Oxytocin, GABA, and dopamine interplay in autism.

Oxytocin plays an important role in brain development and is associated with various neurotransmitter systems in the brain. Abnormalities in the production, secretion, and distribution of oxytocin in the brain, at least during some stages of the development, are critical for the pathogenesis of neuropsychiatric diseases, particularly in the autism spectrum disorder. The etiology of autism includes changes in local sensory and dopaminergic areas of the brain, which are also supplied by the hypothalamic sources of oxytocin. It is very important to understand their mutual relationship. In this review, the relationship of oxytocin with several components of the dopaminergic system, gamma-aminobutyric acid (GABA) inhibitory neurotransmission and their alterations in the autism spectrum disorder is discussed. Special attention has been paid to the results describing a reduced expression of inhibitory GABAergic markers in the brain in the context of dopaminergic areas in various models of autism. It is presumed that the altered GABAergic neurotransmission, due to the absence or dysfunction of oxytocin at certain developmental stages, disinhibits the dopaminergic signaling and contributes to the autism symptoms.

Human-Induced Pluripotent Stem Cell-Derived Neural Progenitor Cells Showed Neuronal Differentiation, Neurite Extension, and Formation of Synaptic Structures in Rodent Ischemic Stroke Brains.

Ischemic stroke is a major cerebrovascular disease with high morbidity and mortality rates; however, effective treatments for ischemic stroke-related neurological dysfunction have yet to be developed. In this study, we generated neural progenitor cells from human leukocyte antigen major loci gene-homozygous-induced pluripotent stem cells (hiPSC-NPCs) and evaluated their therapeutic effects against ischemic stroke. hiPSC-NPCs were intracerebrally transplanted into rat ischemic brains produced by transient middle cerebral artery occlusion at either the subacute or acute stage, and their in vivo survival, differentiation, and efficacy for functional improvement in neurological dysfunction were evaluated. hiPSC-NPCs were histologically identified in host brain tissues and showed neuronal differentiation into vGLUT-positive glutamatergic neurons, extended neurites into both the ipsilateral infarct and contralateral healthy hemispheres, and synaptic structures formed 12 weeks after both acute and subacute stage transplantation. They also improved neurological function when transplanted at the subacute stage with γ-secretase inhibitor pretreatment. However, their effects were modest and not significant and showed a possible risk of cells remaining in their undifferentiated and immature status in acute-stage transplantation. These results suggest that hiPSC-NPCs show cell replacement effects in ischemic stroke-damaged neural tissues, but their efficacy is insufficient for neurological functional improvement after acute or subacute transplantation. Further optimization of cell preparation methods and the timing of transplantation is required to balance the efficacy and safety of hiPSC-NPC transplantation.

Ergosterol promotes neurite outgrowth, inhibits amyloid-beta synthesis, and extends longevity: In vitro neuroblastoma and in vivo Caenorhabditis elegans evidence.

AIMS: Alzheimer's disease (AD), the most common neurodegenerative disorder associated with aging, is characterized by amyloid-ß (Aß) plaques in the hippocampus. Ergosterol, a mushroom sterol, exhibits neuroprotective activities; however, the underlying mechanisms of ergosterol in promoting neurite outgrowth and preventing Aß-associated aging have never been investigated. We aim to determine the beneficial activities of ergosterol in neuronal cells and Caenorhabditis elegans (C. elegans). MATERIALS AND METHODS: The neuritogenesis and molecular mechanisms of ergosterol were investigated in wild-type and Aß precursor protein (APP)-overexpressing Neuro2a cells. The anti-amyloidosis properties of ergosterol were determined by evaluating in vitro Aß production and the potential inhibition of Aß-producing enzymes. Additionally, AD-associated transgenic C. elegans was utilized to investigate the in vivo attenuating effects of ergosterol. KEY FINDINGS: Ergosterol promoted neurite outgrowth in Neuro2a cells through the upregulation of the transmembrane protein Teneurin-4 (Ten-4) mRNA and protein expressions, phosphorylation of the extracellular signal-regulated kinases (ERKs), activity of cAMP response element (CRE), and growth-associated protein-43 (GAP-43). Furthermore, ergosterol enhanced neurite outgrowth in transgenic Neuro2A cells overexpressing either the wild-type APP (Neuro2a-APPwt) or the Swedish mutant APP (Neuro2a-APPswe) through the Ten-4/ERK/CREB/GAP-43 signaling pathway. Interestingly, ergosterol inhibited Aß synthesis in Neuro2a-APPwt cells. In silico analysis indicated that ergosterol can interact with the catalytic sites of ß- and γ-secretases. In Aß-overexpressing C. elegans, ergosterol decreased Aß accumulation, increased chemotaxis behavior, and prolonged lifespan. SIGNIFICANCE: Ergosterol is a potential candidate compound that might benefit AD patients by promoting neurite outgrowth, inhibiting Aß synthesis, and enhancing longevity.

Circulating miR-30e-3p induces disruption of neurite development in SH-SY5Y cells by targeting ABI1, a novel biomarker for schizophrenia.

Schizophrenia (SCZ) represents a set of enduring mental illnesses whose underlying etiology remains elusive, posing a significant challenge to public health. Previous studies have shown that the neurodevelopmental process involving small molecules such as miRNA and mRNA is one of the etiological hypotheses of SCZ. We identified and verified that miR-30e-3p and ABI1 can be used as biomarkers in peripheral blood transcriptome sequencing data of patients with SCZ, and confirmed the regulatory relationship between them. To further explore their involvement, we employed retinoic acid (RA)-treated SH-SY5Y differentiated cells as a model system. Our findings indicate that in RA-induced SH-SY5Y cells, ABI1 expression is up-regulated, while miR-30e-3p expression is down-regulated. Functionally, both miR-30e-3p down-regulation and ABI1 up-regulation promote apoptosis and inhibit the proliferation of SH-SY5Y cells. Subsequently, the immunofluorescence assay detected the expression location and abundance of the neuron-specific protein ß-tubulinIII. The expression levels of neuronal marker genes MAPT, TUBB3 and SYP were detected by RT-qPCR. We observed that these changes of miR-30e-3p and ABI1 inhibit the neurite growth of SH-SY5Y cells. Rescue experiments further support that ABI1 silencing can correct miR-30e-3p down-regulation-induced SH-SY5Y neurodevelopmental defects. Collectively, our results establish that miR-30e-3p's regulation of neurite development in SH-SY5Y cells is mediated through ABI1, highlighting a potential mechanism in SCZ pathogenesis.

MST2 Acts via AKT Activity to Promote Neurite Outgrowth and Functional Recovery after Spinal Cord Injury in Mice.

Spinal cord injury (SCI) constitutes a significant clinical challenge, and there is extensive research focused on identifying molecular activities that can facilitate the repair of spinal cord injuries. Mammalian sterile 20-like kinase 2 (MST2), a core component of the Hippo signaling pathway, plays a key role in apoptosis and cell growth. However, its role in neurite outgrowth after spinal cord injury remains unknown. Through comprehensive in vitro and in vivo experiments, we demonstrated that MST2, predominantly expressed in neurons, actively participated in the natural development of the CNS. Post-SCI, MST2 expression significantly increased, indicating its activation and potential role in the early stages of neural recovery. Detailed analyses showed that MST2 knockdown impaired neurite outgrowth and motor function recovery, whereas MST2 overexpression led to the opposite effects, underscoring MST2's neuroprotective role in enhancing neural repair. Further, we elucidated the mechanism underlying MST2's action, revealing its interaction with AKT and positive regulation of AKT activity, a well-established promoter of neurite outgrowth. Notably, MST2's promotion of neurite outgrowth and motor functional recovery was diminished by AKT inhibitors, highlighting the dependency of MST2's neuroprotective effects on AKT signaling. In conclusion, our findings affirmed MST2's pivotal role in fostering neuronal neurite outgrowth and facilitating functional recovery after SCI, mediated through its positive modulation of AKT activity. In conclusion, our findings confirmed MST2's crucial role in neural protection, promoting neurite outgrowth and functional recovery after SCI through positive AKT activity modulation. These results position MST2 as a potential therapeutic target for SCI, offering new insights into strategies for enhancing neuroregeneration and functional restoration.

Promotion of neurite outgrowth by 3,5,7,3',4'-pentamethoxyflavone is mediated through ERK signaling pathway in Neuro2a cells.

In this study, the effects of 3,5,7,3',4'-pentamethoxyflavone (KP1), a major bioactive ingredient isolated from the Kaempferia parviflora rhizomes, on a neurite outgrowth in Neuro2a cells and its mechanism have been investigated. KP1 increased concentration-dependently the percentage of neurite-bearing cells. KP1 showed a remarkable capability to elicit neurite outgrowth in Neuro2a cells, as evidenced by morphological alterations and immunostaining using anti-class III ß-tubulin and anti-NeuN antibodies. KP1 also displayed a higher neurogenic activity than retinoic acid (RA), a promoter of neurite outgrowth in Neuro2a cells. KP1 treatment caused significant elevation in phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and glycogen synthase kinase-3ß (GSK-3ß). However, KP1-triggered neurite outgrowth was markedly inhibited by treatment with the ERK inhibitor U0126, whereas p38 MAPK inhibitor SB203580 and GSK-3ß inhibitor SB216763 did not influence KP1-induced neurite outgrowth. These results demonstrate that KP1 elicits neurite outgrowth and triggers cell differentiation of Neuro2a cells through ERK signal pathway.

Zinc Deficiency Decreases Neurite Extension via CRMP2 Signal Pathway.

Previous reports indicated that zinc deficiency could increase the risk of infectious diseases and developmental retardation in children. In experimental study, it has been reported that zinc deficiency during the embryonic period inhibited fetal growth, and disturbed neural differentiation and higher brain function later in adulthood. Although it has been suggested that zinc deficiency during development can have significant effects on neuronal differentiation and maturation, the molecular mechanisms of the effects of low zinc on neuronal differentiation during development have not been elucidated in detail. This study was performed to determine the effects of low zinc status on neurite outgrowth and collapsin response mediator protein 2 (CRMP2) signal pathway. Low zinc suppressed neurite outgrowth, and caused increase levels of phosphorylated CRMP2 (pCRMP2) relative to CRMP2, and decrease levels of phosphorylated glycogen synthase kinase 3ß (pGSK3ß) relative to GSK3ß in human neuroblastoma cell line (SH-SY5Y) cells on days 1, 2, and 3 of neuronal differentiation induction. Neurite outgrowth inhibited by low zinc was restored by treatment with the GSK3ß inhibitor CHIR99021. These results suggested that low zinc causes neurite outgrowth inhibition via phosphorylation of CRMP2 by GSK3ß. In conclusion, this study is the first to demonstrate that CRMP signaling is involved in the suppression of neurite outgrowth by low zinc.

Early Infant Prefrontal Cortical Microstructure Predicts Present and Future Emotionality.

BACKGROUND: High levels of infant negative emotionality (NE) and low positive emotionality (PE) predict future emotional and behavioral problems. The prefrontal cortex (PFC) supports emotional regulation, with each PFC subregion specializing in specific emotional processes. Neurite Orientation Dispersion and Density Imaging (NODDI) estimates microstructural integrity and myelination via the neurite density index (NDI) and dispersion via the orientation dispersion index (ODI), with potential to more accurately evaluate microstructural alterations in the developing brain. Yet, no study has used these indices to examine associations between PFC microstructure and concurrent or developing infant emotionality. METHODS: We modeled PFC subregional NDI and ODI at 3 months with caregiver-reported infant NE and PE at 3 months (n=61) and at 9 months (n=50), using multivariable and subsequent bivariate regression models. RESULTS: The most robust statistically-significant findings were positive associations among 3-month rACC ODI and cACC NDI and concurrent NE, and 3-month lOFC ODI and prospective NE; and a negative association between 3-month dlPFC ODI and concurrent PE. Multivariate models also revealed that other PFC subregional microstructure measures, and infant and caregiver sociodemographic and clinical factors, predicted infant 3- and 9-month NE and PE. CONCLUSIONS: Greater NDI and ODI, reflecting greater microstructural complexity, in PFC regions supporting salience perception (rACC), decision-making (lOFC), action selection (cACC), and attentional processes (dlPFC) might result in greater integration of these subregions with other neural networks, greater attention to salient negative external cues, thus higher NE and/or lower PE. These findings provide potential infant cortical markers of future psychopathology risk.

Ginsenoside Rg1 promotes neurite growth of retinal ganglion cells through cAMP/PKA/CREB pathways.

Background: Mechanisms of synaptic plasticity in retinal ganglion cells (RGCs) are complex and the current knowledge cannot explain. Growth and regeneration of dendrites together with synaptic formation are the most important parameters for evaluating the cellular protective effects of various molecules. The effect of ginsenoside Rg1 (Rg1) on the growth of retinal ganglion cell processes has been poorly understood. Therefore, we investigated the effect of ginsenoside Rg1 on the neurite growth of RGCs. Methods: Expression of proteins and mRNA were detected by Western blot and qPCR. cAMP levels were determined by ELISA. In vivo effects of Rg1 on RGCs were evaluated by hematoxylin and eosin, and immunohistochemistry staining. Results: This study found that Rg1 promoted the growth and synaptic plasticity of RGCs neurite by activating the cAMP/PKA/CREB pathways. Meanwhile, Rg1 upregulated the expression of GAP43, Rac1 and PAX6, which are closely related to the growth of neurons. Meantime, H89, an antagonist of PKA, could block this effect of Rg1. In addition, we preliminarily explored the effect of Rg1 on enhancing the glycolysis of RGCs, which could be one of the mechanisms for its neuroprotective effects. Conclusion: Rg1 promoted neurite growth of RGCs through cAMP/PKA/CREB pathways. This study may lay a foundation for its clinical use of optic nerve diseases in the future.

Quantification of Neuronal Dendritic Spine Density and Lengths of Apical and Basal Dendrites in Temporal Lobe Structures Using Golgi-Cox Staining.

The objective of this chapter is to provide an overview of the methods used to investigate the connectivity and structure of the nervous system. These methods allow neuronal cells to be categorized according to their location, shape, and connections to other cells. The Golgi-Cox staining gives a thorough picture of all significant neuronal structures found in the brain that may be distinguished from one another. The most significant characteristic is its three-dimensional integrity since all neuronal structures may be followed continuously from one part to the next. Successions of sections of the brain's neurons are seen with the Golgi stain. The Golgi method is used to serially segment chosen brain parts, and the resulting neurons are produced from those sections.

Attenuated neuronal differentiation caused by acrylamide is not related to oxidative stress in differentiated human neuroblastoma SH-SY5Y cells.

Acrylamide (ACR) is a known neurotoxicant and developmental neurotoxicant. As a soft electrophile, ACR reacts with thiol groups in cysteine. One hypothesis of ACR induced neurotoxicity and developmental neurotoxicity (DNT) is conjugation with reduced glutathione (GSH) leading to GSH depletion, increased reactive oxygen species (ROS) production and further oxidative stress and cellular damage. In this regard, we have investigated the effect of ACR on neuronal differentiation, glutathione levels and ROS production in the human neuroblastoma SH-SY5Y cell model. After 9 days of differentiation and exposure, ACR significantly impaired area neurites per cell at non-cytotoxic concentrations (0.33 µM and 10 µM). Furthermore, 10 µM ACR dysregulated 9 mRNA markers important for neuronal development, 5 of them being associated with cytoskeleton organization and axonal guidance. At the non-cytotoxic concentrations that significantly attenuate neuronal differentiation, ACR did neither decrease the level of GSH or total glutathione levels, nor increased ROS production. In addition, the expression of 5 mRNA markers for cellular stress was assessed with no significant altered regulation after ACR exposure up to 320 µM. Thus, ACR-induced DNT is not due to GSH depletion and increased ROS production, neither at non-cytotoxic nor cytotoxic concentrations, in the SH-SH5Y model during differentiation.

Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain.

BACKGROUND: Bone cancer pain (BCP) is a common primary or metastatic bone cancer complication. Netrin-1 plays an essential role in neurite elongation and pain sensitization. This study aimed to determine the role of netrin-1 from the metastatic bone microenvironment in BCP development and identify the associated signaling pathway for the strategy of BCP management. METHODS: The rat BCP model was established by intratibial implantation of Walker 256 cells. Von Frey filaments measured the mechanical pain threshold. Movement-induced pain was assessed using limb use scores. Expressions of associated molecules in the affected tibias or dorsal root ganglia (DRG) were measured by immunofluorescence, immunohistochemistry, real-time quantitative polymerase chain reaction, or western blotting. Transduction of deleted in colorectal cancer (DCC) signaling was inhibited by intrathecal injection of DCC-siRNA. RESULTS: In BCP rats, the presence of calcitonin gene-related peptide (CGRP)-positive nerve fibers increased in the metastatic bone lesions. The metastatic site showed enrichment of well-differentiated osteoclasts and expressions of netrin-1 and its attractive receptor DCC. Upregulation of DCC and increased phosphorylation levels of focal adhesion kinase (FAK) and Rac family small GTPase 1/Cell division cycle 42 (Rac1/Cdc42) were found in the DRG. Intrathecal administration of DCC-siRNA led to a significant reduction in FAK and Rac1/Cdc42 phosphorylation levels in the DRG, decreased nociceptive nerve innervation, and improved pain behaviors. CONCLUSIONS: Netrin-1 may contribute to the activation of the BCP by inducing nociceptive nerve innervation and improving pain behaviors.

The geometry of photopolymerized topography influences neurite pathfinding by directing growth cone morphology and migration.

Objective. Cochlear implants provide auditory perception to those with severe to profound sensorineural hearing loss: however, the quality of sound perceived by users does not approximate natural hearing. This limitation is due in part to the large physical gap between the stimulating electrodes and their target neurons. Therefore, directing the controlled outgrowth of processes from spiral ganglion neurons (SGNs) into close proximity to the electrode array could provide significantly increased hearing function.Approach.For this objective to be properly designed and implemented, the ability and limits of SGN neurites to be guided must first be determined. In this work, we engineer precise topographical microfeatures with angle turn challenges of various geometries to study SGN pathfinding and use live imaging to better understand how neurite growth is guided by these cues.Main Results.We find that the geometry of the angled microfeatures determines the ability of neurites to navigate the angled microfeature turns. SGN neurite pathfinding fidelity is increased by 20%-70% through minor increases in microfeature amplitude (depth) and by 25% if the angle of the patterned turn is made obtuse. Further, we see that dorsal root ganglion neuron growth cones change their morphology and migration to become more elongated within microfeatures. Our observations also indicate complexities in studying neurite turning. First, as the growth cone pathfinds in response to the various cues, the associated neurite often reorients across the angle topographical microfeatures. Additionally, neurite branching is observed in response to topographical guidance cues, most frequently when turning decisions are most uncertain.Significance.Overall, the multi-angle channel micropatterned substrate is a versatile and efficient system to assess neurite turning and pathfinding in response to topographical cues. These findings represent fundamental principles of neurite pathfinding that will be essential to consider for the design of 3D systems aiming to guide neurite growthin vivo.

Non-canonical retinoid signaling in neural development, regeneration and synaptic function.

Canonical retinoid signaling via nuclear receptors and gene regulation is critical for the initiation of developmental processes such as cellular differentiation, patterning and neurite outgrowth, but also mediates nerve regeneration and synaptic functions in adult nervous systems. In addition to canonical transcriptional regulation, retinoids also exert rapid effects, and there are now multiple lines of evidence supporting non-canonical retinoid actions outside of the nucleus, including in dendrites and axons. Together, canonical and non-canonical retinoid signaling provide the precise temporal and spatial control necessary to achieve the fine cellular coordination required for proper nervous system function. Here, we examine and discuss the evidence supporting non-canonical actions of retinoids in neural development and regeneration as well as synaptic function, including a review of the proposed molecular mechanisms involved.

Simple ammonium salt and sigma-1 receptor ligand dipentylammonium provides neuroprotective effects in cell culture and Caenorhabditis elegans models of Alzheimer's disease.

The sigma-1 receptor (σ-1R), a chaperone protein located at the mitochondria-associated membrane (MAM) of the endoplasmic reticulum, can interact with and modify the signaling pathways of various proteins, thereby modulating many disease pathologies, including Alzheimer's disease (AD). The σ-1R ligand dipentylammonium (DPA) was analyzed for its anti-AD properties using PC12 cells (in vitro) and Caenorhabditis elegans (in vivo) models along with molecular docking (in silico) analysis. DPA at 1 and 10 µM concentrations was able to significantly potentiate NGF-induced neurite growth length by 137.7 ± 12.0 and 187.8 ± 16.4, respectively, when compared to the control 76.9 ± 7.4. DPA also regulated neurite damage caused by Aß(25-35) treatment in differentiated PC12 cells by improving cell viability and neurite length. In C. elegans, DPA could significantly extend the median and maximum lifespan of Aß transgenic strain CL2006 without impacting wild-type nematodes. Additionally, it could significantly reduce the paralysis phenotype of another Aß transgenic strain, CL4176, thereby improving the overall health in AD pathogenesis. This effect depended on σ-1R, as DPA could not modulate the lifespan of σ-1R mutant TM3443. This was further confirmed using agonist PRE084 and antagonist BD1047, wherein the agonist alone could extend the lifespan of CL2006, while the antagonist suppressed the effect of DPA in CL2006. Interestingly, neither had an TM3443. Further, molecular docking analysis showed that DPA had a similar binding affinity as that of PRE084, BD1047 and pentazocine against the σ-1R receptor in humans and C. elegans, which collectively suggests the anti-AD properties of DPA.

Neurite Damage in Patients with Migraine.

We examined neurite orientation dispersion and density imaging in patients with migraine. We found that patients with medication overuse headache exhibited lower orientation dispersion than those without. Moreover, orientation dispersion in the body of the corpus callosum was statistically negatively correlated with migraine attack frequencies. These findings indicate that neurite dispersion is damaged in patients with chronic migraine. Our study results indicate the orientation preference of neurite damage in migraine.

Differentiating SH-SY5Y Cells into Polarized Human Neurons for Studying Endogenous and Exogenous Tau Trafficking: Four Protocols to Obtain Neurons with Noradrenergic, Dopaminergic, and Cholinergic Properties.

Pathological alterations of the neuronal Tau protein are characteristic for many neurodegenerative diseases, called tauopathies. To investigate the underlying mechanisms of tauopathies, human neuronal cell models are required to study Tau physiology and pathology in vitro. Primary rodent neurons are an often used model for studying Tau, but rodent Tau differs in sequence, splicing, and aggregation propensity, and rodent neuronal physiology cannot be compared to humans. Human-induced pluripotent stem cell (hiPSC)-derived neurons are expensive and time-consuming. Therefore, the human neuroblastoma SH-SY5Y cell line is a commonly used cell model in neuroscience as it combines convenient handling and low costs with the advantages of human-derived cells. Since naïve SH-SY5Y cells show little similarity to human neurons and almost no Tau expression, differentiation is necessary to obtain human-like neurons for studying Tau protein-related aspects of health and disease. As they express in principle all six Tau isoforms seen in the human brain, differentiated SH-SY5Y-derived neurons are suitable for investigating the human microtubule-associated protein Tau and, for example, its sorting and trafficking. Here, we describe and discuss a general cultivation procedure as well as four differentiation methods to obtain SH-SY5Y-derived neurons resembling noradrenergic, dopaminergic, and cholinergic properties, based on the treatment with retinoic acid (RA), brain-derived neurotrophic factor (BDNF), and 12-O-tetrade canoylphorbol-13-acetate (TPA). TPA and RA-/TPA-based protocols achieve differentiation efficiencies of 40-50% after 9 days of treatment. The highest differentiation efficiency (~75%) is accomplished by a combination of RA and BDNF; treatment only with RA is the most time-efficient method as ~50% differentiated cells can be obtained already after 7 days.

Early embryogenesis in CHDFIDD mouse model reveals facial clefts and altered cranial neurogenesis.

Congenital heart defects, facial dysmorphism and intellectual development disorder (CHDFIDD) is associated with mutations in CDK13 gene, which encodes a transcription regulating Cyclin-dependent kinase 13 (CDK13). Here, we focused on development of craniofacial structures and analyzed early embryonic stages of CHDFIDD mouse models with hypomorphic mutation in Cdk13 gene, which exhibits cleft lip/palate and knockout of Cdk13 with stronger phenotype including midfacial cleft. Cdk13 was found to be physiologically strongly expressed in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme. We also uncovered that Cdk13-deficiency leads to development of hypoplastic branches of the trigeminal nerve including maxillary branch and additionally, we detected significant gene expression changes of molecules involved in neurogenesis (Ache, Dcx, Mef2c, Neurog1, Ntn1, Pou4f1) within the developing palatal shelves. These results, together with changes of gene expression of other key face-specific molecules (Fgf8, Foxd1, Msx1, Meis2 and Shh) at early stages in Cdk13 mutant embryos, demonstrate a key role of CDK13 in regulation of craniofacial morphogenesis.

Increased extra-neurite conductivity of brain in patients with Alzheimer's disease: A pilot study.

The objectives of this study were to investigate how the extra-neurite conductivity (EC) and intra-neurite conductivity (IC) were reflected in Alzheimer's disease (AD) patients compared with old cognitively normal (CN) people and patients with amnestic mild cognitive impairment (MCI) and to evaluate the association between those conductivity values and cognitive decline. To do this, high-frequency conductivity (HFC) at the Larmor frequency was obtained using MRI-based electrical property tomography (MREPT) and was decomposed into EC and IC using information of multi-shell multi-gradient direction diffusion tensor images. This prospective single-center study included 20 patients with mild or moderate AD, 25 patients with amnestic MCI, and 21 old CN participants. After decomposing EC and IC from HFC for all participants, we performed voxel-based and regions-of-interest analyses to compare conductivity between the three participant groups and to evaluate the association with either age or the Mini-Mental State Examination (MMSE) scores. We found increased EC in AD compared to CN and MCI. EC was significantly negatively associated with MMSE scores in the insula, and middle temporal gyrus. EC might be used as an imaging biomarker for helping to monitor cognitive function.

Combined assessment of progressive apraxia of speech brain microstructure by diffusion tensor imaging tractography and multishell neurite orientation dispersion and density imaging.

BACKGROUND: Progressive apraxia of speech (PAOS) is characterized by difficulties with motor speech programming and planning. PAOS targets gray matter (GM) and white matter (WM) microstructure that can be assessed using diffusion tensor imaging (DTI) and multishell applications, such as neurite orientation dispersion and density imaging (NODDI). In this study, we aimed to apply DTI and NODDI to add further insight into PAOS tissue microstructure. METHODS: Twenty-two PAOS patients and 26 age- and sex-matched controls, recruited by the Neurodegenerative Research Group (NRG) at Mayo Clinic, underwent diffusion MRI on 3T MRI. Brain maps of fractional anisotropy (FA) and mean diffusivity (MD) from DTI and intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) from NODDI were generated. Global WM and GM, and specific WM tracts were identified using tractography and lobar GM regions. RESULTS: Global WM differences between PAOS and controls were greatest for ICVF, and global GM differences were greatest for MD and IsoVF. Abnormalities in key WM tracts involved in PAOS, including the body of the corpus callosum and frontal aslant tract, were identified with FA, MD, and ICVF, with excellent differentiation of PAOS from controls (area under the receiver operating characteristic curves >.90). MD and ICVF identified abnormalities in arcuate fasciculus, thalamic radiations, and corticostriatal tracts. Significant correlations were identified between an index of articulatory errors and DTI and NODDI metrics from the arcuate fasciculus, frontal aslant tract, and inferior longitudinal fasciculus. CONCLUSIONS: DTI and NODDI represent different aspects of brain tissue microstructure, increasing the number of potential biomarkers for PAOS.