Sophie M. Heringa

Disruption of cerebral networks and cognitive impairment in Alzheimer disease.

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.

Improved sensitivity to cerebral white matter abnormalities in Alzheimer's disease with spherical deconvolution based tractography.

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.

Hippocampal subfield volumes at 7T in early Alzheimer's disease and normal aging

We compared hippocampal subfield and entorhinal cortex (ERC) volumes between patients with mild cognitive impairment (MCI), Alzheimers disease (AD), and controls without cognitive impairment. Additionally, we investigated the relation between age and hippocampal subfields and ERC in controls. We performed ultra-high field 0.7 mm(3) 7Tesla magnetic resonance imaging in 16 patients with amnestic MCI, 9 with AD, and 29 controls. ERC, subiculum, cornu ammonis (CA)1, CA2, CA3, and dentate gyrus (DG)&CA4 were traced on T2-weighted images. Analyses of covariance, adjusted for age, sex, and intracranial volume showed that compared with controls and patients with MCI, patients with AD had significantly smaller ERC, subiculum, CA1, CA3, and DG&CA4 volumes. Trend analyses revealed similar associations between ERC and hippocampal subfields and diagnostic group. Older age was significantly associated with smaller CA1 and DG&CA4 volumes. In conclusion, almost all hippocampal subfields and ERC show volume reductions in patients with AD compared with controls and patients with MCI. Future, larger studies should determine which subfields are affected earliest in the disease process and what mechanisms underlie the volume loss.

Associations between retinal microvascular changes and dementia, cognitive functioning, and brain imaging abnormalities: a systematic review.

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.

High Prevalence of Cerebral Microbleeds at 7Tesla MRI in Patients with Early Alzheimer's Disease

The prevalence of microbleeds on magnetic resonance imaging (MRI) in patients with Alzheimers 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.

Markers of low-grade inflammation and endothelial dysfunction are related to reduced information processing speed and executive functioning in an older population – the Hoorn Study

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.

Multiple Microbleeds are Related to Cerebral Network Disruptions in Patients with Early Alzheimer's Disease

BACKGROUND Cerebral microbleeds are a manifestation of small vessel disease and are common in patients with Alzheimers 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.

Working memory binding and episodic memory formation in aging, mild cognitive impairment, and Alzheimer’s dementia

Introduction: Recent studies indicate that in both normal and pathological aging working memory (WM) performance deteriorates, especially when associations have to be maintained. However, most studies typically do not assess the relationship between WM and episodic memory formation. In the present study, we examined WM and episodic memory formation in normal aging and in patients with early Alzheimer’s disease (mild cognitive impairment, MCI; and Alzheimer’s dementia, AD). Method: In the first study, 26 young adults (mean age 29.6 years) were compared to 18 middle-aged adults (mean age 52.2 years) and 25 older adults (mean age 72.8 years). We used an associative delayed-match-to-sample WM task, which requires participants to maintain two pairs of faces and houses presented on a computer screen for short (3 s) or long (6 s) maintenance intervals. After the WM task, an unexpected subsequent associative memory task was administered (two-alternative forced choice). In the second study, 27 patients with AD and 19 patients with MCI were compared to 25 older controls, using the same paradigm as that in Experiment 1. Results: Older adults performed worse than both middle-aged and young adults. No effect of delay was observed in the healthy adults, and pairs that were processed during long maintenance intervals were not better remembered in the subsequent memory task. In the MCI and AD patients, longer maintenance intervals hampered the task performance. Also, both patient groups performed significantly worse than controls on the episodic memory task as well as the associative WM task. Conclusions: Aging and AD present with a decline in WM binding, a finding that extends similar results in episodic memory. Longer delays in the WM task did not affect episodic memory formation. We conclude that WM deficits are found when WM capacity is exceeded, which may occur during associative processing.

Increased risk of psychosis in patients with hearing impairment : Review and meta-analyses

Several studies suggest hearing impairment as a risk factor for psychosis. Hearing impairment is highly prevalent and potentially reversible, as it can be easily diagnosed and sometimes improved. Insight in the association between hearing impairment and psychosis can therefore contribute to prevention of psychosis. This paper provides meta-analyses of all epidemiologic evidence on the association between hearing impairment and psychosis and summarizes mechanisms that potentially underlie this relationship. Meta-analyses showed an increased risk of hearing impairment on all psychosis outcomes, such as hallucinations (OR 1.40(95%CI 1.18-1.65; n=227,005)), delusions (OR 1.55(95%CI 1.36-1.78; n=250,470)), psychotic symptoms (OR 2.23(95%CI 1.83-2.72; n=229,647) and delirium (OR 2.67(95%CI 2.05-3.48; n=12,432). Early exposure to hearing impairment elevated the risk of later development of schizophrenia (OR 3.15(95%CI 1.25-7.95; n=50,490)). Potential mechanisms underlying this association include loneliness, diminished theory of mind, disturbances of source monitoring and top-down processing and deafferentiation. Early assessment and treatment of hearing impairment in patients with (high risk of) psychosis may be essential in psychosis treatment and prevention.

Cerebral Cortical Microinfarcts at 7Tesla MRI in Patients with Early Alzheimer's Disease

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 Alzheimers 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.