Differential Functional Connectivity Correlates of Cerebrospinal Fluid Biomarkers in Dementia of the Alzheimer's Type

Malpas, Charles B; Saling, Michael M.; Velakoulis, Dennis; Desmond, Patricia; O’Brien, Terence J.

doi:10.1159/000438924

Cited by 12 publications

(7 citation statements)

References 23 publications

(24 reference statements)

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“…This finding is congruent with previous studies describing that CSF p- Tau levels are negatively correlated with functional connectivity in the medial temporal lobe, such as the entorhinal cortex [25]. Moreover, Aβ pathology distribution was related to areas in which there was a significant increase of functional connectivity.…”

Section: Discussionsupporting

confidence: 91%

Tau and amyloid β proteins distinctively associate to functional network changes in the aging brain

Sepulcre

Sabuncu

et al. 2017

Alzheimer's & Dementia

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INTRODUCTION Misfolded Tau and amyloid-β (Aβ) proteins progressively accumulate in the brain, causing decreased and increased neuronal function and neurodegeneration. This study sought to investigate whether the wide spectrum of functional reorganization in aging brains of cognitively normal individuals relates to specific pathological patterns of Tau and Aβ deposits. METHODS We used functional connectivity neuroimaging and in vivo Tau and Aβ positron emission tomography (PET) scans to study cortical spatial relationships between imaging modalities. RESULTS We found that a negative association between Tau and functional connectivity combined with a positive association between Aβ and functional connectivity is the most frequent cortical pattern among elderly subjects. Moreover, we found specific brain areas that interrelate hypo- and hyper-connectivity regions. DISCUSSION Our findings have critical implications to understanding how the two main elements of AD-related pathology affect the aging brain and how they cause alterations in large-scale neuronal circuits.

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Section: Discussionsupporting

confidence: 91%

Tau and amyloid β proteins distinctively associate to functional network changes in the aging brain

Sepulcre

Sabuncu

et al. 2017

Alzheimer's & Dementia

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“…Ethics approval was obtained from the institutional ethics committee (Melbourne Health, HREC 2012.148) and all patients gave written informed consent. We have reported resting-state fMRI findings from this cohort elsewhere [7].…”

Section: Participantsmentioning

confidence: 99%

“…The different anatomical distribution of tau-and amyloid-pathology raise the question of whether they preferentially relate to structurofunctional changes in the AD brain. We have previously hypothesised that tau-pathology is preferentially associated with changes in the mesial temporal regions, while amyloid pathology is preferentially associated with diffuse neocortical changes [6,7]. The aim of this study was to investigate this hypothesis using volumetric measurements obtained via structural magnetic resonance imaging and relative cerebral metabolism assessed with [ 18 F]-FDG-PET.…”

Section: Introductionmentioning

confidence: 98%

Cerebrospinal Fluid Biomarkers are Differentially Related to Structural and Functional Changes in Dementia of the Alzheimer’s Type

Malpas

Saling

Velakoulis

et al. 2018

JAD

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The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer's type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks.

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“…This study demonstrated the application of model-based clustering with variable selection in a high-dimensional structural neuroimaging dataset. In a large group of aged participants, two regions were found to discriminate between subgroups, namely Alzheimer's type (DAT) [28]. The significance of this region in AD is supported by evidence that in vivo measurement of entorhinal atrophy allows accurate identification of patients with DAT, and also accurately predicts the evolution of the clinical syndrome from MCI to DAT [29].…”

Section: Discussionmentioning

confidence: 96%

Structural neuroimaging correlates of cognitive status in older adults: A person-oriented approach

Malpas¹

2016

Journal of Clinical Neuroscience

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Person-oriented approaches to clinical research aim to uncover subgroups of patients with different patterns of clinically relevant variables. Such approaches, however, are not yet widely employed in clinical neuroimaging research. This paper demonstrates an accessible approach to person-oriented research using model-based clustering in high-dimensional structural neuroimaging data. Cortical thickness measurements for 369 older adults (182 women, 187 men) were obtained from the Alzheimer's Disease Neuroimaging Initiative. Model-based cluster analysis was performed on these imaging variables and then validated using variables that were not used in the clustering process. Variable selection identified two specific regions that contributed to cluster formation: the left and right entorhinal cortices. Two subgroups were uncovered: a "typical" cluster with higher entorhinal thickness (M = 3.59 mm, 95% confidence interval = 3.57, 3.62), and an "atypical" cluster with relatively lower thickness (M = 2.84 mm, 95% confidence interval = 2.75, 2.92). Members of the atypical cluster also had lower hippocampal volumes, memory scores, and executive function scores, and were also more likely to be clinically classified as cognitively impaired. These findings demonstrate the utility of model-based clustering of structural neuroimaging data in studies of ageing. The role of the entorhinal cortices in cluster formation is consistent with the known pathological substrate of Alzheimer's disease. The entorhinal cortices are implicated in the early genesis of the disease and atrophy of these regions is strongly associated with the cognitive phenotype. Overall, this approach can be readily applied to future neuroimaging investigations.

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Differential Functional Connectivity Correlates of Cerebrospinal Fluid Biomarkers in Dementia of the Alzheimer's Type

Cited by 12 publications

References 23 publications

Tau and amyloid β proteins distinctively associate to functional network changes in the aging brain

Tau and amyloid β proteins distinctively associate to functional network changes in the aging brain

Cerebrospinal Fluid Biomarkers are Differentially Related to Structural and Functional Changes in Dementia of the Alzheimer’s Type

Structural neuroimaging correlates of cognitive status in older adults: A person-oriented approach

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