Neuropathological evaluation of mixed dementia

Mixed dementia (MD) refers to a combination of definite Alzheimer disease (AD) and vascular encephalopathy, but the distinction between both disorders is controversial. For the diagnosis of MD the clinical/neuroimaging criteria of possible AD plus cerebrovascular disease (CVD) as separate entities are used, but causal relations between vascular brain lesions and dementia are unclear. We proposed the combination of autopsy-proven AD with multiple vascular or ischemic lesions with about 30-50 ml of infarcted/damaged brain tissue. The population-based prevalence of MD is unknown. In retrospective and prospective autopsy studies, it ranges from 2 to 58% with reasonable means of 6-12%. In a consecutive autopsy series of 1500 demented elderly subjects, 830 of which with clinically probable AD, in Vienna, Austria, 41.5 to 52.0% showed "pure" AD, 7% atypical AD, 16-20% AD plus cerebrovascular lesions, and 9% AD plus Lewy body pathology; MD was diagnosed in 4.6 and 2.4%, and "pure" vascular dementia (VaD) in 11 and 2.0%, respectively, while 16.3/6.1% were other dementing disorders, and 1% showed no specific pathology. Like the MRC-CFAS and other studies, this indicates frequent coexistence of AD with multiple cerebrovascular lesions in cognitively impaired patients. In both AD and VaD, vascular lesions frequently involved subcortical regions (basal ganglia, thalamus, hippocampus, and white matter) or were multiple microinfarcts, whereas in MD, large/hemispheral infarcts and multiple microinfarcts were more frequent, suggesting different pathogenic mechanisms. In early/mild AD, critically located small vascular lesions may induce/promote cognitive decline, but in full-blown AD they appear of minor importance. Discussion of the major pathogenic factors inducing AD, VaD and MD suggests synergistic relations between these disorders. However, currently available morphological criteria for AD and VaD are of limited value for the diagnosis of MD and generally accepted and validated histopathological criteria for the diagnosis of VaD and MD are currently not available. Therefore, more distinct and critically evaluated clinico-pathological criteria are warranted.     

The Pocket Smell Test: successfully discriminating probable Alzheimer's dementia from vascular dementia and major depression

The present study extended previous work on olfactory dysfunction (odor identification deficits) by using the Pocket Smell Test (PST) to discriminate between groups of patients with Alzheimer's disease (AD), vascular dementia (VaD), and major depression (MD). Sixty patients meeting the DSM-IV criteria for either AD, VaD, or MD (20 per group) underwent assessment with the PST, a three-item screening measure of odor identification, and the Mini-Mental State Examination (MMSE). Patients with AD scored significantly lower than patients with either VaD or MD on the PST, even after controlling for MMSE scores. A PST score of > or =1 (i.e., 1 or 0 correct) discriminated between patients with and without AD with a classification accuracy of 95% (sensitivity 100%, specificity 92.5%). Olfactory assessment may be of diagnostic utility in the differential diagnosis of AD versus VaD versus MD in elderly patients.     

Facts, myths, and controversies in vascular dementia

Significant progress in the field of VaD resulted from publication of the NINIDS-AIREN Diagnostic Criteria for VaD (G.C. Roman, T.K. Tatemichi, T. Erkinjuntti, et al., Vascular dementia (VaD): diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43 (1993) 250-260). Epidemiological studies confirmed the importance of VaD as the second most common cause of dementia in the elderly, representing 15-20% of all cases of dementia. In Europe and North America, Alzheimer's disease (AD) predominates over VaD in a 2:1 ratio; in contrast, in Japan and China VaD accounts for almost 50% of all dementias. Case-control studies have identified risk factors for VaD including ageing, hypertension, diabetes mellitus, hyperlipidemia, recurrent stroke, cardiac disease, smoking, sleep apnea, and more recently, hyperhomocysteinemia, among others. Hypertension treatment may prevent VaD and AD. This finding has enormous importance from the Public Health viewpoint to decrease the future number of patients with dementia in the elderly. Along with advances in the field of VaD came a number of controversies and damaging misconceptions and myths. Myth no. 1--Vascular dementia is a non-entity: The false idea that VaD does not exist is particularly destructive because it creates the perspective that VaD is unworthy of study or research. A condition that either does not exist or represents only a minute proportion of all cases of dementia in the elderly, lacks public health relevance and becomes a low priority for research by funding agencies and industry. In fact, vascular brain lesions are the commonest and most important component of dementia in the elderly. Myth no. 2--Vascular dementia is so difficult to diagnose that only experts can recognize and identify it accurately: VaD does exist and the diagnosis of post-stroke VaD, in particular is straightforward. Most cases fulfill NINDS-AIREN criteria for probable VaD; i.e., (1) there is acute onset of dementia demonstrated by impairment of memory and two other cognitive domains, such as orientation, praxis or executive dysfunction; (2) relevant cerebrovascular lesions are demonstrated by neuroimaging; and (3) a temporal relation between stroke and cognitive loss is evident. In the donepezil trials on VaD, post-stroke dementia represented about 75% of the >1,200 patients enrolled. Myth no. 3--Improvement in clinical trials of cholinergics in VaD is due to underlying AD, not to the vascular lesions. Experimental, clinical and pathological evidence has demonstrated cholinesterase deficits in VaD (independently of any concomitant AD pathology), including low acetylcholine in cerebrospinal fluid, and reduced choline acetyltransferase (ChAT) in the brain.     

Plasma levels of soluble receptor for advanced glycation end products in Alzheimer's disease

Background: A decreased plasma level of soluble form of the receptor for advanced glycation end products (sRAGE) in patients with Alzheimer's disease (AD) has been reported. However, no evidence has shown whether the sRAGE plasma level of AD patients may differentiate from other types of dementia. Methods: Our study assessed sRAGE concentrations in the following 121 individuals in Chongqing area: 36 patients with AD, 12 with vascular dementia (VaD), 14 with mixed dementia (MD), 24 with other dementia (OD) including Parkinson's disease dementia, frontotemporal dementia, paralytic dementia and 35 cognitively normal controls. The total plasma level of sRAGE was determined using sandwich ELISA method. Results: sRAGE concentration in AD is significantly decreased compared with healthy controls. However, the receiver operating characteristic curve analysis of sRAGE between the AD and the control shows a low diagnostic accuracy. Conclusions: Our results demonstrate that sRAGE may assist the diagnosis of AD from normal individuals, but cannot differentiate AD from VaD, MD or OD.     

High b-value diffusion imaging of dementia: application to vascular dementia and alzheimer disease

Alzheimer's disease (AD) and Vascular Dementia (VaD) are the most common types of dementia and are progressive diseases affecting millions of people. Despite the high sensitivity of MRI to neurological disorders it has not thus far been found to be specific for the detection of either of these pathologies. In the present study high b-value q-space diffusion-weighted MRI (DWI) was applied to VaD and AD. Controls (N=4), VaD patients (N=8) and AD patients (N=6) were scanned with high b-value DWI, which emphasizes the water component which exhibits restricted diffusion. VaD patients were found to present major WM loss while, in AD, the major pathology found was GM changes, as expected. Also, WM changes in VaD and AD were of a different pattern, more specific to frontal and temporal areas in AD and more widespread in VaD. This pattern of WM changes may be utilized as a diagnosis criterion. Conventional diffusion tensor imaging did not show significant changes between either of the groups and controls. These results demonstrate the potential of high b-value DWI in the diagnosis of dementia.     

P300 auditory event-related potentials and neuropsychological study during donepezil treatment in vascular dementia

Abstract After Alzheimer’s disease (AD), vascular dementia (VaD) is the most common cause of dementia among the elderly. Abnormalities in neurotransmitter pathways are common pathogenic mechanisms shared by AD and VaD. For one month we studied the effects of donepezil, an acetylcholinesterase inhibitor (5 mg daily), on the cognitive system using P300 auditory event-related potentials (P300) and neuropsychological tests in 10 patients affected by probable VaD according to the NINDS-AIREN criteria. Our data showed a significant improvement of neuropsychological items and P300 latency after one month of donepezil treatment. In conclusion both P300 and neuropsychological tests are indicated in patients with VaD to confirm the efficacy of donepezil treatment during follow-up.     

Vascular dementia in a population-based autopsy study

BACKGROUND: The validity of the clinical diagnosis of vascular dementia (VaD) remains suboptimal. OBJECTIVE: To investigate clinicopathologic correlations in VaD. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to identify incident cases of dementia in Rochester, Minn, from January 1, 1985, through December 31, 1989. Dementia and Alzheimer disease (AD) were defined by the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Vascular dementia was defined by criteria including imaging results. Pathological characteristics of AD were quantified by means of standard scoring methods for neurofibrillary tangles and neuritic plaques. Vascular pathological findings were assessed by expert neuropathological opinion. RESULTS: Of 419 patients with dementia who died before the study, neuropathological examination results were available in 89 (21%) with median age at onset of 80 years (range, 50-96 years; 52 [58%] women). Pathological diagnoses were AD in 45 patients (51%), pure VaD in 12 (13%), combined AD and VaD in 11 (12%), and other diagnoses in the remaining 21 patients. Criteria for VaD that required either a temporal relationship between a stroke and dementia onset or worsening, or bilateral infarctions in specified locations demonstrated on imaging results (Mayo Clinic criteria) had 75% sensitivity and 81% specificity for pure VaD (positive likelihood ratio, 3.9; 95% confidence interval, 2.2-6.7). Five cases of pure VaD lacked the temporal relationship and accounted for the imperfect sensitivity of the criteria. CONCLUSIONS: In this population-based autopsy study, the presence of vascular pathological characteristics in the absence of major AD pathological findings was common. Pure VaD without overt clinical strokes remains a challenge for antemortem diagnosis.     

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.     

Cholinergic dysfunction in vascular dementia

Vascular dementia (VaD) is the second most common type of dementia in the elderly after Alzheimer’s disease (AD). Evidence is presented indicating the occurrence of cholinergic dysfunction in VaD, independent from AD. Controlled clinical trials of cholinesterase inhibitors (ChEIs) in VaD and in patients with AD plus cerebrovascular disease are reviewed. Compared with placebo, ChEI treatment improves cognition, behavior, and activities of daily living. Cholinergic deficits in patients with VaD may result from ischemia of basal forebrain cholinergic nuclei that are irrigated by penetrating arteries that are highly susceptible to arterial hypertension, or from ischemic lesions in basal ganglia or white matter that sever the extensive cholinergic cortical projections. Cholinergic stimulation produces increases in cortical cerebral blood flow that may be relevant to the therapeutic effect of ChEIs.     

Relative frequencies of Alzheimer disease,Lewy body,vascular and frontotemporal dementia,and hippocampal sclerosis in the State of Florida Brain Bank

Alzheimer disease (AD) is the most common dementing illness in the elderly, but there is equivocal evidence regarding the frequency of other disorders such as Lewy body disease (LBD), vascular dementia (VaD), frontotemporal dementia (FTD), and hippocampal sclerosis (HS). This ambiguity may be related to factors such as the age and gender of subjects with dementia. Therefore, the objective of this study was to calculate the relative frequencies of AD, LBD, VaD, FTD, and HS among 382 subjects with dementia from the State of Florida Brain Bank and to study the effect of age and gender on these frequencies. AD was the most frequent pathologic finding (77%), followed by LBD (26%), VaD (18%), HS (13%), and FTD (5%). Mixed pathology was common: Concomitant AD was present in 66% of LBD patients, 77% of VaD patients, and 66% of HS patients. The relative frequency of VaD increased with age, whereas the relative frequencies of FTD and LBD declined with age. Males were overrepresented among those with LBD, whereas females were overrepresented among AD subjects with onset age over 70 years. These estimates of the a priori probabilities of dementing disorders have implications for clinicians and researchers.     

The role of MRI in dementia

Neuroimaging techniques aimed at studying structural changes of the brain may provide useful information for the diagnosis and the clinical management of patients with dementia. Magnetic resonance imaging (MRI) may show abnormalities amenable to surgical treatment in a significant percentage of patients with cognitive impairment. MRI may also assist the differential diagnosis in dementia associated with metabolic or inflammatory diseases.MRI has the potential to detect focal signal abnormalities which may assist the clinical differentiation between Alzheimer's disease (AD) and vascular dementia (VaD). Severe temporal atrophy, hyperintensities involving the hippocampal or insular cortex, and gyral hypointense bands are more frequently noted in AD. Basal ganglionic/thalamic hyperintense foci, thromboembolic infarctions, confluent white matter and irregular periventricular hyperintensities are more common in VaD.The high sensitivity of MRI in detecting T2 hyperintense lesions and the low specificity off white matter lesions have resulted in a poor correlation between MRI findings and both neuropathological and clinical manifestations. In particular, MRI has disclosed a series of white matter focal changes in the elderly population, which are not necessarily associated with cognitive dysfunction.The recent advent of a new MRI method sensitive to the microstructural changes of white matter, the so-called diffusion tensor imaging, may be helpful in correlating clinical manifestations with white matter abnormalities.     

Immediate causes of death of demented and non-demented elderly

Objective – To investigate the immediate causes of death, in autopsied demented and non-demented elderly. Design – Retrospective clinicopathologic correlations. Setting – Acute and intermediate care geriatric hospital. Participants – 342 hospitalized demented and non-demented elderly (mean age 84.94±6.9 years) who underwent consecutive post-mortem examinations: 120 demented patients with either vascular dementia (VaD, n =34), mixed dementia (MD, n =65) or Alzheimer's disease (AD, n =21) neuropathologically confirmed and 222 non-demented elderly. Results – Primary causes of death were similar in both demented and non-demented patients; the commonest were cardiovascular disease and bronchopneumonia. Cardiac causes of death and especially cardiac failure were more frequent in VaD than in AD or MD (respectively P =0.027 and 0.005). Dementia was an underlying but never a primary cause of death. Conclusions – Immediate causes of death are similar in elderly demented and non-demented patients.     

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.     

血管性痴呆的生物学标记物研究进展

血管性痴呆与阿尔茨海默病、混合性痴呆的鉴别诊断面临困难。目前应用的血管性痴呆临床诊断标准的敏感度和特异度偏低。近年一些生物学标记物作为病理生理过程的客观指标被应用于与血管性痴呆的诊断和鉴别诊断。这些生物学标记物包括结构影像学、正电子发射断层扫描（positron emission tomography,PET）、脑脊液标记物[淀粉样β多肽（Amyloidβ-peptide,Aβ）和tau蛋白]、血浆细胞因子和脑血管血液动力学检查等。初步的研究结果提示脑脊液Aβ和脑的脱氧葡萄糖-PET显像对于血管性痴呆的诊断和鉴别诊断具有较高的应用价值。     

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.     

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.     

Differences in risk factors for dementia with neurodegenerative traits and for vascular dementia

In 229 patients with dementia and in 144 control subjects, polymorphisms of apolipoprotein E (ApoE), low-density-lipoprotein (LDL)-receptor-related protein, alpha(2)-macroglobulin, interleukin (IL) 1beta, angiotensin-converting enzyme and of methylene tetrahydrofolate reductase genes were investigated. In plasma, antibodies against Chlamydia pneumoniae and lipids were determined. Dementia was classified as probable Alzheimer's disease (AD), probable dementia of vascular origin (VaD) and mixed dementia (MD). An association of the disease with ApoE and IL-1beta polymorphism and increased levels of LDL cholesterol were observed in AD and in MD but not in 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.     

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.     

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。