| 1. |
- de Flores, Robin, et al.
(författare)
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Characterization of hippocampal subfields using ex vivo MRI and histology data : Lessons for in vivo segmentation
- 2020
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 30:6, s. 545-564
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Tidskriftsartikel (refereegranskat)abstract
- Hippocampal subfield segmentation on in vivo MRI is of great interest for cognition, aging, and disease research. Extant subfield segmentation protocols have been based on neuroanatomical references, but these references often give limited information on anatomical variability. Moreover, there is generally a mismatch between the orientation of the histological sections and the often anisotropic coronal sections on in vivo MRI. To address these issues, we provide a detailed description of hippocampal anatomy using a postmortem dataset containing nine specimens of subjects with and without dementia, which underwent a 9.4 T MRI and histological processing. Postmortem MRI matched the typical orientation of in vivo images and segmentations were generated in MRI space, based on the registered annotated histological sections. We focus on the following topics: the order of appearance of subfields, the location of subfields relative to macroanatomical features, the location of subfields in the uncus and tail and the composition of the dark band, a hypointense layer visible in T2-weighted MRI. Our main findings are that: (a) there is a consistent order of appearance of subfields in the hippocampal head, (b) the composition of subfields is not consistent in the anterior uncus, but more consistent in the posterior uncus, (c) the dark band consists only of the CA-stratum lacunosum moleculare, not the strata moleculare of the dentate gyrus, (d) the subiculum/CA1 border is located at the middle of the width of the hippocampus in the body in coronal plane, but moves in a medial direction from anterior to posterior, and (e) the variable location and composition of subfields in the hippocampal tail can be brought back to a body-like appearance when reslicing the MRI scan following the curvature of the tail. Our findings and this publicly available dataset will hopefully improve anatomical accuracy of future hippocampal subfield segmentation protocols.
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| 2. |
- de Flores, Robin, et al.
(författare)
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Medial Temporal Lobe Networks in Alzheimer's Disease : Structural and Molecular Vulnerabilities
- 2022
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 42:10, s. 2131-2141
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Tidskriftsartikel (refereegranskat)abstract
- The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer's disease (AD), the present study aimed at (1) investigating whether MTL atrophy propagates specifically within the AT and PM networks, and (2) evaluating the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: (1) resting-state functional MRI (rs-fMRI) from the aging brain cohort (ABC) to define the AT and PM networks (n = 68); (2) longitudinal structural MRI from Alzheimer's disease neuroimaging initiative (ADNI)GO/2 to highlight structural covariance patterns (n = 349); and (3) positron emission tomography (PET) data from ADNI3 to evaluate the networks' vulnerability to amyloid and tau (n = 186). Our results suggest that the atrophy of distinct MTL subregions propagates within the AT and PM networks in a dissociable manner. Brodmann area (BA)35 structurally covaried within the AT network while the parahippocampal cortex (PHC) covaried within the PM network. In addition, these networks are differentially associated with relative tau and amyloid burden, with higher tau levels in AT than in PM and higher amyloid levels in PM than in AT. Our results also suggest differences in the relative burden of tau species. The current results provide further support for the notion that two distinct MTL networks display differential alterations in the context of AD. These findings have important implications for disease spread and the cognitive manifestations of AD.SIGNIFICANCE STATEMENT The current study provides further support for the notion that two distinct medial temporal lobe (MTL) networks, i.e., anterior-temporal (AT) and the posterior-medial (PM), display differential alterations in the context of Alzheimer's disease (AD). Importantly, neurodegeneration appears to occur within these networks in a dissociable manner marked by their covariance patterns. In addition, the AT and PM networks are also differentially associated with relative tau and amyloid burden, and perhaps differences in the relative burden of tau species [e.g., neurofibriliary tangles (NFTs) vs tau in neuritic plaques]. These findings, in the context of a growing literature consistent with the present results, have important implications for disease spread and the cognitive manifestations of AD in light of the differential cognitive processes ascribed to them.
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| 3. |
- Dong, Mengjin, et al.
(författare)
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DeepAtrophy : Teaching a neural network to detect progressive changes in longitudinal MRI of the hippocampal region in Alzheimer's disease
- 2021
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119. ; 243
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Tidskriftsartikel (refereegranskat)abstract
- Measures of change in hippocampal volume derived from longitudinal MRI are a well-studied biomarker of disease progression in Alzheimer's disease (AD) and are used in clinical trials to track therapeutic efficacy of disease-modifying treatments. However, longitudinal MRI change measures based on deformable registration can be confounded by MRI artifacts, resulting in over-estimation or underestimation of hippocampal atrophy. For example, the deformation-based-morphometry method ALOHA (Das et al., 2012) finds an increase in hippocampal volume in a substantial proportion of longitudinal scan pairs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, unexpected, given that the hippocampal gray matter is lost with age and disease progression. We propose an alternative approach to quantify disease progression in the hippocampal region: to train a deep learning network (called DeepAtrophy) to infer temporal information from longitudinal scan pairs. The underlying assumption is that by learning to derive time-related information from scan pairs, the network implicitly learns to detect progressive changes that are related to aging and disease progression. Our network is trained using two categorical loss functions: one that measures the network's ability to correctly order two scans from the same subject, input in arbitrary order; and another that measures the ability to correctly infer the ratio of inter-scan intervals between two pairs of same-subject input scans. When applied to longitudinal MRI scan pairs from subjects unseen during training, DeepAtrophy achieves greater accuracy in scan temporal ordering and interscan interval inference tasks than ALOHA (88.5% vs. 75.5% and 81.1% vs. 75.0%, respectively). A scalar measure of time-related change in a subject level derived from DeepAtrophy is then examined as a biomarker of disease progression in the context of AD clinical trials. We find that this measure performs on par with ALOHA in discriminating groups of individuals at different stages of the AD continuum. Overall, our results suggest that using deep learning to infer temporal information from longitudinal MRI of the hippocampal region has good potential as a biomarker of disease progression, and hints that combining this approach with conventional deformation-based morphometry algorithms may lead to improved biomarkers in the future.
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| 4. |
- Hrybouski, Stanislau, et al.
(författare)
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Aging and Alzheimer's disease have dissociable effects on local and regional medial temporal lobe connectivity
- 2023
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Ingår i: Brain Communications. - 2632-1297. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer's disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer's disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer's and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighbourhood-the Anterior-Temporal and Posterior-Medial brain networks-in normal agers, individuals with preclinical Alzheimer's disease and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer's disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted 'U-shaped' relationship between functional connectivity and Alzheimer's stage. According to our results, the preclinical phase of Alzheimer's disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbours in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer's disease. Instead, patients with symptomatic Alzheimer's disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (i) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (ii) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and (iii) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer's disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging versus Alzheimer's disease.
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| 5. |
- Lyu, Xueying, et al.
(författare)
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Tau-neurodegeneration mismatch reveals vulnerability and resilience to comorbidities in Alzheimer's continuum
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Ingår i: Alzheimer's and Dementia. - 1552-5260.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Variability in relationship of tau-based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non-specific nature of N, modulated by non-AD co-pathologies, age-related changes, and resilience factors. METHODS: We used regional T-N residual patterns to partition 184 patients within the Alzheimer's continuum into data-driven groups. These were compared with groups from 159 non-AD (amyloid “negative”) patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T-N residual model to classify 71 patients in an independent cohort into predefined groups. RESULTS: AD groups displayed spatial T-N mismatch patterns resembling neurodegeneration patterns in non-AD groups, similarly associated with non-AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T-N mismatch correlated with TDP-43 co-pathology. DISCUSSION: T-N mismatch may provide a personalized approach for determining non-AD factors associated with resilience/vulnerability in AD.
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| 6. |
- McCollum, Lauren E., et al.
(författare)
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Oh brother, where art tau? Amyloid, neurodegeneration, and cognitive decline without elevated tau
- 2021
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 31
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Tidskriftsartikel (refereegranskat)abstract
- Mild cognitive impairment (MCI) can be an early manifestation of Alzheimer's disease (AD) pathology, other pathologic entities [e.g., cerebrovascular disease, Lewy body disease, LATE (limbic-predominant age-related TDP-43 encephalopathy)], or mixed pathologies, with concomitant AD- and non-AD pathology being particularly common, albeit difficult to identify, in living MCI patients. The National Institute on Aging and Alzheimer's Association (NIA-AA) A/T/(N) [β-Amyloid/Tau/(Neurodegeneration)] AD research framework, which classifies research participants according to three binary biomarkers [β-amyloid (A+/A-), tau (T+/T-), and neurodegeneration (N+/N-)], provides an indirect means of identifying such cases. Individuals with A+T-(N+) MCI are thought to have both AD pathologic change, given the presence of β-amyloid, and non-AD pathophysiology, given neurodegeneration without tau, because in typical AD it is tau accumulation that is most tightly linked to neuronal injury and cognitive decline. Thus, in A+T-(N+) MCI (hereafter referred to as “mismatch MCI” for the tau-neurodegeneration mismatch), non-AD pathology is hypothesized to drive neurodegeneration and symptoms, because β-amyloid, in the absence of tau, likely reflects a preclinical stage of AD. We compared a group of individuals with mismatch MCI to groups with A+T+(N+) MCI (or “prodromal AD”) and A-T-(N+) MCI (or “neurodegeneration-only MCI”) on cross-sectional and longitudinal cognition and neuroimaging characteristics. β-amyloid and tau status were determined by CSF assays, while neurodegeneration status was based on hippocampal volume on MRI. Overall, mismatch MCI was less “AD-like” than prodromal AD and generally, with some exceptions, more closely resembled the neurodegeneration-only group. At baseline, mismatch MCI had less episodic memory loss compared to prodromal AD. Longitudinally, mismatch MCI declined more slowly than prodromal AD across all included cognitive domains, while mismatch MCI and neurodegeneration-only MCI declined at comparable rates. Prodromal AD had smaller baseline posterior hippocampal volume than mismatch MCI, and whole brain analyses demonstrated cortical thinning that was widespread in prodromal AD but largely restricted to the medial temporal lobes (MTLs) for the mismatch and neurodegeneration-only MCI groups. Longitudinally, mismatch MCI had slower rates of volume loss than prodromal AD throughout the MTLs. Differences in cross-sectional and longitudinal cognitive and neuroimaging measures between mismatch MCI and prodromal AD may reflect disparate underlying pathologic processes, with the mismatch group potentially being driven by non-AD pathologies on a background of largely preclinical AD. These findings suggest that β-amyloid status alone in MCI may not reveal the underlying driver of symptoms with important implications for enrollment in clinical trials and prognosis.
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| 7. |
- Ravikumar, Sadhana, et al.
(författare)
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Ex vivo MRI atlas of the human medial temporal lobe : characterizing neurodegeneration due to tau pathology
- 2021
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.
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| 8. |
- Ravikumar, Sadhana, et al.
(författare)
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Improved Segmentation of Deep Sulci in Cortical Gray Matter Using a Deep Learning Framework Incorporating Laplace’s Equation
- 2023
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Ingår i: Information Processing in Medical Imaging - 28th International Conference, IPMI 2023, Proceedings. - 1611-3349 .- 0302-9743. - 9783031340475 ; 13939 LNCS, s. 692-704
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Konferensbidrag (refereegranskat)abstract
- When developing tools for automated cortical segmentation, the ability to produce topologically correct segmentations is important in order to compute geometrically valid morphometry measures. In practice, accurate cortical segmentation is challenged by image artifacts and the highly convoluted anatomy of the cortex itself. To address this, we propose a novel deep learning-based cortical segmentation method in which prior knowledge about the geometry of the cortex is incorporated into the network during the training process. We design a loss function which uses the theory of Laplace’s equation applied to the cortex to locally penalize unresolved boundaries between tightly folded sulci. Using an ex vivo MRI dataset of human medial temporal lobe specimens, we demonstrate that our approach outperforms baseline segmentation networks, both quantitatively and qualitatively.
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| 9. |
- Ravikumar, Sadhana, et al.
(författare)
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Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer’s disease
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer’s Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.
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| 10. |
- Ravikumar, Sadhana, et al.
(författare)
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Unfolding the Medial Temporal Lobe Cortex to Characterize Neurodegeneration Due to Alzheimer’s Disease Pathology Using Ex vivo Imaging
- 2021
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Ingår i: Machine Learning in Clinical Neuroimaging - 4th International Workshop, MLCN 2021, Held in Conjunction with MICCAI 2021, Proceedings. - Cham : Springer International Publishing. - 0302-9743 .- 1611-3349. - 9783030875855 ; 13001 LNCS, s. 3-12
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Konferensbidrag (refereegranskat)abstract
- Neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s Disease (AD). In this work, we investigate the relationship between MTL morphometry features derived from high-resolution ex vivo imaging and histology-based measures of NFT pathology using a topological unfolding framework applied to a dataset of 18 human postmortem MTL specimens. The MTL has a complex 3D topography and exhibits a high degree of inter-subject variability in cortical folding patterns which poses a significant challenge for volumetric registration methods typically used during MRI template construction. By unfolding the MTL cortex, the proposed framework explicitly accounts for the sheet-like geometry of the MTL cortex and provides a two-dimensional reference coordinate space which can be used to implicitly register cortical folding patterns across specimens based on distance along the cortex despite large anatomical variability. Leveraging this framework in a subset of 15 specimens, we characterize the associations between NFTs and morphological features such as cortical thickness and surface curvature and identify regions in the MTL where patterns of atrophy are strongly correlated with NFT pathology.
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| 11. |
- Sadaghiani, Shokufeh, et al.
(författare)
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Associations of phosphorylated tau pathology with whole-hemisphere ex vivo morphometry in 7 tesla MRI
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2355-2364
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neurodegenerative disorders are associated with different pathologies that often co-occur but cannot be measured specifically with in vivo methods. Methods: Thirty-three brain hemispheres from donors with an Alzheimer's disease (AD) spectrum diagnosis underwent T2-weighted magnetic resonance imaging (MRI). Gray matter thickness was paired with histopathology from the closest anatomic region in the contralateral hemisphere. Results: Partial Spearman correlation of phosphorylated tau and cortical thickness with TAR DNA-binding protein 43 (TDP-43) and α-synuclein scores, age, sex, and postmortem interval as covariates showed significant relationships in entorhinal and primary visual cortices, temporal pole, and insular and posterior cingulate gyri. Linear models including Braak stages, TDP-43 and α-synuclein scores, age, sex, and postmortem interval showed significant correlation between Braak stage and thickness in the parahippocampal gyrus, entorhinal cortex, and Broadman area 35. Conclusion: We demonstrated an association of measures of AD pathology with tissue loss in several AD regions despite a limited range of pathology in these cases. Highlights: Neurodegenerative disorders are associated with co-occurring pathologies that cannot be measured specifically with in vivo methods. Identification of the topographic patterns of these pathologies in structural magnetic resonance imaging (MRI) may provide probabilistic biomarkers. We demonstrated the correlation of the specific patterns of tissue loss from ex vivo brain MRI with underlying pathologies detected in postmortem brain hemispheres in patients with Alzheimer's disease (AD) spectrum disorders. The results provide insight into the interpretation of in vivo structural MRI studies in patients with AD spectrum disorders.
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| 12. |
- Tustison, Nicholas J., et al.
(författare)
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The ANTsX ecosystem for quantitative biological and medical imaging
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 9068-9068
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality. Recent enhancements include statistical, visualization, and deep learning capabilities through interfacing with both the R statistical project (ANTsR) and Python (ANTsPy). Additionally, the corresponding deep learning extensions ANTsRNet and ANTsPyNet (built on the popular TensorFlow/Keras libraries) contain several popular network architectures and trained models for specific applications. One such comprehensive application is a deep learning analog for generating cortical thickness data from structural T1-weighted brain MRI, both cross-sectionally and longitudinally. These pipelines significantly improve computational efficiency and provide comparable-to-superior accuracy over multiple criteria relative to the existing ANTs workflows and simultaneously illustrate the importance of the comprehensive ANTsX approach as a framework for medical image analysis.
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| 13. |
- Wisse, Laura E.M., et al.
(författare)
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Cross-sectional and longitudinal medial temporal lobe subregional atrophy patterns in semantic variant primary progressive aphasia
- 2021
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 98, s. 231-241
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Tidskriftsartikel (refereegranskat)abstract
- T1-magnetic resonance imaging (MRI) studies report early atrophy in the left anterior temporal lobe, especially the perirhinal cortex, in semantic variant primary progressive aphasia (svPPA). Improved segmentation protocols using high-resolution T2-MRI have enabled fine-grained medial temporal lobe (MTL) subregional measurements, which may provide novel information on the atrophy pattern and disease progression in svPPA. We aimed to investigate the MTL subregional atrophy pattern cross-sectionally and longitudinally in patients with svPPA as compared with controls and patients with Alzheimer's disease (AD). MTL subregional volumes were obtained using the Automated Segmentation for Hippocampal Subfields software from high-resolution T2-MRIs in 15 svPPA, 37 AD, and 23 healthy controls. All MTL volumes were corrected for intracranial volume and parahippocampal cortices for slice number. Longitudinal atrophy rates of all subregions were obtained using an unbiased deformation-based morphometry pipeline in 6 svPPA patients, 9 controls, and 12 AD patients. Cross-sectionally, significant volume loss was observed in svPPA compared with controls in the left MTL, right cornu ammonis 1 (CA1), Brodmann area (BA)35, and BA36 (subdivisions of the perirhinal cortex). Compared with AD patients, svPPA patients had significantly smaller left CA1, BA35, and left and right BA36 volumes. Longitudinally, svPPA patients had significantly greater atrophy rates of left and right BA36 than controls but not relative to AD patients. Fine-grained analysis of MTL atrophy patterns provides information about the evolution of atrophy in svPPA. These results indicate that MTL subregional measures might be useful markers to track disease progression or for clinical trials in svPPA.
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| 14. |
- Wisse, Laura EM, et al.
(författare)
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Tau pathology mediates age effects on medial temporal lobe structure
- 2022
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 109, s. 135-144
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Tidskriftsartikel (refereegranskat)abstract
- Hippocampal atrophy is endemic in ‘normal aging’ but it is unclear what factors drive age-related changes in medial temporal lobe (MTL) structural measures. We investigated cross-sectional (n = 191) and longitudinal (n = 164) MTL atrophy patterns in cognitively normal older adults from ADNI-GO/2 with no to low cerebral β-amyloid and assessed whether white matter hyperintensities (WMHs) and cerebrospinal fluid (CSF) phospho tau (p-tau) levels can explain age-related changes in the MTL. Age was significantly associated with hippocampal volumes and Brodmann Area (BA) 35 thickness, regions affected early by neurofibrillary tangle pathology, in the cross-sectional analysis and with anterior and/or posterior hippocampus, entorhinal cortex and BA35 in the longitudinal analysis. CSF p-tau was significantly associated with hippocampal volumes and atrophy rates. Mediation analyses showed that CSF p-tau levels partially mediated age effects on hippocampal atrophy rates. No significant associations were observed for WMHs. These findings point toward a role of tau pathology, potentially reflecting Primary Age-Related Tauopathy, in age-related MTL structural changes and suggests a potential role for tau-targeted interventions in age-associated neurodegeneration and memory decline.
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| 15. |
- Xie, Long, et al.
(författare)
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Baseline structural MRI and plasma biomarkers predict longitudinal structural atrophy and cognitive decline in early Alzheimer’s disease
- 2023
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Crucial to the success of clinical trials targeting early Alzheimer’s disease (AD) is recruiting participants who are more likely to progress over the course of the trials. We hypothesize that a combination of plasma and structural MRI biomarkers, which are less costly and non-invasive, is predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a practical alternative to PET or cerebrospinal fluid biomarkers. Methods: Longitudinal T1-weighted MRI, cognitive (memory-related test scores and clinical dementia rating scale), and plasma measurements of 245 cognitively normal (CN) and 361 mild cognitive impairment (MCI) patients from ADNI were included. Subjects were further divided into β-amyloid positive/negative (Aβ+/Aβ−)] subgroups. Baseline plasma (p-tau181 and neurofilament light chain) and MRI-based structural medial temporal lobe subregional measurements and their association with longitudinal measures of atrophy and cognitive decline were tested using stepwise linear mixed effect modeling in CN and MCI, as well as separately in the Aβ+/Aβ− subgroups. Receiver operating characteristic (ROC) analyses were performed to investigate the discriminative power of each model in separating fast and slow progressors (first and last terciles) of each longitudinal measurement. Results: A total of 245 CN (35.0% Aβ+) and 361 MCI (53.2% Aβ+) participants were included. In the CN and MCI groups, both baseline plasma and structural MRI biomarkers were included in most models. These relationships were maintained when limited to the Aβ+ and Aβ− subgroups, including Aβ− CN (normal aging). ROC analyses demonstrated reliable discriminative power in identifying fast from slow progressors in MCI [area under the curve (AUC): 0.78–0.93] and more modestly in CN (0.65–0.73). Conclusions: The present data support the notion that plasma and MRI biomarkers, which are relatively easy to obtain, provide a prediction for the rate of future cognitive and neurodegenerative progression that may be particularly useful in clinical trial stratification and prognosis. Additionally, the effect in Aβ− CN indicates the potential use of these biomarkers in predicting a normal age-related decline.
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| 16. |
- Xie, Long, et al.
(författare)
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Longitudinal atrophy in early Braak regions in preclinical Alzheimer's disease
- 2020
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Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 41:16, s. 4704-4717
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Tidskriftsartikel (refereegranskat)abstract
- A major focus of Alzheimer's disease (AD) research has been finding sensitive outcome measures to disease progression in preclinical AD, as intervention studies begin to target this population. We hypothesize that tailored measures of longitudinal change of the medial temporal lobe (MTL) subregions (the sites of earliest cortical tangle pathology) are more sensitive to disease progression in preclinical AD compared to standard cognitive and plasma NfL measures. Longitudinal T1-weighted MRI of 337 participants were included, divided into amyloid-β negative (Aβ−) controls, cerebral spinal fluid p-tau positive (T+) and negative (T−) preclinical AD (Aβ+ controls), and early prodromal AD. Anterior/posterior hippocampus, entorhinal cortex, Brodmann areas (BA) 35 and 36, and parahippocampal cortex were segmented in baseline MRI using a novel pipeline. Unbiased change rates of subregions were estimated using MRI scans within a 2-year-follow-up period. Experimental results showed that longitudinal atrophy rates of all MTL subregions were significantly higher for T+ preclinical AD and early prodromal AD than controls, but not for T− preclinical AD. Posterior hippocampus and BA35 demonstrated the largest group differences among hippocampus and MTL cortex respectively. None of the cross-sectional MTL measures, longitudinal cognitive measures (PACC, ADAS-Cog) and cross-sectional or longitudinal plasma NfL reached significance in preclinical AD. In conclusion, longitudinal atrophy measurements reflect active neurodegeneration and thus are more directly linked to active disease progression than cross-sectional measurements. Moreover, accelerated atrophy in preclinical AD seems to occur only in the presence of concomitant tau pathology. The proposed longitudinal measurements may serve as efficient outcome measures in clinical trials.
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| 17. |
- Xie, Long, et al.
(författare)
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Tau burden is associated with cross-sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neurofibrillary tangle pathology is thought to drive neurodegeneration in beta-amyloid positive (A+) cognitively normal (CN) individuals, i.e., preclinical Alzheimer’s disease (AD).However, in beta-amyloid negative (A-) CN, the contribution of tau pathology [primary age-related tauopathy (PART)] to neurodegeneration remains uncertain. We investigate the correlation between tau burden measured by PET in the medial temporal lobe (MTL) and MRI-derived cross-sectional and longitudinal structural atrophy in these cohorts. Methods: 420 CN (A-/A+: 294/101, Table 1) individuals from ADNI with AV1451 PET and T1-weighted MRI acquired within one year were included. Bilateral anterior/posterior hippocampal volume and thickness of entorhinal cortex (ERC), Brodmann areas 35/36 (BA35/BA36) and parahipocampal cortex (PHC) were obtained from baseline MRI scans. Bilateral MTL tau burden was computed as AV1451 uptake across ERC and BA35. Beta-amyloid status was determined with PET by standard cut-offs (Florbetapir: 1.11; Florbetaben: 1.08). In a subset of participants with prospective longitudinal MRI scans (up to 4.5 years), annualized volume change rate of each MTL subregion was estimated. Intracranial volume and MRI follow-up time were additional covariates for cross-sectional and longitudinal analysis respectively. We performed the analysis separately for each hemisphere in the whole CN cohort and its A+ and A- subgroups. Results: Tau burden was significantly associated with cross-sectional left BA35/36 thickness in the whole cohort and bilateral volume in both A+ CN and the whole cohort (Table 2, Figure 1), but not in in A- CN. Stronger correlations between MTL tau burden and longitudinal atrophy, despite smaller sample size, was observed in almost all the MTL subregions regardless of amyloid status (Table 3, Figure 1). In general, effects from the left hemisphere were stronger than those from the right hemisphere. All significant correlations were maintained when corrected for beta-amyloid PET SUVR. Conclusions: The results demonstrated that elevated tau predicts subsequent neurodegeneration in early Braak regions in CN subjects regardless of amyloid status. This indicates that PART may be an important driver of neurodegeneration already during normal ageing in cognitively normal individuals.
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| 18. |
- Yushkevich, Paul A., et al.
(författare)
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Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2784-2797
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Tidskriftsartikel (refereegranskat)abstract
- Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.
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| 19. |
- Zuroff, Leah, et al.
(författare)
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Self- and Partner-Reported Subjective Memory Complaints : Association with Objective Cognitive Impairment and Risk of Decline
- 2022
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Ingår i: Journal of Alzheimer's Disease Reports. - 2542-4823. ; 6:1, s. 411-430
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Tidskriftsartikel (refereegranskat)abstract
- Background: Episodic memory decline is a hallmark of Alzheimer's disease (AD). Subjective memory complaints (SMCs) may represent one of the earliest signs of impending cognitive decline. The degree to which self- or partner-reported SMCs predict cognitive change remains unclear. Objective: We aimed to evaluate the relationship between self- and partner-reported SMCs, objective cognitive performance, AD biomarkers, and risk of future decline in a well-characterized longitudinal memory center cohort. We also evaluated whether study partner characteristics influence reports of SMCs. Methods: 758 participants and 690 study partners were recruited from the Penn Alzheimer's Disease Research Center Clinical Core. Participants included those with Normal Cognition, Mild Cognitive Impairment, and AD. SMCs were measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), and were evaluated for their association with cognition, genetic, plasma, and neuroimaging biomarkers of AD, cognitive and functional decline, and diagnostic progression over an average of four years. Results: We found that partner-reported SMCs were more consistent with cognitive test performance and increasing symptom severity than self-reported SMCs. Partner-reported SMCs showed stronger correlations with AD-associated brain atrophy, plasma biomarkers of neurodegeneration, and longitudinal cognitive and functional decline. A 10-point increase on baseline PRMQ increased the annual risk of diagnostic progression by approximately 70%. Study partner demographics and relationship to participants influenced reports of SMCs in AD participants only. Conclusion: Partner-reported SMCs, using the PRMQ, have a stronger relationship with the neuroanatomic and cognitive changes associated with AD than patient-reported SMCs. Further work is needed to evaluate whether SMCs could be used to screen for future decline.
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