Graph theory applied to neuroimaging data reveals key functional connectivity alterations in brain of behavioral variant Frontotemporal Dementia subjects

Brain functional architecture and anatomical structure have been intensively studied to generate efficient models of its complex mechanisms. Functional alterations and cognitive impairments are the most investigated aspects in the recent clinical research as distinctive traits of neurodegeneration. Although specific behaviours are clearly associated to neurodegeneration, information flow breakdown within the brain functional network, responsible to deeply affect cognitive skills, remains not completely understood. Behavioural variant Frontotemporal Dementia (bvFTD) is the most common type of Frontotemporal degeneration, marked by behavioural disturbances, social instabilities and impairment of executive functions. Mathematical modelling offers effective tools to inspect deviations from physiological cognitive functions and connectivity alterations. As a popular recent methodology, graph theoretical approaches applied to imaging data expanded our knowledge of neurodegenerative disorders, although the need for unbiased metrics is still an open issue. In this thesis, we propose an integrated analysis of functional features among brain areas in bvFTD patients, to assess global connectivity and topological network alterations respect to the healthy condition, using a minimum spanning tree (MST) based-model to resting state functional MRI (rs-fMRI) data. Contrary to several graph theoretical approaches, dependent to arbitrary criteria (e.g., correlation thresholds, network density or a priori distribution), MST represents an unambiguous modelling solution, ensuring full reproducibility and robustness in different conditions. Our MSTs were obtained from wavelet correlation matrices derived from mean time series intensities, extracted from 116 regions of interest (ROIs) of 41 bvFTD patients and 39 healthy controls (HC), which underwent rs-fMRI. The resulting graphs were tested for global connectivity and topological differences between the two groups, by applying a Wilcoxon rank sum test with a significance level at 0.05 (nonparametric median difference estimates with 95% confidence interval). The same test was applied for methodological comparison between MST and other common graph theory methods. After methodological comparisons, our MST model achieved the best bvFTD/HC separation performances, without a priori assumptions. Direct MST comparison between bvFTD and healty controls revealed key brain functional architecture differences. Diseased subjects showed a linear-shape network configuration tendency, with high distance between nodes, low centrality parameter values, and a low exchange information capacity (i.e., low network integration) in MST parameters. Moreover, edge-level and node-level features (i.e., superhighways, and node degree and betweenness centrality) indicated a more complex scenario, showing some of the key bvFTD dysfunctions observed in large scale resting-state functional networks (default-mode (DMN), salience (SN), and executive (EN) networks), suggesting an underlying involvement of the limbic system in the observed functional deterioration. Functional isolation has been observed as a generalized process affecting the entire bvFTD network, showing brain macro-regions isolation, with homogeneous functional distribution of brain areas, longer distances between hubs, and longer within-lobe superhighways. Conversely, the HC network showed marked functional integration, where superhighways serve as shortcuts to connect areas from different brain macro-regions. The combination of this theoretical model with rs-fMRI data constitutes an effective method to generate a clear picture of the functional divergence between bvFTD and HCs, providing possible insights on the effects of frontotemporal neurodegeneration and compensatory mechanisms underlying characteristic bvFTD cognitive, social, and executive impairments

Different FDG-PET metabolic patterns at single-subject level in the behavioral variant of fronto-temporal dementia.

BACKGROUND: The diagnosis of probable behavioral variant of fronto-temporal dementia (bvFTD) according to current criteria requires the imaging evidence of frontal and/or anterior temporal atrophy or hypoperfusion/hypometabolism. Different variants of this pattern of brain involvement may, however, be found in individual cases, supporting the presence of heterogeneous phenotypes. OBJECTIVE: We examined in a case-by-case approach the FDG-PET metabolic patterns of patients fulfilling clinical criteria for probable bvFTD, assessing the presence and frequency of specific FDG-PET features. MATERIALS AND METHODS: Fifty two FDG-PET scans of probable bvFTD patients were retrospectively analyzed together with clinical and neuropsychological data. Neuroimaging experts rated the FDG-PET hypometabolism maps obtained at the single-subject level with optimized voxel-based Statistical Parametric Mapping (SPM). The functional metabolic heterogeneity was further tested by hierarchical cluster analysis and principal component analysis (PCA). RESULTS: Both the SPM maps and cluster analysis identified two major variants of cerebral hypometabolism, namely the "frontal" and the "temporo-limbic", which were correlated with different cognitive profiles. Executive and language deficits were the cognitive hallmark in the "frontal" subgroup, while poor encoding and recall on long-term memory tasks was typical of the "temporo-limbic" subgroup. DISCUSSION: SPM single-subject analysis indicates distinct patterns of brain dysfunction in bvFTD, coupled with specific clinical features, suggesting different profiles of neurodegenerative vulnerability. These findings have important implications for the early diagnosis of bvFTD and for the application of the recent international consensus criteria

Right limbic FDG-PET hypometabolism correlates with emotion recognition and attribution in probable behavioral variant of frontotemporal dementia patients

The behavioural variant of frontotemporal dementia (bvFTD) is a rare disease mainly affecting the social brain. FDG-PET fronto-temporal hypometabolism is a supportive feature for the diagnosis. It may also provide specific functional metabolic signatures for altered socio-emotional processing. In this study, we evaluated the emotion recognition and attribution deficits and FDG-PET cerebral metabolic patterns at the group and individual levels in a sample of sporadic bvFTD patients, exploring the cognitive-functional correlations. Seventeen probable mild bvFTD patients (10 male and 7 female; age 67.8±9.9) were administered standardized and validated version of social cognition tasks assessing the recognition of basic emotions and the attribution of emotions and intentions (i.e., Ekman 60-Faces test-Ek60F and Story-based Empathy task-SET). FDG-PET was analysed using an optimized voxel-based SPM method at the single-subject and group levels. Severe deficits of emotion recognition and processing characterized the bvFTD condition. At the group level, metabolic dysfunction in the right amygdala, temporal pole, and middle cingulate cortex was highly correlated to the emotional recognition and attribution performances. At the single-subject level, however, heterogeneous impairments of social cognition tasks emerged, and different metabolic patterns, involving limbic structures and prefrontal cortices, were also observed. The derangement of a right limbic network is associated with altered socio-emotional processing in bvFTD patients, but different hypometabolic FDG-PET patterns and heterogeneous performances on social tasks at an individual level exist

Variant-specific vulnerability in metabolic connectivity and resting-state networks in behavioural variant of frontotemporal dementia.

Brain connectivity measures represent candidate biomarkers of neuronal dysfunction in neurodegenerative diseases. Previous findings suggest that the behavioural variant of frontotemporal dementia (bvFTD) and its variants (i.e., frontal and temporo-limbic) may be related to the vulnerability of distinct functional connectivity networks. In this study, 82 bvFTD patients were included, and two patient groups were identified as frontal and temporo-limbic bvFTD variants. Two advanced multivariate analytical approaches were applied to FDG-PET data, i.e., sparse inverse covariance estimation (SICE) method and seed-based interregional correlation analysis (IRCA). These advanced methods allowed the assessment of (i) the whole-brain metabolic connectivity, without any a priori assumption, and (ii) the main brain resting-state networks of crucial relevance for cognitive and behavioural functions. In the whole bvFTD group, we found dysfunctional connectivity patterns in frontal and limbic regions and in all major brain resting-state networks as compared to healthy controls (HC N = 82). In the two bvFTD variants, SICE and IRCA analyses identified variant-specific reconfigurations of whole-brain connectivity and resting-state networks. Specifically, the frontal bvFTD variant was characterised by metabolic connectivity alterations in orbitofrontal regions and anterior resting-state networks, while the temporo-limbic bvFTD variant was characterised by connectivity alterations in the limbic and salience networks. These results highlight different neural vulnerabilities in the two bvFTD variants, as shown by the dysfunctional connectivity patterns, with relevance for the different neuropsychological profiles. This new evidence provides further insight in the variability of bvFTD and may contribute to a more accurate classification of these patients

Latent profile analysis in frontotemporal lobar degeneration and related disorders: clinical presentation and SPECT functional correlates

<p>Abstract</p> <p>Background</p> <p>Frontotemporal Lobar Degeneration (FTLD) thus recently renamed, refers to a spectrum of heterogeneous conditions. This same heterogeneity of presentation represents the major methodological limit for the correct evaluation of clinical designation and brain functional correlates. At present, no study has investigated clinical clusters due to specific cognitive and behavioural disturbances beyond current clinical criteria.</p> <p>The aim of this study was to identify clinical FTLD presentation, based on cognitive and behavioural profile, and to define their SPECT functional correlations.</p> <p>Methods</p> <p>Ninety-seven FTLD patients entered the study. A clinical evaluation and standardised assessment were preformed, as well as a brain SPECT perfusion imaging study. Latent Profile Analysis on clinical, neuropsychological, and behavioural data was performed. Voxel-basis analysis of SPECT data was computed.</p> <p>Results</p> <p>Three specific clusters were identified and named "pseudomanic behaviour" (LC1), "cognitive" (LC2), and "pseudodepressed behaviour" (LC3) endophenotypes. These endophenotypes showed a comparable hypoperfusion in left temporal lobe, but a specific pattern involving: medial and orbitobasal frontal cortex in LC1, subcortical brain region in LC2, and right dorsolateral frontal cortex and insula in LC3.</p> <p>Conclusion</p> <p>These findings provide evidence that specific functional-cluster symptom relationship can be delineated in FTLD patients by a standardised assessment. The understanding of the different functional correlates of clinical presentations will hopefully lead to the possibility of individuating diagnostic and treatment algorithms.</p

Frontal hypometabolism in neurocognitive disorder with behavioral disturbance

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Executive deficits are related to the inferior frontal junction in early dementia

Executive functions describe a wide variety of higher order cognitive processes that allow the flexible modification of thought and behaviour in response to changing cognitive or environmental contexts. Their impairment is common in neurodegenerative disorders. Executive deficits negatively affect everyday activities and hamper the ability to cope with other deficits, such as memory impairment in Alzheimer's disease or behavioural disorders in frontotemporal lobar degeneration. Our study aimed to characterize the neural correlates of executive functions by relating respective deficits to regional hypometabolism in early dementia. Executive functions were assessed with two classical tests, the Stroop and semantic fluency test and various subtests of the behavioural assessment of the dysexecutive syndrome test battery capturing essential aspects of executive abilities relevant to daily living. Impairments in executive functions were correlated with reductions in brain glucose utilization as measured by [18F]fluorodeoxyglucose positron emission tomography and analysed voxelwise using statistical parametric mapping in 54 subjects with early dementia, mainly Alzheimer's disease and frontotemporal lobar degeneration, and its prodromal stages: subjective and mild cognitive impairment. Although the analysis revealed task-specific frontoparietal networks, it consistently showed that hypometabolism in one region in the left lateral prefrontal cortex—the inferior frontal junction area—was related to performance in the various neuropsychological tests. This brain region has recently been related to the three component processes of cognitive control—working memory, task switching and inhibitory control. Group comparisons additionally showed hypometabolism in this area in Alzheimer's disease and frontotemporal lobar degeneration. Our study underlines the importance of the inferior frontal junction area for cognitive control in general and for executive deficits in early dementia

Brain Connectivity and Information-Flow Breakdown Revealed by a Minimum Spanning Tree-Based Analysis of MRI Data in Behavioral Variant Frontotemporal Dementia

Brain functional disruption and cognitive shortfalls as consequences of neurodegeneration are among the most investigated aspects in current clinical research. Traditionally, specific anatomical and behavioral traits have been associated with neurodegeneration, thus directly translatable in clinical terms. However, these qualitative traits, do not account for the extensive information flow breakdown within the functional brain network that deeply affect cognitive skills. Behavioural variant Frontotemporal Dementia (bvFTD) is a neurodegenerative disorder characterized by behavioral and executive functions disturbances. Deviations from the physiological cognitive functioning can be accurately inferred and modeled from functional connectivity alterations. Although the need for unbiased metrics is still an open issue in imaging studies, the graph-theory approach applied to neuroimaging techniques is becoming popular in the study of brain dysfunction. In this work, we assessed the global connectivity and topological alterations among brain regions in bvFTD patients using a minimum spanning tree (MST) based analysis of resting state functional MRI (rs-fMRI) data. Whilst several graph theoretical methods require arbitrary criteria (including the choice of network construction thresholds and weight normalization methods), MST is an unambiguous modeling solution, ensuring accuracy, robustness, and reproducibility. MST networks of 116 regions of interest (ROIs) were built on wavelet correlation matrices, extracted from 41 bvFTD patients and 39 healthy controls (HC). We observed a global fragmentation of the functional network backbone with severe disruption of information-flow highways. Frontotemporal areas were less compact, more isolated, and concentrated in less integrated structures, respect to healthy subjects. Our results reflected such complex breakdown of the frontal and temporal areas at both intra-regional and long-range connections. Our findings highlighted that MST, in conjunction with rs-fMRI data, was an effective method for quantifying and detecting functional brain network impairments, leading to characteristic bvFTD cognitive, social, and executive functions disorders

Magnetoencephalography of frontotemporal dementia: spatiotemporally localized changes during semantic decisions.

Behavioural variant frontotemporal dementia is a neurodegenerative disorder with dysfunction and atrophy of the frontal lobes leading to changes in personality, behaviour, empathy, social conduct and insight, with relative preservation of language and memory. As novel treatments begin to emerge, biomarkers of frontotemporal dementia will become increasingly important, including functionally relevant neuroimaging indices of the neurophysiological basis of cognition. We used magnetoencephalography to examine behavioural variant frontotemporal dementia using a semantic decision task that elicits both frontal and temporal activity in healthy people. Twelve patients with behavioural variant frontotemporal dementia (age 50-75) and 16 matched controls made categorical semantic judgements about 400 pictures during continuous magnetoencephalography. Distributed source analysis was used to compare patients and controls. The patients had normal early responses to picture confrontation, indicating intact visual processing. However, a predominantly posterior set of regions including temporoparietal cortex showed reduced source activity 250-310 ms after stimulus onset, in proportion to behavioural measures of semantic association. In contrast, a left frontoparietal network showed reduced source activity at 550-650 ms, proportional to patients' deficits in attention and orientation. This late deficit probably reflects impairment in the neural substrate of goal-oriented decision making. The results demonstrate behaviourally relevant neural correlates of semantic processing and decision making in behavioural variant frontotemporal dementia, and show for the first time that magnetoencephalography can be used to study cognitive systems in the context of frontotemporal dementia