Tract-specific white matter hyperintensities disrupt neural network function in Alzheimer's disease.
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ABSTRACT: Introduction
White matter hyperintensities (WMHs) increase the risk of Alzheimer's disease (AD). Whether WMHs are associated with the decline of functional neural networks in AD is debated.Method
Resting-state functional magnetic resonance imaging and WMH were assessed in 78 subjects with increased amyloid levels on AV-45 positron emission tomography (PET) in different clinical stages of AD. We tested the association between WMH volume in major atlas-based fiber tract regions of interest (ROIs) and changes in functional connectivity (FC) between the tracts' projection areas within the default mode network (DMN).Results
WMH volume within the inferior fronto-occipital fasciculus (IFOF) was the highest among all tract ROIs and associated with reduced FC in IFOF-connected DMN areas, independently of global AV-45 PET. Higher AV-45 PET contributed to reduced FC in IFOF-connected, temporal, and parietal DMN areas.Conclusions
High fiber tract WMH burden is associated with reduced FC in connected areas, thus adding to the effects of amyloid pathology on neuronal network function.
SUBMITTER: Taylor ANW
PROVIDER: S-EPMC5319922 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
Publications
Tract-specific white matter hyperintensities disrupt neural network function in Alzheimer's disease.
Taylor Alexander N W ANW Kambeitz-Ilankovic Lana L Gesierich Benno B Simon-Vermot Lee L Franzmeier Nicolai N Araque Caballero Miguel Á MÁ Müller Sophia S Hesheng Liu L Ertl-Wagner Birgit B Bürger Katharina K Weiner Michael W MW Dichgans Martin M Duering Marco M Ewers Michael M
Alzheimer's & dementia : the journal of the Alzheimer's Association 20160716 3
<h4>Introduction</h4>White matter hyperintensities (WMHs) increase the risk of Alzheimer's disease (AD). Whether WMHs are associated with the decline of functional neural networks in AD is debated.<h4>Method</h4>Resting-state functional magnetic resonance imaging and WMH were assessed in 78 subjects with increased amyloid levels on AV-45 positron emission tomography (PET) in different clinical stages of AD. We tested the association between WMH volume in major atlas-based fiber tract regions of ...[more]
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Project description:IntroductionGreater white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) are seen with transactive response DNA-binding protein 43 (TDP-43) pathology in frontotemporal lobar degeneration (FTLD-TDP). WMH associations with TDP-43 pathology in Alzheimer's disease (AD-TDP) remain unclear.MethodsA total of 157 participants from Mayo Clinic Rochester with autopsy-confirmed AD, known TDP-43 status, and antemortem fluid-attenuated inversion recovery (FLAIR) MRI were included. Vascular risk factors were assessed. A semi-automated WMH segmentation-quantification process produced total and regional WMH volumes. Penalized linear regression models adjusting for age at MRI analyzed TDP-43 associations (status and typing) with WMHs.ResultsTDP-43-positive status was not associated with WMH burden overall because opposite effects were seen based on AD-TDP typing. Despite similar antemortem vascular risk factors and postmortem vascular pathologies, AD-TDP type-α showed greater total and regional WMH burden (particularly in subcortical frontotemporal and basal ganglia regions) than TDP-43 negatives and AD-TDP type-β.DiscussionAD-TDP types may have different WMH pathomechanisms, with type-α having associations more like FTLD-TDP than AD.HighlightsIn transactive response DNA-binding protein 43 (TDP-43) pathology in Alzheimer's disease (AD-TDP), TDP-43 status alone is not associated with total or regional WMH burden AD-TDP type-α shows greater total, frontotemporal subcortical, and basal ganglia white matter hyperintensities (WMHs) AD-TDP type-β shows less total and subcortical occipital WMHs AD-TDP type-α effect on WMH burden closely mimics the effects of frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) rather than AD Different relationships of AD-TDP types with WMHs suggest different pathomechanisms.
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Project description:ObjectiveWhite matter hyperintensities (WMH) are the most common neuroimaging manifestation of cerebral small vessel disease, and is frequently observed in Alzheimer's disease (AD). This study aimed to investigate the relationship between WMH and cognition and to verify the mediation of grey matter atrophy in this relationship.MethodsThe diffusion tensor imaging (DTI) technique analyses white matter fiber tract to assess white matter integrity. Voxel-based morphometry was applied to measure the grey matter volume (GMV). A linear regression model was applied to examine the associations between WMH and GMV, and mediation analyses was performed to determine the mediating role of regional GMV in the effect of WMH on cognitive function.ResultsCompared to the HC group, AD group have 8 fiber tract fractional anisotropy (FA) decreased and 16 fiber tract mean diffusivity (MD) increased. Compared to AD without WMH, AD with high WMH had 9 fiber tracts FA decreased and 13 fiber tracts MD increased. High WMH volume was negatively correlated with GMV in the frontal-parietal region. Low WMH volume was also negatively correlated with GMV except for the three regions (right angular gyrus, right superior frontal gyrus and right middle/inferior parietal gyrus), where GMV was positively correlated. Mediation analysis showed that the association between WMH and executive function or episodic memory were mediated by GMV in the frontal-parietal region.ConclusionDamage to white matter integrity was more severe in AD with WMH. Differential changes in DTI metrics may be caused by progressive myelin and axonal damage. There was a negative correlation between WMH and grey matter atrophy in frontal-parietal regions in a volume-dependent manner. This study indicates the correspondence between WMH volume and GMV in cognition, and GMV being a key modulator between WMH and cognition in AD. This result will contribute to understanding the progression of the disease process and applying targeted therapeutic intervention in the earlier stage to delay neurodegenerative changes in frontal-parietal regions to achieve better treatment outcomes and affordability.
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Project description:White matter (WM) tracts shape the brain's dynamical activity and their damage (e.g., white matter hyperintensities, WMH) yields relevant functional alterations, ultimately leading to cognitive symptoms. The mechanisms linking the structural damage caused by WMH to the arising alterations of brain dynamics is currently unknown. To estimate the impact of WMH on brain dynamics, we combine neural-mass whole-brain modeling with a virtual-lesioning (disconnectome) approach informed by empirical data. We account for the heterogeneous effects of WMH either on inter-regional communication (i.e., edges) or on dynamics (i.e., nodes) and create models of their local versus global, and edge versus nodal effects using a large fMRI dataset comprising 188 non-demented individuals (120 cognitively normal, 68 with mild cognitive impairment) with varying degrees of WMH. We show that, although WMH mainly determine local damage to specific WM tracts, these lesions yield relevant global dynamical effects by reducing the overall synchronization of the brain through a reduction of global coupling. Alterations of local nodal dynamics through disconnections are less relevant and present only at later stages of WMH damage. Exploratory analyses suggest that education might play a beneficial role in counteracting the reduction in global coupling associated with WMH. This study provides generative models linking the structural damage caused by WMH to alterations in brain dynamics. These models might be used to evaluate the detrimental effects of WMH on brain dynamics in a subject-specific manner. Furthermore, it validates the use of whole-brain modeling for hypothesis-testing of structure-function relationships in diseased states characterized by empirical disconnections.
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Project description:ObjectiveWhite matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD.MethodsThe study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO.ResultsMutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset.InterpretationAutosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939.
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