Directional information flow in patients with Alzheimer's disease. A source-space resting-state MEG study.

In a recent magnetoencephalography (MEG) study, we found posterior-to-anterior information flow over the cortex in higher frequency bands in healthy subjects, with a reversed pattern in the theta band. A disruption of information flow may underlie clinical symptoms in Alzheimer's disease (AD). In AD, highly connected regions (hubs) in posterior areas are mostly disrupted. We therefore hypothesized that in AD the information flow from these hub regions would be disturbed. We used resting-state MEG recordings from 27 early-onset AD patients and 26 healthy controls. Using beamformer-based virtual electrodes, we estimated neuronal oscillatory activity for 78 cortical regions of interest (ROIs) and 12 subcortical ROIs of the AAL atlas, and calculated the directed phase transfer entropy (dPTE) as a measure of information flow between these ROIs. Group differences were evaluated using permutation tests and, for the AD group, associations between dPTE and general cognition or CSF biomarkers were determined using Spearman correlation coefficients. We confirmed the previously reported posterior-to-anterior information flow in the higher frequency bands in the healthy controls, and found it to be disturbed in the beta band in AD. Most prominently, the information flow from the precuneus and the visual cortex, towards frontal and subcortical structures, was decreased in AD. These disruptions did not correlate with cognitive impairment or CSF biomarkers. We conclude that AD pathology may affect the flow of information between brain regions, particularly from posterior hub regions, and that changes in the information flow in the beta band indicate an aspect of the pathophysiological process in AD.

Alzheimer's disease: The state of the art in resting-state magnetoencephalography.

Alzheimer's disease (AD) is accompanied by functional brain changes that can be detected in imaging studies, including electromagnetic activity recorded with magnetoencephalography (MEG). Here, we systematically review the studies that have examined resting-state MEG changes in AD and identify areas that lack scientific or clinical progress. Three levels of MEG analysis will be covered: (i) single-channel signal analysis, (ii) pairwise analyses over time series, which includes the study of interdependencies between two time series and (iii) global network analyses. We discuss the findings in the light of other functional modalities, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Overall, single-channel MEG results show consistent changes in AD that are in line with EEG studies, but the full potential of the high spatial resolution of MEG and advanced functional connectivity and network analysis has yet to be fully exploited. Adding these features to the current knowledge will potentially aid in uncovering organizational patterns of brain function in AD and thereby aid the understanding of neuronal mechanisms leading to cognitive deficits.

The relation between structural and functional connectivity patterns in complex brain networks.

OBJECTIVE: An important problem in systems neuroscience is the relation between complex structural and functional brain networks. Here we use simulations of a simple dynamic process based upon the susceptible-infected-susceptible (SIS) model of infection dynamics on an empirical structural brain network to investigate the extent to which the functional interactions between any two brain areas depend upon (i) the presence of a direct structural connection; and (ii) the degree product of the two areas in the structural network. METHODS: For the structural brain network, we used a 78×78 matrix representing known anatomical connections between brain regions at the level of the AAL atlas (Gong et al., 2009). On this structural network we simulated brain dynamics using a model derived from the study of epidemic processes on networks. Analogous to the SIS model, each vertex/brain region could be in one of two states (inactive/active) with two parameters ß and δ determining the transition probabilities. First, the phase transition between the fully inactive and partially active state was investigated as a function of ß and δ. Second, the statistical interdependencies between time series of node states were determined (close to and far away from the critical state) with two measures: (i) functional connectivity based upon the correlation coefficient of integrated activation time series; and (ii) effective connectivity based upon conditional co-activation at different time intervals. RESULTS: We find a phase transition between an inactive and a partially active state for a critical ratio τ=ß/δ of the transition rates in agreement with the theory of SIS models. Slightly above the critical threshold, node activity increases with degree, also in line with epidemic theory. The functional, but not the effective connectivity matrix closely resembled the underlying structural matrix. Both functional connectivity and, to a lesser extent, effective connectivity were higher for connected as compared to disconnected (i.e.: not directly connected) nodes. Effective connectivity scaled with the degree product. For functional connectivity, a weaker scaling relation was only observed for disconnected node pairs. For random networks with the same degree distribution as the original structural network, similar patterns were seen, but the scaling exponent was significantly decreased especially for effective connectivity. CONCLUSIONS: Even with a very simple dynamical model it can be shown that functional relations between nodes of a realistic anatomical network display clear patterns if the system is studied near the critical transition. The detailed nature of these patterns depends on the properties of the functional or effective connectivity measure that is used. While the strength of functional interactions between any two nodes clearly depends upon the presence or absence of a direct connection, this study has shown that the degree product of the nodes also plays a large role in explaining interaction strength, especially for disconnected nodes and in combination with an effective connectivity measure. The influence of degree product on node interaction strength probably reflects the presence of large numbers of indirect connections.

Opportunities and methodological challenges in EEG and MEG resting state functional brain network research.

Electroencephalogram (EEG) and magnetoencephalogram (MEG) recordings during resting state are increasingly used to study functional connectivity and network topology. Moreover, the number of different analysis approaches is expanding along with the rising interest in this research area. The comparison between studies can therefore be challenging and discussion is needed to underscore methodological opportunities and pitfalls in functional connectivity and network studies. In this overview we discuss methodological considerations throughout the analysis pipeline of recording and analyzing resting state EEG and MEG data, with a focus on functional connectivity and network analysis. We summarize current common practices with their advantages and disadvantages; provide practical tips, and suggestions for future research. Finally, we discuss how methodological choices in resting state research can affect the construction of functional networks. When taking advantage of current best practices and avoid the most obvious pitfalls, functional connectivity and network studies can be improved and enable a more accurate interpretation and comparison between studies.

Disturbed phase relations in white matter hyperintensity based vascular dementia: an EEG directed connectivity study.

OBJECTIVE: White matter hyperintensities (WMH), a feature seen on magnetic resonance imaging (MRI) and regarded to reflect small vessel disease, can lead to vascular dementia (WMH-VaD). In WMH-VaD, cognitive deficits typically consist of executive function disturbances, and reduced information processing speed, regarded as a result of cerebral hypoperfusion. We aimed to investigate whether this patient group has typical functional differences from controls. METHODS: Resting-state encephalography studies of 17 VaD patients and 17 age- and gender matched non-demented controls were analysed in the delta, theta, alpha1 and 2, and beta frequency bands. Undirected functional connectivity between electrodes was established with the Phase Lag Index (PLI) and directed functional connectivity with the directed Phase Lag Index (dPLI). PLI and dPLI were related to performance in cognitive testing. RESULTS: Mean PLI did not differ between patients and controls. In the control group dPLI showed anterior to posterior phase gradients in all bands except the delta band. In the VaD patient group this pattern was significantly different without a clear directional pattern. No relationship with cognition was demonstrated. CONCLUSIONS: This study shows a clear front-to-back direction of connectivity in non-demented controls. In VaD patients with extensive WMH, this pattern is disturbed. SIGNIFICANCE: Structural damage at the regions of long distance white matter tracts may induce changes in the direction of phase relationships of distinct brain regions.

The trees and the forest: Characterization of complex brain networks with minimum spanning trees.

In recent years there has been a shift in focus from the study of local, mostly task-related activation to the exploration of the organization and functioning of large-scale structural and functional complex brain networks. Progress in the interdisciplinary field of modern network science has introduced many new concepts, analytical tools and models which allow a systematic interpretation of multivariate data obtained from structural and functional MRI, EEG and MEG. However, progress in this field has been hampered by the absence of a simple, unbiased method to represent the essential features of brain networks, and to compare these across different conditions, behavioural states and neuropsychiatric/neurological diseases. One promising solution to this problem is to represent brain networks by a minimum spanning tree (MST), a unique acyclic subgraph that connects all nodes and maximizes a property of interest such as synchronization between brain areas. We explain how the global and local properties of an MST can be characterized. We then review early and more recent applications of the MST to EEG and MEG in epilepsy, development, schizophrenia, brain tumours, multiple sclerosis and Parkinson's disease, and show how MST characterization performs compared to more conventional graph analysis. Finally, we illustrate how MST characterization allows representation of observed brain networks in a space of all possible tree configurations and discuss how this may simplify the construction of simple generative models of normal and abnormal brain network organization.

Go with the flow: use of a directed phase lag index (dPLI) to characterize patterns of phase relations in a large-scale model of brain dynamics.

We introduce a directed phase lag index to investigate the spatial and temporal pattern of phase relations of oscillatory activity in a model of macroscopic structural and functional brain networks. Direction of information flow was determined with the directed phase lag index (dPLI) defined as the probability that the instantaneous phase of X was smaller than the phase of Y (modulo π). X was said to phase-lead Y if 0.5

The organization of physiological brain networks.

One of the central questions in neuroscience is how communication in the brain is organized under normal conditions and how this architecture breaks down in neurological disease. It has become clear that simple activation studies are no longer sufficient. There is an urgent need to understand the brain as a complex structural and functional network. Interest in brain network studies has increased strongly with the advent of modern network theory and increasingly powerful investigative techniques such as "high-density EEG", MEG, functional and structural MRI. Modern network studies of the brain have demonstrated that healthy brains self-organize towards so-called "small-world networks" characterized by a combination of dense local connectivity and critical long-distance connections. In addition, normal brain networks display hierarchical modularity, and a connectivity backbone that consists of interconnected hub nodes. This complex architecture is believed to arise under genetic control and to underlie cognition and intelligence. Optimal brain network organization becomes disrupted in neurological disease in characteristic ways. This review gives an overview of modern network theory and its applications to healthy brain function and neurological disease, in particular using techniques from clinical neurophysiology, such as EEG and MEG.

The spatial distribution of age-related white matter changes as a function of vascular risk factors--results from the LADIS study.

White matter hyperintensities (WMH) are a frequent finding on brain MRI of elderly subjects, and have been associated with various risk factors, as well as with development of cognitive and functional impairment. While an overall association between WMH load and risk factors is well described, possible spatially restricted vulnerability remains to be established. The aim of this study was to investigate the spatial distribution of WMH in normally functioning elderly subjects. We introduce a voxel-based approach in which lesion probability is mapped as a function of clinical risk factors using logistic regression, and validate the method using simulated datasets. The method was then applied in a total of 605 participants of the LADIS study (age 74 ± 5 years, all with WMH), and the location of manually delineated WMH was investigated after spatial normalisation. Particularly strong and widespread associations were found for age, gender and hypertension. Different distribution patterns were found for men and women. Further, increased probability was found in association with self-reported alcohol and tobacco consumption, as well as in those with a history of migraine. It is concluded that the location of WMH is dependent on the risk factors involved pointing towards a regionally different pathogenesis and/or vulnerability of the white matter.

Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3-year follow-up of the LADIS study cohort.

The aim of this 3-year follow-up study was to investigate whether corpus callosum (CC) atrophy may predict future motor and cognitive impairment in an elderly population. On baseline MRI from 563 subjects with age-related white matter changes (ARWMC) from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented and subdivided into five anterior-posterior regions (CC1-CC5). Associations between the CC areas and decline in motor performance and cognitive functions over a 3-year period were analyzed. CC atrophy at baseline was significantly associated with impaired cognitive performance (p<0.01 for CC1, p<0.05 for CC5), motor function (p<0.05 for CC2 and CC5), and walking speed (p<0.01 for CC2 and CC5, p<0.05 for CC3 and total CC), and with development of dementia at 3 years (p<0.05 for CC1) after correction for appropriate confounders (ARWMC volume, atrophy, age, gender and handedness). In conclusion, CC atrophy, an indicator of reduced functional connectivity between cortical areas, seems to contribute, independently of ARWMC load, to future cognitive and motor decline in the elderly.

Incident lacunes influence cognitive decline: the LADIS study.

BACKGROUND: In cerebral small vessel disease, the core MRI findings include white matter lesions (WML) and lacunar infarcts. While the clinical significance of WML is better understood, the contribution of lacunes to the rate of cognitive decline has not been established. This study investigated whether incident lacunes on MRI determine longitudinal cognitive change in elderly subjects with WML. METHODS: Within the Leukoaraiosis and Disability Study (LADIS), 387 subjects were evaluated with repeated MRI and neuropsychological assessment at baseline and after 3 years. Predictors of change in global cognitive function and specific cognitive domains over time were analyzed with multivariate linear regression. RESULTS: After controlling for demographic factors, baseline cognitive performance, baseline lacunar and WML lesion load, and WML progression, the number of new lacunes was related to subtle decrease in compound scores for executive functions (p = 0.021) and speed and motor control (p = 0.045), but not for memory or global cognitive function. Irrespective of lacunes, WML progression was associated with decrease in executive functions score (p = 0.016). CONCLUSION: Incident lacunes on MRI parallel a steeper rate of decline in executive functions and psychomotor speed. Accordingly, in addition to WML, lacunes determine longitudinal cognitive impairment in small vessel disease. Although the individual contribution of lacunes on cognition was modest, they cannot be considered benign findings, but indicate a risk of progressive cognitive impairment.

Frontal lobe white matter hyperintensities and neurofibrillary pathology in the oldest old.

BACKGROUND: Current studies suggest an interaction between vascular mechanisms and neurodegenerative processes that leads to late-onset Alzheimer disease (AD). We tested whether AD pathology was associated with white matter hyperintensities (WMH) or cerebral infarcts in the oldest old individuals. METHODS: Brains from 132 subjects over 85 years old, who came to autopsy from the Vantaa 85+ population-based cohort, were scanned by postmortem MRI and examined for neuropathologic changes. Coronal images were analyzed to determine the degree of frontal and parietal periventricular WMH (PVWMH) and deep WMH (DWMH) and cerebral infarcts. Neuropathologic variables included Consortium to Establish a Registry for Alzheimer's Disease scores for neuritic plaques and Braak staging among subjects in 5 groups: normal aging (NA), borderline with insufficient AD pathology, AD, AD plus other pathology, and other primary degenerative diseases. RESULTS: Frontal DWMH were detected in >50% of the sample. Both frontal PVWMH and DWMH were significantly more extensive in the AD group compared to the NA group or the NA and borderline groups combined. Frontal PVWMH and DWMH were also associated with increased Braak staging (p = 0.03) and the neuritic plaque load (p = 0.01). Further analysis revealed there were a greater number of cerebral infarcts associated with frontal DWMH (p = 0.03) but not with frontal PVWMH. CONCLUSIONS: Our study showed an association between neurofibrillary pathology and frontal PVWMH and DWMH (rather than parietal), as a surrogate of small vessel disease, particularly in very old community-dwelling individuals.

Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study.

OBJECTIVES: In cerebral small vessel disease, white-matter hyperintensities (WMH) and lacunes are both related to cognition. Still, their respective contribution in older people remains unclear. The purpose of this study is to assess the topographic distribution of lacunes and determine whether it has an impact on cognitive functions in a sample of non-disabled patients with age-related white-matter changes. METHODS: Data were drawn from the baseline evaluation of the LADIS (Leucoaraioisis and Disability study) cohort of non-disabled subjects beyond 65 years of age. The neuropsychological evaluation was based on the Mini Mental Status Examination (MMSE), a modified Alzheimer Diseases Assessment Scale for global cognitive functions, and compound Z scores for memory, executive functions, speed and motor control. WMH were rated according to the Fazekas scale; the number of lacunes was assessed in the following areas: lobar white matter, putamen/pallidum, thalamus, caudate nucleus, internal/external capsule, infratentorial areas. An analysis of covariance was performed after adjustment for possible confounders. RESULTS: Among 633 subjects, 47% had at least one lacune (31% at least one within basal ganglia). The presence of lacunes in the thalamus was associated with lower scores of MMSE (beta = -0.61; p = 0.043), and worse compound scores for speed and motor control (beta = -0.25; p = 0.006), executive functions (beta = -0.19; p = 0.022) independently of the cognitive impact of WMH. There was also a significant negative association between the presence of lacunes in putamen/pallidum and the memory compound Z score (beta = -0.13; p = 0.038). By contrast, no significant negative association was found between cognitive parameters and the presence of lacunes in internal capsule, lobar white matter and caudate nucleus. CONCLUSION: In non-disabled elderly subjects with leucoaraisosis, the location of lacunes within subcortical grey matter is a determinant of cognitive impairment, independently of the extent of WMH.

Small vessel versus large vessel vascular dementia: risk factors and MRI findings.

OBJECTIVE: The aim of this study was a cross-sectional comparison of clinical and MRI characteristics and risk factor profiles between patients with small vessel disease (lacunae and white matter hyperintensities) and large vessel disease (large territorial or strategical infarcts) in a large cohort of VaD patients. METHODS: Patients with VaD (NINDS-AIREN) were included in a large multicenter treatment trial (the VantagE study). All patients were examined by a neurologist and interviewed about their medical history. Based on MRI, patients were classified as having large vessel VaD, small vessel VaD, or a combination. Other MRI characteristics included white matter hyperintensities (WMH), medial temporal lobe atrophy (MTA) and general cortical atrophy. RESULTS: Of the 706 patients, 522 (74 %) had small vessel disease, 126 (18 %) had large vessel disease and 58 (8 %) had both. Patients with small vessel disease were older and less educated, and showed more cortical and medial temporal lobe atrophy than patients with large vessel disease. The most prevalent vascular risk factors (hypertension, diabetes and smoking) were equally distributed between the different types of VaD. However, patients with large vessel disease had more hypercholesterolemia and cardiac risk factors compared to patients with small vessel disease. CONCLUSION: Cerebrovascular disease underlying VaD consists in the majority of small vessel disease and in about one fifth of large vessel disease. This study demonstrates heterogeneity between these two groups with regard to risk factor profile and atrophy scores on MRI.

Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study.

OBJECTIVE: The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD). METHODS: VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects. TRIAL REGISTRATION: NCT00099216. RESULTS: 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance. CONCLUSION: Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology.

White matter changes contribute to corpus callosum atrophy in the elderly: the LADIS study.

BACKGROUND AND PURPOSE: The corpus callosum (CC) is the most important structure involved in the transmission of interhemispheric information. The aim of this study was to investigate the potential correlation between regional age-related white matter changes (ARWMC) and atrophy of CC in elderly subjects. MATERIALS AND METHODS: In 578 subjects with ARWMC from the Leukoaraiosis And DISability (LADIS) study, the cross-sectional area of the CC was automatically segmented on the normalized midsagittal MR imaging section and subdivided into 5 regions. The ARWMC volumes were measured quantitatively by using a semiautomated technique and segmented into 6 brain regions. RESULTS: Significant correlation between the area of the rostrum and splenium regions of the CC and the ARWMC load in most brain regions was identified. This correlation persisted after correction for global atrophy. CONCLUSION: Increasing loads of ARWMC volume were significantly correlated with atrophy of the CC and its subregions in nondisabled elderly subjects with leukoaraiosis. However, the pattern of correlation between CC subregions and ARWMC was not specifically related to the topographic location of ARWMC. The results suggest that ARWMC may lead to a gradual loss of CC tissue.

Reliability and sensitivity of visual scales versus volumetry for evaluating white matter hyperintensity progression.

BACKGROUND: Investigating associations between the change of white matter hyperintensities (WMH) and clinical symptoms over time is crucial for establishing a causal relationship. However, the most suitable method for measuring WMH progression has not been established yet. We compared the reliability and sensitivity of cross-sectional and longitudinal visual scales with volumetry for measuring WMH progression. METHODS: Twenty MRI scan pairs (interval 2 years) were included from the Amsterdam center of the LADIS study. Semi-automated volumetry of WMH was performed twice by one rater. Three cross-sectional scales (Fazekas Scale, Age-Related White Matter Changes Scale, Scheltens Scale) and two progression scales (Rotterdam Progression Scale, Schmidt Progression Scale) were scored by 4 and repeated by 2 raters. RESULTS: Mean WMH volume (24.6 +/- 27.9 ml at baseline) increased by 4.6 +/- 5.1 ml [median volume change (range) = 2.7 (-0.6 to 15.7) ml]. Measuring volumetric change in WMH was reliable (intraobserver:intraclass coefficient = 0.88). All visual scales showed significant change of WMH over time, although the sensitivity was highest for both of the progression scales. Proportional volumetric change of WMH correlated best with the Rotterdam Progression Scale (Spearman's r = 0.80, p < 0.001) and the Schmidt Progression Scale (Spearman's r = 0.64, p < 0.01). Although all scales were reliable for assessment of WMH cross-sectionally, WMH progression assessment using visual scales was less reliable, except for the Rotterdam Progression scale which had moderate to good reliability [weighted Cohen's kappa = 0.63 (intraobserver), 0.59 (interobserver)]. CONCLUSION: To determine change in WMH, dedicated progression scales are more sensitive and/or reliable and correlate better with volumetric volume change than cross-sectional scales.

The significance of medial temporal lobe atrophy: a postmortem MRI study in the very old.

BACKGROUND: Medial temporal lobe atrophy (MTA) is a sensitive radiologic marker for Alzheimer disease (AD) and associated with cognitive impairment. The value of MTA in the oldest old (>85 years old) is largely unknown. METHODS: A total of 132 formalin-fixed brains from the Vantaa 85+ community-based study were subjected to postmortem MRI. Visual ratings of MTA were determined in a blinded fashion and compared with neuropathologic findings and clinical assessment (dementia according to Diagnostic and Statistical Manual of Mental Disorders-III-R). RESULTS: A strong relationship was found between MTA scores and Alzheimer pathology (p < 0.001). The previously proposed cutoff MTA score >2 correctly excluded subjects with no or borderline Alzheimer-type pathology (45/48), but was not very sensitive for AD (modified National Institute on Aging-Reagan Institute criteria). MTA scores >2 were also found in subjects with other primary neurodegenerative hippocampal pathology including hippocampal sclerosis, Lewy-related pathology, and argyrophilic grain disease, either alone or in combination with Alzheimer-type pathology. High MTA scores were associated with clinical dementia-in this subgroup, sensitivity was 63% and specificity 69% for AD. CONCLUSION: Medial temporal lobe atrophy (MTA) on postmortem MRI is sensitive to primary degenerative hippocampal pathology in the very old, but not specific for Alzheimer-type pathology. MTA scores of 2 or less are not frequently associated with dementia.

Diabetes mellitus, hypertension and medial temporal lobe atrophy: the LADIS study.

HYPOTHESIS: Based on recent findings on the association between vascular risk factors and hippocampal atrophy, we hypothesized that hypertension and diabetes mellitus (DM) are associated with medial temporal lobe atrophy (MTA) in subjects without disability, independent of the severity of white matter hyperintensities. METHODS: In the Leukoaraiosis And DISability in the elderly (LADIS) study, we investigated the relationships between DM, hypertension, blood pressure and MTA in 582 subjects, stratified by white matter hyperintensity severity, using multinomial logistic regression. MTA was visually scored for the left and right medial temporal lobe (score 0-4), and meaned. RESULTS: Mean age was 73.5 years (sd 5.1), 54% was female. Of the subjects, 15% had DM, and 70% had a history of hypertension. The likelihood of having MTA score 3 was significantly higher in subjects with DM (OR 2.9; 95% CI: 1.1-7.8) compared with an MTA score of 0 (no atrophy). The odds ratio for MTA score 2 was not significantly increased (OR 1.8; CI: 0.9-4). Systolic and diastolic blood pressure and a history of hypertension were not associated with MTA. There was no interaction between DM and hypertension. Stratification on white matter hyperintensities (WMH) did not alter the associations. CONCLUSION: Our study strengthens the observation that MTA is associated with DM, independently of the amount of small vessel disease as reflected by WMH.

Clinical significance of corpus callosum atrophy in a mixed elderly population.

Corpus callosum (CC) is the main tract connecting the hemispheres, but the clinical significance of CC atrophy is poorly understood. The aim of this work was to investigate clinical and functional correlates of CC atrophy in subjects with age-related white matter changes (ARWMC). In 569 elderly subjects with ARWMC from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented on the normalised mid-sagittal magnetic resonance imaging (MRI) slice and subdivided into five regions. Correlations between the CC areas and subjective memory complaints, mini mental state examination (MMSE) score, history of depression, geriatric depression scale (GDS) score, subjective gait difficulty, history of falls, walking speed, and total score on the short physical performance battery (SPPB) were analyzed. Significant correlations between CC atrophy and MMSE, SPPB, and walking speed were identified, and the CC areas were smaller in subjects with subjective gait difficulty. The correlations remained significant after correction for ARWMC grade. In conclusion, CC atrophy was independently associated with impaired global cognitive and motor function in subjects with ARWMC.