| 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. |
- Wuestefeld, Anika, et al.
(författare)
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Age-related and amyloid-beta-independent tau deposition and its downstream effects
- 2023
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 146:8, s. 3192-3205
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.
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| 3. |
- Wuestefeld, Anika, et al.
(författare)
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Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the cortices that make up the parahippocampal gyrus (entorhinal and parahippocampal cortices) and the adjacent Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized (20X resolution) slices with 5 mm spacing. Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed more gradually. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed human neuroimaging research on the MTL cortex.
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| 4. |
- Wuestefeld, Anika, et al.
(författare)
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Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories
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Ingår i: Hippocampus. - 1050-9631.
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Tidskriftsartikel (refereegranskat)abstract
- The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 μm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 μm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.
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| 5. |
- Adams, Jenna N., et al.
(författare)
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Reduced repetition suppression in aging is driven by tau-related hyperactivity in medial temporal lobe
- 2021
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Ingår i: The Journal of Neuroscience. - 0270-6474. ; 41:17, s. 3917-3931
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Tidskriftsartikel (refereegranskat)abstract
- Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI (fMRI) to assess MTL subregional activity in 21 young adults (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using 18F-Flortaucipir for tau and 11C-Pittsburgh compound B (PiB) for amyloid-b (Ab). The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau- OA), to high tau pathology, also occurring in temporal and limbic regions (Tau1 OA). Low levels of tau (Tau- OA vs YA) were associated with reduced repetition suppression activity specifically in anterolateral entorhinal cortex (alEC) and hippocampus, the first regions to accumulate tau. High tau pathology (Tau1 vs Tau- OA) was associated with widespread reductions in repetition suppression across MTL. Further analyses indicated that reduced repetition suppression was driven by hyperactivity to repeated stimuli, rather than decreased activity to novel stimuli. Increased activation was associated with entorhinal tau, but not Ab. These findings reveal a link between tau deposition and neural dysfunction in MTL, in which tau-related hyperactivity prevents deactivation to repeated stimuli, leading to reduced repetition suppression.
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| 6. |
- Ahmadi, Khazar, et al.
(författare)
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Gray matter hypoperfusion is a late pathological event in the course of Alzheimer's disease
- 2023
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - 1559-7016. ; 43:4, s. 565-580
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have shown decreased cerebral blood flow (CBF) in Alzheimer's disease (AD). However, the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, PET, and CSF biomarkers, we investigated the associations between gray matter (GM)-CBF and the key mechanisms in AD including amyloid-β (Aβ) and tau pathology, synaptic and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in temporo-occipito-parietal cortex in the Aβ-positive cognitively impaired compared to both Aβ-negative and Aβ-positive cognitively unimpaired individuals. In participants along the AD spectrum, GM-CBF was associated with tau, synaptic and axonal dysfunction, but not Aβ in similar cortical regions. Axonal degeneration was further associated with hypoperfusion in cognitively unimpaired individuals. Disease progression modeling revealed that GM-CBF disruption Followed the abnormality of biomarkers of Aβ, tau and brain atrophy. These findings indicate that tau tangles and neurodegeneration are more closely connected with GM-CBF changes than Aβ pathology. Although subjected to the sensitivity of the employed neuroimaging techniques and the modeling approach, these findings suggest that hypoperfusion might not be an early event associated with the build-up of Aβ in preclinical phase of AD.
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| 7. |
- Bainbridge, Wilma A., et al.
(författare)
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Memorability of photographs in subjective cognitive decline and mild cognitive impairment : Implications for cognitive assessment
- 2019
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 11, s. 610-618
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Impaired long-term memory is a defining feature of mild cognitive impairment (MCI). We tested whether this impairment is item specific, limited to some memoranda, whereas some remain consistently memorable. Methods: We conducted item-based analyses of long-term visual recognition memory. Three hundred ninety-four participants (healthy controls, subjective cognitive decline [SCD], and MCI) in the multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were tested with images from a pool of 835 photographs. Results: We observed consistent memorability for images in healthy controls, SCD, and MCI, predictable by a neural network trained on another healthy sample. Looking at memorability differences between groups, we identified images that could successfully categorize group membership with higher success and a substantial image reduction than the original image set. Discussion: Individuals with SCD and MCI show consistent memorability for specific items, while other items show significant diagnosticity. Certain stimulus features could optimize diagnostic assessment, while others could support memory.
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| 8. |
- Baumeister, Hannah, et al.
(författare)
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A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 147:7, s. 2400-2413
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Tidskriftsartikel (refereegranskat)abstract
- Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.
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| 9. |
- Berron, David, et al.
(författare)
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A remote digital memory composite to detect cognitive impairment in memory clinic samples in unsupervised settings using mobile devices
- 2024
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Ingår i: npj Digital Medicine. - 2398-6352. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Remote monitoring of cognition holds the promise to facilitate case-finding in clinical care and the individual detection of cognitive impairment in clinical and research settings. In the context of Alzheimer’s disease, this is particularly relevant for patients who seek medical advice due to memory problems. Here, we develop a remote digital memory composite (RDMC) score from an unsupervised remote cognitive assessment battery focused on episodic memory and long-term recall and assess its construct validity, retest reliability, and diagnostic accuracy when predicting MCI-grade impairment in a memory clinic sample and healthy controls. A total of 199 participants were recruited from three cohorts and included as healthy controls (n = 97), individuals with subjective cognitive decline (n = 59), or patients with mild cognitive impairment (n = 43). Participants performed cognitive assessments in a fully remote and unsupervised setting via a smartphone app. The derived RDMC score is significantly correlated with the PACC5 score across participants and demonstrates good retest reliability. Diagnostic accuracy for discriminating memory impairment from no impairment is high (cross-validated AUC = 0.83, 95% CI [0.66, 0.99]) with a sensitivity of 0.82 and a specificity of 0.72. Thus, unsupervised remote cognitive assessments implemented in the neotiv digital platform show good discrimination between cognitively impaired and unimpaired individuals, further demonstrating that it is feasible to complement the neuropsychological assessment of episodic memory with unsupervised and remote assessments on mobile devices. This contributes to recent efforts to implement remote assessment of episodic memory for case-finding and monitoring in large research studies and clinical care.
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| 10. |
- Berron, David, et al.
(författare)
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Early stages of tau pathology and its associations with functional connectivity, atrophy and memory
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2771-2783
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Tidskriftsartikel (refereegranskat)abstract
- In Alzheimer's disease, post-mortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with Brodmann area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 amyloid-β- cognitively unimpaired, 81 amyloid-β+ cognitively unimpaired and 87 amyloid-β+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, Brodmann area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease stage-specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.
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| 11. |
- Berron, David, et al.
(författare)
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Higher CSF Tau Levels Are Related to Hippocampal Hyperactivity and Object Mnemonic Discrimination in Older Adults
- 2019
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 39:44, s. 8788-8797
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Tidskriftsartikel (refereegranskat)abstract
- Mnemonic discrimination, the ability to distinguish similar events in memory, relies on subregions in the human medial temporal lobes (MTLs). Tau pathology is frequently found within the MTL of older adults and therefore likely to affect mnemonic discrimination, even in healthy older individuals. The MTL subregions that are known to be affected early by tau pathology, the perirhinal-transentorhinal region (area 35) and the anterior-lateral entorhinal cortex (alEC), have recently been implicated in the mnemonic discrimination of objects rather than scenes. Here we used an object-scene mnemonic discrimination task in combination with fMRI recordings and analyzed the relationship between subregional MTL activity, memory performance, and levels of total and phosphorylated tau as well as Aβ42/40 ratio in CSF. We show that activity in alEC was associated with mnemonic discrimination of similar objects but not scenes in male and female cognitively unimpaired older adults. Importantly, CSF tau levels were associated with increased fMRI activity in the hippocampus, and both increased hippocampal activity as well as tau levels were associated with mnemonic discrimination of objects, but again not scenes. This suggests that dysfunction of the alEC-hippocampus object mnemonic discrimination network might be a marker for tau-related cognitive decline.SIGNIFICANCE STATEMENT Subregions in the human medial temporal lobe are critically involved in episodic memory and, at the same time, affected by tau pathology. Impaired object mnemonic discrimination performance as well as aberrant activity within the entorhinal-hippocampal circuitry have been reported in earlier studies involving older individuals, but it has thus far remained elusive whether and how tau pathology is implicated in this specific impairment. Using task-related fMRI in combination with measures of tau pathology in CSF, we show that measures of tau pathology are associated with increased hippocampal activity and reduced mnemonic discrimination of similar objects but not scenes. This suggests that object mnemonic discrimination tasks could be promising markers for tau-related cognitive decline.
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| 12. |
- Berron, David, et al.
(författare)
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Hippocampal subregional thinning related to tau pathology in early stages of Alzheimer’s disease
- 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: Subregions in the medial temporal lobe (MTL) are affected early by Alzheimer’s disease (AD) pathology and subject to grey matter atrophy. Measuring the earliest AD-related atrophy in the hippocampus is challenging as region-of-interest (ROI) analyses of hippocampal subregional volumes collapse across voxels within anatomical subregions. PET imaging studies, however, report accumulation of tau pathology between anatomical subregions in the earliest disease stages (Berron et al., 2021) fitting reports from the neuropathological literature (Lace et al., 2019; Ravikumar et al., 2021). Thus, sensitive in vivo methods of point-wise structural measures are needed in order to detect the earliest hippocampal thinning in AD along the anterior-posterior as well as the medial-lateral hippocampal axis. Method: Here we analyzed data from 76 amyloid-beta negative (Ab-) cognitively normal (CN), 46 Ab+ CN individuals and 25 Ab+ patients with mild cognitive impairment (MCI) from the BioFINDER-2 study, who underwent 7 Tesla T2-weighted structural magnetic resonance imaging, tau positron emission tomography imaging (using 18F-RO-948) and cognitive assessments. First, we segmented hippocampal subfields and extrahippocampal subregions. Second, we calculated point-wise hippocampal thickness estimates (Diers et al.) of hippocampal subfields subiculum, cornu ammonis (CA)1, CA2 and CA3 on the level of the hippocampal body. Thirdly, we extracted local tau-PET SUVR from Area 35 (A35), entorhinal cortex and amygdala. Finally, we assessed relationships between hippocampal local thickness and tau accumulation as well as cognitive performance. Result: Our analyses revealed earliest hippocampal thinning associated with tau accumulation in an area spanning the boundary of subiculum and CA1 at the level of the anterior hippocampal body. Ab+ MCI patients showed more posterior thinning in comparison to Ab- CU participants. Median thickness in an ROI comprising vertices with A35 tau-related thinning (A35-TauThinning-ROI) was significantly lower in MCI Ab+ and tended to be lower in CU Ab+ compared to CU Ab-. Higher median thickness in the hippocampal A35-TauThinning-ROI, but not whole CA1 nor subiculum thickness, was associated with better 10-Word-Delayed-Recall and higher PACC scores. Conclusion: Our results suggest that tau-related thinning of hippocampal subregions can be observed already in early disease stages. Tau-related point-wise thickness measures were more sensitive compared to volumetric measures of anatomical subregions.
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| 13. |
- Berron, David, et al.
(författare)
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Medial temporal lobe connectivity and its associations with cognition in early Alzheimer's disease
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:3, s. 1233-1248
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Tidskriftsartikel (refereegranskat)abstract
- Human episodic memory critically depends on subregions of the medial temporal lobe, which are part of functional brain systems such as the anterior-temporal and the posterior-medial system. Here we analysed how Alzheimer's pathology affects functional connectivity within these systems. Data from 256 amyloid-b-negative cognitively unimpaired, 103 amyloid-b-positive cognitively unimpaired, and 83 amyloid-b-positive individuals with mild cognitive impairment were analysed. Amyloid-b and tau pathology were measured using the CSF amyloid-b42/40 ratio and phosphorylated tau, respectively. We found that amyloid-b-positive cognitively unimpaired individuals were mainly characterized by decreased functional connectivity between the medial temporal lobe and regions in the anterior-temporal system, most prominently between left perirhinal/entorhinal cortices and medial prefrontal cortex. Furthermore, correlation analysis in this group revealed decreasing functional connectivity between bilateral perirhinal/entorhinal cortices, anterior hippocampus and posterior-medial regions with increasing levels of phosphorylated tau. The amyloid-b-positive individuals with mild cognitive impairment mostly exhibited reduced connectivity between the medial temporal lobe and posterior-medial regions, predominantly between the anterior hippocampus and posterior cingulate cortex. In addition, they showed hyperconnectivity within the medial temporal lobe and its immediate proximity. Lower medial temporal-cortical functional connectivity networks resulting from the group comparisons of cognitively unimpaired individuals were associated with reduced memory performance and more rapid longitudinal memory decline as shown by linear mixed-effects regression analysis. Finally, we found that reduced medial temporal-cortical connectivity in mildly cognitively impaired individuals was related to reduced entorhinal thickness and white matter integrity of the parahippocampal cingulum and the fornix. No such relationships were found in cognitively unimpaired individuals. In conclusion, our findings show that the earliest changes in preclinical Alzheimer's disease might involve decreased connectivity within the anterior-temporal system, and early changes in connectivity might be related to memory impairment, but not to structural changes. With disease progression and increased tau pathology, medial temporal functional connectivity with posterior-medial regions seems to be increasingly impaired. In individuals with mild cognitive impairment, reduced functional connectivity is associated with structural brain changes as well as the emergence of locally increased connectivity patterns. Thus, functional connectivity between the medial temporal lobe and the anterior-temporal and posterior-medial system could serve as stage-specific functional markers in early Alzheimer's disease.
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| 14. |
- Diers, Kersten, et al.
(författare)
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An automated, geometry-based method for hippocampal shape and thickness analysis
- 2023
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Ingår i: NeuroImage. - 1053-8119. ; 276
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampus is one of the most studied neuroanatomical structures due to its involvement in attention, learning, and memory as well as its atrophy in ageing, neurological, and psychiatric diseases. Hippocampal shape changes, however, are complex and cannot be fully characterized by a single summary metric such as hippocampal volume as determined from MR images. In this work, we propose an automated, geometry-based approach for the unfolding, point-wise correspondence, and local analysis of hippocampal shape features such as thickness and curvature. Starting from an automated segmentation of hippocampal subfields, we create a 3D tetrahedral mesh model as well as a 3D intrinsic coordinate system of the hippocampal body. From this coordinate system, we derive local curvature and thickness estimates as well as a 2D sheet for hippocampal unfolding. We evaluate the performance of our algorithm with a series of experiments to quantify neurodegenerative changes in Mild Cognitive Impairment and Alzheimer's disease dementia. We find that hippocampal thickness estimates detect known differences between clinical groups and can determine the location of these effects on the hippocampal sheet. Further, thickness estimates improve classification of clinical groups and cognitively unimpaired controls when added as an additional predictor. Comparable results are obtained with different datasets and segmentation algorithms. Taken together, we replicate canonical findings on hippocampal volume/shape changes in dementia, extend them by gaining insight into their spatial localization on the hippocampal sheet, and provide additional, complementary information beyond traditional measures. We provide a new set of sensitive processing and analysis tools for the analysis of hippocampal geometry that allows comparisons across studies without relying on image registration or requiring manual intervention.
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| 15. |
- Düzel, E., et al.
(författare)
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European Ultrahigh-Field Imaging Network for Neurodegenerative Diseases (EUFIND)
- 2019
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 11, s. 538-549
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The goal of European Ultrahigh-Field Imaging Network in Neurodegenerative Diseases (EUFIND) is to identify opportunities and challenges of 7 Tesla (7T) MRI for clinical and research applications in neurodegeneration. EUFIND comprises 22 European and one US site, including over 50 MRI and dementia experts as well as neuroscientists. Methods: EUFIND combined consensus workshops and data sharing for multisite analysis, focusing on 7 core topics: clinical applications/clinical research, highest resolution anatomy, functional imaging, vascular systems/vascular pathology, iron mapping and neuropathology detection, spectroscopy, and quality assurance. Across these topics, EUFIND considered standard operating procedures, safety, and multivendor harmonization. Results: The clinical and research opportunities and challenges of 7T MRI in each subtopic are set out as a roadmap. Specific MRI sequences for each subtopic were implemented in a pilot study presented in this report. Results show that a large multisite 7T imaging network with highly advanced and harmonized imaging sequences is feasible and may enable future multicentre ultrahigh-field MRI studies and clinical trials. Discussion: The EUFIND network can be a major driver for advancing clinical neuroimaging research using 7T and for identifying use-cases for clinical applications in neurodegeneration. © 2018 The Authors
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| 16. |
- Düzel, Emrah, et al.
(författare)
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Innovation in der Diagnostik – mobile Technologien
- 2019
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Ingår i: Nervenarzt. - : Springer Science and Business Media LLC. - 0028-2804. ; 90:9, s. 914-920
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Forskningsöversikt (refereegranskat)abstract
- Background: Progressive cognitive deficits are the main clinical symptom of Alzheimer’s disease; however, the precise recording of cognitive deficits and assessment of their progression pose major problems in patient care and early interventions. Objective: Which problems for care and early intervention result from the current practice of cognitive assessment of patients with memory problems and which opportunities arise from the use of mobile apps? Material and methods: Evaluation of current care structures, discussion of basic work, expert recommendations and current developments. Results: The current practice of the pencil and paper-based diagnostics of cognitive deficits, which is temporally and spatially bound to a clinical environment, constrains the feasibility, validity and reliability of cognitive assessment and the quantification of progression. This limits the meaningful use of further diagnostic measures, such as magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analyses. Recent progress in mobile app-based technologies, illustrated here with the example of the neotiv app, can help to overcome these problems. Conclusion: Mobile app-based technologies can help to improve the cognitive assessment of patients with the main symptom of memory complaints. They can reduce overuse and underuse of diagnostic and therapeutic pathways and enable a targeted and meaningful use of advanced diagnostics. In addition, they can structure risk-modifying preventive measures, identify iatrogenic impairment of cognition and in this respect also strengthen patient competence.
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| 17. |
- Grande, Xenia, et al.
(författare)
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Content-specific vulnerability of recent episodic memories in Alzheimer's disease
- 2021
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Ingår i: Neuropsychologia. - : Elsevier BV. - 0028-3932. ; 160
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Tidskriftsartikel (refereegranskat)abstract
- Endel Tulving's episodic memory framework emphasizes the multifaceted re-experiencing of personal events. Indeed, decades of research focused on the experiential nature of episodic memories, usually treating recent episodic memory as a coherent experiential quality. However, recent insights into the functional architecture of the medial temporal lobe show that different types of mnemonic information are segregated into distinct neural pathways in brain circuits empirically associated with episodic memory. Moreover, recent memories do not fade as a whole under conditions of progressive neurodegeneration in these brain circuits, notably in Alzheimer's disease. Instead, certain memory content seem particularly vulnerable from the moment of their encoding while other content can remain memorable consistently across individuals and contexts. We propose that these observations are related to the content-specific functional architecture of the medial temporal lobe and consequently to a content-specific impairment of memory at different stages of the neurodegeneration. To develop Endel Tulving's inspirational legacy further and to advance our understanding of how memory function is affected by neurodegenerative conditions such as Alzheimer's disease, we postulate that it is compelling to focus on the representational content of recent episodic memories.
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| 18. |
- Grande, Xenia, et al.
(författare)
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Holistic Recollection via Pattern Completion Involves Hippocampal Subfield CA3
- 2019
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 39:41, s. 8100-8111
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Tidskriftsartikel (refereegranskat)abstract
- Episodic memories typically comprise multiple elements. A defining characteristic of episodic retrieval is holistic recollection, i.e., comprehensive recall of the elements a memorized event encompasses. A recent study implicated activity in the human hippocampus with holistic recollection of multi-element events based on cues (Horner et al., 2015). Here, we obtained ultra-high resolution functional neuroimaging data at 7 tesla in 30 younger adults (12 female) using the same paradigm. In accordance with anatomically inspired computational models and animal research, we found that metabolic activity in hippocampal subfield CA3 (but less pronounced in dentate gyrus) correlated with this form of mnemonic pattern completion across participants. Our study provides the first evidence in humans for a strong involvement of hippocampal subfield CA3 in holistic recollection via pattern completion.SIGNIFICANCE STATEMENT Memories of daily events usually involve multiple elements, although a single element can be sufficient to prompt recollection of the whole event. Such holistic recollection is thought to require reactivation of brain activity representing the full event from one event element ("pattern completion"). Computational and animal models suggest that mnemonic pattern completion is accomplished in a specific subregion of the hippocampus called CA3, but empirical evidence in humans was lacking. Here, we leverage the ultra-high resolution of 7 tesla neuroimaging to provide first evidence for a strong involvement of the human CA3 in holistic recollection of multi-element events via pattern completion.
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| 19. |
- Grande, Xenia, et al.
(författare)
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Transversal functional connectivity and scene-specific processing in the human entorhinal-hippocampal circuitry
- 2022
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Ingår i: eLife. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Scene and object information reach the entorhinal-hippocampal circuitry in partly segregated cortical processing streams. Converging evidence suggests that such information-specific streams organize the cortical – entorhinal interaction and the circuitry’s inner communication along the transversal axis of hippocampal subiculum and CA1. Here, we leveraged ultra-high field functional imaging and advance Maass, Berron et al. (2015) who report two functional routes segregating the entorhinal cortex (EC) and the subiculum. We identify entorhinal subregions based on preferential functional connectivity with perirhinal Area 35 and 36, parahippocampal and retrosplenial cortical sources (referred to as ECArea35-based, ECArea36-based, ECPHC-based, ECRSC-based, respectively). Our data show specific scene processing in the functionally connected ECPHC-based and distal subiculum. Another route, that functionally connects the ECArea35-based and a newly identified ECRSC-based with the subiculum/CA1 border, however, shows no selectivity between object and scene conditions. Our results are consistent with transversal information-specific pathways in the human entorhinal-hippocampal circuitry, with anatomically organized convergence of cortical processing streams and a unique route for scene information. Our study thus further characterizes the functional organization of this circuitry and its information-specific role in memory function.
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| 20. |
- Grande, Xenia, et al.
(författare)
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Ultra-high field imaging of the human medial temporal lobe
- 2023. - 1
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Ingår i: Ultra-High Field Neuro MRI. - 9780323999533 - 9780323998987 ; 10, s. 259-259
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Ultra-high field (UHF) imaging provides substantial benefits for the structural and functional investigation of the human medial temporal lobe. The medial temporal lobe is a complex system of many subregions that is critically involved in many cognitive functions and vulnerable to neurodegenerative processes. Here, we first lay out the benefits of UHF imaging for visualizing anatomical features with high resolution to delineate subregions. We provide examples of structural imaging studies that critically rely on UHF imaging. Second, we point out how UHF functional imaging advances the investigation of the functional organization of the medial temporal lobe and its involvement in cognitive processes. Examples are given for how UHF imaging is used here to reveal critical mechanisms and information flow on the subregional and layer-specific levels. Finally, we highlight motion and signal dropout as challenges of structural and functional UHF and conclude with perspectives for UHF imaging in the future.
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| 21. |
- Güsten, Jeremie, et al.
(författare)
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Age impairs mnemonic discrimination of objects more than scenes : A web-based, large-scale approach across the lifespan
- 2021
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Ingår i: Cortex. - : Elsevier BV. - 0010-9452. ; 137, s. 138-148
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings suggest that the effect of aging on recognition memory is modality-dependent, affecting memory for objects and scenes differently. However, the lifespan trajectory of memory decline in these domains remains unclear. A major challenge for assessing domain-specific trajectories is the need to utilize different types of stimuli for each domain (objects and scenes). We tested the large sample required to cover much of the adult lifespan using a large stimulus range via web-based assessments. 1554 participants (18–77 years) performed an online mnemonic discrimination task, tested on a pool of 2708 stimuli (Berron et al., 2018). Using corrected hit-rate (Pr) as a measure of performance, we show age-related decline in mnemonic discrimination in both domains, notably with a stronger decline in object memory, driven by a linear increase in the false recognition rate with advancing age. These data are the first to identify a linear age-related decline in mnemonic discrimination and a stronger, linear trajectory of decline in the object domain. Our data can inform basic and clinical memory research on the effects of aging on memory and help advancing the implementation of digital cognitive research tools.
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| 22. |
- Güsten, Jeremie, et al.
(författare)
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Bayesian modeling of item heterogeneity in dichotomous recognition memory data and prospects for computerized adaptive testing
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Most current models of recognition memory fail to separately model item and person heterogeneity which makes it difficult to assess ability at the latent construct level and prevents the administration of adaptive tests. Here we propose to employ a General Condorcet Model for Recognition (GCMR) in order to estimate ability, response bias and item difficulty in dichotomous recognition memory tasks. Using a Bayesian modeling framework and MCMC inference, we perform 3 separate validation studies comparing GCMR to the Rasch model from IRT and the 2-High-Threshold (2HT) recognition model. First, two simulations demonstrate that recovery of GCMR ability estimates with varying sparsity and test difficulty is more robust and that estimates improve from the two other models under common test scenarios. Then, using a real dataset, face validity is confirmed by replicating previous findings of general and domain-specific age effects (Güsten et al. in Cortex 137:138–148, https://doi.org/10.1016/j.cortex.2020.12.017, 2021). Using cross-validation we show better out-of-sample prediction for the GCMR as compared to Rasch and 2HT model. In addition, we present a hierarchical extension of the model that is able to estimate age- and domain-specific effects directly, without recurring to a two-stage procedure. Finally, an adaptive test using the GCMR is simulated, showing that the test length necessary to obtain reliable ability estimates can be significantly reduced compared to a non-adaptive procedure. The GCMR allows to model trial-by-trial performance and to increase the efficiency and reliability of recognition memory assessments.
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| 23. |
- Insel, Philip S., et al.
(författare)
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Time between milestone events in the Alzheimer's disease amyloid cascade
- 2021
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119. ; 227
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Estimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer's disease. Methods: In a cohort of 335 older adults, ranging in cognitive functioning, we estimated the time of initial changes of Aβ, tau, and decreases in cognition with respect to the time of Aβ-positivity. Results: Small effect sizes of change in CSF Aβ42 and regional Aβ PET were estimated to occur several decades before Aβ-positivity. Increases in CSF tau occurred 7–8 years before Aβ-positivity. Temporoparietal tau PET showed increases 4–5 years before Aβ-positivity. Subtle cognitive dysfunction was observed 4–6 years before Aβ-positivity. Conclusions: Increases in tau and cognitive dysfunction occur years before commonly used thresholds for Aβ-positivity. Explicit estimates of the time for these events provide a clearer picture of the time-course of the amyloid cascade and identify potential windows for specific treatments.
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| 24. |
- Janelidze, Shorena, et al.
(författare)
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Associations of Plasma Phospho-Tau217 Levels with Tau Positron Emission Tomography in Early Alzheimer Disease
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:2, s. 149-149
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Tidskriftsartikel (refereegranskat)abstract
- Importance: There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes. Objective: To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology. Design, Setting, and Participants: This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans. Main Outcomes and Measures: Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures. Results: Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P =.02). Conclusions and Relevance: In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.
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| 25. |
- Koster, Raphael, et al.
(författare)
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Big-Loop Recurrence within the Hippocampal System Supports Integration of Information across Episodes
- 2018
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273. ; 99:6, s. 6-1354
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Tidskriftsartikel (refereegranskat)abstract
- Recent evidence challenges the widely held view that the hippocampus is specialized for episodic memory, by demonstrating that it also underpins the integration of information across experiences. Contemporary computational theories propose that these two contrasting functions can be accomplished by big-loop recurrence, whereby the output of the system is recirculated back into the hippocampus. We use ultra-high-resolution fMRI to provide support for this hypothesis, by showing that retrieved information is presented as a new input on the superficial entorhinal cortex—driven by functional connectivity between the deep and superficial entorhinal layers. Further, the magnitude of this laminar connectivity correlated with inferential performance, demonstrating its importance for behavior. Our findings offer a novel perspective on information processing within the hippocampus and support a unifying framework in which the hippocampus captures higher-order structure across experiences, by creating a dynamic memory space from separate episodic codes for individual experiences. The hippocampus is central for storing distinct episodes, while also supporting integration across related episodes. Using ultra-high-resolution fMRI, Koster et al. provide evidence for a core computational principle (big-loop recurrence) that can account for these apparently conflicting hippocampal roles.
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| 26. |
- Loh, Eleanor, et al.
(författare)
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Parsing the Role of the Hippocampus in Approach-Avoidance Conflict
- 2017
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 27:1, s. 201-215
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampus plays a central role in the approach-avoidance conflict that is central to the genesis of anxiety. However, its exact functional contribution has yet to be identified. We designed a novel gambling task that generated approach-avoidance conflict while controlling for spatial processing. We fit subjects' behavior using a model that quantified the subjective values of choice options, and recorded neural signals using functional magnetic resonance imaging (fMRI). Distinct functional signals were observed in anterior hippocampus, with inferior hippocampus selectively recruited when subjects rejected a gamble, to a degree that covaried with individual differences in anxiety. The superior anterior hippocampus, in contrast, uniquely demonstrated value signals that were potentiated in the context of approach-avoidance conflict. These results implicate the anterior hippocampus in behavioral avoidance and choice monitoring, in a manner relevant to understanding its role in anxiety. Our findings highlight interactions between subregions of the hippocampus as an important focus for future study.
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| 27. |
- Maass, Anne, et al.
(författare)
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Alzheimer's pathology targets distinct memory networks in the ageing brain
- 2019
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 142:8, s. 2492-2509
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-β plaques and tau neurofibrillary tangles. Post-mortem studies indicate that in ageing and Alzheimer's disease tau tangles deposit early in the transentorhinal cortex, a region located in the anterior-temporal lobe that is critical for object memory. In contrast, amyloid-β pathology seems to target a posterior-medial network that subserves spatial memory. In the current study, we tested whether anterior-temporal and posterior-medial brain regions are selectively vulnerable to tau and amyloid-β deposition in the progression from ageing to Alzheimer's disease and whether this is reflected in domain-specific behavioural deficits and neural dysfunction. 11C-PiB PET and 18F-flortaucipir uptake was quantified in a sample of 131 cognitively normal adults (age: 20-93 years; 47 amyloid-β-positive) and 20 amyloid-β-positive patients with mild cognitive impairment or Alzheimer's disease dementia (65-95 years). Tau burden was relatively higher in anterior-temporal regions in normal ageing and this difference was further pronounced in the presence of amyloid-β and cognitive impairment, indicating exacerbation of ageing-related processes in Alzheimer's disease. In contrast, amyloid-β deposition dominated in posterior-medial regions. A subsample of 50 cognitively normal older (26 amyloid-β-positive) and 25 young adults performed an object and scene memory task while functional MRI data were acquired. Group comparisons showed that tau-positive (n = 18) compared to tau-negative (n = 32) older adults showed lower mnemonic discrimination of object relative to scene images [t(48) = -3.2, P = 0.002]. In a multiple regression model including regional measures of both pathologies, higher anterior-temporal flortaucipir (tau) was related to relatively worse object performance (P = 0.010, r = -0.376), whereas higher posterior-medial PiB (amyloid-β) was related to worse scene performance (P = 0.037, r = 0.309). The functional MRI data revealed that tau burden (but not amyloid-β) was associated with increased task activation in both systems and a loss of functional specificity, or dedifferentiation, in posterior-medial regions. The loss of functional specificity was related to worse memory. Our study shows a regional dissociation of Alzheimer's disease pathologies to distinct memory networks. While our data are cross-sectional, they indicate that with ageing, tau deposits mainly in the anterior-temporal system, which results in deficits in mnemonic object discrimination. As Alzheimer's disease develops, amyloid-β deposits preferentially in posterior-medial regions additionally compromising scene discrimination and anterior-temporal tau deposition worsens further. Finally, our findings propose that the progression of tau pathology is linked to aberrant activation and dedifferentiation of specialized memory networks that is detrimental to memory function.
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| 28. |
- Nyberg, Lars, 1966-, et al.
(författare)
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Forecasting memory function in aging : pattern-completion ability and hippocampal activity relate to visuospatial functioning over 25 years
- 2020
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 94, s. 217-226
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Tidskriftsartikel (refereegranskat)abstract
- Heterogeneity in episodic memory functioning in aging was assessed with a pattern-completion functional magnetic resonance imaging task that required reactivation of well-consolidated face-name memory traces from fragmented (partial) or morphed (noisy) face cues. About half of the examined individuals (N = 101) showed impaired (chance) performance on fragmented faces despite intact performance on complete and morphed faces, and they did not show a pattern-completion response in hippocampus or the examined subfields (CA1, CA23, DGCA4). This apparent pattern-completion deficit could not be explained by differential hippocampal atrophy. Instead, the impaired group displayed lower cortical volumes, accelerated reduction in mini-mental state examination scores, and lower general cognitive function as defined by longitudinal measures of visuospatial functioning and speed-of-processing. In the full sample, inter-individual differences in visuospatial functioning predicted performance on fragmented faces and hippocampal CA23 subfield activity over 25 years. These findings suggest that visuospatial functioning in middle age can forecast pattern-completion deficits in aging.
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| 29. |
- Olsen, Rosanna K., et al.
(författare)
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Progress update from the hippocampal subfields group
- 2019
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 11, s. 439-449
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence.METHODS: Our international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption.RESULTS: This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures.DISCUSSION: A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.
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| 30. |
- Stouffer, Kaitlin M, et al.
(författare)
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Amidst an amygdala renaissance in Alzheimer's disease
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Ingår i: Brain : a journal of neurology. - 1460-2156.
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Tidskriftsartikel (refereegranskat)abstract
- The amygdala was highlighted as an early site for neurofibrillary tau tangle pathology in Alzheimer's disease in the seminal Braak & Braak article (1991). This knowledge has, however, only received traction recently with advances in imaging and image analysis techniques. Here, we provide a cross-disciplinary overview of pathology and neuroimaging studies on the amygdala. These studies provide strong support for an early role of the amygdala in Alzheimer's disease and the utility of imaging biomarkers of the amygdala in detecting early changes and predicting decline in cognitive functions and neuropsychiatric symptoms in early stages. We summarize the animal literature on connectivity of the amygdala, demonstrating that amygdala nuclei that show the earliest and strongest accumulation of neurofibrillary tangle pathology are those that are connected to brain regions that also show early neurofibrillary tangle accumulation. Additionally, we propose an alternative pathway of neurofibrillary tangle spreading within the medial temporal lobe between the amygdala and the anterior hippocampus. The proposed existence of this pathway is strengthened by novel experimental data on human functional connectivity. Finally, we summarize the functional roles of the amygdala, highlighting the correspondence between neurofibrillary tangle accumulation and symptomatic profiles in Alzheimer's disease. In summary, these findings provide a new impetus for studying the amygdala in Alzheimer's disease and a unique perspective to guide further study on neurofibrillary tangle spreading and the occurrence of neuropsychiatric symptoms in Alzheimer's disease.
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| 31. |
- Vieweg, Paula, et al.
(författare)
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Memory Image Completion : Establishing a task to behaviorally assess pattern completion in humans
- 2019
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 29:4, s. 340-351
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Tidskriftsartikel (refereegranskat)abstract
- For memory retrieval, pattern completion is a crucial process that restores memories from partial or degraded cues. Neurocognitive aging models suggest that the aged memory system is biased toward pattern completion, resulting in a behavioral preference for retrieval over encoding of memories. Here, we built on our previously developed behavioral recognition memory paradigm—the Memory Image Completion (MIC) task—a task to specifically target pattern completion. First, we used the original design with concurrent eye-tracking in order to rule out perceptual confounds that could interact with recognition performance. Second, we developed parallel versions of the task to accommodate test settings in clinical environments or longitudinal studies. The results show that older adults have a deficit in pattern completion ability with a concurrent bias toward pattern completion. Importantly, eye-tracking data during encoding could not account for age-related performance differences. At retrieval, spatial viewing patterns for both age groups were more driven by stimulus identity than by response choice, but compared to young adults, older adults' fixation patterns overlapped more between stimuli that they (wrongly) thought had the same identity. This supports the observation that older adults choose responses perceived as similar to a learned stimulus, indicating a bias toward pattern completion. Additionally, two shorter versions of the task yielded comparable results, and no general learning effects were observed for repeated testing. Together, we present evidence that the MIC is a reliable behavioral task that targets pattern completion, that is easily and repeatedly applicable, and that is made freely available online.
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| 32. |
- Wisse, Laura E.M., et al.
(författare)
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Hippocampal subfield volumetry from structural isotropic 1 mm3 MRI scans : A note of caution
- 2021
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Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 42:2, s. 539-550
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Tidskriftsartikel (refereegranskat)abstract
- Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.
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| 33. |
- Wuestefeld, Anika, et al.
(författare)
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Age-related tau-PET uptake and its downstream effects extend beyond the medial temporal lobe in cognitively normal older adults
- 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: Amyloid-beta (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe (MTL). However, there is evidence that age-related Aβ-independent tau pathology is present outside the MTL (Kaufman et al., Acta Neuropathol, 2018). We examine tau deposition determined by positron emission tomography (PET) in regions typically involved earlier/later in AD and downstream effects on neurodegeneration and cognition in cognitively unimpaired older adults and a low-Aβ subgroup. Methods: We included 488 adults (40-91 years; low-Aβ: n=355, 65.2±11.5 years) from the BioFINDER-2 study. MTL volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex) were obtained, using Automated Segmentation for Hippocampal Subfields packages for T1- and T2-weighted magnetic resonance images. Thickness of early/late neocortical AD-regions (anterior cingulate, precuneus/posterior cingulate (PPC), orbitofrontal, inferior parietal cortex; and middle frontal, lateral occipital, and precentral/postcentral gyrus) was determined using FreeSurfer. [18F]RO948- and [18F]flutemetamol-PET standardized uptake value ratios (SUVRs) were calculated for local tau and global/local Aβ. Aβ status was determined using Aβ-PET or cerebrospinal fluid Aβ-42/40 ratio. Global cognition was measured using delayed word-list recall, trail making test B, and animal fluency. Results: Increasing age was associated with higher tau-PET SUVRs primarily in MTL/frontal/parietal regions. A significant association between age and local tau-PET remained even when including Aβ-PET as a mediator (Fig. 1). Age and local tau-PET, but not Aβ-PET, where negatively associated with structure in most examined regions (Figs. 2-3). Age-structure associations were serially mediated via tau-PET in regions with early AD pathology (SUB/BA35/PPC). Also, in the low-Aβ subgroup, tau-PET mediated the age-structure (SUB/BA35/PPC) associations (Fig. 3D). Finally, the age-global cognition relationship was serially mediated via MTL tau-PET and subiculum volume, even when including global Aβ-PET as additional mediator (Fig. 4). Conclusion: We observe partially Aβ-independent associations between age and tau-PET signal across the neocortex. Interestingly, partially Aβ-independent tau-PET signal appears to mediate the age-structure associations in and outside the MTL (PPC), also in the low-Aβ group, and the age-MTL structure-cognition associations. This potentially provides in vivo support for Primary Age-related Tauopathy downstream effects on structure, beyond the MTL, and cognition.
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| 34. |
- Wuestefeld, Anika, et al.
(författare)
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Medial temporal lobe atrophy patterns in early- versus late-onset amnestic Alzheimer's disease
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfield volumes and drivers of atrophy in amnestic EOAD is lacking.METHODS: BioFINDER-2 participants with memory impairment, abnormal amyloid-β status and tau-PET were included. Forty-one EOAD individuals aged ≤65 years and, as comparison, late-onset AD (LOAD, ≥70 years, n=154) and Aβ-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured.RESULTS: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups, although LOAD showed thinner entorhinal cortices compared to EOAD. EOAD showed lower WMH compared to LOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity was found.CONCLUSIONS: We found in vivo evidence for MTL atrophy in amnestic EOAD and overall similar levels to LOAD of MTL tau pathology and co-pathologies.
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| 35. |
- Young, Peter N.E., et al.
(författare)
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Imaging biomarkers in neurodegeneration : Current and future practices
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Forskningsöversikt (refereegranskat)abstract
- There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course "Biomarkers in neurodegenerative diseases". In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.
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| 36. |
- Öhman, Fredrik, et al.
(författare)
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Current advances in digital cognitive assessment for preclinical Alzheimer's disease
- 2021
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- There is a pressing need to capture and track subtle cognitive change at the preclinical stage of Alzheimer's disease (AD) rapidly, cost-effectively, and with high sensitivity. Concurrently, the landscape of digital cognitive assessment is rapidly evolving as technology advances, older adult tech-adoption increases, and external events (i.e., COVID-19) necessitate remote digital assessment. Here, we provide a snapshot review of the current state of digital cognitive assessment for preclinical AD including different device platforms/assessment approaches, levels of validation, and implementation challenges. We focus on articles, grants, and recent conference proceedings specifically querying the relationship between digital cognitive assessments and established biomarkers for preclinical AD (e.g., amyloid beta and tau) in clinically normal (CN) individuals. Several digital assessments were identified across platforms (e.g., digital pens, smartphones). Digital assessments varied by intended setting (e.g., remote vs. in-clinic), level of supervision (e.g., self vs. supervised), and device origin (personal vs. study-provided). At least 11 publications characterize digital cognitive assessment against AD biomarkers among CN. First available data demonstrate promising validity of this approach against both conventional assessment methods (moderate to large effect sizes) and relevant biomarkers (predominantly weak to moderate effect sizes). We discuss levels of validation and issues relating to usability, data quality, data protection, and attrition. While still in its infancy, digital cognitive assessment, especially when administered remotely, will undoubtedly play a major future role in screening for and tracking preclinical AD.
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| 37. |
- Öhman, Fredrik, et al.
(författare)
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Smartphone-based long-term delayed memory performance is associated with the Preclinical Alzheimer's Cognitive Composite and CSF levels of β-amyloid.
- 2022
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 18:S2
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Tidskriftsartikel (refereegranskat)abstract
- Remote and unsupervised cognitive testing using smartphones may improve sensitivity to detect preclinical Alzheimer's disease (AD). In particular, cognitive testing at-home enables the evaluation of the potentially more sensitive long-term delayed memory retrieval, which is commonly not feasible in a clinical setting.Here, we investigated the association between remote and unsupervised smartphone-based cognitive assessments and in-clinic cognitive measurement in older participants (CDR = 0, MMSE = 29.2, age = 77). The sample (non-demented at age 70) was derived from the Swedish population-based Gothenburg H70 Birth Cohort Studies. In a subsample of participants, the retrospective correlation with cerebrospinal fluid (CSF) biomarkers analyzed at age 70 was further explored. To this point, 177 H70-participants have consented and were enrolled into the smartphone sub-study. They completed an "Object-in-Room Recall Test" (ORR) remotely and unsupervised using own mobile devices, and the recall session was initiated 24 hours after the initial learning phase. Available previously assessed CSF measures included the Aβ42/Aβ40-ratio, t-tau, p-tau, neurofilament light (NFL), and neurogranin, available in-clinic cognitive tests included the Rey Auditory Verbal Learning Test (RAVLT), Semantic Fluency, Digit-Symbol-Coding, and Mini Mental State Examination. The above-mentioned cognitive tests were used to derive the Preclinical Alzheimer's Cognitive Composite (PACC5), a composite designed to be sensitive to cognitive change in preclinical AD. All associations were examined using Pearson correlation coefficient.Preliminary analyses in a subset of participants yielded relatively strong positive correlations between PACC5 (R = .50, p<.001) and the ORR Long-term Delayed Retrieval. The strongest correlation for an individual test was observed between the RAVLT Delayed Retrieval and the ORR Long-term Delayed Retrieval (R = .52, p<.001). Regarding the CSF biomarkers, Aβ42/Aβ40-ratio at age 70 was positively correlated with the ORR Long-term Delayed Retrieval at age 77 (R = .43, p<.01), while measures of t-tau, p-tau, NFL, and neurogranin at age 70 were not.Our findings demonstrate the potential of smartphone-based cognitive assessment to detect features of preclinical AD in a population-based sample of older adults. Future analyses will address the relationship between these novel cognitive measures in relation to longitudinal CSF- and neuroimaging-based biomarkers and clinical progression.
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| 38. |
- Öhman, Fredrik, et al.
(författare)
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Unsupervised mobile app-based cognitive testing in a population-based study of older adults born 1944
- 2022
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Ingår i: Frontiers in Digital Health. - : Frontiers Media SA. - 2673-253X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mobile app-based tools have the potential to yield rapid, cost-effective, and sensitive measures for detecting dementia-related cognitive impairment in clinical and research settings. At the same time, there is a substantial need to validate these tools in real-life settings. The primary aim of this study was thus to evaluate the feasibility, validity, and reliability of mobile app-based tasks for assessing cognitive function in a population-based sample of older adults. Method: A total of 172 non-demented (Clinical Dementia Rating 0 and 0.5) older participants (aged 76–77) completed two mobile app-based memory tasks—the Mnemonic Discrimination Task for Objects and Scenes (MDT-OS) and the long-term (24h) delayed Object-In-Room Recall Task (ORR-LDR). To determine the validity of the tasks for measuring relevant cognitive functions in this population, we assessed relationships with conventional cognitive tests. In addition, psychometric properties, including test-retest reliability, and the participants’ self-rated experience with mobile app-based cognitive tasks were assessed. Result: MDT-OS and ORR-LDR were weakly-to-moderately correlated with the Preclinical Alzheimer's Cognitive Composite (PACC5) (r = 0.3–0.44, p <.001) and with several other measures of episodic memory, processing speed, and executive function. Test-retest reliability was poor–to-moderate for one single session but improved to moderate–to-good when using the average of two sessions. We observed no significant floor or ceiling effects nor effects of education or gender on task performance. Contextual factors such as distractions and screen size did not significantly affect task performance. Most participants deemed the tasks interesting, but many rated them as highly challenging. While several participants reported distractions during tasks, most could concentrate well. However, there were difficulties in completing delayed recall tasks on time in this unsupervised and remote setting. Conclusion: Our study proves the feasibility of mobile app-based cognitive assessments in a community sample of older adults, demonstrating its validity in relation to conventional cognitive measures and its reliability for repeated measurements over time. To further strengthen study adherence, future studies should implement additional measures to improve task completion on time.
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