Vascular cognitive deterioration and stroke

Vascular cognitive impairment, the recent modification of the terminology related to vascular burden of the brain, reflects the all-encompassing effects of vascular disease or lesions on cognition. It incorporates the complex interactions between vascular aetiologies, risk factors and cellular changes within the brain and cognition. The concept covers the frequent poststroke cognitive impairment and dementia, as well as cerebrovascular disease (CVD) as the second most common factor related to dementia. CVD as well as vascular risk factors including arterial hypertension, history of high cholesterol, diabetes or forms of heart disease are independently associated with an increased risk of cognitive impairment and dementia. Traditional vascular risk factors and stroke are also independent factors for the clinical presentation of Alzheimer's disease (AD). In addition to these vascular factors, CVD/strokes, infarcts and white-matter lesions may trigger and modify the progression of AD as the most common cause of neurodegenerative dementia. The main subtypes of previously defined vascular dementia (VaD) include the cortical VaD or multi-infarct dementia also referred as poststroke VaD, subcortical ischaemic vascular disease and dementia or small-vessel dementia and strategic-infarct dementia. Whilst CVD is preventable and treatable, it is clearly a major factor in the prevalence of cognitive impairment in the elderly worldwide.     

Is Alzheimer’s disease a homogeneous disease entity?

The epidemic proportions of dementia in old age are a cause of great concern for the medical profession and the society at large. It is customary to consider Alzheimer’s disease (AD) as the most common cause of dementia, and vascular dementia (VaD) as being the second. This dichotomous view of a primary neurodegenerative disease as opposed to a disorder where extrinsic factors cause brain damage led to separate lines of research in these two entities. New biomarkers, particularly the introduction of modern neuroimaging and cerebrospinal fluid changes, have, in recent years, helped to identify anatomical and chemical changes of VaD and of AD. Nevertheless, there is a substantial difference between the two entities. While it is clear that VaD is a heterogeneous entity, AD is supposed to be a single disorder. Nobody attempts to use CADASIL as a template to develops treatment for sporadic VaD. On the other hand, early-onset AD is used to develop therapy for sporadic AD. This paper will discuss the problems relating to this false concept and its consequences.     

Comparison between Alzheimer's disease and vascular dementia: implications for treatment

Virtually 90% of the elderly with late-onset dementia exhibit neuropathological features consistent with Alzheimer's disease (AD), vascular dementia (VaD) or dementia with Lewy bodies (DLB), alone or in combination. Both AD and DLB reveal extensive senile plaques containing amyloid beta whereas neurofibrillary tangles evident as tau pathology are fewer in DLB, which also bears diffuse cortical Lewy bodies. Interestingly, however, there is considerable overlap between AD and VaD in terms of both risk factors and pathology. Cholinergic deficits are also encountered in VaD, which like AD may respond to cholinergic therapy. Cerebrovascular pathology, ischemic brain damage and autonomic dysregulation resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementias.     

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.     

Alzheimer's disease is a vasocognopathy: a new term to describe its nature

Considerable evidence now indicates that Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences. As a result, AD and vascular dementia (VaD) can each be described as a 'vasocognopathy'. The term better describes the origin of the disease (vaso: vessel/blood flow), its primary effect on a system (-cogno: relating to cognition) and its clinical course (-pathy: disorder). Evidence that AD is a vasocognopathy is partly supported by the following multidisciplinary findings: (1) epidemiologic studies linking AD and vascular risk factors to cerebral hypoperfusion; (2) evidence that AD and vascular dementia (VaD) share practically all reported risk factors; (3) evidence that pharmacotherapy which increases or improves cerebral perfusion lowers AD symptoms; (4) evidence of preclinical detection of AD candidates using regional cerebral perfusion and glucose uptake studies; (5) evidence of overlapping clinical symptoms in AD and VaD; (6) evidence of parallel cerebrovascular and neurodegenerative pathologic markers (including plaques and tangles) in AD and VaD; (7) evidence that cerebral infarction increases AD incidence by 50%; (8) evidence that chronic brain hypoperfusion can trigger hypometabolic, cognitive and neurodegenerative changes typical of AD; (9) evidence that most autopsied AD brains contain cerebrovascular pathology; (10) evidence that mild cognitive impairment (a transition stage for AD) converts to AD or VaD in 48% and 56% of cases, respectively, within several years. The collective evidence presented here poses a powerful argument for the re-classification of AD as a vascular disorder. Re-classification would allow a new strategy that could result in the tactical development and application of genuinely effective treatments, provide earlier diagnosis and reduce AD prevalence by focusing on the root of the problem.     

Rethinking the dementia diagnoses in a population-based study: what is Alzheimer's disease and what is vascular dementia?. A study from the kungsholmen project

OBJECTIVE: To explore the hypothesis that older adults often are affected by more than one disease, making the differential diagnosis between Alzheimer's disease (AD) and vascular dementia (VaD) difficult. METHODS: Incident dementia cases (n = 308) from a population-based longitudinal study of people 75+ years were investigated. The DSM-III-R criteria were used for the clinical diagnosis of dementia. Data on vascular disorders (hypertension, cerebrovascular and ischemic heart diseases, heart failure, atrial fibrillation, diabetes) as well as type of onset/course of dementia were used retrospectively to reclassify dementias. RESULTS: Only 47% of the AD cases were reclassified as pure AD without any vascular disorder. Among subjects with AD and with a vascular component, cerebrovascular disease was the most common (41%). Only 25% of VaD were reclassified as pure VaD. Further, 26% of the pure AD subjects developed a vascular disorder in the following 3 years. CONCLUSIONS: Both vascular and degenerative mechanisms may often contribute to the expression of dementia among the elderly. Most of the AD cases have vascular involvements, and pure dementia types in very old subjects constitute only a minority of dementia cases.     

Epidemiology of non-AD dementias

Dementia is a common neurodegenerative disorder that affects about 10% of the population over 65 years of age. A distinction can be made between primary degenerative dementias and dementia secondary to other diseases. This review focuses on the primary non-Alzheimer's disease (AD) dementias: vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). VaD is after AD most frequent subtype of dementia with a prevalence of about 1%, ranging from 0 to 10% mainly depending on the age group investigated and the criteria used. Its incidence rate is between 1.5 and 4.1 per 1000 person-years, with no clear difference between men and women and with possibly a higher incidence in East Asia compared to Canada and Europe. Most of the VaD cases are sporadic although there are some rare familial forms of VaD as cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy and familial cerebral amyloid angiopathy. Important risk factors for sporadic VaD are cerebrovascular pathology (brain infarction, white matter lesions and brain atrophy), midlife hypertension, and diabetes leading to increasing risk ratios. A protective effect is often found for education and moderate use of alcohol. The association between VaD and amyloid β, cholesterol, and statin use remains unclear yet. DLB and FTD are less frequent forms of dementia with prevalence rates of, respectively, 0.1–0.6 and 0.002–0.015%. FTD affects people in their middle age, accounting for up to 10–20% of the presenile dementia cases. About 14% of the FTD cases are caused by an autosomal dominant tau-mutation. However, since the prevalence of sporadic FTD is relatively low, population-based epidemiological studies are hard to perform and no non-genetic risk factors are known yet. DLB is a relative common form of dementia in old age accounting for 15–20% of cases in hospital autopsy case-series. The only known possible risk factor for DLB is the presence of an apolipoprotein E 4 allele.     

Vascular dementia: European perspectives

Vascular dementia (VaD) is the second most frequent cause of organic acquired cognitive dysfunction in the Western world and is probably the first cause in some Asian countries. Therefore, it represents an important target for drug trials in dementia. This report puts in perspective methodological issues in VaD trials, as opposed to Alzheimer disease (AD), and reproduces in extenso the European Medicinal Products Evaluation Agency (EMEA) guidelines for trials of symptomatic treatments of dementia, particularly in AD. There are no explicit guidelines for VaD trials, but many of the recommendations for AD are already applicable to VaD for drugs aiming at alleviating symptoms of dementia. However, VaD can be viewed as being one of the many possible consequences of cerebrovascular diseases, so that there is more to expect from secondary prevention strategies for VaD than for AD (in which both the etiology and the pathophysiological mechanisms are largely unknown). So it seems logical to put more emphasis on the stabilization of the symptoms of VaD, by preventing progression or recurrence insofar as the vascular risk factors for VaD can often be identified and controlled, than in attempting to improve the existing clinical manifestations of established vascular brain damage. Even if purely symptomatic drugs are developed to improve the symptoms of VaD, they will have to be studied in the context of a tight control of existing vascular risk factors. For secondary prevention, trials of at least 1 year seem advisable.     

Vascular aspects of cognitive impairment and dementia

Hypertension and stroke are highly prevalent risk factors for cognitive impairment and dementia. Alzheimer''s disease (AD) and vascular dementia (VaD) are the most common forms of dementia, and both conditions are preceded by a stage of cognitive impairment. Stroke is a major risk factor for the development of vascular cognitive impairment (VCI) and VaD; however, stroke may also predispose to AD. Hypertension is a major risk factor for stroke, thus linking hypertension to VCI and VaD, but hypertension is also an important risk factor for AD. Reducing these two major, but modifiable, risk factors—hypertension and stroke—could be a successful strategy for reducing the public health burden of cognitive impairment and dementia. Intake of long-chain omega-3 polyunsaturated fatty acids (LC-n3-FA) and the manipulation of factors involved in the renin–angiotensin system (e.g. angiotensin II or angiotensin-converting enzyme) have been shown to reduce the risk of developing hypertension and stroke, thereby reducing dementia risk. This paper will review the research conducted on the relationship between hypertension, stroke, and dementia and also on the impact of LC-n3-FA or antihypertensive treatments on risk factors for VCI, VaD, and AD.     

血管性痴呆和血管性认知障碍的临床研究进展

血管性认知障碍和痴呆是认知障碍和痴呆领域以及脑血管病领域研究方面的交叉点。本文综述了血管性痴呆和认知障碍的定义、诊断标准和药物治疗进展。在诊断方面重点介绍了血管性痴呆各个亚型的临床特点。在治疗方面重点介绍了血管性痴呆和认知障碍的胆碱能递质代谢障碍以及胆碱酯酶抑制剂治疗的进展。     

Regulatory issues in vascular dementia: a European perspective

In many studies vascular dementia (VaD) is the second most frequent cause of organic acquired cognitive dysfunction; accounting for 10% to 50% of the cases, depending on the geographical area, patient population, and diagnostic criteria used. There is growing evidence that VaD does not include only multi-infarct dementia (MID) but relates to complex interactions of different etiologies (risk factors, cerebrovascular disease), structural changes in the brain, host factors and cognition. This resulted in reconceptualization of VaD to emphasize the differences from Alzheimer's disease (AD). However, the diagnostic criteria used (DSM-IV, ICD-10, NINDS-AIREN, or ADDTC) are based on the experience with AD and as such have their limitations and are not interchangeable. From a regulatory point of view, therefore, future research is needed to better define VaD in general and possible subtypes of VaD as targets for drug trials. Methodological issues in VaD trials, as opposed to AD, will be emphasized. The European Medicinal Products Evaluation Agency (EMEA) has adopted a guideline for trials of symptomatic treatments of dementia, particularly in AD. There is no explicit guideline for VaD trials; however, many of the recommendations for AD are already applicable to VaD for drugs aiming at alleviating symptoms of dementia. On the other hand, VaD may be potentially preventable, underscoring the importance of primary and secondary prevention as in other cerebrovascular disorders. Large long-term trials are necessary to study the importance of different risk factors and possible intervention strategies with special reference to VaD.     

Diagnosis and treatment of mixed dementia

Vascular dementia (VaD)--secondary to cerebrovascular disease (CVD)--has been traditionally distinguished from Alzheimer's disease (AD), which is a purely neurodegenerative form of dementia. However, CVDs such as lacunes and white matter lesions are common in patients with AD, whereas certain pathological changes of AD, including senile plaques and tangles, are observed in elderly patients with VaD. These findings indicate that mixed vascular-degenerative dementia (MD) is the most common cause of dementia in the elderly. In the treatment and prevention of dementia, the accurate diagnosis of each individual type of dementia is vital. However, recognizing the distinction between these diseases can be difficult in clinical practice. This article provides an overview of MD, including the incidence, diagnosis, and treatment. In particular, we emphasize that functional brain imaging, including perfusion single photon emission computed tomography and benzodiazepine receptor binding measurement, in combination with morphological imaging (such as magnetic resonance imaging) is useful for distinguishing AD, VaD and MD. In addition to antiplatelet medications, cholinesterase inhibitors and N-methyl-D-aspartic acid antagonists may be effective in treating MD. Moreover the vascular risk factors also should be treated appropriately. The article describes the need for further studies to develop a better understanding of MD.     

Overlap between pathology of Alzheimer disease and vascular dementia

There is overwhelming evidence to suggest that the neuropathology of Alzheimer disease (AD) extends beyond amyloid plaques and neurofibrillary tangles. Review of various consortium data shows that more than 30% of AD cases exhibit cerebrovascular pathology. However, certain vascular lesions such as cerebral amyloid angiopathy, microvascular degeneration, and periventricular white matter lesions are evident in almost all cases of AD. Whether these vascular lesions are coincidental or causal in the pathogenetic processes of AD remains to be defined. Although systemic vascular influences such as hypertension, coronary artery disease, and other cardiovascular disturbances may be responsible for such pathology in AD, it is equally intriguing that about one third of patients diagnosed with vascular dementia (VaD) will have AD-type pathology at autopsy. Moreover, previous studies have revealed that deficits in cholinergic indices related to the basal forebrain neurones are apparent in multi-infarct dementia. In this short review, we evaluate cerebrovascular pathology of AD in light of peripheral vascular pathophysiology implicated in the etiopathogenesis of the dementia. We also consider pathological findings in relation to genetic influences such as apolipoprotein E that may shed light on the link between AD and VaD. In view of these commonalties, it is reasonable to consider the same treatment strategies for both AD and VaD.     

Vascular Cognitive Impairment

Abstract: The term vascular cognitive impairment (VCI) is now employed to capture the spectrum of illness and disability arising from impaired cognitive function of vascular origin. As such, it supplants the more narrowly focussed terms "Vascular dementia (VaD)" and "multi-infarct dementia". It is meant to include both those whose cognitive impairment is different from that assumed by the usual criteria for dementia. Traditionally, dementia criteria have been modelled on AD, a disorder with more characteristic neuropathological and clinical disease expression than is seen in VaD, which can occur in many forms. VCI is common, and is associated with many adverse outcomes, including worse cognition, institutionalization, and death.
One form of VCI is coincident AD and VaD, a category which, although it has been comparatively neglected, may be amongst the most common forms of dementia. Another common form of VCI has a predilection for subcortical ischemic lesions, and for a clinical presentation which reflects frontal and subcortical involvement.
At present, there is no specific treatment for VCI, although several agents appear to offer the hope of both treatment and prevention. Further research on the clinical, pathological and mechanistic underpinnings of this important syndrome is needed. For a long time, VaD has been recognized as the second most common cause of dementia.^1,2) More recently, however, the concept of cognitive impairment in relation to cerebrovascular disease has been expanded. This paper will review the notion of "vascular cognitive impairment" (VCI) as it relates to clinical practice, and to our understanding of disease mechanisms in dementia and related disorders. It will propose that while the expanded concept has merit, within it are to be found distinct subgroups, including some of particular importance as targets for clinical trials of therapeutic and even preventive interventions.     

阿尔茨海默病实验性研究进展

阿尔茨海默病（Alzheiwer's Disease,AD）是最常见的与年龄相关的痴呆性疾病。随着人类平均寿命的增长，AD病人不断增多，医疗消费逐渐增长。所以基础与临床都十分重视AD的研究。AD属进行神经变性疾病。临床特征为认知障碍。其病理学改变是临床诊断的最可靠根据，包括细胞外淀粉样变性斑块和细胞内神经元缠结形成。以病因学角度，AD 属基因异原性遗传性疾病。最近10年的研究显示APP，PS1，PS2以及ApoE基因与AD具有肯定的联系。目前认为前三为AD的致病性基因，而ApoE则是危险性基因。本报告了近10年的AD基础研究进展，着重于淀粉条变致源学说，危险因素ApoE以及其他基因学及危险因素的研究。     

Luigi Amaducci memorial award winner's paper 2003. A neurologist's view of Alzheimer's disease and dementia

Senile dementia was the third most common admission diagnosis for New York psychiatric hospitals at the start of the twentieth century and the distinction between vascular and senile dementia was understood by psychiatrists even then. The term Alzheimer's disease (AD) was originally introduced to distinguish a pre-senile dementia from the common general paresis, but Alzheimer raised the possibility that pre-senile AD might not be distinguishable in clinical or histological terms from senile dementia. By the late 1970s it had become clear that the most common disorder producing dementia in elderly people was clinically and pathologically identical to pre-senile AD. AD is malignant, reducing remaining life expectancy by almost half and raising the risk of death over five years threefold (cancer raises it fourfold). Synapse loss associated with beta amyloid oligomers is a strong determinant of cognitive decline in patients with AD. Tau-containing neurofibrillary tangles usefully track disease severity. Unmodifiable risk factors include mutations in three genes which affect the production or metabolism of beta amyloid, the risk factor gene for Apolipoprotein [see symol in text]4 and female gender. The overriding risk factor is age, the prevalence of AD doubling with every five years of age until 90. Low education, head injury and low folate levels are examples of potentially modifiable risk factors. Since a delay of onset of five years would halve the number of patients with the disease, clinical trials for such putative protective factors as estrogens, folic acid, vitamin E, statins, and NSAIDs have begun. Cognitive and leisure activity may be protective against the development of AD but any protective function can only be confirmed by clinical trials.     

Quantitative measurement of cerebral haemodynamics in early vascular dementia and Alzheimer's disease.

Alzheimer's disease (AD) and vascular dementia (VaD) both share significant vascular risk factors. The present study measures the haemodynamics of these diseases in absolute rather than relative terms. Twenty-four patients were classified as either early AD or VaD and were compared with 12 non-cognitively impaired subjects. Magnetic resonance imaging flow quantification was used to measure arterial inflow and arterial pulse volume. Mean vascular resistance and compliance were calculated. In AD, the arterial inflow was lower by 18%, resistance was higher by 23% and compliance of the arterial tree was lower by 20% compared with normal (p=0.01, 0.02 and 0.05, respectively). In VaD, the arterial pulse volume was higher by 24% and compliance was higher by 35% compared with normal (p=0.05 for both). Early VaD is characterized by normal blood flow, but increased pulsation. Reduced blood flow and an incompliant arterial tree characterize early AD.     

Neuronal repair and replacement in spinal cord injury

OBJECTIVE: To assess age-, gender, and subtype-specific incidence rates of dementia in three populations in central Spain using data from the Neurological Disorders in Central Spain (NEDICES), a population-based survey of elderly participants. METHODS: Individuals were evaluated at baseline (1994-1995) and at follow-up (a median of 3.2 years later in 1997-1998). The evaluation included a screening questionnaire for dementia and a neurological assessment, when possible. RESULTS: Of 5278 participants evaluated at baseline, there were 306 prevalent dementia cases. One hundred and sixty-one incident dementia cases were identified among 3,891 individuals assessed at follow-up. The large majority had Alzheimer's disease (AD): 115 (71.4%) AD, 18 (11.2%) vascular dementia (VaD), 11 (6.8%) dementia associated with parkinsonism, 11 (6.8%) undetermined etiology, and 6 (3.7%) secondary dementia. Average annual incidence rates (per 1,000 person-years) in the population aged 65 to 90 and over years, adjusted to the standard European population, were 10.6 (95% CI, 8.9 to 12.3) for dementia, 7.4 (95% CI=6.0 to 8.8) for AD, and 1.4 (95% CI=0.6 to 2.3) for VaD. Age-specific incidence rates of dementia and AD increased exponentially with advancing age. Age, stroke and illiteracy were independent risk factors for dementia and AD. Aggregation of vascular risk factors was related to a higher risk of both VaD and AD. CONCLUSIONS: In the NEDICES study, incidence of dementia increased with age beyond age 85 and AD was the most frequent type of dementia. The risk of AD and VaD increased with the number of vascular risk factors.     

Therapeutic issues in vascular dementia: studies, designs and approaches

Vascular dementia (VaD) is a heterogeneous disorder resulting from various cerebrovascular diseases (CVD) causing cognitive impairment that reflects severity and location of damage. Epidemiological studies suggest VaD is the second commonest cause of dementia, but autopsy series report that pure VaD is infrequent, while combined CVD and Alzheimer's Disease(AD) is likely the commonest pathological-dementia correlate. Both diseases share vascular risk factors and benefit from their treatment. The most widely used diagnostic criteria for VaD are highly specific but not sensitive. Vascular Cognitive Impairment (VCI) is a dynamic, evolving concept that embraces VaD, Vascular Cognitive Impairment No Dementia (VCIND) and mixed AD and CVD. Clinical trials to date have focused on probable and possible VaD with beneficial effects evident for different drug classes, including cholinergic agents and NMDA agonists. Limitations have included use of cognitive tools suitable for AD that are insensitive to executive dysfunction. Disease heterogeneity has not been adequately controlled and subtypes require further study. Diagnostic VaD criteria now 13 years old need updating. More homogeneous subgroups need to be defined and therapeutically targeted to improve cognitive-behavioural outcomes including optimal control of vascular risk factors. More sensitive testing of executive function outlined in recent VCI Harmonization criteria and longer trial duration are needed to discern meaningful effects. Imaging criteria must be well-defined, with centralized review and standardized protocols. Serial scanning with quantification of tissue atrophy and lesion burden is becoming feasible, and cognitive interventions, including rehabilitation pharmacotherapy, with drugs strategically coupled to cognitive -behavioural treatments, hold promise and need further development.     

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.