Olfactory Loss in Parkinson's Disease

Impairment of olfaction is a characteristic and early feature of Parkinson's disease. Recent data indicate that >95% of patients with Parkinson's disease present with significant olfactory loss. Deficits in the sense of smell may precede clinical motor symptoms by years and can be used to assess the risk for developing Parkinson's disease in otherwise asymptomatic individuals. This paper summarizes the available information about olfactory function in Parkinson's disease, indicating the advantageous use of olfactory probes in early and differential diagnosis

Olfactory fMRI in Patients with Parkinson's Disease

Hyposmia is one of the early signs in idiopathic Parkinson's disease (PD). Olfactory stimuli were applied during fMRI scanning to show disease-related modulation of central nervous system structures and to advance our understanding of olfactory dysfunction in PD patients. All participants received either unpleasant stimuli that smelled like rotten eggs or pleasant ones that smelled like roses. Using a block design at a 1.5 T scanner we investigated a total of 8 PD patients (mean age 60 ± 10.9 years) and 13 age matched controls (mean age 58 ± 9.6 years). PD duration ranged from 1 to 9 years (mean 6.63 years); patients had an average “Unified Parkinson's Disease Rating Scale III” score of 23.25 (range, 6–46). Olfactory function was established using the “Sniffin’ Sticks” test battery. Patients tended to rate the stimuli presented during fMRI scans as less intense, but also as more pleasant than controls. fMRI results revealed differences between PD patients and controls which depended on the type of stimulation. While both pleasant and unpleasant stimulation was associated with lower activation in the amygdalo–hippocampal complex in patients compared to controls, increased activity in response to pleasant stimuli was observed in the striatum and the left inferior frontal gyrus. In contrast, unpleasant stimulation led to hypoactivation of the ventral striatum in patients (but not in controls) and did not enhance left inferior frontal activity. These results may partly reflect differences between PD patients and healthy controls in the processing of primary dimensions of odors, intensity, and valence

Nonlinear association between chemosensory dysfunction and body mass index

Chemosensory (gustatory and olfactory) dysfunction contributes to obesity, but the association between body mass index (BMI) and chemosensory dysfunction are inconsistently reported. The present study included 4,390 subjects at a Smell and Taste Clinic. Results suggested that both the obesity class II group (BMI ≥ 35) and underweight group (BMI < 18.5) exhibited impaired taste function compared with the normal weight group (p <.05). Comparing with the other groups, the obesity class II group exhibited a higher proportion of impaired bitter identification (8.6%), and the underweight group showed a higher proportion of impaired salty identification (7.9%). When investigating differences for individual tastes, subjects with impaired bitter identification had higher BMI (t = 2.79, p =.005) and lower olfactory scores (p <.05) compared with those with intact bitter identification. Finally, reduced taste scores are associated with an increased BMI (r = −.04, p =.022). This correlation becomes more pronounced with age (F = 1.42, p <.001). Practical Application: The nonlinear association between chemosensory dysfunction and BMI suggested that maintaining the gustatory and olfactory function is of significance for normal metabolism. In obesity regulating bitter taste appears to be more important than the other tastes

High Test-Retest Reliability of the Extended Version of the "Sniffin' Sticks” Test

The "Sniffin' Sticks” test kit is a validated and commonly used tool for assessment of olfactory function in subjects with normal sense of smell and in individuals with smell loss. That test incorporates subtests for odor threshold, discrimination, and identification. To gain higher subtest reproducibility, tests on odor discrimination and odor identification were extended using 32 instead of the usually applied 16 single trials each. In developing the extended Sniffin' Sticks test, a number of preliminary experiments were performed in 46 healthy, normosmic individuals 1) to evaluate intensity and familiarity of the additionally selected odors, 2) to select distractors for the discrimination and identification test, and 3) to evaluate the test-retest reliability of each subtest. Furthermore, the extended test was applied to 126 patients with olfactory loss and 71 normosmic individuals. Follow-up investigation could be performed in 69 controls within an average interval of 4 days. Results revealed significant differences between patients and healthy subjects. Estimated intensity and familiarity of the newly selected 16 items of the discrimination test did not differ significantly from the 16 standard items. Test-retest reliability was found to be r = 0.80 (odor discrimination), r = 0.88 (odor identification), and r = 0.92 (odor threshold). In conclusion, the extended test kit allows a precise evaluation of olfactory function, especially when different olfactory tasks are assessed using individual subtests. Furthermore, the high test-retest reliability of both the 16 and the 32-item tests allows the evaluation of even relatively small changes of olfactory function over time by means of either tes

Topical Administration of Mometasone Is Not Helpful in Post-COVID-19 Olfactory Dysfunction

Persistent olfactory dysfunction is a major concern post-COVID-19, affecting up to 5% of all patients. Different therapeutic options, including mometasone nasal spray, have been recommended, only some of which have been validated for post-COVID-19 olfactory dysfunction. In this study we psychophysically assessed the effect of intranasally applied mometasone furoate on the recovery of olfaction. The spray was applied with a long applicator so that the olfactory cleft could be reached effectively. After olfactory dysfunction had been confirmed psychophysically using Sniffin’ Sticks, patients were randomly assigned to two different treatment arms: the study group (n = 40) underwent olfactory training and intranasal administration of mometasone furoate twice daily, whereas the control group (n = 46) performed olfactory training only. After a study duration of three months, psychophysical testing of olfaction was repeated using Sniffin’ Sticks. We found no benefit of an additional topical administration of mometasone furoate compared to olfactory training alone. These results psychophysically confirm two previous studies which were based on patients’ subjective self-ratings. Our findings are in contrast to current recommendations for the management of olfactory dysfunction post-COVID-19, which might have to be adapted accordingly

A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma

Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD. © 2021 Torsten Diesinger et al

Time-Frequency Analysis of Chemosensory Event-Related Potentials to Characterize the Cortical Representation of Odors in Humans

BACKGROUND: The recording of olfactory and trigeminal chemosensory event-related potentials (ERPs) has been proposed as an objective and non-invasive technique to study the cortical processing of odors in humans. Until now, the responses have been characterized mainly using across-trial averaging in the time domain. Unfortunately, chemosensory ERPs, in particular, olfactory ERPs, exhibit a relatively low signal-to-noise ratio. Hence, although the technique is increasingly used in basic research as well as in clinical practice to evaluate people suffering from olfactory disorders, its current clinical relevance remains very limited. Here, we used a time-frequency analysis based on the wavelet transform to reveal EEG responses that are not strictly phase-locked to onset of the chemosensory stimulus. We hypothesized that this approach would significantly enhance the signal-to-noise ratio of the EEG responses to chemosensory stimulation because, as compared to conventional time-domain averaging, (1) it is less sensitive to temporal jitter and (2) it can reveal non phase-locked EEG responses such as event-related synchronization and desynchronization. METHODOLOGY/PRINCIPAL FINDINGS: EEG responses to selective trigeminal and olfactory stimulation were recorded in 11 normosmic subjects. A Morlet wavelet was used to characterize the elicited responses in the time-frequency domain. We found that this approach markedly improved the signal-to-noise ratio of the obtained EEG responses, in particular, following olfactory stimulation. Furthermore, the approach allowed characterizing non phase-locked components that could not be identified using conventional time-domain averaging. CONCLUSION/SIGNIFICANCE: By providing a more robust and complete view of how odors are represented in the human brain, our approach could constitute the basis for a robust tool to study olfaction, both for basic research and clinicians

NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease

Extent: 14p.Background: Without appropriate cellular models the etiology of idiopathic Parkinson’s disease remains unknown. We recently reported a novel patient-derived cellular model generated from biopsies of the olfactory mucosa (termed olfactory neurosphere-derived (hONS) cells) which express functional and genetic differences in a disease-specific manner. Transcriptomic analysis of Patient and Control hONS cells identified the NRF2 transcription factor signalling pathway as the most differentially expressed in Parkinson’s disease. Results: We tested the robustness of our initial findings by including additional cell lines and confirmed that hONS cells from Patients had 20% reductions in reduced glutathione levels and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium, inner salt] metabolism compared to cultures from healthy Control donors. We also confirmed that Patient hONS cells are in a state of oxidative stress due to higher production of H2O2 than Control cultures. siRNA-mediated ablation of NRF2 in Control donor cells decreased both total glutathione content and MTS metabolism to levels detected in cells from Parkinson’s Disease patients. Conversely, and more importantly, we showed that activation of the NRF2 pathway in Parkinson’s disease hONS cultures restored glutathione levels and MTS metabolism to Control levels. Paradoxically, transcriptomic analysis after NRF2 pathway activation revealed an increased number of differentially expressed mRNAs within the NRF2 pathway in L-SUL treated Patient-derived hONS cells compared to L-SUL treated Controls, even though their metabolism was restored to normal. We also identified differential expression of the PI3K/AKT signalling pathway, but only post-treatment. Conclusions: Our results confirmed NRF2 as a potential therapeutic target for Parkinson’s disease and provided the first demonstration that NRF2 function was inducible in Patient-derived cells from donors with uniquely varied genetic backgrounds. However, our results also demonstrated that the response of PD patient-derived cells was not co-ordinated in the same way as in Control cells. This may be an important factor when developing new therapeutics.Anthony L. Cook, Alejandra M. Vitale, Sugandha Ravishankar, Nicholas Matigian, Greg T. Sutherland, Jiangou Shan, Ratneswary Sutharsan, Chris Perry, Peter A. Silburn, George D. Mellick, Murray L. Whitelaw, Christine A. Wells, Alan Mackay-Sim and Stephen A. Woo