| 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. |
- Ferreira, Daniel, et al.
(författare)
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The interactive effect of demographic and clinical factors on hippocampal volume : A multicohort study on 1958 cognitively normal individuals
- 2017
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 27:6, s. 653-667
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.
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| 3. |
- Rauramaa, Tuomas, et al.
(författare)
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Cardiovascular diseases and hippocampal infarcts
- 2011
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 21:3, s. 281-287
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of hippocampal lesions such as hippocampal infarcts have not been studied in detail even though hippocampal alterations are known to be associated with various clinical conditions such as age-related degenerative disorders and epilepsy. Methods: Here we defined the hippocampal infarcts and assessed the prevalence of this lesion in large unselected population of 1,245 subjects age ranging from 1 to 99 years (mean age 79 +/- 1 S.E.M). Furthermore, we assessed the association of these lesions with various cardio- and cerebro-vascular disorders and other neurodegenerative lesions. The prevalence of hippocampal infarct in the study population of 1,245 subjects was 12%, increasing to 13% when only those with a clinically diagnosed cognitive impairment (n = 311) were analyzed. Large hemispheric brain infarcts were seen in 31% of the study subjects and these lesions were strongly associated with cardiovascular risk factors such as hypertension (43%), coronary disease (32%), myocardial infarct (22%), atrial fibrillation (20%), and heart failure (20%). In contrast, hippocampal infarcts displayed a significant association only with large hemispheric brain infarct, heart failure, and cardiovascular index as assessed postmortem. It is noteworthy that only widespread hippocampal infarcts were associated with clinical symptoms of cognitive impairment or epilepsy. The surprisingly low prevalence of 12% of hippocampal infarcts in aged population found here and the failure to detect an association between this lesion and various cerebro- cardio-vascular lesions is intriguing. Whether susceptibility to ischemia in line with susceptibility to neuronal degeneration in this region is influenced by still undetermined risk- factors need further investigation. Furthermore it should be noted that the size of the hippocampal tissue damage, i.e., small vs. large cystic infarcts is of significance regarding clinical alterations.
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| 4. |
- Toft Sörensen, Andreas, et al.
(författare)
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NPY gene transfer in the hippocampus attenuates synaptic plasticity and learning.
- 2008
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 18:6, s. 564-574
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Tidskriftsartikel (refereegranskat)abstract
- Recombinant adeno-associated viral (rAAV) vector-induced neuropeptide Y (NPY) overexpression in the hippocampus exerts powerful antiepileptic and antiepileptogenic effects in rats. Such gene therapy approach could be a valuable alternative for developing new antiepileptic treatment strategies. Future clinical progress, however, requires more detailed evaluation of possible side effects of this treatment. Until now it has been unknown whether rAAV vector-based NPY overexpression in the hippocampus alters normal synaptic transmission and plasticity, which could disturb learning and memory processing. Here we show, by electrophysiological recordings in CA1 of the hippocampal formation of rats, that hippocampal NPY gene transfer into the intact brain does not affect basal synaptic transmission, but slightly alters short-term synaptic plasticity, most likely via NPY Y2 receptor-mediated mechanisms. In addition, transgene NPY seems to be released during high frequency neuronal activity, leading to decreased glutamate release in excitatory synapses. Importantly, memory consolidation appears to be affected by the treatment. We found that long-term potentiation (LTP) in the CA1 area is partially impaired and animals have a slower rate of hippocampal-based spatial discrimination learning. These data provide the first evidence that rAAV-based gene therapy using NPY exerts relative limited effect on synaptic plasticity and learning in the hippocampus, and therefore this approach could be considered as a viable alternative for epilepsy treatment. (c) 2008 Wiley-Liss, Inc.
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| 5. |
- 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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| 6. |
- Zappa Villar, María Florencia, et al.
(författare)
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Insulin-like growth factor 1 gene transfer for sporadic Alzheimer's disease : New evidence for trophic factor mediated hippocampal neuronal and synaptic recovery-based behavior improvement
- 2021
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 31:10, s. 1137-1153
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Tidskriftsartikel (refereegranskat)abstract
- Sporadic Alzheimer's disease (sAD) is the most prevalent neurodegenerative disorder with no cure. Patients typically suffer from cognitive impairment imprinted by irreversible neocortex and hippocampal degeneration with overt synaptic and neuron dysfunction. Insulin-like growth factor 1 (IGF1) has proven to be a potent neuroprotective molecule in animal models of age-related neurodegeneration. In this regard, adenoviral gene transfer aiming at IGF1 brain overexpression has been hitherto an underexplored approach for the sAD treatment. We postulated enhanced IGF1 signaling in the brain as a restorative means in the diseased brain to revert cognitive deficit and restore hippocampal function. We implemented recombinant adenovirus mediated intracerebroventricular IGF1 gene transfer on the streptozotocin (STZ) induced sAD rat model, using 3-month-old male Sprague Dawley rats. This approach enhanced IGF1 signaling in the hippocampus and dampened sAD phosphorylated Tau. We found a remarkable short-term improvement in species-typical behavior, recognition memory, spatial memory, and depressive-like behavior. Histological analysis revealed a significant recovery of immature hippocampal neurons. We additionally recorded an increase in hippocampal microglial cells, which we suggest to exert anti-inflammatory effects. Finally, we found decreased levels of pre- and postsynaptic proteins in the hippocampus of STZ animals. Interestingly, IGF1 gene transfer increased the levels of PSD95 and GAD65/67 synaptic markers, indicating that the treatment enhanced the synaptic plasticity. We conclude that exogenous activation of IGF1 signaling pathway, 1 week after intracerebroventricular STZ administration, protects hippocampal immature neurons, dampens phosphorylated Tau levels, improves synaptic function and therefore performs therapeutically on the sAD STZ model. Hence, this study provides strong evidence for the use of this trophic factor to treat AD and age-related neurodegeneration.
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| 7. |
- Ledri, Marco, et al.
(författare)
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Tuning afferent synapses of hippocampal interneurons by neuropeptide Y.
- 2011
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Ingår i: Hippocampus. - : Wiley. - 1050-9631. ; 21, s. 198-211
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Tidskriftsartikel (refereegranskat)abstract
- Cholecystokinin (CCK)-expressing basket cells encompass a subclass of inhibitory GABAergic interneurons that regulate memory-forming oscillatory network activity of the hippocampal formation in accordance to the emotional and motivational state of the animal, conveyed onto these cells by respective extrahippocampal afferents. Various excitatory and inhibitory afferent and efferent synapses of the hippocampal CCK basket cells express serotoninergic, cholinergic, cannabinoid, and benzodiazepine sensitive receptors, all contributing to their functional plasticity. We explored whether CCK basket cells are modulated by neuropeptide Y (NPY), one of the major local neuropeptides that strongly inhibits hippocampal excitability and has significant effect on its memory function. Here, using GAD65-GFP transgenic mice for prospective identification of CCK basket cells and whole-cell patch-clamp recordings, we show for the first time that excitatory and inhibitory inputs onto CCK basket cells in the dentate gyrus of the hippocampus are modulated by NPY through activation of NPY Y2 receptors. The frequency of spontaneous and miniature EPSCs, as well as the amplitudes of stimulation-evoked EPSCs were decreased. Similarly, the frequency of both spontaneous and miniature IPSCs, and the amplitudes of stimulation-evoked IPSCs were decreased after NPY application. Most of the effects of NPY could be attributed to a presynaptic site of action. Our data provide the first evidence that the excitatory and inhibitory inputs onto the CCK basket cells could be modulated by local levels of NPY, and may change the way these cells process extrahippocampal afferent information, influencing hippocampal function and its network excitability during normal and pathological oscillatory activities. (c) 2009 Wiley-Liss, Inc.
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| 8. |
- Svensson, Maria, et al.
(författare)
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Effect of electroconvulsive seizures on cognitive flexibility.
- 2016
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Ingår i: Hippocampus. - : Wiley. - 1050-9631. ; 26:7, s. 899-910
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Tidskriftsartikel (refereegranskat)abstract
- Electroconvulsive seizures (ECS), an animal model of electroconvulsive therapy, strongly stimulate hippocampal neurogenesis, but it is not known how this relates to the therapeutic effect or to the unwanted cognitive side effects. Recent findings suggest that neurogenesis might be important for flexible learning in changing environments. We hypothesize that animals receiving ECS treatment, which induces hippocampal neurogenesis, will show enhanced cognitive flexibility compared with controls. We have utilized a touch screen based cognitive test (location discrimination (LD) task) to assess how five consecutive ECS treatments affect cognitive flexibility (measured as reversal of cognitive strategy) as well as spatial pattern separation ability. ECS-treated animals performed more reversals in the LD task earlier than controls over the nine experimental weeks irrespective of spatial separation of visual stimuli, indicating an enhanced cognitive flexibility but unaffected pattern separation ability after ECS. We observed no correlation between hippocampal neurogenesis and the number of performed reversals during the last experimental week. This is the first study to elucidate the effect of ECS on cognitive flexibility. Our results indicate that ECS improves cognitive flexibility without affecting spatial pattern separation ability. Whether cognitive flexibility is enhanced via neurogenesis or other ECS-modulated processes, remains unknown. This article is protected by copyright. All rights reserved.
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| 9. |
- Svensson, Maria, et al.
(författare)
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Effect of electroconvulsive seizures on pattern separation
- 2015
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Ingår i: Hippocampus. - : Wiley. - 1050-9631. ; 25:11, s. 1351-1360
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Tidskriftsartikel (refereegranskat)abstract
- Strategies employing different techniques to inhibit or stimulate neurogenesis have implicated a role for adult-born neurons in the therapeutic effect of antidepressant drugs, as well as a role in memory formation. Electroconvulsive seizures, an animal model of electroconvulsive therapy, robustly stimulate hippocampal neurogenesis but it is not known how this relates to either therapeutic efficacy or unwanted cognitive side effects. We hypothesized that the ECS-derived increase in adult-born neurons would manifest in improved pattern separation ability, a memory function that is believed to be both hippocampus-dependent and coupled to neurogenesis. To test this hypothesis, we stimulated neurogenesis in adult rats by treating them with a series of ECS and compared their performances in a trial-unique delayed nonmatching-to-location task (TUNL) to a control group. TUNL performance was analyzed over a 12-week period, during which newly formed neurons differentiate and become functionally integrated in the hippocampal neurocircuitry. Task difficulty was manipulated by modifying the delay between sample and choice, and by varying the spatial similarity between target and distracter location. Although animals learned the task and improved the number of correct responses over time, ECS did not influence spatial pattern separation ability.
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| 10. |
- 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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