Search Results (85)

Background/Objectives: Olfactory impairment has been proposed as an early marker for Alzheimer’s disease (AD), yet the mechanisms linking sensory decline to genetic and environmental risk factors remain unclear. We aimed to identify early biomarkers and brain network alterations associated with AD risk by multimodal analyses in humanized APOE mice. Methods: We evaluated olfactory behavior, diffusion MRI connectomics, and brain and blood transcriptomics in mice stratified by APOE2, APOE3, and APOE4 genotypes, age, sex, high-fat diet, and immune background (HN). Behavioral assays assessed odor salience, novelty detection, and memory. Elastic Net-regularized multi-set canonical correlation analysis (MCCA) was used to link behavior to brain connectivity. Blood transcriptomics and gene ontology analyses identified peripheral molecular correlates. Results: APOE4 mice exhibited accelerated deficits in odor-guided behavior and memory, especially under high-fat diet, while APOE2 mice were more resilient (ANOVA: APOE x HN, F(2, 1669) = 77.25, p < 0.001, eta squared = 0.08). Age and diet compounded behavioral impairments (diet x age: F(1, 1669) = 16.04, p < 0.001). Long-term memory was particularly reduced in APOE4 mice (APOE x HN, F(2,395) = 5.6, p = 0.004). MCCA identified subnetworks explaining up to 24% of behavioral variance (sum of canonical correlations: 1.27, 95% CI [1.18, 1.85], p < 0.0001), with key connections involving the ventral orbital and somatosensory cortices. Blood eigengene modules correlated with imaging changes (e.g., subiculum diffusivity: r = −0.5, p < 1 × 10⁻³⁰), and enriched synaptic pathways were identified across brain and blood. Conclusions: Olfactory behavior, shaped by genetic and environmental factors, may serve as a sensitive, translatable biomarker of AD risk. Integrative systems-level approaches reveal brain and blood signatures of early sensory–cognitive vulnerability, supporting new avenues for early detection and intervention in AD. Full article

Background: There is growing interest in the potential role of manganese (Mn) in the development of Alzheimer’s Disease and related dementias (ADRD). Methods: In this nested pilot study of a ferroalloy worker cohort, we investigated the impact of chronic occupational Mn exposure on cognitive function through β-amyloid (Aβ) deposition and multi-omics profiling. We evaluated six male Mn-exposed workers (median age 63, exposure duration 31 years) and five historical controls (median age: 60 years), all of whom had undergone brain PET scans. Exposed individuals showed significantly higher Aβ deposition in exposed individuals (p < 0.05). The average annual cumulative respirable Mn was 329.23 ± 516.39 µg/m³ (geometric mean 118.59), and plasma Mn levels were significantly elevated in the exposed group (0.704 ± 0.2 ng/mL) compared to controls (0.397 ± 0.18 in controls). Results: LC-MS/MS-based pathway analyses revealed disruptions in olfactory signaling, mitochondrial fatty acid β-oxidation, biogenic amine synthesis, transmembrane transport, and choline metabolism. Simoa analysis showed notable alterations in ADRD-related plasma biomarkers. Protein microarray revealed significant differences (p < 0.05) in antibodies targeting neuronal and autoimmune proteins, including Aβ (25–35), GFAP, serotonin, NOVA1, and Siglec-1/CD169. Conclusion: These findings suggest Mn exposure is associated with neurodegenerative biomarker alterations and disrupted biological pathways relevant to cognitive decline. Full article

Tomatoes are globally esteemed not only for their nutritional value but also for their complex and appealing aroma, a key determinant of consumer preference. The present study aimed to comprehensively characterise the volatilomic fingerprints of three tomato species—Solanum lycopersicum L., S. lycopersicum var. cerasiforme, and S. betaceum—encompassing six distinct varieties, through the application of headspace solid-phase microextraction coupled with gas chromatography–mass spectrometry (HS-SPME/GC-MS). A total of 55 volatile organic compounds (VOCs) spanning multiple chemical classes were identified, of which only 28 were ubiquitously present across all varieties examined. Carbonyl compounds constituted the predominant chemical family, with hexanal and (E)-2-hexenal emerging as putative key contributors to the characteristic green and fresh olfactory notes. Notably, esters were found to dominate the unique volatile fingerprint of cherry tomatoes, particularly methyl 2-hydroxybenzoate, while Kumato and Roma varieties exhibited elevated levels of furanic compounds. Multivariate statistical analyses, including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), demonstrated clear varietal discrimination and identified potential aroma-associated biomarkers such as phenylethyl alcohol, 3-methyl-1-butanol, hexanal, (E)-2-octenal, (E)-2-nonenal, and heptanal. Collectively, these findings underscore the utility of volatilomic fingerprint as a robust tool for varietal identification and quality control within the food industry. Full article

Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism (HH) characterized by gonadotropin-releasing hormone (GnRH) deficiency and anosmia due to defective neuronal migration. While traditionally considered irreversible, cases of spontaneous improvement of HH have been reported, suggesting residual GnRH neuronal function in some individuals. We present a case of a 29-year-old man with KS who exhibited spontaneous recovery of endogenous testosterone production following the cessation of long-term androgen therapy without the use of alternative hormonal agents. After ceasing testosterone therapy for several months, the patient’s total testosterone levels normalized (407–424 ng/dL), accompanied by increased secondary sexual characteristics, stable gonadotropin levels, and normal testicular volume. Persistent anosmia was noted, suggesting that restoration of reproductive endocrine function can occur independently of olfactory recovery. Genetic testing identified heterozygous mutations in PCSK1 and HS6ST1, genes implicated in GnRH regulation and KS pathogenesis. This case highlights the potential role of genetic variation in spontaneous HH improvement and underscores the need for individualized management strategies, including periodic reassessment of gonadal function and fertility potential. Further research is needed to elucidate the mechanisms driving spontaneous HH improvement, identify predictive biomarkers of reversibility, and explore therapeutic strategies that may promote endogenous GnRH activity in select patients with KS. Full article

Background: Membranous nephropathy (MN), a prevalent glomerular disorder, remains poorly understood in terms of its association with mitochondrial dynamics (MD). This study investigated the mechanistic involvement of mitochondrial dynamics-related genes (MDGs) in the pathogenesis of MN. Methods: Comprehensive bioinformatics analyses—encompassing Mendelian randomization, machine-learning algorithms, and single-cell RNA sequencing (scRNA-seq)—were employed to interrogate transcriptomic datasets (GSE200828, GSE73953, and GSE241302). Core MDGs were further validated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Results: Four key MDGs—RTTN, MYO9A, USP40, and NFKBIZ—emerged as critical determinants, predominantly enriched in olfactory transduction pathways. A nomogram model exhibited exceptional diagnostic performance (area under the curve [AUC] = 1). Seventeen immune cell subsets, including regulatory T cells and activated dendritic cells, demonstrated significant differential infiltration in MN. Regulatory network analyses revealed ATF2 co-regulation mediated by RTTN and MYO9A, along with RTTN-driven modulation of ELOA-AS1 via hsa-mir-431-5p. scRNA-seq analysis identified mesenchymal–epithelial transitioning cells as key contributors, with pseudotime trajectory mapping indicating distinct temporal expression profiles: NFKBIZ (initial upregulation followed by decline), USP40 (gradual fluctuation), and RTTN (persistently low expression). RT-qPCR results corroborated a significant downregulation of all four genes in MN samples compared to controls (p < 0.05). Conclusions: These findings elucidate the molecular underpinnings of MDG-mediated mechanisms in MN, revealing novel diagnostic biomarkers and therapeutic targets. The data underscore the interplay between mitochondrial dynamics and immune dysregulation in MN progression, providing a foundation for precision medicine strategies. Full article

Diagnosis and intervention at the earliest stages of cancer are imperative for maximizing patient recovery outcomes and substantially increasing survival rates and quality of life. Recently, to facilitate cancer diagnosis, volatile organic compounds (VOCs) have shown potential with unique characteristics as cancer biomarkers. Various insects with sophisticated sensitivities of odor can be quickly and readily trained to recognize such VOCs using olfactory-linked skills. Furthermore, the approach to analyzing VOCs can be made using electronic noses, commonly referred to as e-noses. Using analytical instruments like GC-MS, LC-MS/MS, etc., chemical blends are separated into their constituent parts. The significance of odorant receptors in triggering neural responses to ambient compounds has received great attention in the last twenty years, particularly in the investigation of insect olfaction. Sensilla, a sophisticated olfactory neural framework, is regulated by a neuronal receptor composed of neuronal, non-neuronal, extracellular lymphatic fluid with an effectively generated shell. This review provides an in-depth exploration of the structural, functional, and signaling mechanisms underlying odorant sensitivities and chemical odor detection in the excretory products of cancer patients, addressing current challenges in VOC-based cancer diagnostics and innovative strategies for advancement while also envisioning the transformative role of artificial olfactory systems in the future of cancer detection. Furthermore, the article emphasizes recent preclinical and clinical advancements in VOC applications, highlighting their potential to redefine early diagnostic approaches in oncology. Full article

Background: Pain is prevalent in almost all populations and may often hinder visual, auditory, tactile, olfactory, and taste perception as it alters brain neural processing. The quantitative methods emerging to define pain and assess its effects on neural functions and perception are important. Identifying pain biomarkers is one of the initial stages in developing such models and interventions. The existing literature has explored chronic and experimentally induced pain, leveraging electroencephalograms (EEGs) to identify biomarkers and employing various qualitative and quantitative approaches to measure pain. Objectives: This systematic review examines the methods, participant characteristics, types of pain states, associated pain biomarkers of the brain’s electrical activity, and limitations of current pain studies. The review identifies what experimental methods researchers implement to study human pain states compared to human control pain-free states, as well as the limitations in the current techniques of studying human pain states and future directions for research. Methods: The research questions were formed using the Population, Intervention, Comparison, Outcome (PICO) framework. A literature search was conducted using PubMed, PsycINFO, Embase, the Cochrane Library, IEEE Explore, Medline, Scopus, and Web of Science until December 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to obtain relevant studies. The inclusion criteria included studies that focused on pain states and EEG data reporting. The exclusion criteria included studies that used only MEG or fMRI neuroimaging techniques and those that did not focus on the evaluation or assessment of neural markers. Bias risk was determined by the Newcastle–Ottawa Scale. Target data were compared between studies to organize the findings among the reported results. Results: The initial search resulted in 592 articles. After exclusions, 24 studies were included in the review, 6 of which focused on chronic pain populations. Experimentally induced pain methods were identified as techniques that centered on tactile perception: thermal, electrical, mechanical, and chemical. Across both chronic and stimulated pain studies, pain was associated with decreased or slowing peak alpha frequency (PAF). In the chronic pain studies, beta power increases were seen with pain intensity. The functional connectivity and pain networks of chronic pain patients differ from those of healthy controls; this includes the processing of experimental pain. Reportedly small sample sizes, participant comorbidities such as neuropsychiatric disorders and peripheral nerve damage, and uncontrolled studies were the common drawbacks of the studies. Standardizing methods and establishing collaborations to collect open-access comprehensive longitudinal data were identified as necessary future directions to generalize neuro markers of pain. Conclusions: This review presents a variety of experimental setups, participant populations, pain stimulation methods, lack of standardized data analysis methods, supporting and contradicting study findings, limitations, and future directions. Comprehensive studies are needed to understand the pain and brain relationship deeper in order to confirm or disregard the existing findings and to generalize biomarkers across chronic and experimentally induced pain studies. This requires the implementation of larger, diverse cohorts in longitudinal study designs, establishment of procedural standards, and creation of repositories. Additional techniques include the utilization of machine learning and analyzing data from long-term wearable EEG systems. The review protocol is registered on INPLASY (# 202520040). Full article

Sickle cell disease (SCD) is a severe inherited blood disorder characterized by abnormal hemoglobin (HbS) that leads to varying degrees of severity, including chronic hemolysis, episodic vaso-occlusion, and damage to multiple organs, causing significant morbidity and mortality. While SCD is a monogenic disease, its complications are influenced by polygenic factors. SCD prevalence is notably high in regions including the Middle East, with Saudi Arabia reporting significant cases, particularly in the Eastern Province. Most genetic factors associated with SCD outcomes have been identified in populations predominantly from Africa or of African ancestry. This study aims to identify genetic variants that characterize Saudi SCD patients with the potential to influence disease outcomes in this population. A multicenter case-control genome-wide association study (GWAS) was conducted involving 350 adult Saudi SCD patients and 202 healthy controls. Participants were genotyped using the Affymetrix Axiom array, covering 683,030 markers. Rigorous quality control measures were applied to ensure data integrity. Fisher’s exact was used to identify genetic variants with a significant difference in allele frequency (p < 5 × 10⁻⁸). Functional annotations and regulatory functions of variants were determined using the Ensembl Variant Effect Predictor (VEP) and RegulomeDB databases. The GWAS identified numerous significant genetic variants characterizing SCD cases in the Saudi population. These variants, distributed across multiple chromosomes, were found in genes with known functional consequences. A substantial proportion of the markers were detected in the olfactory receptor cluster, TRIM family, and HBB locus genes. Many of the identified genes were reported in previous studies showing significant associations with various SCD outcomes, including hemoglobin regulation, inflammation, immune response, and vascular function. The findings highlight the genetic complexity underlying SCD and its clinical manifestations. The identified variants suggest potential molecular biomarkers and therapeutic targets, enhancing our understanding of the molecular basis of SCD in the Saudi population. This is the first genetic analysis characterizing SCD patients compared to healthy individuals, uncovering genetic markers that could serve as diagnostic biomarkers and therapeutic targets. Given the known molecular mechanisms of the detected genetic loci, these provide a foundation for precision medicine in SCD management, highlighting the need for further studies to validate these results and explore their clinical implications. Full article

Alpha-synuclein has been associated with neurodegeneration, especially in Parkinson’s disease (PD). This study aimed to review clinical, biochemical, and neuroimaging markers and management of prodromal synucleinopathies. The prodromal state of synucleinopathies can be better understood with PD pathophysiology, and it can be separated into premotor and pre-diagnostic phases. The incidence of PD in patients with prodromal phase symptoms ranges from 0.07 to 14.30, and the most frequently studied pathology is the REM behavioral disorder (RBD). Neuroimaging markers are related to dopamine denervation, brain perfusion changes, gross anatomy changes, and peripheral abnormalities. α-synuclein assays (SAA) in CSF revealed high sensitivity (up to 97%) and high specificity (up to 92%); in the last decade, there was the development of other matrices (blood, skin, and olfactory mucosa) for obtaining quantitative and qualitative α-synuclein. Other biomarkers are neurofilament light chain, DOPA decarboxylase, and multiplexed mass spectrometry assay. Regarding genetic counseling in α-synucleinopathies, it is an important topic in clinical practice to discuss with patients with high-risk individuals and should involve basic principles of autonomy, beneficence, and non-maleficence. Some of the themes that should be reviewed are the involvement of physical activity, diet (including alcohol, coffee, and vitamin supplementation), smoking, sleep, and stress in the pathophysiology of synucleinopathies. The number of trials related to prodromal symptoms is still scarce, and the number of studies evaluating intervention is even lower. Full article

Background/Objectives: Olfactory decline is common in normal aging and frequent in neurodegenerative diseases such as Alzheimer’s disease (AD). Therefore, it has been suggested as a marker for the Mild Cognitive Impairment (MCI) progression to AD. Although suggested, the relationship between olfactory deficits and cerebral atrophy in MCI conversion to AD is still debated. This study aims at investigating the olfaction-related morphological and behavioural alterations in MCI in order to understand whether they can predict the progression to AD. Methods: Twenty-seven MCI patients and thirty-five healthy controls (HCs) took part in the study, with follow-up showing conversion to AD in thirteen patients (converter-MCI, cMCI). The Burgarth Sniffin’ Sticks Tests (threshold—TT, discrimination—DT, identification—IT) assessed the olfactory capacities. The Voxel-Based Morphometry (VBM) analysis investigated the atrophic patterns. Results: The Receiving Operating Characteristics analyses demonstrated that DT and IT could distinguish HC from MCI (DT Area Under Curve—AUC = 0.8; IT AUC = 0.8), as well as cMCI from sMCI (stable) patients (DT AUC = 0.7; IT AUC = 0.6), similarly to memory and executive functions tests. Olfactory performance positively correlated with memory tests in sMCI (all rhos ≥ 0.8, all ps < 0.01), whereas it positively correlated with executive functions in cMCI (all rhos ≥ 0.6, all ps < 0.05). VBM results revealed distinct atrophic patterns in cMCI, especially in the olfactory cortex, that were already present at the MCI diagnosis, before AD conversion. A larger volume of the olfactory cortex was associated with better memory and executive functions. Conclusions: Quantitative olfactory and morphological patterns represent non-invasive, predictive biomarkers of the MCI progression to AD; thus, their assessments at MCI onset allows earlier interventions for MCI patients. Full article

Neurological and olfactory disturbances are increasingly recognized as potential complications of general anesthesia, particularly in vulnerable populations, such as the elderly, children, and individuals with comorbidities. Recent studies have highlighted the need for tailored anesthetic approaches in these high-risk groups to mitigate potential long-term effects. These disturbances, including postoperative cognitive dysfunction, delirium, and olfactory deficits, often arise from shared pathophysiological mechanisms, such as neuroinflammation, oxidative stress, and disruptions in cerebral perfusion. The olfactory system is particularly susceptible to anesthesia-induced neurotoxicity given its proximity to central nervous system structures and its role in sensory and cognitive processing. Furthermore, the unique regenerative capacity of olfactory neurons may be compromised by prolonged or repeated exposure to anesthetic agents, potentially leading to long-term olfactory dysfunction. Risk factors, such as advanced age, neurodegenerative diseases, diabetes, cardiovascular conditions, genetic predispositions, and the type and duration of anesthesia exposure, further exacerbate these complications. Preventive strategies, including comprehensive preoperative risk assessment, personalized anesthetic protocols based on genetic and physiological profiles, and proactive postoperative care with early intervention programs, are critical for reducing impairments and improving long-term patient outcomes. Emerging evidence highlights the potential role of neuroprotective agents, such as antioxidants and anti-inflammatory therapies, in mitigating the effects of anesthesia-induced neurotoxicity. Longitudinal studies are needed to evaluate the long-term effects of anesthesia on cognitive and sensory health, particularly in high-risk populations. These studies should incorporate advanced neuroimaging techniques and biomarker analysis to elucidate the underlying mechanisms of anesthesia-induced neurological and olfactory disturbances. This narrative review provides a comprehensive overview of the mechanisms, risk factors, and preventive strategies for neurological and olfactory disturbances after general anesthesia and highlights future directions for research to improve patient outcomes. We conducted a comprehensive literature search using databases, such as PubMed and Scopus, to identify relevant studies. Full article

Objectives: Evidence for the usefulness of biomarkers that aid in diagnosis, assessment of severity, and prediction of prognosis in patients with long COVID is limited. The aim of this study was to clarify the characteristics of brain natriuretic peptide (BNP) in long COVID. Methods: We conducted a retrospective observational study of patients who visited the COVID-19 aftercare outpatient clinic at Okayama University Hospital from February 2021 to April 2024. Results: A total of 428 patients were enrolled in this study, and the patients were divided into a group with normal BNP (n = 314, ≤18.4 pg/mL) and a group with increased BNP (n = 114, >18.4 pg/mL). The long COVID group with increased BNP had a higher proportion of females (44.3% vs. 73.7%, p < 0.01) and an older median age (38 vs. 51 years, p < 0.01). Fatigue and brain fog were commonly manifested in both groups, while dyspnea was a more frequent complaint in the group with increased BNP. Various symptoms including fatigue, palpitations, and taste and/or olfactory disorders were associated with elevated BNP (23 to 24 pg/mL). Memory impairment was also linked to higher BNP (OR: 2.36, p = 0.05). In long COVID patients, plasma BNP elevation appears to be more pronounced in females and is often related to cardiogenic factors, in which inflammatory responses are also involved. Conclusions: Plasma BNP measurement may be useful for evaluating the severity of long COVID, especially in female patients and those with respiratory symptoms and/or memory impairment. Full article

Cancer is one of the major causes of death, and as it becomes more malignant, it becomes an intractable disease that is difficult to cure completely. Therefore, early detection is important to increase the survival rate. For this reason, testing with blood biomarkers is currently common. However, in order to accurately diagnose early-stage cancer, new biomarkers and diagnostic methods that enable highly accurate diagnosis are needed. This review summarizes recent studies on cancer biomarker detection. In particular, we focus on the analysis of volatile organic compounds (VOCs) in urine and the development of diagnostic methods using olfactory receptors in living organisms. Urinary samples from cancer patients contain a wide variety of VOCs, and the identification of cancer specific compounds is underway. It has also been found that the olfactory sense of organisms can distinguish cancer-specific odors, which may be applicable to cancer diagnosis. We explore the possibility of novel cancer biomarker candidates and novel diagnostic methods. Full article

Background/Aim: Loss of smell, also known as anosmia, is a prevalent and often prolonged symptom following infection with SARS-CoV-2. While many patients regain olfactory function within weeks, a significant portion experience persistent anosmia lasting over a year post-infection. The underlying mechanisms responsible for this sensory deficit remain largely uncharacterized. Previous studies, including genome-wide association studies (GWAS), have identified genetic variants near the UGT2A1 and UGT2A2 genes that are linked to anosmia in COVID-19 patients. However, the role of epigenetic changes in the development and persistence of smell loss has not been well explored. In this study, we aimed to investigate epigenetic alterations in the form of DNA methylation in the UGT1A1 gene, which is a locus associated with olfactory dysfunction in COVID-19 patients. Methods: We analysed DNA methylation patterns in blood samples from two carefully matched cohorts of 20 COVID-19 patients each, which are differentiated by their olfactory function—those with normal smell (normosmia) and those suffering from smell loss (anosmia). The cohorts were matched for age and sex to minimize potential confounding factors. Results: Using quantitative analysis, we found significantly lower levels of DNA methylation in the UGT1A1 locus in the anosmia group compared to the normosmia group, with a 14% decrease in median methylation values in patients with smell loss (p < 0.0001). These findings highlight potential epigenomic alterations in the UGT1A1 gene that may contribute to the pathogenesis of anosmia following COVID-19 infection. Our results suggest that the methylation status at this locus could serve as a biomarker for olfactory dysfunction in affected individuals. Conclusion: This study is among the first to describe epigenetic changes associated with smell loss in COVID-19, providing a foundation for future research into targeted interventions and potential therapeutic strategies aimed at reversing persistent anosmia. Further investigations involving larger cohorts and additional loci may help elucidate the complex interaction between genetic, epigenetic, and environmental factors influencing long-term sensory impairment post-COVID-19. Full article

Introduction: This study aims to investigate the relationship between olfactory identification (OI) and cognitive impairment by examining OI abilities across various stages of cognitive deterioration. Methods: A total of 264 participants were divided into three groups based on cognitive status: cognitively healthy, subjective cognitive, and mild cognitive impairment. All participants were assessed using the Sniffin’ Sticks Olfactory Identification test and a comprehensive neuropsychological test battery. Results: Our results highlight the main effects of age and cognitive status on OI scores. Regarding cognitive abilities, OI is associated with measures of short-term memory, long-term, working memory, and selective attention. Finally, logistic regression models showed that OI is a significant predictor for discriminating SCD from CH, MCI from CH, and MCI from SCD. Discussion: These findings suggest the addition of olfactory identification measures in neuropsychological assessments could improve the early detection of individuals at risk for cognitive impairment. Full article