Research criteria for subcortical vascular dementia in clinical trials.

Vascular dementia (VaD) incorporate different vascular mechanisms and changes in the brain, and have different causes and clinical manifestations. Variation in defining the cognitive syndrome, in vascular etiologies, and allowable brain changes in current clinical definitions of VaD have resulted in variable estimates of prevalence, of groups of subjects, and of the types and distribution of putative causal brain lesions. Thus current criteria for VaD select an etiologically and clinically heterogeneous group. This definitional heterogeneity may have been a factor in "negative" clinical trials. An alternative for clinical drug trials is to focus on a more homogeneous group, such as those with subcortical (ischemic) VaD. This designation incorporates two small vessel clinical entities "Binswanger's disease" and "the lacunar state". It comprises small vessel disease as the primary vascular etiology, lacunar infarct(s) and ischaemic white matter lesions as the primary type of brain lesions, and subcortical location as the primary location of lesions. The subcortical clinical syndrome is the primary clinical manifestation, a definition which still requires additional empirical data. We expect that subcortical VaD show a more predictable clinical picture, natural history, outcome, and treatment responses. We propose a modification of the NINDS-AIREN criteria as a new research criteria for subcortical VaD.

Limitations of clinical criteria for the diagnosis of vascular dementia in clinical trials. Is a focus on subcortical vascular dementia a solution?

Vascular dementia (VaD) includes several different vascular mechanisms and changes in the brain, and has different causes and clinical manifestations. Critical to its conceptualization and diagnosis are definitions of the cognitive syndrome, vascular etiologies, and changes in the brain. Variation in these has resulted in different definitions of VaD, estimates of prevalence, and types and distribution of brain lesions. This definitional heterogeneity may have been a factor for negative results in prior clinical trials on VaD. We propose that the division of VaD into subtypes can identify a more homogeneous group of patients for drug trials. A so-called "subcortical" VaD could incorporate two old clinical entities "Binswanger's disease" and "the lacunar state." Small vessel disease is the primary vascular etiology, lacunar infarcts and ischemic white matter lesions are the primary type of brain lesions, the subcortical areas and frontal connections are the primary location of lesions, and a subcortical syndrome as the primary clinical manifestation. The clinical syndromes are likely more variable, and urgently need to be categorized. Selection of these patients for clinical trials could mainly be based on brain imaging features, where the essential changes and the main aspects of the lesions include extensive ischemic white matter lesions and lacunar infarcts in the deep gray and white matter structures. Subcortical VaD is expected to show a more predictable clinical picture, natural history, outcomes, and treatment responses.

Frequency and clinical determinants of dementia after ischemic stroke.

OBJECTIVE: To investigate the frequency and clinical determinants of dementia after ischemic stroke. METHODS: The authors administered neurologic, neuropsychological, and functional assessments to 453 patients (age 72.0 +/- 8.3 years) 3 months after ischemic stroke. They diagnosed dementia using modified Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised criteria requiring deficits in memory and two or more additional cognitive domains as well as functional impairment. RESULTS: The authors diagnosed dementia in 119 of the 453 patients (26.3%). Regarding dementia subtypes, 68 of the 119 patients (57.1%) were diagnosed with vascular dementia, 46 patients (38.7%) were diagnosed with AD with concomitant stroke, and 5 patients (4.2%) had dementia for other reasons. Logistic regression suggested that dementia was associated with a major hemispheral stroke syndrome (OR 3.0), left hemisphere (OR 2.1) and right hemisphere (OR 1.8) infarct locations versus brainstem/cerebellar locations, infarcts in the pooled anterior and posterior cerebral artery territories versus infarcts in other vascular territories (OR 1.7), diabetes mellitus (OR 1.8), prior stroke (OR 1.7), age 80 years or older (OR 12.7) and 70 to 79 years (OR 3.9) versus 60 to 69 years, 8 or fewer years of education (OR 4.1) and 9 to 12 years of education (OR 3.0) versus 13 or more years of education, black race (OR 2.6) and Hispanic ethnicity (OR 3.1) versus white race, and northern Manhattan residence (OR 1.6). CONCLUSIONS: Dementia is frequent after ischemic stroke, occurring in one-fourth of the elderly patients in the authors' cohort. The clinical determinants of dementia include the location and severity of the presenting stroke, vascular risk factors such as diabetes mellitus and prior stroke, and host characteristics such as older age, fewer years of education, and nonwhite race/ethnicity. The results also suggest that concomitant AD plays an etiologic role in approximately one-third of cases of dementia after stroke.

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.

Vascular dementia: the role of cerebral infarcts.

Although vascular dementia (VaD) is the second most frequent cause of dementia after Alzheimer disease (AD), the concept remains controversial in terms of delineation. The objective of this review is to investigate, from available literature, the role of cerebral infarcts in the pathogenesis of VaD and to identify areas of interest that need further evaluation and research. The incidence of new onset dementia is increased after stroke. Stroke subtypes, total volume of cerebral infarction and functional tissue loss, and location of the lesions are probably the major determinants of VaD. Any cause of stroke can lead to VaD. In some circumstances the causal relation between stroke and dementia is clear: (1) in young patients who are unlikely to have associated Alzheimer pathology; (2) when the cognitive functioning was normal before stroke, impaired immediately after, and does not worsen over time; (3) when the lesions are located in strategic areas; and (4) when a well-defined vasculopathy known to cause dementia is proven. However, several issues remain unsolved in VaD: lack of specificity of the diagnostic criteria; influence of white matter changes and associated Alzheimer pathology; influence of preexisting cognitive status; possibility of having VaD without stroke and the clinical relevance of silent infarcts to VaD; and best therapeutic strategy to be used to prevent VaD and to prevent stroke in patients with VaD. These questions form the basis for proposals for future research.

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.

Treatment for the secondary prevention of stroke in older patients: the influence of dementia status.

OBJECTIVE: To investigate the influence of dementia status on treatment for the secondary prevention of stroke in older patients. DESIGN: Based on patient examinations and medical record review, we investigated the frequency of aspirin and/or warfarin use at hospital discharge for the prevention of recurrent stroke in older patients hospitalized with acute ischemic stroke. SETTING: A large academic medical center. PARTICIPANTS: A cohort of 272 patients, mean age 72.1 +/- 8.5 years. MEASUREMENTS: We performed neurologic examinations and reviewed medical records to investigate the effects of a clinical diagnosis of dementia and other potentially relevant factors on treatment with aspirin or warfarin at hospital discharge. RESULTS: Thirty-one patients (11.4%) were not prescribed aspirin or warfarin at hospital discharge. Logistic regression determined that dementia (odds ratio (OR) = 2.57, 95% confidence interval (CI), 1.04-6.30) was a significant independent determinant of nontreatment with aspirin or warfarin, adjusting for abnormal gait (OR = 2.01, CI, .88-4.59); discharge to a nursing home or other institutional residence (OR = 2.55, CI, .83-7.81); cardiac disease (OR = .39, CI, .16-.95); cortical infarct location (OR = .45, CI, .18-1.10); male sex (OR = .47, CI, .20-1.15); age 80+ (OR = 1.14, CI, .46-2.82) and age 70-79 (OR = .96, CI, .32-2.88) versus age 60-69. CONCLUSIONS: Our results suggest that dementia is a significant independent determinant of nontreatment with aspirin or warfarin when otherwise indicated for the prevention of recurrent stroke. The underutilization of aspirin and warfarin in older stroke patients with dementia may be a modifiable basis for their increased risk of recurrence and death.

The natural history of CADASIL: a pooled analysis of previously published cases.

BACKGROUND AND PURPOSE: Although numerous families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported, our understanding of the disease remains incomplete. Thus, we performed this study to investigate the phenotypic range and natural history of CADASIL. METHODS: We performed a pooled analysis of previously published cases. RESULTS: We identified 105 symptomatic patients in 33 families. Vascular risk factors were uncommon, with hypertension reported in only 8 patients. The mean age of symptom onset was 36. 7+/-12.9 years. Stroke or transient ischemic attack was an initial symptom in 45 patients, with a mean age of onset of 41.2+/-9.2 years. Migraine was also a common initial symptom, reported by 42 patients at a younger mean age of 28.3+/-11.7 years. Other initial symptoms included depression in 9 patients, cognitive impairment in 6 patients, and seizures in 3 patients. Regarding clinical course, 71 patients experienced a stroke or transient ischemic attack, and 52 of those patients had 1 or more recurrent ischemic events. Dementia was reported in 44 patients. Only 3 additional patients experienced migraine at a later time, while 13 additional patients developed depression. Six patients had seizures. Twenty-two of the 105 patients had died, with a mean age of death of 54.8+/-10.6 years. Nineteen of those 22 patients had experienced a stroke or transient ischemic attack and 19 patients were demented. CONCLUSIONS: CADASIL typically becomes evident in early or middle adulthood with migraine or an ischemic event, later manifests itself through recurrent subcortical ischemic strokes leading to a stepwise decline and dementia, and results in reduced survival.

Risk factors for early recurrence after ischemic stroke: the role of stroke syndrome and subtype.

BACKGROUND AND PURPOSE: Information regarding risk factors for early recurrence is limited. Our aim was to identify the clinical predictors of early recurrence after ischemic stroke. METHODS: We prospectively examined 297 patients (mean age, 72.0+/-8.4 years) hospitalized with ischemic stroke to identify recurrent strokes occurring within 90 days of the index stroke. Survival free of recurrence was estimated using Kaplan-Meier analysis stratified by demographic variables; vascular risk factors; stroke syndrome, subtype, vascular territory, and severity; scores on the Barthel Index and Mini-Mental State Examination during hospitalization; blood pressure on admission; and selected laboratory data. We estimated the relative risk (RR) of early recurrence associated with those variables using proportional hazards analysis. RESULTS: We identified 22 recurrent events in the first 90 days after the index stroke, resulting in an early stroke recurrence rate of 7.4%, and death occurred immediately after recurrence in 6 of the 22 patients. A major hemispheric stroke syndrome (RR=2.9; 95% confidence interval [CI]=1.2 to 7.1), atherothrombotic stroke mechanism (RR=3.3; CI=1.3 to 8.3), and atrial fibrillation (RR=2.2; CI=0.8 to 6.1) were independent predictors of early recurrence, after adjustment for demographic variables. Conclusions-Early recurrence was frequent and resulted in increased mortality. Attention to the clinical features of the index stroke, including the presenting syndrome and the ischemic mechanism, and the recognition of atrial fibrillation may help in the selection of patients for the initiation of targeted interventions to prevent early recurrence and subsequent mortality.

CADASIL in a North American family: clinical, pathologic, and radiologic findings.

OBJECTIVE: To expand the reported phenotypic range of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). BACKGROUND: Despite numerous patient reports, our knowledge of the phenotypic range of CADASIL remains incomplete. METHOD: We performed clinical, pathologic, and radiologic examinations on members of a family with CADASIL. RESULTS: The proband is a 61-year-old man with a history of migraine and depression who has experienced multiple subcortical infarctions resulting in a stepwise decline. Neuropsychological testing documented a dementia syndrome with frontal lobe features and neurologic examination noted a left hemiparesis and a right-sided palmomental reflex. Brain biopsy with light microscopy revealed a nonatherosclerotic small-vessel angiopathy with periodic acid-Schiff positive granular changes in the media and white matter gliosis, with unremarkable cortex. Genetic testing confirmed a Notch3 mutation. The proband's first cousin has a history of depression, one seizure possibly resulting from an acute stroke, and a learning disorder. Neuropsychological testing demonstrated deficits in executive function and neurologic examination noted persistent extraneous adventitial movements, poor coordination, and primitive reflexes. Skin biopsy with electron microscopy demonstrated granular osmiophilic material within the basement membrane of vascular smooth muscle cells, which is considered to be pathognomonic of CADASIL. The proband's older son and younger son have histories of migraine and depression, respectively, and both also had learning disorders. MRI revealed diffuse white matter disease extending into the temporal lobes, and lacunar infarctions in these four nonhypertensive patients. Other family members have experienced migraine, recurrent stroke, dementia, and depression. CONCLUSIONS: CADASIL is a genetic basis for vascular dementia that may be manifest earlier in life than previously reported.

The effect of patient attrition on estimates of the frequency of dementia following stroke.

BACKGROUND: Given that prevalence surveys may underestimate the magnitude of the association between an exposure and a disease with high morbidity or mortality, we investigated the effects of patient attrition on estimates of the frequency of dementia following ischemic stroke. PATIENTS AND METHODS: We examined 251 patients 3 months after stroke and diagnosed dementia in 66 (26.3%) based on the results of neuropsychological and functional assessments and modified criteria from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised. Those 251 patients were drawn from a larger cohort of 297 patients, with the majority of the remaining 46 patients being unavailable for assessment due to death, severe stroke, or comorbid medical disorders. Using the coefficients in a logistic model of the clinical determinants of dementia based on the 251 patients who were examined, we calculated the probability of dementia for each of the 46 patients who were not examined. We considered a patient to have dementia when that probability was higher than the mean of the median probabilities of dementia in the groups of patients with and without dementia who completed the examinations. RESULTS: The sensitivity and specificity of our diagnostic method were 75.8% and 72.4%, respectively. We recognized dementia in 21 (45.7%) of the 46 unavailable patients, a significantly higher frequency than among examined patients. Additional analyses determined that the factors that increased the risk of becoming unavailable for follow-up, which included more severe stroke, left and right hemisphere infarct locations, and a history of prior stroke, are similar to the factors that increase the risk of dementia after stroke. CONCLUSION: Our findings suggest that dementia is differentially associated with early patient attrition, potentially resulting in the underestimation of its frequency and underrecognition of its importance as an outcome of ischemic stroke.

Dementia as a predictor of adverse outcomes following stroke: an evaluation of diagnostic methods.

BACKGROUND AND PURPOSE: Although it is understood that dementia is a risk factor for adverse outcomes, little is known about the predictive validity of the numerous methods that have been proposed for its diagnosis. Thus, we performed the present study to assess the utility of a variety of diagnostic methods in the prediction of adverse outcomes following stroke. METHODS: We administered neuropsychological, neurological, and functional examinations to 244 patients (age, 71.7+/-8.5 years) 3 months after ischemic stroke. We diagnosed dementia using each of the following methods: (1) neuropsychological testing, requiring deficits in increasing numbers of cognitive domains, both with and without memory impairment, as well as functional impairment; (2) Mini-Mental State Examination (MMSE) score of <24; and (3) neurologists' clinical judgment. We then used survival analyses to investigate the ability of diagnoses based on those methods to predict death and recurrent stroke during long-term follow-up. RESULTS: Log-rank tests and Cox proportional hazards analyses, with recurrent stroke entered as a time dependent covariate, determined that all of the paradigms were significant predictors of mortality, but the performance of paradigms based on neuropsychological testing was superior to the use of the MMSE and clinical judgment, particularly when memory impairment was required. Log-rank tests determined that paradigms based on neuropsychological testing were the only significant predictors of recurrent stroke and performed best when memory impairment was required. CONCLUSIONS: Our results suggest that dementia diagnosis based on neuropsychological assessment and an operationalized paradigm requiring deficits in memory and other cognitive domains is superior to other conventional methods in its ability to identify patients at elevated risk of adverse outcomes following stroke.

Meta-analysis of the Hachinski Ischemic Score in pathologically verified dementias.

Our objectives were to investigate the utility of the Hachinski Ischemic Score (HIS) in differentiating patients with pathologically verified Alzheimer's disease (AD), multi-infarct dementia (MID), and "mixed" (AD plus cerebrovascular disease) dementia, and to identify the specific items of the HIS that best discriminate those dementia subtypes. Investigators from six sites participated in a meta-analysis by contributing original clinical data, HIS, and pathologic diagnoses on 312 patients with dementia (AD, 191; MID, 80; and mixed, 41). Sensitivity and specificity of the HIS were calculated based on varied cutoffs using receiver-operator characteristic curves. Logistic regression analyses were performed to compare each pair of diagnostic groups to obtain the odds ratio (OR) for each HIS item. The mean HIS (+/- SD) was 5.4 +/- 4.5 and differed significantly among the groups (AD, 3.1 +/- 2.5; MID, 10.5 +/- 4.1; mixed, 7.7 +/- 4.3). Receiver-operator characteristic curves showed that the best cutoff was < or = 4 for AD and > or = 7 for MID, as originally proposed, with a sensitivity of 89.0% and a specificity of 89.3%. For the comparison of MID versus mixed the sensitivity was 93.1% and the specificity was 17.2%, whereas for AD versus mixed the sensitivity was 83.8% and the specificity was 29.4%. HIS items distinguishing MID from AD were stepwise deterioration (OR, 6.06), fluctuating course (OR, 7.60), hypertension (OR, 4.30), history of stroke (OR, 4.30), and focal neurologic symptoms (OR, 4.40). Only stepwise deterioration (OR, 3.97) and emotional incontinence (OR, 3.39) distinguished MID from mixed, and only fluctuating course (OR, 0.20) and history of stroke (OR, 0.08) distinguished AD from mixed. Our findings suggest that the HIS performed well in the differentiation between AD and MID, the purpose for which it was originally designed, but that the clinical diagnosis of mixed dementia remains difficult. Further prospective studies of the HIS should include additional clinical and neuroimaging variables to permit objective refinement of the scale and improve its ability to identify patients with mixed dementia.

Dementia after stroke increases the risk of long-term stroke recurrence.

BACKGROUND: Although risk factors for first stroke have been identified, the predictors of long-term stroke recurrence are less well understood. We performed the present study to determine whether dementia diagnosed three months after stroke onset is an independent risk factor for long-term stroke recurrence. METHODS: We examined 242 patients (age = 72.0 +/- 8.7 years) hospitalized with acute ischemic stroke who had survived the first three months without recurrence and followed them to identify predictors of long-term stroke recurrence. We diagnosed dementia three months after stroke using modified DSM-III-R criteria based on neuropsychological and functional assessments. The effects of conventional stroke risk factors and dementia status on survival free of recurrence were estimated using Kaplan-Meier analyses, and the relative risks (RR) of recurrence were calculated using Cox proportional hazards models. RESULTS: Dementia (RR = 2.71, 95% CI = 1.36 to 5.42); cardiac disease (RR = 2.18, CI = 1.15 to 4.12); and sex, with women at higher risk (RR = 2.03, CI = 1.01 to 4.10), were significant independent predictors of recurrence, while education (RR = 1.90, CI = 0.77 to 4.68), admission systolic blood pressure >160 mm Hg (RR = 1.80, CI = 0.94 to 3.44) and alcohol intake exceeding 160 grams per week (RR = 1.86, CI = 0.79 to 4.38) were weakly related. CONCLUSIONS: Our results suggest that dementia significantly increases the risk of long-term stroke recurrence, with additional independent contributions by cardiac disease and sex. Cognitive impairment may be a surrogate marker for multiple vascular risk factors and larger infarct volume that may serve to increase the risk of recurrence. Alternatively, less aggressive medical management of stroke patients with cognitive impairment or noncompliance of such patients with medical therapy may be bases for an increased rate of stroke recurrence.

Multifocal hypointense cerebral lesions on gradient-echo MR are associated with chronic hypertension.

PURPOSE: To investigate the basis for multifocal hypointense lesions within the brain as identified on T2*-weighted gradient-echo MR imaging in patients with no known or presumed cause of these lesions. METHODS: In the first of a two-part study design, we retrospectively reviewed a case series of 38 patients whose gradient-echo MR images showed multiple hypointense lesions within the brain parenchyma. Thirty-one cases in which the cause was known or presumed (eg, head trauma or cavernous angioma) were excluded from further review. The MR studies and clinical findings of the remaining seven cases were reexamined. In the second part, using a cohort study design with respect to hypertension, we prospectively reviewed the gradient-echo images from MR studies of 65 patients and control subjects enrolled in two ongoing clinical studies, one on "possible vascular dementia" (n = 33) and the other on "possible motor neuron disorder" (n = 32). RESULTS: In the first part of the study, we found seven cases with a pattern of multiple hypointense lesions involving the deep gray matter nuclei, especially the basal ganglia (n = 6) and thalamus (n = 5). In addition, involvement of the corona radiata (n = 5), brain stem (n = 4), and cerebellum (n = 3) was seen. Clinical review revealed a history of chronic hypertension in all seven patients. In the cohort study, we found three of 65 persons who had two or more focal hypointense lesions that involved the basal ganglia or thalami. Review of the clinical data showed that all three patients were being treated for hypertension; also, all three were patients from the "possible vascular dementia" group. CONCLUSIONS: The MR imaging pattern of multifocal hypointense lesions within the basal ganglia, thalamus, and other deep cerebral structures is more commonly found among patients with a history of chronic hypertension than in patients without chronic hypertension.