Genetic basis of anatomical asymmetry and aberrant dynamic functional networks in Alzheimer's disease.

Genetic associations with macroscopic brain networks can provide insights into healthy and aberrant cortical connectivity in disease. However, associations specific to dynamic functional connectivity in Alzheimer's disease are still largely unexplored. Understanding the association between gene expression in the brain and functional networks may provide useful information about the molecular processes underlying variations in impaired brain function. Given the potential of dynamic functional connectivity to uncover brain states associated with Alzheimer's disease, it is interesting to ask: How does gene expression associated with Alzheimer's disease map onto the dynamic functional brain connectivity? If genetic variants associated with neurodegenerative processes involved in Alzheimer's disease are to be correlated with brain function, it is essential to generate such a map. Here, we investigate how the relation between gene expression in the brain and dynamic functional connectivity arises from nodal interactions, quantified by their role in network centrality (i.e. the drivers of the metastability), and the principal component of genetic co-expression across the brain. Our analyses include genetic variations associated with Alzheimer's disease and also genetic variants expressed within the cholinergic brain pathways. Our findings show that contrasts in metastability of functional networks between Alzheimer's and healthy individuals can in part be explained by the two combinations of genetic co-variations in the brain with the confidence interval between 72% and 92%. The highly central nodes, driving the brain aberrant metastable dynamics in Alzheimer's disease, highly correlate with the magnitude of variations from two combinations of genes expressed in the brain. These nodes include mainly the white matter, parietal and occipital brain regions, each of which (or their combinations) are involved in impaired cognitive function in Alzheimer's disease. In addition, our results provide evidence of the role of genetic associations across brain regions in asymmetric changes in ageing. We validated our findings on the same cohort using alternative brain parcellation methods. This work demonstrates how genetic variations underpin aberrant dynamic functional connectivity in Alzheimer's disease.

Brain morphometric similarity and flexibility.

Background: The cerebral cortex is represented through multiple multilayer morphometric similarity networks to study their modular structures. The approach introduces a novel way for studying brain networks' metrics across individuals, and can quantify network properties usually not revealed using conventional network analyses. Methods: A total of 8 combinations or types of morphometric similarity networks were constructed - 4 combinations of the inter-regional cortical features on 2 brain atlases. The networks' modular structures were investigated by identifying those modular interactions that stay consistent across the combinations of inter-regional morphometric features and individuals. Results: The results provide evidence of the community structures as the property of (i) cortical lobar divisions, and also as (ii) the product of different combinations of morphometric features used for the construction of the multilayer representations of the cortex. For the first time, this study has mapped out flexible and inflexible morphometric similarity hubs, and evidence has been provided about variations of the modular network topology across the multilayers with age and IQ. Conclusions: The results contribute to understanding of intra-regional characteristics in cortical interactions, which potentially can be used to map heterogeneous neurodegeneration patterns in diseased brains.

Degeneration of basal and limbic networks is a core feature of behavioural variant frontotemporal dementia.

The behavioural variant of frontotemporal dementia is a clinical syndrome characterized by changes in behaviour, cognition and functional ability. Although atrophy in frontal and temporal regions would appear to be a defining feature, neuroimaging studies have identified volumetric differences distributed across large parts of the cortex, giving rise to a classification into distinct neuroanatomical subtypes. Here, we extended these neuroimaging studies to examine how distributed patterns of cortical atrophy map onto brain network hubs. We used baseline structural magnetic resonance imaging data collected from 213 behavioural variant of frontotemporal dementia patients meeting consensus diagnostic criteria and having definite evidence of frontal and/or temporal lobe atrophy from a global clinical trial conducted in 70 sites in Canada, United States of America, Australia, Asia and Europe. These were compared with data from 244 healthy elderly subjects from a well-characterized cohort study. We have used statistical methods of hierarchical agglomerative clustering of 68 regional cortical and subcortical volumes (34 in each hemisphere) to determine the reproducibility of previously described neuroanatomical subtypes in a global study. We have also attempted to link the structural findings to clinical features defined systematically using well-validated clinical scales (Addenbrooke's Cognitive Examination Revised, the Mini-Mental Status Examination, the Frontotemporal Dementia Rating Scale and the Functional Assessment Questionnaire) and subscales derived from them. Whilst we can confirm that the subtypes are robust, they have limited value in explaining the clinical heterogeneity of the syndrome. We have found that a common pattern of degeneration affecting a small number of subcortical, limbic and frontal nodes within highly connected networks (most previously identified as rich club members or functional binding nodes) is shared by all the anatomical subtypes. Degeneration in these core regions is correlated with cognitive and functional impairment, but less so with behavioural impairment. These findings suggest that degeneration in highly connected basal, limbic and frontal networks is a core feature of the behavioural variant of frontotemporal dementia phenotype irrespective of neuroanatomical and clinical heterogeneity, and may underly the impairment of integration in cognition, function and behaviour responsible for the loss of insight that characterizes the syndrome.

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia.

BACKGROUND: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. OBJECTIVE: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. METHODS: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug. RESULTS: There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day. CONCLUSIONS: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

Cortical Thickness and Functional Networks Modules by Cortical Lobes.

This study aims to investigate topological organization of cortical thickness and functional networks by cortical lobes. First, I demonstrated modular organization of these networks by the cortical surface frontal, temporal, parietal and occipital divisions. Secondly, I mapped the overlapping edges of cortical thickness and functional networks for positive and negative correlations. Finally, I showed that overlapping positive edges map onto within-lobe cortical interactions and negative onto between-lobes interactions.

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer's Disease.

BACKGROUND: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer's disease (AD) comparing doses in the range 150-250 mg/day with 8 mg/day intended as a control. OBJECTIVE: To determine how drug exposure is related to treatment response. METHODS: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. RESULTS: There are steep concentration-response relationships for steady state plasma levels in the range 0.3-0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4-21 ng/ml produced by the high doses are not associated with any additional benefit. CONCLUSIONS: Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose.

Cortical Thickness and Surface Area Networks in Healthy Aging, Alzheimer's Disease and Behavioral Variant Fronto-Temporal Dementia.

Models of the human brain as a complex network of inter-connected sub-units are important in helping to understand the structural basis of the clinical features of neurodegenerative disorders. The aim of this study was to characterize in a systematic manner the differences in the structural correlation networks in cortical thickness (CT) and surface area (SA) in Alzheimer's disease (AD) and behavioral variant Fronto-Temporal Dementia (bvFTD). We have used the baseline magnetic resonance imaging (MRI) data available from a large population of patients from three clinical trials in mild to moderate AD and mild bvFTD and compared this to a well-characterized healthy aging cohort. The study population comprised 202 healthy elderly subjects, 213 with bvFTD and 213 with AD. We report that both CT and SA network architecture can be described in terms of highly correlated networks whose positive and inverse links map onto the intrinsic modular organization of the four cortical lobes. The topology of the disturbance in structural network is different in the two disease conditions, and both are different from normal aging. The changes from normal are global in character and are not restricted to fronto-temporal and temporo-parietal lobes, respectively, in bvFTD and AD, and indicate an increase in both global correlational strength and in particular nonhomologous inter-lobar connectivity defined by inverse correlations. These inverse correlations appear to be adaptive in character, reflecting coordinated increases in CT and SA that may compensate for corresponding impairment in functionally linked nodes. The effects were more pronounced in the cortical thickness atrophy network in bvFTD and in the surface area network in AD. Although lobar modularity is preserved in the context of neurodegenerative disease, the hub-like organization of networks differs both from normal and between the two forms of dementia. This implies that hubs may be secondary features of the connectivity adaptation to neurodegeneration and may not be an intrinsic property of the brain. However, analysis of the topological differences in hub-like organization CT and SA networks, and their underlying positive and negative correlations, may provide a basis for assisting in the differential diagnosis of bvFTD and AD.

Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial.

BACKGROUND: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. OBJECTIVES: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. METHODS: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. RESULTS: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. CONCLUSIONS: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.

Role of structural inhomogeneities in resting-state brain dynamics.

Brain imaging methods allow a non-invasive assessment of both structural and functional connectivity. However, the mechanism of how functional connectivity arises in a structured network of interacting neural populations is as yet poorly understood. Here we use a modeling approach to explore the way in which functional correlations arise from underlying structural connections taking into account inhomogeneities in the interactions between the brain regions of interest. The local dynamics of a neural population is assumed to be of phase-oscillator type. The considered structural connectivity patterns describe long-range anatomical connections between interacting neural elements. We find a dependence of the simulated functional connectivity patterns on the parameters governing the dynamics. We calculate graph-theoretic measures of the functional network topology obtained from numerical simulations. The effect of structural inhomogeneities in the coupling term on the observed network state is quantified by examining the relation between simulated and empirical functional connectivity. Importantly, we show that simulated and empirical functional connectivity agree for a narrow range of coupling strengths. We conclude that identification of functional connectivity during rest requires an analysis of the network dynamics.

Dynamic changes in network synchrony reveal resting-state functional networks.

Experimental functional magnetic resonance imaging studies have shown that spontaneous brain activity, i.e., in the absence of any external input, exhibit complex spatial and temporal patterns of co-activity between segregated brain regions. These so-called large-scale resting-state functional connectivity networks represent dynamically organized neural assemblies interacting with each other in a complex way. It has been suggested that looking at the dynamical properties of complex patterns of brain functional co-activity may reveal neural mechanisms underlying the dynamic changes in functional interactions. Here, we examine how global network dynamics is shaped by different network configurations, derived from realistic brain functional interactions. We focus on two main dynamics measures: synchrony and variations in synchrony. Neural activity and the inferred hemodynamic response of the network nodes are simulated using a system of 90 FitzHugh-Nagumo neural models subject to system noise and time-delayed interactions. These models are embedded into the topology of the complex brain functional interactions, whose architecture is additionally reduced to its main structural pathways. In the simulated functional networks, patterns of correlated regional activity clearly arise from dynamical properties that maximize synchrony and variations in synchrony. Our results on the fast changes of the level of the network synchrony also show how flexible changes in the large-scale network dynamics could be.

Functional connectivity of distant cortical regions: role of remote synchronization and symmetry in interactions.

Functional MRI (fMRI) of ongoing brain activity at rest i.e. without any overt-directed behavior has revealed patterns of coherent activity, so called resting-state functional networks. The dynamical organization of nodes into these functional networks is closely related to the underlying structural connections. However, functional correlations have also been observed between cortical regions without apparent neural links, and mechanisms generating functional connectivity between distant cortical regions are largely unknown. It has been suggested that indirect connections and collective effects governed by the network properties of the cortex play a significant role. We use numerical simulations to investigate these mechanisms with reference to remote synchronization and network symmetry. Neural activity and the inferred hemodynamic response of the network nodes are modeled as sets of self-sustained oscillators, which are embedded in topologies of complex functional brain interactions. The coupling topology is based on connectivity maps derived from fMRI and DTI experiments. Consequently, our network model includes important information on whether direct or indirect neural connections exist between functionally associated regions. In the simulated functional networks, remote synchrony between pairs of nodes clearly arises from symmetry in the interactions, which are quantified by the number of shared neighbors. A larger joint neighborhood positively correlates with a higher level of synchrony. Therefore, our results indicate that a large overlapping neighborhood in complex networks of brain interactions gives rise to functional similarity between distant cortical regions.

Contractions of the whole and longitudinally cut rat's portal vein.

To investigate the role of lateral interactions, we quantified spontaneous contractions of whole and longitudinally cut rat´s portal vein in vitro. The disruption of the wall had no effect on basic frequency determined from spectra and complexity index (CI) calculated by multiscale entropy analysis. Endothelium was disrupted and nonfunctional in all samples. Considering amplitude, frequency and CI we identified two modes of contractions. Neither mode of contractions nor the effect of aminopyridine (4-AP) depended on the integrity of the wall. We concluded that contractions in vitro originate in smooth muscle cells without involvement of the endothelium and lateral interactions.

Spontaneous contractions of isolated rat portal vein under temperature perturbations.

We studied nonlinear dynamics underlying spontaneous rhythmical contractions of isolated rat portal vein. The signals were acquired at four different temperatures important in isolated blood vessels preparations: 4, 22, 37 and 40 degrees C. To characterize the system's nonlinearity, we calculated the largest Lyapunov exponent, sample entropy and scaling exponents. Evidence for nonlinearity was provided by analysis of surrogate data generated from the phase-randomized Fourier transform of the original sequences. Positive values of the largest Lyapunov exponent were obtained for the time series recorded under applied conditions, indicating that the system preserves its chaotic deterministic nature even far from the physiological temperature range. Scaling exponents revealed three distinctive regions with different correlation properties. The calculated measures that characterize the time series obtained at 4 degrees C were significantly different from those derived from data obtained at higher temperatures. System's dynamics becomes more complex or less predictable as temperature approaches physiological value. The computation of the largest Lyapunov exponent, sample entropy and correlation measures gave an insight into the complex dynamics of the isolated blood vessels rhythmicity. We identified different modes of rhythmical contractions of isolated rat portal vein which could improve understanding of possible control mechanisms in vivo.

Nonlinear relationship between level of blood flow and skin temperature for different dynamics of temperature change.

We present a study of the relationship between blood flow and skin temperature under different dynamics of skin-temperature-change: locally induced thermal shock and well controlled, gradual change. First, we demonstrate memory phenomena for blood flow and skin temperature under both conditions. Secondly, we point out that the "hysteresis" loops obtained are dependent on initial conditions, indicating physiological response times of more than twenty minutes. We also show that under thermal shock the level of blood flow is preserved up to some characteristic temperature limit, independently of subject.

Heart rate variability in mental stress aloud.

Previous investigations on arithmetic stress with verbalization showed that spectral measures of heart rate variability (HRV) did not assess changes in autonomic modulation, although the heart rate (HR) increased. In this study non-linear measures of HRV are determined and linear measures are re-examined in order to understand this apparent discrepancy between HR and HRV changes. In 23 healthy subjects 5-min electrocardiograms (ECGs) were recorded at rest and during arithmetic stress aloud. We determined non-linear (short-term scaling exponent, sensitivity to the initial condition and signal complexity) and linear (low-frequency and high-frequency spectral powers) measures. Our results showed that averaging concealed out an opposite effect of mental stress aloud on spectral measures and that this could be the main reason why the effect was not quantified. We found that increase of HR upon mental stress aloud could be achieved through the decreased as well as increased modulation in high-frequency band (HF). We also showed that non-linear measures distinguished this opposite effect of mental stress aloud on linear measures. Decreased HF power is associated with increase in short-term scaling exponent and decrease in signal complexity, while increased HF power increased sensitivity to the initial conditions. Apart from their opposite response to the mental stress, the two groups differed in baseline in sensitivity to the initial conditions. We suggest that variety of changes in HR dynamics upon different perturbation could be due to some differences in intrinsic properties of the system.

[Analysis of heart rhythm variability by linear and non-linear dynamics methods].

INTRODUCTION: Spectral analysis of heart rhythm variability is a noninvasive method to study cardiovascular autonomic control. Nonlinear methods of analysis of heart rhythm variability may provide an additional information on properties of RR interval dynamics, which cannot be revealed by linear methods. The aim of this study was to investigate and to compare some parameters of deterministic chaos, tractal and spectral properties of heart rhythm variability in healthy subjects. METHODS: Sixty healthy subjects, who participated in this study, were divided in four different age groups: children (< 15 years old), young (15-24 years), adults (25-39 years) and middle-aged (40-61 years). We analyzed the heart period variability extracted from a 5-minute electrocardiograms recordings in supine rest. Short-term fractal scaling exponent, sample entropy, minimum embedding dimension and the largest Lyapunov exponent along with the spectral measures (low-frequency and high-frequency power) were determined. RESULTS: Heart frequency, short-term fractal scaling exponent, and the largest Lyapunov exponent did not differ between the tested groups (p > 0.05). Middle-aged subjects had the lower low-frequency power as compared to the children (p < 0.001) and the young (p < 0.05), and the lower high-frequency power as compared to the other three groups (p < 0.001). Middle-aged also had a significantly lower power of high frequency and sample entropy as compared to the other three groups (p < 0.001). Children had lower values of minimum embedding dimension compared to the middle aged (p < 0.001). Significant negative correlation between the age of the tested subjects, and the low-and, high-frequency power and sample entropy was found. CONCLUSION: The obtained results suggested that healthy aging was associated with significant alteration in heart rhythm dynamics reflected on a higher regularity and lower variability of heart rhythm time-series. Significant decrease in a high-frequency power with aging suggested that reduction in parasympathetic activity was the basic cause of these changes.

Correlation properties and regularity of heart period time series: influence of posture and heart disease.

Nonlinear measures of heart period variability (HPV) were determined in supine rest and standing posture in children and young adults with heart disease and compared to the control. The aim was to study influence of posture and heart disease on heart period dynamics. It was found that standing increases short-term scaling exponent in all subjects and decreases sample entropy in healthy and less severely ill patients. Severely ill patients compared to control have higher short-term scaling exponent in supine. Changes in nonlinear measures of HPV upon standing are more pronounced in healthy than diseased subjects due to different vagal activity.

Nonlinear and chaos characteristics of heart period time series: healthy aging and postural change.

In this study we investigated nonlinear and linear characteristics of heart period variability with aging in supine and standing posture. Sixty healthy subjects (8-61 years) divided in three age groups participated in the study. Heart period variability was assessed by measurement of short-term scaling exponent, sample entropy, largest Lyapunov exponent and spectral low-frequency and high-frequency power. In standing, there was significant increase in short-term scaling exponent and largest Lyapunov exponent in all subjects, and significant decrease in sample entropy in children (<15 years) and young adults (15-39 years). Increasing age is associated with reduction in sample entropy in supine posture. Mutual effect of aging and postural change was reflected on heart rate and sample entropy. Correlation between low-frequency-to-high-frequency power ratio and short-term scaling exponent was found in supine posture. In standing both low-frequency and high-frequency powers are correlated with short-term scaling exponent and sample entropy. These results show that posture, standing compared to supine, has significant effect on nonlinear properties of heart period variability in healthy subjects while the influence of healthy aging is less pronounced. The findings indicate that intrinsic properties of heart period dynamics, reflected on nonlinear measures, are altered only by robust changes of autonomic modulation of heart rate.

Effect of posture on heart rate variability spectral measures in children and young adults with heart disease.

BACKGROUND: Reduction of heart rate variability as a consequence of heart disease and postural change has been well documented. However, the data on the effect of postural change in pediatric patients are incomplete and the effect is not fully understood. The aim of the study was to investigate effect of postural change on heart rate variability in relation to the extent of severity of heart disease. METHODS: The dependence of heart rate variability on posture in 41 children and young adults (8-20 years) with heart disease has been investigated and compared with control. Short-term electrocardiograms (ECGs) were assessed in supine rest and active standing, and spectral measures of heart rate variability were determined. RESULTS: Two types of response to the change of supine to standing posture were determined in both healthy and diseased subjects. In majority of subjects, the increased heart rate induced by standing was accompanied by a decrease in high-frequency power. However, in about 30% of all subjects, increased heart rate during standing was accompanied by an increased high-frequency power. Independently of posture and disease, high-frequency and low-frequency power were positively correlated. In subjects characterized by a reduction of heart rate variability in standing, the high-frequency power in both postures is reduced in diseased subjects compared to control. CONCLUSIONS: These results demonstrate that in this age range, the response to posture is not unique because of the difference in high-frequency power, which implies a variety of vagal modulations of heart rate.