Alpha-synuclein pathology in the olfactory pathways of dementia patients

Abstract

Lewy-type pathology is a characteristic of a number of neurodegenerative disorders, including Parkinson's disease and dementia with Lewy bodies. Thus far, the definitive diagnosis of these dementias can only be confirmed at post-mortem. However, it is known that the loss of smell (anosmia) is an early symptom in patients who develop dementia, and the use of the smell test has been proposed as an early diagnostic procedure. The aim of this study was to understand further the extent of Lewy pathology in the olfactory system of patients with neurodegenerative disorders. Post-mortem tissue from 250 subjects was obtained from the OPTIMA brain bank. Five areas of the olfactory pathway were examined by immunolabelling for alpha-synuclein - a major component of Lewy pathology: the olfactory tract/bulb (n = 79), the anterior olfactory nucleus in the lateral olfactory gyrus (n = 193), the region of olfactory projection to the orbito-frontal cortex (n = 225), the hippocampus (n = 236) and the amygdala (n = 201). Results show that Lewy pathology affects different parts of the olfactory pathways differentially, suggesting a specific pattern of development of pathology. Clinical Parkinson's disease is most likely to be identified if the orbito-frontal cortex is affected, while the diagnosis is less likely if the pathology is restricted to the olfactory bulb or tract. These results suggest that pathology in the olfactory bulb and tract occurs prior to clinical signs of Parkinson's disease. Furthermore, the results presented here provide further evidence supporting the possible value of a smell test to aid the clinical diagnosis of neurodegenerative diseases.

Fig. 1

Lewy pathology. (A) High-magnification photomicrograph of a Lewy body (arrowhead) in a pyramidal neuron of the OF of a subject diagnosed with neocortical stage AD. (B) Lewy neurites in an amyloid plaque. Toluidine blue counterstaining allows the visualization of Alzheimer-type plaques (centre, labelled with asterisk), into which Lewy neurites have developed. The majority of Lewy neurites are observed in cross-section (transverse), appearing as dots rather than lines of axonal labelling. (C) A Lewy neurite in horizontal section. It is notable that Lewy neurites can extend for long distances. The neurite visible in C is from a region of the AON and is approximately 220 µm in length. Scale bar = 25 µm.

Fig. 2

Lewy pathology progresses along olfactory pathways. The odds of Lewy pathology in each region if the lower-order region in the pathway is affected. OBT = olfactory bulb and tract, AON = anterior olfactory nucleus, OF = orbitofrontal cortex, Am = amygdala, Hi = hippocampus.

Fig. 3

Progression of Lewy pathology along different parts of the olfactory system. (A–D) Orbitofrontal cortex (A), anterior olfactory nucleus near the insertion of the olfactory tract (B), amygdala (C) and hippocampus (D). (E–H) If the olfactory bulb and tract are affected by Lewy pathology the likelihood of similar pathology is highest in the anterior olfactory nucleus (E) followed by the amygdala and hippocampus (F and G, respectively), with the orbitofrontal cortex (H) least affected. AON = anterior olfactory nucleus, OF = orbitofrontal cortex, Am = amygdala, EC = entorhinal cortex, Hi = hippocampus.

Fig. 4

Relationship between Lewy pathology and PD. (A) When Lewy pathology in each olfactory region is compared with the diagnosis of PD, it is apparent that pathology in the olfactory bulb occurs prior to clinical diagnosis of PD. (B) Comparison of Lewy pathology with PD diagnosis shows that a diagnosis of PD becomes more likely if Lewy pathology is present in the higher olfactory regions.