Prospects for prevention and treatment of vascular cognitive impairment

With the aging population and rising prevalence of vascular disease in developed and developing countries, increasing numbers of individuals are at risk of cognitive impairment. Despite the potential of the therapeutics that are currently under investigation, none have yet fulfilled their promise for the prevention and treatment of dementia. The term vascular cognitive impairment (VCI) describes individuals with significant cognitive impairment arising from vascular disease. Risk factors predisposing to stroke correlate with brain changes, cognitive loss and Alzheimer's disease pathology. The volume of the infarcts and white matter changes, silent lacunar infarcts, and global and regional brain atrophy may be imaged non-invasively, targeted as surrogates of the dementia processes and considered parameters to be targeted for interventional strategies. As the greatest chance to prevent cognitive impairment and its progression is by intervening in the early stages or prior to any change, the development of preventative therapeutics is an important strategy. Non-invasive magnetic resonance imaging techniques may help to identify a subgroup of patients in whom infarct prevention, via risk factor control, may be of paramount importance. As the pathophysiology of dementia becomes more fully understood by coupling neuropsychological with neuroimaging, genetic and pathological features, there is the potential for the establishment of diagnostic criteria of the early phase of VCI and the testing of novel interventional strategies.     

Brain imaging in type 2 diabetes

Type 2 diabetes mellitus (T2DM) is associated with cognitive dysfunction and dementia. Brain imaging may provide important clues about underlying processes. This review focuses on the relationship between T2DM and brain abnormalities assessed with different imaging techniques: both structural and functional magnetic resonance imaging (MRI), including diffusion tensor imaging and magnetic resonance spectroscopy, as well as positron emission tomography and single-photon emission computed tomography.Compared to people without diabetes, people with T2DM show slightly more global brain atrophy, which increases gradually over time compared with normal aging. Moreover, vascular lesions are seen more often, particularly lacunar infarcts. The association between T2DM and white matter hyperintensities and microbleeds is less clear. T2DM has been related to diminished cerebral blood flow and cerebrovascular reactivity, particularly in more advanced disease. Diffusion tensor imaging is a promising technique with respect to subtle white matter involvement. Thus, brain imaging studies show that T2DM is associated with both degenerative and vascular brain damage, which develops slowly over the course of many years. The challenge for future studies will be to further unravel the etiology of brain damage in T2DM, and to identify subgroups of patients that will develop distinct progressive brain damage and cognitive decline.     

Neuropsychology of cognitive ageing, minimal cognitive impairment, Alzheimer's disease, and vascular cognitive impairment

In this review, the neuropsychological symptoms of different diseases in the elderly are described. After a brief explanation of relevant principles in the neuropsychological assessment of older individuals, a summary of the complex relation between ageing and cognition is presented. It may be concluded that cognitive decline is not an inevitable outcome of ageing, and may well be the result of unrecognised pathology. The term mild cognitive impairment is reserved for patients whose impairment is objectively demonstrable but is not pronounced in more than one domain of cognition and does not seriously affect activities of daily living. The initial phase of Alzheimer's disease is marked by a progressive deterioration of episodic memory. When the process advances, the impairment spreads to other functions, such as semantic memory, language and visuo-spatial ability. Vascular dementia is the second most common type of dementia; however, it is increasingly being recognised that vascular dementia is actually a heterogeneous syndrome and that several vascular pathologies can lead to cognitive deterioration. In contrast to the striking deficits produced by cortical infarcts, lesions of the subcortical white matter are mainly associated with a non-specific slowing of behaviour. Cerebrovascular disease also plays an important role in forms of cognitive decline other than dementia, and as such, it appears to be no less prevalent in old age than Alzheimer's disease. Neuropsychology is an important asset to the study and treatment of cognitive decline, but must be embedded in a multi-disciplinary context.     

Treatment of leukoaraiosis: a futuristic view

Leukoaraiosis (LA or white matter changes of the brain) is a common finding on brain imaging studies in the elderly people. LA predisposes to dementia, ischemic stroke, intracerebral hemorrhage, and cognitive decline as well as associates with a significant increase in falls and gait disorders. As population ages, the incidence of LA increases and is becoming a major global health problem. Therefore, strategies for its prevention and management are urgently needed. This review includes basic knowledge on the pathophysiology, patterns of clinical presentation, risk factors, and imaging findings of LA. The very last and the most comprehensive part of this review discusses potential therapeutic approaches of the future.     

左侧丘脑结节动脉梗死患者的认知功能障碍：1例病例报告及文献复习

血管性认知功能障碍目前正逐步成为脑卒中后临床关注的重点。多种机制介导的血管性认知功能障碍是一类异质性疾病,而作为与血管性事件直接相关的重要部位的梗死在其中起着重要作用。左侧丘脑结节动脉梗死所造成的急性认知功能障碍因病变部位较局限,易为临床医生忽略。本文报告1例左侧丘脑结节动脉梗死患者的诊治情况,并就此种重要部位梗死患者的认知功能障碍作一简要介绍。     

Cytokines in dementias

Knowledge regarding putative inflammatory component(s) participating in Alzheimer's disease (AD) and in vascular dementia (VAD) remains scarce. Recently, we have demonstrated the presence of inflammatory components, such as cytokines, in the CSF of demented patients. Although the initial events triggering the neurodegenerative processes in AD versus VAD may be different and thus lead to different neuropathological outcome, they may initiate a similar cascade of cytokine production in response to neuronal injury. The cytokines released in the CNS may in turn, act in a similar manner in both diseases, amplifying certain pathological changes such as amyloidogenesis and amyloid accumulation in the blood vessels, white matter lesions and angiogenesis. This hypothesis is supported by clinical studies demonstrating the presence of white matter infarcts and cerebrovascular pathology in patients with AD as well as the presence of senile plaques in patients with VAD. This review will focus on the production of pro-inflammatory and anti-inflammatory cytokines in dementia, and their putative role for glia cell activation, amyloidogenesis, vascular changes, white matter damage and neurodegeneration.     

脑白质疏松与血管性痴呆的相关因素分析

目的 探讨脑白质疏松与血管性痴呆的相关因素。方法 对2000～2003年住院经颅脑CT或MRI检查出现脑白质疏松的52例患者的临床资料进行统计分析。结果 52例头颅CT或NIRI均存在白质疏松,其中高血压41例,脑梗死灶39例,脑萎缩43例,认知功能下降37例。血管性痴呆组包括26例Binswanger脑病型。血管性痴呆组慢性脑外器官功能障碍高于非痴呆组,以2～4个器官障碍为多,预后差。结论 脑白质疏松与高血压和血管性痴呆密切相关,痴呆组有较多的血管危险因素和中风事件,死亡率高。对患有脑白质疏松的病人需仔细诊断、评估并给予发展成痴呆者以有效的控制措施。     

《中国卒中后认知障碍管理专家共识》解读

中国是卒中和痴呆的大国,卒中后认知障碍是卒中常见的并发症,不仅严重影响患者生活质量,而且显著降低卒中患者的生存时间,给家庭及社会带来了沉重的负担。卒中后早期干预可以减少血管性痴呆的发生,血管性因素的可控性为痴呆的治疗提供了新的思路。《中国卒中后认知障碍管理专家共识》将切实指导临床,使得卒中患者的生活质量得以提高。     

脑梗死后血管性痴呆发病危险因素研究

摘要 目的：探讨脑梗死后血管性痴呆（VD）的发病危险因素。方法：随机选择392例急性脑梗死患者,收集临床及实验室资料,采用多因素Logistic回归分析,分析脑梗死后VD发病危险因素。结果：84名患者诊断为VD（21.4%）。单因素分析中,VD与病灶的数目、部位,脑萎缩及WMLs相关,多因素分析中发现左侧或双侧大脑半球病变、病灶的数目和脑萎缩为VD发病的独立危险因素,OR值分别为8.958、1.375和2.297。2组间一般情况,血脂水平无差异（P ﹥0.05）。结论 脑梗死后VD很常见,小血管病变是VD的主要类型,应早期进行针对性的预防和治疗,以减少和延缓VD的发生。     

卒中后认知功能损害的演变及治疗进展

脑卒中是我国中老人群最主要的死亡原因之一.卒中可导致神经功能缺损、行为、情感障碍外,认知功能损害很常见.认知功能损害是卒中复发的重要危险因子,使血管性痴呆发生的风险增高并影响病人的康复.研究卒中后认知功能损害的特征,以及病程中的演变轨迹及其相关影响因素,给予针对性干预及治疗,以减少及延缓认知损害的发生.该文对卒中后认知功能损害的演变及治疗进展进行综述.     

Drug therapy for the secondary prevention of stroke in hypertensive patients: current issues and options

Hypertension is the major risk factor for ischaemic and haemorrhagic clinical strokes as well as for silent brain infarcts with a continuous association between both systolic and diastolic blood pressures. Epidemiological data highlight the increasing burden to come over the next decades. Without any doubt, antihypertensive treatment is the most important therapy to reduce the risk of stroke by approximately 30-40%. International guidelines recommend antihypertensive treatment for primary prevention with evidence level A.Recurrent strokes or transient ischaemic attack (TIA) are an important practical, clinical and economic problem, and have a major impact on the development of vascular dementia. All stroke patients and patients with TIA have to be regarded as very high-risk patients. Hypertension increases the risk of recurrent strokes. Only limited data directly address the role of blood pressure treatment among individuals with stroke or TIA.There is a general lack of definitive data regarding when to start antihypertensive treatment in the initial phase, and treatment of hypertension in the acute period after stroke is still under debate. Experimental and clinical data suggest that reducing the activity of the renin-angiotensin aldosterone system (RAAS) may have beneficial effects beyond the lowering of blood pressure. There is increasing evidence of cerebroprotective effects for medication influencing the RAAS, such as angiotensin receptor antagonists or ACE inhibitors. The MOSES study showed for the first time superiority of an angiotensin receptor antagonist compared with a calcium channel antagonist in antihypertensive treatment for secondary stroke prevention. Optimal blood pressure range in secondary prevention seems to be 120-140/80-90 mm Hg, but questions about a J- or U-shaped curve are still not answered sufficiently. The effects of additional antihypertensive treatment in the evening for stroke patients with 'non-dipping' blood pressure need to be investigated.Currently, the most important goal in primary and secondary prevention of stroke is a strict normotensive blood pressure control. Antihypertensive treatment is recommended for both prevention of recurrent stroke and prevention of other vascular events in individuals who have had an ischaemic stroke or TIA (class I, level of evidence A). Many open questions remain and funding of stroke research needs to be increased in the near future.     

静止性脑小血管病与认知功能障碍的关系

脑小血管病（cerebral small vessel disease, CSVD）在影像学上主要以腔隙性梗死、白质病变和脑微出血的形态存在。静止性CSVD与认知功能障碍密切相关,其导致的认知功能障碍主要表现为执行功能障碍、反应迟钝和注意力下降等,与病灶部位、数量和大小相关。本文就静止性CSVD的主要影像学表现及其与认知功能障碍的关系作一综述,以期加深临床医生对静止性CSVD及其危害的认识并提高识别率,由此尽早干预而延缓患者认知功能障碍的发生和发展,提高患者的生活质量。     

Hyperhomocysteinemia in movement disorders: Current evidence and hypotheses

Elevated plasma levels of homocysteine (Hcy) are a risk factor for systemic vascular diseases, stroke and vascular dementia. In recent years, increasing Hcy levels have been detected in neurological disorders that are not vascular in origin including Alzheimer's Disease and movement disorders (MD) such as idiopathic Parkinson's Disease (PD), Huntington's Disease (HD) and primary dystonia. Hyperhomocysteinemia (HHcy) in PD results from L-Dopa administration and its O-methylation dependent from catechol-O-methyltransferase and may be implicated in the development of motor complications and non-motor symptoms, such as dementia. In a recent study, HHcy has been evidenced in HD patients, compared to controls. Because mutated Huntington protein influences Hcy metabolism by modulating cystathionine-beta-synthase activity, Hcy could represent a biological marker of neurodegeneration and could explain the leading role of cardiovascular and cerebrovascular diseases as causes of death in HD. Finally, several cases of homocystinuria associated with dystonia, and some recent reports of elevated Hcy in patients with primary adult onset dystonia have been published. Increased Hcy plasma levels may have important implications in patients affected by these basal ganglia disturbances, by exerting neurotoxic effects, contributing to neurotransmitter imbalance in motor circuits, and increasing the risk for vascular insults and cognitive dysfunctions.     

Clinical analysis of first-ever acute ischemic stroke involving the territory of paramedian mesencephalic arteries

To determine one-year clinical outcome of patients with first-ever acute ischemic stroke involving the territory of paramedian mesencephalic arteries (PMAS), we conducted a prospective study evaluating the cognitive functions of 28 patients with PMAS. Neuropsychological tests were performed during the first month of stroke onset and at the 12^th month of follow-up. There were 12 women and 16 men. Mean age of onset for women and men was 70 years and 65 years, respectively. Progressing strokes occurred in 62% of patients and 96% developed a full-blown picture of the clinical triad of akinetic mutism, hypersomnolence, and bilateral blepharoptosis and ophthalmoparesis. Involuntary movements occurred in 6, and focal myoclonus in 4 patients. The top four associated risk factors were hypertension (68%), hyperlipidemia (57%), diabetes mellitus (46%), and atrial fibrillation (36%). Unilateral midbrain infarctions occurred in 12 patients and bilateral lesions in 16. Thalamic infarctions were unilateral in 10 and bilateral in 13 cases. Three of the 28 (11%) patients died of recurrent cerebral infarctions within 1 year of the onset of PMAS. The recurrent infarctions involved the basilar artery territory in two cases and the carotid system in another. One patient died of acute myocardial infarction. Of the 24 patients who had survived the stroke by 1 year, 20 (71%) developed dementia. We conclude that first-ever ischemic stroke with PMAS is not a benign syndrome. Most patients developed dementia by 1 year after the stroke.     

Cognitive decline as a consequence of essential hypertension

Hypertension is a leading cardiovascular risk for cardiovascular morbidity and mortality. Age is the strongest risk factor for dementia and with the increasing life expectancy the number of patients living with dementia worldwide is estimated to progressively rise. A number of studies support an association between hypertension, particularly in midlife, and the development of cognitive disorders and dementia, including Alzheimer's disease. According to this, considering hypertension as a possible modifiable risk factor for the cognitive decline is of great clinical interest. Treatment of hypertension in midlife seems to promote considerable benefits with regard to cardiovascular outcomes. Longitudinal studies examining the possible benefit of anti-hypertensive treatments on cognitive decline have produced promising results. Nevertheless, the results from randomised controlled clinical trials on treatment of hypertension are not conclusive for the effect on cognitive decline and dementia. New randomized controlled trials are needed to definitively clarify clinical advantages and specifically elucidate the relationship between anti-hypertensive treatments and cognitive function or dementia.     

Insulin resistance in the brain: An old-age or new-age problem?

Life expectancy is rising however with more people living longer there is a concomitant rise in the incidence of dementia. In addition to age-related cognitive decline there is a higher risk of going on to develop vascular dementia and Alzheimer's disease associated with aspects of modern lifestyle. Most worryingly, recent data reports accelerated cognitive decline in adolescents associated with poor diet (high fat and calorie intake). Thus the increase in dementia in 'old-age' may have as much to do with 'new-age' lifestyle as it does with normal ageing. It would seem wise therefore to investigate the molecular connections between lifestyle and cognitive decline in more detail. Epidemiological evidence suggests an increased risk of developing dementia (including Alzheimer's disease) in individuals with obesity and type 2 diabetes but also in those with poor insulin sensitivity without diabetes, implicating a mechanistic link between adiposity, insulin sensitivity and dementia. Insulin receptors are expressed in the brain and physiological roles for insulin in the CNS are starting to be delineated. Indeed disrupted neuronal insulin action may underlie the link between diabetes and neurodegenerative disorders. This review discusses the difficulties in quantifying insulin sensitivity of the brain and why it is vital that we develop technology for this purpose so that we can establish its role in this 'new-age' dementia. This has particular relevance to the design and interpretation of clinical trials in progress to assess potential benefits of insulin and insulin sensitisers on prevention of cognitive decline.     

血管性痴呆模型及信号通路研究进展

血管性痴呆是指由缺血性卒中、出血性卒中和造成脑区低灌注的脑血管疾病所致的严重认知功能障碍综合征。血管性痴呆是可以预防的,因为针对致病性脑血管疾病已建立了例如控制血管危险因素、抗血小板治疗和抗凝治疗等预防措施,然而目前尚无针对血管性痴呆的对症治疗方法。了解其基本机制及模型对于血管性痴呆的治疗至关重要。本文简述了血管性痴呆的多种动物模型,并简要介绍了目前针对其发病机制的相关通路研究,为血管性痴呆的治疗和用药提供参考。     

White matter NMDA receptors: an unexpected new therapeutic target?

Axons, their ensheathing myelin and supporting glia that make up the white matter in the mammalian brain and spinal cord are fundamentally important for the normal operation of the central nervous system. Prevalent human disorders such as stroke, vascular dementia, multiple sclerosis, brain and spinal cord trauma, HIV-associated dementia, periventricular leukomalacia of premature infants, and seemingly traditional 'gray matter disorders' such as Alzheimer's disease and schizophrenia, exhibit white matter pathology that contributes to morbidity and mortality. N-Methyl-D-aspartate (NMDA) receptors have been shown to have an important role in mediating Ca2+-dependent injury of oligodendrocytes and the myelin sheath; newly recognized family members of the NMDA receptor, known as NR3 subunits, seem to be involved. Recently developed uncompetitive NMDA channel blockers such as memantine hold therapeutic promise because these agents are well tolerated clinically and might prove to be effective at protecting certain white matter elements from a variety of insults.     

老年缺血性卒中患者的认知功能与代谢综合征及炎症反应的关系

目的探讨老年缺血性脑卒中患者的认知功能与代谢综合征(MS)及炎症反应的关系。方法94例缺血性脑卒中患者分为认知功能正常组(NC,34例),轻度血管性认知功能障碍组(MVCI,37例),血管性痴呆组(VD,23例);分别测定其空腹血糖(FBG)、空腹胰岛素(FI NS)、C反应蛋白(CRP)及血压、血脂、体质量指数(BMI),观察各组代谢综合征的发生率,检测炎症标记物,进行对比研究。结果NC组、MVCI组、VD组代谢综合征的发生率(12、33、49%,P<0.05)显著递增;CRP:MVCI组(1.4±0.5)mg/L与VD组(2.1±0.7)mg/L高于NC组(0.8±0.4)mg/L(P<0.05);CRP与胰岛素抵抗指数显著相关(r=0.39,P<0.05)。结论MS及炎症反应是老年缺血性脑卒中患者认知功能下降的重要危险因素。     

Vascular cognitive impairment and Alzheimer’s disease: role of cerebral hypoperfusion and oxidative stress

Cerebrovascular disease may lead to a wide range of cognitive changes, referred to collectively as vascular cognitive impairment. Stroke increases the risk of cognitive impairment and dementia, and may contribute to the progression of Alzheimer's disease (AD). Apart from clinical stroke itself, vascular risk factors are associated with the development of cognitive impairment and dementia. Animal models involving a temporary or permanent interruption of blood flow in the common carotid arteries develop nonprogressive cognitive impairment. Oxidative stress during cerebral hypoperfusion in animal models plays a key role in neuronal death and may thus contribute to the development of cognitive impairment in cerebrovascular disease. Genetic and pharmacological interventions to inhibit the major source of reactive oxygen species, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, are neuroprotective in experimental cerebral ischemia. Recent studies have demonstrated that inhibition of NADPH oxidase activity can mitigate cognitive impairment in rodent models of cerebral hypoperfusion. In this article, we review the evidence linking cognitive impairment and/or AD with NADPH oxidase-dependent oxidative stress, including the renin-angiotensin system.