Dementia and Atrial Fibrillation: Pathophysiological Mechanisms and Therapeutic Implications

Atrial fibrillation increases the risk of stroke by a factor of four- to fivefold, and dementia is a common consequence of stroke. However, atrial fibrillation has been associated with cognitive impairment and dementia, even in patients without prior overt stroke. Nonischemic mechanisms include cerebral hypoperfusion, vascular inflammation, brain atrophy, genetic factors, and shared risk factors such as age or hypertension. Critical appraisal of studies evaluating the association between atrial fibrillation and dementia in stroke-free patients reveals that several suffer from methodological issues, such as not including silent stroke or anticoagulation therapy in multivariate analyses. Some studies show a close relationship between atrial fibrillation and dementia due to silent stroke, in the absence of overt stroke. Evidence is accumulating that anticoagulation may be effective to decrease the risk of dementia in atrial fibrillation patients. Overall, the pathogenesis linking atrial fibrillation to dementia is likely multifactorial. Cerebral infarctions, including silent stroke, play a central role. These findings underscore the importance of stroke prevention measures in atrial fibrillation patients.     

Atrial Fibrillation and Cognitive Function: JACC Review Topic of the Week

Numerous vascular risk factors and vascular diseases contribute to cognitive impairment and dementia. Many studies and registries show an association of atrial fibrillation (AF) with cognitive impairment, cognitive decline, and dementia. This is true for vascular dementia and Alzheimer's disease. The assumed multifactorial mechanisms include ischemic stroke, both apparent and silent, cerebral microinfarcts, cerebral hemorrhage, and reduced cerebral blood flow. A number of retrospective observational and prospective studies support that anticoagulation in patients with AF may reduce the risk of cognitive decline and dementia. This holds for both vitamin K antagonists (e.g., warfarin) and direct oral anticoagulants. However, it still remains unproven if anticoagulation reduces cognitive decline and dementia in AF patients based on randomized trials.     

Hypertension and Dementia: A comprehensive review from the HOPE Asia Network

Approximately 365 million people in Asia were classified as elderly in 2017. This number is rising and expected to reach approximately 520 million by 2030. The risk of hypertension and cognitive impairment/dementia increases with age. Recent data also show that the prevalence of hypertension and age‐related dementia are rising in Asian countries. Moreover, not many people in Asian countries are aware of the relationship between hypertension and cognitive impairment/dementia. Furthermore, hypertension control is poorer in Asia than in developed countries. Hypertension is known to be a major risk factor for damage to target organs, including the brain. Decreased cognitive function can indicate the presence of target organ damage in the brain. Twenty‐four‐hour blood pressure profiles and blood pressure variability have been associated with cognitive impairment and/or silent cerebral diseases, such as silent cerebral infarction or white matter lesions, which are predisposing conditions for cognitive impairment and dementia. Hypertension that occurs in midlife also affects the incidence of cognitive impairments in later life. Managing and controlling blood pressure could preserve cognitive functions, such as by reducing the risk of vascular dementia and by reducing the global burden of stroke, which also affects cognitive function.     

Vascular Dementia: Distinguishing Characteristics, Treatment, and Prevention

Vascular dementia (VaD) is the second-most-common cause of dementia in the elderly, after Alzheimer's disease (AD). VaD is defined as loss of cognitive function resulting from ischemic, hypoperfusive, or hemorrhagic brain lesions due to cerebrovascular disease or cardiovascular pathology. Diagnosis requires the following criteria: cognitive loss, often predominantly subcortical; vascular brain lesions demonstrated by imaging; a temporal link between stroke and dementia; and exclusion of other causes of dementia. Poststroke VaD may be caused by large-vessel disease with multiple strokes (multiinfarct dementia) or by a single stroke (strategic stroke VaD). A common form is subcortical ischemic VaD caused by small-vessel occlusions with multiple lacunas and by hypoperfusive lesions resulting from stenosis of medullary arterioles, as in Binswanger's disease. Unlike with AD, in VaD, executive dysfunction is commonly seen, but memory impairment is mild or may not even be present. The cholinesterase inhibitors used for AD are also useful in VaD. Prevention strategies should focus on reduction of stroke and cardiovascular disease, with attention to control of risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, and hyperhomocysteinemia.     

Microbleeds in vascular dementia: Clinical aspects

Microbleeds are small dot-like lesions which can be appreciated on gradient echo, T2*-weighted magnetic resonance images as hypointensities. They are considered as an expression of small vessel disease on MRI, next to lacunes and white matter hyperintensities (WMH). Microbleeds are relatively common in vascular dementia, with reported prevalences between 35% and 85%. In the context of vascular dementia, microbleeds are mainly thought to result from hypertensive vasculopathy, but the frequent co-occurrence of lobar microbleeds suggests that neurodegenerative pathology and/or cerebral amyloid angiopathy is also of importance. The presence of multiple microbleeds in vascular dementia or in patients with vascular cognitive impairment is related to worse performance on cognitive tests, mainly in psychomotor speed and executive functioning. They may have some predictive value in terms of predicting development of (vascular) dementia, mortality and disability. Data on the occurrence of stroke and post-stroke dementia in patients with microbleeds are to date not available. New definitions and diagnostic criteria for vascular dementia and vascular cognitive impairment are needed and should take into account microbleeds.     

Association between diabetes mellitus and post‐stroke cognitive impairment

Stroke survivors suffer from various physical, emotional, and cognitive impairments. These changes are dynamic and depend on multiple factors, including underlying diseases, baseline brain function and pathology, the site of the stroke and the post‐stroke inflammation, neurogenesis as well as the subsequent remodeling of the neuro‐network. First we review the structural and pathological changes of the brain in stroke survivors with diabetes mellitus, which may lead to post‐stroke cognitive dysfunction. Second, we provide evidence of hyperglycemia, diabetes mellitus, hypoglycemia, and their relationship with post‐stroke cognitive impairment (PSCI) and post‐stroke dementia (PSD). In addition to conventional biomarkers, such as HbA1c, we also provide other novel tools to predict PSCI/PSD, such as glycemic variability, receptor for advanced glycation end products, and gut microbiota. Finally, we attempt to provide some modifying methods for glycemic control, focusing on the prevention of PSCI/PSD.     

Preventing cognitive decline.

Many studies of age-related cognitive decline have failed to distinguish between usual and successful aging. Although some degree of cognitive impairment is associated with aging, when one looks at average performance, there is great variability among individuals, with many showing little or no deleterious effects of aging on intellectual abilities. Many of the risk factors for dementia and for conditions associated with cognitive impairments can be treated or controlled. Among the preventable causes of cognitive decline are the following: AIDS, Alcohol and drug abuse, Cerebrovascular disease, Exposure to organic solvents or lead, Head trauma, Overmedication, Syphilis. Other conditions that may cause cognitive decline can be controlled or treated: Atherosclerosis, Depression, Diabetes, Emphysema, High blood pressure, Obesity, Sleep disorders, Thyroid dysfunction. In addition, it may be possible to enhance the cognitive performance of even healthy elderly people through changes in diet and lifestyle. Recent data raise the possibility that improved prenatal and perinatal care and greater access to educational opportunities may result in a decreased incidence of dementia in future generations of older adults. Although they are rapidly becoming more numerous, the efficacy of cognitive training programs in preventing or slowing cognitive decline has not yet been demonstrated. Nevertheless, such programs may ameliorate cognitive impairment by reducing the psychiatric disabilities associated with anxiety and depression. The general principle underlying these strategies for limiting cognitive impairment with age is to maximize brain reserve and minimize brain damage.     

Homocysteine and cognitive function

The prevention and treatment of age-related cognitive impairment and dementia is one of the greatest and most elusive challenges of our time. The prevalence of dementia increases exponentially with age, as does the prevalence of those with micronutrient deficiency. Several studies have shown that elevated homocysteine is correlated with cognitive decline and with cerebral atrophy and that it predicts the subsequent development of dementia in cognitively intact middle-aged and elderly individuals. If elevated homocysteine promotes cognitive dysfunction, then lowering homocysteine by means of B-vitamin supplementation may protect cognitive function by arresting or slowing the disease process.     

社区脑卒中高危人群非痴呆性血管性认知功能障碍筛查及相关因素分析

目的了解社区脑卒中高危人群认知功能现状及其相关影响因素。方法采用横断面调查方法对天津市河西区4个社区539例脑卒中高危人群进行筛查,采用简易智能状态检查量表及临床痴呆量表评估认知功能,以是否诊断非痴呆性血管性认知功能障碍(VCIND)分为认知正常组401例和认知障碍组138例,比较分析脑卒中高危人群认知功能障碍与脑卒中危险因素的相关性。结果与认知正常组比较,认知障碍组男性(57.2%vs 46.1%)、年龄≥65岁(60.9%vs 39.7%)、高中以下文化程度(87.0%vs 75.1%)、高脂血症(68.8%vs 55.1%)、脑卒中史(34.1%vs 21.7%)、高同型半胱氨酸血症(63.8%vs 53.6%)认知障碍发生率明显升高(P<0.05,P<0.01);高中以下文化程度是影响脑卒中高危人群认知功能的独立危险因素(OR=0.494,95%CI:0.276⁰.883,P<0.05)。结论社区脑卒中高危人群是VCIND的易患人群,提示及早对具有血管性危险因素的社区人群进行认知功能筛查,对防治VCIND的发生具有重要意义。     

Hypertension and Mild Cognitive Impairment

The brain is an early target for organ damage due to high blood pressure. Hypertension is the major modifiable risk factor for stroke and small vessel disease. It has been suggested that cerebral microvascular disease contributes to vascular cognitive impairment. The mechanisms underlying hypertension-related cognitive changes are complex and not yet fully understood. Both high and, especially in the elderly, low blood pressure (BP) have been linked to cognitive decline and dementia. There is some evidence that antihypertensive drug treatment could play a role in the prevention of cognitive impairment through BP control. The BP levels that should be targeted to achieve optimal perfusion while preventing cognitive decline are still under debate.     

Vascular Cognitive Impairment and Dementia: JACC Scientific Expert Panel

Cognitive impairment associated with aging has emerged as one of the major public health challenges of our time. Although Alzheimer’s disease is the leading cause of clinically diagnosed dementia in Western countries, cognitive impairment of vascular etiology is the second most common cause and may be the predominant one in East Asia. Furthermore, alterations of the large and small cerebral vasculature, including those affecting the microcirculation of the subcortical white matter, are key contributors to the clinical expression of cognitive dysfunction caused by other pathologies, including Alzheimer’s disease. This scientific expert panel provides a critical appraisal of the epidemiology, pathobiology, neuropathology, and neuroimaging of vascular cognitive impairment and dementia, and of current diagnostic and therapeutic approaches. Unresolved issues are also examined to shed light on new basic and clinical research avenues that may lead to mitigating one of the most devastating human conditions.     

Hypertension and cognitive function: Pathophysiologic effects of hypertension on the brain

Accumulating evidence supports a causal role of hypertension for cognitive decline above and beyond its relationship to frank stroke. Hypertension-associated pathologic changes in the brain and its vasculature include vascular remodeling, impaired cerebral autoregulation, cerebral microbleeds, white matter lesions, unrecognized lacunar infarcts, and Alzheimer-like changes such as amyloid angiopathy and cerebral atrophy. White matter lesions and retinal vascular changes, both of which can be imaged noninvasively, may reveal the general condition of the cerebral vasculature or the presence of arteriosclerotic or hypertensive encephalopathy. These noninvasive indicators may also identify a subgroup in whom infarct prevention, particularly via blood pressure reduction, is of paramount importance. Optimal control of blood pressure on a population-wide basis, but particularly in those prone to cognitive loss, is thus a critically important but as yet elusive goal that should be fully exploited for its potential to reduce future cognitive impairment.     

急性缺血性卒中患者认知损害的危险因素

大多数缺血性卒中患者在急性期已有认知损害的表现,以执行功能障碍为主,兼见多个认知域的损害.认知损害的表现和转归与多种因素有关,包括高龄、低教育水平、女性、种族、基因等人口统计学差异;卒中前认知水平;梗死灶的部位、大小、数量、梗死次数等梗死特点;脑血管、非脑血管等血管因素;以及既往史、药物使用史、心理状况、生活方式等其他因素.对相关危险因素进行分析有助于深入理解急性缺血性卒中对认知功能的影响,为后期认知恢复和血管性痴呆的二级预防提供借鉴.     

Association between diabetes mellitus and post-stroke cognitive impairment

Stroke survivors suffer from various physical, emotional, and cognitive impairments. These changes are dynamic and depend on multiple factors, including underlying diseases, baseline brain function and pathology, the site of the stroke and the post-stroke inflammation, neurogenesis as well as the subsequent remodeling of the neuro-network. First we review the structural and pathological changes of the brain in stroke survivors with diabetes mellitus, which may lead to post-stroke cognitive dysfunction. Second, we provide evidence of hyperglycemia, diabetes mellitus, hypoglycemia, and their relationship with post-stroke cognitive impairment (PSCI) and post-stroke dementia (PSD). In addition to conventional biomarkers, such as HbA1c, we also provide other novel tools to predict PSCI/PSD, such as glycemic variability, receptor for advanced glycation end products, and gut microbiota. Finally, we attempt to provide some modifying methods for glycemic control, focusing on the prevention of PSCI/PSD.     

Potential for antihypertensive treatment with an AT(1)-receptor blocker to reduce dementia in the elderly

Hypertension is an established risk factor for stroke and other cerebrovascular disorders. Both stroke and small lacunar infarcts or white matter lesions can cause cognitive impairment and dementia, and there is evidence that vascular risk factors play a major role in the development of both Alzheimer's disease and vascular dementia. Several large epidemiological studies have shown that raised blood pressure in midlife is a strong risk factor for dementia later in life; however, blood pressure often decreases following the development of dementia. The cognitive function hypothesis proposes that elevated blood pressure increases the risk of decline of cognitive function, and that this can be reversed by active lowering of blood pressure. Evidence in support of this hypothesis comes from the Syst-Eur Dementia project, and from a number of smaller studies. SCOPE (Study on Cognition and Prognosis in the Elderly) is a large prospective study involving almost 5000 elderly patients (age 70-89 years), who are randomised to receive candesartan cilexetil, 8-16 mg, or placebo. Candesartan was chosen for this study because it is effective and well tolerated in elderly patients. SCOPE should provide important information on the long-term effects of AT(1)-receptor blocker treatment with candesartan on morbidity-including effects on cognitive function-and cardiovascular mortality in elderly hypertensive patients.     

Endovascular middle cerebral artery occlusion in rats as a model for studying vascular dementia

Vascular dementia (VaD), incorporating cognitive dysfunction with vascular disease, ranks as the second leading cause of dementia in the United States, yet no effective treatment is currently available. The challenge of defining the pathological substrates of VaD is complicated by the heterogeneous nature of cerebrovascular disease and coexistence of other pathologies, including Alzheimer’s disease (AD) types of lesion. The use of rodent models of ischemic stroke may help to elucidate the type of lesions that are responsible for cognitive impairment in humans. Endovascular middle cerebral artery (MCA) occlusion in rats is considered to be a convenient and reliable model of human cerebral ischemia. Both sensorimotor and cognitive dysfunction can be induced in the rat endovascular MCA occlusion model, yet sensorimotor deficits induced by endovascular MCA occlusion may improve with time, whereas data presented in this review suggest that in rats this model can result in a progressive course of cognitive impairment that is consistent with the clinical progression of VaD. Thus far, experimental studies using this model have demonstrated a direct interaction of cerebral ischemic damage and AD-type neuropathologies in the primary ischemic area. Further, coincident to the progressive decline of cognitive function, a delayed neurodegeneration in a remote area, distal to the primary ischemic area, the hippocampus, has been demonstrated in a rat endovascular MCA occlusion model. We argue that this model could be employed to study VaD and provide insight into some of the pathophysiological mechanisms of VaD.     

Type 2 diabetes mellitus,cognitive impairment and dementia

Aims We set out to examine the evidence for an association between cognitive impairment or dementia and the presence of Type 2 diabetes mellitus (DM). We also sought evidence of potential mechanisms for such an association. Methods A literature search of three databases was performed and the reference lists of the papers so identified were examined, using English language papers only. Results We found evidence of cross-sectional and prospective associations between Type 2 DM and cognitive impairment, probably both for memory and executive function. There is also evidence for an elevated risk of both vascular dementia and Alzheimer’s disease in Type 2 DM albeit with strong interaction of other factors such as hypertension, dyslipidaemia and apolipoprotein E phenotype. Both vascular and non-vascular factors are likely to play a role in dementia in diabetes. Conclusions Current classification structures for dementia may not be adequate in diabetes, where mixed pathogenesis is likely. Further research into the mechanisms of cognitive impairment in Type 2 DM may allow us to challenge the concept of dementia, at least in these patients, as an irremediable disease. Diabet. Med. 16, 93–112 (1999)     

The Impact of Atrial Fibrillation and Its Treatment on Dementia

Atrial fibrillation (AF) is a very common tachyarrhythmia and is becoming increasingly prevalent, while dementia is a neurological condition manifested as loss of memory and cognitive ability. Both these conditions share several common risk factors. It is becoming increasingly evident that AF increases the risk of dementia. There are several pathophysiological mechanisms by which AF can cause dementia. AF increases the stroke risk and strokes are strongly associated with dementia. Besides stroke, altered cerebral blood flow in AF and cerebral microbleeds from anticoagulation may enhance the risk of dementia. Maintaining sinus rhythm may therefore decrease this risk. Catheter ablation is emerging as an effective alternative to maintain patients in sinus rhythm. This procedure has also shown promise in decreasing the risk of all types of dementia. Besides maintaining sinus rhythm and oral anticoagulation, aggressive risk factor modification may reduce the likelihood or delay the onset of dementia.     

心房颤动和认知功能下降的关系研究

心房颤动(房颤)是老年人常见的心律失常,并随着年龄增长发病率及病死率增高.众多的血管危险因素和血管疾病导致认知功能障碍和痴呆,而年龄亦是认知功能障碍的最主要因素.房颤和认知功能障碍相关的可能机制有:共同危险因素及共患病、缺血性卒中(有症状或无症状)和房颤的促炎状态等.房颤患者窦律的恢复和抗凝治疗有可能降低认知功能障碍的...     

Alzheimer’s Disease and Vascular Aging: JACC Focus Seminar

Alzheimer’s disease, the leading cause of dementia in the elderly, is a neurodegenerative condition characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, age-related vascular changes accompany or even precede the development of Alzheimer’s pathology, raising the possibility that they may have a pathogenic role. This review provides an appraisal of the alterations in cerebral and systemic vasculature, the heart, and hemostasis that occur in Alzheimer’s disease and their relationships to cognitive impairment. Although the molecular pathogenesis of these alterations remains to be defined, amyloid-β is a likely contributor in the brain as in the heart. Collectively, the evidence suggests that vascular pathology is a likely pathogenic contributor to age-related dementia, including Alzheimer’s disease, inextricably linked to disease onset and progression. Consequently, the contribution of vascular factors should be considered in preventive, diagnostic, and therapeutic approaches to address one of the major health challenges of our time.