A non-invasive hidden-goal test for spatial orientation deficit detection in subjects with suspected mild cognitive impairment

Bažadona, Danira; Fabek, Ivan; Leko, Mirjana Babić; Rasonja, Mihaela Bobić; Kalinić, Dubravka; Bilić, Ervina; Raguž, Jakov Domagoj; Mímica, Ninoslav; Borovečki, Fran; Hof, Patrick R.; Šimić, Goran

doi:10.1016/j.jneumeth.2019.108547

Cited by 9 publications

(5 citation statements)

References 37 publications

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“…The major developmental events in EC structure and connectivity have broad implications for understanding its normal function, hemispheric asymmetry, modular variability, age‐related changes (Šimić et al., 2005) as well as deficits in brain diseases, such as epilepsy, autism spectrum disorder, schizophrenia, or Alzheimer's disease (Bažadona et al., 2020; Babić Leko et al., 2021; Jazvinšćak Jembrek et al., 2015; Kobro‐Flatmoen et al., 2021; Mladinov et al., 2016; Mihelčić et al., 2017; Palmen et al., 2004; Polšek et al., 2011; Šimić et al., 1997; 2000; 2009; 2014; 2016; 2017; 2019; Špeljko et al., 2011; Španić et al., 2019). The two main critical periods of EC development in human fetuses are the first period of intensive early histogenetic differentiation between 10 and 14 w.g., and the second period of intensive development of EC afferent systems, which takes place from the 20th w.g.…”

Section: Discussionmentioning

confidence: 99%

Prenatal development of the human entorhinal cortex

Šimić

Krsnik

Knezović

et al. 2022

J of Comparative Neurology

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Little is known about the development of the human entorhinal cortex (EC), a major hub in a widespread network for learning and memory, spatial navigation, high‐order processing of object information, multimodal integration, attention and awareness, emotion, motivation, and perception of time. We analyzed a series of 20 fetal and two adult human brains using Nissl stain, acetylcholinesterase (AChE) histochemistry, and immunocytochemistry for myelin basic protein (MBP), neuronal nuclei antigen (NeuN), a pan‐axonal neurofilament marker, and synaptophysin, as well as postmortem 3T MRI. In comparison with other parts of the cerebral cortex, the cytoarchitectural differentiation of the EC begins remarkably early, in the 10th week of gestation (w.g.). The differentiation occurs in a superficial magnocellular layer in the deep part of the marginal zone, accompanied by cortical plate (CP) condensation and multilayering of the deep part of CP. These processes last until the 13–14th w.g. At 14 w.g., the superficial lamina dissecans (LD) is visible, which divides the CP into the lamina principalis externa (LPE) and interna (LPI). Simultaneously, the rostral LPE separates into vertical cell‐dense islands, whereas in the LPI, the deep LD emerges as a clear acellular layer. In the 16th w.g., the LPE remodels into vertical cell‐dense and cell‐sparse zones with a caudorostral gradient. At 20 w.g., NeuN immunoreactivity is most pronounced in the islands of layer II cells, whereas migration and differentiation inside‐out gradients are seen simultaneously in both the upper (LPE) and the lower (LPI) pyramidal layers. At this stage, the EC adopts for the first time an adult‐like cytoarchitectural organization, the superficial LD becomes discernible by 3T MRI, MBP‐expressing oligodendrocytes first appear in the fimbria and the perforant path (PP) penetrates the subiculum to reach its molecular layer and travels along through the Cornu Ammonis fields to reach the suprapyramidal blade of the dentate gyrus, whereas the entorhinal‐dentate branch perforates the hippocampal sulcus about 2–3 weeks later. The first AChE reactivity appears as longitudinal stripes at 23 w.g. in layers I and II of the rostrolateral EC and then also as AChE‐positive in‐growing fibers in islands of superficial layer III and layer II neurons. At 40 w.g., myelination of the PP starts as patchy MBP‐immunoreactive oligodendrocytes and their processes. Our results refute the possibility of an inside‐out pattern of the EC development and support the key role of layer II prospective stellate cells in the EC lamination. As the early cytoarchitectural differentiation of the EC is paralleled by the neurochemical development, these developmental milestones in EC structure and connectivity have implications for understanding its normal function, including its puzzling modular organization and potential contribution to consciousness content (awareness), as well as for its insufficiently explored deficits in developmental, psychiatric, and degenerative brain disorders.

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Section: Discussionmentioning

confidence: 99%

Prenatal development of the human entorhinal cortex

Šimić

Krsnik

Knezović

et al. 2022

J of Comparative Neurology

Self Cite

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“…We have compared the evaluation of human spatial navigation obtained with previously validated tests to a new system composed of a multi-test circular arena and a novel protocol simulating a complex maze. Our arena is freely inspired by previously reported circular mazes [28][29][30] including a new system with a laser beam to point a spot in any position on the floor, inside wall-screens to present spatial cues, and a video camera to track the path and distances, able to recreate many different spatial navigation tests for humans, and versatile enough to implement new protocols. The new system was created with the goal of including free body movement, in a complex maze, in real space, but all enclosed in a reduced space, while allowing evaluation of both egocentric and allocentric navigation, neural activity recording, and difficulty level customization, in all cases if/when required.…”

Section: Discussionmentioning

confidence: 99%

“…However, the relative limitation to free movement is still a challenge [25][26][27]. To solve this problem, circular mazes for humans have been developed [28] allowing us to compare interventions and therapies both in laboratory rodents and humans, by using tests relying on the same conceptual features, as is the case for the hidden goal test and the one presented here.…”

Section: Introductionmentioning

confidence: 99%

A Multiple-Choice Maze-like Spatial Navigation Task for Humans Implemented in a Real-Space, Multipurpose Circular Arena

et al. 2022

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Spatial navigation is a key aspect of human behavior and it is still not completely understood. A number of experimental approaches exist, although most of the published data in the last decades have relied on virtual maze on-screen simulation or not-completely freely moving 3D devices. Some interesting recent developments, such as circular mazes, have contributed to analyze critical aspects of freely moving human spatial navigation in real space, although dedicated protocols only allow for simple approaches. Here, we have developed both specifically designed and home-assembled hardware equipment, and a customized protocol for spatial navigation evaluation in freely moving humans in a real space circular arena. The spatial navigation protocol poses an imitation of a real-space multiple-choice path maze with cul-de-sac and instances of non-linear movement. We have compared the results of this system to those of a number of validated, both virtual and real, spatial navigation tests in a group of participants. The system composed by hardware, the test protocol, and dedicated measure analysis designed in our laboratory allows us to evaluate human spatial navigation in a complex maze with a small and portable structure, yielding a highly flexible, adaptable, and versatile access to information about the subjects’ spatial navigation abilities.

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“…In contrast, the lateral EC is strongly connected with olfactory areas, insular, medial- and orbitofrontal areas, and the perirhinal cortex—these areas are likely more involved in the processing of object information, attention, and motivation [ 66 ]. Therefore, from an anatomical and functional point of view, the procedure of injection of tau into the mEC mimics neurofibrillary changes that occur in early AD and is responsible for cognitive decline and spatial disorientation seen in humans [ 67 ].…”

Section: Methodsmentioning

confidence: 99%

Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model

et al. 2023

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The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some aspects of in vivo tau spreading have been replicated in transgenic mice models expressing a mutated human MAPT (tau) gene and in wild-type mice. In this study, we aimed to characterize the propagation of different forms of tau species in non-transgenic 3–4 months old wild-type rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether different variants of the inoculated human tau protein, tau fibrils, and tau oligomers, would induce similar neurofibrillary changes and propagate in an AD-related pattern, and how tau-related pathological changes would correlate with presumed cognitive impairment. We injected human tau fibrils and tau oligomers stereotaxically into the mEC and examined the distribution of tau-related changes at 3 days and 4, 8, and 11 months post-injection using antibodies AT8 and MC1, which reveal early phosphorylation and aberrant conformation of tau, respectively, HT7, anti-synaptophysin, and the Gallyas silver staining method. Human tau oligomers and tau fibrils exhibited some similarities and some differences in their ability to seed and propagate tau-related changes. Both human tau fibrils and tau oligomers rapidly propagated from the mEC anterogradely into the hippocampus and various parts of the neocortex. However, using a human tau-specific HT7 antibody, 3 days post-injection we found inoculated human tau oligomers in the red nucleus, primary motor, and primary somatosensory cortex, a finding not seen in animals inoculated with human tau fibrils. In animals inoculated with human tau fibrils, 3 days post-injection the HT7 antibody showed fibrils in the pontine reticular nucleus, a finding explained only by uptake of human tau fibrils by incoming presynaptic fibers to the mEC and retrograde transport of inoculated human tau fibrils to the brainstem. Rats inoculated with human tau fibrils showed as early as 4 months after inoculation a spread of phosphorylated tau protein at the AT8 epitopes throughout the brain, dramatically faster propagation of neurofibrillary changes than with human tau oligomers. The overall severity of tau protein changes 4, 8, and 11 months after inoculation of human tau oligomers and tau fibrils correlated well with spatial working memory and cognition impairments, as measured by the T-maze spontaneous alternation, novel object recognition, and object location tests. We concluded that this non-trangenic rat model of tauopathy, especially when using human tau fibrils, demonstrates rapidly developing pathologic alterations in neurons, synapses, and identifiable pathways together with cognitive and behavioral changes, through the anterograde and retrograde spreading of neurofibrillary degeneration. Therefore, it represents a promising model for future experimental studies of primary and secondary tauopathies, especially AD.

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A non-invasive hidden-goal test for spatial orientation deficit detection in subjects with suspected mild cognitive impairment

Cited by 9 publications

References 37 publications

Prenatal development of the human entorhinal cortex

Prenatal development of the human entorhinal cortex

A Multiple-Choice Maze-like Spatial Navigation Task for Humans Implemented in a Real-Space, Multipurpose Circular Arena

Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model

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