F.E. de Leeuw

Cerebral white matter lesions and subjective cognitive dysfunction: The Rotterdam Scan Study

Objective: To determine the relationship between cerebral white matter lesions (WML) and subjective cognitive dysfunction. Background: Subjective cognitive dysfunction is present when a person perceives failures of cognitive function. When annoying enough, these failures will be expressed as complaints. Subjective cognitive dysfunction may be a prelude to or coincide with objective cognitive impairment. WML have been related to objective cognitive impairment and dementia, but their relationship with subjective cognitive dysfunction is not clear. Previous population-based studies on the latter relationship have been limited in sample size, recording of subjective cognitive function, and assessment of WML severity. Methods: We randomly sampled 1,049 elderly nondemented participants from the general population. Data on subjective cognitive dysfunction and its progression were derived from a 15-item questionnaire. Objective cognitive performance was assessed using a series of neuropsychological tests. WML were scored on MRI for periventricular and subcortical regions separately. Results: WML were associated with more subjective cognitive failures. WML were more severe for participants reporting progression of these failures compared with participants without these failures, especially within participants with better than average cognitive performance (p = 0.008, for periventricular WML). Participants with severe WML reported progression of cognitive failures more than twice as often than did those with little or no WML. The relationship between the severity of WML and subjective cognitive failures was present for periventricular and subcortical WML. Conclusions: WML are associated with subjective cognitive failures and in particular with reporting progression of these failures, even in the absence of objective cognitive impairment.

Cerebral vasomotor reactivity and cerebral white matter lesions in the elderly

Objective: The pathogenesis of white matter lesions is still uncertain, but an ischemic-hypoxic cause has been suggested. Cerebral vasomotor reactivity reflects the compensatory dilatory mechanism of the intracerebral arterioles to a vasodilatory stimulus and provides a more sensitive hemodynamic index than the level of resting flow. Methods: The authors determined the association between vasomotor reactivity and white matter lesions in 73 consecutive individuals from the Rotterdam Scan Study who also participated in the Rotterdam Study, a large population-based prospective follow-up study of individuals ≥55 years old. Vasomotor reactivity was measured by means of CO2-enhanced transcranial Doppler, and in all individuals axial T1*-, T2*-, and proton density (PD)-weighted MRI scans (1.5 T) were obtained. White matter lesions were scored according to location, size, and number by two independent readers. Results: Vasomotor reactivity was inversely associated with the deep subcortical and total periventricular white matter lesions (OR 0.5, 95% CI 0.3 to 1.1; and OR 0.7, 95% CI 0.4 to 1.1, respectively). A strong association was found between impaired vasomotor reactivity and periventricular white matter lesions adjacent to the lateral ventricular wall (OR 0.6, 95% CI 0.4 to 1.0; p = 0.001). No association was found with periventricular white matter lesions near the frontal and occipital horns. Conclusions: Our data confirm the association between vasomotor reactivity and white matter lesions and support the hypothesis that some white matter lesions may be associated with hemodynamic ischemic injury to the brain.

Carotid atherosclerosis and cerebral white matter lesions in a population based magnetic resonance imaging study

Abstract Cerebral white matter lesions are frequently observed on magnetic resonance imaging of elderly, nondemented persons. There is evidence that white matter lesions are involved in the pathophysiology of cognitive decline and dementia. White matter lesions can be divided into those in the periventricular and those in the subcortical region. Pathological and epidemiological studies suggest that atherosclerosis is involved in the pathogenesis of these lesions. Our study reports on the association between atherosclerosis in the carotid arteries and white matter lesions in a population-based study among 1077 elderly subjects. We randomly sampled 1077 subjects aged between 60–90 years from two prospective population-based studies. All subjects underwent ultrasonography of the carotid artery. In addition, 1.5 T magnetic resonance imaging was performed; white matter lesions in the subcortical and periventricular regions were rated separately. With increasing number of plaques in the carotid artery the severity of periventricular white matter lesions increased (Ptrend = 0.03), but not the severity of subcortical white matter lesions (Ptrend = 0.19). In addition, an increase in intima media thickness was borderline significantly associated with an increased severity of periventricular white matter lesions (Ptrend = 0.09), but not of subcortical white matter lesions (Ptrend = 0.68). These findings suggest that partly dissimilar pathogenetic mechanisms are involved in the etiology of periventricular and subcortical white matter lesions.

White matter lesions and hippocampal atrophy in Alzheimer’s disease

White matter lesions (WML) and hippocampal atrophy (HA) on MRI commonly co-occur in Alzheimer’s disease (AD) and are thought to play a role in the etiology of AD. It is still not known whether WML and HA are independent or related. The authors investigated the relation between WML and HA in 179 patients with probable AD who had a cerebral MRI. A linear relation was found between WML and HA, especially for WML in the frontal and parieto-occipital regions. The results suggest that vascular pathology and typical AD pathology (HA) are related.

Atrial fibrillation and the risk of cerebral white matter lesions

Background: Cerebral white matter lesions are often observed on MRI scans of elderly nondemented and demented persons. Their pathogenesis is not fully understood but cerebral hypoperfusion may be involved. Atrial fibrillation is a common finding in elderly subjects and may lead to a reduced cardiac output with cerebral hypoperfusion. The authors investigated the association between atrial fibrillation and the presence of white matter lesions. Methods: From 1995 through 1996, the authors randomly sampled 1077 subjects from two ongoing prospective population-based studies. From each participant, an electrocardiogram (ECG) was recorded; atrial fibrillation and left ventricular hypertrophy were diagnosed with a computer program. For one of the two groups (553 subjects), earlier ECGs were available (mean follow-up 4.7 years). All subjects underwent 1.5-T MRI scanning; white matter lesions were separately rated for the periventricular and subcortical regions. Results: The prevalence of atrial fibrillation was 1.9% among subjects younger than 75 years and 5.5% in subjects older than 75 years. The total number of subjects with atrial fibrillation was 28. Subjects with atrial fibrillation had severe periventricular white matter lesions more than twice as often as subjects who did not (RR 2.2; 95% CI 1.0 to 5.2) but had no increased risk of subcortical white matter lesions (RR 1.1; 95% CI 0.4 to 2.6). For seven subjects with atrial fibrillation both at baseline and at follow up, these relative risks were 6.3 (95% CI 1.1 to 37.1) and 0.7 (95% CI 0.1 to 3.7). Conclusions: Atrial fibrillation is associated with periventricular white matter lesions, but not with subcortical white matter lesions.

Subjective cognitive failures and hippocampal volume in elderly with white matter lesions.

Background: Subjective cognitive failures (SCF) and subjective memory failures (SMF) have been reported to be an early predictor of Alzheimer disease (AD) and have been attributed to white matter lesions (WML). Since AD is characterized by hippocampal degeneration, it is surprising that its relation with hippocampal atrophy has been investigated only sparsely. Previous studies on this are rare, limited in sample size, and did not adjust for WML. Objective: To determine the relation between SCF and hippocampal volume in strata of objective cognitive performance among elderly without dementia with incidental WML. Methods: The Radboud University Nijmegen Diffusion tensor and MRI Cohort study is a prospective cohort study among 503 subjects with WML aged between 50 and 85 years. All subjects underwent FLAIR and T1 MRI scanning. The amount of SCF and SMF was rated by the Cognitive Failure Questionnaire. Cognitive function was assessed by a cognitive screening battery. Volumetric measures of hippocampus and WML were manually performed. We assessed the relation between hippocampal volume and SCF and SMF adjusted for age, sex, education, depression, intracranial volume, and WML volume. Results: Subjects with SCF and SMF had lower hippocampal volumes than those without (p = 0.01 and p = 0.02). This was most noteworthy in subjects with good objective cognitive performance (ptrend = 0.007 and ptrend = 0.03), and not in those with poor objective cognitive performance. Conclusion: Subjective cognitive failures (SCF) are associated with lower hippocampal volume, even in subjects without objective cognitive impairment and independent of white matter lesions. SCF has a radiologic detectable pathologic-anatomic substrate.

Physical activity is related to the structural integrity of cerebral white matter

Objective: To investigate the relation between physical exercise and the microstructural integrity of cerebral white matter. Methods: Four hundred forty individuals with cerebral small-vessel disease, aged between 50 and 85 years, without dementia, were included and underwent MRI scanning. Physical exercise was assessed with a structured questionnaire. The cross-sectional relation between physical exercise and the microstructural integrity of the white matter was assessed by applying Tract-Based Spatial Statistics to diffusion tensor imaging parameters. Results: Being more physically active was negatively related to the mean, axial, and radial diffusivity in numerous regions of the white matter, indicative of higher white matter integrity. Conclusions: These data indicate an association between physical activity and the integrity of the cerebral white matters microstructure. Prospective studies are required to investigate a possible causal association between physical activity and cognitive decline.

MR spectroscopy detection of lactate and lipid signals in the brains of healthy elderly people

Abstract. Magnetic resonance spectroscopy was used to assess the presence of brain lactate and lipid signals, frequently associated with the presence of pathology, in healthy persons of 60–90xa0years old (n=540). Lactate and lipid signals were observed in, respectively, 25 and 6% of women, and 18 and 2% of men. Upon adjustment for age, and for MRI-detected cerebral atrophy and white matter lesions, the gender differences in lactate and lipid remained the same (p=0.05 and p=0.03, respectively). Brain lactate and lipid signals appear to be intrinsic to aging. However, the presence of these metabolites in very focal areas only, rather than in any distributed fashion within the brain (the latter generally the case with cerebral atrophy and white matter lesions), strongly suggests the existence of asymptomatic focal pathology not shown on MRI.

1H chemical shift Imaging of the human brain at age 60-90 years reveals metabolic differences between women and men

1H magnetic resonance spectroscopy was used to compare brain metabolism in 540 elderly persons, stratified by sex and age (60–90 years old). An 8 × 8 × 2 cm3 supraventricular brain volume, a transverse plane parallel to the canthomeatal line, was examined by automated 1H chemical shift imaging [point‐resolved spectroscopy (PRESS), TE of 35 msec]. Regional choline (Cho), creatine (Cr), and N‐acetyl aspartate (NAA) peak areas in the 518 successful examinations (96%) were studied by division through the total area of the particular metabolite in each spectral map. This procedure eliminated intersubject variance, maximized intervoxel variance (26 ≤ F ≤ 149, P < 0.0001) and reduced the standard deviations in the voxel metabolite signals threefold. Normalized signals in women (n = 257) and men (n = 261) differed in 9 (Cho/ΣCho), 8 (Cr/ΣCr), and 10 (NAA/ΣNAA) of 36 voxels examined (P ≤ 0.001). In the cingulate gyrus Cho/ΣCho, Cr/ΣCr, and NAA/ΣNAA were reduced in men compared with women. These findings are consistent with a sex‐related reduction of glucose metabolism in the same brain lobe revealed by positron emission tomography. Magn Reson Med 42:24–31, 1999.

Cerebral CO2 reactivity, cholesterol, and high-density lipoprotein cholesterol in the elderly.

Article abstract Cholesterol and its subfractions play a role in the development of atherosclerosis. Cerebral CO2 reactivity reflects the compensatory capacity of cerebral arterioles. The authors investigated the relationship between total cholesterol, high-density lipoprotein (HDL), their ratio, and cerebral CO2 reactivity in 826 participants from the Rotterdam Study. Cerebral CO2 reactivity increased significantly with increasing levels of HDL and decreased significantly with an increasing total cholesterol/HDL ratio. This suggests that blood lipids may also affect smaller cerebral blood vessels.