Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheimer's disease: From early olfactory-related omics signatures to computational repurposing of drug candidates.

Alzheimer's disease (AD) is the most common form of dementia, characterized by an early olfactory dysfunction, progressive memory loss, and behavioral deterioration. Albeit substantial progress has been made in characterizing AD-associated molecular and cellular events, there is an unmet clinical need for new therapies. In this study, olfactory tract proteotyping performed in controls and AD subjects (n = 17/group) showed a Braak stage-dependent proteostatic impairment accompanied by the progressive modulation of amyloid precursor protein and tau functional interactomes. To implement a computational repurposing of drug candidates with the capacity to reverse early AD-related olfactory omics signatures (OMSs), we generated a consensual OMSs database compiling differential omics datasets obtained by mass-spectrometry or RNA-sequencing derived from initial AD across the olfactory axis. Using the Connectivity Map-based drug repurposing approach, PKC, EGFR, Aurora kinase, Glycogen synthase kinase, and CDK inhibitors were the top pharmacologic classes capable to restore multiple OMSs, whereas compounds with targeted activity to inhibit PI3K, Insulin-like growth factor 1 (IGF-1), microtubules, and Polo-like kinase (PLK) represented a family of drugs with detrimental potential to induce olfactory AD-associated gene expression changes. To validate the potential therapeutic effects of the proposed drugs, in vitro assays were performed. These validation experiments revealed that pretreatment of human neuron-like SH-SY5Y cells with the EGFR inhibitor AG-1478 showed a neuroprotective effect against hydrogen peroxide-induced damage while the pretreatment with the Aurora kinase inhibitor Reversine reduced amyloid-beta (Aß)-induced neurotoxicity. Taken together, our data pointed out that OMSs may be useful as substrates for drug repurposing to propose novel neuroprotective treatments against AD.

The Olfactory System: Basic Anatomy and Physiology for General Otorhinolaryngologists.

Olfaction is one of the five basic human senses, and it is known to be one of the most primitive senses. The sense of olfaction may have been critical for human survival in prehistoric society, and although many believe its importance has diminished over time, it continues to have an impact on human interaction, bonding, and propagation of the species. Even if we are unaware of it, the sense of smell greatly affects our lives and is closely related to overall quality of life and health. Nonetheless, olfaction has been neglected from a scientific perspective compared to other senses. However, olfaction has recently received substantial attention since the loss of smell and taste has been noted as a key symptom of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Studies investigating olfaction loss in association with coronavirus disease 2019 (COVID-19) have revealed that olfactory dysfunction can be both conductive and sensorineural, possibly causing structural changes in the brain. Olfactory training is an effective treatment for olfactory dysfunction, suggesting the reorganization of neural associations. A reduced ability to smell may also alert suspicion for neurodegenerative or psychiatric disorders. Here, we summarize the basic knowledge that we, as otorhinolaryngologists, should have about the sense of smell and the peripheral and central olfactory pathways for managing and helping patients with olfactory dysfunction.

Quantitative analysis of the olfactory system in pediatric epilepsy: a magnetic resonance imaging study

PURPOSE: Olfactory dysfunction is a well-known complication in epilepsy. Studies have demonstrated that olfactory bulb volume (OBV), olfactory tract length (OTL), and olfactory sulcus depth (OSD) can be reliably evaluated using magnetic resonance imaging (MRI). In this study, we compared the OBV, OTL, and OSD values of children with epilepsy and those of healthy children (controls) of similar age. Our aim was to determine the presence of olfactory dysfunction in children with epilepsy and demonstrate the effects of the epilepsy type and treatment on olfactory function in these patients. METHODS: Cranial MRI images of 36 patients with epilepsy and 108 controls (3-17 years) were evaluated. The patients with epilepsy were divided into groups according to the type of disease and treatment method. Subsequently, OBV and OSD were measured from the coronal section and OTL from the sagittal section. The OBV, OTL, and OSD values were compared between the epilepsy group, subgroups, and controls. RESULTS: OBV was significantly reduced in the children with epilepsy compared with the control group (P < 0.001). No significant difference between the healthy children and those with epilepsy was determined in terms of OTL and OSD. Although OBV was moderately positively correlated with age in the control group (r = 0.561, P < 0.001), it was poorly correlated with age in children with epilepsy (r = 0.393, P = 0.018). CONCLUSION: The results of our study indicate that OBV decreases in children with epilepsy, but epilepsy type and treatment method do not affect OBV, OTL, or OSD (P > 0.05).

Detection of ß-N-methylamino-l-alanine in postmortem olfactory bulbs of Alzheimer's disease patients using UHPLC-MS/MS: An autopsy case-series study.

Introduction: Cyanobacterial blooms produce toxins that may become aerosolized, increasing health risks through inhalation exposures. Health related effects on the lower respiratory tract caused by these toxins are becoming better understood. However, nasal exposures to cyanotoxins remain understudied, especially for those with neurotoxic potential. Here, we present a case series study evaluating exposure to ß-N-methylamino-l-alanine (BMAA), a cyanobacterial toxin linked to neurodegenerative disease, in postmortem olfactory tissues of individuals with varying stages of Alzheimer's disease (AD). Methods: Olfactory bulb (Ob) tissues were collected during autopsies performed between 2014 and 2017 from six South Florida brain donors (ages 47-78) with residences less than 140 m from a freshwater body. A triple quadrupole tandem mass spectrometry (UHPLC-MS/MS) method validated according to peer AOAC International guidelines was used to detect BMAA and two BMAA isomers: 2,4-diaminobutyric acid (2,4-DAB) and N-(2-aminoethyl)glycine (AEG). Quantitative PCR was performed on the contralateral Ob to evaluate the relative expression of genes related to proinflammatory cytokines (IL-6 & IL-18), apoptotic pathways (CASP1 & BCL2), and mitochondrial stress (IRF1 & PINK1). Immunohistochemistry was also performed on the adjacent olfactory tract (Ot) to evaluate co-occurring neuropathology with BMAA tissue concentration. Results: BMAA was detected in the Ob of all cases at a median concentration of 30.4 ng/g (Range

Brain-derived neurotrophic factor (BDNF) induces antagonistic action to Nogo signaling by the upregulation of lateral olfactory tract usher substance (LOTUS) expression.

Neurons in the central nervous system (CNS) have limited capacity for axonal regeneration after trauma and neurological disorders due to an endogenous nonpermissive environment for axon regrowth in the CNS. Lateral olfactory tract usher substance (LOTUS) contributes to axonal tract formation in the developing brain and axonal regeneration in the adult brain as an endogenous Nogo receptor-1 (NgR1) antagonist. However, how LOTUS expression is regulated remains unclarified. This study examined molecular mechanism of regulation in LOTUS expression and found that brain-derived neurotrophic factor (BDNF) increased LOTUS expression in cultured hippocampal neurons. Exogenous application of BDNF increased LOTUS expression at both mRNA and protein levels in a dose-dependent manner. We also found that pharmacological inhibition with K252a and gene knockdown by siRNA of tropomyosin-related kinase B (TrkB), BDNF receptor suppressed BDNF-induced increase in LOTUS expression. Further pharmacological analysis of the TrkB signaling pathway revealed that BDNF increased LOTUS expression through mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) cascades, but not phospholipase C-γ (PLCγ) cascade. Additionally, treatment with c-AMP response element binding protein (CREB) inhibitor partially suppressed BDNF-induced LOTUS expression. Finally, neurite outgrowth assay in cultured hippocampal neurons revealed that BDNF treatment-induced antagonism for NgR1 by up-regulating LOTUS expression. These findings suggest that BDNF may acts as a positive regulator of LOTUS expression through the TrkB signaling, thereby inducing an antagonistic action for NgR1 function by up-regulating LOTUS expression. Also, BDNF may synergistically affect axon regrowth through the upregulation of LOTUS expression.

LOTUS suppresses amyloid ß-induced dendritic spine elimination through the blockade of amyloid ß binding to PirB.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aß) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aß and Aß-PirB molecular interactions that cause synapse elimination and synaptic dysfunction. PirB deletion has been shown to suppress Aß-induced synaptic dysfunction and behavioral deficits in AD model mice, implying that PirB mediates Aß-induced AD pathology. Therefore, inhibiting the Aß-PirB molecular interaction could be a successful approach for combating AD pathology. We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB and that LOTUS overexpression promotes neuronal regeneration following damage to the central nervous system, including spinal cord injury and ischemic stroke. Therefore, in this study, we investigated whether LOTUS inhibits Aß-PirB interaction and Aß-induced dendritic spine elimination. METHODS: The inhibitory role of LOTUS against Aß-PirB (or leukocyte immunoglobulin-like receptor subfamily B member 2: LilrB2) binding was assessed using a ligand-receptor binding assay in Cos7 cells overexpressing PirB and/or LOTUS. We assessed whether LOTUS inhibits Aß-induced intracellular alterations and synaptotoxicity using immunoblots and spine imaging in a primary cultured hippocampal neuron. RESULTS: We found that LOTUS inhibits the binding of Aß to PirB overexpressed in Cos7 cells. In addition, we found that Aß-induced dephosphorylation of cofilin and Aß-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice. Moreover, primary cultured hippocampal neurons from LOTUS-tg mice improved the Aß-induced decrease in dendritic spine density. Finally, we studied whether human LOTUS protein inhibits Aß binding to LilrB2, a human homolog of PirB, and found that human LOTUS inhibited the binding of Aß to LilrB2 in a similar manner. CONCLUSIONS: This study implied that LOTUS improved Aß-induced synapse elimination by suppressing Aß-PirB interaction in rodents and inhibited Aß-LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aß-induced AD pathologies.

A Journey to the Central Nervous System: Routes of Flaviviral Neuroinvasion in Human Disease.

Many arboviruses, including viruses of the Flavivirus genera, are known to cause severe neurological disease in humans, often with long-lasting, debilitating sequalae in surviving patients. These emerging pathogens impact millions of people worldwide, yet still relatively little is known about the exact mechanisms by which they gain access to the human central nervous system. This review focusses on potential haematogenous and transneural routes of neuroinvasion employed by flaviviruses and identifies numerous gaps in knowledge, especially regarding lesser-studied interfaces of possible invasion such as the blood-cerebrospinal fluid barrier, and novel routes such as the gut-brain axis. The complex balance of pro-inflammatory and antiviral immune responses to viral neuroinvasion and pathology is also discussed, especially in the context of the hypothesised Trojan horse mechanism of neuroinvasion. A greater understanding of the routes and mechanisms of arboviral neuroinvasion, and how they differ between viruses, will aid in predictive assessments of the neuroinvasive potential of new and emerging arboviruses, and may provide opportunity for attenuation, development of novel intervention strategies and rational vaccine design for highly neurovirulent arboviruses.

Comparison of Olfactory Tract Diffusion Measures Between Early Stage Parkinson's Disease Patients and Healthy Controls Using Ultra-High Field MRI.

BACKGROUND: MRI is a valuable method to assist in the diagnostic work-up of Parkinson's disease (PD). The olfactory tract (OT) has been proposed as a potential MRI biomarker for distinguishing PD patients from healthy controls. OBJECTIVE: This study aims to further investigate whether diffusion measures of the OT differ between early stage PD patients and healthy controls. METHODS: Twenty hyposmic/anosmic PD patients, 65 normosmic PD patients, and 36 normosmic healthy controls were evaluated and a 7T diffusion weighted image scan was acquired. Manual seed regions of interest were drawn in the OT region. Tractography of the OT was performed using a deterministic streamlines algorithm. Diffusion measures (fractional anisotropy and mean- radial- and axial diffusivity) of the generated streamlines were compared between groups. RESULTS: Diffusion measures did not differ between PD patients compared to healthy controls and between hyposmic/anosmic PD patients, normosmic PD patients, and normosmic healthy controls. A positive correlation was found between age and mean- and axial diffusivity within the hyposmic/anosmic PD subgroup, but not in the normosmic groups. A positive correlation was found between MDS-UPDRSIII scores and fractional anisotropy. CONCLUSION: This study showed that fiber tracking of the OT was feasible in both early stage PD and healthy controls using 7T diffusion weighted imaging data. However, 7T MRI diffusion measures of the OT are not useful as an early clinical biomarker for PD. Future work is needed to clarify the role of other OT measurements as a biomarker for PD and its different subgroups.

The Everted Amygdala of Ray-Finned Fish: Zebrafish Makes a Case.

The amygdala, a complex array of nuclei in the forebrain, controls emotions and emotion-related behaviors in vertebrates. Current research aims to understand the amygdala's evolution in ray-finned fish such as zebrafish because of the region's relevance for social behavior and human psychiatric disorders. Clear-cut molecular definitions of the amygdala and its evolutionary-developmental relationship to the one of mammals are critical for zebrafish models of affective disorders and autism. In this review, I argue that the prosomeric model and a focus on the olfactory system's organization provide ideal tools for discovering deep ancestral relationships between the emotional systems of zebrafish and mammals. The review's focus is on the "extended amygdala," which refers to subpallial amygdaloid territories including the central (autonomic) and the medial (olfactory) amygdala required for reproductive and social behaviors. Amphibians, sauropsids, and lungfish share many characteristics with the basic amygdala ground plan of mammals, as molecular and hodological studies have shown. Further exploration of the evolution of the amygdala in basally derived fish vertebrates requires researchers to test these "tetrapod-based" concepts. Historically, this has been a daunting task because the forebrains of basally derived fish vertebrates look very different from those of more familiar tetrapod ones. An extreme case are ray-finned fish (Actinopterygii) like zebrafish because their telencephalon develops through a distinct outward-growing process called eversion. To this day, scientists have struggled to determine how the everted telencephalon compares to non-actinopterygian vertebrates. Using the teleost zebrafish as a genetic model, comparative neurologists began to establish quantifiable molecular definitions that allow direct comparisons between ray-finned fish and tetrapods. In this review, I discuss how the most recent discovery of the zebrafish amygdala ground plan offers an opportunity to identify the developmental constraints of amygdala evolution and function. In addition, I explain how the zebrafish prethalamic eminence (PThE) topologically relates to the medial amygdala proper and the nucleus of the lateral olfactory tract (nLOT). In fact, I consider these previously misinterpreted olfactory structures the most critical missing evolutionary links between actinopterygian and tetrapod amygdalae. In this context, I will also explain why recognizing both the PThE and the nLOT is crucial to understanding the telencephalon eversion. Recognizing these anatomical hallmarks allows direct comparisons of the amygdalae of zebrafish and mammals. Ultimately, the new concepts of the zebrafish amygdala will overcome current dogmas and reach a holistic understanding of amygdala circuits of cognition and emotion in actinopterygians.

Excitable Axonal Domains Adapt to Sensory Deprivation in the Olfactory System.

The axon initial segment (AIS), nodes of Ranvier, and the oligodendrocyte-derived myelin sheath have significant influence on the firing patterns of neurons and the faithful, coordinated transmission of action potentials (APs) to downstream brain regions. In the olfactory bulb (OB), olfactory discrimination tasks lead to adaptive changes in cell firing patterns, and the output signals must reliably travel large distances to other brain regions along highly myelinated tracts. Whether myelinated axons adapt to facilitate olfactory sensory processing is unknown. Here, we investigate the morphology and physiology of mitral cell (MC) axons in the olfactory system of adult male and female mice and show that unilateral sensory deprivation causes system-wide adaptations in axonal morphology and myelin thickness. MC spiking patterns and APs also adapted to sensory deprivation. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system.SIGNIFICANCE STATEMENT Successful transmission of information from the olfactory bulb (OB) to piriform cortex through the lateral olfactory tract (LOT) relies on synchronized arrival of action potentials (APs). The coincident arrival of APs is dependent on reliable generation of APs in the axon initial segment (AIS) and fast conduction mediated by axon myelination. Here, we studied changes in mitral cell (MC) firing and AIS structure as well as changes in myelination of the LOT on unilateral olfactory deprivation in the adult mouse. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system.

Mapping the Microstructure and Striae of the Human Olfactory Tract with Diffusion MRI.

The human sense of smell plays an important role in appetite and food intake, detecting environmental threats, social interactions, and memory processing. However, little is known about the neural circuity supporting its function. The olfactory tracts project from the olfactory bulb along the base of the frontal cortex, branching into several striae to meet diverse cortical regions. Historically, using diffusion magnetic resonance imaging (dMRI) to reconstruct the human olfactory tracts has been prevented by susceptibility and motion artifacts. Here, we used a dMRI method with readout segmentation of long variable echo-trains (RESOLVE) to minimize image distortions and characterize the human olfactory tracts in vivo We collected high-resolution dMRI data from 25 healthy human participants (12 male and 13 female) and performed probabilistic tractography using constrained spherical deconvolution (CSD). At the individual subject level, we identified the lateral, medial, and intermediate striae with their respective cortical connections to the piriform cortex and amygdala (AMY), olfactory tubercle (OT), and anterior olfactory nucleus (AON). We combined individual results across subjects to create a normalized, probabilistic atlas of the olfactory tracts. We then investigated the relationship between olfactory perceptual scores and measures of white matter integrity, including mean diffusivity (MD). Importantly, we found that olfactory tract MD negatively correlated with odor discrimination performance. In summary, our results provide a detailed characterization of the connectivity of the human olfactory tracts and demonstrate an association between their structural integrity and olfactory perceptual function.SIGNIFICANCE STATEMENT This study provides the first detailed in vivo description of the cortical connectivity of the three olfactory tract striae in the human brain, using diffusion magnetic resonance imaging (dMRI). Additionally, we show that tract microstructure correlates with performance on an odor discrimination task, suggesting a link between the structural integrity of the olfactory tracts and odor perception. Lastly, we generated a normalized probabilistic atlas of the olfactory tracts that may be used in future research to study its integrity in health and disease.

Representations of the olfactory bulb and tracts in images of the medieval cell doctrine.

This article presents a collection of previously overlooked, stereotyped, abstract, anatomical representations of the olfactory bulbs and tracts that were printed as part of schematic woodcuts of the medieval cell doctrine, generally in the early-sixteenth century but extending into the seventeenth century and, in at least one case, to the mid-nineteenth century. A representation of the olfactory bulbs is incorporated into many of these woodcuts, beginning with an illustration by German physician, philosopher, and theologian Magnus Hundt in 1501 in his Antropologium, which showed central projections of the two olfactory bulbs joining in the meshwork of the rete mirabile. German physician and anatomist Johann Eichmann, known as Johannes Dryander, modified Hundt's figure for his own monograph in 1537 but retained the representation of the olfactory bulbs. In 1503, German Carthusian humanist writer Gregor Reisch published an influential and highly copied woodcut in his Margarita philosophica, showing connections from the olfactory bulbs overlying the bridge of the nose (as well as from other special sense organs) to the sensus communis in the anterior cell or ventricle. In the following centuries, numerous authors derived similar figures from Reisch's original schematic illustration of the medieval cell doctrine, including Brunschwig (1512, 1525), Glogowczyk (1514), Romberch/Host (1520), Leporeus/Le Lièvre (1520, 1523), Dolce (1562), Lull/Bernardus de Lavinheta (1612), and Elliotson (1835). Similar representations were provided by Peyligk (1518) and Eck (1520). These stereotyped schematic images linked the olfactory bulbs to olfaction before the advent of more realistic images beginning in the mid-sixteenth century.

Combined rare anatomic variants: persistent primitive olfactory artery and azygos pericallosal artery.

The persisting primitive olfactory artery (PPOA) is a rare anatomic variation of the anterior cerebral artery (ACA), being encountered in less than 1% of cases. Different morphological types were reported previously. In type 3, only once reported previously, the PPOA gives off two branches, a nasal one which courses in the olfactory sulcus to supply the territory of the anterior ethmoidal artery, and the callosomarginal artery. It is reported here a combination of rare anatomic variants found in a 71-year-old male patient investigated by computed tomography angiography. A left PPOA left the A1 segment of the ACA and was classified as subtype 3b, as its branches were the nasal one and a frontal trunk, not the callosomarginal artery. That PPOA had a characteristic hairpin turn applied on the anterior fossa floor. The ACA continued as azygos pericallosal artery, which is also a rare finding. As the nasal branch of the PPOA and its hairpin turn is closely related to the anterior fossa floor, such variant should be carefully documented when combined approaches of the skull base are planned by rhinologists and neurosurgeons.

What's that smell? A pictorial review of the olfactory pathways and imaging assessment of the myriad pathologies that can affect them.

The olfactory pathway is composed of peripheral sinonasal and central sensorineural components. The wide variety of different pathologies that can affect the olfactory pathway reflect this complex anatomical relationship. Localising olfactory pathology can present a challenge to the reporting radiologist. This imaging review will illustrate the normal anatomy of the olfactory system and describe a systematic approach to considering olfactory dysfunction. Key concepts in image interpretation will be demonstrated using examples of olfactory pathway pathologies.

Quantitative analysis of healthy olfactory sulcus depth, olfactory tract length and olfactory bulb volume in the paediatric population: a magnetic resonance study.

BACKGROUND: The aim of this study was to determine the normal reference values for olfactory sulcus depth, olfactory tract length and olfactory bulb volume in the paediatric population with routine magnetic resonance imaging (MRI) and determine the relationship, if any, between these values and patient sex and age. MATERIALS AND METHODS: Ninety patients with a median age of 8 years (age range: 3-17 years), consisting of 45 males and 45 females with normal brain MRI scans were evaluated. The patients were divided into three subgroups based on age range, with n = 30 per subgroup; group 1: young children (3-6 years), group 2: children (7-11 years) and group 3: adolescents (12-17 years). In the cranial MRI examination of all groups, the right, left and total olfactory bulb volume values were measured in mm3, the right and left olfactory tract length values and the right and left olfactory sulcus depth values were calculated manually in mm. Demographic data including sex and age were recorded. RESULTS: There was no significant difference between the age groups in terms of sex. Right-left olfactory sulcus depth; right-left olfactory tract length and right-left total olfactory bulb volume values increased significantly when they are compared in terms of age groups (p < 0.0001, = 0.028; < 0.0001, < 0.0001; < 0.0001, < 0.0001; < 0.0001, respectively). There was no significant difference between right and left olfactory tract length and olfactory bulb volumes in all groups (p = 0.792 and p = 0.478), but the right olfactory sulcus depth was significantly larger than the left (p = 0.003). CONCLUSIONS: Especially as the age progresses, olfactory tract length and olfactory bulb volume dimensions of olfactory nerve and olfactory sulcus depth should be checked during diagnosis of respective illnesses in paediatric population.

Amyotrophic Lateral Sclerosis Is Accompanied by Protein Derangements in the Olfactory Bulb-Tract Axis.

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive muscle paralysis due to the degeneration of upper and lower motor neurons. Recent studies point out an involvement of the non-motor axis during disease progression. Despite smell impairment being considered a potential non-motor finding in ALS, the pathobiochemistry at the olfactory level remains unknown. Here, we applied an olfactory quantitative proteotyping approach to analyze the magnitude of the olfactory bulb (OB) proteostatic imbalance in ALS subjects (n = 12) with respect to controls (n = 8). Around 3% of the quantified OB proteome was differentially expressed, pinpointing aberrant protein expression involved in vesicle-mediated transport, macroautophagy, axon development and gliogenesis in ALS subjects. The overproduction of olfactory marker protein (OMP) points out an imbalance in the olfactory signal transduction in ALS. Accompanying the specific overexpression of glial fibrillary acidic protein (GFAP) and Bcl-xL in the olfactory tract (OT), a tangled disruption of signaling routes was evidenced across the OB-OT axis in ALS. In particular, the OB survival signaling dynamics clearly differ between ALS and frontotemporal lobar degeneration (FTLD), two faces of TDP-43 proteinopathy. To the best of our knowledge, this is the first report on high-throughput molecular characterization of the olfactory proteostasis in ALS.

Experimental Demyelination of the Lateral Olfactory Tract and Anterior Commissure.

Demyelination significantly affects brain function. Several experimental methods, each inducing varying levels of myelin and neuronal damage, have been developed to understand the process of myelin loss and to find new therapies to promote remyelination. The present work investigates the effect of one such method, lysolecithin administration, on the white matter tracts in the olfactory system. The olfactory forebrain contains two distinct tracts with differing developmental histories, axonal composition, and function: the lateral olfactory tract (LOT), which carries ipsilateral olfactory information from the olfactory bulb to olfactory cortex, and the anterior commissure (AC), which interconnects olfactory regions across hemispheres. The effects of lysolecithin injections were assessed in two ways: (1) the expression of myelin basic protein, a component of compacted myelin sheaths, was quantified using immunohistochemistry and (2) electron microscopy was used to obtain measurements of myelin thickness of individual axons as well as qualitative descriptions of the extent of damage to myelin and surrounding tissue. Data were collected at 7, 14, 21, and 30 days post-injection (dpi). While both the LOT and AC exhibited significant demyelination at 7 dpi and had returned to control levels by 30 dpi, the process differed between the two tracts. Remyelination occurred more rapidly in the LOT: substantial recovery was observed in the LOT by 14 dpi, but not in the AC until 21 dpi. The findings indicate that (a) the LOT and AC are indeed suitable tracts for studying lysolecithin-induced de- and remyelination and (b) experimental demyelination proceeds differently between the two tracts.

Nogo receptor antagonist LOTUS exerts suppression on axonal growth-inhibiting receptor PIR-B.

Damaged axons in the adult mammalian central nervous system have a restricted regenerative capacity mainly because of Nogo protein, which is a major myelin-associated axonal growth inhibitor with binding to both receptors of Nogo receptor-1 (NgR1) and paired immunoglobulin-like receptor (PIR)-B. Lateral olfactory tract usher substance (LOTUS) exerts complete suppression of NgR1-mediated axonal growth inhibition by antagonizing NgR1. However, the regulation of PIR-B functions in neurons remains unknown. In this study, protein-protein interactions analyses found that LOTUS binds to PIR-B and abolishes Nogo-binding to PIR-B completely. Reverse transcription-polymerase chain reaction and immunocytochemistry revealed that PIR-B is expressed in dorsal root ganglions (DRGs) from wild-type and Ngr1-deficient mice (male and female). In these DRG neurons, Nogo induced growth cone collapse and neurite outgrowth inhibition, but treatment with the soluble form of LOTUS completely suppressed them. Moreover, Nogo-induced growth cone collapse and neurite outgrowth inhibition in Ngr1-deficient DRG neurons were neutralized by PIR-B function-blocking antibodies, indicating that these Nogo-induced phenomena were mediated by PIR-B. Our data show that LOTUS negatively regulates a PIR-B function. LOTUS thus exerts an antagonistic action on both receptors of NgR1 and PIR-B. This may lead to an improvement in the defective regeneration of axons following injury.

Intracranial brain parenchymal spread of mucormycosis through olfactory tract: a diffusion-weighted imaging-based concept.

Mucormycosis is an opportunistic fungal infection involving among others the paranasal sinuses, nasal fossa and brain parenchyma. Mucor can invade the brain parenchyma by either contiguous spread from the paranasal sinuses or through vascular invasion. We report a case of fatal rhino-cerebral mucormycosis in whom cytotoxic edema at magnetic resonance diffusion-weighted imaging was symmetrically restricted to both neocortical and paleocortical primary areas of olfactory projection at earliest phase of the disease process. Shortly later tissue damage extended into the whole brain. This undescribed observation raised the hypothesis of preferential way of brain invasion by Mucor through the olfactory tract.

Comparison of the Olfactory Bulb Volume and the Olfactory Tract Length Between Patients Diagnosed with Essential Tremor and Healthy Controls: Findings in Favor of Neurodegeneration.

Purpose Essential tremor (ET) is the most common movement disorder. In recent years, an increasing number of studies have shown that this disease also has a variety of non-motor findings and may be of a neurodegenerative nature. This study aimed to evaluate the olfactory bulb volume (OBV) and the olfactory tract length (OTL) and to demonstrate possible neurodegeneration in ET patients using magnetic resonance imaging (MRI). Methods The study included 30 ET patients (mean age=29.53±11.82 years) and 30 healthy controls (mean age=30.00±11.68 years). In the cranial MRI examination of both groups, the right, left and total OBV values ​​were measured in mm3 and the right and left OTL values ​​were calculated manually in mm. Results There was no significant difference between the patient and control groups in the measured OBV values, but the OTL value of the patient group was statistically significantly lower than the control group. Conclusion Our study showed that the olfactory system might be involved in ET cases. We think that olfactory dysfunction, one of the non-motor symptoms in ET, can be clearly elucidated through both anatomical and functional studies, to be conducted with larger patient groups.