Efficacy and safety of choline alphoscerate for amnestic mild cognitive impairment: a randomized double-blind placebo-controlled trial.

BACKGROUND: Effective interventions for overall healthy subjects with mild cognitive impairment are currently limited. Choline alphoscerate (alpha glyceryl phosphorylcholine, αGPC) is a choline-containing phospholipid used to treat cognitive function impairments in specific neurological conditions. This study aimed to investigate the efficacy and safety of αGPC in individuals diagnosed with mild cognitive impairment. METHODS: In this multicenter, randomized, placebo-controlled trial, 100 study subjects with mild cognitive impairment underwent a double-blind SHCog™ soft capsule (600 mg αGPC) or placebo treatment for 12 weeks. The primary efficacy outcome included changes from baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Safety assessments included regular monitoring of adverse events, and clinical laboratory tests were conducted at baseline and the end of the trial. RESULTS: After 12 weeks of αGPC treatment, the ADAS-cog score decreased by 2.34 points, which was significantly greater than the change observed in the placebo group. No serious AEs were reported, and no study subjects discontinued the intervention because of AEs. There was no significant difference in incidence rate of AEs between the αGPC group and the placebo group. CONCLUSION: This study suggests that αGPC is a safe and effective intervention for improving cognitive function in study subjects with mild cognitive impairment. TRIAL REGISTRATION: Clinical Research Information Service; Osong (Chungcheongbuk-do): Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); KCT0008797; A 12-week, multicenter, randomized, double-blind, placebo-controlled human application study to evaluate the efficacy and safety of SH_CAPK08 on cognitive function improvement in mild cognitive decline.

The Nutritional Supplement L-Alpha Glycerylphosphorylcholine Promotes Atherosclerosis.

L-alpha glycerylphosphorylcholine (GPC), a nutritional supplement, has been demonstrated to improve neurological function. However, a new study suggests that GPC supplementation increases incident stroke risk thus its potential adverse effects warrant further investigation. Here we show that GPC promotes atherosclerosis in hyperlipidemic Apoe-/- mice. GPC can be metabolized to trimethylamine N-oxide, a pro-atherogenic agent, suggesting a potential molecular mechanism underlying the observed atherosclerosis progression. GPC supplementation shifted the gut microbial community structure, characterized by increased abundance of Parabacteroides, Ruminococcus, and Bacteroides and decreased abundance of Akkermansia, Lactobacillus, and Roseburia, as determined by 16S rRNA gene sequencing. These data are consistent with a reduction in fecal and cecal short chain fatty acids in GPC-fed mice. Additionally, we found that GPC supplementation led to an increased relative abundance of choline trimethylamine lyase (cutC)-encoding bacteria via qPCR. Interrogation of host inflammatory signaling showed that GPC supplementation increased expression of the proinflammatory effectors CXCL13 and TIMP-1 and activated NF-κB and MAPK signaling pathways in human coronary artery endothelial cells. Finally, targeted and untargeted metabolomic analysis of murine plasma revealed additional metabolites associated with GPC supplementation and atherosclerosis. In summary, our results show GPC promotes atherosclerosis through multiple mechanisms and that caution should be applied when using GPC as a nutritional supplement.

Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years.

Importance: L-α glycerylphosphorylcholine (α-GPC, choline alphoscerate) is used globally by individuals older than 50 years based on its potential function as a precursor of acetylcholine. However, choline has previously been linked to a higher risk of cardiovascular disease via trimethylamine-N-oxide, a metabolite of choline by microbiota. Objective: To investigate the association between α-GPC use and subsequent 10-year stroke risk. Design, Setting, and Participants: A population-based, retrospective cohort study was conducted using data from the National Health Insurance Service of South Korea. Participants included men and women aged 50 years or older without underlying stroke or Alzheimer disease (N = 12 008 977). Main Outcomes and Measures: All participants were divided into whether they were prescribed α-GPC during 2006-2008. α-GPC users were matched with nonusers for all covariates to create a matched cohort. α-GPC use was further divided into durations less than 2, 2 to 6, 6 to 12, and more than 12 months of α-GPC prescriptions. The adjusted hazard ratios (aHRs) and 95% CIs for total stroke, ischemic stroke, and hemorrhagic stroke from January 1, 2009, to January 31, 2018, were calculated by multivariate Cox proportional hazards regression. Results: A total of 12 008 977 individuals (6 401 965 [53.3%] women) aged 50 years or older were included in the study. The mean (SD) age was 61.6 (9.4) years for nonusers and 68.3 (10.0) years for users, and that of the matching cohort was 68.2 (9.9) years for both groups. Compared with α-GPC nonusers (n = 11 900 100), users (n = 108 877) had a higher risk for total stroke (aHR, 1.46; 95% CI, 1.43-1.48), ischemic stroke (aHR 1.36; 95% CI, 1.33-1.39), and hemorrhagic stroke (aHR, 1.36; 95% CI, 1.28-1.44). After matching for all covariates, α-GPC users had a higher risk for total stroke (aHR, 1.43; 95% CI, 1.41-1.46), ischemic stroke (aHR, 1.34; 95% CI, 1.31-1.37), and hemorrhagic stroke (aHR, 1.37; 95% CI, 1.29-1.46). Increasing intake of α-GPC was associated with a higher risk for total stroke in a dose-response manner. Conclusions and Relevance: In this cohort study, use of α-GPC was associated with a higher 10-year incident stroke risk in a dose-response manner after adjusting for traditional cerebrovascular risk factors. Future studies are needed to determine the possible mechanisms behind the potential cerebrovascular risk-elevating effects of α-GPC.

Efficacy and Safety of the Association of Nimodipine and Choline Alphoscerate in the Treatment of Cognitive Impairment in Patients with Cerebral Small Vessel Disease. The CONIVaD Trial.

BACKGROUND: No approved treatment is available for patients with vascular cognitive impairment (VCI) due to cerebral small vessel disease (SVD). OBJECTIVE: The CONIVaD (Choline Alphoscerate and Nimodipine in Vascular Dementia) study aimed to investigate the feasibility, efficacy, and safety of a combined treatment with choline alphoscerate and nimodipine in patients with SVD and mild-to-moderate cognitive impairment. METHODS: Within this pilot, single-center (university hospital), double-blinded, randomized clinical trial, patients were randomized to two arms: 1-year treatment with nimodipine 30 mg three times a day (TID) plus choline alphoscerate 600 mg twice a day (BID) (arm 1) or nimodipine 30 mg TID plus placebo BID (arm 2). Patients underwent an evaluation at baseline and after 12 months. Cognitive decline, defined as a ≥ 2-point loss on the Montreal Cognitive Assessment, was the primary endpoint. Functional, quality of life, other cognitive measures, and safety were secondary endpoints. Treatment adherence was measured by the count of medicine bottles returned by patients. RESULTS: Sixty-two patients were randomized (31 each arm). Fourteen patients (22%) dropped out for reasons including consent withdrawal (n = 9), adverse reactions (n = 4), and stroke (n = 1). Forty-eight patients (mean ± SD age 75.1 ± 6.8 years), well balanced between arms, completed the study. Regarding adherence, of the prescribed total drug dose, > 75% was taken by 96% of patients for choline alphoscerate, 87.5% for placebo, and 15% for nimodipine. No statistically significant differences were found between the treatment groups for the primary cognitive outcome, nor for the secondary outcomes. Eight patients had non-serious adverse reactions; five presented adverse events. CONCLUSION: Patients' adherence to treatment was low. With this limitation, the combined choline alphoscerate-nimodipine treatment showed no significant effect in our cohort of VCI patients with SVD. The safety profile was good overall. TRIAL REGISTRATION: Clinical Trial NCT03228498. Registered 25 July 2017.

Choline and Choline alphoscerate Do Not Modulate Inflammatory Processes in the Rat Brain.

Choline is involved in relevant neurochemical processes. In particular, it is the precursor and metabolite of acetylcholine (ACh). Choline is an essential component of different membrane phospholipids that are involved in intraneuronal signal transduction. On the other hand, cholinergic precursors are involved in ACh release and carry out a neuroprotective effect based on an anti-inflammatory action. Based on these findings, the present study was designed to evaluate the effects of choline and choline precursor (Choline alphoscerate, GPC) in the modulation of inflammatory processes in the rat brain. Male Wistar rats were intraperitoneally treated with 87 mg of choline chloride/kg/day (65 mg/kg/day of choline), and at choline-equivalent doses of GPC (150 mg/kg/day) and vehicle for two weeks. The brains were dissected and used for immunochemical and immunohistochemical analysis. Inflammatory cytokines (Interleukin-1ß, IL-1ß; Interleukin-6 , IL-6 and Tumor Necrosis Factor-α, TNF-α) and endothelial adhesion molecules (Intercellular Adhesion Molecule, ICAM-1 and Vascular cell Adhesion Molecule, VCAM-1) were studied in the frontal cortex, hippocampus, and cerebellum. The results clearly demonstrated that treatment with choline or GPC did not affect the expression of the inflammatory markers in the different cerebral areas evaluated. Therefore, choline and GPC did not stimulate the inflammatory processes that we assessed in this study.

[Detection of effective treatment of amnestic mild cognitive impairement with cereton by testing of lipids markers]. / Issledovanie éffektivnosti tseretona pri miagkom kognitivnom snizhenii amnesticheskogo tipa na osnove testirovaniia markerov lipidnoi prirody.

AIM: Determination of effectivity and safety of Cereton (Choline alfoscerate, production by Sotex) 1200 mg/day in the treatment of cognitive functioning disorders in patients with amnestic mild cognitive impairment (aMCI) and determining its influence in the process (after a 3 month course of taking the drug) and 3 months after the end of treatment of aMCI on the change in the content of phosphatidylcholine, sphingomyelin, ceramide-metabolite sphingolipids and the activity of genes controlling the synthesis of enzymes, which control ithe metabolism of sphingomyelin and ceramide (sphingomyelinase and ceramidase). MATERIAL AND METHODS: The study involved a group of elderly patients (20 people), consisting of 14 women and 6 men, aged 51 to 82 years (mean age 70.3±9.1 years). The patients' condition met the criteria for diagnosing aMCI syndrome. Analysis of phosphatidylcholine, sphingomyelin and ceramide in the blood plasma of patients was carried out by thin layer chromatography, expression of sphingomyelinase and ceramidase genes by RtPCR. RESULTS AND CONCLUSION: A sharp increase in the content of phosphatidylcholine and ceramide, the product of sphingomyelin hydrolysis, was detected. Expression of genes (acidic sphingomyelinase and ceramidase), controlling the metabolism of ceramide, is significantly reduced in the majority of patients in the treatment with ceretone. An increase in the level of phosphatidylcholine and a decrease in the expression level of the ceramide metabolism genes during treatment with ceretone and other drugs that affect the metabolism of phosphatidylchodine and sphingolipids can be used as markers of the effectiveness of therapy.

[Centrally acting cholinomimetics in the complex therapy of progressive glaucomatous optic neuropathy].

UNLABELLED: Many factors exist that are associated with higher risk of glaucoma progression. Arterial hypotension, low perfusion pressure, vasospastic syndrome, diabetes mellitus, myopia, etc. increase the need for neuroprotective therapy, which is aimed at stabilizing the pathological process and creating favorable conditions for maintaining visual functions. The aim of this study was to assess the therapeutic efficacy of Gliatilin as part of the complex treatment of progressive glaucomatous optic neuropathy. MATERIAL AND METHODS: A total of 240 patients were randomly selected and divided into 2 groups, 120 patients each. Both groups were matched for age, somatic comorbidity, and the gravity of the glaucomatous process. Patient age averaged 71.3±1.6 years. Advanced glaucoma prevailed in both groups: 70.0 and 76.6% correspondingly. Neuroprotective therapy included drugs from different pharmacological classes so that different aspects of pathogenesis were addressed. Apart from that, patients from Group I first received intravenous Gliatilin (1000 mg/4ml, 12--15 doses) and then switched to oral (1 capsule b.i.d. for 4 months). All patients underwent standard ophthalmic examination and static perimetry. RESULTS: No adverse effects were observed over the first two weeks of Gliatilin course, during which the patients stayed in the hospital. IOP level was normal and stable. Although neuroprotective therapy does not directly affect IOP, stability of the latter describes the dynamics of the glaucomatous process. When assessing changes in visual functions, particular attention was paid to the central visual field, foveolar and total light sensitivity, peripheral visual field, and MD and PSD indices. All mean values showed a tendency toward improvement, more pronounced in the Gliatilin group. CONCLUSION: A complex therapy cannot be limited to a single drug only, and to make better decisions, one should consider not only ocular, but also general condition of the patient. Adjuvant Gliatilin in the complex therapy of progressive glaucoma is appropriate and efficient, especially in case of systemic atherosclerosis and cerebrovascular insufficiency. The frequency of stabilization therapy depends on the efficacy of the latest course and clinical manifestations of the glaucomatous process.

[The use of cereton in patients with chronic brain ischemia and moderate cognitive impairment].

OBJECTIVE: To study the efficacy and safety of cereton in the treatment of patients with chronic brain ischemia and moderate cognitive impairment. MATERIAL AND METHODS: The study included 25 patients, 16 women and 9 men, mean age 53,8 ± 1,3 years. Moderate cognitive impairment measured with MMSE and HADS was found in all patients. Quality of life was assessed with SF-36. Somatic and neurological studies as well as brain MRI were carried out. Inpatients received cereton in dose 1000 mg in 200 ml of physiological solution during 15 days, after the discharge from the hospital patients received 1 capsule three times a day during 3 months. RESULTS AND СONCLUSION: Cereton had a significant positive effect on patient's condition including cognitive function. Subjective effect was recorded after 5-6 days of treatment, more evident and stable effect was seen from the 15th day. In the end of treatment, clinicians recorded "moderate" effect in 11 patients and "marked" effect in 8 patients (according to patients' reports, those effects were noted in 9 and 12 cases, respectively). The drug was well-tolerated and had a positive effect on quality of life of the patients.

[The use of cerepro (choline alfoscerate) in the treatment of outpatients with chronic progressive cerebrovascular disease].

The main aim of the study was the evaluation of the efficacy and drug safety of cerepro (choline alfoscerate) used for treating outpatients with cerebrovascular disease. Ninety patients with cerebrovascular disease, who had motor, coordination, emotional and cognitive disturbances were enrolled in the study. Sixty patients of the group 1 had stroke, 30 patients (group 2) had chronic ischemic brain disease. All patients received basic therapy (antihypertensive, antiaggregant or anticoagulant, cholesterol-lowering drugs). Cerepro was administrated in combined therapy according to the scheme: 1000 mg cerepro (in 200 ml of the 0.9% NaCl solution) once a day intravenously in drops during 10 days; then 1200 mg daily per os during 6 weeks. We assessed the dynamic of neurological symptoms and restoration of lost functions (MMSE, Feeling-activity-mood test, HDRS, GCI). The results indicate the efficacy of cerepro in outpatients with chronic cerebrovascular disease and stroke. It was demonstrated that cerepro led to improvement of coordination neurological symptoms, cognitive and emotional functions, activity and mood in patients of both groups. Clinical effect was higher in patients after stroke. Cerepro was well tolerated.

Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Parallel with the development of hypotheses regarding cholinergic involvement in geriatric memory dysfunction, the first attempts to treat patients with Alzheimer's disease (AD) involved the cholinergic-precursor loading approach. Despite encouraging early results, well-controlled clinical trials did not confirm a clinical utility of cholinergic precursors such as choline and lecithin (phosphatidylcholine) in AD. OBJECTIVE: This study assessed the efficacy and tolerability of the cholinergic precursor choline alfoscerate (CA) in the treatment of cognitive impairment due to mild to moderate AD. METHODS: In this multicenter, double-blind, randomized, placebo-controlled trial, patients affected by mild to moderate dementia of the Alzheimer type were treated with CA (400-mg capsules) or placebo capsules, 3 times daily, for 180 days. Efficacy outcome measures that were assessed at the beginning of the investigation and after 90 and 180 days of treatment included scores of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Mini-Mental State Examination (MMSE), the Global Deterioration Scale (GDS), the Alzheimer's Disease Assessment Scale-Behavioral Subscale (ADAS-Behav), all items of the Alzheimer's Disease Assessment Scale (ADAS-Total), and the Clinical Global Impression (CGI) scale. The Global Improvement Scale (GIS) score was assessed after 90 and 180 days of treatment. RESULTS: A total of 261 patients (132 in the CA group, 129 in the placebo group) were enrolled in the study. The mean (SD) age in the CA group was 72.2(7.5) years (range, 60-80 years), and in the placebo group it was 71.7 (7.4) years(range, 60-80 years). The CA group comprised 105 women and 27 men; the placebo group, 94 women and 35 men. The mean decrease in ADAS-Cog score in patients treated with CA was 2.42 points after 90 days of treatment and 3.20 points at the end of the study (day 180) (P < 0.001 vs baseline for both), whereas in patients receiving placebo the mean increase in ADAS-Cog score was 0.36 point <1 after 90 days of treatment and 2.90 points after 180 days of treatment(P < 0.001 vs baseline). In the CA group, all other assessed parameters (MMSE,GDS, ADAS-Behav, ADAS-Total, and CGI) consistently improved after 90 and 180 days versus baseline, whereas in the placebo group they remained unchanged or worsened. Statistically significant differences were observed between treatments after 90 and 180 days in ADAS-Cog, MMSE, GDS, ADAS-Total, and CGI scores and after 180 days of treatment in ADAS-Behav and GIS scores. CONCLUSION: The results of this study suggest the clinical usefulness and tolerability of CA in the treatment of the cognitive symptoms of dementia disorders of the Alzheimer type.

[Preliminary evaluation of risk and effectiveness of early choline alphoscerate treatment in craniocerebral injury]. / Wstepna ocena ryzyka oraz skutecznosci wczesnego wlaczenia alfosceranu choliny w leczeniu urazów czaszkowo-mózgowych.

UNLABELLED: Pharmacological treatment of craniocerebral injuries (CCI) to a large extent involves correction of metabolic disturbances resulting from primary and secondary mechanisms of trauma. Choline alphoscerate (CA), a substrate of phosphatydylocholine and a carrier of choline, plays a major role in phospholipidic transformation of the neuronal cell wall. OBJECTIVE: To goal of the study was to evaluate the risk and efficacy of early CA treatment in patients with CCI. MATERIAL: Twenty three CCI patients were treated with CA in the years 2001-2002. In 8 cases an acute subdural haematoma with multiple hemorrhagic foci was diagnosed. Six patients were diagnosed with cerebral contusion with multiple hemorrhagic foci, while 9 patients suffered from concussion of the brain. The patients' condition was assessed at admission using the adult trauma score (ATS)--11 patients scored 8 points on the ATS, 4 patients scored 9, and 8 patients scored 11 points. METHODS: The inclusion criterion was the patient's clinical status at admission in the range 8-11 ATS points. CA was administered according to the following schedule: 1.0 g/d i.m. for 14 days, then 0.8 g/d orally for the next 28 days. AC (Gliatilin) produced by Italfarmaco was used in the study. The cost of this CA treatment was estimated by the producer at PLN 424. RESULTS: After three months of the treatment an improvement was noted in 96% of the patients. Fourteen patients were independent and professionally active, another five were independent, but did not work, while three patients required permanent care. One patient died because of pneumonia. No complications due to the CA treatment were observed in the group studied. CONCLUSIONS: Early treatment with CA is safe and as a component of complex pharmacotherapy has a beneficial effect on the treatment outcome in CCI patients.

alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial.

The clinical efficacy and the tolerability of alpha-glycerophosphocholine (alpha-GPC), a drug able to provide high levels of choline for the nervous cells of the brain and to protect their cell walls, have been tested in a clinical open multicenter trial on 2044 patients suffering from recent stroke or transient ischemic attacks. alpha-GPC was administered after the attack at the daily dose of 1000 mg im for 28 days and orally at the dose of 400 mg tid during the following 5 months after the first phase. The evaluation of the efficacy on the psychic recovery was done by the Mathew Scale (MS) during the period of im drug administration, and using the Mini Mental State Test (MMST), the Crichton Rating Scale (CRS), and the Global Deterioration Scale (GDS) during the following period of oral administration. The MS mean increased 15.9 points in 28 days in a statistically significant way (p < 0.001) from 58.7 to 74.6. At the end of the 5 month oral administration, the CRS mean significantly decreased 4.3 points, from 20.2 to 15.9 (p < 0.001); the MMST mean significantly increased (p < 0.001) from 21 to 24.3 at the end of the trial, reaching the "normality" score at the 3rd month assessment. The GDS score at the end of the trial corresponded to "no cognitive decline" or "forgetfulness" in 71% of the patients. Adverse events were complained of by 44 patients (2.14%); in 14 (0.7%) the investigator preferred to discontinue therapy. The most frequent complaints were heartburn (0.7%), nausea-vomit (0.5%), insomnia-excitation (0.4%), and headache (0.2%). The trial confirms the therapeutic role of alpha-GPC on the cognitive recovery of patients with acute stroke or TIA, and the low percentage of adverse events confirms its excellent tolerability.

Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with probable senile dementia of Alzheimer's type.

A multicentre, randomised, controlled study compared the efficacy of l-alpha-glyceryl-phosphorylcholine (alpha GPC) and ST200 (acetyl-l-carnitine) among 126 patients with probable senile dementia of Alzheimer's type (SDAT) of mild to moderate degree. Efficacy was evaluated by means of behavioural scales and psychometric tests. The results showed significant improvements in most neuropsychological parameters in the alpha GPC recipients. Improvements also occurred in the ST200 recipients but to a lesser extent. Tolerability was good in both groups. These positive findings require replication in larger, double-blind, longitudinal studies coupling clinical and biological determinations.