Asymmetry in parkinsonism, spreading pathogens and the nose

Hobson, Douglas E.

doi:10.1016/j.parkreldis.2011.06.011

Cited by 17 publications

(6 citation statements)

References 124 publications

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“…Viruses (and toxins, see further below) can reach the brain through the ORNs ( Baltazar et al, 2014 ; Dando et al, 2014 ; Doty, 2008 ; Prediger et al, 2011 ; Tjälve and Henriksson, 1999 ; van Riel et al, 2015 ) (reviews; ( Hobson, 2012 ; van Riel et al, 2015 )). By penetrating ORNs, they can travel via axonal transport, within the olfactory ensheathing cells, or within the perineural space, and pass through the cribriform plate to access the subarachnoid space ( Dando et al, 2014 ).…”

Section: Why Are the Olfactory Epithelium And Olfactory Bulb So Vumentioning

confidence: 99%

“…We and others have predicted that the olfactory bulb (OB)—the first stage of olfactory system processing and in close contact with the external world—serves as an entry point for pathogens or an access point for environmental insults, which can trigger pathological changes that then can spread throughout the brain via olfactory pathways ( Dando et al, 2014 ; Doty, 2008 ; Hobson, 2012 ). Since these neurodegenerative disorders involve proteinaceous pathogens, this prediction is in accord with the prion hypothesis, which states that by spreading in the brain and acting as templates for endogenous proteins to form pathological aggregates, misfolded proteins resistant to degradation are responsible for disease ( Aguzzi et al, 2008 ; Griffith, 1967 ; Pattison and Jones, 1967 ; Prusiner, 1982 ).…”

Section: Introductionmentioning

confidence: 99%

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The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases

Rey

Wesson

Brundin

2018

Neurobiology of Disease

207

181

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Olfactory deficits are present in numerous neurodegenerative disorders and are accompanied by pathology in related brain regions. In several of these disorders, olfactory disturbances appear early and are considered as prodromal symptoms of the disease. In addition, pathological protein aggregates affect olfactory regions prior to other regions, suggesting that the olfactory system might be particularly vulnerable to neurodegenerative diseases. Exposed to the external environment, the olfactory epithelium and olfactory bulb allow pathogen and toxin penetration into the brain, a process that has been proposed to play a role in neurodegenerative diseases. Determining whether the olfactory bulb could be a starting point of pathology and of pathology spread is crucial to understanding how neurodegenerative diseases evolve. We argue that pathological changes following environmental insults contribute to the initiation of protein aggregation in the olfactory bulb, which then triggers the spread of the pathology within the brain by a templating mechanism in a prion-like manner.We review the evidence for the early involvement of olfactory structures in neurodegenerative diseases and the relationship between neuropathology and olfactory function. We discuss the vulnerability and putative underlying mechanisms by which pathology could be initiated in the olfactory bulb, from the entry of pathogens (promoted by increased permeability of the olfactory epithelium with aging or inflammation) to the sensitivity of the olfactory system to oxidative stress and inflammation. Finally, we review changes in protein expression and neural excitability triggered by pathogenic proteins that can promote pathogenesis in the olfactory bulb and beyond.

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Section: Why Are the Olfactory Epithelium And Olfactory Bulb So Vumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases

Rey

Wesson

Brundin

2018

Neurobiology of Disease

207

181

View full text Add to dashboard Cite

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“…Surprisingly, little is known about the neuropathology underlying this phenomenon (Hobson 2012). In their review, Riederer et al (2018) explain the reasons for the asymmetrical onset of PD and point out the asymmetrical development of the pathological process involved in nuclei and cortical fields.…”

Section: Section 2: Circuitriesmentioning

confidence: 99%

Special issue “Parkinson’s disease”

2018

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“…As concluded in commentary 7, there is overwhelming evidence of PD pathology incipience predating cardinal motor symptoms (resting tremor, postural instability, rigidity, and bradykinesia) likely stemming from early brainstem involvement and manifested in non-motor sense alteration such as olfaction and eye-movement behavior disruption. The olfactory system in particular is a candidate entry point for environmental insults that may be the inception point of pathological proteins (αsynuclein and other proteins such as ubiquitin and Tau) of which Lewy bodies are composed (8)(9)(10)(11). Moreover, brainstem (e.g., the vagus nerve dorsal motor nucleus) and spinal cord Lewy body pathology could also explain preclinical PD occurrence of gastrointestinal complication and constipation (1,(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Non-motor Clinical and Biomarker Predictors Enable High Cross-Validated Accuracy Detection of Early PD but Lesser Cross-Validated Accuracy Detection of Scans Without Evidence of Dopaminergic Deficit

2020

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Background: Early stage (preclinical) detection of Parkinson's disease (PD) remains challenged yet is crucial to both differentiate it from other disorders and facilitate timely administration of neuroprotective treatment as it becomes available. Objective: In a cross-validation paradigm, this work focused on two binary predictive probability analyses: classification of early PD vs. controls and classification of early PD vs. SWEDD (scans without evidence of dopamine deficit). It was hypothesized that five distinct model types using combined non-motor and biomarker features would distinguish early PD from controls with > 80% cross-validated (CV) accuracy, but that the diverse nature of the SWEDD category would reduce early PD vs. SWEDD CV classification accuracy and alter model-based feature selection. Methods: Cross-sectional, baseline data was acquired from the Parkinson's Progressive Markers Initiative (PPMI). Logistic regression, general additive (GAM), decision tree, random forest and XGBoost models were fitted using non-motor clinical and biomarker features. Randomized train and test data partitions were created. Model classification CV performance was compared using the area under the curve (AUC), sensitivity, specificity and the Kappa statistic. Results: All five models achieved >0.80 AUC CV accuracy to distinguish early PD from controls. The GAM (CV AUC 0.928, sensitivity 0.898, specificity 0.897) and XGBoost (CV AUC 0.923, sensitivity 0.875, specificity 0.897) models were the top classifiers. Performance across all models was consistently lower in the early PD/SWEDD analyses, where the highest performing models were XGBoost (CV AUC 0.863, sensitivity 0.905, specificity 0.748) and random forest (CV AUC 0.822, sensitivity 0.809, specificity 0.721). XGBoost detection of non-PD SWEDD matched 1-2 years curated diagnoses in 81.25% (13/16) cases. In both early PD/control and early PD/SWEDD analyses, and across Interpretation: Non-motor clinical and biomarker variables enable high CV discrimination of early PD vs. controls but are less effective discriminating early PD from SWEDD.

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Asymmetry in parkinsonism, spreading pathogens and the nose

Cited by 17 publications

References 124 publications

The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases

The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases

Special issue “Parkinson’s disease”

Non-motor Clinical and Biomarker Predictors Enable High Cross-Validated Accuracy Detection of Early PD but Lesser Cross-Validated Accuracy Detection of Scans Without Evidence of Dopaminergic Deficit

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