Search

In the alpaca brainstem, the distribution of the cholinergic system by the immunohistochemical detection of the enzyme choline acetyltransferase (ChAT) has been described, and its relationship with the distribution of somatostatin-28(1-12) is analyzed by double-immunostaining techniques. Overlapping distribution patterns for both substances were observed in many brainstem regions, suggesting that interactions between them may occur in the reticular formation, nucleus ambiguus or laterodorsal tegmental nucleus. Colocalization of the two substances in the same cell bodies was only observed in restricted areas, such as the nucleus of the solitary tract, reticular formation and nucleus ambiguus. In addition, in several regions, an apparent high innervation of the peptidergic fibers on cholinergic neurons has been observed. The results suggest that chemospecific interactions could be crucial for the control of specific cardiorespiratory and/or digestive functions in alpacas. These interactions may represent brain-adaptive mechanisms to particular environments and have a potential therapeutic use in respiratory disorders.

To know the processes involved in feeding, the dysregulation of hypothalamic neuropeptides promoting anorexigenic/orexigenic mechanisms must be investigated. Many neuropeptides are involved in this behavior and in overweight/obesity. Current pharmacological strategies for the treatment of obesity are unfortunately not very effective and, hence, new therapeutic strategies must be investigated and developed. Due to the crucial role played by orexins in feeding behavior, the aim of this review is to update the involvement of the orexinergic system in this behavior. The studies performed in experimental animal models and humans and the relationships between the orexinergic system and other substances are mentioned and discussed. Promising research lines on the orexinergic system are highlighted (signaling pathways, heterogeneity of the hypothalamic orexinergic neurons, receptor-receptor interaction, and sex differences). Each of the orexin 1 and 2 receptors plays a unique role in energy metabolism, exerting a differential function in obesity. Additional preclinical/clinical studies must be carried out to demonstrate the beneficial effects mediated by orexin receptor antagonists. Because therapies applied are in general ineffective when they are directed against a single target, the best option for successful anti-obesity treatments is the development of combination therapies as well as the development of new and more specific orexin receptor antagonists.

Neurodegenerative disorders are associated with different pathologies that often co-occur but cannot be measured specifically with in vivo methods.Thirty-three brain hemispheres from donors with an Alzheimer's disease (AD) spectrum diagnosis underwent T2-weighted magnetic resonance imaging (MRI). Gray matter thickness was paired with histopathology from the closest anatomic region in the contralateral hemisphere.Partial Spearman correlation of phosphorylated tau and cortical thickness with TAR DNA-binding protein 43 (TDP-43) and α-synuclein scores, age, sex, and postmortem interval as covariates showed significant relationships in entorhinal and primary visual cortices, temporal pole, and insular and posterior cingulate gyri. Linear models including Braak stages, TDP-43 and α-synuclein scores, age, sex, and postmortem interval showed significant correlation between Braak stage and thickness in the parahippocampal gyrus, entorhinal cortex, and Broadman area 35.We demonstrated an association of measures of AD pathology with tissue loss in several AD regions despite a limited range of pathology in these cases.Neurodegenerative disorders are associated with co-occurring pathologies that cannot be measured specifically with in vivo methods. Identification of the topographic patterns of these pathologies in structural magnetic resonance imaging (MRI) may provide probabilistic biomarkers. We demonstrated the correlation of the specific patterns of tissue loss from ex vivo brain MRI with underlying pathologies detected in postmortem brain hemispheres in patients with Alzheimer's disease (AD) spectrum disorders. The results provide insight into the interpretation of in vivo structural MRI studies in patients with AD spectrum disorders.

Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01275-7.

The perinatal period, sensitive for newborn survival, is also one of the most critical moments in human brain development. Perinatal hypoxia due to reduced blood supply to the brain (ischemia) is one of the main causes of neonatal mortality. Brain damage caused by perinatal hypoxia–ischemia (HI) can lead to neuro‐ and psychological disorders. However, its impact seems to be region‐dependent, with the hippocampus being one of the most affected areas. Among the neuronal populations of the hippocampus, some interneuron groups – such as somatostatin‐ or neuropeptide Y‐expressing neurons – seem to be particularly vulnerable. The limited information available about the effects of HI in the hippocampus comes mainly from animal models and adult human studies. This article presents an immunohistochemical analysis of somatostatin (SOM) and neuropeptide Y (NPY) expression in the developing human hippocampus after perinatal HI. Two rostrocaudal sections of the body of the hippocampus were analysed, and the number of immunostained cells in the polymorphic layer of the dentate gyrus (DG) and the pyramidal cell layer and stratum oriens of the CA3, CA2 and CA1 fields of the hippocampus proper were quantified. The results showed a lower density of both neuropeptides in hypoxic compared to control cases. In the HI group, the number of SOM‐immunoreactive cell bodies was statistically significantly lower in the pyramidal cell layer and stratum oriens of CA1, while the number of NPY‐expressing neurons was statistically lower in the pyramidal cell layer of CA2. Besides, the number of SOM‐expressing neurons was significantly higher in the stratum oriens of CA1 compared to that in CA2. In sum, we observed a different vulnerability of SOM‐ and NPY‐containing neurons in the developing human hippocampus following perinatal HI damage. Our results could contribute to a better understanding of the behaviour of these neuronal populations under stressful conditions during the perinatal period., Hypoxia‐ischemia during the perinatal period could damage the hippocampal interneuron populations which might lead to the appearance of different problems during subsequent development. Interneurons containing Somatostatin and Neuropeptide Y located in the hippocampal ammonic fields are affected differently, although there is a global reduction after suffering perinatal hypoxia‐ischemia. This work is the first study that describes this issue in depth in the developmental human hippocampus.

Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on conventional 2D histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe (MTL) specimens were used to construct 3D quantitative maps of NFT burden in the MTL at individual and group levels. These maps reveal significant variation in NFT burden along the anterior-posterior axis. While early NFT pathology is thought to be confined to the transentorhinal region, we find similar levels of NFT burden in this region and other MTL subregions, including amygdala, temporopolar cortex, and subiculum/CA1.

Neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s Disease (AD). In this work, we investigate the relationship between MTL morphometry features derived from high-resolution ex vivo imaging and histology-based measures of NFT pathology using a topological unfolding framework applied to a dataset of 18 human postmortem MTL specimens. The MTL has a complex 3D topography and exhibits a high degree of inter-subject variability in cortical folding patterns which poses a significant challenge for volumetric registration methods typically used during MRI template construction. By unfolding the MTL cortex, the proposed framework explicitly accounts for the sheet-like geometry of the MTL cortex and provides a two-dimensional reference coordinate space which can be used to implicitly register cortical folding patterns across specimens based on distance along the cortex despite large anatomical variability. Leveraging this framework in a subset of 15 specimens, we characterize the associations between NFTs and morphological features such as cortical thickness and surface curvature and identify regions in the MTL where patterns of atrophy are strongly correlated with NFT pathology.

Tau protein neurofibrillary tangles (NFT) are linked to neuronal and synaptic loss and cognitive decline in Alzheimer's disease (AD) and related dementias. In AD, NFT pathology is known to spread through the cortex in a characteristic pattern, starting in the medial temporal lobe. However, the exact 3D pattern of NFT progression has not been described, and capturing this pattern quantitatively can help inform in vivo AD imaging biomarkers. We present a computational framework for generating 3D maps of NFT load from ex vivo MRI and serial histology. Weakly supervised deep learning is used to detect NFTs on histology slides prepared with an anti-tau immunohistochemistry stain, and a multi-stage registration pipeline that leverages 3D printing is used for histology-MRI alignment. Derived maps of NFT density are strongly concordant with manual NFT counting, as well as categorical NFT severity ratings used for clinical diagnosis.

Earliest neuropathological changes in Alzheimer's Disease (AD) emerge in the medial temporal lobe (MTL). In order for MRI biomarkers to detect changes linked specifically to AD pathology (as opposed to aging or other pathological factors) macroscopic patterns of structural change in the MTL must be linked to the underlying neuropathology. To provide such a linkage, we are conducting an autopsy imaging study combining ex vivo MRI and serial histopathology. Information from multiple subjects can be studied by creating a “population average” atlas of the MTL. We present a groupwise registration approach for constructing the atlas that is able to successfully capture the complex structure of the MTL, and anatomical variability across subjects. This atlas allows us to generate maps of cortical thickness measurements and identify regions in the MTL where structural changes correlate most strongly with AD progression. We show that using this atlas, we are able to find a significant correlation between atrophy and AD pathology in the MTL sub-regions associated with the earliest stages of AD pathology as described by Braak and Braak [1].