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.     

Dementia Poststroke

Abstract : The frequency of dementia poststroke is high, and stroke considerably increases the risk of dementia. The risk factors for dementia related to stroke are still incompletely understood. In addition to age and low level of education, different combinations of vascular risk factors and stroke features have been associated with poststroke dementia. A single explanation for poststroke dementia is not adequate; rather, multiple factors including stroke features (dysphasia, major dominant stroke syndrome), infarct features (type, side, site, number, and volume), extent and type of white matter lesions (WMLs), degree and site of atrophy, host characteristics (e.g. age, educational level), and risk factors for stroke (e.g. prior cerebrovascular disease, diabetes) each contribute to the risk of dementia poststroke.
Dementia after first ever clinical stroke is also frequent. Cognitive decline is present prior to stroke in up to one-third of patients developing post-stroke dementia. Medial temporal lobe atrophy, a marker of an increased risk of Alzheimer's disease (AD), is more frequent in stroke patients who have preexisting dementia or cognitive decline, as well as poststroke dementia. This may be explained by co-existing AD and cerebrovascular disease (CVD). The magnitude of this mixed dementia (AD with CVD/Vascular Dementia (VaD)) group has been previously underestimated, and it is a diagnostic challenge in the older population.
Dementia due to CVD is a rather advanced stage of is chemic brain changes, and outcome of treatment and prevention may be limited. Accordingly, the focus should be placed on the entire spectrum of cognitive impairment related to CVD, focusing especially the early cognitive changes.     

Treatment of vascular dementia--evidence from clinical trials with cholinesterase inhibitors

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. In addition, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitor agents used in AD. Controlled clinical trials with donepezil, galantamine and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvements in cognition, behavior and activities of daily living.     

Treatment of vascular dementia-evidence from clinical trials with cholinesterase inhibitors

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior and activities of daily living.     

Treatment of vascular dementia—evidence from clinical trials with cholinesterase inhibitors

Abstract

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demostrated improvement in cognition, behavior and activites of daily living.     

Prevention and early intervention for vascular dementia in community dwelling elderly: Findings from the Nakayama study

Cerebrovascular disease (CVD) may be the single most common risk factor for age‐associated dementia (in particular for vascular dementia (VaD)), and there is definite potential for prevention and treatment of CVD. After one of the most comprehensive and precise type‐specific prevalence surveys of dementia (first Nakayama study), we have continued the preventive and early interventional approaches to CVD and VaD, including treatment of cardiovascular risk factors. In this cohort study, 88% of patients with ‘vascular cognitive impairment without dementia’, who were alive at 3‐years follow up, were still diagnosed with ‘vascular cognitive impairment without dementia’ and only 12% progressed to dementia. Compared with the results of previous studies, active control of risk factors and prevention of recurrent stroke may reduce the incidence of dementia and slow the progression of cognitive impairment in patients with ‘vascular cognitive impairment without dementia’.     

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。     

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.     

The pathology of "vascular dementia": a critical update

The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive disorder (VCD), are a matter of discussion.VaD is suggested in 8-15% of cognitively impaired aged subjects. Its prevalence in autopsy series ranges from 0.03 to 58% (mean 8-15% in Western series, 22-35% in Japan). Neuropathology shows multifocal and/or diffuse lesions, ranging from lacunes and microinfarcts, often involving subcortical and strategically important brain areas (thalamus, frontobasal, limbic system), white matter lesions and hippocampal sclerosis to multi-infarct encephalopathy and diffuse post-ischemic lesions. They result from systemic, cardiac and local large and small vessel disease. Pathogenesis is multifactorial and pathophysiology affects neuronal networks involved in cognition, behavior, execution and memory. Vascular lesions often coexist with Alzheimer's disease (AD) and other pathologies. Minor vascular lesions hardly contribute to cognitive decline in full-blown AD, while both mild Alzheimer pathology and small vessel disease interact synergistically. AD pathology is less severe in the presence of vascular lesions. The lesion pattern in "pure" VaD/VCD) related to microangiopathies differs from that in "mixed dementia" (AD + vascular encephalopathy), often associated with large infarcts, suggesting different pathogenesis. Due to the heterogeneity of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are currently available, and a large variability across laboratories still exists in morphologic examination procedures and techniques. Further prospective clinico-pathologic studies are needed to validate diagnostic criteria for VaD and to clarify the impact of vascular lesions on cognitive impairment.     

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.     

Apolipoprotein E phenotypes in demented and cognitively impaired patients with and without cerebrovascular disease

Controversy exists regarding the apolipoprotein E (ApoE) epsilon4 allele association with vascular dementia (VaD), ranging from increased epsilon4 frequency, similar to that found for Alzheimer's disease (AD), to no association between the epsilon4 allele and VaD. To clarify further the relationship between ApoE alleles polymorphism and cerebrovascular disease (CVD) in demented and cognitively impaired patients, we examined the ApoE phenotypes in a sample of 280 patients: 155 with AD, 21 with VaD, 32 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) but without CVD, and 27 in which vascular disease was the most probable cause of cognitive decline [vascular mild cognitive impairment (VMCI)]. Our results show that the frequency of the ApoE epsilon4 allele in patients over 70 years old with clinically diagnosed VaD and VMCI does not differ significantly from that of controls. In contrast, ApoE epsilon4 allele-bearing individuals had greater risk of having late-onset AD (OR = 8.8; 95% CI 3.7-21.0), or non-vascular cognitive impairment (OR = 7.0; 95% CI 2.5-19.0).     

Imaging of static brain lesions in vascular dementia: implications for clinical trials

Vascular dementia (VaD) relates to different vascular mechanisms and changes in the brain and has different causes and clinical manifestations, reflecting complex interactions between vascular etiologies, changes in the brain, host factors, and cognition. Critical elements to the concept and diagnosis of VaD are defining the vascular causes, the vascular etiologies, and changes in the brain. Verifying the relation between brain lesions and cognition (i.e., the extent to which brain changes cause, compound, or coexist with cognitive impairment) and establishing the types, extent, side, site, and tempo of brain lesions that relate to incident cognitive impairment are major diagnostic challenges. Previous work on interactions between brain lesion and cognition in to cerebrovascular disease (CVD) have shown variation in the definitions and measures of cognitive impairment, in the techniques and methods used to reveal different brain changes, and in the selection of patient populations. Furthermore, small sample sizes and the absence of multivariate statistics have been design limitations. Accordingly, the different sets of criteria used and methods applied identify different numbers and clusters of subjects and different distribution of brain changes. Furthermore, this heterogeneity is reflected in variation in natural history such as the rate of progression of decline in different cognitive domains over time. All these factors have hampered optimal designs of clinical drug trials. A summary of generalizations regarding lesion and cognition interaction in VaD can be made. (1) Not a single feature, but a combination of infarct features--extent and type of white matter lesions (WMLs), degree and site of atrophy, and host factor characteristics--constitues correlates of VaD. (2) Infarct features favoring VaD include bilaterality, multiplicity (>1), location in the dominant hemisphere, and location in the limbic structures (fronto- and mediolimbic). (3) WML features favoring VaD are extensive WMLs (extensive periventricular WMLs and confluent to extensive WMLs in the deep WM). (4) It is doubtful that only a single small lesion could provide imaging evidence for a diagnosis of VaD. (5) Absence of CVD lesions on computed tomography or magnetic resonance imaging is strong evidence against a diagnosis of VaD. In forthcoming protocols on CVD-associated cognitive impairment, the following brain imaging features should be specified: detailed characterization of brain changes; use of possible predefined subtypes based on brain imaging; use of rating of vascular burden; defining the type and extent of WMLs favoring a diagnosis of VaD; defining the extent of medial temporal lobe atrophy disfavoring a diagnosis of VaD; and technical harmonization of methods of scanning and analysis.     

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.     

Coffee intake in midlife and risk of dementia and its neuropathologic correlates

While animal data suggest a protective effect of caffeine on cognition, studies in humans remain inconsistent. We examined associations of coffee and caffeine intake in midlife with risk of dementia, its neuropathologic correlates, and cognitive impairment among 3494 men in the Honolulu-Asia Aging Study (mean age 52 at cohort entry, 1965-1968) examined for dementia in 1991-1993, including 418 decedents (1992-2004) who underwent brain autopsy. Caffeine intake was determined according to self-reported coffee, tea, and cola consumption at baseline. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for overall dementia, Alzheimer's disease (AD), vascular dementia (VaD), cognitive impairment (Cognitive Abilities Screening Instrument score <74), and neuropathologic lesions at death (Alzheimer lesions, microvascular ischemic lesions, cortical Lewy bodies, hippocampal sclerosis, generalized atrophy), according to coffee and caffeine intake. Dementia was diagnosed in 226 men (including 118 AD, 80 VaD), and cognitive impairment in 347. There were no significant associations between coffee or caffeine intake and risk of cognitive impairment, overall dementia, AD, VaD, or moderate/high levels of the individual neuropathologic lesion types. However, men in the highest quartile of caffeine intake (>277.5 mg/d) were less likely than men in the lowest quartile (≤115.5 mg) to have any of the lesion types (adjusted-OR, 0.45; 95% CI, 0.23-0.89; p, trend = 0.04). Coffee and caffeine intake in midlife were not associated with cognitive impairment, dementia, or individual neuropathologic lesions, although higher caffeine intake was associated with a lower odds of having any of the lesion types at autopsy.     

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.     

Morphologic diagnosis of "vascular dementia" - a critical update

Vascular dementia/vascular cognitive impairment (VaD/VCI) is not a single entity, but a large group of conditions characterized by various clinical and morphological findings and variable pathophysiology. Clinical diagnostic criteria show moderate sensitivity (50-70%) and variable specificity (64-98%). Epidemiological studies are hampered by the lack of clear and validated diagnostic criteria, the complexity of brain pathologies, ethnic and geographic variations. In Western clinic-based series VaD/VCI is suggested in 8-15% of cognitively impaired aged subjects, with age-standardized incidence ratios 0.42-2.6 and clinical prevalence at age 70+ of 6-15/1000 person/year. Prevalence in autopsy series ranges from 0.03 to 58% (real mean 8-15% in Western series, 22-35% in Japan). Both prevalence and incidence increase with age. Neuropathology shows multifocal and/or diffuse lesions, ranging from lacunes and microinfarcts, white matter lesions, hippocampal sclerosis to multi-infarct encephalopathy, mixed cortico-subcortical and diffuse post-ischemic lesions. They result from systemic, cardiac, local large and small vessel disease. Pathogenesis is multifactorial and cognitive decline is commonly associated with small ischemic/vascular lesions, often involving subcortical and strategically important brain areas (thalamus, frontobasal, limbic system). Pathophysiology affects neuronal networks involved in cognition, behavior, execution and memory. Vascular lesions often coexist with Alzheimer disease (AD) and other lesions, multiple pathologies greatly increasing the odds of dementia; 25-80% of demented subjects show both AD and cerebrovascular lesions. While both factors by synergistic interaction contribute significantly to the risk of dementia, AD pathology is often less severe in the presence of vascular lesions. Due to the heterogeneity of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are currently available, and a large variability across laboratories still exists in morphologic examination procedures and techniques. Harmonization of neuropathologic procedures and evaluation criteria in future prospective clinico-pathologic studies are needed to validate diagnostic criteria for VaD and to clarify the impact of vascular lesions on cognition.     

Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia

Vascular cognitive impairment (VCI) was proposed as an umbrella term to include subjects affected with any degree of cognitive impairment resulting from cerebrovascular disease (CVD), ranging from mild cognitive impairment (MCI) to vascular dementia. VCI may or may not exclude the host of "focal" circumscribed impairments of specialized functions such as language (aphasia), intentional gesture (apraxia), or categorical recognition (agnosia), among others, that may result from a stroke. Therefore, there are no universally accepted diagnostic criteria for VCI. We conclude that this concept could be more useful if it were to be limited to cases of vascular MCI without dementia, by analogy with the concept of amnestic MCI, currently considered the earliest clinically diagnosable stage of Alzheimer disease (AD). In agreement with our view,the Canadian Study on Health and Aging successfully implemented a restricted definition of VCI, excluding cases of dementia (i.e., vascular cognitive impairment no dementia, VCI-ND). The Canadian definition and diagnostic criteria could be utilized for future studies of VCI. This definition excludes isolated impairments of specialized cognitive functions.Vascular dementia (VaD): The main problem of this diagnostic category stems from the currently accepted definition of dementia that requires memory loss as the sine qua non for the diagnosis. This may result in over-sampling of patients with AD worsened by stroke (AD+CVD). This problem was minimized in controlled clinical trials of VaD by excluding patients with a prior diagnosis of AD, those with pre-existing memory loss before the index stroke, and those with amnestic MCI. We propose a definition of dementia in VaD based on presence of abnormal executive control function, severe enough to interfere with social or occupational functioning. Vascular cognitive disorder (VCD): This term, proposed by Sachdev [P. Sachdev, Vascular cognitive disorder. Int J Geriat Psychiatry 14 (1999)402-403.] would become the global diagnostic category for cognitive impairment of vascular origin, ranging from VCI to VaD. It would include specific disease entities such as post-stroke VCI, post-stroke VaD, CADASIL, Binswanger disease, and AD plus CVD. This category explicitly excludes isolated cognitive dysfunctions such as those mentioned above.     

Non-cognitive benefits of galantamine (Reminyl®) treatment in vascular dementia

Vascular dementia (VaD) is a condition that involves deterioration in cognitive and non-cognitive areas. Although cognitive impairment is the defining symptom evaluated during clinical trials, changes in non-cognitive areas such as behavior, global functioning and activities of daily living are assessed because they assist in determining quality of life and overall well-being. Therapy has focused traditionally on preventing and controlling risk factors, as no approved treatments are currently available for these patients. Acetylcholinesterase inhibitors (AChEIs), the treatment of choice in patients with Alzheimer's disease (AD), are a potential treatment option for patients with VaD. Galantamine, an AChEI with nicotinic receptor modulation, has demonstrated clinically relevant benefits (cognition, global functioning, functional ability, behavior) in patients with either AD with cerebrovascular disease (AD with CVD) or probable VaD in a 6-month, randomized, double-blind, placebo-controlled study.     

Metabolic syndrome, mild cognitive impairment, and dementia

At present, the search for preventive strategies for cognitive decline and dementia appears to be of crucial importance, given that the therapeutic options currently available have demonstrated limited efficacy. Cumulative epidemiological evidence suggested that vascular and vascular-related factors may be important for the development of age-related cognitive decline (ARCD), mild cognitive impairment (MCI), and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). Among vascular-related factors, metabolic syndrome (MetS) has been associated with the reduced risk of predementia syndromes (ARCD and MCI), overall dementia, and VaD, but contrasting findings also exist on the possible role of MetS in AD. In the next future, trials could then be undertaken to determine if modifications of these risks including inflammation, another factor probably related to MetS, could lower risk of developing cognitive decline. If MetS is associated with increased risk of developing cognitive impairment, then early identification and treatment of these individuals at risk might offer new avenues for disease course modification. Future research aimed at identifying mechanisms that underlie comorbid associations will not only provide important insights into the causes and interdependencies of predementia and dementia syndromes, but will also inspire novel strategies for treating and preventing these disorders. At present, vascular risk factor management could be decisive in delaying the onset of dementia syndromes or in preventing the progression of predementia syndromes.     

The enigma of vascular cognitive disorder and vascular dementia

The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive impairment, are a matter of discussion, and currently used clinical diagnostic criteria show moderate sensitivity (average 50%) and variable specificity (range 64–98%). In Western clinic-based series, VaD is suggested in 8–10% of cognitively impaired aged subjects. Its prevalence in autopsy series varies from 0.03 to 58%, with reasonable values of 8–15%, while in Japan it is seen in 22–35%. Neuropathologic changes associated with cognitive impairment include multifocal and/or diffuse disease and focal lesions: multi-infarct encephalopathy, white matter lesions or arteriosclerotic subcortical (leuko)encephalopathy, multilacunar state, mixed cortico-subcortical type, borderline/watershed lesions, rare granular cortical atrophy, post-ischemic encephalopathy and hippocampal sclerosis. They result from systemic, cardiac and local large or small vessel disease. Recent data indicate that cognitive decline is commonly associated with widespread small ischemic/vascular lesions (microinfarcts, lacunes) throughout the brain with predominant involvement of subcortical and functionally important brain areas. Their pathogenesis is multifactorial, and their pathophysiology affects neuronal networks involved in cognition, memory, behavior and executive functioning. Vascular lesions often coexist with Alzheimer disease (AD) and other pathologies. Minor cerebrovascular lesions, except for severe amyloid angiopathy, appear not essential for cognitive decline in full-blown AD, while both mild Alzheimer pathology and small vessel disease may interact synergistically. The lesion pattern of “pure” VaD, related to arteriosclerosis and microangiopathies, differs from that in mixed-type dementia (AD with vascular encephalopathy), more often showing large infarcts, which suggests different pathogenesis of both types of lesions. Due to the high variability of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are available, and a large variability across laboratories still exists in the procedures for morphologic examination and histology techniques. After a lecture at the XI International Congress of Neuropathology, San Francisco, CA, on 11 September 2006. Addendum In a recent clinicopathological evaluation of 79 autopsy cases derived from a prospective longitudinal study of subcortical ischemic vascular disease (SIVD) and Alzheimer disease (AD), Chui et al. [555] found significant cerebrovascular lesions (CVL) in 30%, AD pathology in 54%, and hippocampal sclerosis (HS) in 18%. Statistical assessment showed that all three pathology variables contributed independently to cognitive status, but only the neuritic Braak scores contributed significantly to cognitive impairment, indicating that advancing AD pathology overwhelms the effects of the two other factors that, in the absence of considerable AD, contribute to mild cognitive impairment. A recent histologic-neuroimaging study in two patients with SIVD showed correspondence between subinsular T2 hyperintensive lesions and demyelination, gliosis, and dilated perivascular spaces [556].