Strategies for the use of Ginkgo biloba extract, EGb 761®, in the treatment and management of mild cognitive impairment in Asia: Expert consensus

Abstract Background Mild cognitive impairment (MCI) is a neurocognitive state between normal cognitive aging and dementia, with evidence of neuropsychological changes but insufficient functional decline to warrant a diagnosis of dementia. Individuals with MCI are at increased risk for progression to dementia; and an appreciable proportion display neuropsychiatric symptoms (NPS), also a known risk factor for dementia. Cerebrovascular disease (CVD) is thought to be an underdiagnosed contributor to MCI/dementia. The Ginkgo biloba extract, EGb 761®, is increasingly being used for the symptomatic treatment of cognitive disorders with/without CVD, due to its known neuroprotective effects and cerebrovascular benefits. Aims To present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761® in MCI. Materials & Methods The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, including the efficacy and safety of EGb 761® as a treatment option. Results EGb 761® has demonstrated symptomatic improvement in at least four randomized trials, in terms of cognitive performance, memory, recall and recognition, attention and concentration, anxiety, and NPS. There is also evidence that EGb 761® may help delay progression from MCI to dementia in some individuals. Discussion EGb 761® is currently recommended in multiple guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761® may benefit MCI patients with underlying CVD. Conclusion As an expert group, we suggest it is clinically appropriate to incorporate EGb 761® as part of the multidomain intervention for MCI.


| INTRODUC TI ON
The global burden of cognitive disorders is rapidly becoming a major chronic health issue worldwide. Currently, approximately 50 million individuals are living with dementia, and this number is expected to approximately double in the next two decades, with much of the increase likely to be attributable to low-to-middle income countries, particularly within Asia. 1 As well as dementia sufferers, a great many more elderly individuals have less pronounced, but nonetheless distressing, signs of cognitive decline and memory loss. 2,3 Mild cognitive impairment (MCI) is a clinically defined neurocognitive state between normal cognitive aging and dementia, with evidence of neuropsychological changes but without sufficient functional decline to warrant a diagnosis of dementia. 4,5 Individuals with MCI are at increased risk for progression to dementia, 3,6-9 but only a small proportion of these patients are likely to present for diagnosis and treatment. Hence, there is a need to raise greater awareness of this syndrome and its management. 4 The current prevalence of MCI is difficult to establish due to a lack of standardized diagnostic criteria and assessment procedures. 2,10 Estimates vary depending on the country, the diagnostic criteria used, and the age of the study population. 10,11 MCI prevalence increases with advancing cohort age; it is estimated that 6.7% of individuals aged 60-64 have MCI, increasing to 8.4% for ages [65][66][67][68][69]10.1% for ages [70][71][72][73][74]14.8% for ages 75-79, and 25.2% for ages 80-84. 3 Depending on the arbitrary criteria used to define MCI, the global prevalence of MCI is reported to be approximately threefold higher than the global prevalence of dementia (5%-7% in all individuals over 60 years of age). 12 Asian data suggest an overall MCI standardized prevalence of around 5%-20%, depending on the country, the age of the cohort, and the criteria applied. 11,[13][14][15][16][17][18] A recent meta-analysis of 48 studies from China reported a pooled prevalence of 14.7% in individuals aged ≥60 years. 18 Overall, these MCI data are approximately double the reported prevalence of dementia across various Asian countries (2%-13%). 19,20

| Definition of MCI
Making a distinction between normal cognitive aging and MCI remains a clinical challenge. Following subjective memory complaints, a diagnosis requires the use of validated tools for cognitive testing and functional assessment. 21 Historically, the criteria for MCI have included subjective complaints and objective cognitive impairments in domains such as memory, executive functioning, attention, language, and visuospatial skills, but without impairment in function or activities of daily living (ADL). 2,6,22 However, more recently, it is acknowledged that subtle deficits in more complex instrumental ADL may indeed be present in patients with MCI. 6,23 Two broad subtypes of MCI (amnestic and nonamnestic) are recognized, based on whether or not memory impairment is present. Depending on whether more than one domain is impaired, both subtypes can be further categorized as either single domain or multidomain. 24

| Neuropsychiatric symptoms in MCI
Neuropsychiatric symptoms (NPS), also known as "noncognitive behavioral and psychological symptoms of dementia," may include depression, anxiety, irritability, apathy, and changes in personality or usual behaviors. [25][26][27] NPS are observed across the severity spectrum of dementia, and are common in patients with MCI. 25,26 Reports are variable, but between 35% and 85% of MCI patients may display NPS. [25][26][27][28] The presence of NPS in MCI increases the caregiver's burden 29 and is also associated with an increased risk of incident dementia. 30-32

| Pathophysiology of MCI
Pathologic evidence of Alzheimer's disease (AD) has been observed in individuals with memory impairment but no clinical manifestation of AD, indicating that the degenerative process may begin years before clinical manifestation. [33][34][35] The pathophysiology of ageassociated memory disorders appears to be multifactorial. Across the spectrum of age-related memory and cognitive disorders, neurodegenerative changes (ie, synaptic deficits and neuronal loss) and histopathological alterations (ie, increased production of β-amyloid leading to extracellular amyloid-containing plaques, and formation of intracellular hyperphosphorylated tau-protein tangles) have been observed. 36 Impaired cerebral glucose metabolism in memoryrelated brain regions has also been reported. 37 There is increasing evidence that mitochondrial dysfunction, in terms of reduced mitochondrial enzyme function and increased oxidative stress, is a major pathomechanistic contributor to these findings. 36 As well as neurodegenerative brain changes, vascular pathologies such as small vessel disease (eg, ischemic white matter changes, multiple lacunar infarcts), large vessel disease (eg, multiple infarcts, single strategically placed infarcts), or hemorrhage (eg, multiple microbleeds) have been frequently reported in dementia, and may be evident before overt clinical symptoms arise. 38

| Risk of progression from MCI to dementia
Because MCI is a known risk factor for, and an early manifestation of, dementia and other neurodegenerative disorders, 3,6-9 early, accurate diagnosis of MCI represents an important opportunity for therapeutic intervention. 2,3,22 The rate of progression to dementia has been estimated at between 10% and 19% per year in individuals with MCI, compared with 1%-2% in the general population. 3,22,[43][44][45] Consistent with this, a large systematic review reported MCI-to-dementia progression rates of 10%-36% over 2 years, 43 while the German AgeCoDe study reported that approximately 40% of patients aged ≥75 years with amnestic MCI progressed to dementia over 3 years of follow-up. 46 In a large, prospective Australian study, over 30% of individuals with MCI (mean age, 76 years) transitioned to AD within an 18-month follow-up period. 47 Although between 15% and 50% of patients may revert to normal cognition after a diagnosis of MCI, 3,46,48 these individuals remain at significantly higher risk of MCI re-diagnosis and ultimate progression to dementia. 3,48 It is important to identify MCI patients who are at higher risk for dementia, to ensure early intervention. As well as the presence of NPS, 30-32 risk factors such as age, 45 diabetes mellitus, 30 baseline memory impairment, 33,49 sharp decline in functional ability, 49 impaired executive performance, 33 and instrumental ADL deficits 23 may increase the likelihood of further cognitive decline. A number of biomarkers such as hippocampal volume, medial temporal lobe cortical thickness, and indicators of CVD such as infarcts, white matter hyperintensities, lacunes, and microbleeds, have all shown an association with progression to dementia. 33,45,49 The knowledge that CVD markers may serve as prognostic indicators for further cognitive decline underlines the importance of managing vascular risk factors to slow the progression of MCI to dementia. 41,50,51

| Ginkgo biloba extract, EGb 761 ®
EGb 761 ® is a dry extract from the leaves of the Ginkgo biloba plant, derived through a proprietary process. Depending on local regulatory frameworks across Asia, EGb 761 ® may be either classified as a drug, a supplement, or a phytopharmaceutical. This extract has increasingly been used over the past two decades for the symptomatic treatment of cognitive disorders, including AD with or without CVD. [52][53][54][55][56][57] A recent comprehensive review reported that EGb 761 ® improved cognitive performance across the spectrum of age-associated cognitive disorders, from age-associated memory complaints through to AD and vascular dementia (VaD). 36 EGb 761 ® exhibits various beneficial properties, although its mechanism of action in cognitive disorders is not yet fully understood. Preclinical evidence suggests that EGb 761 ® has profound effects on mitochondrial function via several mechanisms, including potent antioxidant activity. 36 This agent has been shown to reduce oxidative cell damage through reducing mitochondrial production of reactive oxygen species, due to its high levels of antioxidants (flavonoids and terpenoids). 36,58 EGb 761 ® also protects neurons from amyloid-beta (Aβ)-induced toxicity through inhibiting the formation of Aβ oligomers, 36,59 and affects the insulin receptor by influencing acetylcholine reduction. 36,[60][61][62] Secondary to these important properties, EGb 761 ® appears to have profound effects on neuronal function, neuroplasticity, neuroregeneration, and neuroinflammation, 36,60 and positively influences synaptic plasticity and brain functions that require high amounts of cellular energy. 36 Additionally, evidence suggests that EGb 761 ® increases cerebral blood flow and brain perfusion by decreasing cerebral blood viscosity, and protects cerebral blood vessels against processes involved in atherosclerosis. [63][64][65][66] EGb 761 ® has also been shown to increase dopamine levels in the prefrontal cortex. 67 Thus, the known mechanisms of action of EGb 761 ® provide strong rationale for its use in age-related cognitive disorders. 36,58,60-62

| Rationale for this article
The ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) consists of more than twenty members, primarily from the Asian region. The group first convened in 2017, and consists of experts from various specialties, including neurology, geriatrics, psychiatry, and pharmacy.
Following the first meeting, the ASCEND group published a set of evidence-based regional consensus recommendations on the use of EGb 761 ® in the treatment of dementia and MCI with or without CVD. 58 Among the core consensus statements published, the ASCEND Expert Group recommended the use of EGb 761 ® 240 mg/day as part of the treatment approach for AD (±CVD), VaD, and mixed dementia, with or without NPS. It was further agreed that EGb 761 ® might be considered for use in patients with MCI (Class IIB recommendation; Level A evidence). 58 These recommendations are consistent with a number of current guidelines and consensus documents from around the world, including Asia, that support the use of EGb 761 ® for the treatment of MCI symptoms. 58,[68][69][70][71][72] The purpose of this article is to expand upon these recommendations, with a specific focus on the role of EGb 761 ® in the management of MCI. The potential role of EGb 761 ® in slowing cognitive decline is also discussed.

| ME THODS
The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, particularly with respect to the clinical efficacy and safety of EGb 761 ® as a treatment option for MCI. The preplanned output from the meeting was the construction of another regional consensus document to assist Asian countries in formulating strategies to improve the treatment and management of MCI.

| General principles of MCI management
Ideally, goals of treatment for dementia-and indeed for MCI-are improvement of cognitive function and psychological and behavioral symptoms, stabilization or slowing of disease progression, improvement of quality of life (QoL), and alleviation of caregiver burden. 19 As mixed pathology is common in MCI, a multidomain management approach that benefits both neurodegenerative and vascular pathology is a rational strategy. 73 Based on the literature and clinical experience, the ASCEND Expert Group recommends that clinicians first assess for reversible causes of subjective cognitive impairment (SCI), such as depression, medications, alcohol use disorders, or hearing loss, and manage these appropriately. 3,74 Validated neurocognitive and functional assessment tools should be used for the diagnosis and monitoring of MCI in individuals with persistent memory complaints. 3 Other investigations may include a blood panel and brain imaging. 21,75 Second, it is important to mitigate any vascular and lifestyle risk factors. This approach has recently proven successful as an early intervention for dementia prevention and delay. 76,77 To this end, recent recommendations from the WHO (2019) 74

| Pharmacological interventions
Symptomatic pharmacological treatment options for MCI are limited; at present, there are no FDA-approved treatments indicated specifically for MCI. 3 While acetylcholinesterase inhibitors (AChEIs; eg, donepezil, rivastigmine, and galantamine) are used first-line in AD and AD+CVD in Asia, 19 these have not shown robust ability to improve MCI symptoms in well-controlled randomized trials. [83][84][85][86] Thus, the AAN guidelines for MCI state that clinicians may choose not to offer cholinesterase inhibitors (Level B evidence), and, if offered, they should first discuss with patients the lack of evidence (Level A). 3 A number of other off-label treatments have been trialled. 87 Among them, EGb 761 ® is increasingly being used in the treatment of cognitive disorders, 53,56,57 and the evidence supporting its efficacy in individuals with MCI is growing.

| Efficacy of EGb 761 ® in MCI
Based on evidence from randomized trials 52,54,55 and meta-analyses, 88 Four key trials have reported benefit from EGb 761 ® in patients with MCI ( Figure 1 and Table 1

| Studies of EGb 761 ® in cognitively healthy volunteers
In addition, two randomized, placebo-controlled studies have shown encouraging results in healthy subjects ( Figure 1 and

| Trials of EGb 761 ® in delaying dementia
Given that individuals with MCI progress to clinically evident AD at an accelerated rate compared with healthy individuals, 3,6-9 diagnosis of MCI has been recognized as an important opportunity to attempt preventative intervention.

Diagnosis of MCI
It is recommended that clinicians assess for MCI using validated tools, including testing for functional assessment (ADL).
Level of evidence C (expert opinion) Biomarker assessments, including imaging, may help confirm a diagnosis of MCI, and establish the presence of CVD (vascular pathology).

Class of recommendation IIa Level of evidence B
As far as possible, we recommend the use of consistent MCI diagnostic criteria in clinical trials, to enable more robust conclusions.
Level of evidence C (expert opinion)

General management principles
It is important to identify MCI patients who are at higher risk for dementia, to ensure early intervention.
Level of evidence C (expert opinion) Clinicians should first assess for reversible causes of MCI impairment, and treat and follow-up accordingly.
Level of evidence C (expert opinion) A multidomain intervention strategy is useful in MCI to benefit both neurodegenerative and vascular pathologies. Such a strategy should at least include physical exercise, smoking cessation, management of hypertension and diabetes, cognitive training, and psychosocial interventions.
Class of recommendation I Level of evidence B

Symptomatic MCI treatment with EGb 761®
There is a lack of robust evidence supporting the use of AChEI in improving MCI symptoms.

Class of recommendation III Level of recommendation A
EGb 761 ® has demonstrated improvement in MCI symptoms in at least four randomized trials, and is the only pharmacological agent recommended in existing guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761 ® may benefit MCI patients with CVD.
Level of evidence C (expert opinion)

Role of EGb 761 ® in delaying dementia
Given that individuals with MCI progress to clinically evident AD at an accelerated rate compared with healthy individuals, diagnosis of MCI represents an important opportunity for initiating therapy.
Level of evidence C (expert opinion) Based on post hoc evidence from two randomized studies, EGb 761 ® may help delay progression of MCI to dementia in some individuals.

Class of recommendation IIb
Level of evidence C There is justification for well-controlled, long-term prospective studies of EGb 761 ® in patients with early cognitive decline and MCI, to more fully establish the role of this agent in delaying or preventing dementia.
Level of evidence C (expert opinion)

EGb 761 ® Safety in MCI
EGb 761 ® has a favorable risk-benefit profile. Level of evidence A

| EGb 761 ® safety
EGb 761 ® has demonstrated a positive risk-benefit profile. 52,88 Studies and meta-analyses have consistently shown no significant increase in overall risk of adverse events with EGb 761 ® versus placebo. 52,[54][55][56]89,93,95,107 Indeed, one meta-analysis showed a numerically lower rate of discontinuation in EGb 761 ® -treated patients versus those receiving placebo. 89 Historically, some concern has been raised regarding increased bleeding risk in patients treated with EGb 761 ® . This issue was discussed in detail in our previous consensus publication. 58 Briefly, the data from published trials and meta-analyses show no evidence of an increased risk of bleeding with EGb 761 ® , 107,108 nor any clinically important changes in bleeding time, coagulation parameters, or platelet aggregation in doses up to 480 mg/day. [108][109][110][111] There also appears to be no additive effect of EGb 761 ® with aspirin, 112 and EGb 761 ® does not change the pharmacokinetic or pharmacodynamic properties of simultaneously administered warfarin. 113

| CON CLUS I ON S AND E XPERT CONS ENSUS
Key studies that evaluated EGb 761 ® in MCI patients, individuals with SCI, and cognitively healthy individuals, are summarized in Table 1. In Table 2 Furthermore, based on the known effects of EGb 761 ® in promoting brain circulation, protecting against oxidative stress, and providing neuroprotective effects, 58 it is rational to expect that EGb 761 ® may benefit MCI patients with concomitant CVD, but this hypothesis needs to be verified in further clinical trials. This knowledge may be particularly important among Asian populations who appear to have a higher likelihood of vascular involvement. 41,42 The higher risk of developing dementia after an MCI diagnosis represents a strong argument to initiate treatment at this earlier stage of the disease continuum. The evidence suggests a possible role for EGb 761 ® in delaying the progression of cognitive decline and reducing the risk of progression to dementia in some patients, 93,95 but further studies are warranted. The risk of progression from MCI to dementia may be further reduced by eliminating risk factors, including vascular risk factors. Future studies should attempt to clarify the impact of early lifestyle interventions with or without EGb 761 ® .
Additional data are desirable to further inform clinical practice and select appropriate patients for EGb 761 ® treatment.
Longitudinal studies with imaging investigations and biomarker analyses would be helpful, to assess the efficacy of EGb 761 ® in subgroups of MCI patients with differing underlying pathologies, including those with CVD or amyloid plaques. The role of EGb 761 ® in MCI patients with mild behavioral impairment is also currently not clarified; nor is there any clear information as to the differential benefit of EGb 761 ® in amnestic versus nonamnestic MCI. Further targeted research in these areas will be important future pursuits. We were able to locate only one small randomized trial of EGb 761 ® in subjective memory impairment. Given that individuals with SCI are understood to be at higher risk for future cognitive decline, 114,115 additional evidence investigating earlier EGb 761 ® initiation before clinically diagnosable MCI or dementia would be highly informative. In addition, data specific to Asian patients are lacking; replication in Asian populations of RCTs previously conducted in Western populations would provide valuable comparisons between populations.
More information is also needed on how and when to initiate EGb 761 ® treatment, and for how long. Subanalysis of the existing EGb 761 ® efficacy data stratified by patient body weight would clarify whether the 240 mg daily dose of EGb 761 ® is effective independent of weight. Furthermore, longer-term EGb 761 ® data will be highly valuable, given that clinically diagnosed MCI is a chronic condition, often with underlying CVD or other pathologies which take time to manifest improvement. The available randomized trials that assessed symptom improvement in MCI or SCI followed patients over only 2-6 months of treatment. Study of EGb 761 ® efficacy by treatment duration would be a valuable addition to the existing body of data, to help inform clinicians as to the optimum duration of therapy, and whether ongoing improvement, or a plateau in benefit, might be expected over the long term. There is also a lack of multidomain trials evaluating the benefits of combining EGb 761 ® in combination with nonpharmacological strategies such as cognitive training, physical activity, nutritional interventions, and cardiovascular risk factor management.
Summing up the results presented herein, the ASCEND2 group concluded that, based on the available data, the Ginkgo biloba extract, EGb 761 ® has a role in the multidomain intervention strategy for MCI management. Our recommendations are intended to further contribute to the improvement of clinical practice and patient outcomes within Asia. Healthcare professionals within the region are encouraged to consider these recommendations when formulating appropriate strategies for the treatment and management of MCI, with a view to improving patient outcomes.

ACK N OWLED G EM ENT
Medical writing and editorial assistance were provided by Geraldine K Skidmore of PharmaMED LLC.