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- Mijalkov, M., et al.
(författare)
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Directed Functional Brain Connectivity is Altered in Sub-threshold Amyloid-beta Accumulation in Cognitively Normal Individuals
- 2023
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Ingår i: Neuroscience Insights. - : SAGE Publications. - 2633-1055. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have shown that amyloid-beta (A beta) deposition below the clinically relevant cut-off levels is associated with subtle changes in cognitive function and increases the risk of developing future Alzheimer's disease (AD). Although functional MRI is sensitive to early alterations occurring during AD, sub-threshold changes in A beta levels have not been linked to functional connectivity measures. This study aimed to apply directed functional connectivity to identify early changes in network function in cognitively unimpaired participants who, at baseline, exhibit A beta accumulation below the clinically relevant threshold. To this end, we analyzed baseline functional MRI data from 113 cognitively unimpaired participants of the Alzheimer's Disease Neuroimaging Initiative cohort who underwent at least one 18F-florbetapir-PET after the baseline scan. Using the longitudinal PET data, we classified these participants as A beta negative (A beta-) non-accumulators (n = 46) and A beta- accumulators (n = 31). We also included 36 individuals who were amyloid-positive (A beta+) at baseline and continued to accumulate A beta (A beta+ accumulators). For each participant, we calculated whole-brain directed functional connectivity networks using our own anti-symmetric correlation method and evaluated their global and nodal properties using measures of network segregation (clustering coefficient) and integration (global efficiency). When compared to A beta- non-accumulators, the A beta- accumulators showed lower global clustering coefficient. Moreover, the A beta+ accumulator group exhibited reduced global efficiency and clustering coefficient, which at the nodal level mainly affected the superior frontal gyrus, anterior cingulate cortex, and caudate nucleus. In A beta- accumulators, global measures were associated with lower baseline regional PET uptake values, as well as higher scores on the Modified Preclinical Alzheimer Cognitive Composite. Our findings indicate that directed connectivity network properties are sensitive to subtle changes occurring in individuals who have not yet reached the threshold for A beta positivity, which makes them a potentially viable marker to detect negative downstream effects of very early A beta pathology.
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- Mijalkov, M., et al.
(författare)
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Nonlinear changes in delayed functional network topology in Alzheimer's disease: relationship with amyloid and tau pathology
- 2023
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Ingår i: Alzheimers Research & Therapy. - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlzheimer's disease is a neurodegenerative disorder associated with the abnormal deposition of pathological processes, such as amyloid-ss and tau, which produces nonlinear changes in the functional connectivity patterns between different brain regions across the Alzheimer's disease continuum. However, the mechanisms underlying these nonlinear changes remain largely unknown. Here, we address this question using a novel method based on temporal or delayed correlations and calculate new whole-brain functional networks to tackle these mechanisms.MethodsTo assess our method, we evaluated 166 individuals from the ADNI database, including amyloid-beta negative and positive cognitively normal subjects, patients with mild cognitive impairment, and patients with Alzheimer's disease dementia. We used the clustering coefficient and the global efficiency to measure the functional network topology and assessed their relationship with amyloid and tau pathology measured by positron emission tomography, as well as cognitive performance using tests measuring memory, executive function, attention, and global cognition.ResultsOur study found nonlinear changes in the global efficiency, but not in the clustering coefficient, showing that the nonlinear changes in functional connectivity are due to an altered ability of brain regions to communicate with each other through direct paths. These changes in global efficiency were most prominent in early disease stages. However, later stages of Alzheimer's disease were associated with widespread network disruptions characterized by changes in both network measures. The temporal delays required for the detection of these changes varied across the Alzheimer's disease continuum, with shorter delays necessary to detect changes in early stages and longer delays necessary to detect changes in late stages. Both global efficiency and clustering coefficient showed quadratic associations with pathological amyloid and tau burden as well as cognitive decline.ConclusionsThis study suggests that global efficiency is a more sensitive indicator of network changes in Alzheimer's disease when compared to clustering coefficient. Both network properties were associated with pathology and cognitive performance, demonstrating their relevance in clinical settings. Our findings provide an insight into the mechanisms underlying nonlinear changes in functional network organization in Alzheimer's disease, suggesting that it is the lack of direct connections that drives these functional changes.
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- Vereb, D., et al.
(författare)
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Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions
- 2023
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Ingår i: eLife. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because of its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown that the LC has heterogeneous connections and cellular features, no studies have yet assessed its functional topography in vivo, how this heterogeneity changes over aging, and whether it is associated with cognition and mood. Here, we employ a gradient-based approach to characterize the functional heterogeneity in the organization of the LC over aging using 3T resting-state fMRI in a population-based cohort aged from 18 to 88 years of age (Cambridge Centre for Ageing and Neuroscience cohort, n=618). We show that the LC exhibits a rostro-caudal functional gradient along its longitudinal axis, which was replicated in an independent dataset (Human Connectome Project [HCP] 7T dataset, n=184). Although the main rostro-caudal direction of this gradient was consistent across age groups, its spatial features varied with increasing age, emotional memory, and emotion regulation. More specifically, a loss of rostral-like connectivity, more clustered functional topography, and greater asymmetry between right and left LC gradients was associated with higher age and worse behavioral performance. Furthermore, participants with higher-than-normal Hospital Anxiety and Depression Scale (HADS) ratings exhibited alterations in the gradient as well, which manifested in greater asymmetry. These results provide an in vivo account of how the functional topography of the LC changes over aging, and imply that spatial features of this organization are relevant markers of LC-related behavioral measures and psychopathology.
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- Veréb, D, et al.
(författare)
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Age-related differences in the functional topography of the locus coeruleus: implications for cognitive and affective functions
- 2023
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because of its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown that the LC has heterogeneous connections and cellular features, no studies have yet assessed its functional topography in vivo, how this heterogeneity changes over aging and whether it is associated with cognition and mood. Here we employ a gradient-based approach to characterize the functional heterogeneity in the organization of the LC over aging using 3T resting-state fMRI in a population-based cohort aged from 18 to 88 years old (Cambridge Centre for Ageing and Neuroscience cohort, n=618). We show that the LC exhibits a rostro-caudal functional gradient along its longitudinal axis, which was replicated in an independent dataset (Human Connectome Project 7T dataset, n=184). Although the main rostro-caudal direction of this gradient was consistent across age groups, its spatial features varied with increasing age, emotional memory and emotion regulation. More specifically, a loss of rostral-like connectivity, more clustered functional topography and greater asymmetry between right and left LC gradients was associated with higher age and worse behavioral performance. Furthermore, participants with higher-than-normal Hospital Anxiety and Depression Scale ratings exhibited alterations in the gradient as well, which manifested in greater asymmetry. These results provide an in vivo account of how the functional topography of the LC changes over aging, and imply that spatial features of this organization are relevant markers of LC-related behavioral measures and psychopathology.
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- Vereb, D, et al.
(författare)
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Functional Connectivity Lateralisation Shift of Resting State Networks is Linked to Visuospatial Memory and White Matter Microstructure in Relapsing-Remitting Multiple Sclerosis
- 2022
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Ingår i: Brain topography. - : Springer Science and Business Media LLC. - 1573-6792 .- 0896-0267. ; 35:2, s. 268-275
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Tidskriftsartikel (refereegranskat)abstract
- Laterality patterns of resting state networks (RSN) change in various neuropsychiatric conditions. Multiple sclerosis (MS) causes neuro-cognitive symptoms involving dysfunctional large-scale brain networks. Yet, whether healthy laterality patterns of RSNs are maintained in MS and whether altered laterality patterns explain disease symptoms has not been explicitly investigated. We analysed functional MRI and diffusion tensor imaging data from 24 relapsing–remitting MS patients and 25 healthy participants. We performed group-level independent component analysis and used dual regression to estimate individual versions of well-established RSNs. Voxelwise laterality indices were calculated for each RSN. Group differences were assessed via a general linear model-based approach. The relationship between functional laterality and white matter microstructural asymmetry was assessed using Tract-Based Spatial Statistics. Spearman’s correlation was calculated between laterality indices and Brief International Cognitive Assessment for Multiple Sclerosis scores. Functional laterality of the dorsal attention network showed a significant leftward shift in the MS group in the posterior intraparietal sulcus (p < 0.033). Default-mode network laterality showed a significant leftward shift in the MS group in the angular gyrus (p < 0.005). Diminished dorsal attention network laterality was associated with increased fractional anisotropy asymmetry in the superior longitudinal fasciculus (p < 0.02). In the default-mode network, leftward laterality of the angular gyrus was associated with higher BVMT-R scores (R = − 0.52, p < 0.023). Our results confirm previous descriptions of RSN dysfunction in relapsing–remitting MS and show that altered functional connectivity lateralisation patterns of RSNs might contibute to cognitive performance and structural remodellation even in patients with mild clinical symptoms.
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- Vereb, D., et al.
(författare)
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Functional gradients of the medial parietal cortex in a healthy cohort with family history of sporadic Alzheimer's disease
- 2023
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Ingår i: Alzheimers Research & Therapy. - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe medial parietal cortex is an early site of pathological protein deposition in Alzheimer's disease (AD). Previous studies have identified different subregions within this area; however, these subregions are often heterogeneous and disregard individual differences or subtle pathological alterations in the underlying functional architecture. To address this limitation, here we measured the continuous connectivity gradients of the medial parietal cortex and assessed their relationship with cerebrospinal fluid (CSF) biomarkers, ApoE epsilon 4 carriership and memory in asymptomatic individuals at risk to develop AD.MethodsTwo hundred sixty-three cognitively normal participants with a family history of sporadic AD who underwent resting-state and task-based functional MRI using encoding and retrieval tasks were included from the PREVENT-AD cohort. A novel method for characterizing spatially continuous patterns of functional connectivity was applied to estimate functional gradients in the medial parietal cortex during the resting-state and task-based conditions. This resulted in a set of nine parameters that described the appearance of the gradient across different spatial directions. We performed correlation analyses to assess whether these parameters were associated with CSF biomarkers of phosphorylated tau(181) (p-tau), total tau (t-tau), and amyloid-ss(1-42) (Ass). Then, we compared the spatial parameters between ApoE epsilon 4 carriers and noncarriers, and evaluated the relationship between these parameters and memory.ResultsAlterations involving the superior part of the medial parietal cortex, which was connected to regions of the default mode network, were associated with higher p-tau, t-tau levels as well as lower Ass/p-tau levels during the resting-state condition (p < 0.01). Similar alterations were found in ApoE epsilon 4 carriers compared to non-carriers (p < 0.003). In contrast, lower immediate memory scores were associated with changes in the middle part of the medial parietal cortex, which was connected to inferior temporal and posterior parietal regions, during the encoding task (p = 0.001). No results were found when using conventional connectivity measures.ConclusionsFunctional alterations in the medial parietal gradients are associated with CSF AD biomarkers, ApoE epsilon 4 carriership, and lower memory in an asymptomatic cohort with a family history of sporadic AD, suggesting that functional gradients are sensitive to subtle changes associated with early AD stages.
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