Small vessel versus large vessel vascular dementia

Objective   

The aim of this study was a cross-sectional comparison of clinical and MRI characteristics and risk factor profiles between patients with small vessel disease (lacunae and white matter hyperintensities) and large vessel disease (large territorial or strategical infarcts) in a large cohort of VaD patients.     

Cognitive profiles in degenerative dementia without evidence of small vessel pathology and small vessel vascular dementia

Although a large number of studies have examined possible differences in cognitive performance between Alzheimer’s disease (AD) and vascular dementia (VaD), the data in the literature are conflicting. The aims of this study were to analyze the neuropsychological pattern of subjects affected by degenerative dementia without evidence of small vessel pathology (DD) and small vessel VaD subjects in the early stages and to investigate differences in the progression of cognitive impairment. Seventy-five patients with probable VaD and 75 patients with probable DD were included. All the subjects underwent a standard neuropsychological evaluation, including the following test: Visual Search, Attentional matrices, Story Recall, Raven’s Coloured Progressive Matrices, Phonological and Semantic Verbal Fluency, Token, and Copying Drawings. The severity of cognitive impairment was stratified according to the MMSE score. Fifteen subjects with probable DD and 10 subjects with probable VaD underwent a 12-month cognitive re-evaluation. No significant difference was found between DD and VaD subjects in any of the neuropsychological tests except Story Recall in the mild cognitive impairment (P < 0.001). The re-test value was significantly worse than the baseline value in the MMSE (P = 0.037), Corsi (P = 0.041), Story Recall (P = 0.032), Phonological Verbal Fluency (P = 0.02), and Copying Drawings (P = 0.043) in DD patients and in the Visual Search test (P = 0.036) in VaD subjects. These results suggest that a neuropsychological evaluation might help to differentiate degenerative dementia without evidence of small vessel pathology from small vessel VaD in the early stages of these diseases.     

Small vessel disease and Alzheimer's dementia: pathological considerations

Current evidence suggests that the neuropathology of Alzheimer type of dementia comprises more than amyloid plaques and neurofibrillary tangles. At least a third of Alzheimer disease (AD) cases may exhibit significant cerebrovascular pathology, which constitutes distinct small vessel disease (SVD). Cerebral amyloid angiopathy, microvascular degeneration affecting the cerebral endothelium and smooth muscle cells, basal lamina alterations, hyalinosis and fibrosis are often evident in AD. These changes may be accompanied by perivascular denervation that is causal in the cognitive decline of AD. Amyloid beta protein may cause degeneration of both the larger perforating arterial vessels as well as cerebral capillaries, which represent the blood-brain barrier. In addition, macro- and microinfarctions, haemorrhages, lacunes and ischaemic white matter changes are also present in AD. The development of SVD in late-onset AD may engage an interaction of perivascular mediators as well as circulation-derived factors that perturb the brain vasculature. Peripheral vascular disease such as long-standing hypertension, atrial fibrillation, coronary or carotid artery disease and diabetes could further modify the cerebral circulation such that a sustained hypoperfusion or oligaemia is impacted upon the ageing brain.     

Short-term evolution as a marker of vascular dementia versus Alzheimer's disease

The diagnosis of vascular dementia (VaD) remains a controversial issue in many aspects and concepts. These nosologic problems are caused both by the methods, insufficient to ascertain the diagnosis, as well as by the weak consistency of the clinical concept of VaD itself. One of the most intriguing issues on VaD, and in particular on post-stroke dementia (PSD), is related to the time of development of cognitive decline. In clinical practice, the 3-month time threshold is usually chosen to enable resolution of a possible acute post-stroke delirium, and to obtain a more reliable cognitive assessment with a complete regression of acute neuropsychological stroke-related deficits. Another relevant issue is the possibility to predict which patient will develop PSD. In this regard, recent data indicate an overlap between Alzheimer's disease (AD) and PSD, which seems to share risk factors and neuropathology. In most population samples these two disorders appear together, and the consensus is growing that a degenerative component has a more important role in determining PSD onset shortly after stroke than previously recognized. Therefore, anamnestic data have a fundamental role in this prognostic approach.     

New approaches to clinical trials in vascular dementia: memantine in small vessel disease

Although criteria for the diagnosis of vascular dementia (VaD) are established, the diagnostic concept is still controversial and there is no regulatory guidance for clinical drug development. Clinical trials in VaD present a number of pitfalls and challenges and, so far, no compound has received regulatory approval for this indication. The methodological issues of clinical VaD trials are discussed using the development of memantine for this indication as an example. In a pooled analysis of two placebo-controlled trials with the NMDA-antagonist memantine in VaD, the cognitive benefit by memantine treatment was more pronounced for patients with 'small vessel disease' than for those with other neuroradiological findings at baseline. In a subgroup of patients with 'large vessel disease' or macrolesions, there was less cognitive decline among the placebo patients. It may therefore be helpful to use predefined diagnostic subcategories in clinical studies in this indication. The findings further suggest that stroke or multiple infarctions may not be the primary reason for cognitive decline in VaD patients.     

Small vascular and Alzheimer disease-related pathologic determinants of dementia in the oldest-old

The relative contributions of Alzheimer disease (AD) and vascular lesion burden to the occurrence of cognitive decline are more difficult to define in the oldest-old than they are in younger cohorts. To address this issue, we examined 93 prospectively documented autopsy cases from 90 to 103 years with various degrees of AD lesions, lacunes, and microvascular pathology. Cognitive assessment was performed prospectively using the Clinical Dementia Rating scale. Neuropathologic evaluation included the Braak neurofibrillary tangle (NFT) and β-amyloid (Aβ) protein deposition staging and bilateral semiquantitative assessment of vascular lesions. Statistics included regression models and receiver operating characteristic analyses. Braak NFTs, Aβ deposition, and cortical microinfarcts (CMIs) predicted 30% of Clinical Dementia Rating variability and 49% of the presence of dementia. Braak NFT and CMI thresholds yielded 0.82 sensitivity, 0.91 specificity, and 0.84 correct classification rates for dementia. Using these threshold values, we could distinguish 3 groups of demented cases and propose criteria for neuropathologic definition of mixed dementia, pure vascular dementia, and AD in very old age. Braak NFT staging and severity of CMI allow for defining most of demented cases in the oldest-old. Most importantly, single cutoff scores for these variables that could be used in the future to formulate neuropathologic criteria for mixed dementia in this age group were identified.     

Everyday action in dementia: evidence for differential deficits in Alzheimer's disease versus subcortical vascular dementia.

The relationship between dementia diagnosis and everyday action (e.g., meal preparation, grooming) is not well understood. This study examines differences between individuals diagnosed with vascular dementia (VaD; n = 25) versus Alzheimer's disease (AD; n = 23) on the Naturalistic Action Test (NAT; Schwartz et al., 2003), a performance-based measure that includes three tasks of increasing complexity. The percentage of task steps accomplished, number of errors, and performance times were recorded for each task. While the groups did not differ in dementia severity or overall impairment on the NAT, the VaD group committed more errors (3.3 vs. 1.6, p = 02). The VaD group also accomplished significantly fewer steps when salient distractor objects were present (74.0% vs. 91.3%, p < .01). Correlations between NAT variables and neuropsychological tests suggest the executive control deficits associated with VaD may contribute to specific action difficulties, such as distractor interference and inefficient, error-prone action on complex tasks. In AD, everyday action may be negatively influenced by episodic memory failures. Thus, dementia diagnosis has relevance to everyday function.     

小血管病性血管性认知障碍非痴呆型患者神经心理学特征的研究

目的通过系列神经心理学测试对小血管病性血管性认知障碍非痴呆型(VCIND-SVD)患者的神经心理学特征进行分析,寻找适用于VCIND-SVD患者的敏感且简捷的神经心理评估工具。方法VCIND-SVD患者33例,正常对照组40例,进行MMSE及多个包括5个认知域在内的神经心理学测试,确定VCIND-SVD患者受损的认知域,筛选出识别能力较好的单项测试,检测其敏感度和特异度,以便临床使用。结果VCIND-SVD患者为多个认知域损害,包括记忆力、注意力、语言功能、视空间结构技能及执行功能均有损害;即刻逻辑记忆测试、积木测试、伦敦塔完成时间及计划时间等检测项目能敏感反映这些损害。结论各单项测试的综合对VCIND-SVD具有较强的识别能力,有重要的应用价值。     

Subcortical vascular dementia

Vascular dementia (VaD) incorporates different vascular mechanisms and changes in the brain, and has different causes and clinical manifestations. Current criteria for VaD select an aetiologically and clinically heterogeneous group and this definitional heterogeneity has affected clinical trial results. Focus on a more homogeneous group, such as that with subcortical (ischaemic) VaD, could be an alternative in clinical drug trials. This subtype incorporates two small vessel clinical entities - 'Binswanger's disease' and 'the lacunar state'. It comprises small vessel disease as the primary vascular aetiology, lacunar infarct(s) and ischaemic white matter lesions as the primary type of brain lesions, subcortical location as the primary location of lesions, and the subcortical clinical syndrome as the primary clinical manifestation. Subcortical VaD is expected to show a more predictable clinical picture, natural history, outcome and treatment responses.     

Intravenous thrombolysis versus antiplatelet therapy in minor stroke patients with large vessel occlusion

Aim

Our study aimed to explore the effectiveness and safety of intravenous t-PA compared with dual antiplatelet therapy (DAPT) and aspirin alone for minor stroke with National Institutes of Health Stroke Scale (NIHSS) score ≤5 and large vessel occlusion (LVO).

Methods

Patients with minor stroke harboring LVO within 4.5-h time window were included from the Third China National Stroke Registry (CNSR-III) between August 2015 and March 2018 in China. Clinical outcomes including modified Rankin scale (mRS) score, recurrent stroke, and all-cause mortality at 90 days and 36-h symptomatic intracerebral hemorrhage (sICH) were collected. Multivariable logistic regression models and propensity score matching analyses were used to determine the association between treatment groups and clinical outcomes.

Results

A total of 1401 minor stroke patients with LVO were included. Overall 251 patients (17.9%) received intravenous t-PA, 722 patients (51.5%) received DAPT, and 428 patients (30.5%) received aspirin alone. The intravenous t-PA was associated with greater proportions of mRS 0–1 (aspirin versus t-PA: adjusted odds ratio [aOR], 0.50; 95% confidence interval [CI], 0.32 to 0.80; p = 0.004; DAPT versus t-PA: aOR, 0.76; 95% CI, 0.49 to 1.19; p = 0.23). Using propensity score matching analyses, the results were similar. There was no difference in 90-day recurrent stroke among the groups. The rates of all-cause mortality in intravenous t-PA, DAPT, and aspirin groups were 0%, 0.55%, 2.34%, respectively. No patient developed sICH within 36 h of intravenous t-PA.

Conclusion

In patients with minor stroke harboring LVO within 4.5-h time window, intravenous t-PA was associated with higher odds for the excellent functional outcome, as compared with the aspirin alone. Further randomized controlled trials are warranted.     

Subcortical ischemic vascular dementia

Subcortical ischemic vascular dementia (SIVD) has been proposed as a subtype of vascular cognitive impairment. MRI often discloses "silent" hyperintensities in 20% to 40% of community-dwelling elderly. Efforts to relate MRI-measured lacunes and white matter changes to cognitive impairment have not been straightforward. The possibility that Alzheimer's disease pathology contributes to cognitive impairment increases with age. A rare disorder known as cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) provides an opportunity to study SIVD in the absence of Alzheimer's disease. Lacunes and deep white matter changes are associated with dysexecutive syndrome. Hypertension, the leading risk factor for sporadic SIVD, is treatable. High priority must be given to reducing vascular risk profiles.     

Drugs and vascular dementia

Between 20 and 35% of all dementias are vascular in origin, their etiology is due to cerebrovascular disease and the risk factors are known (e.g. hypertension, diabetes, smoking, or hyperlipidemia). Primary and secondary preventions are the basis of therapeutics. Symptomatic treatment is emerging, notably in the field of cognitive disorders. In that respect, monoamine oxidase inhibitors, and more recently acetylcholinesterase inhibitors, are in the process of being recognized as first-line treatments of established vascular dementia.     

Prevention of vascular dementia

Stroke is an important public health problem worldwide. Those at high risk of stroke may be at high risk of cognitive impairment and dementia after stroke. Modifiable cardiovascular risk factors in midlife including hypertension, alcohol use, cigarette smoking, and certain dietary factors may be important targets for prevention of vascular causes of cognitive impairment. These same types of factors may also be associated with Alzheimer disease. Better control of cardiovascular disease risk factors might lead to delay or prevention of vascular dementia and Alzheimer disease.     

Rivastigmine in vascular dementia

Vascular dementia (VaD), like Alzheimer's disease (AD), is associated with cholinergic deficits. Rivastigmine provides sustained, brain-selective inhibition of acetylcholinesterase and butyrylcholinesterase. Preliminary data suggest that rivastigmine may provide significant benefits in patients with AD and cerebrovascular disease (mixed dementia), and in patients with VaD. Open-label rivastigmine treatment has been associated with improved cognitive and functional abilities, behavioral symptoms, and reduced caregiver stress in a small pilot study in these patients. Larger, prospective, double-blind studies of rivastigmine in patients with VaD are under way. These studies will confirm whether rivastigmine is an efficacious treatment option for a range of patients for whom, until now, there have been few symptomatic therapies.     

Neuroprotection in vascular dementia

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease (AD), and one of the major causes of mental and physical disability in developed countries. As such, the identification and implementation of strategies which prevent the development of the condition or enable improvements in patients with VaD are healthcare objectives of the first order. VaD is now regarded as a combined group of clinical-pathological entities rather than one disease, that is, multiple pathogenic mechanisms and lesion types underlie a cognitive impairment of vascular origin. The clinical diagnosis of VaD is complex and difficult because of the heterogeneous nature of its clinical presentation and progression and the low sensitivity of existing clinical criteria. Moreover, there is growing evidence of the epidemiological significance of mixed forms of dementia, and that ischemic processes may precipitate and exacerbate cognitive impairment in AD. Numerous compounds have been proposed as potentially useful in the treatment of patients with VaD, comprising vasodilatative, antithrombotic, hemorrheological, nootropic, antiserotoninergic and, most recently, antiglutamatergic and cholinergic approaches. In spite of some initially favorable reports based on the use of memantine, donepezil and galantamine, there is as yet no conclusive evidence of a definitive treatment for VaD. Unsatisfactory results from VaD drug trials may be attributed in part to the diversity of the patients included (underlying pathogenic mechanisms, number, type, and location of vascular lesions), and to methodological limitations in the design of the trials (outcome measures, end-points, size, follow-up period). The treatment of modifiable vascular risk factors - hypertension, diabetes mellitus, hypercholesterolemia and heart disease - is an important strategy for the reduction of the risk of dementia, and is likely to slow the progress of cognitive decline.