Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis

Synucleinopathies including Parkinsons disease and dementia with Lewy bodies are neurodegenerative diseases characterized by the intracellular accumulation of the protein alpha-synuclein called Lewy pathology. Alpha-synuclein within Lewy pathology is aggregated into protease resistant filamentous structures and is predominantly phosphorylated at serine 129 (PSER129). Lewy pathology has been hypothesized to spread throughout the nervous system as the disease progresses. Cross-sectional studies have shown the olfactory bulb and olfactory tract consistently bare LP for common synucleinopathies, making these structures likely starting points for the spreading process, and thus disease. Here we examined the distribution of PSER129 in non-diseased brain. To do this we used a sensitive tyramide signal amplification (TSA) technique to detect low abundance endogenous PSER129 under ideal antibody binding conditions. In wild-type non-diseased mice, PSER129 was detected in the olfactory bulb and several brain regions of the olfactory cortex across the neuroaxis (i.e., olfactory bulb to brain stem). PSER129 was particularly apparent in the mitral cell layer and the outer plexiform layer of the olfactory bulb where it was observed as cytosolic/nuclear puncta or fibers, respectively. PSER129 immunoreactivity in the healthy olfactory bulb was abolished by pretreatment of the tissue with proteinase K, pre-absorption of the primary antibody against the purified PSER129 peptide fragment, or the omission of the PSER129 antibody. Furthermore, PSER129 immunoreactivity was not observed in any brain region of alpha-synuclein knockout mice. Dual labeling for the PSER129 and the mitral cell marker TBX21 showed that PSER129 positive structures of the healthy OB were found in mitral cells. We found evidence of the same PSER129 positive structures in the olfactory bulb of non-diseased rats, non-human primates, healthy humans, but not individuals diagnosed with PD. Results suggest biological pathways responsible for alpha-synuclein phosphorylation are constitutively active in OB mitral cells and alpha-synuclein in these cells may be predisposed to pathological aggregation. Pathological seeds originating in mitral cells may act as a source for alpha-synuclein spread competent assemblies that spreads throughout the brain via fibers of the olfactory tract. Future studies should investigate the normal function of alpha-synuclein in the mitral cells of the olfactory bulb, which may give insight into synucleinopathy disease origins.

The Role of TRPA1 Channels in the Central Processing of Odours Contributing to the Behavioural Responses of Mice

Transient receptor potential ankyrin 1 (TRPA1), a nonselective cation channel, contributes to several (patho)physiological processes. Smell loss is an early sign in several neurodegenerative disorders, such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases; therefore, we focused on its role in olfaction and social behaviour with the aim to reveal its potential therapeutic use. The presence of Trpa1 mRNA was studied along the olfactory tract of mice by combined RNAscope in situ hybridisation and immunohistochemistry. The aversive effects of fox and cat odour were examined in parallel with stress hormone levels. In vitro calcium imaging was applied to test if these substances can directly activate TRPA1 receptors. The role of TRPA1 in social behaviour was investigated by comparing Trpa1 wild-type and knockout mice (KO). Trpa1 mRNA was detected in the olfactory bulb and piriform cortex, while its expression was weak in the olfactory epithelium. Fox, but not cat odour directly activated TRPA1 channels in TRPA1-overexpressing Chinese Hamster Ovary cell lines. Accordingly, KO animals showed less aversion against fox, but not cat odour. The social interest of KO mice was reduced during social habituation–dishabituation and social interaction, but not during resident–intruder tests. TRPA1 may contribute to odour processing at several points of the olfactory tract and may play an important role in shaping the social behaviour of mice. Thus, TRPA1 may influence the development of certain social disorders, serving as a potential drug target in the future.

Pontine demyelination as a late complication of resolved mild COVID-19 infection

Previous case reports have demonstrated COVID-19 related neurotropism. Neural infection may result from trans-lamina cribrosa invasion that allows COVID-19 to reach the brain through the olfactory tract. A wide range of symptoms from headaches, anosmia, dysgeusia to neuropathy, encephalitis, cerebrovascular stroke, and rarely demyelination has been reported. Here, we report a case of pontine demyelination causing generalized weakness as a rare neurological complication in a COVID-19 survivor. Our case highlights that even mild and moderate COVID-19 infection can have late neurological sequelae. Keywords: COVID-19, demyelination, neurological complications, corticosteroids

1481 Is Imaging for the Evaluation of Anosmia Really Necessary?

Aim Although it is rare for anosmia to be caused by olfactory lesions, it is commonplace for some form of imaging to be undertaken to investigate olfactory loss in patients. This study aimed to identify the pick-up rate of pathology in patients who had an isolated complaint of anosmia. Method We undertook a retrospective study over a 2-year period between 2018 to 2020 in a teaching hospital. The cases were identified using the hospital radiology database for patients referred for CT or MRI of their head or sinuses due to anosmia. Patients referred with symptoms other than olfactory loss were excluded. Results Out of the 132 scans undertaken in this period, 52 were included with 47 being MRI scans. There were 5 (10%) patients who had intracranial pathology identified and these were all on MRI scans. Only 2 (4%) cases had actual olfactory tract-related abnormalities. This included absent olfactory bulbs and a soft tissue lesion within the region of the olfactory apparatus. Conclusions This study suggests a 4% pick up rate of olfactory tract-related pathology which demonstrates some value when investigating anosmia. However, with the large number of scans that do not alter management and the ever-increasing burden on our health system, large scale studies are needed to develop an evidence-based risk stratification approach.

MRI of the Olfactory Tract in a Case of Post-COVID-19 Persistent Anosmia

Anosmia is a prevalent and pathognomonic symptom in patients with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), often accompanied by changes of taste or dysgeusia. It is also one of the symptoms that lasts the most even after the recovery. The studies that examine the migration path and timing of SARS-CoV-2 are needed in order to determinate the ideal timing for realizing an MRI so as to possibly find an abnormal signal on the olfactory bulb.

Sim1-expressing cells illuminate the origin and course of migration of the nucleus of the lateral olfactory tract in the mouse amygdala

We focus this report on the nucleus of the lateral olfactory tract (NLOT), a superficial amygdalar nucleus receiving olfactory input. Mixed with its Tbr1-expressing layer 2 pyramidal cell population (NLOT2), there are Sim1-expressing cells whose embryonic origin and mode of arrival remain unclear. We examined this population with Sim1-ISH and a Sim1-tauLacZ mouse line. An alar hypothalamic origin is apparent at the paraventricular area, which expresses Sim1 precociously. This progenitor area shows at E10.5 a Sim1-expressing dorsal prolongation that crosses the telencephalic stalk and follows the terminal sulcus, reaching the caudomedial end of the pallial amygdala. We conceive this Sim1-expressing hypothalamo-amygdalar corridor (HyA) as an evaginated part of the hypothalamic paraventricular area, which participates in the production of Sim1-expressing cells. From E13.5 onwards, Sim1-expressing cells migrated via the HyA penetrate the posterior pallial amygdalar radial unit and associate therein to the incipient Tbr1-expressing migration stream which swings medially past the amygdalar anterior basolateral nucleus (E15.5), crosses the pallio-subpallial boundary (E16.5), and forms the NLOT2 within the anterior amygdala by E17.5. We conclude that the Tbr1-expressing NLOT2 cells arise strictly within the posterior pallial amygdalar unit, involving a variety of required gene functions we discuss. Our results are consistent with the experimental data on NLOT2 origin reported by Remedios et al. (Nat Neurosci 10:1141–1150, 2007), but we disagree on their implication in this process of the dorsal pallium, observed to be distant from the amygdala.