Frank-Erik de Leeuw

Periventricular cerebral white matter lesions predict rate of cognitive decline

The prospect of declining cognitive functions is a major fear for many elderly persons. Cerebral white matter lesions, as commonly found with magnetic resonance imaging, have been associated with cognitive dysfunction in cross‐sectional studies. Only a few longitudinal studies using small cohorts confirmed these findings. We examined the relation between severity of white matter lesions and cognitive decline over a nearly 10‐year period in 563 elderly subjects sampled from the general nondemented Dutch population. Severity of white matter lesions was scored for periventricular and subcortical regions separately using an extensive semiquantitative scale. Cognitive function was measured by the Mini‐Mental State Examination at regular time intervals during 1990 to 2000, and magnetic resonance imaging scans were made in 1995 to 1996. More severe white matter lesions were associated with more rapid cognitive decline over a mean follow‐up period of 7.3 years (standard deviation, 1.5). After adjusting for age, gender, educational level, measures of depression, and brain atrophy and infarcts, subjects with severe periventricular white matter lesions experienced cognitive decline nearly three times as fast (0.28 Mini‐Mental State Examination points/year [95% confidence interval, 0.20–0.36]) as the average (0.10 points/year [95% confidence interval, 0.09–0.11]). There was no independent relationship between severity of subcortical white matter lesions and rate of cognitive decline.

Brain Imaging in Patients With Diabetes A systematic review

Diabetes is associated with impaired cognitive functioning and an increased risk of dementia (1,2). Patients with type 1 diabetes may show mild to moderate slowing of mental speed and diminished mental flexibility, whereas learning and memory are relatively spared (3). In patients with type 2 diabetes, cognitive impairment may be relatively more pronounced, particularly affecting verbal memory or complex information processing (4,5). The pathogenesis is still uncertain, but chronic hyperglycemia, vascular disease, repeated hypoglycemic episodes, and possibly direct effects of insulin on the brain have been implicated (6). Brain imaging studies can help to clarify the pathogenesis. An increasing number of studies report both focal vascular and more global (e.g., atrophy) cerebral changes, but the results are not always consistent. Our aim was to systematically review brain imaging studies in patients with diabetes. Data on the relation of imaging with cognition and with relevant disease variables were also recorded. Medline and EMBASE (1966 to February 2006) were searched with the following medical subject heading terms: computed tomography (CT) and magnetic resonance imaging (MRI) studies: white matter, leukoaraiosis, lacunar infarction, subcortical, periventricular, brain, cerebral, hippocampus, atrophy, MRI, magnetic resonance imaging, CT, and tomography; magnetic resonance spectroscopy (MRS) studies: magnetic resonance spectroscopy, MRS, brain, and cerebral; positron emission tomography (PET), single-photon emission CT (SPECT), and Xenon-enhanced CT studies: cerebral blood flow, glucose metabolism, brain, cerebral, PET, SPECT, Xenon, positron emission tomography, single-photon emission tomography, and tomography; all combined with “diabetes.” The abstracts were screened and potentially relevant articles retrieved. These articles were included if they met the following four criteria: 1 ) original article, written in English, on brain imaging in adult patients with diabetes in comparison with control subjects; 2 ) diagnostic criteria for diabetes specified; 3 ) sample size of at least 20 diabetic patients, or a total sample …

A follow-up study of blood pressure and cerebral white matter lesions.

White matter lesions are often observed on cerebral magnetic resonance imaging scans of elderly people and may play a role in the pathogenesis of dementia. Cross‐sectional studies have shown an association between elevated blood pressure and white matter lesions. We prospectively studied the relation between blood pressure and white matter lesions in 1,077 subjects aged 60 to 90 years who were randomly sampled from two prospective population‐based studies. One study had blood pressure measurements 20 years before, the other 5 years before. Overall response for the magnetic resonance imaging study was 63%, and declined from 73% among 60‐ to 70‐year‐olds to 48% for 80‐ to 90‐year‐olds. Diastolic and systolic blood pressure levels assessed 20 years before were significantly associated with subcortical and periventricular white matter lesions. The association between 20‐year change in diastolic blood pressure and subcortical white matter lesions was J‐shaped (relative risk, 2.2; 95% confidence interval, 1.0–5.2; and relative risk, 3.2; 95% confidence interval, 1.4–7.4, for decrease or increase of more than 10 mm Hg, respectively). The association between concurrent diastolic blood pressure level and white matter lesions was linear in subjects without, and J‐shaped in subjects with, a history of myocardial infarction. Our results indicate that the J‐shape relationship of diastolic blood pressure is not restricted to cardiovascular disease, but is also manifest in cerebrovascular disease.

Interaction between hypertension, apoE, and cerebral white matter lesions

Background and Purpose— Cerebral white matter lesions (WMLs) are frequently found on magnetic resonance imaging scans in both cognitively intact and demented elderly persons. Vascular risk factors, especially hypertension, are related to their presence. However, not every person with vascular risk factors has WMLs, which suggests interaction with other determinants, eg, genetic factors. The ε4 allele of the apolipoprotein E gene (apoE) may be a candidate because this allele is associated with both the vascular risk factors and the consequences (cognitive impairment, dementia) of WMLs. Methods— We investigated apoE genotype, blood pressure levels, and their interaction in relation to subcortical and periventricular WMLs in 971 participants in the Rotterdam Scan Study. Results— ApoE ε4 carriers had a significantly higher subcortical WML volume than did apoE ε3ε3 carriers (adjusted mean difference, 0.5; 95% confidence interval, 0.2 to 0.8), irrespective of hypertension. This was not found for periventricular WMLs. Participants with both hypertension and at least 1 apoE ε4 allele had the highest degree of both types of WML; the interaction was statistically significant for subcortical WMLs (P = 0.016). Conclusions— apoE ε4 carriers are at increased risk for WMLs if they suffer from hypertension as well. This may reflect a diminished capacity for neuronal repair in apoE ε4 carriers.

Loss of white matter integrity is associated with gait disorders in cerebral small vessel disease

Gait disturbances are common in the elderly. Cerebral small vessel disease, including white matter lesions and lacunars infarcts, is thought to disrupt white matter tracts that connect important motor regions, hence resulting in gait disturbances. Pathological studies have demonstrated abnormalities in white matter that may appear normal on brain imaging. The loss of integrity in such normal-appearing white matter may partly be due to small vessel disease and may play a role in causing gait disturbances. The white matter regions involved in these gait disturbances, both in white matter lesions and normal-appearing white matter, remain unclear. We, therefore, aimed to investigate the relation between the location of white matter lesions and gait using voxel-based morphometry analysis, as well as between white matter integrity and gait by applying tract-based spatial statistics to diffusion tensor imaging parameters. Magnetic resonance imaging was carried out on 429 individuals in the age range of 50 and 85 years, with cerebral small vessel disease without dementia or parkinsonism. Gait was assessed quantitatively. White matter lesions, especially in the centrum semiovale and periventricular frontal lobe, were related to a lower gait velocity, shorter stride length and broader stride width. Loss of white matter integrity, as indicated by a lower fractional anisotropy and higher mean diffusivity, in numerous regions was related to a lower gait performance. Most of these regions were located in the normal-appearing white matter. The strongest significant association was found in the corpus callosum, particularly the genu. Most of the associations in the normal-appearing white matter disappeared after controlling for white matter lesions and lacunar infarcts, except for some in the corpus callosum. In conclusion, our study showed that using a combination of voxel-based morphometry analysis of the white matter lesions and diffusion tensor imaging is of added value in investigating the pathophysiology of gait disturbances in subjects with small vessel disease. Our data demonstrate that, in elderly subjects with small vessel disease, widespread disruption of white matter integrity, predominantly in the normal-appearing white matter, is involved in gait disturbances. In particular, loss of fibres interconnecting bilateral cortical regions, especially the prefrontal cortex that is involved in cognitive control on motor performance, may be important. The most important mechanisms underlying affected normal-appearing white matter are probably a direct effect of small vessel disease or, indirectly, remote effects of white matter lesions and lacunar infarcts.

Operational definitions for the NINDS-AIREN criteria for vascular dementia: an interobserver study.

Background and Purpose— Vascular dementia (VaD) is thought to be the most common cause of dementia after Alzheimer’s disease. The commonly used International Workshop of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (AIREN) criteria for VaD necessitate evidence of vascular disease on CT or MRI of the brain. The purposes of our study were to operationalize the radiological part of the NINDS-AIREN criteria and to assess the effect of this operationalization on interobserver agreement. Methods— Six experienced and 4 inexperienced observers rated a set of 40 MRI studies of patients with clinically suspected VaD twice using the NINDS-AIREN set of radiological criteria. After the first reading session, operational definitions were conceived, which were subsequently used in the second reading session. Interobserver reproducibility was measured by Cohen’s &kgr;. Results— Overall agreement at the first reading session was poor (&kgr;=0.29) and improved slightly after application of the additional definitions (&kgr;=0.38). Raters in the experienced group improved their agreement from almost moderate (&kgr;=0.39) to good (0.62). The inexperienced group started out with poor agreement (&kgr;=0.17) and did not improve (&kgr;=0.18). The experienced group improved in both the large- and small-vessel categories, whereas the inexperienced group improved generally in the extensive white matter hyperintensities categories. Conclusions— Considerable interobserver variability exists for the assessment of the radiological part of the NINDS-AIREN criteria. Use of operational definitions improves agreement but only for already experienced observers.

Aortic Atherosclerosis at Middle Age Predicts Cerebral White Matter Lesions in the Elderly

BACKGROUND AND PURPOSE MRI scans of the brains of elderly people frequently show white matter lesions. Clinically, these lesions are associated with cognitive impairment and dementia. A relation between atherosclerosis and white matter lesions was found in some small cross-sectional studies. However, atherosclerosis is a gradual process that starts early in life. We investigated the longitudinal association between aortic atherosclerosis assessed during midlife and late life and cerebral white matter lesions. METHODS We randomly sampled subjects between 60 and 90 years old from 2 population-based follow-up studies in which subjects had their baseline examinations in 1975 to 1978 (midlife) and in 1990 to 1993 (late life). In 1995 to 1996, subjects underwent 1.5-T MRI scanning; white matter lesions were rated in the deep subcortical and periventricular regions separately. Aortic atherosclerosis was assessed on abdominal radiographs that were obtained from 276 subjects in midlife and 531 subjects in late life. RESULTS The presence of aortic atherosclerosis during midlife was significantly associated with the presence of periventricular white matter lesions approximately 20 years later (adjusted relative risk, 2.4; 95% CI, 1.2 to 5.0); the relative risks increased linearly with the severity of aortic atherosclerosis. No association was found between midlife aortic atherosclerosis and subcortical white matter lesions (adjusted relative risk, 1.1; 95% CI, 0.5 to 2.3) or between late-life aortic atherosclerosis and white matter lesions. CONCLUSIONS The pathogenetic process that leads to cerebral periventricular white matter lesions starts already in or before midlife. The critical period for intervention directed at prevention of white matter lesions and its cognitive consequences may be long before these lesions become clinically detectable.

Long-term Mortality After Stroke Among Adults Aged 18 to 50 Years

IMPORTANCE Long-term data on mortality after first-ever stroke in adults aged 18 through 50 years are scarce and usually restricted to ischemic stroke. Moreover, expected mortality not related to first-ever stroke is not taken in account. OBJECTIVES To investigate long-term mortality and cause of death after acute stroke in adults aged 18 through 50 years and to compare this with nationwide age- and sex-matched mortality rates. DESIGN, SETTING, AND PARTICIPANTS The Follow -Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study, a prospective cohort study of prognosis after transient ischemic attack (TIA), ischemic stroke, or hemorrhagic stroke in adults aged 18 through 50 years admitted to Radboud University Nijmegen Medical Centre, the Netherlands, between January 1, 1980, and November 1, 2010. The survival status of 959 consecutive patients with a first-ever TIA (n = 262), ischemic stroke (n = 606), or intracerebral hemorrhage (n = 91) was assessed as of November 1, 2012. Mean follow-up duration was 11.1 (SD, 8.7) years (median, 8.3 [interquartile range, 4.0-17.4]). Observed mortality was compared with the expected mortality, derived from mortality rates in the general population with similar age, sex, and calendar-year characteristics. MAIN OUTCOME MEASURES Cumulative 20-year mortality among 30-day survivors of stroke. RESULTS At the end of follow-up, 192 patients (20.0%) had died. Among 30-day survivors, cumulative 20-year risk of death was 24.9% (95% CI, 16.0%-33.7%) for TIA, 26.8% (95% CI, 21.9%-31.8%) for ischemic stroke, and 13.7% (95% CI, 3.6%-23.9%) for intracerebral hemorrhage. Observed mortality was increased compared with expected mortality (standardized mortality ratio [SMR], 2.6 [95% CI, 1.8-3.7] for TIA, 3.9 [95% CI, 3.2-4.7] for ischemic stroke, and 3.9 [95% CI, 1.9-7.2 for intracerebral hemorrhage, respectively). For ischemic stroke, cumulative 20-year mortality among 30-day survivors was higher in men than in women (33.7% [95% CI, 26.1%-41.3%] vs 19.8% [95% CI, 13.8%-25.9%]). The SMR was 4.3 (95% CI, 3.2-5.6) for women and 3.6 (95% CI, 2.8-4.6) for men. For all etiologic subtypes of ischemic stroke, observed mortality exceeded expected mortality. CONCLUSIONS AND RELEVANCE Among adults aged 18 through 50 years, 20-year mortality following acute stroke was relatively high compared with expected mortality. These findings may warrant further research evaluating secondary prevention strategies in these patients.

Association between blood pressure levels over time and brain atrophy in the elderly

The relation between blood pressure level and degree of global brain atrophy is equivocal. We evaluated past and present blood pressure levels and change in blood pressure over 20 years in relation to the degree of cortical atrophy on magnetic resonance imaging (MRI). In 1995-1996, we measured blood pressure and performed MRI in 1077 nondemented elderly (age 60-90 years). For 513 of these, we had information on a blood pressure level 20 years before. The degree of cortical atrophy was semi-quantitatively scored (range 0-15). In late life, a high (>/=90 mmHg) and low (<65 mmHg) diastolic blood pressure were associated with more cortical atrophy than a diastolic blood pressure level between 65-74 mmHg (adjusted difference 0.60 units (95% confidence interval (CI), 0.18-1.02) and 0.77 units (0.28-1.25), respectively). Persons whose diastolic blood pressure had declined more than 10 mmHg over 20 years had more cortical atrophy than those with stable blood pressure levels (adjusted difference 0.53 units, 0.05-1.02). Both high and declining diastolic blood pressure levels are associated with more global brain atrophy on MRI.

Cigarette smoking is associated with reduced microstructural integrity of cerebral white matter

Cigarette smoking doubles the risk of dementia and Alzheimers disease. Various pathophysiological pathways have been proposed to cause such a cognitive decline, but the exact mechanisms remain unclear. Smoking may affect the microstructural integrity of cerebral white matter. Diffusion tensor imaging is known to be sensitive for microstructural changes in cerebral white matter. We therefore cross-sectionally studied the relation between smoking behaviour (never, former, current) and diffusion tensor imaging parameters in both normal-appearing white matter and white matter lesions as well as the relation between smoking behaviour and cognitive performance. A structured questionnaire was used to ascertain the amount and duration of smoking in 503 subjects with small-vessel disease, aged between 50 and 85 years. Cognitive function was assessed with a neuropsychological test battery. All subjects underwent 1.5 Tesla magnetic resonance imaging. Using diffusion tensor imaging, fractional anisotropy and mean diffusivity were calculated in both normal-appearing white matter and white matter lesions. A history of smoking was associated with significant higher values of mean diffusivity in normal-appearing white matter and white matter lesions (P-trend for smoking status = 0.02) and with poorer cognitive functioning compared with those who never smoked. Associations with smoking and loss of structural integrity appeared to be strongest in normal-appearing white matter. Furthermore, the duration of smoking cessation was positively related to lower values of mean diffusivity and higher values of fractional anisotropy in normal-appearing white matter [β = -0.004 (95% confidence interval -0.007 to 0.000; P = 0.03) and β = 0.019 (95% confidence interval 0.001-0.038; P = 0.04)]. Fractional anisotropy and mean diffusivity values in normal-appearing white matter of subjects who had quit smoking for >20 years were comparable with subjects who had never smoked. These data suggest that smoking affects the microstructural integrity of cerebral white matter and support previous data that smoking is associated with impaired cognition. Importantly, they suggest that quitting smoking may reverse the impaired structural integrity.