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Region of interest placement for each white matter tract. Within ExploreDTI the blue lines indicate a 'seed/or' gate, the green line an 'and' gate, red lines indicate 'not' gates. Tracts are shown for the left hemisphere in a template subject. A) fornix, B) parahippocampal cingulum, C) retrosplenial cingulum, D) subgenual cingulum, and E) uncinate fasciculus. https://doi.org/10.1371/journal.pone.0222977.g001
Source publication
Introduction
The earliest changes in the brain due to Alzheimer’s disease are associated with the neural networks related to memory function. We investigated changes in functional and structural connectivity among regions that support memory function in prodromal Alzheimer’s disease, i.e., during the mild cognitive impairment (MCI) stage.
Methods...
Contexts in source publication
Context 1
... whole-brain tractography, the different tracts were extracted by manually drawing several regions of interest (ROIs) defined according to published methods for the fornix [73,74], the subgenual and retrosplenial branches of the cingulum [75], the parahippocampal branch of the cingulum [76], and the uncinate fasciculus [73]. See Fig 1 for further details on the placement of the ROIs. ...
Context 2
... in this group it would both reduce sample size as one participant declined to complete the GDS and risk over-fitting the model. In any case, in this cohort depression did not correlate with worsening measures of cognition (see Fig B in S1 File). FDR-corrections were performed within each class of measures. ...
Context 3
... the current sample global white and grey matter atrophy are present in the MCI group-(see Table K and Fig K in S1 File). However, while both the white matter and the connectivity strength analyses reveal insults to the system, no relationship between the different types of damage was apparent. ...
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The thalamus has complex connections with the cortex and is involved in various cognitive processes. Despite increasing interest in the thalamus and the underlying thalamo-cortical interaction, little is known about thalamo-cortical connections after paediatric arterial ischaemic stroke. Therefore, the aim of this study was to investigate thalamo-c...
Citations
... Surprisingly, we can find studies describing significant relationships between sFC and DTI measures, [64][65][66] and at the same time alternative sFC-based investigations that do not find a relationship between these two markers. [67][68][69] Based on a relatively large sample, the correlations found in this study between dFC and white matter degradation in the pre-dementia phase of the AD continuum contrast with those reported using sFC and motivate further investigation to unveil the potential sensitivity of dFC to early structural changes in the brain. ...
Alzheimer’s disease (AD) represents a major challenge in neurodegenerative disease research, as it is characterized by a complex pathophysiology that involves not only structural but also functional changes in the brain. While changes in static functional connectivity have already been linked to AD, there is still a lack of research studying dynamic functional connectivity (dFC) across the AD continuum, which could be crucial for identifying potential biomarkers for early diagnosis and tracking disease progression. This study leverages the high temporal resolution of MEG to dissect the dynamics of brain connectivity alterations across various stages of AD and their association with cognitive decline and structural brain changes.
321 participants were included in this study, categorized into healthy control, subjective cognitive decline (SCD), and mild cognitive impairment (MCI) groups. Amplitude envelope correlation with leakage correction was calculated over MEG signals using a sliding window, and the correlation across epochs was studied to assess dFC at whole-brain and node level. Finally, we explored dFC associations with cognitive scores, grey matter volume, and white matter fractal anisotropy.
The study unveils a significant reduction in whole-brain dFC, especially within the alpha and beta frequency bands, as individuals advance along the AD continuum. Notably, the frontal and temporal lobes, as well as regions within the default mode network, exhibited pronounced dFC reductions. Finally, these reduced dFC significantly correlated with cognitive performance and changes in structural brain, suggesting the potential of the proposed dFC metric as sensitive indicator for monitoring disease progression.
This investigation provides crucial insights into the temporal dynamics of brain connectivity alterations in the early stages of the AD spectrum, underlining the importance of dFC changes as reflective of cognitive and anatomical degeneration. The findings hint towards a strong relationship between connectivity profiles and white matter integrity, especially for high frequency activity in the association cortices.
Key Points
Dynamic functional connectivity declines over the AD spectrum.
Dynamic functional connectivity reductions are most prominent in orbitofrontal, temporal, and DMN-related areas.
Cognitive performance, brain volumetrics, and white matter integrity parameters positively correlate with dynamic functional connectivity over the whole AD spectrum, and most significantly among mild cognitive impairment participants.
... When investigating brain network alterations in MCI, studies report DMN abnormalities similar to those found in dementia patients, but to a lesser extentthat is, with integrity values that fall between those of dementia patients and healthy elderly controls [10]. MCI patients have also been found to show lower FC between hippocampi and posterior cingulate cortex (PCC) compared to healthy elderly controls [15], decreased whole-brain connectivity in PCC and precuneus [16], reduced connectivity between DMN nodes and between regions of the cortico-striatal-thalamic loop [17] and decreases in FC within the DMN and between the hippocampus and the DMN [18]. ...
... Regarding WM structure, a meta-analysis reported reliable abnormalities in WM integrity in MCI patients in the fornix, uncinate fasciculus and parahippocampal cingulum [19], further confirmed by later studies [2,18]. ...
Background:
Malfunctioning of the default mode network (DMN) has been consistently related to mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, evidence on differences in this network between MCI converters (MCI-c) and non-converters (MCI-nc), which could mark progression to AD, is still inconsistent.
Objective:
To multimodally investigate the DMN in the AD continuum.
Methods:
We measured gray matter (GM) volume, white matter (WM) integrity, and functional connectivity (FC) at rest in healthy elderly controls, MCI-c, MCI-nc, and AD patients, matched on sociodemographic variables.
Results:
Significant differences between AD patients and controls were found in the structure of most of the regions of the DMN. MCI-c only differed from MCI-nc in GM volume of the left parahippocampus and bilateral hippocampi and middle frontal gyri, as well as in WM integrity of the parahippocampal cingulum connecting the left hippocampus and precuneus. We found significant correlations between integrity in some of those regions and global neuropsychological status, as well as an excellent discrimination ability between converters and non-converters for the sum of GM volume of left parahippocampus, bilateral hippocampi, and middle frontal gyri, and WM integrity of left parahippocampal cingulum. However, we found no significant differences in FC.
Conclusion:
These results further support the relationship between abnormalities in the DMN and AD, and suggest that structural measures could be more accurate than resting-state estimates as markers of conversion from MCI to AD.
... For MCI classification (eMCI vs. NC and lMCI vs. NC), we can observe that frontal lobe, Cingulum, Postcentral, Fusiform and inferior temporal gyrus are the most discriminative brain regions. Previous research has shown that abnormal changes in these brain regions accelerates the conversion of people with mild cognitive impairment to Alzheimer's disease (25)(26)(27)(28)(29)(30). Similarly, for AD classification, the regions of the posterior cingulate gyrus, postcentral gyrus, c, hippocampus, middle temporal gyrus, and inferior temporal gyrus are the most discriminative brain areas, which have been previously documented to be involved in AD (31-34). ...
Introduction
The analysis of functional brain networks (FBNs) has become a promising and powerful tool for auxiliary diagnosis of brain diseases, such as Alzheimer’s disease (AD) and its prodromal stage. Previous studies usually estimate FBNs using full band Blood Oxygen Level Dependent (BOLD) signal. However, a single band is not sufficient to capture the diagnostic and prognostic information contained in multiple frequency bands.
Method
To address this issue, we propose a novel multi-band network fusion framework (MBNF) to combine the various information (e.g., the diversification of structural features) of multi-band FBNs. We first decompose the BOLD signal adaptively into two frequency bands named high-frequency band and low-frequency band by the ensemble empirical mode decomposition (EEMD). Then the similarity network fusion (SNF) is performed to blend two networks constructed by two frequency bands together into a multi-band fusion network. In addition, we extract the features of the fused network towards a better classification performance.
Result
To verify the validity of the scheme, we conduct our MBNF method on the public ADNI database for identifying subjects with AD/MCI from normal controls.
Discussion
Experimental results demonstrate that the proposed scheme extracts rich multi-band network features and biomarker information, and also achieves better classification accuracy.
... 60 subjects (29 participants between 18 and 29 years old, and 31 participants over 65 years old) were scanned with the protocols approved by the St. James Hospital and the Adelaide and Meath Hospital, incorporating the National Children Hospital Research Ethics Committee. All participants were adults recruited for a larger study [37][38][39] and came from the greater Dublin area. All participants underwent the Cambridge Neuropsychological Test Automated Battery (CANTAB; [40]) which has been used to detect changes in neuropsychological performance and include tests of working memory, learning and executive function; visual, verbal and episodic memory; attention, information processing and reaction time; social and emotion recognition, decision making and response control. ...
Unlabelled:
Getting older affects both the structure of the brain and some cognitive capabilities. Until now, magnetic resonance imaging (MRI) approaches have been unable to give a coherent reflection of the cognitive declines. It shows the limitation of the contrast mechanisms used in most MRI investigations, which are indirect measures of brain activities depending on multiple physiological and cognitive variables. However, MRI signals may contain information of brain activity beyond these commonly used signals caused by the neurovascular response. Here, we apply a zero-spin echo (ZSE) weighted MRI sequence, which can detect heartbeat-evoked signals (HES). Remarkably, these MRI signals have properties only known from electrophysiology. We investigated the complexity of the HES arising from this sequence in two age groups; young (18-29 years) and old (over 65 years). While comparing young and old participants, we show that the complexity of the HES decreases with age, where the stability and chaoticity of these HES are particularly sensitive to age. However, we also found individual differences which were independent of age. Complexity measures were related to scores from different cognitive batteries and showed that higher complexity may be related to better cognitive performance. These findings underpin the affinity of the HES to electrophysiological signals. The profound sensitivity of these changes in complexity shows the potential of HES for understanding brain dynamics that need to be tested in more extensive and diverse populations with clinical relevance for all neurovascular diseases.
Supplementary information:
The online version contains supplementary material available at 10.1140/epjs/s11734-022-00696-2.
... The study by Yao and collaborators [27] determined the metrics of graphs comparing individuals with MCI and control individuals, showing no significant difference in clustering coefficient and characteristic path length, but there was a decrease in degree. Other studies [34,35] have shown that the functional connectivity of DMN in MCI and AD individuals suffer a rupture in connectivity by decreasing the clustering coefficient and increasing local efficiency and the characteristic path length. Our results showed a decrease in DMN in local efficiency and clustering coefficient in the CN-MCI group. ...
Resting-State functional magnetic resonance imaging (rs-fMRI) provides the assessment of some brain functions without tasks. Through rs-fMRI, it is possible to discover that the brain is organized in spatially distributed and interconnected brain regions. Studies suggest that aging and certain neurological or neuropsychiatric diseases affect brain connectivity, such as Alzheimer’s disease (AD) and mild cognitive impairment (MCI). The general objective of this work is to investigate the evolution of the brain connectivity of individuals with healthy aging who convert to MCI and individuals with MCI who convert to AD, using rs-fMRI and analysis based on graph theory (GT). The processing was implemented in SPM12-MATLAB, and the analysis was performed in the CONN Toolbox. The GT metrics chosen to describe the main topological characteristics of the networks were: characteristic path length, global efficiency, local efficiency, clustering coefficient, and degree. Two main findings emerged from this study. When using GT metrics and analyzing healthy subjects converting to MCI, it was possible to observe a decrease in all GT metrics. Second, changes in GT metrics indicated a rupture in the functional connectivity when the cognitive decline occurs from healthy aging to MCI and from MCI to AD.KeywordsBrain connectivityGraph theoryADMCI
... Interestingly, plasma P-tau181 was found to be correlated with microstructural changes in the left hippocampal cingulum in our study, highlighting the role of the cingulum in the pathological progression of the disease (Gilligan et al. 2019). The cingulum bundle links the frontal, parietal, and medial temporal lobes, connecting the subcortical nucleus to the cingulate gyrus and extending into the hippocampal and parahippocampal regions. ...
Alzheimer’s Disease (AD) is characterized by cognitive impairments that hinder daily activities and lead to personal and behavioral problems. Plasma hyperphosphorylated tau protein at threonine 181 (p-tau181) has recently emerged as a new sensitive tool for the diagnosis of AD patients. We herein investigated the association of plasma P-tau181 and white matter (WM) microstructural changes in AD. We obtained data from a large prospective cohort of elderly individuals participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which included baseline measurements of plasma P-tau181 and imaging findings. A subset of 41 patients with AD, 119 patients with mild cognitive impairments (MCI), and 43 healthy controls (HC) was included in the study, all of whom had baseline blood P-tau181 levels and had also undergone Diffusion Tensor Imaging. The analysis revealed that the plasma level of P-tau181 has a positive correlation with changes in Mean Diffusivity (MD), Radial Diffusivity (RD), and Axial Diffusivity (AxD), but a negative with Fractional Anisotropy (FA) parameters in WM regions of all participants. There is also a significant association between WM microstructural changes in different regions and P-tau181 plasma measurements within each MCI, HC, and AD group. In conclusion, our findings clarified that plasma P-tau181 levels are associated with changes in WM integrity in AD. P-tau181 could improve the accuracy of diagnostic procedures and support the application of blood-based biomarkers to diagnose WM neurodegeneration. Longitudinal clinical studies are also needed to demonstrate the efficacy of the P-tau181 biomarker and predict its role in structural changes.
... Previous studies had demonstrated that the volume of ber tract of thalamus can effectively distinguish between mild cognitive impairment (MCI) and healthy control [15] and white matter integrity in right thalamus was decreased in both MCI [16] and AD [17].Meanwhile, restingstate functional magnetic resonance imaging (rs-fMRI) analysis enable us to further understand the mechanism of functional connectivity during rTMS intervention. Functional connectivity in thalamus was reduced [18] and the connection between default mode network and thalamus was signi cant changed in MCI [19]. ...
Background: Stimulating superficial brain regions highly associated with the hippocampus by repetitive transcranial magnetic stimulation (rTMS) may improve memory of Alzheimer disease (AD) spectrum patients.
Methods: We recruited 26 mild cognitive impairment (MCI) and AD patients. All the patients were stimulated to the left angular gyrus, which was confirmed a strong link to the hippocampus through neuroimaging studies, by the neuro-navigated rTMS for four weeks. Automated fiber quantification (AFQ) using diffusion tensor imaging (DTI) metrics and graph theory analysis on functional network were employed to detect the neuroplasticity of brain networks.
Results: After neuro-navigated rTMS intervention, the episodic memory and language function of patients were significantly improved. Increased white matter integrity of right anterior thalamic radiation among MCI patients, while decreased functional network properties of thalamus subregions were observed. It is worth noting that the improvement of cognition was associated with the neuroplasticity of thalamic system
Conclusions: We speculated that the rTMS intervention targeting left angular gyrus may be served as a strategy to improve cognitive impairment in AD spectrum patients, supporting by the neuroplasticity of thalamic system, especially in the early disease process at the stage of MCI.
... Interestingly, plasma P-tau181 was found to be correlated with microstructural changes in the left hippocampal cingulum in our study, highlighting the role of the cingulum in the pathological progression of the disease (57). The cingulum bundle links the frontal, parietal, and medial temporal lobes, connecting the subcortical nucleus to the cingulate gyrus and extending into the hippocampal and parahippocampal regions. ...
Alzheimer’s Disease (AD) is characterized by cognitive impairments and memory difficulties that hinder daily activities and lead to personal and behavioral problems. Plasma hyperphosphorylated tau protein at threonine 181 (p-tau181), a blood-based biomarker, has recently emerged as a new tool with sufficient sensitivity for distinguishing AD patients from healthy people. We herein investigated the association of plasma P-tau181 and white matter (WM) microstructural changes in AD. We examined data from a large prospective cohort of elderly individuals participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) which covers a wide clinical spectrum from normal cognition to AD dementia with measurements of plasma P-tau181 and imaging findings at baseline. A subset of 41 patients with AD, 119 patients with mild cognitive impairments (MCI), and 43 healthy controls (HC) were included in the study, all of whom had baseline blood P-tau181 levels and had also undergone Diffusion Tensor Imaging (DTI). The analysis revealed that the plasma level of P-tau181 have positive correlation with changes in Mean Diffusivity (MD), Radial Diffusivity (RD), and Axial Diffusivity (AxD), but a negative with Fractional Anisotropy (FA) parameters in WM regions of all participants. There is also a significant association between WM microstructural changes in different regions and P-tau181 plasma measurements within each MCI, HC and AD group. In conclusion, our findings clarified that plasma P-tau181 levels are associated with changes in WM integrity in AD. P-tau181 could improve the accuracy of diagnostic procedures and support the application of blood-based biomarkers to diagnose WM neurodegeneration. Longitudinal clinical studies are also needed to demonstrate the efficacy of the P-tau181 biomarker and predict its role in structural changes.
Background:
Stimulating superficial brain regions highly associated with the hippocampus by repetitive transcranial magnetic stimulation (rTMS) may improve memory of Alzheimer's disease (AD) spectrum patients.
Objective:
We recruited 16 amnesic mild cognitive impairment (aMCI) and 6 AD patients in the study. All the patients were stimulated to the left angular gyrus, which was confirmed a strong link to the hippocampus through neuroimaging studies, by the neuro-navigated rTMS for four weeks.
Methods:
Automated fiber quantification using diffusion tensor imaging metrics and graph theory analysis on functional network were employed to detect the neuroplasticity of brain networks.
Results:
After neuro-navigated rTMS intervention, the episodic memory of aMCI patients and Montreal Cognitive Assessment score of two groups were significantly improved. Increased FA values of right anterior thalamic radiation among aMCI patients, while decreased functional network properties of thalamus subregions were observed, whereas similar changes not found in AD patients. It is worth noting that the improvement of cognition was associated with the neuroplasticity of thalamic system.
Conclusion:
We speculated that the rTMS intervention targeting left angular gyrus may be served as a strategy to improve cognitive impairment at the early stage of AD patients, supporting by the neuroplasticity of thalamic system.
Background:
The fornix is the primary axonal tract of the hippocampus, connecting it to modulatory subcortical structures. This review reveals that fornix damage causes cognitive deficits that closely mirror those resulting from hippocampal lesions.
Methods:
We reviewed the literature on the fornix, spanning non-human animal lesion research, clinical case studies of human patients with fornix damage, as well as diffusion-weighted imaging (DWI) work that evaluates fornix microstructure in vivo.
Results:
The fornix is essential for memory formation because it serves as the conduit for theta rhythms and acetylcholine, as well as providing mnemonic representations to deep brain structures that guide motivated behavior, such as when and where to eat. In rodents and non-human primates, fornix lesions lead to deficits in conditioning, reversal learning, and navigation. In humans, damage to the fornix manifests as anterograde amnesia. DWI research reveals that the fornix plays a key role in mild cognitive impairment and Alzheimer's Disease, and can potentially predict conversion from the former to the latter. Emerging DWI findings link perturbations in this structure to schizophrenia, mood disorders, and eating disorders. Cutting-edge research has investigated how deep brain stimulation of the fornix can potentially attenuate memory loss, control epileptic seizures, and even improve mood.
Conclusions:
The fornix is essential to a fully functioning memory system and is implicated in nearly all neurological functions that rely on the hippocampus. Future research needs to use optimized DWI methods to study the fornix in vivo, which we discuss, given the difficult nature of fornix reconstruction. Impact Statement The fornix is a white matter tract that connects the hippocampus to several subcortical brain regions and is pivotal for episodic memory functioning. Functionally, the fornix transmits essential neurotransmitters, as well as theta rhythms, to the hippocampus. In addition, it is the conduit by which memories guide decisions. The fornix is biomedically important because lesions to this tract result in irreversible anterograde amnesia. Research using in vivo imaging methods has linked fornix pathology to cognitive aging, mild cognitive impairment, psychosis, epilepsy, and, importantly, Alzheimer's Disease.
