Modern concept of vascular cognitive impairment.

BACKGROUND: Vascular cognitive impairment (VCI) has superseded vascular dementia and multi-infarct dementia as the concept to be used in cognitive decline due to cerebrovascular disease. METHOD: The literature was reviewed with regard to the concept of VCI and its incidence, pathophysiological substrate, clinical features and management. RESULTS: A change in the diagnostic paradigm from the current Alzheimer-based definition of vascular dementia to VCI will allow the earlier identification of cases and will identify a different population from that recognized using the current criteria for vascular dementia. CONCLUSIONS: Case identification at the earliest possible stage affords the greatest opportunity for treatment that may slow the rate of progression.

The concept of vascular cognitive impairment.

Vascular dementia (VaD) is increasingly recognised to reflect an outmoded concept in that it identifies cases too late for preventive therapy to have an opportunity to prevent the development of dementia and uses a cognitive paradigm inappropriately based on Alzheimer's disease. A replacement is urgently required and a new concept, that of vascular cognitive impairment (VCI), has been proposed to meet this need. It is imperative that criteria for VCI are developed on the basis of knowledge and data rather than supposition and assumption, as was the case for VaD. This review details the state of knowledge that we have now reached concerning the fundamental points of severity and cognitive paradigm and also covers a number of other imaging-related essential points embracing atrophy, leukoaraiosis, infarct volume and infarct location. Finally, the increasingly important concept of mixed dementia (co-existent Alzheimer's disease and VCI) is discussed.

Peripheral nerve granuloma in a patient with tuberculosis.

The cause of peripheral neuropathy associated with tuberculosis is controversial. Possibilities include an immune mediated neuropathy, direct invasion of nerves, vasculitic neuropathy, compressive neuropathy, a meningitic reaction, and the toxic effects of antituberculous chemotherapy. This report describes the unusual finding of granulomas in the peripheral nerve of a patient with tuberculosis. The pathological findings were of a delayed hypersensitivity reaction, but with no more specific indications of the mechanism of the neuropathy.

Profiles of cognitive decline in Alzheimer disease.

Most recent studies have used only two observations to estimate the rate of cognitive decline in patients with Alzheimer disease (AD); few have data taken from more than a 2-year period; and none report on autopsy-verified cases. Repeated observations over the complete course of the disease are necessary to quantitatively evaluate hypotheses such as the triphasic linear model of Brooks et al. (1993). The goal of this study is to compare the triphasic linear and quadratic models of decline in a group of 12 AD patients confirmed at autopsy with a group of age- and sex-matched normal control subjects. Both groups were taken from the University of Western Ontario Dementia Study, and the Extended Scale for Dementia was used as the outcome measure. The squared multiple correlation as a measure of goodness of fit suggested the superiority of the more parsimonious quadratic model over the triphasic linear model. Quantitative models more accurately reflect the profiles of change in AD and may prove more sensitive in measuring the effects of drugs on these patterns.

The cognitive syndrome of vascular dementia: implications for clinical trials.

Dementia is common among patients with cerebrovascular disease, particularly in a setting of one or more clinically evident strokes. Prior cohort and case studies have suggested that the cognitive syndrome of vascular dementia is characterized by predominant executive dysfunction, in contrast to the deficits in memory and language function that are typical of patients with Alzheimer disease. The course of cognitive decline may also differ between those dementia subtypes, with many, but not all, patients with vascular dementia exhibiting a stepwise course of decline caused by recurrent stroke and most patients with Alzheimer disease exhibiting a gradually progressive course of decline. The findings of prior studies of the cognitive syndrome of vascular dementia must be interpreted with caution, however, because of (1) possible inaccuracies in the determination of the dementia subtype and the loss of precision that might result from pooling heterogeneous subgroups of patients with vascular dementia, (2) difficulties inherent in identifying a pattern of strengths and weaknesses in patients who are required to have memory impairment and other deficits to meet operationalized criteria for dementia, and (3) the use of limited test batteries whose psychometric properties are incompletely understood. Specific questions that should be addressed by future studies are discussed.

Conceptual background to vascular cognitive impairment.

The current criteria for vascular dementia use a paradigm that first diagnoses dementia on the basis of Alzheimer-type criteria and then superimposes upon this vascular events and risk factors to convert a diagnosis of Alzheimer disease to one of vascular dementia. There are two fundamental flaws with this approach. First, the neuropsychological features of Alzheimer disease are not the same as those for vascular dementia and so use of the current criteria will fail to diagnose many cases, particularly those in whom memory loss is not prominent. Second, progression of vascular dementia should be modifiable by adjustment of risk factors and, possibly, by the use of neuroprotective agents. Given this, it is absurd to wait until patients are frankly demented. It is far more appropriate to detect patients at risk of developing cognitive loss as soon as possible. This could be in the earliest symptomatic stage (vascular cognitive impairment) or even prior to this (brain-at-risk) stage. New criteria, based on evidence rather than on supposition, that focus on early disease are urgently needed.

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.

White matter changes in stroke patients. Relationship with stroke subtype and outcome.

White matter changes (WMC), detected by imaging techniques, are frequent in stroke patients. The aim of the study was to determine how WMC relate to stroke subtypes and to stroke outcome. We made a systematic Medline search for articles appearing with two of the following key words: either 'WMC or white matter lesions or leukoencephalopathy or leukoaraiosis' and 'stroke or cerebral infarct or cerebral hemorrhage or cerebrovascular disease or transient ischemic attack (TIA)'. WMC, as defined radiologically, are present in up to 44% of patients with stroke or TIA and in 50% of patients with vascular dementia. WMC are more frequent in patients with lacunar infarcts, deep intracerebral hemorrhages, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and cerebral amyloid angiopathy. After an acute ischemic stroke, WMC are associated with a higher risk of death or dependency, recurrent stroke of any type, cerebral bleeding under anticoagulation, myocardial infarction, and poststroke dementia. WMC in stroke patients are often associated with small-vessel disease and lead to a higher risk of death, and poor cardiac and neurological outcome. However, several questions remain open and need further investigations.

Factors affecting the age of onset and rate of progression of Alzheimer's disease.

OBJECTIVES: To assess the role of cerebrovascular disease, sex, education, occupation, year of birth, leukoaraiosis, congophilic angiopathy, family history, and other demographic factors on the reported age of onset and rate of progression of Alzheimer's disease. METHODS: Analysis of data from the University of Western Ontario Dementia Study, a prospective longitudinal study of dementia patients with clinical and 6 monthly psychometric follow up to postmortem based in a university memory disorders clinic with secondary and tertiary referrals. There were 172 patients with dementia. The main outcome measures were the reported age of onset of cognitive decline as described by the family (available in 168) and rate of progression as measured during the linear phase of the extended scale for dementia, which could be calculated in 66. The cases subdivided into 49 cases of definite Alzheimer's disease without infarcts, 25 cases of otherwise definite Alzheimer's disease with infarcts, 79 cases of probable Alzheimer's disease without infarcts, and 19 such cases with infarcts. RESULTS: The age of onset was not influenced by the rate of progression, the presence of cerebral infarcts, or congophilic angiopathy. Educational level, occupational level, sex, family history, year of birth, reported age of onset, severity at entry, an ischaemic score, and the presence of leukoariosis, affected neither age of onset nor the rate of progression. An earlier year of birth had a major effect and higher education had a minor effect on earlier age of onset. The earlier the year of birth, the lower the educational level and the greater the accrual of cerebral infarcts. CONCLUSIONS: Contrary to series without pathological verification, age of onset in this study was not affected by occupation. Education had a modest effect on earlier reported onset, probably reflecting earlier recognition. As birth year has a strong effect on educational level and the occurrence of cerebral infarcts, this must be taken into account when analysing for risk factors for Alzheimer's disease.

Fallacies in the pathological confirmation of the diagnosis of Alzheimer's disease.

OBJECTIVE: Necropsy confirmed clinical diagnostic accuracy for Alzheimer's disease is claimed to exceed 90%. This figure contains two fallacies; it includes cases in which Alzheimer's disease exists with other diseases affecting cognition and the studies that report these figures excluded cases without necropsy (verification bias). The effect of these errors is estimated. METHODS: Data were taken from the University of Western Ontario Dementia Study, a registry of dementia cases with clinical and psychometric follow up to necropsy based in a university memory disorders clinic with secondary and tertiary referrals. Data were available on 307 patients; 200 (65%) had clinically diagnosed Alzheimer's disease, 12 (4%) vascular dementia, 47 (15%) mixed dementia, and 48 (16%) had other diagnoses. One hundred and ninety two of 307 cases (63%) died and 122 of 192 fatalities (64%) had necropsies. The pathological material was interpreted in two ways, allowing and disallowing coexistent disease in making a diagnosis of Alzheimer's disease. In cases without necropsy, progressive cognitive loss was used as a marker for degenerative dementia. The outcome measures of interest were the positive predictive value of a clinical diagnosis of Alzheimer's disease allowing and disallowing coexistent diseases and with and without correction for cases that were not necropsied. RESULTS: The clinical diagnoses differed significantly between the population who died and those who did not. In cases without necropsy, 22% had no dementia on follow up, concentrated in early cases and men, showing considerable scope for verification bias. The positive predictive value of a diagnosis of Alzheimer's disease was 81% including coexistent diseases, falling to 44% when limited to pure cases. Combined, these factors reduce the positive predictive value to 38% for pure Alzheimer's disease. CONCLUSIONS: Correction for dual pathology and verification bias halves the positive predictive value of the clinical diagnosis of Alzheimer's disease. Data derived from necropsy studies cannot be extrapolated to the whole population. This has important implications including uncertainty about diagnosis and prognosis and a dilution effect in therapeutic trials in Alzheimer's disease.

Natural history of the spontaneous reperfusion of human cerebral infarcts as assessed by 99mTc HMPAO SPECT.

OBJECTIVE: Little is known about the effect of spontaneous reperfusion of human cerebral infarcts. Single photon emission computerised tomography (SPECT) data were analysed from a study using 99Tc(m) HMPAO (99Tc(m) hexamethylpropyleneamine oxime) in human cerebral infarction for the frequency of reperfusion and to see if it affected infarct size, oedema, haemorrhagic transformation, or functional outcome. METHODS: Fifty sequential cases of ischaemic stroke were studied with 124 99Tc(m) HMPAO SPECT at around one day, one week, and three months after stroke along with detailed clinical and functional assessments. RESULTS: Visually apparent reperfusion occurred in 14 of 50 patients (28%) with a mean delay of 5.8 days and reperfusion was seen in seven others in whom it was identified on the basis of changes in perfusion deficit volume. It occurred in 13 of 23 embolic events but only in three of 23 other events. In only two cases did spontaneous reperfusion occur early enough to preserve tissue or function. Reperfusion did not otherwise reduce infarct size, or improve clinical or functional outcome, and was not associated with oedema but an association with haemorrhagic transformation was suggested. Reperfusion significantly decreased the apparent perfusion defect as measured by SPECT one week from the ictus, but was mostly non-nutritional and transient. The mean volume of tissue preserved by nutritional reperfusion was 10 cm3, but this was unequally distributed between cases. Late washout of 99Tc(m) HMPAO from areas of hyperaemic reperfusion may be a good prognostic marker but is a rare phenomenon and too insensitive to be of general applicability. CONCLUSIONS: Spontaneous reperfusion after cerebral infarction occurs in 42% of cases within the first week but is associated with clinical improvement in only 2%. It has few adverse consequences although it may be associated with haemorrhagic transformation.

Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia.

OBJECTIVE: To compare the evolution of Alzheimer disease (AD), vascular dementia (VaD), and mixed dementia by cognitive domain. SETTING: The University of Western Ontario Dementia Study, which is a registry of cases of dementia seen for secondary and tertiary assessment in a university memory disorders clinica with extensive follow-up data and histopathological confirmation of clinical diagnoses. PATIENTS: One hundred twenty-nine patients with definite or probable AD, 12 patients with definite or probable VaD, and 36 patients with definite or probable mixed dementia. METHODS: Patients were grouped as having an early, moderate, or advanced stage of disease according to the extended scale for dementia (ESD). The ESD was subdivided into cognitive domains, and the domain scores were compared for each stage of disease by diagnostic category with the use of a 2-way analysis of variance with repeated measures. RESULTS: As expected, the scores in all domains decreased significantly with increasing severity. There was a significant difference in the decline in memory among the diagnostic groups (P = .02) that was mostly attributable to the difference between AD and mixed dementia (P = .03), with the difference between AD and VaD only approaching significance (P = .06). There was a similar finding for praxis. The interaction between diagnosis (AD and VaD) and severity was significant only for memory (P = .02), showing a less severe memory deficit at onset but a proportionately more rapid progression in VaD and arithmetic ability (AD and mixed dementia [P = .03]). CONCLUSIONS: Alzheimer disease, VaD, and mixed dementia evolve similarly as assessed using cognitive domains obtained by subdivision of the ESD in a patient population derived from a memory clinic and by analyzing VaD as a single entity. Only memory impairment evolves differently between AD and VaD, with this depending on the severity. Memory is more severely impaired in the early stage of AD; however, with increasing severity of dementia, memory impairment in VaD accelerates and catches up with AD at the level of moderate impairment. The differences between AD and mixed dementia are greater than those between mixed dementia and VaD, suggesting an important role for the ischemic component of mixed dementia. Simple neuropsychological tools (eg, the ESD) may be incapable of distinguishing between AD and VaD, and more focused instruments may be required. Inherent bias in case selection may prevent extrapolation of these results to VaD in general, but the neuropsychological criteria for VaD may need to vary, depending on the severity.

Single-photon emission computed tomography using hexamethylpropyleneamine oxime in the prognosis of acute cerebral infarction.

BACKGROUND AND PURPOSE: The role of single-photon emission CT (SPECT) in the prognosis of cerebral infarction is controversial, but most studies report that SPECT using a variety of radiopharmaceutical agents gives useful prognostic information. Only one study has questioned whether acute perfusion deficits independently add to a valid clinical prognostic score. This study was limited to middle cerebral artery territory infarcts and was negative. We present data on the prognostic utility of SPECT using 99mTc-hexamethylpropyleneamine oxime (HMPAO) in cerebral infarction, unselected by site. METHODS: Fifty consecutive unselected patients admitted to the hospital with acute cerebral infarction, of whom 10 died and 7 withdrew, had SPECT performed serially at onset and at 1 week and 3 months after stroke onset using 99mTc-HMPAO and the NOVO 810 dedicated high-resolution head tomograph. Clinical severity at presentation and outcome was measured with the Canadian Neurological Scale and the Barthel Index. Infarct volumes were measured from both the SPECT and CT scans. The data for the 43 subjects who completed the study or died were evaluated to determine the most powerful prognostic measures. Predictors were the Canadian Neurological Scale score at onset and 1 week, the Barthel Index at 1 week, the CT infarct volume typically done between 3 and 7 days after stroke onset, and the infarct volumes at the first and second SPECT. Outcome measures were the Canadian Neurological Scale score and Barthel Index score at 3 months, scored as zero for those patients who died. RESULTS: The clinical prognostic indicators correlated with the outcome measures, with coefficients between .617 and .821 (P < .0006 in all cases). The Canadian Neurological Scale score measured at 1 week was the best of these. Infarct volumes measured from SPECT correlated less well (coefficients between -.518 and -.683, P < .0019 in all cases). CT infarct volume was the poorest predictor. Although SPECT infarct volumes predicted outcome, they did so less well than clinical examination. Spontaneous infarct reperfusion did not affect outcome. CONCLUSIONS: Although the measurement of infarct volume on SPECT using 99mTc-HMPAO provides a predictor of stroke outcome, it is not a better predictor than the Canadian Neurological Scale score.

Vascular cognitive impairment: a new approach to vascular dementia.

Vascular dementia has remained a confused concept since its origin over a century ago. Recently developed criteria, which have not met with universal acceptance, erroneously base their description of vascular dementia on Alzheimer's disease, an error that is founded in the historical confusion of the two conditions. These errors include requirements for prominent memory loss and the occurrence of a substantial degree of cognitive impairment before dementia can be diagnosed. They also treat vascular dementia as a single condition and fail to address the question of aetiology. Furthermore, these criteria largely ignore such data as is already available regarding vascular dementia. Vascular dementia is preventable. Thus cases need to be detected as soon as possible to avoid unnecessary deterioration. To correct these errors a new concept, that of vascular cognitive impairment, is proposed. This concept seeks to identify cognitive impairment due to cerebrovascular disease at the very earliest stage and, by identifying the aetiology, enable the institution of appropriate preventive therapy.