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Alzheimer's Research & Therapy May 2024As one major symptom of Alzheimer's disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal...
BACKGROUND
As one major symptom of Alzheimer's disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD.
METHODS
mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK) mice. Animals' cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation.
RESULTS
Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists.
CONCLUSIONS
Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia.
Topics: Animals; Alzheimer Disease; Mice; Receptor, Cholecystokinin B; Amnesia, Anterograde; Cholecystokinin; Mice, Transgenic; Disease Models, Animal; Entorhinal Cortex; Male; Mice, Knockout; Mice, Inbred C57BL; Long-Term Potentiation; Hippocampus; Aging
PubMed: 38750512
DOI: 10.1186/s13195-024-01472-1 -
Nature Communications May 2024Visual information is important for accurate spatial coding and memory-guided navigation. As a crucial area for spatial cognition, the medial entorhinal cortex (MEC)...
Visual information is important for accurate spatial coding and memory-guided navigation. As a crucial area for spatial cognition, the medial entorhinal cortex (MEC) harbors diverse spatially tuned cells and functions as the major gateway relaying sensory inputs to the hippocampus containing place cells. However, how visual information enters the MEC has not been fully understood. Here, we identify a pathway originating in the secondary visual cortex (V2) and directly targeting MEC layer 5a (L5a). L5a neurons served as a network hub for visual processing in the MEC by routing visual inputs from multiple V2 areas to other local neurons and hippocampal CA1. Interrupting this pathway severely impaired visual stimulus-evoked neural activity in the MEC and performance of mice in navigation tasks. These observations reveal a visual cortical-entorhinal pathway highlighting the role of MEC L5a in sensory information transmission, a function typically attributed to MEC superficial layers before.
Topics: Animals; Entorhinal Cortex; Visual Cortex; Spatial Navigation; Mice; Neurons; Male; Mice, Inbred C57BL; Photic Stimulation; CA1 Region, Hippocampal; Visual Pathways; Visual Perception
PubMed: 38750027
DOI: 10.1038/s41467-024-48483-y -
Journal of Inflammation Research 2024Inflammatory Bowel Disease (IBD) patients may experience cognitive impairments in Visuospatial Working Memory (VSWM), significantly impacting their quality of life....
BACKGROUND
Inflammatory Bowel Disease (IBD) patients may experience cognitive impairments in Visuospatial Working Memory (VSWM), significantly impacting their quality of life. However, the mechanisms underlying these impairments remain poorly understood.
METHODS
We studied functional MRI and graph theory analysis to investigate changes in functional connectivity networks during the Mental Rotation Task (MRT) in IBD patients. Twenty IBD patients (13 males, 7 females; mean age = 34.95 ± 13.80 years; mean disease duration = 2.43 ± 2.37 years) participated in the study. Exclusion criteria encompassed recent use of analgesics, 5-Aminosalicylate, corticosteroids, or immunosuppressants within the past three months. Additionally, we recruited 20 age-, gender-, and education-matched healthy controls for comparison.
RESULTS
Compared to a control group, IBD patients exhibited significantly longer reaction times and reduced accuracy during the MRT. Our analysis revealed abnormalities in multiple nodal attributes within the functional connectivity network, particularly in regions such as the bilateral orbitofrontal cortex, right supplementary motor area, bilateral parahippocampal gyrus, and bilateral anterior temporal lobe. We observed that the nodal efficiency in the left temporal pole is negatively correlated with Red Blood Cell Distribution Width (RDW) and positively correlated with response time of MRT.
CONCLUSION
Our findings revealed notable abnormalities in multiple node attributes among IBD patients during MRT, providing evidence of cognitive impairments in VSWM in IBD patients. This study found RDW maybe can serve as a clinical indicator for predicting early VSWM impairment in patients with IBD.
PubMed: 38737113
DOI: 10.2147/JIR.S462268 -
NPJ Systems Biology and Applications May 2024Connectome studies have shown how Alzheimer's disease (AD) disrupts functional and structural connectivity among brain regions. But the molecular basis of such...
Connectome studies have shown how Alzheimer's disease (AD) disrupts functional and structural connectivity among brain regions. But the molecular basis of such disruptions is less studied, with most genomic/transcriptomic studies performing within-brain-region analyses. To inspect how AD rewires the correlation structure among genes in different brain regions, we performed an Inter-brain-region Differential Correlation (Inter-DC) analysis of RNA-seq data from Mount Sinai Brain Bank on four brain regions (frontal pole, superior temporal gyrus, parahippocampal gyrus and inferior frontal gyrus, comprising 264 AD and 372 control human post-mortem samples). An Inter-DC network was assembled from all pairs of genes across two brain regions that gained (or lost) correlation strength in the AD group relative to controls at FDR 1%. The differentially correlated (DC) genes in this network complemented known differentially expressed genes in AD, and likely reflects cell-intrinsic changes since we adjusted for cell compositional effects. Each brain region used a distinctive set of DC genes when coupling with other regions, with parahippocampal gyrus showing the most rewiring, consistent with its known vulnerability to AD. The Inter-DC network revealed master dysregulation hubs in AD (at genes ZKSCAN1, SLC5A3, RCC1, IL17RB, PLK4, etc.), inter-region gene modules enriched for known AD pathways (synaptic signaling, endocytosis, etc.), and candidate signaling molecules that could mediate region-region communication. The Inter-DC network generated in this study is a valuable resource of gene pairs, pathways and signaling molecules whose inter-brain-region functional coupling is disrupted in AD, thereby offering a new perspective of AD etiology.
Topics: Alzheimer Disease; Humans; Gene Regulatory Networks; Brain; Connectome; Transcriptome; Gene Expression Profiling; Male; Female; Aged
PubMed: 38724582
DOI: 10.1038/s41540-024-00376-y -
In Vivo Reactive Astrocyte Imaging in Patients With Schizophrenia Using Fluorine 18-Labeled THK5351.JAMA Network Open May 2024In vivo imaging studies of reactive astrocytes are crucial for understanding the pathophysiology of schizophrenia because astrocytes play a critical role in glutamate...
IMPORTANCE
In vivo imaging studies of reactive astrocytes are crucial for understanding the pathophysiology of schizophrenia because astrocytes play a critical role in glutamate imbalance and neuroinflammation.
OBJECTIVE
To investigate in vivo reactive astrocytes in patients with schizophrenia associated with positive symptoms using monoamine oxidase B (MAO-B)-binding fluorine 18 ([18F])-labeled THK5351 positron emission tomography (PET).
DESIGN, SETTING, AND PARTICIPANTS
In this case-control study, data were collected from October 1, 2021, to January 31, 2023, from the internet advertisement for the healthy control group and from the outpatient clinics of Seoul National University Hospital in Seoul, South Korea, for the schizophrenia group. Participants included patients with schizophrenia and age- and sex-matched healthy control individuals.
MAIN OUTCOMES AND MEASURES
Standardized uptake value ratios (SUVrs) of [18F]THK5351 in the anterior cingulate cortex (ACC) and hippocampus as primary regions of interest (ROIs), with other limbic regions as secondary ROIs, and the correlation between altered SUVrs and Positive and Negative Syndrome Scale (PANSS) positive symptom scores.
RESULTS
A total of 68 participants (mean [SD] age, 32.0 [7.0] years; 41 men [60.3%]) included 33 patients with schizophrenia (mean [SD] age, 32.3 [6.3] years; 22 men [66.7%]) and 35 healthy controls (mean [SD] age, 31.8 [7.6] years; 19 men [54.3%]) who underwent [18F]THK5351 PET scanning. Patients with schizophrenia showed significantly higher SUVrs in the bilateral ACC (left, F = 5.767 [false discovery rate (FDR)-corrected P = .04]; right, F = 5.977 [FDR-corrected P = .04]) and left hippocampus (F = 4.834 [FDR-corrected P = .04]) than healthy controls. Trend-level group differences between the groups in the SUVrs were found in the secondary ROIs (eg, right parahippocampal gyrus, F = 3.387 [P = .07]). There were positive correlations between the SUVrs in the bilateral ACC and the PANSS positive symptom scores (left, r = 0.423 [FDR-corrected P = .03]; right, r = 0.406 [FDR-corrected P = .03]) in patients with schizophrenia.
CONCLUSIONS AND RELEVANCE
This case-control study provides novel in vivo imaging evidence of reactive astrocyte involvement in the pathophysiology of schizophrenia. Reactive astrocytes in the ACC may be a future target for the treatment of symptoms of schizophrenia, especially positive symptoms.
Topics: Humans; Schizophrenia; Male; Female; Adult; Astrocytes; Case-Control Studies; Positron-Emission Tomography; Fluorine Radioisotopes; Gyrus Cinguli; Hippocampus
PubMed: 38722627
DOI: 10.1001/jamanetworkopen.2024.10684 -
Nature Communications May 2024Understanding the functional connectivity between brain regions and its emergent dynamics is a central challenge. Here we present a theory-experiment hybrid approach...
Understanding the functional connectivity between brain regions and its emergent dynamics is a central challenge. Here we present a theory-experiment hybrid approach involving iteration between a minimal computational model and in vivo electrophysiological measurements. Our model not only predicted spontaneous persistent activity (SPA) during Up-Down-State oscillations, but also inactivity (SPI), which has never been reported. These were confirmed in vivo in the membrane potential of neurons, especially from layer 3 of the medial and lateral entorhinal cortices. The data was then used to constrain two free parameters, yielding a unique, experimentally determined model for each neuron. Analytic and computational analysis of the model generated a dozen quantitative predictions about network dynamics, which were all confirmed in vivo to high accuracy. Our technique predicted functional connectivity; e. g. the recurrent excitation is stronger in the medial than lateral entorhinal cortex. This too was confirmed with connectomics data. This technique uncovers how differential cortico-entorhinal dialogue generates SPA and SPI, which could form an energetically efficient working-memory substrate and influence the consolidation of memories during sleep. More broadly, our procedure can reveal the functional connectivity of large networks and a theory of their emergent dynamics.
Topics: Entorhinal Cortex; Animals; Neurons; Models, Neurological; Male; Connectome; Nerve Net; Membrane Potentials; Neural Pathways; Computer Simulation; Mice
PubMed: 38719802
DOI: 10.1038/s41467-024-47617-6 -
Acta Neuropathologica Communications May 2024Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to...
BACKGROUND
Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology.
METHODS
The morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis.
RESULTS
Morphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases.
CONCLUSIONS
In conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.
Topics: Humans; Lewy Body Disease; Alzheimer Disease; Female; Male; Aged; Aged, 80 and over; Neuroinflammatory Diseases; Microglia; Astrocytes; alpha-Synuclein; tau Proteins; Antigens, CD; Amyloid beta-Peptides; Middle Aged; Antigens, Differentiation, Myelomonocytic; Brain; CD68 Molecule
PubMed: 38715119
DOI: 10.1186/s40478-024-01786-z -
BioRxiv : the Preprint Server For... Apr 2024There are well-established relationships between aging and neurodegenerative changes, and between aging and hearing loss. The goal of this study was to determine how...
INTRODUCTION
There are well-established relationships between aging and neurodegenerative changes, and between aging and hearing loss. The goal of this study was to determine how structural brain aging is influenced by hearing loss.
METHODS
Human Connectome Project Aging (HCP-A) data were analyzed, including T1-weighted MRI and Words in Noise (WIN) thresholds (n=623). Freesurfer extracted gray and white matter volume, and cortical thickness, area, and curvature. Linear regression models targeted (1) interactions between age and WIN threshold and (2) correlations with WIN threshold adjusted for age, both corrected for false discovery rate (p<0.05).
RESULTS
WIN threshold moderated age-related increase in volume in bilateral inferior lateral ventricles, with higher threshold associated with increased age-related ventricle expansion. Age-related deterioration in occipital cortex was also increased with higher WIN thresholds. When controlling for age, high WIN threshold was correlated with reduced cortical thickness in Heschl's gyrus, calcarine sulcus, and other sensory regions, and reduced temporal lobe white matter. Older volunteers with poorer hearing and cognitive scores had the lowest volume in left parahippocampal white matter.
CONCLUSIONS
Preserved hearing abilities in aging associated with a reduction of age-related changes to medial temporal lobe, and preserved hearing at any age associated with preserved cortical tissue in auditory and other sensory regions. Future longitudinal studies are needed to assess the causal nature of these relationships, but these results indicate interventions which preserve hearing function may combat some neurodegenerative changes in aging.
PubMed: 38712119
DOI: 10.1101/2024.04.22.590589 -
Scientific Reports May 2024Differentiating clinical stages based solely on positive findings from amyloid PET is challenging. We aimed to investigate the neuroanatomical characteristics at the...
Differentiating clinical stages based solely on positive findings from amyloid PET is challenging. We aimed to investigate the neuroanatomical characteristics at the whole-brain level that differentiate prodromal Alzheimer's disease (AD) from cognitively unimpaired amyloid-positive individuals (CU A+) in relation to amyloid deposition and regional atrophy. We included 45 CU A+ participants and 135 participants with amyloid-positive prodromal AD matched 1:3 by age, sex, and education. All participants underwent F-florbetaben positron emission tomography and 3D structural T1-weighted magnetic resonance imaging. We compared the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) between CU A+ and prodromal AD groups using independent t-tests, and employed the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction. After applying False Discovery Rate correction at < 0.1, there were no differences in global and regional SUVR between CU A+ and prodromal AD groups. Regional volume differences between the two groups were observed in the amygdala, hippocampus, entorhinal cortex, insula, parahippocampal gyrus, and inferior temporal and parietal cortices. LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was associated with an increased likelihood of prodromal AD (Odds ratio [OR] 1.602, p = 0.014), particularly in participants with lower regional volume (OR 3.389, p < 0.001). Only regional volume differences, not amyloid deposition, were observed between CU A+ and prodromal AD. The reduced volume in the superior parietal cortex may play a significant role in the progression to prodromal AD through its interaction with amyloid deposition in that region.
Topics: Humans; Alzheimer Disease; Male; Female; Aged; Positron-Emission Tomography; Magnetic Resonance Imaging; Prodromal Symptoms; Brain; Middle Aged; Atrophy; Amyloid beta-Peptides; Cognition; Aged, 80 and over; Amyloid; Aniline Compounds; Stilbenes
PubMed: 38698190
DOI: 10.1038/s41598-024-60843-8 -
Frontiers in Neuroscience 2024Cognitive impairment (CI) is a common complication of end-stage renal disease (ESRD) that is associated with structural and functional changes in the brain. However,...
INTRODUCTION
Cognitive impairment (CI) is a common complication of end-stage renal disease (ESRD) that is associated with structural and functional changes in the brain. However, whether a joint structural and functional alteration pattern exists that is related to CI in ESRD is unclear.
METHODS
In this study, instead of looking at brain structure and function separately, we aim to investigate the covariant characteristics of both functional and structural aspects. Specifically, we took the fusion analysis approach, namely, multimodal canonical correlation analysis and joint independent component analysis (mCCA+jICA), to jointly study the discriminative features in gray matter volume (GMV) measured by T1-weighted (T1w) MRI, fractional anisotropy (FA) in white matter measured by diffusion MRI, and the amplitude of low-frequency fluctuation (ALFF) measured by blood oxygenation-level-dependent (BOLD) MRI in 78 ESRD patients versus 64 healthy controls (HCs), followed by a mediation effect analysis to explore the relationship between neuroimaging findings, cognitive impairments and uremic toxins.
RESULTS
Two joint group-discriminative independent components (ICs) were found to show covariant abnormalities across FA, GMV, and ALFF (all < 0.05). The most dominant joint IC revealed associative patterns of alterations of GMV (in the precentral gyrus, occipital lobe, temporal lobe, parahippocampal gyrus, and hippocampus), alterations of ALFF (in the precuneus, superior parietal gyrus, and superior occipital gyrus), and of white matter FA (in the corticospinal tract and inferior frontal occipital fasciculus). Another significant IC revealed associative alterations of GMV (in the dorsolateral prefrontal and orbitofrontal cortex) and FA (in the forceps minor). Moreover, the brain changes identified by FA and GMV in the above-mentioned brain regions were found to mediate the negative correlation between serum phosphate and mini-mental state examination (MMSE) scores (all < 0.05).
CONCLUSION
The mCCA+jICA method was demonstrated to be capable of revealing covariant abnormalities across neuronal features of different types in ESRD patients as contrasted to HCs, and joint brain changes may play an important role in mediating the relationship between serum toxins and CIs in ESRD. Our results show the mCCA+jICA fusion analysis approach may provide new insights into similar neurobiological studies.
PubMed: 38686326
DOI: 10.3389/fnins.2024.1374948