Cortical morphological alterations in cognitively normal Parkinson's disease with severe hyposmia.

Olfactory dysfunction is a common non-motor symptom of Parkinson's disease(PD) and may hold valuable insights into the disease's underlying pathophysiology. This study aimed to investigate cortical morphometry alterations in PD patients with severe hyposmia(PD-SH) and mild hyposmia(PD-MH) using surface-based morphometry(SBM) methods. Participants included 36 PD-SH patients, 38 PD-MH patients, and 40 healthy controls(HCs). SBM analysis revealed distinct patterns of cortical alterations in PD-SH and PD-MH patients. PD-MH patients exhibited reduced cortical thickness in the right supramarginal gyrus, while PD-SH patients showed widespread cortical thinning in regions including the bilateral pericalcarine cortex, bilateral lingual gyrus, left inferior parietal cortex, left lateral occipital cortex, right pars triangularis, right cuneus, and right superior parietal cortex. Moreover, PD-SH patients displayed reduced cortical thickness in the right precuneus compared to PD-MH patients. Fractal dimension analysis indicated increased cortical complexity in PD-MH patients' right superior temporal cortex and right supramarginal gyrus, as well as decreased complexity in the bilateral postcentral cortex, left superior parietal cortex, and right precentral cortex. Similarly, cortical gyrification index and cortical sulcal depth exhibited heterogeneous patterns of changes in PD-SH and PD-MH patients compared to HCs. These findings underscore the multifaceted nature of olfactory impairment in PD, with distinct patterns of cortical morphometry alterations associated with different degrees of hyposmia. The observed discrepancies in brain regions showing alterations reflect the complexity of PD's pathophysiology. These insights contribute to a deeper understanding of olfactory dysfunction in PD and provide potential avenues for early diagnosis and targeted interventions.

Comparative imaging study of patients with persistent olfactory dysfunction due to mild COVID-19 using structural and functional MRI.

INTRODUCTION: Persistent post-COVID olfactory dysfunction continues to be studied due to the controversy in its pathophysiology and neuroimaging. MATERIALS AND METHODS: The patients had confirmed mild COVID-19 infection with olfactory dysfunction of more than one month of evolution and they were compared to controls with normal olfaction, assessed using the Sniffin' Sticks Olfactory Test and underwent brain, magnetic resonance imaging (MRI) of the olfactory bulb and olfactory function. RESULTS: A total of 8 patients and 2 controls participated. The average age of the patients was 34.5 years (SD 8.5), and that of the controls was 28.5 (SD 2.1). The average score in the patients' olfactory test was 7.9 points (SD 2.2). In brain and olfactory bulb MRI tests, no morphological differences were found. When evaluated by functional MRI, none of the patients activated the entorhinal area in comparison to the controls, who did show activation at this level. Activation of secondary olfactory areas in cases and controls were as follows: orbitofrontal (25% vs 100%), basal ganglia (25% vs 50%) and insula (38% vs 0%) respectively. CONCLUSIONS: There were no observed morphological changes in the brain MRI. Unlike the controls, none of the patients activated the entorhinal cortex in the olfactory functional MRI.

Unraveling olfactory subtypes in Parkinson's disease and their effect on the natural history of the disease.

BACKGROUND: Hyposmia in Parkinson's disease (PD) had been studied before but had not been detailed by its temporal progression. This study observed how each olfactory subtype evolved in terms of motor symptoms, cardiac sympathetic innervation, and cognition. METHODS: Two hundred and three early PD patients were classified as normosmia, hyposmia-converter (hypo-converter), and hyposmia. Their presynaptic monoamine availability at the time of diagnosis was assessed by positron emission tomography imaging using 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane and compared across the subtypes. Motor symptoms were evaluated in all patients, cardiac denervation was examined in 183 patients, and cognition in 195 patients were assessed using a neuropsychological battery. The domains were re-assessed 2-4 times, and the longitudinal data were analyzed to discern the natural course of each subtype. RESULTS: Twenty-nine (14.3%) patients belonged to the normosmia group, 34 (16.7%) to the hypo-converter group, and the rest to the hyposmia (69.0%) group. 85.7% of the total population became hyposmic during an average 3 years of follow-up. The baseline motor symptoms, cardiac denervation, and cognition were comparable across the olfactory subtypes. Across the subtypes, a decline in the presynaptic monoamine densities of the caudate, especially the ventral-anterior subdivisions, correlated inversely with olfaction dysfunction. Over time, motor and cardiac denervation burdens worsened regardless of olfactory subtypes, but hypo-converters experienced faster cognitive deterioration than the other two groups. CONCLUSIONS: The results suggest that the olfactory subtypes have differential significance along the disease course, which might reflect the involvement of different neuro-biochemical circuitries.

Noninvasive Diagnostic Method to Objectively Measure Olfaction and Diagnose Smell Disorders by a Molecularly Targeted Fluorescence Imaging Agent.

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.

Brain microstructure and connectivity in COVID-19 patients with olfactory or cognitive impairment.

INTRODUCTION: The COVID-19 pandemic has affected millions worldwide, causing mortality and multi-organ morbidity. Neurological complications have been recognized. This study aimed to assess brain structural, microstructural, and connectivity alterations in patients with COVID-19-related olfactory or cognitive impairment using post-acute (time from onset: 264[208-313] days) multi-directional diffusion-weighted MRI (DW-MRI). METHODS: The study included 16 COVID-19 patients with cognitive impairment (COVID-CM), 35 COVID-19 patients with olfactory disorder (COVID-OD), and 14 controls. A state-of-the-art processing pipeline was developed for DW-MRI pre-processing, mean diffusivity and fractional anisotropy computation, fiber density and cross-section analysis, and tractography of white-matter bundles. Brain parcellation required for probing network connectivity, region-specific microstructure and volume, and cortical thickness was based on T1-weighted scans and anatomical atlases. RESULTS: Compared to controls, COVID-CM patients showed overall gray matter atrophy (age and sex corrected p = 0.004), and both COVID-19 patient groups showed regional atrophy and cortical thinning. Both groups presented an increase in gray matter mean diffusivity (corrected p = 0.001), decrease in white matter fiber density and cross-section (corrected p < 0.05), , and COVID-CM patients also displayed an overall increased diffusivity (p = 0.022) and decreased anisotropy (corrected p = 0.038) in white matter. Graph-based analysis revealed reduced network modularity, with an extensive pattern of connectivity increase, in conjunction with a localized reduction in a few connections, mainly located in the left hemisphere. The left cingulate, anterior cingulate, and insula were primarily involved. CONCLUSION: Expanding upon previous findings, this study further investigated significant alterations in brain morphology, microstructure, and connectivity in COVID-19 patients with olfactory or cognitive disfunction. These findings suggest underlying neurodegeneration, neuroinflammation, and concomitant compensatory mechanisms. Future longitudinal studies are required to monitor the alterations over time and assess their transient or permanent nature.

Cerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue.

After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition, marked by neurologic symptoms such as cognitive deficits, olfactory dysfunction, and fatigue. Despite this, biomarkers and pathophysiological understandings of this condition remain limited. Employing magnetic resonance imaging, we conduct a comparative analysis of cerebral microstructure among patients with Post-COVID-Condition, healthy controls, and individuals that contracted COVID-19 without long-term symptoms. We reveal widespread alterations in cerebral microstructure, attributed to a shift in volume from neuronal compartments to free fluid, associated with the severity of the initial infection. Correlating these alterations with cognition, olfaction, and fatigue unveils distinct affected networks, which are in close anatomical-functional relationship with the respective symptoms.

Correlation Between Cortical Thickness Abnormalities of the Olfactory Sulcus and Olfactory Identification Disorder and Persistent Auditory Verbal Hallucinations in Chinese Patients With Chronic Schizophrenia.

BACKGROUND AND HYPOTHESIS: Persistent auditory verbal hallucinations (pAVHs) and olfactory identification impairment are common in schizophrenia (SCZ), but the neuroimaging mechanisms underlying both pAVHs and olfactory identification impairment are unclear. This study aimed to investigate whether pAVHs and olfactory identification impairment in SCZ patients are associated with changes in cortical thickness. STUDY DESIGN: In this study, cortical thickness was investigated in 78 SCZ patients with pAVHs (pAVH group), 58 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) using 3T magnetic resonance imaging. The severity of pAVHs was assessed by the Auditory Hallucination Rating Scale. Olfactory identification deficits were assessed using the Odor Stick Identification Test for Japanese (OSIT-J). In addition, the relationship between the severity of pAVHs and olfactory identification disorder and cortical thickness abnormalities was determined. STUDY RESULTS: Significant reductions in cortical thickness were observed in the right medial orbital sulcus (olfactory sulcus) and right orbital sulcus (H-shaped sulcus) in the pAVH group compared to both the non-AVH and HC groups (P < .003, Bonferroni correction). Furthermore, the severity of pAVHs was found to be negatively correlated with the reduction in cortical thickness in the olfactory sulcus and H-shaped sulcus. Additionally, a decrease in cortical thickness in the olfactory sulcus showed a positive correlation with the OSIT-J scores (P < .05, false discovery rate correction). CONCLUSIONS: Cortical thickness abnormalities in the olfactory sulcus may be a common neuroimaging mechanism for pAVHs and olfactory identification deficits in SCZ patients.

Longitudinal brain changes in Parkinson's disease with severe olfactory deficit.

INTRODUCTION: Olfactory dysfunction and REM sleep behavior disorder (RBD) are associated with distinct cognitive trajectories in the course of Parkinson's disease (PD). The underlying neurobiology for this relationship remains unclear but may involve distinct patterns of neurodegeneration. This study aimed to examine longitudinal cortical atrophy and thinning in early-stage PD with severe olfactory deficit (anosmia) without and with concurrent probable RBD. METHODS: Longitudinal MRI data over four years of 134 de novo PD and 49 healthy controls (HC) from the Parkinson Progression Marker Initiative (PPMI) cohort were analyzed using a linear mixed-effects model. Patients were categorized into those with anosmia by the University of Pennsylvania Smell Identification Test (UPSIT) score ≤ 18 (AO+) and those without (UPSIT score > 18, AO-). The AO+ group was further subdivided into AO+ with probable RBD (AO+RBD+) and without (AO+RBD-) for subanalysis. RESULTS: Compared to subjects without baseline anosmia, the AO+ group exhibited greater longitudinal declines in both volume and thickness in the bilateral parahippocampal gyri and right transverse temporal gyrus. Patients with concurrent anosmia and RBD showed more extensive longitudinal declines in cortical volume and thickness, involving additional brain regions including the bilateral precuneus, left inferior temporal gyrus, right paracentral gyrus, and right precentral gyrus. CONCLUSIONS: The atrophy/thinning patterns in early-stage PD with severe olfactory dysfunction include regions that are critical for cognitive function and could provide a structural basis for previously reported associations between severe olfactory deficit and cognitive decline in PD. Concurrent RBD might enhance the dynamics of cortical changes.

Long-term effects of SARS-CoV-2 infection in patients with and without chemosensory disorders at disease onset: a psychophysical and magnetic resonance imaging exploratory study.

A preserved sense of smell and taste allows us to understand many environmental "messages" and results in meaningfully improvements to quality of life. With the COVID-19 pandemic, it became clear how important these senses are for social and nutritional status and catapulted this niche chemosensory research area towards widespread interest. In the current exploratory work, we assessed two groups of post-COVID-19 patients who reported having had (Group 1) or not (Group 2) a smell/taste impairment at the disease onset. The aim was to compare them using validated smell and taste tests as well as with brain magnetic resonance imaging volumetric analysis. Normative data were used for smell scores comparison and a pool of healthy subjects, recruited before the pandemic, served as controls for taste scores. The majority of patients in both groups showed an olfactory impairment, which was more severe in Group 1 (median UPSIT scores: 24.5 Group 1 vs 31.0 Group 2, p = 0.008), particularly among women (p = 0.014). No significant differences emerged comparing taste scores between Group 1 and Group 2, but dysgeusia was only present in Group 1 patients. However, for taste scores, a significant difference was found between Group 1 and controls (p = 0.005). No MRI anatomical abnormalities emerged in any patients while brain volumetric analysis suggested a significant difference among groups for the right caudate nucleus (p = 0.028), although this was not retained following Benjamini-Hochberg correction. This exploratory study could add new information in COVID-19 chemosensory long-lasting impairment and address future investigations on the post-COVID-19 patients' research.

Differential connectivity of the posterior piriform cortex in Parkinson's disease and postviral olfactory dysfunction: an fMRI study.

Olfactory dysfunction is a common feature of both postviral upper respiratory tract infections (PV) and idiopathic Parkinson's disease (PD). Our aim was to investigate potential differences in the connectivity of the posterior piriform cortex, a major component of the olfactory cortex, between PV and PD patients. Fifteen healthy controls (median age 66 years, 9 men), 15 PV (median age 63 years, 7 men) and 14 PD patients (median age 70 years, 9 men) were examined with task-based olfactory fMRI, including two odors: peach and fish. fMRI data were analyzed with the co-activation pattern (CAP) toolbox, which allows a dynamic temporal assessment of posterior piriform cortex (PPC) connectivity. CAP analysis revealed 2 distinct brain networks interacting with the PPC. The first network included regions related to emotion recognition and attention, such as the anterior cingulate and the middle frontal gyri. The occurrences of this network were significantly fewer in PD patients compared to healthy controls (p = 0.023), with no significant differences among PV patients and the other groups. The second network revealed a dissociation between the olfactory cortex (piriform and entorhinal cortices), the anterior cingulate gyrus and the middle frontal gyri. This second network was significantly more active during the latter part of the stimulation, across all groups, possibly due to habituation. Our study shows how the PPC interacts with areas that regulate higher order processing and how this network is substantially affected in PD. Our findings also suggest that olfactory habituation is independent of disease.

Impaired olfactory identification in dementia-free individuals is associated with the functional abnormality of the precuneus.

OBJECTIVE: Olfactory dysfunction indicates a higher risk of developing dementia. However, the potential structural and functional changes are still largely unknown. METHODS: A total of 236 participants were enrolled, including 45 Alzheimer's disease (AD) individuals and 191dementia-free individuals. Detailed study methods, comprising neuropsychological assessment and olfactory identification test (University of Pennsylvania smell identification test, UPSIT), as well as structural and functional magnetic resonance imaging (MRI) were applied in this research. The dementia-free individuals were divided into two sub-groups based on olfactory score: dementia-free with olfactory dysfunction (DF-OD) sub-group and dementia-free without olfactory dysfunction (DF-NOD) sub-group. The results were analyzed for subsequent intergroup comparisons and correlations. The cognitive assessment was conducted again three years later. RESULTS: (i) At dementia-free stage, there was a positive correlation between olfactory score and cognitive function. (ii) In dementia-free group, the volume of crucial brain structures involved in olfactory recognition and processing (such as amygdala, entorhinal cortex and basal forebrain volumes) are positively associated with olfactory score. (iii) Compared to the DF-NOD group, the DF-OD group showed a significant reduction in olfactory network (ON) function. (iv) Compared to DF-NOD group, there were significant functional connectivity (FC) decline between PCun_L(R)_4_1 in the precuneus of posterior default mode network (pDMN) and the salience network (SN) in DF-OD group, and the FC values decreased with falling olfactory scores. Moreover, in DF-OD group, the noteworthy reduction in FC were observed between PCun_L(R)_4_1 and amygdala, which was a crucial component of ON. (v) The AD conversion rate of DF-OD was 29.41%, while the DF-NOD group was 12.50%. The structural and functional changes in the precuneus were also observed in AD and were more severe. CONCLUSIONS: In addition to the olfactory circuit, the precuneus is a critical structure in the odor identification process, whose abnormal function underlies the olfactory identification impairment of dementia-free individuals.

Multiple Early Biomarkers to Predict Cognitive Decline in Dementia-Free Older Adults.

INTRODUCTION: Baseline olfactory impairment, poor performance on cognitive test, and medial temporal lobe atrophy are considered biomarkers for predicting future cognitive decline in dementia-free older adults. However, the combined effect of these predictors has not been fully investigated. METHODS: A group of 110 participants without dementia were continuously recruited into this study, and underwent olfactory, cognitive tests and MRI scanning at baseline and 5-year follow-up. Olfactory function was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). Participants were divided into the cognitive decliners and non-decliners. RESULTS: Among 87 participants who completed the 5-year follow-up, cognitive decline was present in 32 cases and 55 remained stable. Compared with non-decliners, cognitive decliners presented lower scores on both the UPSIT and the Montreal Cognitive Assessment (MoCA), and smaller hippocampal volume at baseline (all P < .001). The logistic regression analysis revealed that lower scores on UPSIT and MoCA, and smaller hippocampal volume were strongly associated with subsequent cognitive decline, respectively (all P < .001). For the prediction of cognitive decline, lower score on UPSIT performed the sensitivity of 63.6% and specificity of 81.2%, lower score on MoCA with the sensitivity of 74.5% and specificity of 65.6%, smaller hippocampal volume with the sensitivity of 70.9% and specificity of 78.1%, respectively. Combining three predictors resulted in the sensitivity of 83.6% and specificity of 93.7%. CONCLUSIONS: The combination of olfactory test, cognitive test with structural MRI may enhance the predictive ability for future cognitive decline for dementia-free older adults.

Intra and inter-regional functional connectivity of the human brain due to Task-Evoked fMRI Data classification through CNN & LSTM.

BACKGROUND AND PURPOSE: Olfaction is an early marker of neurodegenerative disease. Standard olfactory function is essential due to the importance of olfaction in human life. The psychophysical evaluation assesses the olfactory function commonly. It is patient-reported, and results rely on the patient's answers and collaboration. However, methodological difficulties attributed to the psychophysical evaluation of olfactory-related cerebral areas led to limited assessment of olfactory function in the human brain. MATERIALS AND METHODS: The current study utilized clustering approaches to assess olfactory function in fMRI data and used brain activity to parcellate the brain with homogeneous properties. Deep neural network architecture based on ResNet convolutional neural networks (CNN) and Long Short-Term Model (LSTM) designed to classify healthy with olfactory disorders subjects. RESULTS: The fMRI result obtained by k-means unsupervised machine learning model was within the expected outcome and similar to those found with the conn toolbox in detecting active areas. There was no significant difference between the means of subjects and every subject. Proposing a CRNN deep learning model to classify fMRI data in two different healthy and with olfactory disorders groups leads to an accuracy score of 97 %. CONCLUSIONS: The K-means unsupervised algorithm can detect the active regions in the brain and analyze olfactory function. Classification results prove the CNN-LSTM architecture using ResNet provides the best accuracy score in olfactory fMRI data. It is the first attempt conducted on olfactory fMRI data in detail until now.

Anterior Skull Base Abnormalities in Congenital Anosmia.

INTRODUCTION: The structures of the skull and the brain are related to each other. Prior work in individuals with isolated congenital anosmia (ICA) showed that these individuals were characterized by olfactory bulb (OB) defects. The aim of this study was to compare the morphological pattern of the anterior skull base surrounding the OB between individuals with ICA and normosmic controls. We meant to investigate whether these features can help distinguish abnormalities from normal variation. METHODS: We conducted a retrospective study to acquire T2-weighted magnetic resonance images from individuals diagnosed with ICA (n = 31) and healthy, normosmic controls matched for age and gender (n = 62). Between both groups, we compared the depth and width of the olfactory fossa, the angle of the ethmoidal fovea, as well as the angle of the lateral lamella of the cribriform plate. Within the ICA group, we further performed subgroup analyses based on the presence or absence of the OB, to investigate whether the morphology of the anterior skull base relates to the presence of OBs. The diagnostic performance of these parameters was evaluated using receiver operating characteristic analysis. RESULTS: Individuals with ICA exhibited a flattened ethmoid roof and shallower olfactory fossa when compared to controls. Further, the absence of the OB was found to be associated with a higher degree of flattening of the ethmoid roof and a shallow olfactory fossa. We reached the results in the following areas under the receiver operating characteristic curves: 0.80 - angle of fovea ethmoidalis, 0.76 - depth of olfactory fossa, 0.70 - angle of lateral lamella of the cribriform plate for significant differentiation between individuals with ICA and normosmic controls. CONCLUSION: Individuals with ICA exhibited an unusual anterior skull base surrounding the OB. This study supports the idea of an integrated development of OB and anterior skull base. Hence, the morphological pattern of the anterior skull base surrounding the OB helps distinguish individuals with ICA from normosmic controls and may therefore be useful for the diagnosis of ICA, although it is certainly not an invariable sign of congenital anosmia.

Olfactory Bulb Volume and Morphology Changes in COVID-19 Patients With Olfactory Disorders Using Magnetic Resonance Imaging.

OBJECTIVES: The aims of the study are to explore the morphological changes of olfactory bulb (OB) and olfactory sulcus in COVID-19 patients with associated olfactory dysfunction (OD) by measuring the OB volume (OBV) and olfactory sulcus depth (OSD) and to compare the measurement values with those of healthy individuals. METHODS: Between March 2020 and January 2022, 31 consecutive hospitalized patients with a diagnosis of COVID-19 with anosmia and hyposmia who underwent brain magnetic resonance imaging and 35 normosmic control individuals were retrospectively included in the study. Bilateral OBV and OSD were measured and shape of the OB was determined based on the consensus by a neuroradiologist and an otorrhynolaryngologist. RESULTS: The mean measurements for the right and the left sides for OBV (38 ± 8.5 and 37.1 ± 8.4, respectively) and OSD (7.4 ± 0.1 and 7.4 ± 1.0 mm, respectively) were significantly lower in COVID-19 patients with OD than those in control group (for the right and the left sides mean OBV 56.3 ± 17.1 and 49.1 ± 13.5, respectively, and mean OSD 9.6 ± 0.8 and 9.4 ± 0.8 mm, respectively). Abnormally shaped OB (lobulated, rectangular, or atrophic) were higher in patient group than those of controls.For the optimal cutoff values, OBV showed sensitivity and specificity values of 90.32% and, 57.14%, for the right, and 87.1% and 62.86% for the left side, respectively (area under the curve, 0.819 and 0.780). Olfactory sulcus depth showed sensitivity and specificity values of 90.32% and 94.29%, for the right, and 96.77% and 85.71%, for the left side, respectively (area under the curve, 0.960 and 0.944). CONCLUSIONS: Decrease in OBV and OSD measurements in COVID-19 patients with OD at the early chronic stage of the disease supports direct damage to olfactory neuronal pathways and may be used to monitor olfactory nerve renewal while returning back to normal function.

Can MRI predict olfactory loss and improvement in posttraumatic olfactory dysfunction?

BACKGROUND: Although most patients with post-traumatic olfactory dysfunction (PTOD) undergo MRI, there is no consensus about its diagnostic or prognostic value. The aims were: 1) to classify the extent of post-traumatic neurodegeneration; 2) to determine its relationship with chemosensory dysfunction (smell, taste, trigeminal); and 3) to establish whether MRI can predict olfactory improvement. METHODOLOGY: We conducted a retrospective cohort study based on a series of 56 patients with PTOD. All patients underwent validated psychophysical tests of their smell, taste, and trigeminal functions, otorhinolaryngologic evaluation, and MRI. An experienced radiologist blinded to patient data evaluated 40 chemosensory-relevant brain regions according to a four-point scale (0=no lesion to 3=large lesion). Follow up data after 4 years (on average) were available in 46 patients. RESULTS: The cluster analysis showed 4 brain lesion patterns that differed in lesion localization and severity. They are associated with diagnostic categories: anosmia, hyposmia and normosmia. Two clusters were highly specific for anosmia (100% specificity)and could accurately predict this condition (100% positive predictive value). No clusters were associated with trigeminal or taste dysfunction. Regarding improvement, 72.7% of patients in the cluster with mild lesions experienced subjective and measurable olfactory improvement whereas this was only the case in 21.7-37.5% of patients with larger lesions. The odds of subjective smell improvement were 5.9 times higher in patients within the milder cluster compared to larger ones. CONCLUSIONS: The analysis of brain lesions in PTOD allows corroboration of smell test results and prediction of subjective and measurable improvement.

Functional magnetic resonance imaging in coronavirus disease 2019 induced olfactory dysfunction.

OBJECTIVE: To evaluate the functional magnetic resonance imaging changes in the olfactory structures of coronavirus disease 2019 patients experiencing olfactory dysfunction. METHODS: This study included patients aged 25-65 years who presented with a sudden loss of smell, confirmed coronavirus disease 2019 infection, and persistent olfactory dysfunction for a minimum of 2 months without any treatment. RESULTS: Irrespective of the side of brain activation, the analysis of the cumulative maximum diameter of the activation zones revealed significantly lower activation in the upper frontal lobe (p = 0.037) and basal ganglia (p = 0.023) in olfactory dysfunction patients. Irrespective of the side of activation, the analysis of the number of activation points demonstrated significantly lower activation in the upper frontal lobe (p = 0.036) and basal ganglia (p = 0.009) in olfactory dysfunction patients. CONCLUSION: Patients with coronavirus-triggered olfactory dysfunction exhibited lower activity in their basal ganglia and upper frontal lobe.

Functional connectivity patterns in parosmia.

OBJECTIVE: Parosmia is a qualitative olfactory dysfunction presenting as "distorted odor perception" in presence of an odor source. Aim of this study was to use resting state functional connectivity to gain more information on the alteration of olfactory processing at the level of the central nervous system level. METHODS: A cross sectional study was performed in 145 patients with parosmia (age range 20-76 years; 90 women). Presence and degree of parosmia was diagnosed on the basis of standardized questionnaires. Participants also received olfactory testing using the "Sniffin' Sticks". Then they underwent resting state scans using a 3 T magnetic resonance imaging scanner while fixating on a cross. RESULTS: Whole brain analyses revealed reduced functional connectivity in salience as well as executive control networks. Region of interest-based analyses also supported reduced functional connectivity measures between primary and secondary olfactory eloquent areas (temporal pole, supramarginal gyrus and right orbitofrontal cortex; dorso-lateral pre-frontal cortex and the right piriform cortex). CONCLUSIONS: Participants with parosmia exhibited a reduced information flow between memory, decision making centers, and primary and secondary olfactory areas.

Hyposmia and apathy in early, de novo Parkinson's disease: Lessons from structural brain connectivity.

INTRODUCTION: The neuroanatomical structures implicated in olfactory and emotional processing overlap significantly. Our understanding of the relationship between hyposmia and apathy, common manifestations of early Parkinson's disease (PD), is inadequate. MATERIALS AND METHODS: We analyzed data on 40 patients with early de-novo idiopathic PD enrolled within 2 years of motor symptom onset in the Parkinson's Progression Markers Initiative (PPMI) study. To be included in the analysis, patients must have smell dysfunction but no apathy at the baseline visit and had completed a diffusion MRI (dMRI) at the baseline visit and at the 48-month follow-up visit. We used the FMRIB Software Library's diffusion tool kit to measure fractional anisotropy (FA) in six regions of interest on dMRI: bilateral anterior corona radiata, left cingulum, left superior corona radiata, genu and body of the corpus callosum. We compared the FA in each region from the dMRI done at the beginning of the study with the follow up studies at 4 years. RESULTS: We found a significant decrease of FA at the bilateral anterior corona radiata, and the genu and body of the corpus callosum comparing baseline scans with follow up images at 4-years after starting the study. CONCLUSION: Structural connectivity changes associated with apathy can be seen early in PD patients with smell dysfunction.

The brain functional connectivity alterations in traumatic patients with olfactory disorder after low-level laser therapy demonstrated by fMRI.

BACKGROUND: Low-level laser therapy (LLLT) has been clinically accepted to accelerate the nerve regeneration process after a nerve injury or transection. We aimed to investigate the neuronal basis and the influence of LLLT on brain functional networks in traumatic patients with olfactory dysfunction. METHODS: Twenty-four Patients with traumatic anosmia/hyposmia were exposed to pleasant olfactory stimuli during a block-designed fMRI session. After a 10-week period, patients as control group and patients who had completed the sessions of LLLT were invited for follow-up testing using the same fMRI protocol. Two-sample t-tests were conducted to explore group differences in activation responding to odorants (p-FDR-corrected <0.05). Differences of functional connectivity were compared between the two groups and the topological features of the olfactory network were calculated. Correlation analysis was performed between graph parameters and TDI score. RESULTS: Compared to controls, laser-treated patients showed increased activation in the cingulate, rectus gyrus, and some parts of the frontal gyrus. Shorter pathlength (p = 0.047) and increased local efficiency (p = 0.043) within the olfactory network, as well as decreased inter-network connectivity within the whole brain were observed in patients after laser surgery. Moreover, higher clustering and local efficiency were related to higher TDI score, as manifested in increased sensitivity to identify odors. CONCLUSIONS: The results support that low-level laser induces neural reorganization process and make new connections in the olfactory structures. Furthermore, the connectivity parameters may serve as potential biomarkers for traumatic anosmia or hyposmia by revealing the underlying neural mechanisms of LLLT.