© 2007 European Society of Cardiology
Brain magnetic resonance imaging abnormalities in patients with heart failure
a Department of Neurology, Sint Lucas-Andreas Hospital Amsterdam, The Netherlands
b Department of Neurology and Alzheimer Center, VU University Medical Center Amsterdam, The Netherlands
c Department of Neurology, Medical Center Leeuwarden Leeuwarden, The Netherlands
d Department of Cardiology, Sint Lucas-Andreas Hospital Amsterdam, The Netherlands
* Corresponding author. Department of Neurology, VU Medical Center PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 205108911; fax: +31 206837198. E-mail address: r.vogels{at}vumc.nl
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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Background: Although heart failure (HF) is a common cardiovascular disorder, to date little research has been conducted into possible associations between HF and structural abnormalities of the brain.
Aims: To determine the frequency and pattern of magnetic resonance imaging (MRI) abnormalities in outpatients with chronic HF, and to identify any demographic and clinical correlates.
Methods: Brain MRI scans were compared between a sample of 58 HF patients, 48 controls diagnosed with cardiovascular disease uncomplicated by HF (cardiac controls) and 42 healthy controls. Deep, periventricular and total white matter hyperintensities (WMH), lacunar and cortical infarcts, global and medial temporal lobe atrophy (MTA) were investigated.
Results: Compared to cardiac and healthy controls, HF patients had significantly more WMH, lacunar infarcts and MTA, whereas cardiac controls only had more MTA, compared to healthy controls. Age and left ventricular ejection fraction (LVEF) were independently associated with total WMH. Age and systolic hypotension were associated with MTA in HF patients and cardiac controls.
Conclusion: Our results suggest that cardiac dysfunction contributes independently to the development of cerebral MRI abnormalities in patients with HF. Age and low LVEF are the principal predictors of cerebral WMH in patients with HF and in cardiac controls.
Key Words: Heart failure • Magnetic resonance imaging • White matter hyperintensities
Received February 26, 2007; Revised June 18, 2007; Accepted July 12, 2007
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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Cerebral structural abnormalities, including white matter hyperintensities (WMH) are frequently detected on brain images of both asymptomatic and cognitively impaired elderly individuals. Many magnetic resonance imaging (MRI) based studies have demonstrated the existence of an association between WMH and risk factors for cerebrovascular disease [1-4]. In addition, it has been suggested that the cardiovascular disease that leads to heart failure (HF) is also associated with a high risk of cerebrovascular complications. To date only four studies have investigated structural brain abnormalities among HF patients [5-8]. However, methodological shortcomings limit the interpretation of the results obtained.
HF is a recognised risk factor for dementia and stroke [9-11]. Cerebral hypoperfusion resulting from left ventricular dysfunction and cerebral emboli as a consequence of cardiac valvulopathies, arrhythmias and heart wall disorders, are thought to be responsible for the observed cerebral changes [12]. Among patients with HF and atrial fibrillation, the risk of cardiogenic stroke is two to four times greater for those between 50 and 80 years of age [13] and, in case of multiple emboli may lead to vascular dementia [14].
The cause of cerebral WMH, however, remains a matter of debate. WMH may be associated with ischaemic cerebral changes resulting from various cerebrovascular risk factors [1] or represent non-specific cerebral processes, such as normal aging and generalized vascular disease [15].
In view of the increasing proportion of elderly individuals with HF in the population, the relative importance of the various risk factors for cerebral ischaemic change need to be determined as a matter of urgency. This is of particular importance in patients without clinical evidence of stroke or dementia, as risk factors might still be amenable to treatment or prevention.
The purpose of the present study was to prospectively determine the frequency and pattern of cerebral abnormalities in independently living outpatients with chronic HF, and to identify the demographic and clinical correlates involved. Aging and hypertension are important risk factors for cerebral WMH and global atrophy. We therefore used a case-control design, including HF patients, age-matched controls with a similar cardiovascular risk profile but without HF (cardiac controls), and healthy controls. Our working hypothesis was that both generalized cardiovascular burden and reduced cardiac function render HF patients more susceptible to cerebral damage, relative to cardiac controls and healthy controls.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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2.1. Patients
The study population comprised consecutive patients with a primary diagnosis of HF, who were recruited from the Cardiology Outpatient Department of St Lucas-Andreas hospital, Amsterdam, over a 12 month period. All of the participants had a documented diagnosis of HF, predating the study by at least six months. Furthermore, all patients had been on a stable, optimized medication regime for at least one month prior to the study. The diagnosis of HF was based on the clinical judgement of the attending cardiologist and on two-dimensional echocardiography. Left ventricular ejection fraction (LVEF) was calculated using the modified Simpson's rule [16]. Clinical status was categorized according to the New York Heart Association (NYHA) classification system [17].
Patients were considered eligible to participate in the study if they fulfilled the following criteria: (1.) clinical diagnosis of chronic HF in NYHA functional class II-IV; (2.) LVEF of less than 45%; (3.) age 50 or above; (4.) ability to undergo MRI scanning. Exclusion criteria were: psychiatric illness and other serious or life-threatening diseases, prior diagnosis of dementia, history of stroke associated with the development of neurological signs or symptoms, current diagnosis of depressive episode (ICD-10), use of psychoactive drugs, history of alcohol abuse (>4 units/day) or serious head injury and pacemaker-implant or other implanted metal devices. On the basis of the inclusion and exclusion criteria, 58 HF patients were found to be eligible for participation in the current study.
The aetiology of cardiomyopathy was determined to be ischaemic in 65% of the HF patients, hypertrophic in 15%, idiopathic in 4% and 16% had dilated cardiomyopathy. This distribution of aetiologic subgroups, mainly involving ischaemic cardiomyopathy, is thought to be representative of HF populations in general outpatient departments. Most HF patients were classified as NYHA class II or III, with a history of heart disease ranging from 1 to 20 years. Medications used to treat hypertension included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, beta blockers and calcium channel blockers.
Cardiac control patients were simultaneously recruited from the Cardiology Outpatient Clinic. All 48 subjects had a history of ischaemic cardiac disease but no clinical diagnosis of HF, in addition to a LVEF in excess of 45% (as measured by echocardiography). We aimed to establish an equal distribution of cardiovascular risk factors in the cardiac control group. Finally, an age-matched comparison group, consisting of 42 healthy controls was also studied. Healthy control subjects were either spouses or neurological outpatients attending the hospital with a peripheral nerve problem. Medical history and physical examination did not reveal symptoms suggestive of HF, central neurological disorders or cardiovascular risk factors.
Baseline data were collected by means of a structured interview including information on demographic characteristics, smoking habit, relevant medical history, alcohol consumption, current use of medication, and neurological complaints. Historical and current clinical evidence of hypertension (blood pressure above 140 mm systolic or 90 mm diastolic), diabetes mellitus, coronary artery bypass graft (CABG), hypercholesterolaemia or atrial fibrillation, were derived either from medical records or from laboratory test results. All subjects underwent a physical examination, laboratory blood tests, MRI brain scans, and neuropsychological testing. The laboratory blood tests included B-type natriuretic peptide (BNP), which is a biomarker of myocardial stress.
The ethical review board approved the study. Written informed consent was obtained from all of the subjects, once the study procedures had been fully explained.
2.2. MRI
Cerebral MRI was performed using a 1.5 T GE-Signa Horizon LX scanner. A standardized imaging protocol was used, consisting of sagittal T1-weighted (repetition time TR 300 ms, echo time TE 4 ms), axial T2-weighted (TR 6500 ms, TE 105 ms) and fast fluid-attenuated inversion recovery (FLAIR) (TR 10000 ms, TE 160 ms), as well as coronal flair images. A slice thickness of 5 mm, with no intersectional gaps, was used for all images.
WMH were rated using the Scheltens scale [18]. Each cerebral region was initially scored on the size of the lesions, then on their number. In accordance with this scale, the periventricular white matter hyperintensities (PVH) were scored in three regions, the frontal and occipital caps, and the periventricular bands. They were rated as follows: none (score 0); 5 mm or less (score 1); confluent lesions and greater than 5 mm (score 2). The deep white matter hyperintensities (DWMH) were examined in four subcortical regions (frontal, parietal, temporal and occipital lobe). Five basal ganglia (BG) regions (caudate nucleus, putamen, globus pallidus, thalamus and internal capsule) were examined for hyperintensities and infratentorial foci of hyperintensities (ITF) were inspected in four regions (cerebellum, mesencephalon, pons and medulla). These lesions were rated as follows: none (score 0); 3 mm and less and five or less lesions (score 1); 3 mm or less and six or more lesions (score 2); 4-10 mm and five or less lesions (score 3); 4-10 mm and six or more lesions (score 4); 10 mm or greater and one or more lesions (score 5); and large confluent lesions (score 6). The total white matter hyperintensities score (total WMH; range 0-30) is the sum of the DWMH and PVH subscores. In addition, we used visual rating scales to evaluate MTA (possible range of scores for each side: 0 to 4) [19], and global cortical atrophy (GCA)(possible range of scores: 0 to 3) [20]. Cortical and lacunar infarctions were recorded by number and location. Examples of MRI scans showing the presence of DWMH, PVH and MTA are illustrated in Fig. 1.
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2.3. Statistical analysis
Data analysis was performed using SPSS version 12.0.1 for Windows (SPSS, Inc., Chicago, Ill). The total WMH score, DWMH, PVH, BG and ITF scores underwent square root transformation before statistical analysis to uphold a normal distribution. Group differences were evaluated by analyses of variance (ANOVA). Categorical data (sex, cardiovascular risk factors) were compared using chi-square tests. ANOVAs with post hoc Bonferroni tests were used to assess group differences with respect to the MRI parameters, corrected for age and sex. A second model used age, sex, hypertension, smoking, diabetes and hypercholesterolemia as covariates. Where appropriate (MTA and global atrophy), data were analysed using non-parametric tests. In the two patient groups (HF and cardiac controls) partial correlations were calculated, controlling for age and sex in order to examine the association between baseline variables (cardiovascular parameters) and MRI variables. Variables (age, sex, LVEF, systolic blood pressure, NYHA-class, duration of heart disease, use of anti-hypertensive medication) which showed a significant correlation with MRI parameters were then entered into a stepwise multiple linear regression analysis, with total WMH and MTA as the dependent variables. The threshold of significance was set at 0.05.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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Baseline characteristics for all subjects are presented in Table 1. There were no differences between the patient groups with respect to age. The healthy control group contained relatively more female subjects than both patient groups, although the difference was not significant. With the exception of a higher prevalence of hypercholesterolaemia in the cardiac control group, cardiovascular risk factors were equally distributed between the two patient groups. The groups differed significantly in terms of smoking habit, with the lowest frequency reported among healthy controls. Furthermore, significant baseline differences were found for LVEF, BNP, systolic and diastolic blood pressure, number of anti-hypertensive drugs used, and duration of heart disease. Consistent with their diagnosis of HF, these patients presented with lower LVEF and higher BNP plasma levels. In addition, we found that HF patients had lower blood pressure values than either the cardiac controls or the healthy controls. Statins were used by 35 (66%) patients in the HF group and by 38 (79%) in the cardiac control group. Eleven of these patients had no prior documented diagnosis of hypercholesterolaemia.
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After correction for age and sex, the MRI findings shown in Table 2 indicate a group effect on total WMH, PVH, DWMH, BG, MTA and presence of lacunar infarcts. This group effect remained significant after additional correction for hypertension, diabetes, hypercholesterolemia and smoking. Post hoc analysis using Bonferroni correction showed that HF patients had a significantly greater number of abnormal MRI findings than either the cardiac controls or the healthy controls. The cardiac controls differed from the healthy controls only in the degree of MTA. By contrast, the severity of GCA was similar in all three groups. In additional models in which we compared the MRI findings between the four different cardiomyopathy aetiologic subgroups of HF patients, no intergroup differences in severity of cerebral abnormalities were found (data not shown).
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Partial correlation coefficients (adjusted for age and sex) of baseline cardiovascular variables with MRI parameters (Table 3) revealed associations with DWMH for systolic blood pressure, LVEF, NYHA class, duration of heart disease, and number of anti-hypertensive medications being used, whereas BG only correlated with LVEF. Significant correlations with PVH were found for LVEF and NYHA class. Correlations with MTA involved systolic blood pressure, duration of heart disease and number of anti-hypertensive medications being used.
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A stepwise linear regression analysis was performed to identify any independent predictors of WMH and MTA in the two patient groups. Age (β=0.043; SE=0.01; p<0.01) and LVEF (β=–0.029; SE=0.005; p<0.01) were independently associated with total WMH in both HF patients and cardiac controls (Fig. 2). Age (β=0.033; SE=0.005; p<0.01) and systolic blood pressure (β=–0.006; SE=003; p=0.02) were associated with MTA.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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Our findings indicate that independently living HF outpatients, without clinical evidence of dementia or stroke display relatively frequent cerebral abnormalities, consisting of WMH, BG, lacunar infarcts and MTA. Using a case-control design, correcting for common cardiovascular risk factors, we found that it was not the cardiovascular risk profile but the decreased heart function itself, represented by a low LVEF, which was independently related to the WMH in HF patients. The decreased cardiac function tended to affect the deep cerebral white matter more than the periventricular white matter. Furthermore, these cerebral WMH were found to be associated with the severity and duration of HF. The finding that systolic blood pressure was negatively related to DWMH can probably be explained by the anti-hypertensive treatment and low absolute blood pressure values in the HF group, compared to the cardiac controls. It may simply reflect that left ventricular dysfunction and anti-hypertensive treatment might further reduce cerebral perfusion in the presence of impaired cerebrovascular autoregulation [21].
Only four studies have previously reported structural brain abnormalities in relation to cardiac function parameters in small numbers of patients with HF [5-8]. Schmidt and colleagues found that patients who were suffering from idiopathic dilated cardiomyopathy exhibited a significantly higher rate of cerebral infarcts and cortical atrophy, and ventriculomegaly on MRI brain scan than twenty controls [6]. In contrast to our results, their MRI findings were not associated with LVEF or severity of illness. Two other studies found no significant differences between the prevalence of WMH in HF patients and in control subjects [5,7]. Finally, Woo et al. reported the preliminary results of a study in which volumetric structural MRI scans were performed to assess regional gray matter volumes in nine patients with HF and in 27 healthy controls [8]. The HF patients showed significant gray matter loss in deep cerebral structures and in areas related to autonomic and respiratory functions. However, small patient samples limit the interpretation of their results.
In HF patients, lower LVEF is the most important predictor of risk for cerebral infarction and ventricular thrombus formation [22]. Not surprisingly therefore, our findings also indicated a high rate of silent cerebral infarction both in HF patients and in cardiac controls.
MTA, disproportional to global cerebral atrophy was another important finding in patients suffering from chronic HF. The high vulnerability of the temporal structures (i.e. hippocampus) to the inadequate oxygenation that results from hypoperfusion may support a pathophysiological mechanism that is haemodynamically mediated, a view that is supported by the finding that MTA was associated with the duration of HF in this study. The recently reported association of HF with an increased risk of Alzheimer's disease [10] suggests that this finding is of considerable importance. To our knowledge no such finding has been reported previously.
The strength of our study lies in its use of a cardiac control group. This allowed us to adjust for common cardiovascular risk factors, thereby leaving HF as the major discriminator between patient groups. However, our study does have some methodological limitations, which need to be addressed. Firstly, we used visual rating scales instead of volumetric MRI analysis, which may be more accurate. Although widely used in the literature [23], a MRI slice thickness of 5 mm might have led to underdetection of small WMH. Nevertheless, recent studies have repeatedly reported similar results using either automated assessment methods or a visual rating scale [24,25]. Secondly, the exclusion of patients with pacemaker devices might have introduced selection bias. These patients may be in a more severe state of HF, so their inclusion might have resulted in even more pronounced cerebral abnormalities in the HF group than was actually observed.
Although the prevalence of hypertension was similar among the two patient groups, its premorbid severity and exact duration are difficult to measure. Substantial differences in lifetime exposure to such a cardinal risk factor for WMH like hypertension and the effects of treatment may therefore be masked in the two patient groups.
4.1. Pathophysiological considerations
Cardiovascular risk factors that frequently coexist in HF patients, such as hypertension, atrial fibrillation and hypercholesterolaemia are regarded as the main cause of so-called "subcortical ischaemic vascular disease" (SIVD) [26]. The lesions in SIVD arise from small vessel disease leading to incomplete white matter ischaemia, lacunar strokes and areas of micro-infarction. In addition to micro-angiopathy, cerebral hypoperfusion due to left ventricular dysfunction may contribute equally to the development of structural and functional cerebral abnormalities in HF patients. Recently, Roman discussed the susceptibility of elderly subjects to cerebral hypoperfusion as an important risk factor for the development of cognitive impairment and vascular dementia [14]. He argued that both the white matter in the centrum semi-ovale and periventricular white matter, which are distal watershed territories irrigated by deep-penetrating medullary arteries, are particularly sensitive to hypoperfusion. Decreased auto-regulation, together with the endothelial changes that result in blood-brain barrier dysfunction, lead to local hypoperfusion and incomplete infarction of the deep white matter. Moreover, it has been suggested that SIVD is associated with cortical and hippocampal atrophy [27]. This relation has been linked to a deficient autoregulatory response and an increased risk of ischaemic brain injury. Cerebral WMH may therefore provide a useful marker for more extensive cerebrovascular disease. Potentially, the cerebral perfusion deficits in this population may be further aggravated by the use of vasodilating agents. In our two patient groups, the number of anti-hypertensive medications used was positively correlated with the presence of total WMH and DWMH score. Nevertheless, these relations can be explained by collinearity with the duration and severity of heart disease.
In conclusion, our observations in HF patients, cardiac controls, and healthy controls support the notion that HF, in addition to general cardiovascular disease, imposes an increased risk of vascular brain abnormalities that are independently associated with left ventricular dysfunction. Next to WMH, MTA is an important element in this respect. It remains to be determined whether systematic MRI-scanning of the brain can be used to identify patients at risk of developing neurological and neuropsychological deficits in the early stages of heart disease.
Further studies are required to clarify the relation between structural brain abnormalities and the specific neuropsychological deficits encountered in these populations.
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Author contributions |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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R. Vogels wrote the original manuscript and takes responsibility for the integrity of the data and the accuracy of the data analysis.
A. Gouw rated the MRI-scans.
W. van der Flier was involved in the analysis and interpretation of data and reviewed the manuscript.
H. Weinstein and Ph. Scheltens were responsible for the study concept and critical revision of the manuscript.
J. Schroeder-Tanka and B. van Harten were involved in acquisition of subjects and critically reviewed the manuscript.
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Financial disclosures |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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There are no financial disclosures to be reported.
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Role of the funding source/sponsor's role |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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No funding source was involved in the preparation of this article.
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Conflict of interest |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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There are no conflicts of interest to be reported.
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAuthor contributionsFinancial disclosuresRole of the funding...Conflict of interestReferences |
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