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.     

Arterial hypertension: a cause of cognitive impairment and of vascular dementia

Arterial hypertension is a well-documented modifiable risk factor for cerebrovascular disease and for both cerebral infarction and intracerebral hemorrhage. Recent studies indicate a relationship between high blood pressure in midlife and dementia in late life and suggest that arterial hypertension may represent a cause of vascular dementia (VaD). This paper has reviewed the main evidence of a link between arterial hypertension and vascular cognitive impairment or VaD. Brain lesions induced by hypertension, diagnostic procedures for early diagnosis of vascular cognitive impairment in at risk subjects and the need to include cognitive assessment in patient's general visits in hypertension units are discussed.     

静息态功能磁共振在皮质下缺血性血管性认知损害中的应用

皮质下缺血性血管病(subcortical ischemic vascular disease, SIVD)被认为是引起血管性认知损害(vascular cognitive impairment, VCI)的最重要和常见的原因。若能早期发现皮质下缺血性血管性认知损害(subcortical ischemic vascular cognitive impairment, SIVCI)或皮质下血管性认知损害(subcortical vascular cognitive impairment, sVCI)患者,会使血管性痴呆(vascular dementia, VaD)在发生之前得到识别甚至逆转其进程成为可能。最近的研究显示,静息态功能磁共振(resting-state fMRI, rsfMRI)有可能为 SIVCI 的诊断提供客观依据。文章对 rsfMRI 在 SIVCI 诊断中的应用进行了综述。     

缺血性卒中后认知功能障碍的患病率和危险因素

目的 明确卒中后认知功能障碍(PSCI)的患病率和危险因素.方法 526例缺血性卒中患者被分为无认知障碍、认知障碍非痴呆(CIND)和血管性痴呆(VaD),根据影像学表现,患者分为皮质下缺血性血管病、皮质型缺血性血管病和其他类型,登记患者人口学、血管危险凶素和卒中病情等.结果 PSCI患病率36.7%.与无认知障碍相比,PSCI患者年龄大、女性比例高、教育程度低、彳T侧瘫痪多、抑郁评分高,但血管危险因素无差别.与无认知障碍者相比,VaD者经济水平低、配偶照料少、失语多、尿失禁多、皮质型缺血性血管病多;CIND者则有较多的皮质下缺血性血管病.VaD者较CIND者皮质型缺血性血管病多、抑郁评分低.高龄、女性、低社会经济水平、失语、皮质下缺血性血管病、皮质型缺血性血管病和抑郁评分高为PSCI的独立危险因素.结论 PSCI常见于缺血性卒中患者,与人口学因素、卒中类型及抑郁有关.     

皮质下缺血性血管病患者注意执行功能损害特征的研究

目的探讨皮质下缺血性血管病(SIVD)患者注意-执行功能损害的特征。方法收集SIVD患者95例,并按照认知功能分为无认知障碍组(NCI)29例、血管性认知障碍非痴呆组(VCI-ND组)40例、血管性痴呆组(VaD组)26例。对所有患者进行全面神经心理测查并分析。结果 95例SIVD患者中,有VCI患者66例,占69.5%,其中VCI-ND患者40例,占VCI总数的60.6%。3组患者执行功能各项测验(DS-F除外)均以VaD组损害最严重,NCI组最轻,3组比较差异有统计学意义(P<0.01)。VCI-ND组和VaID组注意-执行标准分数在各项认知域评分中最低。结论 SIVD患者认知损害的突出领域是注意执行功能,再认和即刻记忆相对保留是其记忆损害的特点。抑郁和其他精神行为异常多见于认知障碍患者。     

N-甲基-D-天冬氨酸受体和突触后致密物质95在血管性痴呆大鼠中作用机制的研究

目的观察血管性痴呆(VaD)大鼠N-甲基-D-天冬氨酸-2B亚基受体(NR2B)和突触后致密物质95(PSD-95)在VaD发生、发展中的作用。方法采用永久性结扎双侧颈总动脉方法将96只Wistar大鼠随机分为假手术组(32只)、VaD模型组(模型组,32只)和美金刚治疗组(治疗组,32只)。用免疫组织化学法检测术后4、8、12、16周大鼠海马NR2B和PSD-95的表达,并同时采用Morris水迷宫测试大鼠的学习记忆水平。结果随着缺血时间的延长,与假手术组比较,模型组大鼠术后4、8、12、16周学习记忆能力下降,差异显著(P<0.01);术后4周时NR2B和PSD-95的表达明显高于假手术组(P<0.01),此后逐渐减少,显著低于假手术组(P<0.01),术后16周时表达最少。治疗组大鼠术后4周时学习记忆水平及NR2B、PSD-95的表达与假手术组比较无显著差异,术后8、12、16周时,上述指标较模型组显著好转但仍差于假手术组(P<0.05,P<0.01)。结论大鼠海马NR2B和PSD-95作为复合体参与VaD的形成和发展,适量的美金刚通过调节NR2B的表达进而改善VaD大鼠的认知功能。     

RNA指纹法分离血管性痴呆大鼠海马内的差异表达基因

目的：分离血管性痴呆（VD）大鼠海马内疾病相关基因，方法：用改良的Pulsinelli-4血管阻断全脑缺血法4－VO法建立VD模型，Morris水迷宫检测其痴呆，以RNA指纹法对比正常老龄大鼠和血管性痴呆大鼠海马组织基因表达，并分离疾病情况下表达差异的基因。结果：在成功建立VD大鼠模型的基础上，分离、筛选、克隆到32条VD海马内疾病相关差异表达基因片段，选取2条VD特异表达的片段进行Northern杂交验证，通过测序与GenBank比较证均为新基因片段，登录号为BG937392、BG937393，结论：RNA指纹法是快速、简便，有效的分离差异基因的方法，本实验分离的差异表达基因可能是直接参与疾病发生，发展过程的致病基因或保护基因。     

血管性痴呆发病机制的研究进展

血管性痴呆(VaD)是因脑缺血后缺血组织缺氧和出血性脑损害所导致的智能及认知功能障碍的临床综合征。VaD目前已经成为致我国人民精神和躯体残疾的主要因素之一。随着人口老龄化,其发病率日益增高。VaD患者生活水平下降,给社会、家庭带来沉重的负担,而其发病机制不明确。VaD是老年期痴呆中有希望预防和治疗的痴呆,因此各方面研究日益受重视,探索其发病机制尤为重要。     

血管性痴呆与血管性认知障碍

由于传统痴呆定义的束缚,目前的血管性痴呆诊断标准不能发现非痴呆的认知障碍,也难以与混合性痴呆相区别,更不能促进血管性痴呆的防治。用血管性认知障碍的概念则可以涵盖所有与血管危险因素和脑血管病变有关的各种程度的认知障碍,促进早期识别和早期干预。     

Melatonin decreases matrix metalloproteinase-9 activation and expression and attenuates reperfusion-induced hemorrhage following transient focal cerebral ischemia in rats

We have previously shown that melatonin reduces postischemic rises in the blood-brain barrier (BBB) permeability and improves neurovascular dysfunction and hemorrhagic transformation following ischemic stroke. It is known that activation of the matrix metalloproteinases (MMPs) plays a crucial role in the pathogenesis of brain edema and hemorrhagic transformation after ischemic stroke. We, herein, investigated whether melatonin would ameliorate MMP-2 and MMP-9 activation and expression in a rat model of transient focal cerebral ischemia. Adult male Sprague-Dawley rats were subjected to a 90-min middle cerebral artery (MCA) occlusion using an intraluminal filament. Melatonin (5 mg/kg) or vehicle was intravenously injected upon reperfusion. Brain infarction and hemorrhage within infarcts were measured, and neurological deficits were scored. The activity and expression of MMP-2 and MMP-9 were determined by zymography, in situ zymography and Western immunoblot analysis. Cerebral ischemia-reperfusion induced increased pro-MMP-9 and MMP-9 activity and expression 24 hr after reperfusion onset. Relative to controls, melatonin-treated animals, however, had significantly reduced levels in the MMP-9 activity and expression (P < 0.01), in addition to reduced brain infarct volume and hemorrhagic transformation as well as improved sensorimotor neurobehavioral outcomes. No significant change in MMP-2 activity was observed throughout the course experiments. Our results indicate that the melatonin-mediated reductions in ischemic brain damage and reperfusion-induced hemorrhage are partly attributed to its ability to reduce postischemic MMP-9 activation and increased expression, and further support the fact that melatonin is a suitable as an add-on to thrombolytic therapy for ischemic stroke patients.     

Functional magnetic resonance imaging of reorganization in rat brain after stroke

Functional recovery after stroke has been associated with brain plasticity; however, the exact relationship is unknown. We performed behavioral tests, functional MRI, and histology in a rat stroke model to assess the correlation between temporal changes in sensorimotor function, brain activation patterns, cerebral ischemic damage, and cerebrovascular reactivity. Unilateral stroke induced a large ipsilateral infarct and acute dysfunction of the contralateral forelimb, which significantly recovered at later stages. Forelimb impairment was accompanied by loss of stimulus-induced activation in the ipsilesional sensorimotor cortex; however, local tissue and perfusion were only moderately affected and cerebrovascular reactivity was preserved in this area. At 3 days after stroke, extensive activation-induced responses were detected in the contralesional hemisphere. After 14 days, we found reduced involvement of the contralesional hemisphere, and significant responses in the infarction periphery. Our data suggest that limb dysfunction is related to loss of brain activation in the ipsilesional sensorimotor cortex and that restoration of function is associated with biphasic recruitment of peri- and contralesional functional fields in the brain.     

大鼠左右大脑中动脉缺血再灌注模型比较

目的探讨大鼠左右大脑中动脉缺血再灌注模型的差异。方法选择右利雄性Wistar大鼠48只,按照随机数字表分为左侧大脑中动脉缺血再灌注组(左侧优势组)、右侧大脑中动脉缺血再灌注组(右侧非优势组),每组24只,每组使用各自侧别的假手术对照。血管内线栓法阻塞大脑中动脉2h,然后再灌注。测试神经功能,取脑分别进行常规TTC染色和HE染色,测量脑梗死体积,光镜下观察脑组织病理变化。结果左侧优势组再灌注24、48和72h神经功能缺损评分明显低于右侧非优势组(P<0.05)。左侧优势组缺血程度较右侧非优势组重。左侧优势组神经元数量严重缺失,海马细胞排列紊乱,脑梗死体积明显大于右侧非优势组[(102.1±8.8)mm3 vs(97.0±11.2)mm3,P<0.05]。结论大鼠优势半球大脑中动脉阻塞后,神经功能缺损程度较非优势侧严重,脑梗死体积更大。大鼠优势半球局灶性脑缺血模型重复性好,而且可靠。     

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.     

补阳还五汤对血管性痴呆大鼠学习记忆和海马N-甲基-D-天冬氨酸受体表达的影响

目的观察补阳还五汤对血管性痴呆(VaD)大鼠海马CA1区N甲基D-天冬氨酸受体表达及长时程增强(LTP)的影响及机制。方法选择SD大鼠144只,随机分为假手术组、VaD模型组(模型组)、尼莫地平组和补阳还五汤组,每组36只。采用四血管阻断法制备VaD大鼠模型。Morris水迷宫实验评估大鼠学习记忆功能,大鼠海马CA3-CA1区记录海马CA1区LTP,免疫组织化学、Western blot法和实时荧光定量PCR检测大鼠海马NR1、NR2A、NR2B蛋白和mRNA表达的变化。结果与假手术组比较,模型组大鼠逃避潜伏期延长和平均探索次数减少(P<0.05),大鼠海马CA1区LTP明显降低(P<0.05),CA1区NR1、NR2A、NR2B蛋白及mRNA表达水平明显降低(P<0.05);与模型组比较,补阳还五汤组、尼莫地平组大鼠学习、记忆成绩明显提高(P<0.05),海马CA1区NR1、NR2A、NR2B蛋白及mRNA表达水平明显升高(P<0.05)。结论补阳还五汤可上调脑缺血再灌注海马CA1区脑组织NR1、NR2A、NR2B蛋白的表达,促进LTP,进而改善VaD大鼠学习记忆能力。     

Alzheimer病和血管性痴呆的病理学关联

Alzheimer病和血管性痴呆是老年人最常见的2种痴呆类型,两者的病理学存在显著关联。Alzheimer病的病理学特征主要是老年斑和神经原纤维缠结,与其相关的血管病理学表现还包括脑淀粉样血管病、微血管病变、脑白质损害、微梗死、腔隙性梗死和脑出血;相对而言,血管性痴呆的病理学变化具有不均一性,既包括传统的多发性脑梗死、微血管损害和缺血后脑病,也存在神经变性性病理学改变。     

大鼠局灶性脑缺血再灌流半暗带神经细胞坏死与凋亡的动态变化

目的探讨脑缺血半暗带转归过程中神经细胞的死亡机制。方法采用大鼠大脑中动脉（ＭＣＡ）闭塞及再通模型,ＭＣＡ闭塞时间分别为３０、６０、９０、１２０和１８０分钟,再灌流４８小时,用ＨＥ染色和ＴＵＮＥＬ原位标记法分别对缺血半暗带和缺血中心区细胞坏死和凋亡的动态变化进行定量观察,并计算两种死亡细胞在缺血中心区和半暗带所占的百分比。结果脑缺血６０～１８０分钟的各时间点,半暗带的神经细胞凋亡率（分别为７６％、１２４％、２３８％和２９４％）,显著高于缺血中心区（分别为６９％、７８％、７９％和８２％）,并随缺血时间的延长而显著升高,细胞坏死率在缺血９０分钟以上时无明显变化。结论脑缺血半暗带恶化过程中神经细胞死亡以及由此所引起的不可逆性损伤病灶的扩大,可能主要是通过细胞凋亡机制实现的。     

Serum uric acid level and association with cognitive impairment and dementia: systematic review and meta-analysis

Serum uric acid (sUA) level may be associated with cognitive impairment/dementia. It is possible this relationship varies with dementia subtype, particularly between vascular dementias (VaD) and Alzheimer’s (AD) or Parkinson’s disease (PDD)-related dementia. We aimed to present a synthesis of all published data on sUA and relationship with dementia/cognition through systematic review and meta-analysis. We included studies that assessed the association between sUA and any measure of cognitive function or a clinical diagnosis of dementia. We pre-defined subgroup analyses for patients with AD, VaD, PDD, mild cognitive impairment (MCI), and mixed or undifferentiated. We assessed risk of bias/generalizability, and where data allowed, we performed meta-analysis to describe pooled measures of association across studies. From 4811 titles, 46 papers (n?=?16,688 participants) met our selection criteria. Compared to controls, sUA was lower in dementia (SDM ?0.33 (95%CI)). There were differences in association by dementia type with apparent association for AD (SDM ?0.33 (95%CI)) and PDD (SDM ?0.67 (95%CI)) but not in cases of mixed dementia (SDM 0.19 (95%CI)) or VaD (SDM ?0.05 (95%CI)). There was no correlation between scores on Mini-Mental State Examination and sUA level (summary r 0.08, p?=?0.27), except in patients with PDD (r 0.16, p?=?0.003). Our conclusions are limited by clinical heterogeneity and risk of bias in studies. Accepting this caveat, the relationship between sUA and dementia/cognitive impairment is not consistent across all dementia groups and in particular may differ in patients with VaD compared to other dementia subtypes.     

THE CHOLINERGIC APPROACH FOR THE TREATMENT OF VASCULAR DEMENTIA: EVIDENCE FROM PRE-CLINICAL AND CLINICAL STUDIES

The involvement of an impaired cholinergic neurotransmission in the pathophysiology of cognitive impairment occurring in vascular dementia (VaD), as well as the possibility of treating it by stimulating cholinergic neurotransmission was reviewed. Pre-clinical data suggest that similarly as documented in dementia disorders of neurodegenerative origin, a cholinergic deficit is involved in the pathophysiology of cognitive impairment of vascular origin. In the past, clinical trials have evaluated cholinergic precursors such as lecithin, citicoline and choline alphoscerate. More recent investigations have assessed acetylcholinesterase (AChE) and cholinesterase (ChE) inhibitors such as donepezil, rivastigmine and galantamine.

In general, treatment with citicoline, choline alphoscerate, as well as with AChE and ChE inhibitors induced favourable effects on cognitive function in dementia disorders of vascular origin. These positive results should be regarded with caution due to the small number of patients included in controlled clinical trials using cholinergic precursors and to the limited number and sample size of trials with AChE and ChE inhibitors. Among compounds investigated, choline alphoscerate was well tolerated, improved cognitive function in VaD patients to a better extent than citicoline and to similar or better extent than other more recently developed drugs. This particular profile would justify reconsideration of the compound in larger controlled clinical trials for the treatment of cognitive dysfunction associated with dementia disorders of vascular origin.     

APP17肽对脑缺血大鼠记忆能力及海马Bcl-2和Bax蛋白表达的影响

目的研究APP17肽对脑缺血大鼠记忆能力及海马Bcl-2和Bax蛋白表达的影响。方法采用双侧颈总动脉结扎方法制备前脑缺血致血管性痴呆大鼠模型,将大鼠随机分为假手术组、手术组和治疗组,每组24只,并观察APP17肽的保护作用,采用Morris水迷宫检测记忆能力,免疫组织化学检测海马Bcl-2和Bax蛋白表达。结果手术组与假手术组比较,记忆能力明显下降(P<0.01),Bcl-2和Bax免疫阳性细胞数增多(P<0.01),治疗组较手术组记忆功能改善明显(P<0.01)。Bcl-2免疫阳性细胞数明显增多(P<0.01),Bax免疫阳性细胞数明显减少(P<0.01)。结论APP17肽可能通过调节Bcl-2和Bax蛋白表达来抑制细胞凋亡,从而改善脑缺血大鼠的记忆能力。     

The cholinergic approach for the treatment of vascular dementia: evidence from pre-clinical and clinical studies

The involvement of an impaired cholinergic neurotransmission in the pathophysiology of cognitive impairment occurring in vascular dementia (VaD), as well as the possibility of treating it by stimulating cholinergic neurotransmission was reviewed. Pre-clinical data suggest that similarly as documented in dementia disorders of neurodegenerative origin, a cholinergic deficit is involved in the pathophysiology of cognitive impairment of vascular origin. In the past, clinical trials have evaluated cholinergic precursors such as lecithin, citicoline and choline alphoscerate. More recent investigations have assessed acetylcholinesterase (AChE) and cholinesterase (ChE) inhibitors such as donepezil, rivastigmine and galantamine. In general, treatment with citicoline, choline alphoscerate, as well as with AChE and ChE inhibitors induced favourable effects on cognitive function in dementia disorders of vascular origin. These positive results should be regarded with caution due to the small number of patients included in controlled clinical trials using cholinergic precursors and to the limited number and sample size of trials with AChE and ChE inhibitors. Among compounds investigated, choline alphoscerate was well tolerated, improved cognitive function in VaD patients to a better extent than citicoline and to similar or better extent than other more recently developed drugs. This particular profile would justify reconsideration of the compound in larger controlled clinical trials for the treatment of cognitive dysfunction associated with dementia disorders of vascular origin.