Search Results (86)

Background: Olfactory dysfunction (OD)—including anosmia and hyposmia—is a common and often persistent outcome of viral infections. This systematic review consolidates findings from structural and functional MRI studies to explore how COVID-19 SARS-CoV-2-induced smell loss alters the brain. Considerable heterogeneity was observed across studies, influenced by differences in methodology, population characteristics, imaging timelines, and OD classification. Methods: Following PRISMA guidelines, we conducted a systematic search of PubMed/MEDLINE, Scopus, and Web of Science to identify MRI-based studies examining COVID-19’s SARS-CoV-2 OD. Twenty-four studies were included and categorized based on imaging focus: (1) olfactory bulb (OB), (2) olfactory sulcus (OS), (3) grey and white matter changes, (4) task-based brain activation, and (5) resting-state functional connectivity. Demographic and imaging data were extracted and analyzed accordingly. Results: Structural imaging revealed consistent reductions in olfactory bulb volume (OBV) and olfactory sulcus depth (OSD), especially among individuals with OD persisting beyond three months, suggestive of inflammation and neurodegeneration in olfactory-associated regions like the orbitofrontal cortex and thalamus. Functional MRI studies showed increased connectivity in early-stage OD within regions such as the piriform and orbitofrontal cortices, possibly reflecting compensatory activity. In contrast, prolonged OD was associated with reduced activation and diminished connectivity, indicating a decline in olfactory processing capacity. Disruptions in the default mode network (DMN) and limbic areas further point to secondary cognitive and emotional effects. Diffusion tensor imaging (DTI) findings—such as decreased fractional anisotropy (FA) and increased mean diffusivity (MD)—highlight white matter microstructural compromise in individuals with long-term OD. Conclusions: COVID-19’s SARS-CoV-2 olfactory dysfunction is associated with a range of cerebral alterations that evolve with the duration and severity of smell loss. Persistent dysfunction correlates with greater neural damage, underscoring the need for longitudinal neuroimaging studies to better understand recovery dynamics and guide therapeutic strategies. Full article

Parkinson’s disease (PD) associated with GBA1 mutations—recently termed Sidransky syndrome—differs from idiopathic PD (iPD) by earlier onset, more rapid progression, and higher rates of non-motor symptoms. Our objective was to assess whether GBA1 mutations contribute to olfactory dysfunction in PD and in asymptomatic carriers of the mutation. We compared olfactory and motor functions in 119 participants: Sidransky syndrome (n = 18), iPD (n = 30), GBA1 variant carriers without PD (n = 21), Gaucher disease patients (n = 20), and healthy controls (n = 30). All were evaluated with the Brief Smell Identification Test (BSIT^®) and the motor part of the Movement Disorders Society Unified PD Rating Scale (MDS-mUPDRS). Mean age was 59.2 ± 11.7 years. Mean disease duration was 2.5 ± 2.2 years in Sidransky syndrome and 5.4 ± 4.9 years in iPD. We found that both PD groups had significantly lower BSIT^® scores than non-PD groups (p < 0.001), particularly for leather, smoke, natural gas, pineapple, clove, rose, and lemon. Sidransky syndrome patients scored lower than iPD patients (p = 0.04). No significant olfactory deficits were observed in GBA1 carriers or Gaucher patients without PD. We conclude that hyposmia is more pronounced in Sidransky syndrome than in iPD. However, normal olfaction in non-parkinsonian GBA1 carriers suggests that GBA1 variants alone do not account for olfactory loss in PD. Hyposmia likely reflects broader PD pathology rather than a direct effect of the GBA1 mutation. Full article

Congenital hypogonadotropic hypogonadism (CHH) is a rare and heterogeneous genetic disorder with variable penetrance caused by GnRH deficiency, leading to delayed puberty and infertility. In 50–60% of cases, CHH is associated with non-reproductive abnormalities, most commonly anosmia/hyposmia (Kallmann syndrome, KS). Over 60 genes have been implicated in CHH pathogenesis. We aimed to perform genetic screening in a cohort of 14 patients (10 males, 4 females; mean age 22 ± 7.72 years) with suspected or diagnosed HH/KS. Genetic analysis was conducted using next-generation sequencing (NGS) with a custom panel of 46 candidate genes. Variant interpretation followed ACMG standards and guidelines. Multiple tools were used to predict the structural effects of variants on tertiary protein structure, assessing their pathogenicity. Novel variants were functionally characterized by qRT-PCR on mRNA extracted from peripheral leukocytes. NGS identified nine rare variants and four novel variants in genes previously associated with normosmic isolated HH (nHH) and/or KS (FGFR1, PROK2, TAC3R, DCC, WDR11, IL17RD, DUSP6, KAL1, FGF8, IL17RD and DCC). The variant in TAC3R (p.Trp275Ter) was pathogenic; variants in ANOS1 (c.541+1G>A), IL17RD (c.1303_1304dup, p.Lys436ThrfsTer58), and TAC3R (p.Lys361Ter) were likely pathogenic. Nine variants were classified as variants of uncertain significance (VUS). Our study identified a possible genetic cause in 71% of the CHH/KS cohort, emphasizing the importance of genetic screening and functional characterization of genetic variants in patients with a phenotypically and genetically heterogeneous disorder like CHH. Full article

Background: Split-hand/foot malformation (SHFM) is a rare congenital limb anomaly defined by the absence or hypoplasia of the central rays of the autopod. SHFM occurs as an isolated entity or part of genetic syndromes with several causative copy-number variations or monogenic alterations known to be involved in the disease pathomechanism. On the other hand, cleft lip/palate (CL/P) usually results from polygenic and environmental factors, with the complex interplay of both leading to this malformation. Pathogenic variants in FGFR1 have been linked to phenotypically distinct disorders, including Hartsfield syndrome, Kallmann syndrome, Jackson–Weiss syndrome, osteoglophonic dysplasia, and Pfeiffer syndrome. Although pathogenic variants in FGFR1 can contribute to syndromic SHFM or CL/P, their role in isolated SHFM or CL remains poorly described in the literature. Methods: We conducted targeted next-generation sequencing (NGS) in the proband with SHFM, followed by segregation analysis in the family members. Results: In this study, we report an index patient presenting with isolated SHFM and his brother with CL and facial dysmorphism, as well as their father with isolated hyposmia. Targeted next-generation sequencing revealed a previously reported heterozygous missense pathogenic variant in FGFR1 (c.830G>A; p.Cys277Tyr) in both affected siblings and their hyposmic father. Conclusions: This study expands the phenotypic spectrum associated with FGFR1 pathogenic variants, emphasizing their involvement in non-syndromic SHFM and CL or isolated hyposmia. Our findings highlight the importance of considering FGFR1 in the molecular diagnosis of isolated SHFM or orofacial clefting, point to the high intrafamilial variability of FGFR1 pathogenic variants, and demonstrate the diagnostic value of targeted NGS in rare congenital malformations. Full article

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of chronic rhinosinusitis (CRS) characterized by bilateral nasal polyps, primarily affecting adults. It is often associated with hyposmia and asthma and driven by persistent Th2 inflammation, particularly in Caucasian patients. The disease is recurrent and significantly impacts quality of life, yet its pathophysiology remains poorly understood. Management includes intranasal steroids, short courses of systemic corticosteroids, surgery for refractory cases, and biologics. However, despite these treatment options, disease control remains challenging. Low vitamin D levels have been associated with worse clinical outcomes, while supplementation studies show promise in improving symptoms in deficient patients. Emerging research suggests that vitamin D modulates immunity, fibroblast activity, and epithelial integrity, potentially contributing to CRSwNP pathogenesis, though the exact mechanisms remain unclear. This review synthesizes current research on vitamin D’s role in systemic and local inflammation in CRSwNP. By highlighting its potential therapeutic implications, this work aims to guide future research and inform clinical practice. Additionally, it may serve as a foundation for understanding the broader impact of vitamin D deficiency in sinonasal diseases and other atopic conditions. Full article

The sense of smell plays a crucial role in food perception, influencing dietary choices and eating behavior. This narrative review explores the relationship between olfactory function and obesity, addressing the question: how does smell influence the perception, selection, and eating behavior of food? The review highlights that individuals with obesity may experience reduced olfactory sensitivity due to hormonal imbalances, such as elevated leptin and reduced ghrelin levels, which can alter odor perception and lead to unhealthy food preferences. Additionally, those with olfactory dysfunction may compensate by seeking saltier or sweeter foods, increasing the risk of obesity. The review also notes that olfactory responses vary across age groups, with some obese adolescents exhibiting greater olfactory sensitivity. The impact of the COVID-19 pandemic on olfactory function and eating habits is discussed, emphasizing the need for interventions that incorporate sensory aspects of eating to combat obesity. A comprehensive approach involving neuroscience, psychology, and public health is recommended to develop effective and personalized solutions for obesity prevention and treatment. Full article

Head and neck cancer affects millions worldwide. The risk factors are numerous, including smoking, alcohol consumption, and human papillomavirus to name a few. While improved preventative, diagnostic, and treatment methods have decreased mortality rates, the treatments (chemotherapy, radiotherapy, or surgery) often result in smell and/or taste impairments. These can impact quality of life during and after cancer treatment. A scoping review was performed to understand current research and future directions regarding smell and taste impairments in head and neck cancer patients. PRISMA guidelines were followed and Rayyan.ai was used to search and compile journal articles. Three databases, EBSCOhost, Google Scholar, and PubMed, were also searched. Search terms included smell, taste, dysgeusia, ageusia, hypogeusia, parosmia, anosmia, hyposmia, dysosmia, and head and neck cancer. A total of 1580 articles were found through Rayyan.ai and 8022 were found through the three databases, which were manually screened. Articles assessing patients with a different malignancy, benign tumors, pediatric populations, animal studies, abstracts, and review articles were excluded. A total of 47 articles were found using this strategy. Of those we identified, 37 articles discussed taste impairments, 12 articles discussed smell impairments, and 3 articles discussed treatments for smell and/or taste impairments. All 37 articles concluded that there was some taste alteration in head and neck cancer patients due to their treatment. However, the specific taste qualities (sweet, sour, salty, or bitter) that were impaired, whether taste function returned to baseline, and which treatments led to impairments varied. For the 12 studies that assessed smell impairments, the results also varied. Some studies found significant objective impairments in smell while others found no significant impairment. Zinc sulfate was not found to be an effective treatment option for taste impairments; however, a liposomal spray showed some potential. Future studies should aim to understand which treatments and types of head and neck cancer lead to chemosensory impairments, whether chemosensory alterations negatively impact a patient’s nutritional status, and treatments or preventative measures for smell and taste changes. Full article

Background: Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a chronic inflammatory disease associated with frustrating symptoms, particularly nasal obstruction and loss of smell. We conducted a patient survey on the significant burden of the disease, with a specific focus on conditions that affect health, sleep quality, absenteeism, and presenteeism, including the caregivers’ perspectives. Methods: An online questionnaire was sent to 4230 randomly selected recipients, and 200 matched the inclusion criteria for self-reported CRSwNPs symptoms. A total of 100 participants not matching the inclusion criteria for CRSwNPs were recruited as a control group. The study also collected the perspectives of 50 caregivers. Results: Patients with CRSwNPs experienced very bothersome symptoms, such as nasal congestion, headache, and rhinorrhoea, with a profound impact on their health-related quality of life (HRQoL). The patients and their caregivers showed significantly lower quality of sleep, experiencing a poor night’s sleep on average 72.1 and 51.7 days per year, respectively. Smell and taste impairments significantly impacted patients’ social and working lives, with 39.5% feeling in danger because of hyposmia and 34.5% because of limited taste. Out-of-pocket costs were up to EUR 40/month for 68.5% of patients. CRSwNPs alone was responsible for an average of 24.7 days of absenteeism and 25.1 days of presenteeism. Conclusions: Our results highlight how CRSwNPs has a negative impact on patients’ and caregivers’ HRQoL. Most bothersome and health-conditioning symptoms involve nose symptoms and poor sleep quality, resulting in patient absenteeism and presenteeism with a strong burden on cognitive and emotional functioning for both patients and their caregivers. Full article

Parkinson’s disease (PD) is a neurological disorder characterized by heterogeneous symptomatology, in which the classical motor features of Parkinsonism are associated with clinically significant non-motor symptoms. Olfactory alteration, as a manifestation of PD’s premotor or prodromal phase, is well known. These impairments can lead to malnutrition, decreased appetite, and depression, thereby worsening patients’ quality of life. However, only a few studies clarify the mechanisms, characteristics, and clinical diagnostic and therapeutic implications of impaired taste perception. Moreover, unlike most motor features of PD, non-motor symptoms often have limited treatment options or responses. The purpose of this review is to collate and describe all relevant studies on taste and smell alterations in patients with PD and how these alterations could affect nutritional status. Our search aimed to identify English-language research articles and reviews published in peer-reviewed journals over the past two decades (2004–2024), while also including older foundational studies when relevant. Several studies show that hyposmia in PD worsens over time, potentially linked to structural changes in the brain’s basal ganglia and piriform cortex. Severe hyposmia is also associated with a higher risk of dementia in PD patients and can negatively influence quality of life, affecting social interactions and nutrition. Regarding taste perception, recent studies have suggested that hypogeusia may occur even in the prodromal stage of PD, such as in patients with REM sleep disorder, although the exact mechanisms remain unclear. Additionally, research has explored the role of bitter taste receptors and their possible involvement in inflammation and α-synuclein misfolding, suggesting a link between taste dysfunction and immune system changes in PD. Attention was then focused on the gut microbiota’s link to the central nervous system and its contribution to gustatory dysfunctions, as well as how the nasal microbiome influences PD progression by altering the olfactory system. Nowadays, the primary role of a correct diet in the overall treatment of PD patients is becoming increasingly important for practitioners. Diet should be included among the available aids to counteract some aspects of the pathology itself. For all these reasons, it is also crucial to determine whether these chemosensory impairments could serve as disease markers, helping to better understand the underlying mechanisms of the disease. Full article

Background: Sour taste is associated with acid-base homeostasis, which is critical to cell metabolism and health conditions. Vinegar, which contains acetic acid as the main component, is a sour food considered the second most common condiment in Italy. Objectives: The aim of the study was to assess differences in sourness perception in subjects with olfactory deficits compared to controls and evaluate myrtle aromatization’s potential effect in modulating sourness perception in subjects with hyposmia. Methods: To this end, olfactory function was assessed with the Sniffin’ Sticks test and gustatory function by the Taste Strips test. Sensory perception of a traditional white wine vinegar (WV) and a WV aromatized with myrtle (AWV) was evaluated. The sourness perception of the two vinegars was estimated through the rates of odor and taste pleasantness, intensity, and familiarity using a labeled hedonic Likert-type scale. Results: Our data indicated that in patients with hyposmia, a significant decrease was observed only in sour taste perception compared to controls. The increase in vinegar aroma due to the myrtle aromatization modulated sourness perception in patients with hyposmia. Conclusions: Myrtle aromatization increased the number of significant correlations between odor and the taste dimensions of the vinegar in controls and in patients with hyposmia in a different manner. Full article

Kallmann syndrome is a rare disorder characterized by hypogonadotropic hypogonadism and an impaired sense of smell (anosmia or hyposmia) caused by congenital defects in the development of the gonadotropin-releasing hormone (GnRH) and olfactory neurons. Mutations in several genes have been associated with Kallmann syndrome. However, genetic testing of this disorder often reveals variants of uncertain significance (VUS) that remain uninterpreted without experimental validation. The aim of this study was to analyze the functional consequences of a heterozygous missense VUS in the CHD7 gene (c.4354G>T, p.Val1452Leu), in a patient with Kallmann syndrome with reversal of hypogonadism. The variant, located in the first nucleotide of exon 19, was analyzed using minigene assays to determine its effect on ribonucleic acid (RNA) splicing. These showed that the variant generates two different transcripts: a full-length transcript with the missense change (p.Val1452Leu), and an abnormally spliced transcript lacking exon 19. The latter results in an in-frame deletion (p.Val1452_Lys1511del) that disrupts the helicase C-terminal domain of the CHD7 protein. The variant was reclassified as likely pathogenic. These findings demonstrate that missense variants can exert more extensive effects beyond simple amino acid substitutions and underscore the critical role of functional analyses in VUS reclassification and genetic diagnosis. Full article

The loss of the sense of smell has not produced as many technological developments to mitigate the inconvenience it causes compared to the loss of vision or hearing. Anosmia or hyposmia concerns approximately 20% of the current European population and is associated with a loss of quality of life and an increased rate of household accidents. Restoring olfaction would therefore be beneficial, but it represents a technological challenge. Electrical stimulation of the nasal cavity triggers sensations that may be helpful to patients in detecting environmental odorant stimuli. We present an electrical stimulator fabricated using commercial flexible PCB technology and compare two different placement designs: A standard design based on existing medical technology that uses a metallic rod, bent to ensure contact with the nasal cavity; and a self-holding design featuring two magnets, placed across the nasal septum to ensure contact. The detection thresholds were measured for both configurations on seven normosmic individuals and show a good correlation between the two designs. Full article

Parkinson’s disease (PD) affects movement; however, most patients with PD also develop nonmotor symptoms, such as hyposmia, sleep disorder, and depression. Dopamine levels in the brain have a critical influence on movement control, but other neurotransmitters are also involved in the progression of PD. This study analyzed the fluctuation of neurotransmitters in PC12 cells during neurogenesis and neurodegeneration by performing mass spectrometry. We found that the dopaminergic metabolism pathway of PC12 cells developed vigorously during the neuron differentiation process and that the neurotransmitters were metabolized into 3-methoxytyramine, which was released from the cells. The regulation of the intracellular and extracellular concentrations of adenosine indicated that adenine nucleotides were actively utilized in neural differentiation. Moreover, we exposed the differentiated PC12 cells to rotenone, which is a suitable material for modeling PD. The cells exposed to rotenone in the early stage of differentiation exhibited stimulated serotoninergic metabolism, and the contents of the serotoninergic neurotransmitters returned to their normal levels in the late stage of differentiation. Interestingly, the nondifferentiated cells can resist the toxicant rotenone and produce normal dopaminergic metabolites. However, when differentiated neuron cells were exposed to rotenone, they were seriously damaged, leading to a failure to produce dopaminergic neurotransmitters. In the low-dosage damage process, the amino acids that functioned as dopaminergic pathway precursors could not be absorbed by the cells, and dopamine and L-dopa were secreted and unable to be reuptaken to trigger the cell damage. Full article

Neuroscience has revolved around brain structural changes, functional activity, and connectivity alteration in Parkinson’s Disease (PD); however, how the network topology organization becomes altered is still unclear, specifically in Parkinson’s patients with severe hyposmia. In this study, we have examined the functional network topological alteration in patients affected by Parkinson’s Disease with normal cognitive ability (ODN), Parkinson’s Disease with severe hyposmia (ODP), and healthy controls (HCs) using resting-state functional magnetic resonance imaging (rsfMRI) data. We have analyzed brain topological organization using popular graph measures such as network segregation (clustering coefficient, modularity), network integration (participation coefficient, path length), small-worldness, efficiency, centrality, and assortativity. Then, we used a feature ranking approach based on the diagonal adaptation of neighborhood component analysis, aiming to determine a graph measure that is sensitive enough to distinguish between these three different groups. We noted significantly lower segregation and local efficiency and small-worldness in ODP compared to ODN and HCs. On the contrary, we did not find differences in network integration in ODP compared to ODN and HCs, which indicates that the brain network becomes fragmented in ODP. At the brain network level, a progressive increase in the DMN (Default Mode Network) was observed from healthy controls to ODN to ODP, and a continuous decrease in the cingulo-opercular network was observed from healthy controls to ODN to ODP. Further, the feature ranking approach has shown that the whole-brain clustering coefficient and small-worldness are sensitive measures to classify ODP vs. ODN, as well as HCs. Looking at the brain regional network segregation, we have found that the cerebellum and limbic, fronto-parietal, and occipital lobes have higher ODP reductions than ODN and HCs. Our results suggest network topological measures, specifically whole-brain segregation and small-worldness decreases. At the network level, an increase in DMN and a decrease in the cingulo-opercular network could be used as biomarkers to characterize ODN and ODP. Full article

Background/Objectives: Primary Familial Brain Calcification is a rare neurodegenerative disorder of adulthood characterized by calcium deposition in the basal ganglia and other brain areas; the main clinical manifestations include movement disorders, mainly parkinsonism. Non-motor symptoms are not well defined in PFBC. This work aims at defining the burden of non-motor symptoms in PFBC. Methods: A clinical, genetic and neuropsychological evaluation of a cohort of PFBC patients, COMPASS-31 scale administration. Results: A total of 50 PFBC patients were recruited; in 25, the genetic test was negative; 10 carried mutations in SLC20A2 gene, 8 in MYORG, 3 in PDGFB, 1 in PDGFRB, 2 in JAM2 (single mutations), and one test is still ongoing. The main motor manifestation was parkinsonism. Headache was reported in 26% of subjects (especially in PDGFB mutation carriers), anxiety or depression in 62%, psychosis or hallucinations in 10–12%, sleep disturbances in 34%; 14% of patients reported hyposmia, 32% constipation, and 34% urinary disturbances. A neuropsychological assessment revealed cognitive involvement in 56% (sparing memory functions, to some extent). The COMPASS-31 mean score was 20.6, with higher sub-scores in orthostatic intolerance and gastrointestinal problems. MYORG patients and subjects with cognitive decline tended to have higher scores and bladder involvement compared to other groups. Conclusions: The presence of non-motor symptoms is frequent in PFBC and should be systematically assessed to better meet patients’ needs. Full article