times/week, totally 12 weeks, combined with memantine, post-stroke aphasia would improve significantly at the treatment beginning of 4 weeks compared with baseline and showed differences between groups at week 8 and week 12, lasted to the drug washout period, providing strong evidence on aphasia recovery after stroke. The shortcoming of this study is that this study is a single-center study. In the future, a larger multi-center study is needed to confirm its mechanism to help stroke patients recover their language function. Conclusions From the above discussion, the conclusion can be reached that memantine combined with SLT are useful for improving non-fluency aphasia after stroke, especially spontaneous speech and auditory comprehension. Abbreviations SLT Speech Language Therapy MMSE Mini-Mental State Examination PSA Post-Stroke Aphasia AQ Aphasia Quotient WAB Western Aphasia Battery LSM Least-Square Mean of difference rTMS Repetitive Transcranial Magnetic Stimulation tDCS Repetitive Transcranial Direct Current Stimulation Declarations Data availability statement The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author. Ethics statement The study involving human participants was reviewed and approved by the China Rehabilitation Research Center Ethics Committee (approval number: 2017-093-1) on Aug 10, 2017. The patients/participants provided their written informed consent to participate in this study. Consent for publication Written informed consent was obtained from every patient for publication of this study. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding Support for this study was provided by Funding-National Key R&D Program of China (2020YFC2004105). Author contributions and information C.J.Z.L is the first author and wrote the manuscript. X.X.D and L.P.S contributed equally to this work and should be considered co-corresponding authors. X.X.D is a primary corresponding author. H.X.M, Y.Y.T, R.S implemented and collected data. X.X.L was the clinical scale tester. Data were statistically analyzed by L.X, J.L, S.X. All authors discussed results, article, and approved the submitted version. Acknowledgments We are grateful to everyone who contributed to this study. References Engelter ST, Gostynski M, Papa S, Frei M, Born C, Ajdacic-Gross V, Gutzwiller F, Lyrer PA. 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Disability and rehabilitation.2020. DOI：10.1080/09638288.2020.1843079 Tables Table 1 Baseline characteristics of the Memantine group and SLT group. Variable Memantine group n = 25 SLT group n = 24 p value Mean age (SE a ) range, years 55.5 ± 13.4 50.3 ± 13.0 0.18 Male sex, n (%) 19 (38.8 %) 19 (38.8 %) 0.79 Mean education (SE) Junior middle school and below Senior middle school and above 9 (18.4 %) 16 (32.7 %) 8 (16.3 %) 16 (32.7 %) 0.84 Aphasia duration (months) 4.1 ± 4.8 4.3 ± 4.9 0.88 Right handedness, n (%) 25(100%) 24(100%) Stroke types Infarctions Hemorrhages 11 (22.4 %) 14 (28.6 %) 12 (24.5 %) 12 (24.5 %) 0.67 Glasgow value 14.2 ± 0.9 14.3 ± 1.1 0.91 MMSE 10.1 ± 7.0 12.9 ± 6.5 0.18 Mean WAB-AQ b (SE), range (maximum = 100) 44.5 ± 27.3 53.6 ± 17.4 0.17 Spontaneous speech 8.3 ± 5.4 10.8 ± 4.3 0.08 Auditory comprehension 5.9 ± 2.5 7.1 ± 2.3 0.10 Repetition 5.4 ± 4.1 6.6 ± 2.9 0.24 Naming 2.7 ± 2.7 2.7 ± 1.9 0.99 a SE, standard error. b WAB-AQ: Western Aphasia Battery-Aphasia Quotient Table 2 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files supplementarymaterialtable12.docx table2.xlsx Table 2 Within-group and between-group comparisons between baseline and scores on each time point from visit 1 to 4 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4020634","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":281795756,"identity":"e73788bf-358c-4e5a-8d0e-d2e5b90661aa","order_by":0,"name":"Chaojinzi Li","email":"","orcid":"","institution":"School of Rehabilitation Medicine, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chaojinzi","middleName":"","lastName":"Li","suffix":""},{"id":281795758,"identity":"ef80487e-4604-4905-bccb-44e515380355","order_by":1,"name":"Haixia Mi","email":"","orcid":"","institution":"School of Rehabilitation Medicine, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Haixia","middleName":"","lastName":"Mi","suffix":""},{"id":281795759,"identity":"b8c11e6f-cff9-44a0-8914-644968e6f34b","order_by":2,"name":"Yuanyuan Tao","email":"","orcid":"","institution":"School of Rehabilitation Medicine, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuanyuan","middleName":"","lastName":"Tao","suffix":""},{"id":281795760,"identity":"ef74ffe0-bb11-46cd-8862-fa061a571f59","order_by":3,"name":"Xingxing Lei","email":"","orcid":"","institution":"School of Rehabilitation Medicine, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xingxing","middleName":"","lastName":"Lei","suffix":""},{"id":281795761,"identity":"c4a447f7-ae74-4027-bc97-9bee0ad1b304","order_by":4,"name":"Rong Sun","email":"","orcid":"","institution":"School of Rehabilitation Medicine, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Rong","middleName":"","lastName":"Sun","suffix":""},{"id":281795762,"identity":"eb991cb8-7a1d-4070-841c-9fa1b0ba357b","order_by":5,"name":"Lin Xiao","email":"","orcid":"","institution":"School of Rehabilitation Medicine, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Xiao","suffix":""},{"id":281795763,"identity":"ec7d2ced-eafb-4a20-be8b-d8b45b7f1623","order_by":6,"name":"Jie Le","email":"","orcid":"","institution":"School of Rehabilitation Medicine, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Le","suffix":""},{"id":281795764,"identity":"7d829ca9-0153-47d2-baff-8ce0fe398dee","order_by":7,"name":"Shu Xu","email":"","orcid":"","institution":"School of Rehabilitation Medicine, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shu","middleName":"","lastName":"Xu","suffix":""},{"id":281795765,"identity":"113a1e8f-049f-4f85-8d81-536371045513","order_by":8,"name":"Luping Song","email":"","orcid":"","institution":"Shenzhen Sixth People's Hospital (Nanshan Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Luping","middleName":"","lastName":"Song","suffix":""},{"id":281795766,"identity":"c96cf059-4e22-4859-b5c3-587f1b41ea48","order_by":9,"name":"Xiaoxia Du","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYBACefaGxAcJFf/lGNsbiNRi2HPgscGHM8zGzD0HiLXmhuMzyZktzIntMxKI1ME4gzlNmreBzZh35uONNxhqbKIJamGXbku25t3BIyc5O63YguFYWm4DQVvmnEm8zXtGwthwdo6ZBGPDYcJaGG7kf5DmbTNI3H/zDNFaEpIkZ7YlJDbO4CFSCzCQk4GBfMCYsQfolwRi/AKNygPAqDy88caHGhsiHIYEDCQSSFEO0UKqjlEwCkbBKBgZAAAtT0XFXZK4lAAAAABJRU5ErkJggg==","orcid":"","institution":"School of Rehabilitation Medicine, Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Xiaoxia","middleName":"","lastName":"Du","suffix":""}],"badges":[],"createdAt":"2024-03-06 11:19:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4020634/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4020634/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53197344,"identity":"3ca12a20-55d3-4c8e-a8de-a634c2a3b2a4","added_by":"auto","created_at":"2024-03-21 18:38:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":32053,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4020634/v1/213f959c8e2ff292fc305ed6.jpg"},{"id":53198538,"identity":"98d62e59-f6c7-4610-9a40-e5909e3bcf59","added_by":"auto","created_at":"2024-03-21 18:46:54","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":109175,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe CONSORT diagram shows the flow of participants in the randomized, placebo-controlled trail.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4020634/v1/a00c6be9e5de94eea5ddf36c.jpg"},{"id":53197349,"identity":"fde02644-ec90-4a68-9929-83e0faf1ce0b","added_by":"auto","created_at":"2024-03-21 18:38:54","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":56744,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe change of WAB-AQ scores in two groups. \u003c/strong\u003eThe black dots and black circle represented the mean scores of the change of WAB-AQ in the Memantine and SLT group separately. X-axis: time points from baseline to week 16. Y axis: the change of WAB-AQ scores. ***：p\u0026lt;0.05\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4020634/v1/7ccc2cb280c53becc96c3371.jpg"},{"id":58971826,"identity":"dff114a0-8774-4630-8c13-ff3dfaca62ef","added_by":"auto","created_at":"2024-06-24 21:16:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":712294,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4020634/v1/c11755a4-e65d-4055-9b5f-56f85d4429bb.pdf"},{"id":53197346,"identity":"86bd1f3f-950b-47bf-aec1-a2b501b66cec","added_by":"auto","created_at":"2024-03-21 18:38:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28057,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterialtable12.docx","url":"https://assets-eu.researchsquare.com/files/rs-4020634/v1/ce2b6c2f2bfbb4e19becfb00.docx"},{"id":53197347,"identity":"052f8d44-1ba9-42c1-9c84-084998b2bb17","added_by":"auto","created_at":"2024-03-21 18:38:54","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12501,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 2 Within-group and between-group comparisons between baseline and scores on each time point from visit 1 to 4\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4020634/v1/1ccafd598d85ef648b85b962.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The efficacy of Memantine combined with Speech language therapy for post stroke non-fluent aphasia rehabilitation: A randomized controlled clinical study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eStroke is one of the leading causes of disability worldwide and aphasia is common among survivors. Post-stroke aphasia (PSA) is an acquired neurological disorder of language processing that affects listening, speaking, writing, reading and gesturing. Approximately 30\u0026ndash;35% of acute stroke patients suffer from aphasia[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], which is associated with their life dependence, less social participation, poorer rehabilitation outcomes and worsen quality of life[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVarious methods of rehabilitation have been used to treat patients with stroke-related aphasia, speech language therapy is a conventional intervention for aphasia, has been proposed to be beneficial for improving language functions of stroke patients at acute and sub-acute phases, in addition to the spontaneous recovery[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].Preliminary data reveals that combining neuroscience based intensive aphasia techniques (constraint-induced aphasia therapy) and drugs acting on cholinergic and glutamatergic neurotransmitter systems are associated with better outcomes than other strategies and long-term maintenance of benefits[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Memantine is a non-competitive, use-dependent N-methyl-D-aspartate receptor antagonist, which has been proved to reduce infarct volume[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and to improve function[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] by blocking the excitability of glutamate toxicity[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Recently, a few clinical researches had shown memantine in conjunction with constraint-induced aphasia therapy had promising effects on improving language and cognitive function in chronic post stroke aphasia[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we identify whether subacute PSA can be improved more substantially by conjoined application of intensive SLT together with drug treatment.\u003c/p\u003e"},{"header":"Subjects and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003ePatients were recruited from China Rehabilitation Research Center. Inclusion criteria were: (1) age between 18 and 70 years, (2) unilateral cortical-subcortical or subcortical lesions caused by a single infarction or hemorrhage diagnosed as stroke by CT/MRI, (3) aphasia diagnosis according to the Western Aphasia Battery (WAB), Fluency\u0026thinsp;\u0026le;\u0026thinsp;6 was classified as non-fluency aphasia. (4) presence of aphasia for 4 weeks to 6 months prior to the Screening visit, (5) Patients and caregivers are given written informed consent to participate in this trial. Exclusion criteria were: (1) Presence of a severe language deficit (mutism, recurrent utterances in aphasia, neologistic jargon aphasia, or WAB comprehension score\u0026thinsp;\u0026lt;\u0026thinsp;4), (2) history of any other neurological or psychiatric disease impairing language and communicative ability (eg, dementia), (3) severe visual agnosia (eg, inability to identify visually presented objects),(4) severe limb apraxia (eg, inability to manipulate objects) and severe speech apraxia (difficulty executing or sequencing oral-motor movements, or both), (5) severe depression,(6) epilepsy,(7) pregnancy, (8) recent myocardial infarction, (9) uncompensated congestive heart failure, (10) uncontrolled hypertension, (11) hypersensitivity toward memantine, and (12) ongoing medication with agents interfering with memantine (including amantadine, dextromethorphan, or ketamine).Any concomitant medication was kept unchanged during the study.\u003c/p\u003e \u003cp\u003eThe study was undertaken during 2017\u0026ndash;2019. The study is registered with EudraCT(2004-002337-39), and the protocol for the study was filed with the open clinical trial registry (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.clinicaltrials.gov\u003c/span\u003e\u003cspan address=\"http://www.clinicaltrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; Identification No. NCT00196703).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis study is designed as a randomized controlled, single-blinded, open-labled 16-week clinical study. All the scales will be evaluated by the same raters who is blinded to the patient\u0026rsquo;s group. A database will need to be established to collect clinical and rehabilitative information of patients with post stroke aphasia.\u003c/p\u003e \u003cp\u003ePatients were randomized divided into the speech language therapy (SLT) group or Memantine group respectively in a ratio of 1:1 with random number table (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The SLT group received treatment with SLT and placebo while the Memantine group received memantine and SLT simultaneously.\u003c/p\u003e \u003cp\u003eBlinding was established with identical film-coated tablets for oral intake containing either memantine (5 mg) or placebo. Tablets were dispensed into patient-coded containers by a nonblinded pharmacist. Researchers, as well as patients and their caregivers, were unaware of and could not determine the study drug assignment by appearance or otherwise.\u003c/p\u003e \u003cp\u003eThe outcome measures are the mean score change of the Aphasia Quotient (AQ) of the WAB from baseline to endpoints. The study evaluations will take place on the baseline(Day1),week4(Visit 1), week 8(Visit 2), week 12 (Visit 3), week 16 (Visit 4) respectively.\u003c/p\u003e \u003cp\u003eThe study design is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDrug Treatment\u003c/h2\u003e \u003cp\u003eAll patients underwent a 3-week up-titration phase of either memantine or placebo. memantine was titrated in 5mg weekly increments from a starting dose of 5 to 20mg/day. After the dose-escalation phase, patients receive a fixed treatment dose of memantine (20mg once daily) during the next 9 weeks (week 4th -12nd ) followed by a 4-week period of drug washout (weeks 13rd -16th ). During the drug washout period, all patients continue speech language therapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSpeech and Language therapy\u003c/h2\u003e \u003cp\u003eAll SLT was performed by the experienced therapist, 30min/each time, one language therapy/day, 5 times/week, totally 12 weeks. The SLT plan is made according to the patient\u0026rsquo;s language function, including understanding, orofacial movement, pronounce, reading, naming, writing et al. Homework that matched with SLT after training are requested to finish by the patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measure\u003c/h2\u003e \u003cp\u003eTo detect the possible correlation between cognitive function and aphasia severity. The primary outcome measures were set as the mean score change from baseline to end points in the Aphasia Quotient (AQ) of the Western Aphasia Battery(WAB)[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] at week 16 (drug washout). The Chinese version of the Mini-Mental State Examination (MMSE) score was evaluated at baseline, Week 4,8,12 and 16.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThe sample size is determined using the treatment effect size from literature[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. A two-group T-test with a 0.050 two-sided significance level will have 85% power to detect a difference in means of 5,000 in AQ of the WAB, assuming that the common SD is 4,000 when the sample size in each group is 20.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCategorical variables (sex, risk factors and handedness) will be analyzed using Chi-Square Test. Numeric variables (age, duration of disease) will be analyzed by using an independent T-test. Statistical analysis will be performed using SPSS software, V.16.0 (Statistical Product and Service Solutions Inc).The curative effect was evaluated according to the change of each score and baseline value in two groups at each time point. Using paired T-tests to compare the baseline with the score of each time point within group. Calculating the least-square mean of difference (LSM) and 95% confidence interval (mean,95%CI) for the change of the same outcome measure at the same time point. Then using T-test to compare LSM of two groups and correcting the values with the baseline value (Analysis of Covariance) of sex, age, education, duration, stroke types, type of aphasia.\u003c/p\u003e \u003cp\u003eThis is an exploratory RCT study firstly to observe the effect of memantine on non-fluent aphasia patients, the number of 60 patients planned to recruit is actually more than the sample size calculated with statistical method(Power Analysis and Sample Size11, PASS11).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eA total of 60 patients were included ,50 of them were no-fluent aphasia, 49 of them completed the trial. The CONSORT diagram showing the flow of participants is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Baseline characteristics of memantine and as are shown in Table\u0026nbsp;1. Groups were well matched with respect to baseline demographic and clinical characteristics. The analyses were adjusted for these baseline characteristics. All patients had lesions in the left perisylvian region. No patients developed adverse events to memantine or placebo treatments.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eTable\u0026nbsp;1 Baseline characteristics of the Memantine group and SLT group.\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measure: Aphasia severity\u003c/h2\u003e \u003cp\u003eWithin-group comparisons between baseline and the end of up-titration phase assessment (week 4) demonstrated a significant increase in WAB-AQ and subtests in both the Memantine group and SLT group(p\u0026lt;0.001 or p\u0026thinsp;=\u0026thinsp;0.001). But there\u0026rsquo;s no positive changes in WAB-AQ scores were observed in the Memantine group compared with SLT group at this time point (mean difference 1.5, 95%CI -0.6 to 3.6, p\u0026thinsp;=\u0026thinsp;0.31), while the change of auditory comprehension improvement in the Memantine group compared with SLT group was significant (mean difference 0.4, 95%CI 0.0 to 0.8, p\u0026thinsp;=\u0026thinsp;0.04). (Table\u0026nbsp;2)\u003c/p\u003e\u003cp\u003eWithin-group comparisons between baseline and the drug/placebo maintenance period demonstrated a significant increase in WAB-AQ scores and all the WAB subtests in both the Memantine group and SLT group at the drug/placebo maintenance period (week 4 to week 12, p＜0.001). A significant improvement in WAB-AQ scores was observed in the Memantine group compared with SLT group at the drug/placebo maintenance period.（week 8:mean difference 5.6,95%CI 1.4 to 9.8,p=0.04;week 12: mean difference 8.0,95%CI 2.9 to 13.0,p=0.01）.Positive changes were also observed in WAB subtests-spontaneous speech at week 8 (mean difference 1.7,95%CI 0.7 to 2.7,p=0.006) and week 12（mean difference 2.5,95%CI 1.4 to 3.5,p＜0.001）,auditory comprehension（mean difference 1.3 , 95%CI 0.3 to 2.4,p=0.03）at week12. (Table 2)\u003c/p\u003e\n\u003cp\u003eDuring the drug washout period, both groups showed a significant improvement on WAB-AQ and WAB subtests over the baseline(p＜0.001), and a significant between-group difference also emerged when comparing improvements between week 12 （mean difference 8.0 ,95%CI 2.9 to 13.0，p=0.01）and week 16（mean difference 9.3 , 95%CI 3.4 to 15.1，p=0.01）, indicating that a significant improvement in WAB-AQ scores was observed in the Memantine group during washout period, thus we can infer that the effect of memantine was still continued. (Table 2)（Fig. 3）.\u0026nbsp;\u003c/p\u003e \u003cp\u003eA significant increase in MMSE score was found in both the Memantine group and SLT group at all the time points compared with baseline. A significant improvement of MMSE between-group was observed only at weeks 8 and12, reflecting the effect of memantine on cognition (Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003e \u003cb\u003eTable\u0026nbsp;2 Within-group and between-group comparisons between baseline and scores on each time point from visit 1 to 4\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, the significant improvement on language and cognitive function over continuous 16 weeks period could been observed in both SLT group and Memantine group. It is notable that after 8 to 12 weeks of treatment, the WAB-AQ scores increased more significantly in Memantine group, that represented the speech and recognition improvement in PSA patients. Memantine combined with SLT is an effective method in post-stroke aphasia.\u003c/p\u003e \u003cp\u003eThe manifestations of aphasia is closely related to the location of ischemia or hemorrhage damage and the dominant hemisphere. From the pathophysiological mechanism, due to ischemia and hypoxia in the local brain tissue after ischemia and hemorrhage, edema, a large number of harmful substances are produced, such as free radicals and excitatory amino acids that was the primary mechanism for neuron death. The FDA approved memantine in 2003 for its use in moderate to severe Alzheimer\u0026rsquo;s disease. In the treatment of Alzheimer's disease in recent years, it has shown a relatively good effect, memantine can enhance neuronal synaptic plasticity in the brain, improve memory, and act as a neuroprotectant against the destruction of neurons caused by excitatory neurotransmitters [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Not only that, memantine hydrochloride has also shown good curative effects in basic studies of stroke animal models [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].In stroke studies, memantine has been proven to provide post-ischemic neuroprotection via multiple mechanisms, including inhibition of apoptosis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], NMDA inhibition mediated excitotoxicity [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], preserving intracellular ATP stores [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and increasing tissue concentration of neuron-specific growth factors [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe main performance of aphasia is difficulty in comprehension and expression, their abilities of communicating are limited, which decrease the effectiveness of rehabilitation training. Aphasia examination mainly includes six basic aspects: oral comprehension, spontaneous language expression, repeating, naming, reading, and writing. For many years an effort has been made to target language therapy techniques that help the recovery of patients with aphasia [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Treatment guidelines for aphasia recommend intensive speech and language therapy for aphasia after stroke [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e][\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e],but also with neuromodulation technology combined with speech therapy, Repetitive Transcranial Magnetic Stimulation(rTMS) and transcranial Direct Current Stimulation(tDCS) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Drug treatment of large-scale, class 1 randomized controlled trials specifically for aphasia after stroke are scarce. In this study, we investigated the effects of SLT, memantine combined with SLT in patients with subacute PSA. The results showed that the mean WAB-AQ increased from visit 1 to visit 4, indicating both methods can improve overall language function after 4\u0026ndash;16 weeks. But the improvement is more significant in Memantine group at week 8 to week 16. The effect of memantine was still continued during medicine washout period. The results of WAB-AQ subitem analysis showed that compared with SLT group, significant improvement in auditory comprehension-AQ at visit 1, auditory comprehension-AQ and spontaneous speech-AQ at visit 2,3,4 was observed in Memantine group. In the four follow-ups, the increase in MMSE scores was more obvious in the Memantine group, and there was a statistical difference compared with the control group at the second and third follow-up. We considered that there was no difference between groups in WAB-AQ at week 4 because the effect of memantine on aphasia recovery during a 3-week up-titration phase was unstable. These findings suggest that memantine combined with intensive speech and language therapy have a positive effect on the recovery of aphasia after subacute stroke, especially after eight weeks of continuous treatment.\u003c/p\u003e \u003cp\u003eStudies on stroke at different stages have shown controversial effects of drug therapy. In acute stroke studies, a case series study has shown that intravenous thrombolysis or endovascular therapy result in improvement of acute aphasia recovery[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. A study consisted of 33 subacute stroke patients suggests that speech and language therapy, 30\u0026ndash;60 minutes per day, 2 days a week, for 8 successive weeks, are effective in the treatment of subacute-stroke aphasic [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In chronic phase of stroke recovery, no study has provided evidence that pharmaceutical intervention results in significant improvement in chronic post-stroke aphasia in the absence of SLT [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. However, several trials have provided primary evidence that some medications may augment the effects of speech therapy. A plausible mechanism is that language recovery depends on neuroplasticity. Medications that alter the availability of neurotransmitters could enhance neuroplasticity [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].In a study of 27 patients with chronic post-stroke aphasia, constraint-induced aphasia therapy was beneficial when used combined with memantine 10 mg twice daily [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Meanwhile, no insufficient evidence to recommend an optimal dosage that would result in maximum treatment outcome. [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In this RCT study, SLT was performed 30min/each time, once/day, 5 times/week, totally 12 weeks, combined with memantine, post-stroke aphasia would improve significantly at the treatment beginning of 4 weeks compared with baseline and showed differences between groups at week 8 and week 12, lasted to the drug washout period, providing strong evidence on aphasia recovery after stroke.\u003c/p\u003e \u003cp\u003eThe shortcoming of this study is that this study is a single-center study. In the future, a larger multi-center study is needed to confirm its mechanism to help stroke patients recover their language function.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eFrom the above discussion, the conclusion can be reached that memantine combined with SLT are useful for improving non-fluency aphasia after stroke, especially spontaneous speech and auditory comprehension.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSLT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSpeech Language Therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMMSE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMini-Mental State Examination\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePSA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePost-Stroke Aphasia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAphasia Quotient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWAB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWestern Aphasia Battery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLSM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLeast-Square Mean of difference\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003erTMS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRepetitive Transcranial Magnetic Stimulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003etDCS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRepetitive Transcranial Direct Current Stimulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study\u0026nbsp;involving human participants was reviewed and approved by the China Rehabilitation Research Center Ethics Committee\u0026nbsp;(approval number: 2017-093-1) on Aug 10, 2017. The patients/participants provided their written informed consent to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from\u0026nbsp;every\u0026nbsp;patient for publication of this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupport for this study was provided by Funding-National Key R\u0026amp;D Program of China (2020YFC2004105).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions and information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC.J.Z.L is the first author and wrote the manuscript. X.X.D and L.P.S contributed equally to this work and should be considered co-corresponding authors. X.X.D is a primary corresponding author. H.X.M, Y.Y.T, R.S implemented and collected data. X.X.L was the clinical scale tester. Data were statistically analyzed by L.X, J.L, S.X. All authors discussed results, article, and approved the submitted version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to everyone who contributed to this study.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEngelter ST, Gostynski M, Papa S, Frei M, Born C, Ajdacic-Gross V, Gutzwiller F, Lyrer PA. Epidemiology of aphasia attributable to first ischemic stroke: incidence, severity, fluency, etiology, and thrombolysis. Stroke. 2006.doi: 10.1161/01.STR.0000221815.64093.8c.\u003c/li\u003e\n\u003cli\u003eLee H, Lee Y, Choi H, Pyun SB. 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DOI：10.1080/09638288.2020.1843079\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 Baseline characteristics of the Memantine group and SLT group.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eVariable\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003eMemantine group\u003c/p\u003e\n \u003cp\u003en = 25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003eSLT group\u003c/p\u003e\n \u003cp\u003en = 24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003ep value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eMean age (SE\u003csup\u003ea\u003c/sup\u003e) range, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e55.5 \u0026plusmn; 13.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e50.3 \u0026plusmn; 13.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eMale sex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e19 (38.8 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e19 (38.8 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eMean education (SE)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Junior middle school and below\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Senior middle school and above\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (18.4 %)\u003c/p\u003e\n \u003cp\u003e16 (32.7 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (16.3 %)\u003c/p\u003e\n \u003cp\u003e16 (32.7 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eAphasia duration (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e4.1 \u0026plusmn; 4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e4.3 \u0026plusmn; 4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eRight handedness, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e25(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e24(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eStroke types\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Infarctions\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Hemorrhages\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (22.4 %)\u003c/p\u003e\n \u003cp\u003e14 (28.6 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (24.5 %)\u003c/p\u003e\n \u003cp\u003e12 (24.5 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eGlasgow value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e14.2 \u0026plusmn; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e14.3 \u0026plusmn; 1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eMMSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e10.1 \u0026plusmn; 7.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e12.9 \u0026plusmn; 6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003eMean WAB-AQ\u003csup\u003eb\u0026nbsp;\u003c/sup\u003e(SE), range\u003c/p\u003e\n \u003cp\u003e(maximum = 100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e44.5 \u0026plusmn; 27.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e53.6 \u0026plusmn; 17.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;Spontaneous speech\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e8.3 \u0026plusmn; 5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e10.8 \u0026plusmn; 4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Auditory comprehension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e5.9 \u0026plusmn; 2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e7.1 \u0026plusmn; 2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Repetition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e5.4 \u0026plusmn; 4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e6.6 \u0026plusmn; 2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.67631103074141%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Naming\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.24231464737794%\" valign=\"top\"\u003e\n \u003cp\u003e2.7 \u0026plusmn; 2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.806509945750452%\" valign=\"top\"\u003e\n \u003cp\u003e2.7 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.2748643761302%\" valign=\"top\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e SE, standard error.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e WAB-AQ: Western Aphasia Battery-Aphasia Quotient\u003c/p\u003e\n\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"stroke, non-fluent aphasia, memantine, speech language therapy","lastPublishedDoi":"10.21203/rs.3.rs-4020634/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4020634/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAphasia is a common complication after stroke, and traditional speech or language therapy has a limited effect on post-stroke aphasia. This randomized, controlled, open-label study aimed to evaluate the effectiveness of intensive speech and language therapy together with memantine on speech and cognitive function in patients with non-fluent aphasia after stroke.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFifty post stroke non-fluent aphasia patients with unilateral left hemispheric infarction or hemorrhage were recruited and randomly divided into speech language therapy (SLT) group or Memantine group. The SLT group will receive only SLT treatment and placebo, while Memantine group will receive memantine combined with SLT treatment. Primary outcome measure will include the Western Aphasia Battery (WAB)-Aphasia Quotient from baseline to endpoint, Secondary outcomes measure will include Mini-Mental State Examination score. Assessment data were collected at baseline, Week4(Visit 1), Week 8 (Visit 2), Week 12 (Visit 3), and Week 16 (Visit 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn the basis of consistent baseline data, the language function of the two groups improved after treatment (p \u0026lt; 0.001). Compared with the control group, the memantine group had significant benefits in auditory comprehension-AQ at week 4 (p = 0.04), WAB-AQ (p = 0.04) and spontaneous speech-AQ(p = 0.006) at week 8, WAB-AQ(p = 0.01) and spontaneous speech-AQ(p \u0026lt; 0.001), auditory comprehension-AQ(p = 0.03) at week 12, WAB-AQ (p = 0.01) and spontaneous speech-AQ(p \u0026lt; 0.001), auditory comprehension-AQ(p = 0.04) at week 16. The increase in the change of MMSE scores was higher in Memantine group at week 8 (p = 0.04) and week 12(p = 0.048).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMemantine combined with SLT are useful for improving non-fluency aphasia after stroke, especially spontaneous speech and auditory comprehension. Cognitive function has also improved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003ewww.clinicaltrials.gov ; TRN: NCT00196703;\u003c/p\u003e","manuscriptTitle":"The efficacy of Memantine combined with Speech language therapy for post stroke non-fluent aphasia rehabilitation: A randomized controlled clinical study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-21 18:38:49","doi":"10.21203/rs.3.rs-4020634/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5ca6dac9-9dc1-49f2-b9bd-7a9b57e6a390","owner":[],"postedDate":"March 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-24T21:08:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-21 18:38:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4020634","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4020634","identity":"rs-4020634","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}