Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761

Background:The Ginkgo biloba special extract, EGb 761  has been widely used in the treatment of neuropsychiatric disorders, including Alzheimer's disease (AD).Methods: To guide clinical practice in the Asian region, the Asian Clinical ExpertGroup on Neurocognitive Disorders compiled evidence-based consensus recommendations regarding the use of EGb 761  in neurocognitive disorders with/without cerebrovascular disease.| 289KANDIAH et Al.

## | introduc ti on
The rapid aging of the global population is resulting in an increasing prevalence of mild cognitive impairment (MCI) and dementias. [bib_ref] Alleviating neuropsychiatric symptoms in dementia: the effects of Ginkgo biloba extract EGb..., Bachinskaya [/bib_ref] [bib_ref] Dementia and cognitive impairment: epidemiology, diagnosis, and treatment, Hugo [/bib_ref] Age is a key risk factor for dementia and Alzheimer's disease (AD) 1 ;
after the age of 65 years, the prevalence of dementia doubles with every five additional years. [bib_ref] Dementia and cognitive impairment: epidemiology, diagnosis, and treatment, Hugo [/bib_ref] Prevalence is higher among women than men, largely because women tend to live longer. [bib_ref] Dementia and cognitive impairment: epidemiology, diagnosis, and treatment, Hugo [/bib_ref] In 2018, the number of individuals worldwide with dementia was estimated to be 50 million. This number has been projected to increase exponentially to 82 million by 2030, and to 152 million by 2050.In high-income countries, estimates of dementia prevalence are around 5%-10% in the population aged 65 years or older 2 ; however, evidence suggests the prevalence in such countries may be reaching a plateau. [bib_ref] A two-decade comparison of prevalence of dementia in individuals aged 65 years..., Matthews [/bib_ref] [bib_ref] Trends in the incidence and prevalence of Alzheimer's disease, dementia, and cognitive..., Rocca [/bib_ref] In the developing world, however, the increasingly maturing population is expected to be mirrored by a continued rise in the prevalence of dementia, [bib_ref] The Global Impact of Dementia. An Analysis of Prevalence, Incidence, Cost and..., Prince [/bib_ref] [bib_ref] Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk..., Kalaria [/bib_ref] [bib_ref] Epidemiology of dementia in Asia: insights on prevalence, trends and novel risk..., Catindig [/bib_ref] with an estimated 68% of dementia cases expected to be found in low-to-middle income countries by the year 2050. [bib_ref] The Global Impact of Dementia. An Analysis of Prevalence, Incidence, Cost and..., Prince [/bib_ref] Asian data indicate a crude estimated dementia prevalence of 4.7% in the over-60 population; although there is country-to-country variation. [bib_ref] The Global Impact of Dementia. An Analysis of Prevalence, Incidence, Cost and..., Prince [/bib_ref] [bib_ref] Epidemiology of dementia in Asia: insights on prevalence, trends and novel risk..., Catindig [/bib_ref] National reports of dementia prevalence in various Asian countries range between approximately 2%-13%, [bib_ref] Epidemiology of dementia in Asia: insights on prevalence, trends and novel risk..., Catindig [/bib_ref] [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] and this is expected to rise dramatically in coming years. [bib_ref] Epidemiology of dementia in Asia: insights on prevalence, trends and novel risk..., Catindig [/bib_ref] Cerebrovascular disease (CVD) frequently coexists with AD. In Asia, AD + CVD accounts for up to 20% of all dementia cases, [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] and there is some evidence for a higher prevalence of AD + CVD in the Asian region compared with Western populations. [bib_ref] Association between white matter hyperintensity and medial temporal atrophy at various stages..., Kandiah [/bib_ref] Globally, but also in Asia, AD + CVD is thought to be underdiagnosed, primarily due to lack of awareness resulting from a lack of defined diagnostic criteria, but also due to the high cost of investigations, a lack of adequate diagnostic facilities, and other resource constraints. [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] It has been suggested that some Asian epidemiology studies may be influenced by "survivor bias" due to a high proportion of early deaths. [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] Epidemiology study methodologies and findings are also heterogeneous; among dementia patients across Asia, estimated proportions of dementia patients with AD + CVD range between 7% (Sri Lanka) and 50% (Japan). [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] Dementias place an appreciable burden on patients, their families, and the healthcare system. Quality of life (QoL) is decreased for patients as well as for their families and caregivers, and a severe cost burden also results from long-term medication use, hospitalization, and home-based healthcare. 2,11

## | definitions and symptoms
Mild cognitive impairment is understood to be a neurocognitive state between normal cognitive aging and dementia, and can be an early manifestation of, and a risk factor for, AD or other neurodegenerative disorders. [bib_ref] The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from..., Albert [/bib_ref] [bib_ref] Mild cognitive impairment: incidence and vascular risk factors in a population-based cohort, Ganguli [/bib_ref] MCI is not linked to any specific etiology, [bib_ref] Mild cognitive impairment: incidence and vascular risk factors in a population-based cohort, Ganguli [/bib_ref] but in the context of AD biomarkers, MCI is considered to be a prodromal stage of AD dementia. [bib_ref] The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from..., Albert [/bib_ref] 

## K e y w o r d s
Alzheimer disease, cerebrovascular disease, dementia, EGb 761  , Ginkgo biloba in one or more cognitive domains, but, in contrast to overt AD dementia, no significant social or occupational impairments are present; individuals are generally able to maintain independence in daily functioning with minimal assistance. [bib_ref] The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from..., Albert [/bib_ref] [bib_ref] Mild cognitive impairment, Gauthier [/bib_ref] [bib_ref] The diagnosis of dementia due to Alzheimer's disease: recommendations from the National..., Mckhann [/bib_ref] Clinically overt dementia has a spectrum ranging from mild to severe. [bib_ref] The diagnosis of dementia due to Alzheimer's disease: recommendations from the National..., Mckhann [/bib_ref] Diagnosis involves clinical assessment, neuropsychological evaluation, and often neuroimaging. [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] Core clinical criteria for all-cause dementia, based on DSM-5 criteria for neurocognitive disorders, include cognitive impairments and behavioral symptoms that interfere with functioning and activities of daily living (ADL). Typical cognitive symptoms may include impairments in complex attention, executive function, learning and memory, language function, perceptual motor function, and social cognition. [bib_ref] The diagnosis of dementia due to Alzheimer's disease: recommendations from the National..., Mckhann [/bib_ref] Noncognitive behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms (NPS), are observed across the severity spectrum of dementia, [bib_ref] Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from..., Lyketsos [/bib_ref] and can include changes in personality or usual conduct, anxiety, agitation, elation, irritability, apathy/indifference, depression/dysphoria, disinhibition, aberrant motor behavior, sleep or appetite changes, and hallucinations or delusions. [bib_ref] The diagnosis of dementia due to Alzheimer's disease: recommendations from the National..., Mckhann [/bib_ref] [bib_ref] Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from..., Lyketsos [/bib_ref] The term "AD dementia" specifically refers to a clinical syndrome arising secondary to the pathophysiological process that leads to AD. [bib_ref] The diagnosis of dementia due to Alzheimer's disease: recommendations from the National..., Mckhann [/bib_ref] AD and vascular dementia (VaD) are considered to be the most common forms of dementia, 9 but more recently, attention has focused on the co-existence of AD and CVD. [bib_ref] Mixed brain pathologies account for most dementia cases in community-dwelling older persons, Schneider [/bib_ref] [bib_ref] Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's..., Esiri [/bib_ref] AD and VaD may be considered to be a disease continuum, with pure AD at one end of the spectrum, VaD at the other, and AD with concomitant CVD comprising the majority of cases. [bib_ref] Mixed brain pathologies account for most dementia cases in community-dwelling older persons, Schneider [/bib_ref] [bib_ref] Global epidemiology of dementia: Alzheimer's and vascular types, Rizzi [/bib_ref] [bib_ref] Mixed dementia: epidemiology, diagnosis, and treatment, Zekry [/bib_ref] AD and CVD contribute independently, but additively, to the risk of dementia. [bib_ref] Clinical and imaging features of mixed Alzheimer and vascular pathologies, Chui [/bib_ref] It is important to distinguish between AD, VaD, and AD + CVD, because of differences in clinical course and cognitive profiles, and differential treatment responses. [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] Diagnosis of AD + CVD can be made when (a) clinical signs of AD dementia are accompanied by evidence of CVD (vascular lesions) on brain imaging; or (b) dementia clinically presenting as sudden-onset, is accompanied by biomarker evidence of AD such as amyloid plaques on positron emission tomography. [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] The neuroimaging hallmarks of CVD include chronic lacunes, white matter hyperintensities (WMH), perivascular spaces, and microbleeds. 9 CVD has been demonstrated to be a risk factor for progression from MCI to AD. [bib_ref] White matter disease independently predicts progression from mild cognitive impairment to Alzheimer's..., Prasad [/bib_ref] WMH have also been shown to be independently associated with BPSD. [bib_ref] Cerebral white matter disease is independently associated with BPSD in Alzheimer's disease, Kandiah [/bib_ref] 

## | management options
Goals of dementia treatment are stabilization or slowing of disease progression, reduction in psychological and behavioral symptoms, improvement of QoL, and reduction of caregiver burden. [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] Acetylcholinesterase inhibitors (AChEIs; eg, donepezil, rivastigmine, and galantamine) are first-line agents for the treatment of AD and AD + CVD in Asia. Second-line options include N-methyl-D-aspartate (NMDA) receptor antagonists (eg, memantine). [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] The Ginkgo biloba special extract, EGb 761  has also been used widely in the treatment of cognitive disorders, including AD and AD + CVD. [bib_ref] Ginkgo biloba extract (EGb 761) in Alzheimers disease: is there any evidence?, Ramassamy [/bib_ref] [bib_ref] A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for..., Bars [/bib_ref] Different parts of the Ginkgo biloba tree have been used for centuries in Chinese herbal medicine to treat a variety of health conditions, and evidence for the use of EGb 761  in the symptomatic treatment of dementia, particularly in the presence of NPSs, dates back more than two decades. [bib_ref] A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for..., Bars [/bib_ref] [bib_ref] Effects of Ginkgo biloba in dementia: systematic review and meta-analysis, Weinmann [/bib_ref] The EGb 761  extract is derived through a specific, proprietary process under strict procedural control. EGb 761  is a dry extract from Ginkgo biloba leaves, adjusted to 22.0%-27.0% ginkgo flavonoids and 5.0%-7.0% terpene lactones consisting of 2.8%-3.4% ginkgolides A, B, and C, and 2.6%-3.2% bilobalide, and containing less than 5 ppm ginkgolic acids. Depending on local regulatory frameworks, EGb 761  is classified as a drug in some countries, including China, the Philippines, Thailand and Vietnam. In Singapore and Malaysia, EGb 761  is currently classified as a supplement; in Indonesia, it is classified as a "phytopharmaceutical."
EGb 761  exhibits various beneficial properties in patients with AD and AD + CVD. The molecular basis for these effects is not fully understood; however, the extract appears to have neuroprotective properties. It is a polyvalent free radical scavenger that improves mitochondrial function, decreases blood viscosity and enhances microperfusion, modulates serotonin levels in various brain areas, increases dopamine levels in prefrontal cortical areas, decreases amyloid- fibrillogenesis, and attenuates a hyperactivated hypothalamus-pituitary-adrenal axis. [bib_ref] Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract..., Hoyer [/bib_ref] 

## | me thods
The Asian Clinical Expert Group on Neurocognitive Disorders consists of twenty members including neurologists, geriatricians, psychiatrists and a pharmacist, from around the Asia region. There was also involvement of an expert advisory member from Germany. English language publications on the use of EGb 761  in dementia and MCI with or without CVD, and were given sufficient time to review the literature. Experts then completed a pre-meeting survey before gathering to discuss amendments to a series of proposed consensus statements. On the day of the consensus meeting, two presentations on key published findings were delivered by experts in the field. All proposed statements were then discussed in depth, and when necessary, polling of Expert Group members was carried out to choose or formulate statements that were accepted unanimously or by majority vote. This document is intended as a collection of consensus recommendations only, and is not designed to be used as a treatment algorithm. Experts' clinical opinions were based on the available data, and were unrelated to different regulatory classifications in respective countries.

## | re sults
The Expert Group identified English language articles relevant to the use of EGb 761  in MCI, AD, VaD, and BPSD in the literature. The
Group also identified a number of salient aspects relating to the use of EGb 761  in clinical practice, and formed specific consensus recommendations based on the available evidence . Key trials evaluating EGb 761  are summarized in , and key meta-analyses are discussed below.

## | efficacy of egb 761  in placebocontrolled trials
Older placebo-controlled clinical trials have been heterogeneous in study design, EGb 761  dosage, and effect sizes, but overall have shown modest improvement in cognitive function and ADL. [bib_ref] A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for..., Bars [/bib_ref] [bib_ref] Proof of efficacy of the ginkgo biloba special extract EGb 761 in..., Kanowski [/bib_ref] [bib_ref] The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease, Oken [/bib_ref] However, more recently, three multicenter, randomized, doubleblind, placebo-controlled trials of comparable design were con- . [bib_ref] Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb..., Ihl [/bib_ref] [bib_ref] Ginkgo biloba extract EGb 761(R) in dementia with neuropsychiatric features: a randomised,..., Herrschaft [/bib_ref] Randomized, double-blind, placebo-controlled trials in patients with MCI have also shown significant improvements in NPS, cognitive performance, memory function, concentration, and anxiety with EGb 761  vs placebo. 44,45

## | efficacy findings in key meta-analyses
Results of a 2014 meta-analysis by Gauthier and Schlaefke con- EGb 761  . Caregiver distress was also reduced. [bib_ref] Treatment effects of Ginkgo biloba extract EGb 761(R) on the spectrum of..., Savaskan [/bib_ref] 

## | does egb 761  prevent progression to dementia?
Two multicenter, randomized, double-blind, placebo-controlled trials (the GuidAge 51 and Gingko Evaluation of Memory [GEM] 52 studies) evaluated the use of EGb 761  in the prevention of dementia.
The GuidAge trial included 2,850 French primary care patients with memory complaints, who were prospectively followed up over five years. [bib_ref] Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's..., Vellas [/bib_ref] The GEM study (USA) randomized a total of 3069 individuals aged 75 years with normal cognition or MCI at baseline, and assessed them every six months, with a median follow-up of 6.1 years. [bib_ref] Ginkgo biloba for prevention of dementia: a randomized controlled trial, Dekosky [/bib_ref] Neither study demonstrated a clear preventative effect in initial analyses. [bib_ref] Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's..., Vellas [/bib_ref] 

## | egb 761  safety
EGb 761  has been shown to have a positive risk-benefit profile. [bib_ref] Proof of efficacy of the ginkgo biloba special extract EGb 761 in..., Kanowski [/bib_ref] [bib_ref] Efficacy and tolerability of Ginkgo biloba extract EGb 761(R) in dementia: a..., Gauthier [/bib_ref] Studies have consistently shown no significantly increased overall risk of adverse events (AEs) compared with placebo. [bib_ref] A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for..., Bars [/bib_ref] [bib_ref] Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb..., Ihl [/bib_ref] [bib_ref] Ginkgo biloba extract EGb 761(R) in dementia with neuropsychiatric features: a randomised,..., Herrschaft [/bib_ref] [bib_ref] Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled,..., Napryeyenko [/bib_ref] [bib_ref] Efficacy and safety of Ginkgo biloba extract EGb 761 in mild cognitive..., Gavrilova [/bib_ref] [bib_ref] Effects of Ginkgo Biloba special extract EGb 761  i n very..., Grass-Kapanke [/bib_ref] This finding was confirmed in a recent safety meta-analysis of 44 trials in a total of over 6000 patients; odds ratios for dizziness and nausea in fact favoured EGb 761  over placebo.

## Consensus statement 3: management of comorbidities
Concomitant management of co-morbidities, such as hypertension, in patients with AD, VaD, and BPSD is highly important Expert recommendation

## Prevention of dementia

## Consensus statement 4: egb 761  does not appear to prevent dementia
EGb 761  cannot currently be recommended for the prevention of dementia Class of recommendation III; level of evidence A

## Safety of egb 761 

## Consensus statement 5: egb 761  is well tolerated
Current safety evidence suggests a good tolerability profile with EGb 761  in the treatment of MCI, AD, VaD, and BPSD

## Level of evidence a

## Consensus statement 6: no overall increased bleeding risk
Based on existing data in AD, VaD, and mixed dementia (including the GINDEM, GOTADAY, and GOT-IT! studies), and two meta-analyses, there appears to be no overall added risk of bleeding with EGb 761 

## Level of evidence a
Further studies are required in certain patient subgroups, including those with a high cerebral microbleed load (>4 microbleeds) in the cortical areas. In such cases, patients should be warned of a possible increased risk of bleeding Expert recommendation showed significantly higher dropout rates due to side effects, compared with placebo. [bib_ref] Metaanalysis of the efficacy and safety of Ginkgo biloba extract for the..., Hashiguchi [/bib_ref] In a comparative trial, combination therapy with EGb 761  plus donepezil resulted in fewer AEs compared with donepezil monotherapy. [bib_ref] Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment..., Yancheva [/bib_ref] Some concern has been raised regarding a possible increased risk

## Consensus statement 7: no significant interaction with anticoagulants or antiplatelet agents

## | current guidelines regarding the use of egb 761 
The Expert Panel is in agreement that there is a pressing need to take into account the evidence supporting EGb 761  from the above key clinical trials [bib_ref] Alleviating neuropsychiatric symptoms in dementia: the effects of Ginkgo biloba extract EGb..., Bachinskaya [/bib_ref] [bib_ref] A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for..., Bars [/bib_ref] [bib_ref] Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb..., Ihl [/bib_ref] [bib_ref] Ginkgo biloba extract EGb 761(R) in dementia with neuropsychiatric features: a randomised,..., Herrschaft [/bib_ref] [bib_ref] Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled,..., Napryeyenko [/bib_ref] [bib_ref] Proof of efficacy of the ginkgo biloba special extract EGb 761 in..., Kanowski [/bib_ref] [bib_ref] Efficacy and safety of Ginkgo biloba extract EGb 761 in mild cognitive..., Gavrilova [/bib_ref] [bib_ref] Effects of Ginkgo Biloba special extract EGb 761  i n very..., Grass-Kapanke [/bib_ref] and recent meta-analyses. [bib_ref] Efficacy and tolerability of Ginkgo biloba extract EGb 761(R) in dementia: a..., Gauthier [/bib_ref] [bib_ref] Efficacy of Ginkgo biloba extract EGb 761((R)) in dementia with behavioural and..., Von Gunten [/bib_ref] [bib_ref] Treatment effects of Ginkgo biloba extract EGb 761(R) on the spectrum of..., Savaskan [/bib_ref] Notably, there are no specific diagnostic and treatment guidelines for AD + CVD in Asia, [bib_ref] Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region, Chen [/bib_ref] representing an unmet need in the region. Respective countries have their own guidelines. Countries approach the issue of "level of evidence" slightly differently, based on the system used to evaluate the data, and based on the local classification of EGb 761  (drug vs supplement).
In Importantly, EGb 761  does not appear to increase overall bleeding risk, [bib_ref] Is there a risk of bleeding associated with standardized Ginkgo biloba extract..., Kellermann [/bib_ref] [bib_ref] No alteration in platelet function or coagulation induced by EGb761 in a..., Balditsollier [/bib_ref] [bib_ref] No alteration in the PFA-100 in vitro bleeding time induced by the..., Halil [/bib_ref] nor to interact with common antiplatelet agents or anticoagulants. [bib_ref] Does Ginkgo biloba special extract EGb 761 provide additional effects on coagulation..., Wolf [/bib_ref] [bib_ref] Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin..., Jiang [/bib_ref] However, these studies were performed in young, healthy volunteers, and it is unclear how accurately the data can be extrapolated to the elderly patient population with multiple co-morbidities. Further data are also required to address this concern in certain patient subgroups, such as those harboring a high microbleed load; or those with a history of gastrointestinal bleeding or mild renal insufficiency who are usually excluded from clinical trials. In addition, data are needed to assess bleeding risks at higher EGb 761  doses. It is suggested that future studies should include imaging criteria as outcome measures, allowing for better insights into the mechanism of action of EGB 761  . The inclusion of gradient recalled echo imaging will also allow for risk estimates of cerebral bleeding among patients with cognitive impairment having microbleeds.

## Ack n owled g em ent
Medical writing and editorial assistance was provided by Geraldine K Hosking of Pharma-Med Ltd.