Olfactory system pathology as a model of Lewy neurodegenerative disease

I would like to elaborate on Dr. Langston's comments about the olfactory bulb as a possible model of PD pathology. I believe that, as a field, we continue to place too much emphasis on understanding the pathophysiology of dopaminergic neuron demise in PD, because the insights gained may not be relevant to the majority of neurons in the brain that are affected by Lewy pathology. I agree completely that the olfactory system may be a valuable model of the neurodegenerative disease process in PD for several reasons. As Dr. Langston pointed out, the olfactory bulb took center stage in PD pathology when Heiko Braak and Kelly Del Tredici identified it as one of the earliest areas to accumulate Lewy pathology in patients with incidential Lewy pathology (defined as patients with Lewy pathology and no clinical history of Parkinsonism or dementia). This, in combination with the recognition that olfactory dysfunction occurs very early on in the course of PD and may even be used to predict who will develop PD in high risk populations, suggests that the olfactory system may be one of the few 'induction' sites of Lewy pathology in the nervous system.

Studying olfactory system pathology in cases of incidental Lewy pathology seems an ideal way to better understand the early pathological changes in Lewy neurodegeneration that might be particularly relevant to the development of neuroprotective therapies. The olfactory bulb is also ideally suited for study because it is one of the best characterized neuronal systems in the nervous system with relatively few neuronal populations, whose synaptic connections are well defined. As I discussed in 2004, I believe that Lewy pathology within axons may be particularly important in the pathophysiology of PD and the well-defined circuitry of the olfactory bulb provides an opportunity to test this hypothesis as it is one of the few easily dissected preparations that include entire neurons, including dendritic arborizations, cell body, axon and synaptic terminal, that are susceptible to Lewy neurodegeneration. In addition, as has been hypothesized by Heiko Braak and demonstrated in a recent study by Desplats and colleagues, there is reason to believe that Lewy pathology may be transmitted trans-synaptically from neuron to neuron and the olfactory bulb seems an ideal system in which to investigate this phenomenon. Finally, current ideas proposed by Del Tredici and Braak regarding neuronal features that confer selective vulnerability to Lewy pathology can be investigated in the olfactory bulb as well.

With this in mind, several groups have begun investigating Lewy pathology in the olfactory bulb and tract in subjects without clinical Parkinsonism or dementia. In the most thorough examination reported to date, Sengoku and colleagues reported that of 320 consecutive autopsies, 26.6% had Lewy pathology in the olfactory bulb and by dividing the bulb into the 'peripheral' bulb and the anterior olfactory nucleus (AON), they found more brains with pathology limited to the peripheral bulb than the AON, suggesting that pathology progresses from the periphery to the AON. Confirming earlier results, they found very little evidence of Lewy pathology in the primary source of dopaminergic cells in the bulb, the periglomerular dopaminergic cells. In studies from my own laboratory involving pathological analysis of brains from the Honolulu Asian Aging Study cohort, we have observed similar results regarding the frequency of Lewy pathology in non-demented, non-Parkinsonian elderly males, as well as a predilection for Lewy pathology to form in mitral and tufted cells prior to accumulation in downstream AON neurons. I believe that these investigations of the olfactory system have much more to tell us about the pathophysiology of Lewy neurodegeneration. For further discussion of the value of the olfactory system as a model of Lewy pathology, a report with the same title as this comment is currently in press at the Journal of the Neurological Sciences.