[show abstract][hide abstract] ABSTRACT: Low-grade inflammation and endothelial dysfunction are related to cognitive decline and dementia, in a complex interplay with vascular factors and aging. We investigated, in an older population, low-grade inflammation and endothelial dysfunction in relation to detailed assessment of cognitive functioning. Furthermore, we explored this association within the context of vascular factors.
377 participants (73 ± 6 years) of the population-based Hoorn Study were included. In plasma samples of 2000–2001 (n = 363) and/or 2005–2008 (n = 323), biomarkers were determined of low-grade inflammation (CRP, TNF-alpha, IL-6, IL-8, SAA, MPO, and sICAM-1) and endothelial dysfunction (vWF, sICAM-1, sVCAM-1, sTM, sE-selectin). In 2005–2008, all participants underwent neuropsychological examination. Composite z-scores were computed for low-grade inflammation and endothelial dysfunction at both time points, and for six domains of cognitive functioning (abstract reasoning, memory, information processing speed, attention and executive functioning, visuoconstruction, and language). The association between low-grade inflammation and endothelial dysfunction, and cognitive functioning was evaluated with linear regression analysis. In secondary analyses, we explored the relation with vascular risk factors and cardiovascular disease.
Low-grade inflammation and endothelial dysfunction were associated with worse performance on information processing speed and attention and executive functioning, in prospective and cross-sectional analyses (standardized betas ranging from −0.20 to −0.10). No significant relation with other cognitive domains was observed. Adjusting for vascular factors slightly attenuated the associations. Low-grade inflammation and endothelial dysfunction accounted for only 2.6% explained variance in cognitive functioning, on top of related vascular risk factors and cardiovascular disease. Bootstrapping analyses show that low-grade inflammation and endothelial dysfunction mediate the relation between vascular risk factors and cognitive functioning.
This study shows that low-grade inflammation and endothelial dysfunction contribute to reduced information processing speed and executive functioning in an older population.
[show abstract][hide abstract] ABSTRACT: Cerebral microinfarcts (CMIs) are a common finding in neuropathological studies of aging and dementia. Recently, it has become possible to detect CMIs in vivo. We studied CMI occurrence in 29 patients with mild cognitive impairment or early Alzheimer's disease (AD) and 22 non-demented individuals on 7Tesla MRI. CMI occurrence in patients (55%) and controls (45%) was not significantly different. In patients, CMI number tended to be related to microbleed number (p = 0.07). This first in vivo study of CMIs in early AD does not confirm findings from autopsy studies. Further studies are needed to clarify the role of CMIs in AD.
Journal of Alzheimer's disease: JAD 10/2013; · 4.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Cerebral microbleeds are a manifestation of small vessel disease and are common in patients with Alzheimer's disease (AD). However, their clinical significance in this condition is uncertain. We hypothesized that microbleeds contribute to disturbances of the cerebral network in AD and as such may affect cognition. Objective: The goal of this study was to examine the relationship between microbleeds and brain networks in patients with amnestic mild cognitive impairment (aMCI) or early AD. Methods: Sixty-seven patients (77.9 ± 7.5 years) with aMCI (n = 29) or early AD (n = 38) underwent cognitive testing and 3Tesla MRI. Microbleeds were rated visually. Diffusion tensor imaging and graph theoretical analysis were used to reconstruct brain networks and to quantify network efficiency for each patient. Network measures were compared between patients without and with ≥1 microbleeds and between patients without or with ≥3 microbleeds. In secondary analyses, cognitive functioning was compared between groups. Analyses were adjusted for age and gender, and additionally for other markers of small vessel disease and atrophy. Results: Network measures did not differ between patients with ≥1 microbleed (n = 26) and patients without microbleeds (n = 41). However, patients with ≥3 microbleeds (n = 11) showed significant white matter disruptions, longer path length, and less global efficiency than patients without microbleeds, independent of other markers of small vessel disease and atrophy. Cognitive functioning did not differ between patients without microbleeds and patients with ≥1 or ≥3 microbleeds. Conclusion: Multiple microbleeds are related to structural network disruption in patients with early AD, but their direct impact on cognitive functioning appears to be limited.
Journal of Alzheimer's disease: JAD 08/2013; · 4.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Retinal microvascular changes can be visualized noninvasively and have been associated with cognitive decline and brain changes in relation to aging and vascular disease. We systematically reviewed studies, published between 1990 and November 2012, on the association between retinal microvascular changes and dementia, cognitive functioning, and brain imaging abnormalities, in the context of aging and vascular risk factors. In cross-sectional studies (k=26), retinal microvascular changes were associated with the presence of dementia (range of odds ratios (ORs) 1.17;5.57), with modest decrements in cognitive functioning in nondemented people (effect sizes -0.25;0.03), and with brain imaging abnormalities, including atrophy and vascular lesions (ORs 0.94;2.95). Longitudinal studies were more sparse (k=9) and showed no consistent associations between retinal microvascular changes and dementia or cognitive dysfunctioning 3 to 15 years later (ORs and hazard ratios 0.77;1.55). However, there were indications of prospective associations with brain imaging abnormalities ((ORs) 0.81;3.19). In conclusion, particularly in cross-sectional studies there is a correlation between retinal microvascular changes and dementia, cognitive impairment, and brain imaging abnormalities. Associations are strongest for more severe retinal microvascular abnormalities. Retinal microvascular abnormalities may offer an important window on the brain for etiological studies.Journal of Cerebral Blood Flow & Metabolism advance online publication, 17 April 2013; doi:10.1038/jcbfm.2013.58.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2013; · 5.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To examine the relation between measures of whole-brain white matter connectivity and cognitive performance in patients with early Alzheimer disease (AD) using a network-based approach and to assess whether network parameters provide information that is complementary to conventional MRI markers of AD. METHODS: Fifty patients (mean age 78.8 ± 7.1 years) with early AD were recruited via a memory clinic. In addition, 15 age-, sex-, and education-matched control participants were used as a reference group. All participants underwent a 3-T MRI scan and cognitive assessment. Diffusion tensor imaging-based tractography was used to reconstruct the brain network of each individual, followed by graph theoretical analyses. Overall network efficiency was assessed by measures of local (clustering coefficient, local efficiency) and global (path length, global efficiency) connectivity. Age-, sex-, and education-adjusted cognitive scores were related to network measures and to conventional MRI parameters (i.e., degree of cerebral atrophy and small-vessel disease). RESULTS: The structural brain network of patients showed reduced local efficiency compared to controls. Within the patient group, worse performance in memory and executive functioning was related to decreased local efficiency (r = 0.434; p = 0.002), increased path length (r = -0.538; p < 0.001), and decreased global efficiency (r = 0.431; p = 0.005). Measures of network efficiency explained up to 27% of the variance in cognitive functioning on top of conventional MRI markers (p < 0.01). CONCLUSION: This study shows that network-based analysis of brain white matter connections provides a novel way to reveal the structural basis of cognitive dysfunction in AD.
[show abstract][hide abstract] ABSTRACT: Cerebral microbleeds are associated with vascular disease and dementia. They can be detected on MRI and receive increasing attention. Visual rating is the current standard for microbleed detection, but is rater dependent, has limited reproducibility, modest sensitivity, and can be time-consuming. The goal of the current study is to present a tool for semi-automated detection of microbleeds that can assist human raters in the rating procedure. The radial symmetry transform is originally a technique to highlight circular-shaped objects in two-dimensional images. In the current study, the three-dimensional radial symmetry transform was adapted to detect spherical microbleeds in a series of 72 patients from our hospital, for whom a ground truth visual rating was made by four raters. Potential microbleeds were automatically identified on T2*-weighted 3.0 T MRI scans and the results were visually checked to identify microbleeds. Final ratings of the radial symmetry transform were compared to human ratings. After implementing and optimizing the radial symmetry transform, the method achieved a high sensitivity, while maintaining a modest number of false positives. Depending on the settings, sensitivities ranged from 65%-84% compared to the ground truth rating. Rating of the processed images required 1-2 minutes per participant, in which 20-96 false positive locations per participant were censored. Sensitivities of individual raters ranged from 39%-86% compared to the ground truth and required 5-10 minutes per participant per rater. The sensitivities that were achieved by the radial symmetry transform are similar to those of individual experienced human raters, demonstrating its feasibility and usefulness for semi-automated microbleed detection.
PLoS ONE 01/2013; 8(6):e66610. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The prevalence of microbleeds on magnetic resonance imaging (MRI) in patients with Alzheimer's disease (AD) is lower than that of its presumed pathological correlate, cerebral amyloid angiopathy. We examined 18 patients with early AD or mild cognitive impairment (MCI) and 18 non-demented controls with ultra-high field strength 7Tesla MRI, to assess if the actual prevalence of microbleeds could be higher than is currently reported. One or more microbleeds were visualized in 78% of the MCI/AD patients and in 44% of the controls (p = 0.04). 7Tesla MRI shows that presence of microbleeds may be the rule, rather than exception in patients with MCI/AD.
[show abstract][hide abstract] ABSTRACT: Diffusion tensor imaging (DTI) based fiber tractography (FT) is the most popular approach for investigating white matter tracts in vivo, despite its inability to reconstruct fiber pathways in regions with "crossing fibers." Recently, constrained spherical deconvolution (CSD) has been developed to mitigate the adverse effects of "crossing fibers" on DTI based FT. Notwithstanding the methodological benefit, the clinical relevance of CSD based FT for the assessment of white matter abnormalities remains unclear. In this work, we evaluated the applicability of a hybrid framework, in which CSD based FT is combined with conventional DTI metrics to assess white matter abnormalities in 25 patients with early Alzheimer's disease. Both CSD and DTI based FT were used to reconstruct two white matter tracts: one with regions of "crossing fibers," i.e., the superior longitudinal fasciculus (SLF) and one which contains only one fiber orientation, i.e. the midsagittal section of the corpus callosum (CC). The DTI metrics, fractional anisotropy (FA) and mean diffusivity (MD), obtained from these tracts were related to memory function. Our results show that in the tract with "crossing fibers" the relation between FA/MD and memory was stronger with CSD than with DTI based FT. By contrast, in the fiber bundle where one fiber population predominates, the relation between FA/MD and memory was comparable between both tractography methods. Importantly, these associations were most pronounced after adjustment for the planar diffusion coefficient, a measure reflecting the degree of fiber organization complexity. These findings indicate that compared to conventionally applied DTI based FT, CSD based FT combined with DTI metrics can increase the sensitivity to detect functionally significant white matter abnormalities in tracts with complex white matter architecture.
PLoS ONE 01/2012; 7(8):e44074. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Markers of vascular disease elsewhere in the body may reflect vascular abnormalities in the brain relevant to age-related cognitive decline and dementia. We examined the association between albuminuria, as a marker of microvascular damage, and cognition in older individuals.
380 individuals (age 73 ± 6 years), participating in the population-based Hoorn Study, underwent extensive neuropsychological examination in 2005-2008, and urinary albumin-to-creatinine ratios measurements in 2000-2001 (n = 378) and/or 2005-2008 (n = 346). Cognition was expressed in z-scores on 6 domains.
In 2000-2001, 42 participants were with and 336 without albuminuria, and in 2005-2008 51 were with and 295 were without. In age-, sex- and premorbid IQ-adjusted analyses, participants with albuminuria 5-7 years earlier had slightly lower z-scores for the domains attention and executive functioning [mean difference: -0.21 (95% CI -0.40 to -0.02)] and language [-0.36 (95% CI -0.63 to -0.09)]. No statistically significant differences in cognition were found between participants with and without albuminuria at the time of neuropsychological testing.
Albuminuria predicts future modest cognitive decrements, but concurrent albuminuria is unrelated to cognitive functioning. The link between albuminuria and cognitive dysfunction may convey an etiological message, but because effect sizes were modest its value in prognostic models for cognitive decline may be limited.