Auke P.A. Appelman

Diabetes Increases Atrophy and Vascular Lesions on Brain MRI in Patients With Symptomatic Arterial Disease

Background and Purpose— Diabetes type 2 (DM2) is associated with accelerated cognitive decline and structural brain abnormalities. Macrovascular disease has been described as a determinant for brain MRI changes in DM2, but little is known about the involvement of other DM2-related factors. Methods— Brain MRI was performed in 1043 participants (151 DM2) with symptomatic arterial disease. Brain volumes were obtained through automated segmentation. Results— Patients with arterial disease and DM2 had more global and subcortical brain atrophy (−1.20% brain/intracranial volume [95%CI −1.58 to −0.82], P<0.0005 and 0.20% ventricular/intracranial volume [0.05 to 0.34], P<0.01), larger WMH volumes (0.22 logtransformed volume [0.07 to 0.38], P<0.005), and more lacunar infarcts (OR 1.75 [1.13 to 2.69], P<0.01) than identical patients without DM2. In patients with DM2, high glucose levels (B−0.12% per mmol/L [−0.23 to −0.01], P<0.05) and diabetes duration (B−0.05% per year [−0.10 to −0.001], P<0.05) were associated with global brain atrophy. Conclusion— In patients with symptomatic arterial disease, DM2 has an added detrimental effect on the brain. In patients with DM2, hyperglycemia and diabetes duration contribute to brain atrophy.

Brain volumes and cerebrovascular lesions on MRI in patients with atherosclerotic disease. The SMART-MR study

OBJECTIVE To estimate brain volumes, white matter lesion (WML) volume and asymptomatic infarcts on MRI in a large cohort of patients with atherosclerotic disease. METHODS Within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) study, a prospective cohort study on determinants and course of brain changes on MRI, cross-sectional analyses were performed in 1044 patients (mean age 58+/-10 years, 80% male) with coronary artery disease, cerebrovascular disease, peripheral arterial disease, or abdominal aortic aneurysm. Brain segmentation was used to quantify volumes of cortical gray matter, white matter, sulcal and ventricular cerebrospinal fluid, and WML. All volumes were expressed relative to intracranial volume. Brain infarcts were rated visually and distinctions were made between cortical infarcts, large subcortical infarcts, lacunar infarcts, and infarcts in the cerebellum and brainstem. RESULTS With older age a nonlinear (quadratic) decrease in total brain volume was observed and a nonlinear increase in ventricular volume and WML. Cortical gray matter volume showed a linear decrease with age and was stronger in men than in women. WML volumes also increased more strongly in men than in women, while ventricular volume decrease showed no sex difference. Silent brain infarcts were present in 14% of men and women, and increased to 24% of subjects aged 65 years or older. CONCLUSION In a population with atherosclerotic diseases, decrease in brain volumes with increasing age is comparable with findings from the general population. However, vascular pathology on MRI, as indicated by white matter lesions and silent brain infarcts may be more common.

White matter lesions and brain atrophy: more than shared risk factors? A systematic review.

Background: White matter lesions (WML) and brain atrophy are often found on MRI in the elderly. Shared vascular risk factors may be an explanation for their concomitance. However, disturbances of white matter integrity could also be involved in the pathogenesis of brain atrophy. Our objective was to systematically review studies that investigated the relation between WML and brain atrophy on MRI, and to investigate whether there is sufficient evidence to indicate that this relation is independent of shared risk factors. Methods: We searched PubMed for studies published in English between 1980 and October 2007, combining search terms for WML and brain atrophy. Articles that studied the relation between WML and brain atrophy were included if they met the following criteria: (1) original study, (2) MRI used for imaging, (3) assessment methods for WML and brain atrophy specified, and (4) a sample size of at least 20 participants. We recorded type and age of the study population, type and assessment of WML and brain atrophy, and variables for which adjustments were made in the analyses. Results: We identified 48 studies that met our inclusion criteria. A significant relation between WML and brain atrophy was found in 37 out of 48 studies. The source of the study population (e.g. clinic or population based) did not affect this relation. However, only 10 studies adjusted for shared risk factors, of which 9 found an association. Conclusions: The majority of studies found an association between WML and brain atrophy, but it is not yet clear if this association is independent of shared risk factors.

Total cerebral blood flow, white matter lesions and brain atrophy: the SMART-MR study

We investigated whether total cerebral blood flow (CBF) was associated with brain atrophy, and whether this relation was modified by white matter lesions (WML). Within the Second Manifestations of ARTerial disease-magnetic resonance (SMART-MR) study, a prospective cohort study among patients with arterial disease, cross-sectional analyses were performed in 828 patients (mean age 58±10 years, 81% male) with quantitative flow, atrophy, and WML measurements on magnetic resonance imaging (MRI). Total CBF was measured with MR angiography and was expressed per 100 mL brain volume. Total brain volume and ventricular volume were divided by intracranial volume to obtain brain parenchymal fraction (BPF) and ventricular fraction (VF). Lower BPF indicates more global brain atrophy, whereas higher VF indicates more subcortical brain atrophy. Mean CBF was 52.0±10.2 mL/min per 100 mL, mean BPF was 79.2±2.9%, and mean VF was 2.03±0.96%. Linear regression analyses showed that lower CBF was associated with more subcortical brain atrophy, after adjusting for age, sex, vascular risk factors, intima-media thickness, and lacunar infarcts, but only in patients with moderate to severe WML (upper quartile of WML): Change in VF per s.d. decrease in CBF 0.18%, 95% CI: 0.02 to 0.34%. Our findings suggest that cerebral hypoperfusion in the presence of WML may be associated with subcortical brain atrophy.

Association of White Matter Lesions and Lacunar Infarcts With Executive Functioning The SMART-MR Study

The authors investigated the association of white matter lesions and lacunar infarcts with cognitive performance and whether brain atrophy mediates these associations. Within the Second Manifestations of Arterial Disease-Magnetic Resonance study (2001-2005, the Netherlands), cross-sectional analyses of 522 patients were performed (mean age, 57 years (standard deviation, 10); 76% male). Brain segmentation was used to quantify volumes of brain tissue, cerebrospinal fluid, and white matter lesions. Infarcts were rated visually. Brain volume, ventricular volume, and gray matter volume were divided by intracranial volume to obtain indicators of brain atrophy. Neuropsychological tests assessing executive functioning and memory were performed, and scores were transformed into z scores. The authors used linear regression analyses, adjusted for age, sex, education, intelligence, and vascular risk factors, to investigate the association of white matter lesions and number of lacunar infarcts with cognitive performance. A 1-standard-deviation higher volume of white matter lesions (beta = -0.12, 95% confidence interval: -0.20, -0.04) and the presence of >or=2 lacunar infarcts (beta = -0.48, 95% confidence interval: -0.87, -0.09) were associated with worse executive functioning. These associations remained after adjusting for brain atrophy. Both were not associated with worse memory. Results suggest that subcortical ischemic vascular lesions are associated with decreased executive functioning, but not with memory functioning, independent of brain atrophy.

White Matter Lesions and Lacunar Infarcts Are Independently and Differently Associated with Brain Atrophy: The SMART-MR Study

Objective: To investigate the independent association of white matter lesions (WML) and lacunar infarcts (LI) with measures of global brain atrophy on MRI. Methods: Within the SMART-MR study, a cohort study among patients with manifest arterial disease, cross-sectional analyses were performed in 840 patients (mean age 58 ± 10 years, 80% male) without cortical, large subcortical or infratentorial infarcts. Brain segmentation was used to quantify volumes of brain tissue, cerebrospinal fluid and WML. Total brain volume, ventricular volume and cortical gray matter volume were divided by intracranial volume to obtain brain parenchymal fraction (BPF), ventricular fraction (VF) and cortical gray matter fraction (GMF). Location and number of infarcts were rated visually. Results: Mean ± SD BPF was 79.3 ± 2.8%, mean ± SD VF was 2.01 ± 0.95%, and mean ± SD GMF was 36.6 ± 3.3%. Linear regression analyses, adjusted for age, sex, vascular risk factors, intima media thickness and LI showed that in patients with moderate to severe WML (upper quartile) BPF was lower (–0.51%; 95% CI –0.93 to –0.08%), VF was higher (0.48%; 95% CI 0.31–0.65%) and GMF was lower (–1.48%; 95% CI –2.07 to –0.88%) than in patients with few WML (lower quartile). Presence of LI was associated with lower BPF (–0.52%; 95% CI –0.96 to –0.07%) and higher VF (0.25%; 95% CI 0.07–0.42%), but not with GMF, independent of WML and other potential confounders. Conclusion: WML are associated with total, subcortical and cortical brain atrophy, whereas LI are associated with total and subcortical atrophy, but not with cortical atrophy, suggesting an independent role for WML and LI in the pathogenesis of brain atrophy.

Brain atrophy and cognition: Interaction with cerebrovascular pathology?

We examined the interaction of brain atrophy and white matter lesions (WML) with cognitive functioning in 605 patients (mean age, 58±10; 76% men) with atherosclerotic disease from the Second Manifestations of ARTerial disease-MR substudy (SMART-MR study). Automated brain segmentation was used to quantify volumes of brain tissue, cerebrospinal fluid, and WML on MRI. Total brain, ventricular, and cortical gray matter volume were divided by intracranial volume (ICV). Neuropsychological tests assessing executive functioning and memory performance were performed and composite scores were calculated. We observed that smaller total brain volume, larger ventricular volume, and smaller cortical gray matter volume (all as % of ICV) were associated with worse executive performance and that this association became stronger with presence of brain infarcts or severe WML volume (P-values for interaction <0.05). No interaction between measures of brain volume and cerebrovascular pathology on memory performance was observed. Our findings suggest that patients with cerebrovascular pathology on MRI may be more vulnerable to impairment in executive functioning related to global as well as focal brain atrophy.

Combined Effect of Cerebral Hypoperfusion and White Matter Lesions on Executive Functioning – The SMART-MR Study

Background/Aims: It has been hypothesized that cerebral hypoperfusion may contribute to cognitive deterioration. Patients with white matter lesions (WML) may be more vulnerable to a decrease in cerebral blood flow (CBF) due to an impaired autoregulation. We investigated the association between CBF and cognitive performance and whether WML modified this relation. Methods: Within the SMART-MR study, a cohort study among patients with manifest arterial disease, cross-sectional analyses were performed in 472 patients (mean age 57 ± 10 years, 77% male). Total CBF was measured with magnetic resonance angiography in the internal carotid arteries and basilar artery, and was expressed per 100 ml brain volume. Neuropsychological tests assessing executive functioning and memory were performed and composite scores were calculated. We used linear regression analyses, adjusted for age, sex, education and intelligence, to investigate the association between CBF and cognitive performance. Results: We found that WML modified the association between CBF and executive functioning (p for interaction <0.001); the association between lower CBF and worse performance on executive functioning became stronger and significant with increasing volumes of WML. Lower CBF was not associated with worse memory. Conclusion: Our results suggest that a combination of lower CBF and WML may impair executive functioning but not memory.

Visual rating of the hippocampus in non-demented elders: Does it measure hippocampal atrophy or other indices of brain atrophy? The SMART-MR study

Visual rating of hippocampal atrophy is often used to differentiate between normal aging and Alzheimers disease. We investigated whether two visual rating scales of hippocampal atrophy were related to hippocampal volumes, and if visual rating was related to global, cortical and subcortical brain atrophy in persons without dementia. Within the SMART‐MR study, a prospective cohort study among patients with manifest arterial disease, medial temporal lobe atrophy was qualitatively rated in 95 participants without dementia (mean age 62 ± 10 years) using two visual rating scales: the medial temporal lobe (MTA) score was rated on coronal oriented images and the perihippocampal cerebrospinal fluid (HCSF) score was rated on axial oriented images. Hippocampal volume assessed by manual segmentation on a 3‐dimensional FFE T1‐weighted MR image. Automated segmentation was used to quantify volumes of brain tissue and cerebrospinal fluid. Total brain volume, gray matter volume, and ventricular volume were divided by intracranial volume to obtain brain parenchymal fraction (BPF), gray matter fraction (GMF) and ventricular fraction (VF). Using ANOVA, crude hippocampal volumes were smaller with increasing MTA and HSCF scores as were hippocampal volumes normalized for intracranial volume (P < 0.05). However, hippocampal volumes normalized for total brain size were not smaller with increasing MTA or HSCF scores (P = 0.33 and P = 0.49). Also, with increasing visual rating scores, BPF was smaller and VF was larger (P < 0.001), and the GMF decreased with increasing HCSF score (P = 0.008). In this nondemented population, visual rating of the medial temporal lobe reflects hippocampal atrophy as well as global and subcortical atrophy.

Total cerebral blood flow and hippocampal volume in patients with arterial disease. The SMART-MR study

It has been suggested that compared with other brain tissues, the hippocampus in particular is vulnerable to chronic hypoperfusion. We investigated whether total parenchymal cerebral blood flow (pCBF) was associated with hippocampal atrophy, and also whether this relationship was modified by white matter lesions (WMLs). In a cross-sectional analysis within the SMART-MR (Second Manifestations of ARTerial disease-magnetic resonance) study, which is a cohort study among patients with arterial disease, total CBF (tCBF) and hippocampal volume were assessed in 392 patients (mean age: 62±9 years, 84% men). Total CBF was expressed in per 100 mL brain volume for obtaining pCBF. Manual volumetric measurements of the hippocampus were carried out on a three-dimensional fast field-echo T1-weighted magnetic resonance imaging scan with isotropic voxels. Automated brain segmentation was used to quantify volumes of the WML and the total brain. A linear regression analysis showed that reduced pCBF was not associated with smaller hippocampal volume after adjustments were made for age and sex. The association attenuated further after additional adjustments were made for vascular risk factors, lacunar infarcts, and WMLs (β=0.01 mL per s.d. decrease in pCBF; 95% confidence interval: −0.06 to 0.08). The association was not modified by WML (P-value for interaction term pCBF∗WML=0.84). We found no evidence of the fact that lower parenchymal blood flow contributes to the neurodegeneration of the hippocampus in a population of patients with arterial disease.