rudyvdbrink/CitationDatabase huggingface dataset:
Multi-modal latent factor exploration of atrophy, cognitive and tau heterogeneity in Alzheimer's disease.
NeuroImage, 2019

Individuals with Alzheimer's disease (AD) dementia exhibit significant heterogeneity across clinical symptoms, atrophy patterns, and spatial distribution of Tau deposition. Most previous studies of AD heterogeneity have focused on atypical clinical subtypes, defined subtypes with a single modality, or restricted their analyses to a priori brain regions and cognitive tests. Here, we considered a data-driven hierarchical Bayesian model to identify latent factors from atrophy patterns and cognitive deficits simultaneously, thus exploiting the rich dimensionality within each modality. Unlike most previous studies, our model allows each factor to be expressed to varying degrees within an individual, in order to reflect potential multiple co-existing pathologies. By applying our model to ADNI-GO/2 AD dementia participants, we found three atrophy-cognitive factors. The first factor was associated with medial temporal lobe atrophy, episodic memory deficits and disorientation to time/place ("MTL-Memory"). The second factor was associated with lateral temporal atrophy and language deficits ("Lateral Temporal-Language"). The third factor was associated with atrophy in posterior bilateral cortex, and visuospatial executive function deficits ("Posterior Cortical-Executive"). While the MTL-Memory and Posterior Cortical-Executive factors were discussed in previous literature, the Lateral Temporal-Language factor is novel and emerged only by considering atrophy and cognition jointly. Several analyses were performed to ensure generalizability, replicability and stability of the estimated factors. First, the factors generalized to new participants within a 10-fold cross-validation of ADNI-GO/2 AD dementia participants. Second, the factors were replicated in an independent ADNI-1 AD dementia cohort. Third, factor loadings of ADNI-GO/2 AD dementia participants were longitudinally stable, suggesting that these factors capture heterogeneity across patients, rather than longitudinal disease progression. Fourth, the model outperformed canonical correlation analysis at capturing associations between atrophy patterns and cognitive deficits. To explore the influence of the factors early in the disease process, factor loadings were estimated in ADNI-GO/2 mild cognitively impaired (MCI) participants. Although the associations between the atrophy patterns and cognitive profiles were weak in MCI compared to AD, we found that factor loadings were associated with inter-individual regional variation in Tau uptake. Taken together, these results suggest that distinct atrophy-cognitive patterns exist in typical Alzheimer's disease, and are associated with distinct patterns of Tau depositions before clinical dementia emerges.
Time Cells in Hippocampal Area CA3.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016

Studies on time cells in the hippocampus have so far focused on area CA1 in animals performing memory tasks. Some studies have suggested that temporal processing within the hippocampus may be exclusive to CA1 and CA2, but not CA3, and may occur only under strong demands for memory. Here we examined the temporal and spatial coding properties of CA3 and CA1 neurons in rats performing a maze task that demanded working memory and a control task with no explicit working memory demand. In the memory demanding task, CA3 cells exhibited robust temporal modulation similar to the pattern of time cell activity in CA1, and the same populations of cells also exhibited typical place coding patterns in the same task. Furthermore, the temporal and spatial coding patterns of CA1 and CA3 were equivalently robust when animals performed a simplified version of the task that made no demands on working memory. However, time and place coding did differ in that the resolution of temporal coding decreased over time within the delay interval, whereas the resolution of place coding was not systematically affected by distance along the track. These findings support the view that CA1 and CA3 both participate in encoding the temporal and spatial organization of ongoing experience.
Neural mechanisms of the spacing effect in episodic memory: A parallel EEG and fMRI study.
Cortex; a journal devoted to the study of the nervous system and behavior, 2015

Although behavioral studies have consistently reported the spacing effect in learning, its cognitive and neural mechanisms are still not clearly elucidated. According to the storage/retrieval strength framework proposed by Bjork (1999; Bjork & Bjork, 1992), which was built on the study-phase retrieval hypothesis and the deficient processing hypothesis, the spacing effect is achieved by reducing memomtary retrieval strength during subsequent repetitions and thus enhancing storage strength. The present study tested this hypothesis with parallel fMRI and EEG. Participants were asked to study 180 words that were repeated three times, with half of the words having an inter-repetition-lag of 1-3 words (i.e., massed learning) and the other half an inter-repetition-lag of 25-35 words (i.e., spaced learning). An unexpected recognition test was administered 24 h after learning. Consistent with Bjork's hypothesis, the EEG data suggested that spaced learning was associated with weaker retrieval strength, as indicated by a reduced familiarity effect in frontal N400. Meanwhile, spaced learning effectively enhanced the encoding process and thus led to stronger storage strength, as indicated by greater fMRI responses during learning in brain regions whose activities were associated with subsequent memory. Interestingly, no direct association was found between repetition priming and episodic memory. These results furthered our understanding of the neural mechanisms underlying the spacing effect.
Reconstructing three-dimensional hand movements from noninvasive electroencephalographic signals.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010

It is generally thought that the signal-to-noise ratio, the bandwidth, and the information content of neural data acquired via noninvasive scalp electroencephalography (EEG) are insufficient to extract detailed information about natural, multijoint movements of the upper limb. Here, we challenge this assumption by continuously decoding three-dimensional (3D) hand velocity from neural data acquired from the scalp with 55-channel EEG during a 3D center-out reaching task. To preserve ecological validity, five subjects self-initiated reaches and self-selected targets. Eye movements were controlled so they would not confound the interpretation of the results. With only 34 sensors, the correlation between measured and reconstructed velocity profiles compared reasonably well to that reported by studies that decoded hand kinematics from neural activity acquired intracranially. We subsequently examined the individual contributions of EEG sensors to decoding to find substantial involvement of scalp areas over the sensorimotor cortex contralateral to the reaching hand. Using standardized low-resolution brain electromagnetic tomography (sLORETA), we identified distributed current density sources related to hand velocity in the contralateral precentral gyrus, postcentral gyrus, and inferior parietal lobule. Furthermore, we discovered that movement variability negatively correlated with decoding accuracy, a finding to consider during the development of brain-computer interface systems. Overall, the ability to continuously decode 3D hand velocity from EEG during natural, center-out reaching holds promise for the furtherance of noninvasive neuromotor prostheses for movement-impaired individuals.
Metabolic effects of chronic sleep restriction in rats.
Sleep, 2012

Chronic partial sleep loss is associated with obesity and metabolic syndrome in humans. We used rats with lesions in the ventrolateral preoptic area (VLPO), which spontaneously sleep about 30% less than intact rats, as an animal model to study the consequences of chronic partial sleep loss on energy metabolism.
Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease.
Neuropathology and applied neurobiology, 2017

Our understanding of the underlying biology of Alzheimer's disease (AD) has been steadily progressing; however, this is yet to translate into a successful treatment in humans. The use of transgenic mouse models has helped to develop our understanding of AD, not only in terms of disease pathology, but also with the associated cognitive impairments typical of AD. Plaques and neurofibrillary tangles are often among the last pathological changes in AD mouse models, after neuronal loss and gliosis. There is a general consensus that successful treatments need to be applied before the onset of these pathologies and associated cognitive symptoms. This review discusses the different types of AD mouse models in terms of the temporal progression of the disease, how well they replicate the pathological changes seen in human AD and their cognitive defects. We provide a critical assessment of the behavioural tests used with AD mice to assess cognitive changes and decline, and discuss how successfully they correlate with cognitive impairments in humans with AD. This information is an important tool for AD researchers when deciding on appropriate mouse models, and when selecting measures to assess behavioural and cognitive change.
Microglial interactions with the neurovascular system in physiology and pathology.
Developmental neurobiology, 2018

Microglia as immune cells of the central nervous system (CNS) play significant roles not only in pathology but also in physiology, such as shaping of the CNS during development and its proper maintenance in maturity. Emerging research is showing a close association between microglia and the neurovasculature that is critical for brain energy supply. In this review, we summarize the current literature on microglial interaction with the vascular system in the normal and diseased brain. First, we highlight data that indicate interesting potential involvement of microglia in developmental angiogenesis. Then we discuss the evidence for microglial participation with the vasculature in neuropathologies from brain tumors to acute injuries such as ischemic stroke to chronic neurodegenerative conditions. We conclude by suggesting future areas of research to advance the field in light of current technical progress and outstanding questions. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 604-617, 2018.
The Role of Estrogen in Brain and Cognitive Aging.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2019

There are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated with a number of changes in the brain, including cognitive changes, effects on sleep, and effects on mood. These effects have been demonstrated in both rodent and non-human preclinical models. Furthermore, E2 interactions have been indicated in a number of neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. In normal brain aging, there are a number of systems that undergo changes and a number of these show interactions with E2, particularly the cholinergic system, the dopaminergic system, and mitochondrial function. E2 treatment has been shown to ameliorate some of the behavioral and morphological changes seen in preclinical models of menopause; however, in clinical populations, the effects of E2 treatment on cognitive changes after menopause are mixed. The future use of sex hormone treatment will likely focus on personalized or precision medicine for the prevention or treatment of cognitive disturbances during aging, with a better understanding of who may benefit from such treatment.
Reaction time changes with the hazard rate for a behaviorally relevant event when monkeys perform a delayed wrist movement task.
Neuroscience letters, 2008

Anticipating the timing of behaviorally relevant events is crucial for organizing movement. The time to initiate actions based on events (i.e., reaction time (RT)) is a useful measure to quantify states of anticipation. Few studies have examined how anticipation affects the timing of limb movements. We addressed this question behaviorally with two macaque monkeys performing delayed wrist movement tasks. The interval between target onset and go signal (i.e., foreperiod) varied randomly from 1 to 2 s. The probability that the go signal was about to occur (i.e., hazard rate) increased as the foreperiod increased. The kinematics of wrist movements was not influenced by foreperiod duration. Analyzing RT data with the LATER model indicated that RT distributions swiveled on reciprobit plots as foreperiods increased, suggesting that changes in RT distributions were due to changes in anticipation. RT was inversely related to hazard rate. To better understand the general implications of anticipatory states, we introduced an additional rectangular foreperiod distribution that ranged from 0.9 to 1.5 s. For that distribution, the hazard rate peaks were higher than those of the 1-2 s distribution. Changes in RT were clearly explained by quantitative differences in hazard rate. The decrease in RT in the 0.9-1.5 s foreperiod distribution was greater than that in the 1-2 s foreperiod. Thus, monkeys learned the temporal structure of foreperiod distributions and anticipated the onset of the go signal, based on hazard rates.
Neurobiological pathways linking socioeconomic position and health.
Psychosomatic medicine, 2010

Across individuals, risk for poor health varies inversely with socioeconomic position (SEP). The pathways by which SEP affects health have been viewed from many epidemiological perspectives. Central to these perspectives is the notion that socioeconomic health disparities arise from an interplay between nested, recursive, and cumulative environmental, social, familial, psychological, behavioral, and physiological processes that unfold over the life span. Epidemiological perspectives on socioeconomic health disparities, however, have not yet formally integrated emerging findings from neuropharmacological, molecular genetic, and neuroimaging studies demonstrating that indicators of SEP relate to patterns of brain neurotransmission, brain morphology, and brain functionality implicated in the etiology of chronic medical conditions and psychological disorders. Here, we survey these emerging findings and consider how future neurobiological studies in this area can enhance our understanding of the pathways by which different dimensions of SEP become embodied by the brain to influence health throughout life.
MouSensor: A Versatile Genetic Platform to Create Super Sniffer Mice for Studying Human Odor Coding.
Cell reports, 2016

Typically, ∼0.1% of the total number of olfactory sensory neurons (OSNs) in the main olfactory epithelium express the same odorant receptor (OR) in a singular fashion and their axons coalesce into homotypic glomeruli in the olfactory bulb. Here, we have dramatically increased the total number of OSNs expressing specific cloned OR coding sequences by multimerizing a 21-bp sequence encompassing the predicted homeodomain binding site sequence, TAATGA, known to be essential in OR gene choice. Singular gene choice is maintained in these "MouSensors." In vivo synaptopHluorin imaging of odor-induced responses by known M71 ligands shows functional glomerular activation in an M71 MouSensor. Moreover, a behavioral avoidance task demonstrates that specific odor detection thresholds are significantly decreased in multiple transgenic lines, expressing mouse or human ORs. We have developed a versatile platform to study gene choice and axon identity, to create biosensors with great translational potential, and to finally decode human olfaction.
Dual Contrast - Magnetic Resonance Fingerprinting (DC-MRF): A Platform for Simultaneous Quantification of Multiple MRI Contrast Agents.
Scientific reports, 2017

Injectable Magnetic Resonance Imaging (MRI) contrast agents have been widely used to provide critical assessments of disease for both clinical and basic science imaging research studies. The scope of available MRI contrast agents has expanded over the years with the emergence of molecular imaging contrast agents specifically targeted to biological markers. Unfortunately, synergistic application of more than a single molecular contrast agent has been limited by MRI's ability to only dynamically measure a single agent at a time. In this study, a new Dual Contrast - Magnetic Resonance Fingerprinting (DC - MRF) methodology is described that can detect and independently quantify the local concentration of multiple MRI contrast agents following simultaneous administration. This "multi-color" MRI methodology provides the opportunity to monitor multiple molecular species simultaneously and provides a practical, quantitative imaging framework for the eventual clinical translation of molecular imaging contrast agents.
Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma.
Cell death & disease, 2016

Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) - two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the in vitro findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells.
Human nocturnal frontal lobe epilepsy: pharmocogenomic profiles of pathogenic nicotinic acetylcholine receptor beta-subunit mutations outside the ion channel pore.
Molecular pharmacology, 2008

Certain mutations in specific parts of the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4, CHRNB2, and probably CHRNA2, can cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). All but one of the known causative mutations are located in the second transmembrane region (TM2), which serves as the major ion poreforming domain of the receptor. Functional characterization of these ADNFLE mutations has shown that although each mutant exhibits specific properties, they all confer a gain of function with increased sensitivity to acetylcholine. In this work, we characterize the second and third ADNFLE-associated mutations that are external to TM2 but affect different amino acid residues within the third transmembrane region (TM3). The two new CHRNB2 mutations were identified in three families of Turkish Cypriot, Scottish, and English origin. These TM3 mutations elicit the same gain of function pathomechanism as observed for the TM2 mutations with enhanced acetylcholine sensitivity, despite their unusual localization within the gene. Electrophysiological experiments, including single channel measurements, revealed that incorporation of these new mutant subunits does not affect the conductance of the ionic pore but increases the probability of opening. Determination of the sensitivity to nicotine for nAChRs carrying mutations in TM2 and TM3 showed clear differences in the direction and the extent to which the window current for nicotine sensitivity was shifted for individual mutations, indicating differences in pharmacogenomic properties that are not readily correlated with increased ACh affinity.
The efficacy and safety of the Chinese herbal medicine Di-Tan decoction for treating Alzheimer's disease: protocol for a randomized controlled trial.
Trials, 2015

Alzheimer's disease (AD) is the most common type of dementia in the elderly. It is estimated that the global prevalence of dementia will rise from 24.3 million in 2005 to 81.1 million in 2040. AD has a devastating impact on sufferers, caregivers, their communities and the healthcare system in general. "Di-tan decoction" (DTD) is a traditional Chinese medicine (TCM) formula frequently used to treat symptoms that are now defined as AD in clinical treatment. However, the existing evidence for recommending DTD in clinical practice derives from studies that were methodologically flawed. In this study, we aim to determine the efficacy and safety of DTD in AD patients based on a rigidly randomized controlled trial. It will provide critical information on sample size and treatment regimen for conducting a full-scale clinical trial of DTD later.
Human cytomegalovirus UL7, a homologue of the SLAM-family receptor CD229, impairs cytokine production.
Immunology and cell biology, 2011

Human cytomegalovirus (HCMV), the β-herpesvirus prototype, has evolved a wide spectrum of mechanisms to counteract host immunity. Among them, HCMV uses cellular captured genes encoding molecules capable of interfering with the original host function or of fulfilling new immunomodulatory tasks. Here, we report on UL7, a novel HCMV heavily glycosylated transmembrane protein, containing an Ig-like domain that exhibits remarkable amino acid similarity to CD229, a cell-surface molecule of the signalling lymphocyte-activation molecule (SLAM) family involved in leukocyte activation. The UL7 Ig-like domain, which is well-preserved in all HCMV strains, structurally resembles the SLAM-family N-terminal Ig-variable domain responsible for the homophilic and heterophilic interactions that trigger signalling. UL7 is transcribed with early-late kinetics during the lytic infectious cycle. Using a mAb generated against the viral protein, we show that it is constitutively shed, through its mucine-like stalk, from the cell-surface. Production of soluble UL7 is enhanced by PMA and reduced by a broad-spectrum metalloproteinase inhibitor. Although UL7 does not hold the ability to interact with CD229 or other SLAM-family members, it shares with them the capacity to mediate adhesion to leukocytes, specifically to monocyte-derived DCs. Furthermore, we demonstrate that UL7 expression attenuates the production of proinflammatory cytokines TNF, IL-8 and IL-6 in DCs and myeloid cell lines. Thus, the ability of UL7 to interfere with cellular proinflammatory responses may contribute to viral persistence. These results enhance our understanding of those HCMV-encoded molecules involved in sustaining the balance between HCMV and the host immune system.