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Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease.

ABSTRACT: Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer's disease cause atrophy within two major networks, an anterior 'Salience Network' (atrophied in behavioural variant frontotemporal dementia) and a posterior 'Default Mode Network' (atrophied in Alzheimer's disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer's disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer's disease) and the Default Mode Network (disrupted in Alzheimer's disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer's disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer's disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic connectivity enhancement within the reciprocal network. In behavioural variant frontotemporal dementia, clinical severity correlated with loss of right frontoinsular Salience Network connectivity and with biparietal Default Mode Network connectivity enhancement. Based on these results, we explored whether a combined index of Salience Network and Default Mode Network connectivity might discriminate between the three groups. Linear discriminant analysis achieved 92% clinical classification accuracy, including 100% separation of behavioural variant frontotemporal dementia and Alzheimer's disease. Patients whose clinical diagnoses were supported by molecular imaging, genetics, or pathology showed 100% separation using this method, including four diagnostically equivocal 'test' patients not used to train the algorithm. Overall, the findings suggest that behavioural variant frontotemporal dementia and Alzheimer's disease lead to divergent network connectivity patterns, consistent with known reciprocal network interactions and the strength and deficit profiles of the two disorders. Further developed, intrinsic connectivity network signatures may provide simple, inexpensive, and non-invasive biomarkers for dementia differential diagnosis and disease monitoring.

SUBMITTER: Zhou J

PROVIDER: S-EPMC2912696 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease.

Zhou Juan J Greicius Michael D MD Gennatas Efstathios D ED Growdon Matthew E ME Jang Jung Y JY Rabinovici Gil D GD Kramer Joel H JH Weiner Michael M Miller Bruce L BL Seeley William W WW

Brain : a journal of neurology 20100421 Pt 5

Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer's disease cause atrophy within two major networks, an anterior 'Salience Network' (atrophied in behavioural variant frontotemporal dementia) and a posterior 'Default Mode Network' (atrophied in Alzheimer's disease). These networks exhibit an anti ...[more]

PMID: 20410145

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Project description:BackgroundAlzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social-emotional functional deficits.MethodsIn total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled.ResultsOur results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes.ConclusionsOur findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

Project description:Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

Project description:ObjectivesThis study explored group-wise quantitative measures of tract-specific white matter (WM) microstructure and functional default mode network (DMN) connectivity to establish an initial indication of their clinical applicability for early-stage and follow-up differential diagnosis of Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD).MethodsEleven AD and 12 bvFTD early-stage patients and 18 controls underwent diffusion tensor imaging and resting state functional magnetic resonance imaging at 3 T. All AD and 6 bvFTD patients underwent the same protocol at 1-year follow-up. Functional connectivity measures of DMN and WM tract-specific diffusivity measures were determined for all groups. Exploratory analyses were performed to compare all measures between the three groups at baseline and between patients at follow-up. Additionally, the difference between baseline and follow-up diffusivity measures in AD and bvFTD patients was compared.ResultsFunctional connectivity of the DMN was not different between groups at baseline and at follow-up. Diffusion abnormalities were observed widely in bvFTD and regionally in the hippocampal cingulum in AD. The extent of the differences between bvFTD and AD was diminished at follow-up, yet abnormalities were still more pronounced in bvFTD. The rate of change was similar in bvFTD and AD.ConclusionsThis study provides a tentative indication that quantitative tract-specific microstructural WM abnormalities, but not quantitative functional connectivity of the DMN, may aid early-stage and follow-up differential diagnosis of bvFTD and AD. Specifically, pronounced microstructural changes in anterior WM tracts may characterise bvFTD, whereas microstructural abnormalities of the hippocampal cingulum may characterise AD.Key points• The clinical applicability of quantitative brain imaging measures for early-stage and follow-up differential diagnosis of dementia subtypes was explored using a group-wise approach. • Quantitative tract-specific microstructural white matter abnormalities, but not quantitative functional connectivity of the default mode network, may aid early-stage and follow-up differential diagnosis of behavioural variant frontotemporal dementia and Alzheimer's disease. • Pronounced microstructural white matter (WM) changes in anterior WM tracts characterise behavioural variant frontotemporal dementia, whereas microstructural WM abnormalities of the hippocampal cingulum in the absence of other WM changes characterise Alzheimer's disease.

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Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease.

Publications

Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease.

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