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

BackgroundMild 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.AimsTo present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761^® in MCI.Materials & MethodsThe 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.ResultsEGb 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.DiscussionEGb 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.ConclusionAs an expert group, we suggest it is clinically appropriate to incorporate EGb 761^® as part of the multidomain intervention for MCI.     

Treatment of vascular dementia—evidence from clinical trials with cholinesterase inhibitors

Abstract

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demostrated improvement in cognition, behavior and activites of daily living.     

Diagnosis and management of vascular cognitive impairment and dementia

Vascular dementias (VaDs) are the second most common cause of dementia. Cerebrovascular disease (CVD) and stroke relates to high risk of cognitive impairment, but also relate to Alzheimer's disease (AD): Vascular cognitive impairment (VCI) and dementias extend beyond the traditional multi-infarct dementia. Pathophysiology of VaD incorporates interactions between vascular etiologies (CVD and vascular risk-factors), changes in the brain (infarcts, white matter lesions, atrophy), host factors (age, education) and cognition. Variation in defining the cognitive syndrome, in vascular etiologies, and allowable brain changes in current criteria have resulted in variable estimates of prevalence, of groups of subjects, and of the types and distribution of putative causal brain lesions. Should new criteria be developed? Ideally in constructing new criteria the diagnostic elements should be tested with prospective studies with clinical-pathological correlation: replace dogma with data. Meanwhile focus on more homogenous subtypes of VaD, and on imaging criteria could be a solution. Subcortical ischemic vascular disease and dementia (SIVD) incorporate small vessel disease as the chief vascular etiology, lacunar infarct and ischaemic white matter lesions as primary type of brain lesions, subcortical location as the primary location of lesions, and subcortical syndrome as the primary clinical manifestation. It incorporates two clinical entities "Binswanger's disease" and "the lacunar state". AD with VaD (mixed dementia) has been underestimated as a prevalent cause in the older population. In addition to simple co-existence, VaD and AD have closer interaction: several vascular risk factors and vascular brain changes relate to clinical manifestation of AD, and they share also common pathogenetic mechanisms. Vascular cognitive impairment (VCI) is a category aiming to replace the "Alzhemerized" dementia concept in the setting of CVD, and substitute it with a spectrum that includes subtle cognitive deficits of vascular origin, post-stroke dementia, and the complex group of the vascular dementias. As far there is no standard treatment for VaDs, and still little is known on the primary prevention (brain at risk for CVD) and secondary prevention (CVD brain at risk for VCI/VaD). There is no standard symptomatic treatment for VaD. Recently symptomatic cholinergic treatment has shown promise in AD with VaD, as well as probable VaD. Future focus should be directed to the distinct etiological and pathological factors: the vascular and the AD burden of the brain.     

Galantamine in the treatment of vascular dementia

Vascular dementia (VaD) is a disorder with no cure and limited treatment options. Similarities between VaD and Alzheimer's disease (AD) arise on a number of levels. Both involve progressive decline in cognition, functional ability, and behavior, and there is evidence for a central role of reduced cholinergic neurotransmission in the two illnesses. Treatment strategies in VaD have historically focused on prevention, although evidence of cognitive benefits with preventative treatment is scarce. Acetylcholinesterase inhibitors represent a rational treatment possibility for symptomatic therapy of patients with VaD. A recent large-scale trial of galantamine in patients with VaD or AD with cerebrovascular disease (AD + CVD) represents the first placebo-controlled trial showing clinically relevant benefits in these important patient populations.     

Dementia Poststroke

Abstract : The frequency of dementia poststroke is high, and stroke considerably increases the risk of dementia. The risk factors for dementia related to stroke are still incompletely understood. In addition to age and low level of education, different combinations of vascular risk factors and stroke features have been associated with poststroke dementia. A single explanation for poststroke dementia is not adequate; rather, multiple factors including stroke features (dysphasia, major dominant stroke syndrome), infarct features (type, side, site, number, and volume), extent and type of white matter lesions (WMLs), degree and site of atrophy, host characteristics (e.g. age, educational level), and risk factors for stroke (e.g. prior cerebrovascular disease, diabetes) each contribute to the risk of dementia poststroke.
Dementia after first ever clinical stroke is also frequent. Cognitive decline is present prior to stroke in up to one-third of patients developing post-stroke dementia. Medial temporal lobe atrophy, a marker of an increased risk of Alzheimer's disease (AD), is more frequent in stroke patients who have preexisting dementia or cognitive decline, as well as poststroke dementia. This may be explained by co-existing AD and cerebrovascular disease (CVD). The magnitude of this mixed dementia (AD with CVD/Vascular Dementia (VaD)) group has been previously underestimated, and it is a diagnostic challenge in the older population.
Dementia due to CVD is a rather advanced stage of is chemic brain changes, and outcome of treatment and prevention may be limited. Accordingly, the focus should be placed on the entire spectrum of cognitive impairment related to CVD, focusing especially the early cognitive changes.     

Association of Arterial Spin Labeling Parameters With Cognitive Decline,Vascular Events,and Mortality in a Memory-Clinic Sample

BackgroundCognitive decline in older adults has been attributed to reduced cerebral blood flow (CBF). Recently, the spatial coefficient of variation (sCoV) of ASL has been proposed as a proxy marker of cerebrovascular insufficiency. We investigated the association between baseline ASL parameters with cognitive decline, incident cerebrovascular disease, and risk of vascular events and mortality.Design, Setting, and ParticipantsAbout 368 memory-clinic patients underwent three-annual neuropsychological assessments and brain MRI scans at baseline and follow-up. MRIs were graded for white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), cortical infarcts, and intracranial stenosis. Baseline gray (GM) and white matter (WM) CBF and GM-sCoV were obtained with ExploreASL from 2D-EPI pseudo-continuous ASL images. Cognitive assessment was done using a validated neuropsychological battery. Data on incident vascular events (heart disease, stroke, transient ischemic attack) and mortality were obtained.ResultsHigher baseline GM-sCoV was associated with decline in the memory domain over 3 years of follow-up. Furthermore, higher GM-sCoV was associated with a decline in the memory domain only in participants without dementia. Higher baseline GM-sCoV was associated with progression of WMH and incident CMBs. During a mean follow-up of 3 years, 29 (7.8%) participants developed vascular events and 18 (4.8%) died. Participants with higher baseline mean GM-sCoV were at increased risk of vascular events.ConclusionsHigher baseline GM-sCoV of ASL was associated with a decline in memory and risk of cerebrovascular disease and vascular events, suggesting that cerebrovascular insufficiency may contribute to accelerated cognitive decline and worse clinical outcomes in memory clinic participants.     

Prevention and early intervention for vascular dementia in community dwelling elderly: Findings from the Nakayama study

Cerebrovascular disease (CVD) may be the single most common risk factor for age‐associated dementia (in particular for vascular dementia (VaD)), and there is definite potential for prevention and treatment of CVD. After one of the most comprehensive and precise type‐specific prevalence surveys of dementia (first Nakayama study), we have continued the preventive and early interventional approaches to CVD and VaD, including treatment of cardiovascular risk factors. In this cohort study, 88% of patients with ‘vascular cognitive impairment without dementia’, who were alive at 3‐years follow up, were still diagnosed with ‘vascular cognitive impairment without dementia’ and only 12% progressed to dementia. Compared with the results of previous studies, active control of risk factors and prevention of recurrent stroke may reduce the incidence of dementia and slow the progression of cognitive impairment in patients with ‘vascular cognitive impairment without dementia’.     

Quantitative gait,cognitive decline,and incident dementia: The Rotterdam Study

IntroductionPoor gait has recently emerged as a potential prodromal feature of cognitive decline and dementia. We assessed to what extent various aspects of poor gait are independently associated with cognitive decline and incident dementia.MethodsWe leveraged detailed quantitative gait (GAITRite™) and cognitive assessments in 4258 dementia-free participants (median age 67 years, 55% women) of the population-based Rotterdam Study (baseline 2009–2013). We summarized 30 gait parameters into seven mutually independent gait domains and a Global Gait score. Participants underwent follow-up cognitive assessments between 2014 and 2016 and were followed up for incident dementia until 2016 (median 4 years).ResultsThree independent gait domains (Base of Support, Pace, and Rhythm) and Global Gait were associated with cognitive decline. Two independent gait domains (Pace and Variability) and Global Gait were associated with incident dementia. Associations of gait with cognitive decline and incident dementia were only present in individuals who had been cognitively unimpaired at baseline.DiscussionPoor performance on several independent gait domains precedes cognitive decline and incident dementia.     

Long-term safety and cognitive effects of galantamine in the treatment of probable vascular dementia or Alzheimer's disease with cerebrovascular disease.

The relationship between cholinergic dysfunction and cognitive and functional impairment in patients with vascular dementia (VaD) and Alzheimer's disease (AD) with cerebrovascular disease (CVD) suggests a potential role for cholinomimetic therapy. Initial studies of galantamine demonstrated cognitive, behavioral, and functional benefits in these populations. 326 patients with VaD or AD with CVD who completed an initial 12-month trial were treated with galantamine 24 mg/day in a 24-month, open-label extension. This interim analysis was performed at month 12 of the open-label extension (248 completed the trial). Galantamine (up to 24 months total) was well tolerated in both groups. The most frequently reported adverse events, characteristic of older dementia patients, included depression, agitation, and insomnia. Gastrointestinal adverse events were less common than initially, indicating declining incidence with long-term therapy. Patients taking galantamine for the entire study demonstrated the least cognitive decline on AD Assessment Scale-cog/11: 2.7 points vs. 3.1 points in those given placebo initially (P < 0.001 and P = 0.003, respectively). The long-term benefits of galantamine were evident in both groups; cognitive baseline levels were maintained for approximately 21 months in VaD patients and for 12 months in patients with AD with CVD. Long-term (up to 24 months) galantamine therapy in patients with VaD and AD with CVD is well tolerated and associated with prolonged maintenance of cognitive function.     

Cognitive reserve in Parkinson's disease: A systematic review and meta-analysis

BackgroundThe concept of cognitive reserve is proposed to explain the mismatch between the degree of pathological changes and their clinical manifestations and has been used to help understand the variation in the rate of cognitive decline and the development of dementias. It is not clear whether this concept applies to cognitive performance, cognitive decline and dementia in Parkinson's disease (PD).MethodsA systematic review was conducted using the most commonly described proxies for cognitive reserve of education, occupation and leisure activities. Thirty four papers were found on education and cognition in PD but there were no studies of the other proxies of reserve. A random effects meta-analysis was used to assess the associations between education and cross-sectional cognitive assessments, longitudinal global cognitive decline and a long term dementia diagnosis.ResultsThere was a significant association between higher education and cross-sectional performance of MMSE, global cognition, mild cognitive impairment, attention, executive function, visuospatial function and memory. There was a small but significant association between higher education and a reduced rate of cognitive decline. There was no association with a final dementia diagnosis. There was not enough information to perform an analysis on the rate and timing of transition to dementia.ConclusionsHigher levels of education are associated with significantly better cognitive performance and a small but significant slowing in cognitive decline but are not associated with a reduction in long-term dementia in PD. More detailed, standardized, longitudinal studies are required to study conclusively the effects cognitive reserve in PD.     

Vascular cognitive impairment

Cerebrovascular disease is the second most common cause of acquired cognitive impairment and dementia and contributes to cognitive decline in the neurodegenerative dementias. The current narrow definitions of vascular dementia should be broadened to recognise the important part cerebrovascular disease plays in several cognitive disorders, including the hereditary vascular dementias, multi-infarct dementia, post-stroke dementia, subcortical ischaemic vascular disease and dementia, mild cognitive impairment, and degenerative dementias (including Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies). Here we review the current state of scientific knowledge on the subject of vascular brain burden. Important non-cognitive features include depression, apathy, and psychosis. We propose use of the term vascular cognitive impairment, which is characterised by a specific cognitive profile involving preserved memory with impairments in attentional and executive functioning. Diagnostic criteria have been proposed for some subtypes of vascular cognitive impairment, and there is a pressing need to validate and further refine these. Clinical trials in vascular cognitive impairment are in their infancy but support the value of therapeutic interventions for symptomatic treatment.     

Dementia with cerebrovascular disease: the benefits of early treatment

Patients with vascular dementia (VaD) and Alzheimer's disease with cerebrovascular disease (AD + CVD) have dementia associated with underlying CVD. Although diagnosis of VaD is challenging, VaD is typically characterized by a stepwise progression of dementia that is closely associated with stroke and focal neurological findings, and a symptom profile that often includes executive dysfunction leading to decreased ability to perform instrumental activities of daily living (IADL). In contrast, AD + CVD patients typically present with progressive deterioration of cognition/memory that may also be influenced by concurrent cerebrovascular events. Early diagnosis and intervention are desirable to prevent further decline due to subsequent vascular events. Management of CVD can limit deterioration of cognitive symptoms in VaD patients, and treatment benefits with cholinesterase inhibitors may be realized as improvement above baseline levels in dementia symptoms. Results from a combined analysis of two 24-week, placebo-controlled clinical trials show that donepezil-treated VaD patients improve in cognition, global function, and performance of IADL. In contrast, AD + CVD patients may continue to decline despite management of CVD, and treatment benefits should be recognized as initial improvements followed by stabilization or slowed decline of dementia symptoms over time. In post-marketing studies, donepezil-treated AD and AD + CVD patients show similar benefits in cognition, global function, and quality of life. The results of these studies support the use of donepezil in treatment of patients with VaD or AD + CVD.     

Cerebral white matter hyperintensities in the prediction of cognitive decline and incident dementia

Abstract

Cerebral white matter hyperintensities (WMH), detected in vivo with magnetic resonance imaging (MRI), are commonly used to assess cerebrovascular burden in cognitive impairment. However, the association between WMH and cognition is not consistent across the literature. The present review examines evidence from published longitudinal studies. We reviewed the PubMed data base from January 1990 to March 2013 and included studies investigating the association of WMH with (1) the risk of dementia in the general population, (2) the risk of conversion to dementia in the mild cognitive impairment (MCI) population, and (3) cognitive decline in the general population. WMH were associated with all types of dementia in the general population, but not in MCI patients. Results are discrepant for global decline. WMH appear to be early predictors of the risk of dementia, but this association appears to be modulated by cognitive reserve, age and the spatial distribution of lesions. There are, however, some limits in the use of WMH as a marker of vascular burden. In addition to their ischaemic origin, WMH may be the result of co-occurring morbidity. Further research is needed to elucidate to what extent WMH actually reflect vascular risk to evaluate the likely efficacy of interventions specifically targeting WMH reduction.     

The relationships between atherosclerosis,heart disease,type 2 diabetes and dementia

Abstract

Type 2 diabetes in the elderly is associated with increased incidence of vascular disease, particularly, atherosclerosis of large blood vessels. Together with other risk factors such as dyslipidemia, atherosclerosis increases the risk for coronary heart disease and stroke. Most studies that have examined the impact of type 2 diabetes and other heart disease risk factors on cognitive functions do not provide evidence that heart disease risk factors (with the possible exception of triglycerides) further increase the likelihood of observing cognitive deficits in diabetic patients. However, none of these studies used imaging techniques to evaluate atherosclerosis or evidence of cerebrovascular disease, such as infarctions. The few studies that have included brain imaging suggest that evidence of cerebrovascular disease further increases the risk for dementia in diabetic patients. The results of longitudinal studies suggest that diabetes is an independent risk factor for cognitive decline and dementia. The pattern of neuropsychological performance observed in type 2 diabetic patients appears to be the result of multiple interacting processes developing over time. In addition to the detrimental effects of protracted impaired glucose regulation on the central nervous system, type 2 diabetes pathology also encompasses the detrimental effects of associated complications such as cerebrovascular disease, which is likely the main cause of the observed processing speed/reaction time decrements.     

Treatment of vascular dementia--evidence from clinical trials with cholinesterase inhibitors

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. In addition, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitor agents used in AD. Controlled clinical trials with donepezil, galantamine and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvements in cognition, behavior and activities of daily living.     

Treatment of vascular dementia-evidence from clinical trials with cholinesterase inhibitors

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior and activities of daily living.     

Cerebrovascular disease, APOE epsilon4 allele and cognitive decline in a cognitively normal population

OBJECTIVES: To investigate whether cerebrovascular disease (CVD) and apolipoprotein E (APOE) epsilon4 allele were associated with cognitive decline and whether the relationship between CVD and cognitive decline varied by APOE epsilon4 status. METHODS: A total of 809 cognitively normal community-dwelling residents aged >75 years were followed to detect subjects with cognitive decline, defined as follow-up. Mini-mental state examination (MMSE) score was >10% decease of the baseline score. Logistic and multinomial logistic models were developed to estimate odds ratio (OR) and 95% confidence interval (CI) of cognitive decline related to a history of CVD and APOE epsilon4 by taking into account major potential confounders including baseline MMSE score. RESULTS: During the mean 3.5 years of follow-up, 190 subjects experienced cognitive decline. Multi-adjusted ORs (95% CIs) of overall cognitive decline were 2.27 (1.23-4.17) for CVD and 1.69 (1.13-2.54) for APOE epsilon4, but no interaction was detected. Multinomial logistic analysis led to the CVD-related ORs of 1.42 (0.75-2.67) for cognitive decline without progression to dementia and 3.41 (1.55-7.55) for the decline progressing to dementia; similar analysis from a separate model led to adjusted OR of 2.28 (0.88-5.87; p=0.09) for the decline progressing to Alzheimer's disease. The risk effects of CVD on cognitive decline with progression to dementias were statistically significant mainly among individuals without APOE epsilon4 allele. CONCLUSIONS: CVD is a major risk factor for cognitive decline associated with progression to dementia and Alzheimer's disease. There appears no interaction between CVD and APOE epsilon4 on cognitive decline in very old people.     

Oral disease in relation to future risk of dementia and cognitive decline: Prospective cohort study based on the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial

ObjectiveExamine the association of oral disease with future dementia/cognitive decline in a cohort of people with type 2 diabetes.MethodsA total of 11,140 men and women aged 55–88 years at study induction with type 2 diabetes participated in a baseline medical examination when they reported the number of natural teeth and days of bleeding gums. Dementia and cognitive decline were ascertained periodically during a 5-year follow-up.ResultsRelative to the group with the greatest number of teeth (more than or equal to 22), having no teeth was associated with the highest risk of both dementia (hazard ratio; 95% confidence interval: 1.48; 1.24, 1.78) and cognitive decline (1.39; 1.21, 1.59). Number of days of bleeding gums was unrelated to these outcomes.ConclusionsTooth loss was associated with an increased risk of both dementia and cognitive decline.     

Secular trends in cognitive trajectories of diverse older adults

IntroductionThis study aimed to determine if later birth year influences trajectory of age-related cognitive decline across racial/ethnic groups and to test whether years of school, childhood socioeconomic status, and cardiovascular disease burden explain such secular trends.MethodsWe compared cognitive trajectories of global cognition and subdomains in two successive racially/ethnically and educationally diverse birth cohorts of a prospective cohort study.ResultsLater birth year was associated with higher initial cognitive levels for Whites and Blacks, but not Hispanics. Later birth year was also associated with less rapid rate of decline in all three racial/ethnic groups. More years of education, higher childhood socioeconomic status, and, to a smaller extent, greater cardiovascular disease burden accounted for higher intercepts in the later-born cohort, but did not account for attenuated slope of cognitive decline.DiscussionLater birth year is related to a slower rate of age-related decline in some cognitive domains in some racial/ethnic groups. Our analyses suggest that racial/ethnic and social inequalities are part of the mechanisms driving secular trends in cognitive aging and dementia.     

Neuropsychiatric Symptoms as Risk Factors for Cognitive Decline in Clinically Normal Older Adults: The Cache County Study

IntroductionThere has been considerable progress in identifying early cognitive and biomarker predictors of Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are common in AD and appear to predict progression after the onset of mild cognitive impairment or dementia.ObjectivesThe objective of the study is to examine the relationship between NPS in clinically normal older adults and subsequent cognitive decline in a population-based sample.MethodsThe Cache County Study on Memory in Aging consists of a population-based sample of 5,092 older adults. We identified 470 clinically normal adults who were followed for an average period of 5.73 years. NPS were evaluated at the baseline clinical assessment using the Neuropsychiatric Inventory (NPI). NPI domain scores were quantified as the product of frequency X severity in individual NPI domains, and then summed for the NPI-Total. Neuropsychological measures were collected at baseline and at each subsequent follow-up wave. Linear mixed-effects models assessed the association of NPI-Total, NPI-Depression, and NPI-Anxiety scores (obtained at baseline) on longitudinal change in neuropsychological performance, controlling for age, sex, and education.ResultsBaseline NPI-Total score was associated with a more rapid rate of decline in word list memory, praxis recall, and animal fluency. Baseline NPI-Depression was not associated with later decline on any of the cognitive tests, while baseline NPI-Anxiety was associated with decline in Symbol Digit Modality.ConclusionIn conclusion, among clinically normal older adults derived from this population-based study, total burden of NPS was associated with longitudinal cognitive decline. These results add to the evidence that NPS are risk factors for or clinical indicators of preclinical dementia syndrome. Our study was an exploratory study and we did not control for multiple comparisons.