Effects of a Ginkgo biloba extract on cognitive functions.

Given the high incidence of stroke events and subsequent cognitive impairment, there is a great need for new therapeutic options that can be used in early post-stroke phases. A randomized multicenter trial in an open-label design investigated the effects of a standardized ginkgo preparation on cognitive function in patients after a recent mild or moderate ischemic stroke.

Several large population-based studies found that cognitive impairment manifested more rapidly in stroke victims compared with the normal population during long-term follow-up [1,2]. The underlying mechanisms, extent, and possible predictors are not fully understood to date. Other than brain stimulation techniques and physical activity, there are few options to date to treat cognitive decline in this patient population [3]. The ginkgo special extract EGb ^761® has already repeatedly demonstrated in humans blood circulation-promoting effects in the brain and an improvement in the blood’s flow properties [4]. In a meta-analysis published in 2015, Ginkgo biloba led to stabilization of cognitive performance or slowing of performance decline in individuals with cognitive impairment or dementia [5]. In a small randomized-controlled six-month trial of Ginkgo biloba in patients with vascular cognitive impairment ( VCI**) published in 2017, a positive effect could be observed with respect to the Clinical Global Impression scale (CGI) [6]. Moreover, there are findings from in vivo ischemia studies in which Ginkgo biloba reduced infarct size, neurological deficits, and motor dysfunction. With this in mind, it is natural to investigate the efficacy of EGb ^761® for the treatment of cognitive deficits in patients after ischemic stroke [7].

** VCI = any cognitive impairment associated with cerebrovascular injury or ischemic/hemorrhagic stroke.

Ginkgo biloba extract as add-on to standard treatment

For the present study, 201 patients aged ≥50 years who had suffered an ischemic stroke 7-14 days previously and scored ≤20 or less on the NIH (National Institutes of Health) stroke scale were recruited from seven Chinese medical centers [7]. Exclusion criteria included dementia diagnosed before stroke or other serious neurological disease (e.g., Parkinson’s disease, Huntington’s disease, Creutzfeldt-Jakob disease) and mental disorders (e.g., major depression, generalized anxiety disorder). All included patients received standard guideline-based treatment to prevent recurrent stroke, including general supportive care, antiplatelet agents, and measures for acute complications; nootropics were not allowed. 100 patients were randomly assigned to add-on treatment with 240 mg/d EGb ^761®, while 101 patients received standard treatment alone, without add-on therapy (=control group) [7]. Various relevant parameters were collected from all study participants during a follow-up period of 24 weeks.

Significant improvements manifested in the EGb ^761® group

At week 24, the Ginkgo group showed significant improvements in the Montreal Cognitive Assessment (MoCA) and other test domains compared with the KG (Table 1, Review 1) [7]:

MoCA total score: mean change since baseline was 2.92 vs. 1.33 (95% CI; 0.51-2.67; p<0.001). This corresponds to a performance 1.59 points better than in the KG. The mean change in the overall MoCA value was thus clearly in favor of the EGb ^761® group.
MoCA subscore delayed retrieval: change of 0.88 vs. 0.17 in the KG (95% CI; 0.31-1.10; p<0.001).
MoCA subscore orientation: change of 0.28 vs -0.11 in the KG (95% CI; 0.18-0.60; p<0.001).
MoCA subscore language: change of 0.45 versus 0.09 in the KG (95% CI; 0.06-0.66; p<0.05).
Hopkins Verbal Learning Test (Total Recall): 1.89 points more improvement than KG (p<0.05)
Shape Trail Test-Trail 1: 22.6 points better improvement than KG (p<0.05)

Furthermore, in the EGb 761^® group, a proportion of 80.2% achieved a great or very great improvement in the Clinical Global Impression of Change scale (CGI-C) compared to baseline. In the control group (KG), this was true for only 20.8% of patients. In contrast, some tests showed no significant differences between the EGb 761^® group and the KG at week 24: Shape Trail Test Trail 2, Verbal Fluency Test, Digit Symbol Substitution Test of the Wechsler Adult Intelligence Scale-Revised, Hospital Anxiety and Depression Scale, neuropsychiatric index.

Beneficial risk-benefit profile

The incidence of adverse events was similar in both study arms [7]. It was 11.1% in the EGb 761^® group and 9.9% in the KG. Nasopharyngitis was reported most frequently, affecting 3% of each of the two study arms. Most adverse events were mild to moderate, with a total of five serious adverse events reported: one patient each with cerebral infarction and chronic renal failure in the EGb ^761® group; in the KG, two cerebral infarctions occurred in one patient, and a lacunar infarction in another. A causal relationship with treatment could not be excluded in the following cases: Skin rash, dizziness (possibly treatment-related), and chronic renal failure (association with treatment unlikely). While there was evidence in several previously published studies that EGb ^761® may increase bleeding risk [8,9]In the present study, the results support the assumption that the use of EGb 761^® at a dose of 240 mg/d over a period of 24 weeks has a favorable effect on cognitive performance, but without increasing the risk of bleeding. This is consistent with studies showing that taking EGb ^761®paralell to anticoagulants/antiplatelets does not increase the risk of bleeding [19,20].

Conclusion
Consistent with previous findings, the results of the present study indicate that EGb 761^® at a dose of 240 mg/d for 24 weeks is a valid, well-tolerated treatment option for alleviating cognitive symptoms and improving quality of life in patients after ischemic stroke [7]. EGb 761^® was found to result in slight improvements in cognitive performance, mainly reflected in a greater increase in MoCA scores compared to the control group. The Montreal Cognitive Assessment (MoCA) has been shown to be a sensitive measure to map changes in cognitive functions, especially regarding executive deficits, which have prognostic relevance for cognitive impairment after stroke [14,15]. In this study, only patients with mild neurological disorders were included. In general, it can be stated that drug interventions in an early phase of cognitive impairment are more sustainable with regard to the maintenance of corresponding functional domains [16,17]. Ginkgo biloba extract contains several components that have been shown to stimulate blood flow to the brain, reduce oxidative stress, and increase neurotransmitter activity (e.g., acetylcholine), which is relevant to learning and memory functions [18]. In summary, the authors hold that the neuroprotective effects of EGb 761^® have a modest but consistent beneficial effect on slowing or stabilizing the progression of cognitive impairment when ginkgo extract is used early enough.

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