Rationale: Adult neurogenesis in the subventricular zone (SVZ) is essential for maintaining neural homeostasis, and its dysregulation contributes to anosmia and delayed tissue healing in neurological disorders, such as Parkinson\'s disease (PD). Despite intricate regulatory networks identified in SVZ neurogenesis, the molecular mechanisms dynamically maintaining neural stem/progenitor cells (NSPCs) in response to physiological and pathological stimuli remain incompletely elucidated. Methods: We generated an RNA binding motif protein 24 (Rbm24) knockout model to investigate its impact on adult neurogenesis in the SVZ, employing immunofluorescence, immunoblot, electrophysiology, RNA-sequencing, and in vitro experiments. Further investigations utilized a PD mouse model, along with genetic and pharmacological manipulations, to elucidate Rbm24 involvement in PD pathology. Results: Rbm24, a multifaceted post-transcriptional regulator of cellular homeostasis, exhibited broad expression in the SVZ from development to aging. Deletion of Rbm24 significantly impaired NSPC proliferation in the adult SVZ, ultimately resulting in collapsed neurogenesis in the olfactory bulb. Notably, Rbm24 played a specific role in maintaining Notch1 mRNA stability in adult NSPCs. The Rbm24/Notch1 signaling axis was significantly downregulated in the SVZ of PD mice. Remarkably, overexpression of Rbm24 rescued disruption of adult neurogenesis and olfactory dysfunction in PD mice, and these effects were hindered by DAPT, a potent inhibitor of Notch1. Conclusions: Our findings highlight the critical role of the Rbm24/Notch1 signaling axis in regulating adult SVZ neurogenesis under physiological and pathological circumstances. This provides valuable insights into the dynamic regulation of NSPC homeostasis and offers a potential targeted intervention for PD and related neurological disorders.

BACKGROUND: Olfactory dysfunction has been reported for its association with cognitive impairment and incident dementia. However, the underlying role of neurodegeneration in this relationship is not fully understood.
METHODS: This prospective cohort study included participants from the Shanghai Aging Study (SAS) who were 60 years or older and diagnosed as dementia-free at baseline and completed at least one follow-up interview between 2010 and 2022. At baseline, olfactory identification function was assessed by the 12-item Sniffin\' Sticks Smell test (SSST-12). Olfactory dysfunction was defined as SSST-12 < 7, 6, and 5 in three age groups of participants with (age < 70, 70 ≤ age < 80, and age ≥ 80), respectively, according to previously reported normative data of olfaction in the SAS. Baseline blood Neurofilament Light Chain (NfL) was quantified using the ultra-sensitive Single Molecular Array technology (Quanterix), and dichotomized into low and high levels according to the median concentration. Multiple cognitive function assessments were administered by the Mini-mental State Examination (MMSE) at baseline and follow-ups. We used the linear mixed-effect model to fit the MMSE trajectories in participants with and without olfactory dysfunction adjusting for baseline age, sex, education year, smoking, and APOE ε4, with person-specific MMSE intercept and slope. Stratified analysis was conducted in participants with low and high NfL.
RESULTS: Among 1125 participants included in this study, 296 were defined as having olfactory dysfunction at baseline. Less education, higher proportion of APOE ε4 allele, and lower baseline and follow-up MMSE scores were observed in participants with olfactory dysfunction (Table 1). During the median 9.4 years follow-up, participants with olfactory dysfunction at baseline evidenced a faster MMSE decline compared with those without olfactory dysfunction (b [95% CI]: -0.08 [-0.15, -0.02], P = 0.02) (Figure 1). Such association remained statistically significant (-0.18 [-0.31, -0.06], P = 0.005) in the subgroup with high NfL, but not in the subgroup with low NfL (0.004 [-0.07, 0.07], P = 0.92) (Figure 2).
CONCLUSIONS: Blood NfL may modify the association of olfactory dysfunction with long-term cognitive decline in community-dwelling older adults. In individuals with high potential neurodegeneration, olfactory dysfunction may be an independent indicator of future cognitive deterioration.

Olfactory disorders is one of the first symptoms of diseases from various departments of medicine (otorhinolaryngology, psychology, neurology, etc.). Based on international clinical recommendations, olfactory tests are the gold standard for the diagnosis of olfactory disorders. There are many different psychophysical tests: UPSIT (USA, Pennsylvania), Sniffin\' Sticks test (Germany), BAST-24 (Spain), etc. Currently, there is an acute shortage of olfactory tests available for clinical practice In Russia. This problem is related to the fact that there are no olfactory tests registered as medical devices on the territory of the Russian Federation. Also, a significant limitation is the unrecognizability of odors by the population of our country, which include foreign analogues (licorice, anise, turpentine, etc.).
OBJECTIVE: To develop and validate the national olfactory test on healthy volunteers.
METHODS: The development and validation of the olfactory test included several stages. First, the development of an olfactory test was carried out, the selection of aromas to assess the threshold and identification ability of olfaction. 25 dilutions of n-butanol were used for the assessment of the threshold olfactory ability. For the stage of assessing the identification ability of the sense of smell, in our previous study, an assessment of the recognition of odor names in the territory of the Russian Federation was carried out. A total of 3.000 people from 8 federal districts of the Russian Federation were interviewed. During the development of the test, 20 names of flavors with the highest rating were used. By the 8th, the selection of monocomponent substances was carried out. Commercially available certified food and perfume flavorings have been used for fragrances whose equivalent in the test cannot be a monocomponent substance. A group of 25 healthy volunteers selected a flavor or a monocomponent for each of the 20 positions. To carry out the identification stage of testing, a booklet was developed with answer options for each fragrance, including 80 images associated with the smell. A methodology for conducting diagnostics has been created. Next, the validation of the developed olfactory test was carried out on 150 healthy volunteers. The study included an assessment of the threshold and identification ability of the sense of smell using the developed test and conducting a comparative analysis with a set of flavors and descriptors corresponding to the Sniffin\' Sticks test.
RESULTS: The developed test includes: 2 panels - panel 1 to assess the threshold ability of smell, panel 2 to assess the identification ability of smell, a booklet with 80 images and captions to them. The norms of threshold and identification olfactory abilities were also determined in the developed test. The domestic test was validated against the relative foreign Sniffin\' Sticks test. Spearman\'s correlation between the accuracy values of the domestic test (17-20; 85.00-100.00%) and the values of the foreign test (11-16; 68.75-100.00%) did not reveal statistically significant differences (rs=0.065, p=0.432), which confirms the equally effective assessment of olfactory ability by the domestic olfactory test in comparison with its foreign counterpart.
CONCLUSIONS: In this work, a methodology for the use of Russian olfactory test was developed and validated on healthy volunteers. The features of the developed test are an assessment of the threshold and identification ability of smell, an adapted set of odors for the Russian population, the use of paper blotters when applying flavor and visual images of descriptors. Despite the wide variety of psychophysical tests, this problem requires further study and comparative analysis of olfactory tests available In Russia and foreign analogues in order to obtain a universal and effective diagnostic method for the populations of our country.
This work was supported by the Russian Foundation for Basic Research (Project No. 24-25-00415).
Нарушение обоняния является одним из первых симптомов заболеваний из различных областей медицины (оториноларингология, психология, неврология и др.). По данным международных клинических рекомендаций, обонятельные тесты признаны «золотым стандартом» диагностики нарушений обоняния. Предложено большое количество различных психофизических тестов. К ним относятся UPSIT (США), Sniffin’ Sticks test (Германия), BAST-24 (Испания) и др. В настоящее время определяется острая нехватка обонятельных тестов, доступных для клинической практики в России. Данная проблема связана с тем, что на территории Российской Федерации отсутствуют зарегистрированные в качестве медицинских изделий обонятельные тесты. Существенным ограничением является неузнаваемость населением нашей страны запахов, которые включают в себя зарубежные аналоги (лакрица, анис, скипидар и др.).
UNASSIGNED: Разработать отечественный обонятельный тест и провести его валидизацию на здоровых добровольцах.
UNASSIGNED: Разработка и валидизация обонятельного теста включали в себя несколько этапов. Сначала разработан обонятельный тест, выполнен подбор ароматов для оценки пороговой и идентификационной способности обоняния. Для этапа оценки пороговой способности обоняния использованы 25 разведений n-бутанола. Для этапа оценки идентификационной способности обоняния в нашем предыдущем исследовании проведена оценка узнаваемости наименований запахов на территории Российской Федерации. Всего опрошены 3000 человек из 8 федеральных округов Российской Федерации. При разработке теста использованы названия 20 ароматов с наибольшим рейтингом. К 8 из них осуществлен подбор монокомпонентных веществ. Для ароматов, эквивалентом которых в тесте не может служить монокомпонентное вещество, использованы коммерчески доступные сертифицированные пищевые и парфюмерные ароматизаторы. Здоровыми добровольцами группы исследования, включавшей 25 человек, осуществлен выбор ароматизатора либо монокомпонента для каждой из 20 позиций. Для проведения этапа идентификации тестирования разработан буклет с вариантами ответа к каждому аромату, включающий 80 изображений, ассоциирующихся с конкретным запахом. Создана методология проведения диагностики. Далее проведена валидизация разработанного обонятельного теста на 150 здоровых добровольцах. Исследование включало оценку пороговой и идентификационной способности обоняния с использованием разработанного теста и проведение сравнительного анализа с набором ароматизаторов и дескрипторов, соответствующих тесту Sniffin’ Sticks.
UNASSIGNED: Разработанный тест включает в себя две панели (панель 1 для оценки пороговой способности обоняния, панель 2 для оценки идентификационной способности обоняния), буклет с 80 изображениями и подписями к ним. Определены нормы пороговой и идентификационной способностей обоняния в разработанном тесте. Отечественный тест валидизирован относительного зарубежного теста Sniffin’ Sticks. Корреляция Спирмена между значениями точности отечественного теста (17—20; 85,00—100,00%) и зарубежного теста (11—16; 68,75—100,00%) не показала статистически значимых различий (rs=0,065, p=0,432), что подтверждает неменьшую эффективность оценки обонятельной способности отечественным обонятельным тестом по сравнению с зарубежным аналогом.
UNASSIGNED: Разработана и валидизирована на здоровых добровольцах методика применения отечественного обонятельного теста. Особенностями разработанного теста являются оценка пороговой и идентификационной способности обоняния, адаптированный набор запахов для населения России, использование бумажных блоттеров при нанесении ароматизатора и визуальных изображений дескрипторов. Ввиду большого разнообразия психофизических тестов необходимы дальнейшее изучение данной проблемы и сравнительный анализ применяемых на территории России обонятельных тестов и зарубежных аналогов для получения универсального и эффективного способа диагностики расстройств обоняния.

The psychophysical Sniffin\' Sticks test, which includes an odor identification test, is the gold standard for assessing the sense of smell in clinical and scientific practice. A necessary requirement for the odor identification test is a close familiarity with the odors used by the inhabitants of the region in which it is used. We studied 77 healthy volunteers and 51 patients with olfactory dysfunction and we found that Russians are not familiar with the three smells from the test (licorice, turpentine and anise) and are completely unfamiliar with the one proposed alternative answer (chives). Moreover, four odors demonstrated very low recognition (less than 75%). The test has been adapted for the use In Russia. In the booklet, licorice is replaced by cough syrup, turpentine by paint thinner, and chives by bay leaf. For odors with low recognition (lemon, apple, pineapple), the alternative fruity odors in the booklet were replaced with more contrasting ones. Based on the data obtained, we are going to develop a domestic version of the odor identification test.
Психофизический тест Sniffin’ Sticks, включающий тест на идентификацию запахов, принято считать «золотым стандартом» для оценки обоняния в клинической и научной практике. Необходимое требование к тесту на идентификацию запахов — близкое знакомство с используемыми запахами жителей региона, в котором проводится исследование. Мы обследовали 77 здоровых добровольцев и 51 пациента с ольфакторной дисфункцией и пришли к выводу, что россияне плохо знакомы с тремя запахами из теста (лакрица, скипидар и анис) и совсем не знакомы с одним предлагаемым альтернативным ответом (шнитт-лук). Кроме того, 4 запаха имеют очень низкое распознавание (менее 75%). Тест адаптирован для применения в России. В буклете «лакрица» заменена «сиропом от кашля», «скипидар» — «растворителем краски», «шнитт-лук» — «лавровым листом». У запахов с низким распознаванием (лимон, яблоко, ананас) альтернативные фруктовые запахи в буклете заменены более контрастными. На основании полученных данных предложена разработка отечественного теста на идентификацию запахов, в котором все запахи будут хорошо знакомы россиянам.

BACKGROUND General paresis of the insane (GPI) is characterized by cognitive impairment, neuropsychiatric symptoms, and brain structural abnormalities, mimicking many neuropsychiatric diseases. Olfactory dysfunction has been linked to cognitive decline and neuropsychiatric symptoms in numerous neuropsychiatric diseases. Nevertheless, it remains unclear whether patients with GPI experience olfactory dysfunction and whether olfactory dysfunction is associated with their clinical manifestations. MATERIAL AND METHODS Forty patients with GPI and 37 healthy controls (HCs) underwent the \"Sniffin Sticks\" test battery, Mini-Mental State Examination, and Neuropsychiatric Inventory to measure olfactory function, cognitive function, and neuropsychiatric symptoms, respectively. Brain structural abnormalities were evaluated using visual assessment scales including the medial temporal lobe atrophy (MTA) visual rating scale and Fazekas scale. RESULTS Compared with HCs, patients with GPI exhibited significant olfactory dysfunction, as indicated by deficits in the odor threshold (OT) (P=0.001), odor discrimination (OD) (P<0.001), and odor identification (OI) (P<0.001). In patients with GPI, the OI was positively correlated with cognitive function (r=0.57, P<0.001), but no significant correlation was found between olfactory function and neuropsychiatric symptoms, blood, or cerebrospinal fluid biomarkers (rapid plasma reagin circle card test and Treponema pallidum particle agglutination test), or brain structural abnormalities (MTA and Fazekas scale scores). Mediation analysis indicated that the impaired OI in patients with GPI was mediated by cognitive impairment and impaired OT respectively. CONCLUSIONS Patients with GPI exhibited overall olfactory dysfunction. OI is correlated with cognitive function and the impaired OI is mediated by cognitive impairment in patients with GPI. Thus, OI may serve as a marker for reflecting cognitive function in patients with GPI.

BACKGROUND:  Olfactory dysfunction (OD) represents a frequent manifestation of the coronavirus disease 2019 (COVID-19). Apolipoprotein E (APOE) is a protein that interacts with the angiotensin-converting enzyme receptor, essential for viral entry into the cell. Previous publications have suggested a possible role of APOE in COVID-19 severity. As far as we know, no publications found significant associations between this disease\'s severity, OD, and APOE polymorphisms (E2, E3, and E4).
OBJECTIVE:  To analyze the epidemiology of OD and its relationship with APOE polymorphisms in a cohort of Long-COVID patients.
METHODS:  We conducted a prospective cohort study with patients followed in a post-COVID neurological outpatient clinic, with OD being defined as a subjective reduction of olfactory function after infection, and persistent OD being defined when the complaint lasted more than 3 months after the COVID-19 infection resolution. This cross-sectional study is part of a large research with previously reported data focusing on the cognitive performance of our sample.
RESULTS:  The final sample comprised 221 patients, among whom 186 collected blood samples for APOE genotyping. The persistent OD group was younger and had a lower hospitalization rate during the acute phase of the disease (p < 0.001). Furthermore, the APOE variant E4 allele frequency was lower in this group (p = 0.035). This study evaluated OD in an outpatient population with COVID-19. In the current literature on this disease, anosmia is associated with better clinical outcomes and the E4 allele is associated with worse outcomes.
CONCLUSIONS:  Our study provides new information to these correlations, suggesting APOE E4 as a protective factor for OD.
BACKGROUND:  A disfunção olfatória (DO) é uma manifestação frequente da doença do coronavírus 2019 (COVID-19). A apolipoproteína E (APOE) é uma proteína que interage com o receptor da enzima conversora de angiotensina, essencial para a entrada viral na célula. Publicações anteriores sugeriram um possível papel da APOE na gravidade da COVID-19. Até onde sabemos, nenhuma publicação encontrou associações significativas entre a gravidade dessa doença, DO e polimorfismos da APOE (E2, E3 e E4).
OBJECTIVE:  Analisar a epidemiologia da DO e sua relação com os polimorfismos do gene APOE em uma coorte de pacientes com COVID longa. MéTODOS:  Um estudo de coorte prospectiva com pacientes acompanhados em ambulatório neurológico pós-COVID, com DO sendo definida como uma redução subjetiva da função olfativa após a infecção e a DO persistente sendo definida quando a queixa durou mais de 3 meses após a resolução da infecção por COVID-19. Este estudo transversal é parte de uma pesquisa maior com dados anteriormente relatados, focando na performance cognitiva dos pacientes.
RESULTS:  Foram selecionados 221 pacientes para esse estudo, dos quais 186 haviam coletado amostras de sangue para genotipagem APOE. O grupo DO persistente foi mais jovem e apresentou menor taxa de internação na fase aguda da doença (p < 0,001). Além disso, a frequência do alelo E4 da APOE foi menor nesse grupo (p = 0,035). Este estudo avaliou a DO em uma população com COVID longa. Na literatura atual sobre essa doença, a anosmia está associada a melhores desfechos clínicos e o alelo E4 está associado a piores desfechos. CONCLUSãO:  Nosso estudo acrescenta novas informações a essas correlações, sugerindo a APOE E4 como um fator de proteção para DO.

BACKGROUND: Smell loss significantly impacts the quality of life in patients. However, there is limited research on smell loss in individuals with amyotrophic lateral sclerosis (ALS), and the correlation between smell loss and cognitive impairment is unclear. This study aimed to investigate the correlation between smell loss and cognition impairment in ALS patients.
METHODS: The study included 216 ALS patients. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and smell identification test specifically for the Chinese population (CSIT) were administered to evaluate participants\' cognitive and olfactory function, respectively.
RESULTS: After covarying for age, sex, BMI, education level, degree of hunger, dietary bias, eagerness for food, stress, smoking status, alcohol consumption, and upper respiratory tract infection (URTI) or rhinitis, CSIT scores were significantly correlated with ECAS scores (r = 0.162, p = 0.028), especially the ALS-specific scores (r = 0.158, p = 0.031). Even after excluding patients with URTI or rhinitis, the results were similar. CSIT scores were significantly correlated with ECAS scores (r = 0.224, p = 0.011), especially the ALS-specific scores (r = 0.205, p = 0.019).
CONCLUSIONS: In patients with ALS, smell loss is significantly correlated with cognitive impairment, particularly frontotemporal dysfunction. Cognitive dysfunction may lead to worse olfactory performance in ALS patients.

BACKGROUND: This longitudinal prospective study aims to investigate the potential of circulating calprotectin (cCLP) as a biomarker in persistent olfactory dysfunctions following COVID-19 infection.
METHODS: Thirty-six patients with persistent hyposmia or anosmia post COVID-19 were enrolled (HT0) and re-evaluated after three months of olfactory training (HT1). Two control groups included 18 subjects without olfactory defects post COVID-19 (CG1) and 18 healthy individuals (CG2). Nasal brushing of the olfactory cleft and blood collection were performed to assess circulating calprotectin levels.
RESULTS: Higher calprotectin levels were observed in serum and nasal supernatant of hyposmic patients (HT0) compared to control groups (CG1 and CG2). Post-olfactory training (HT1), olfactory function improved significantly, paralleled by decreased calprotectin levels in serum and nasal samples. Circulating calprotectin holds potential as a biomarker in persistent olfactory dysfunctions after COVID-19. The decrease in calprotectin levels post-olfactory training implies a role in monitoring and evaluating treatment responses.
CONCLUSIONS: These findings contribute to the growing literature on potential biomarkers in post-COVID-19 olfactory dysfunctions and underscore the importance of investigating novel biomarkers for personalized patient management. Nevertheless, further studies are needed to validate the application of calprotectin assay in nasal diseases and its correlation with nasal cytology.

Despite the recent advances in understanding the mechanisms of olfaction, no tools are currently available to noninvasively identify loss of smell. Because of the substantial increase in patients presenting with coronavirus disease 2019-related loss of smell, the pandemic has highlighted the urgent need to develop quantitative methods. Methods: Our group investigated the use of a novel fluorescent probe named Tsp1a-IR800P as a tool to diagnose loss of smell. Tsp1a-IR800P targets sodium channel 1.7, which plays a critical role in olfaction by aiding the signal propagation to the olfactory bulb. Results: Intuitively, we have identified that conditions leading to loss of smell, including chronic inflammation and coronavirus disease 2019, correlate with the downregulation of sodium channel 1.7 expression in the olfactory epithelium, both at the transcript and at the protein levels. We demonstrated that lower Tsp1a-IR800P fluorescence emissions significantly correlate with loss of smell in live animals-thus representing a potential tool for its semiquantitative assessment. Currently available methods rely on delayed subjective behavioral studies. Conclusion: This method could aid in significantly improving preclinical and clinical studies by providing a way to objectively diagnose loss of smell and therefore aid the development of therapeutic interventions.

BACKGROUND: More than a year after recovering from COVID-19, a large proportion of individuals, many of whom work in the healthcare sector, still report olfactory dysfunctions. However, olfactory dysfunction was common already before the COVID-19 pandemic, making it necessary to also consider the existing baseline prevalence of olfactory dysfunction. To establish the adjusted prevalence of COVID-19 related olfactory dysfunction, we assessed smell function in healthcare workers who had contracted COVID-19 during the first wave of the pandemic using psychophysical testing.
METHODS: Participants were continuously tested for SARS-CoV-2 IgG antibodies since the beginning of the pandemic. To assess the baseline rate of olfactory dysfunction in the population and to control for the possibility of skewed recruitment of individuals with prior olfactory dysfunction, consistent SARS-CoV-2 IgG naïve individuals were tested as a control group.
RESULTS: Fifteen months after contracting COVID-19, 37% of healthcare workers demonstrated a quantitative reduction in their sense of smell, compared to only 20% of the individuals in the control group. Fifty-one percent of COVID-19-recovered individuals reported qualitative symptoms, compared to only 5% in the control group. In a follow-up study 2.6 years after COVID-19 diagnosis, 24% of all tested recovered individuals still experienced parosmia.
CONCLUSIONS: In summary, 65% of healthcare workers experienced parosmia/hyposmia 15 months after contracting COVID-19. When compared to a control group, the prevalence of olfactory dysfunction in the population increased by 41 percentage points. Parosmia symptoms were still lingering two-and-a half years later in 24% of SARS-CoV-2 infected individuals. Given the amount of time between infection and testing, it is possible that the olfactory problems may not be fully reversible in a plurality of individuals.