Effect of olfactory bulb pathology on olfactory function in normal aging

Tremblay, Cécilia; Serrano, Geidy E.; Intorcia, Anthony; Sue, Lucia I.; Wilson, Jeffrey R.; Adler, Charles H.; Shill, Holly A.; Driver‐Dunckley, Erika; Mehta, Shyamal H.; Beach, Thomas G.

doi:10.1111/bpa.13075

Cited by 21 publications

(12 citation statements)

References 11 publications

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“…We detected no evidence for a relationship between COVID-19 illness and p-tau deposition in the OB or AON at autopsy. Consistent with recent findings by Tremblay and colleagues [47], 90% of our cohort, including control participants, displayed at least some degree of tau pathology. This is perhaps not surprising given that the process of tau hyperphosphorylation and aggregation is not confined to primary neurodegenerative diseases.…”

Section: Discussionsupporting

confidence: 93%

“…This is perhaps not surprising given that the process of tau hyperphosphorylation and aggregation is not confined to primary neurodegenerative diseases. Indeed, changes in tau metabolism are increasingly recognized as sequelae of diverse insults to the brain, including seizures, trauma, viral infections and autoimmune disease [48,49], and as a part of physiological ageing [47]. In this context, the prevalence of tau pathology in the OB and AON across our entire cohort may represent a morphological surrogate for a variety of insults, including pathogen-induced inflammation, sustained by individuals throughout their lifetime.…”

Section: Discussionmentioning

confidence: 99%

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Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19

Lengacher,

Tomlinson,

Jochum

et al. 2023

Preprint

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SummaryThe majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble α-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) frequently experience hyposmia. We previously hypothesized that α-synuclein and tau misprocessing could occur following host responses to microbial triggers. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19+ patients (n=22), individuals with Lewy body disease (e.g., PD and dementia with Lewy bodies (DLB; n=6)), Alzheimer disease (AD; n=3), other non-synucleinopathy-linked degenerative diseases (e.g., progressive supranuclear palsy (PSP; n=2) and multisystem atrophy (MSA; n=1)). Further, we included neurologically healthy controls (HCO; n=9) and those with an inflammation-rich brain disorder as neurological controls (NCO; n=7). When probing for inflammatory changes focusing on anterior olfactory nuclei (AON) using anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, inflammation on average was not significantly altered in COVID19+ patients relative to controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-αSyn and phospho-tau signals were detected in the AON of tauopathy-and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes -when present-in the rostral, intracranial portion of the olfactory circuitry generally reflected neurodegenerative processes seen elsewhere in the brain. In general, inflammation correlated best with the degree of Alzheimer’s-linked tauopathy and declined with progression of age in COVID19+ patients.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19

Lengacher,

Tomlinson,

Jochum

et al. 2023

Preprint

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“…Recently evidence of this was observed following alpha-synuclein pathology induction in the OB of non-human primates which subsequently suppressed glycolytic functions (36), suggesting that aggregates are suppressing glycolysis which we found to be functionally associated with PSER129. Factors such as normal aging that converge on cellular pathways identified here are likely to have particular significance for mitral cell alpha-synuclein pathology and olfactory function (5, 37).…”

Section: Discussionmentioning

confidence: 95%

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

Killinger

Brundin

Kordower

et al. 2021

Preprint

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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.

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“…The apparently closer association between hyposmia and bodyfirst LBD can be explained in two ways. Recent postmortem studies have reported that hyposmia, measured before death, correlates with the total burden of CNS Lewy pathology, but show little or no correlation with the burden of Lewy pathology in the OB itself 41,42 . This means that hyposmia is a symptom of widespread CNS Lewy pathology, but not so much of pathology in the OB per se.…”

Section: Discussionmentioning

confidence: 99%

A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson’s disease

Borghammer

Just

Horsager

et al. 2022

npj Parkinsons Dis.

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The dual-hit hypothesis of Parkinson’s disease (PD) originally postulated that a neurotropic pathogen leads to formation of α-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with α-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-predominant Lewy pathology (early brain-first LBD cases) nearly always showed OB pathology. This is compatible with the first pathology being triggered in the OB or amygdala followed by secondary spreading to connected structures, but without early involvement of the ENS or lower brainstem. These observations support that the pathologic process starts in either the olfactory bulb or the ENS, but rarely in the olfactory bulb and gut simultaneously. More studies on neuropathological datasets are warranted to reproduce these findings. The agreement between the revised single-hit hypothesis and the recently proposed brain-first vs. body-first model of LBD is discussed.

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Effect of olfactory bulb pathology on olfactory function in normal aging

Cited by 21 publications

References 11 publications

Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19

Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19

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

A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson’s disease

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